Room-temperature copper-catalyzed arylation of dimethylamine and methylamine in neat water

Article abstract of DOI:10.1002/adsc.201400785

The first room-temperature copper-catalyzed arylations of dimethylamine and methylamine in neat water have been developed. Using a combination of CuI and 6,7-dihydroquinolin-8(5 H)-one oxime as catalyst, dimethylamine is arylated with various aryl halides to give the corresponding products in good to excellent yields. Further, this catalysis enables the selective arylation of methylamine to afford the high yields of monoarylated methylamines as the sole products.

Full text of DOI:10.1002/adsc.201400785

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DOI: 10.1002/adsc.201400785
Room-Temperature Copper-Catalyzed Arylation of Dimethyla-
mine and Methylamine in Neat Water
a,
a
a
a
Deping Wang, * Daizhi Kuang, Fuxing Zhang, Chunlin Yang,
a
and Xiaoming Zhu
a
Department of Chemistry and Materials Science, Hengyang Normal University, 165# Huangbai Road, Hengyang 421008,
Hunan Province, People’s Republic of China
Fax : +86-7348484932; e-mail: wdping0119@gmail.com or wangdeping@hynu.cn
Received: August 8, 2014; Revised: November 22, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400785.
Abstract: The first room-temperature copper-cata-
lyzed arylations of dimethylamine and methylamine
in neat water have been developed. Using a combi-
nation of CuI and 6,7-dihydroquinolin-8(5H)-one
oxime as catalyst, dimethylamine is arylated with
various aryl halides to give the corresponding prod-
ucts in good to excellent yields. Further, this cataly-
sis enables the selective arylation of methylamine
to afford the high yields of monoarylated methyl-
amines as the sole products.
to be used as the reductant for the methylation pro-
cess with Zn/NHC, Ru/BuPAd2 or Ru(tri-
a
phos)(tmm) as catalyst at high temperature and pres-
sure. Subsequently, a practical methylation of anilines
to form N,N-dimethylanilines with the use of DMSO
as methylating reagent at 1508C was reported by
[
6]
Xiao et al.
In the past years, great progress has been made for
palladium- and copper-catalyzed coupling reactions to
[
7]
construct CÀN bonds. Thus, it is more attractive to
approach N,N-dimethylanilines and N-methylanilines
directly from dimethylamine and methylamine with
aryl halides via the well established transition-metal-
catalyzed CÀN coupling reactions. The groups of
Keywords: copper; N,N-dimethylanilines; N-meth-
ylanilines; room-temperature arylation; water
[
8]
[9]
Buchwald and Stradiotto have reported highly effi-
cient Pd-catalyzed systems, which promote the cou-
pling reactions of aryl halides with dimethylamine
N,N-Dimethylanilines and N-methylanilines are and methylamine under mild conditions. Nevertheless,
common units found throughout the pharmaceutical, the necessary use of elaborate phosphine ligands,
[
1]
dye, and agrochemical industries. Common methods moisture-sensitive strong bases, as well as a toxic and
for their preparation include methylation of anilines an expensive palladium precatalyst are drawbacks
[
7e]
in the presence of a base and reductive amination of when compared with copper-catalyzed reactions.
[
2]
anilines with formaldehyde. Both methods are re- More recently, Wei and coworkers have developed
stricted by the lack of selectivity (over-methylation a simple protocol using copper powder as precatalyst,
usually occurs), the toxicity of the methylating re- which allow amination of aryl halides with aqueous
[
10]
agents, and functional groups compatibility for reduc- methylamine at 1008C in water.
This protocol is
tive aminations. A recent means of assembling is the very efficient and eco-friendly for mono-arylation of
Cu(OAc) -promoted methylation of anilines with methylamine, but the arylation of more challenging
2
[
1c]
methylboronic acid at 1008C reported by Cruces.
dimethylamine is not successful even using N-methyl-
This method is useful for the preparation of N-meth- 2-pyrrolidone as co-solvent.
ylanilines, but it is encumbered with the crucial re-
Organic reactions in aqueous media have recently
quirement of over-stoichiometric quantities of copper attracted much attention, because water is an eco-
[11]
salts and costly methylboronic acid, and the resulting nomical, safe, and environmentally benign media.
products often mixed with mono- and dimethylani- However, organometallic-catalyzed synthesis of or-
[
3]
[4]
lines. Very recently, Cantat, Beller, Klankermay- ganic molecules in water usually need to overcome
[5]
er and their coworkers reported that N,N-dimethyla- the problems such as the water tolerance for the cata-
[12]
nilines and/or N-methylanilines could be produced lyst systems, the substrate reactivity, and solubility.
from anilines by using CO as methylating reagent. In light of the low boiling points of dimethylamine
2
Nevertheless, hydrosilanes or molecular hydrogen had and methylamine and their very high solubility in
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Deping Wang et al.
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Table 1. Copper-Catalyzed Arylation of Dimethylamine at when other two comparatively stronger bases of KOH
[a]
R.T. in Water: Effect of Ligands and Bases.
and CsOH were used, respectively (Table 1, entries 8–
). These results, brought together, reveal that higher
9
alkalinity is favorable for the formation of the desired
product. As expected, we were pleased to find that
the yield was increased to 95% by elevating the
amount of KOH to 5.0 equivalents (Table 1, entry 8).
It should be noted that a 94% yield of desired prod-
uct was obtained even reducing the amount of L5 to
6
mol% (Table 1, entry 7). In addition, no products
were obtained in the absence of CuI (entry 8).
Entry
Ligand
Base
Yield [%]
Having established an efficient catalytic system for
a facile route to preparation of N,N-dimethylanilines
in water, we next set out to explore the scope of the
room-temperature CÀN cross-coupling reactions. As
1
2
3
4
5
6
7
8
–
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
0
<5
0
L1
L2
L3
L4
L5
L5
L5
0
shown in Table 2, a series of aryl iodides, including
both electron rich and electron deficient aryl iodides,
were successfully coupled with dimethylamine in ex-
cellent yields. Moreover, the coupling reactions of
aryl iodides containing kinds of functional groups,
such as bromo, nitro, cyano, acetyl, hydroxyl, and
amino with dimethylamine proceeded smoothly at
room-temperature in water (Table 2, entries 4–11). To
our delight, ortho-aryl iodides coupled with dimethyl-
amine to afford the desired products in satisfied
yields at an elevated temperature of 658C although
poor yields were obtained at room temperature
26
67
55
83
Cs CO
2
3
KOH
[
[
b]
c]
9
9
0
5
4
[
c,d]
9
L5
CsOH
91
[
a]
Unless otherwise noted, reactions were conducted with
4
1
-iodoanisole (1.0 mmol), dimethylamine (5.0 mmol,
.1 mL 30% solution in water), CuI (0.05 mmol), Ligand
(
5
5
0.1 mmol), base (3.0 mmol), at 258C for 24 h.
.0 equiv KOH.
.0 equiv KOH, 6.0 mol% L5.
(
Table 2, entries 12–13). A wide range of N-heteroaryl
[
[
[
b]
c]
d]
iodides were well tolerated (Table 2, entries 14–18). It
is noteworthy that a good yield (89%) was also ob-
tained when the reaction carried out at gram-scale
Without CuI.
(
Table 2, entry 1).
water, we now disclose general copper-catalyzed N-ar-
Although Pd- or Cu-catalyzed monoarylation of
ylations of both aqueous dimethylamine and methyl- primary amines has long been established, the mono-
amine at room temperature (258C) in neat water for arylation of methylamine, the smallest aliphatic pri-
the first time.
mary amine, remains a challenging work, because dia-
[
6i,7a]
Initially, we selected the challenging coupling of 4- rylation is most likely to take place.
Using CuI/L5
iodoanisole with dimethylamine as a model to opti- catalyst system, methylamine was successfully coupled
mize the conditions. As shown in Table 1, the cou- with aryl iodides to afford only monoarylation prod-
pling reaction did not take place without additional ucts in excellent yields at room temperature in water
ligand at room temperature in neat water (entry 1). (Table 3). Various functional groups, including elec-
The catalyst systems based on the combination of CuI tron rich, electron deficient and even active groups
and l-proline provided trace amounts of desired prod- were well compatible under our optimal conditions. It
uct (Table 1, entry 2). The use of 2-acetylcyclohexa- is worth mentioning that methylamine coupled with
none or 1,1-bi(2-naphthol) as ligand failed to produce aryl iodides in 12 h, while 24 h was required for the
product (Table 1, entries 3-4). We have reported that amination of aryl iodides with dimethylamine.
[
13]
6,7-dihydroquinolin-8(5H)-one oxime (L5)
serves
In addition to aryl iodides, the coupling of aryl bro-
as an efficient ligand for the CuI-catalyzed N-aryla- mides with dimethylamine or methylamine took place
tion of imidazoles in water. On the basis of that, we smoothly at 858C in water. A wide range of aryl bro-
were delighted to find that moderate yields of 4-me- mides (Table 4, entries 1–8) and N-heteroaryl bro-
thoxy-N,N-dimethylaniline were obtained when utiliz- mides (Table 4, entries 9-10) were aminated with di-
ing oximes, especially the conformational constrained methylamine catalyzed by the CuI/L5 system to
6
,7-dihydroquinolin-8(5H)-one oxime (L5), as ligands afford the corresponding products in excellent yields.
Table 1, entries 5–6). Next, by replacing NaOH with Furthermore, methylamine could undergo selective
the relatively weaker base Cs CO , the yield of the re- monoarylation with various aryl bromides at 858C in
(
2
3
action dropped to 55% (Table 1, entry 7). Good to 12 h (Table 4, entries 11–14). For example, aryl bro-
excellent yields of 83% and 91% were achieved mides contained active group such as 4-bromoanilines
2
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Room-Temperature Copper-Catalyzed Arylation
Table 2. Room-Temperature Amination of Aryl Iodides with
Dimethylamine in Water.
Table 3. Room-Temperature Amination of Aryl Iodides with
Methylamine in Water.
[a]
[a]
Entry Product
Yield Entry Product
%]
Yield
[%]
Entry Product
Yield Entry Product
[%]
Yield
[%]
[
[b]
1
2
3
4
5
6
95
90
95
88
85
95
7
81
94
92
1
2
3
4
5
89
10
11
12
13
14
91
88
8
90
87
95
85
9
2
8
1
9
[
[
c]
c]
[
[
b]
b]
10
11
12
97
95
95
2
9
0
3
95
6
7
8
9
93
81
86
86
15
16
17
18
92
90
93
78
[
a]
Unless otherwise noted, reactions were conducted with
aryl iodides (1.0 mmol), methylamine (5.0 mmol, 0.5 mL
3
0% solution in water), CuI (0.05 mmol), L5 (0.6 mmol),
KOH (5.0 mmol), at 258C for 12 h.
At 658C.
[b]
formed at room temperature with excellent yields of
only monoarylated products. Further, this protocol
utilized KOH as base and enabled the arylation pro-
cess to take place in neat water. In comparison with
the use of stronger base and the moisture sensitive
conditions for the Pd-catalyzed process, this would
highlight the potential industrial application of the
Cu/L5 catalyst system, because of the environmental-
friendly and milder reaction conditions, as well as
readily available dimethylamine and methylamine in
aqueous solutions.
[c]
[
a]
Unless otherwise noted, reactions were conducted with
aryl iodides (1.0 mmol), dimethylamine (5.0 mmol,
.1 mL 30% solution in water), CuI (0.05 mmol), L5
0.06 mmol), KOH (5.0 mmol), at 258C for 24 h.
0 mmol scale.
At 658C.
1
(
1
[
[
b]
c]
and 4-bromophenol coupled with methylamine selec-
tively with excellent yields of 85% and 90%, respec- Experimental Section
tively (Table 4, entries 13–14). ortho-Aryl bromides
reacted with methylamine with satisfactory yields in General procedure for the room-temperature
a longer reaction time of 24 h. In contrast, the amina- coupling of aryl iodides with dimethylamine or
tions of less active 4-chloroanisole with dimethyl- methylamine
amine or methylamine were not successful even at
A 10 mL sealed tube equipped with a Teflon valve was
a higher temperature (1008C) (Table 4, entries 1 and
charged with a magnetic stir bar, CuI (9 mg, 5 mol%), L5
1
1).
(
10 mg, 6 mol%), KOH (280 mg, 5.0 mmol) and solid aryl
In summary, a general copper-catalyst system for
room-temperature arylation of dimethylamine in neat
water has been developed. Using this Cu-catalyst Under a counter flow of Argon, H O (1.0 mL), 1.0 mmol
iodides (1.0 mmol). The tube was evacuated and backfilled
with argon (this procedure was repeated three times).
2
system, arylations of methylamine were also per- aryl iodides (if liquid), 5.0 mmol aqueous dimethylamine
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Deping Wang et al.
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[a]
Table 4. Copper-Catalyzed Amination of Aryl Bromides in Water.
Entry
Product
Yield
%]
Entry
Product
Yield
[%]
[
9
0
0
[b]
1
2
3
4
9
92
87
95
83
10
11
12
93
[
c]
8
0
7
[b,d]
[
[
c]
c]
82
85
5
88
13
[
[
c]
6
7
82
89
14
15
90
90
d]
[d]
8
90
16
75
[
a]
Unless otherwise noted, reactions were conducted with aryl bromides (1.0 mmol), dimethylamine (5.0 mmol, 1.1 mL 30%
solution in water), CuI (0.05 mmol), L5 (0.06 mmol), KOH (5.0 mmol), at 858C for 24 h.
Ar-Cl (1.0 mmol) at 1008C.
Methylamine (5.0 mmol), 12 h.
Methylamine (5.0 mmol), 24 h.
[
[
[
b]
c]
d]
(
30%) or 5.0 mmol aqueous methylamine (30%) were References
added by syringe. The tube was sealed quickly. The reaction
mixture was allowed to stir at room-temperature (258C) for
[1] a) M. Negwer, Organic-Chemical Drugs and their Syno-
nyms: An International Survey, 7th ed.; Akademie
Verlag, Berlin, 1994; b) J. H. Montgomery, Agrochemi-
cals Desk Reference: Environmental Data, Lewis Pub-
lishers, Chelsea, MI, 1993; c) I. Gonzalez, J. Mosquera,
C. Guerrero, R. Rodrꢂguez, J. Cruces, Org. Lett. 2009,
11, 1677.
[2] a) A. B. Shivarkar, S. P. Gupte, R. V. Chaudhari, J. Mol.
Catal. A: Chem. 2005, 226, 49; b) R. A. da Silva, I. H. S.
Estevam, L. W. Bieber, Tetrahedron Lett. 2007, 48,
24 h (12 h for methylamine). Then the mixture was diluted
with ethyl acetate (10 mL). The organic layer was separated
and the aqueous layer was extracted by ethyl acetate (3ꢁ
10 mL). The combined extracts were dried by anhydrous
sodium sulfate, filtered and the solvent was removed under
vacuum. The residue was purified by column chromatogra-
phy on silica gel with an eluent of petroleum ether and ethyl
acetate to afford the corresponding compounds.
7
680.
Acknowledgements
[3] O. Jacquet, X. Frogneux, C. D. N. Gomes, T. Cantat,
Chem. Sci. 2013, 4, 2127.
We thank the National Natural Science Foundation of China
[4] a) Y. Li, X. Fang, K. Junge, M. Beller, Angew. Chem.
2013, 125, 9747; Angew. Chem. Int. Ed. 2013, 52, 9568;
b) Y. Li, I. Sorribes, T. Yan, K. Junge, M. Beller,
(
No. 21202041) and the Key Discipline Project of Hunan
Province for their financial support.
4
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These are not the final page numbers!

COMMUNICATIONS
Room-Temperature Copper-Catalyzed Arylation
Angew. Chem. 2013, 125, 12378; Angew. Chem. Int. Ed.
013, 52, 12156.
5] K. Beydoun, T. vom Stein, J. Klankermayer, W. Leit-
ner, Angew. Chem. 2013, 125, 9733; Angew. Chem. Int.
Ed. 2013, 52, 9554.
6] X. Jiang, C. Wang, Y. Wei, D. Xue, Z. Liu, J. Xiao,
Chem. Eur. J. 2014, 20, 58.
7] For reviews, see: a) J. F. Hartwig, Nature 2008, 455,
[9] a) R. J. Lundgren, A. Sappong-Kumankumah, M. Stra-
diotto, Chem. Eur. J. 2010, 16, 1983; b) C. A. Wheaton,
J.-P. J. Bow, M. Stradiotto, Organometallics 2013, 32,
6148.
[10] J. Jiao, X.-R. Zhang, N.-H. Chang, J. Wang, J.-F. Wei,
X.-Y. Shi, Z.-G. Chen, J. Org. Chem. 2011, 76, 1180.
11] a) U. M. Lindstrçm, Chem. Rev. 2002, 102, 2751; b) S.
Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209;
c) N. Akiya, P. E. Savage, Chem. Rev. 2002, 102, 2725;
d) J. M. Desimone, Science 2002, 297, 799; e) M. Poliak-
off, J. M. Fitzpatrick, T. R. Farren, P. T. Anastas, Science
2
[
[
[
[
3
14; b) D. S. Surry, S. L. Buchwald, Angew. Chem.
2
008, 120, 6438; Angew. Chem. Int. Ed. 2008, 47, 6338;
c) D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450; d) G.
Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108,
2
002, 297, 807; f) C.-J. Li, Chem. Rev. 2005, 105, 3095;
3
1
054; e) F. Monnier, M. Taillefer, Angew. Chem. 2009,
21, 7088; Angew. Chem. Int. Ed. 2009, 48, 6954;
g) R. A. Sheldon, Green Chem. 2005, 7, 267; h) D. G.
Blackmond, A. Armstrong, V. Coombe, A. Wells,
Angew. Chem. 2007, 119, 3872; Angew. Chem. Int. Ed.
f) D. S. Surry, S. L. Buchwald, Chem. Sci. 2010, 1, 13;
g) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27;
h) G. C. Fortman, S. P. Nolan, Chem. Soc. Rev. 2011, 40,
2
007, 46, 3798; i) C. I. Herrerias, X. Yao, Z. Li, C.-J. Li,
Chem. Rev. 2007, 107, 2546; j) S. Minakata, M. Komat-
su, Chem. Rev. 2008, 108, 825; k) A. Chanda, V. V.
Fokin, Chem. Rev. 2009, 109, 725; l) R. N. Butler, A. G.
Coyne, Chem. Rev. 2010, 110, 6302; m) Metal-Catalyzed
Reactions in Water (Eds.: P. H. Dixneuf, V. Cadierno),
Wiley-VCH, Weinheim, 2013.
5
151; i) I. P. Beletskaya, A. V. Cheprakov, Organome-
tallics 2012, 31, 7753; j) C. Sambiagio, S. P. Marsden,
A. J. Blacker, P. C. McGowan, Chem. Soc. Rev. 2014,
4
3, 3525.
[
8] a) B. P. Fors, D. A. Watson, M. R. Biscoe, S. L. Buch-
wald, J. Am. Chem. Soc. 2008, 130, 13552; b) B. K. Lee,
M. R. Biscoe, S. L. Buchwald, Tetrahedron Lett. 2009,
[
[
12] D. Sinou, Adv. Synth. Catal. 2002, 344, 221.
13] D. Wang, F. Zhang, D. Kuang, J. Yu, J. Li, Green Chem.
5
0, 3672; c) J. L. Henderson, S. L. Buchwald, Org. Lett.
2
012, 14, 1268.
2
010, 12, 4442; d) B. P. Fors, S. L. Buchwald, J. Am.
Chem. Soc. 2010, 132, 15914.
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6
Room-Temperature Copper-Catalyzed Arylation of
Dimethylamine and Methylamine in Neat Water
Adv. Synth. Catal. 2015, 357, 1 – 6
Deping Wang,* Daizhi Kuang, Fuxing Zhang,
Chunlin Yang, Xiaoming Zhu
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