Copper(II) triflate catalyzed intermolecular aromatic substitution of N,N-disubstituted anilines with diazo esters

Article abstract of DOI:10.1002/ejoc.201001083

The intermolecular aromatic substitution of N,N-disubstituted anilines with diazo esters is achieved under mild conditions in the presence of a catalytic amount of copper(II) triflate (up to 89 % yield). The scope and limitations regarding substrates, diazo esters, and ligands in this reaction are described. The intermolecular aromatic substitution of N,N-disubstituted anilines with diazo esters is shown to proceed under mild conditions in the presence of a catalytic amount of copper(II) triflate/ligand complex(up to 89 % yield). The scope and limitations regarding substrates, diazoesters, and ligands in this reaction are described. Copyright

Full text of DOI:10.1002/ejoc.201001083

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001083
Copper(II) Triflate Catalyzed Intermolecular Aromatic Substitution of
N,N-Disubstituted Anilines with Diazo Esters
Eiji Tayama,*[a] Tomoyo Yanaki,[a] Hajime Iwamoto,[a] and Eietsu Hasegawa[a]
Keywords: Aromatic substitution / Substituent effects / Synthetic methods / Arenes / Diazo compounds
The intermolecular aromatic substitution of N,N-disubsti-
tuted anilines with diazo esters is achieved under mild condi-
tions in the presence of a catalytic amount of copper(II) tri-
flate (up to 89% yield). The scope and limitations regarding
substrates, diazo esters, and ligands in this reaction are de-
scribed.
ylaniline (path B). Prompted by this result, we decided to
investigate the scope and limitations of this copper(II)-cata-
lyzed intermolecular aromatic substitution reaction.
Introduction
Aromatic substitution of α-diazo carbonyl compounds
promoted by rhodium catalysts is a powerful and efficient
synthetic method for the construction of functionalized
aromatic compounds, because they enable the formation of
C–C bonds between aromatic and aliphatic carbon atoms
under mild conditions.[1] Whereas intramolecular aromatic
substitution reactions have been extensively studied, suc-
cessful intermolecular examples have been quite scarce to
date, except for some reactions with heteroaromatic sub-
strates.[2,3] In 2004, Davies et al. reported that electron-de-
ficient rhodium catalysts enhance the intermolecular aro-
matic substitution over C–H insertion in the study on the
C–H activation of N,N-dimethylanilines.[2b] However, fur-
ther studies on the intermolecular aromatic substitution
have not been advanced. In the course of our studies on the
formation of ammonium ylides derived from N,N-dialk-
ylanilines and α-diazo esters in the presence of copper(II)
salt (Scheme 1, path A),[4] we observed intermolecular aro-
matic substitution affording a para-substituted N,N-dialk-
Results and Discussion
First, we examined the reaction of N-[(ethoxycarbonyl)-
methyl]-N-methylaniline (1a) with methyl 2-diazo-2-phenyl-
acetate (2a) in dichloromethane at room temperature in the
presence of 10 mol-% of copper(II) acetylacetonate [Cu-
(acac)2] (Table 1, Entry 1). Small amounts of the corre-
sponding intermolecular aromatic substitution product 3a
were obtained in 9% yield with recovery of the starting ma-
terials. When the reaction was carried out at reflux, the
Table 1. Screening of catalysts for the intermolecular aromatic sub-
stitution of 1a with 2a.
Entry
Catalyst (mol-%)
T
t [h]
Yield [%][a]
1
2
3
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(hfacac)2 (10)
room temp.
reflux
room temp.
6
3
6
9
32
6
4
5
6
7
8
9
10
11
12
13
14
15
Cu(OAc)2·H2O (10) room temp.
6
6
6
6
12
12
12
12
6
12
12
6
0
Cu(OTf)2 (10)
Cu(OTf)2 (20)
Cu(OTf)2 (5)
Cu(OTf)2 (2)
Cu(OTf)2 (1)
BF3·OEt2 (10)
BF3·OEt2 (100)
BF3·OEt2 (100)
Sn(OTf)2 (2)
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
reflux
71
55
78
89
53
4
Scheme 1. Reactions of N,N-dialkylaniline with α-diazo ester in the
presence of a copper(II) catalyst.
47[b]
70
0
[a] Department of Chemistry, Faculty of Science,
Niigata University
room temp.
room temp.
room temp.
2-8050, Ikarashi, Nishi-ku, 950-2181 Niigata, Japan
Fax: +81-25-262-7741
Sc(OTf)3 (2)
2
39
Rh2(OAc)4 (2)
E-mail: tayama@chem.sc.niigata-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001083.
1
[a] Isolated yield. [b] Determined by H NMR assay using aceto-
phenone as an internal standard.
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E. Tayama, T. Yanaki, H. Iwamoto, E. Hasegawa
SHORT COMMUNICATION
yield was slightly improved (Entry 2, 32%). To further im- estingly, β-alkoxyethyl derivatives 1f or 1g were converted
prove the yield of 3a, we attempted the reactions in the into 3f or 3g, respectively, in moderate yields (Entry 5, 59%;
presence of other copper(II) salts. Copper(II) hexafluo- Entry 6, 59%). However, reactions of simpler substrates
roacetoacetate [Cu(hfacac)2] (Entry 3) and copper(II) acet- such as N-benzyl-N-methylaniline (1h) or N,N-dimethyl-
ate [Cu(OAc)2] (Entry 4) did not show any improvement. aniline (1i) were unsatisfactory, and unreacted 2a was reco-
Surprisingly, copper(II) triflate [Cu(OTf)2] showed a re- vered (Entry 7, 35%, 28% recovery of 2a; Entry 8, 2%, 81%
markable catalytic activity, and the intermolecular aromatic recovery of 2a). An appreciable amount of any C–H inser-
substitution proceeded efficiently to give 3a in 71% yield tion products was not observed.
(Entry 5). By varying the amount of catalyst from 1 to
These results suggested that the substrates 1 function as
20 mol-% (Entries 6–9), we found that the use of 2 mol-% ligands of Cu(OTf)2, and the catalytic activity is determined
of Cu(OTf)2 afforded 3a exclusively (Entry 8, 89%). We by the structure of the complexes. Thus, we prepared li-
thought that Lewis acids might accelerate the intermo- gands 4a–4c, masking the para-position with a methyl
lecular aromatic substitution; thus, we attempted to use group (Figure 1) to improve the chemical yield of 3, and
other Lewis acid catalysts for this reaction (Entries 10–14). carried out reactions in the presence of 2 mol-% of Cu-
Use of 10 mol-% of boron trifluoride–diethyl ether (OTf)2–4 complexes (Table 3). Although the yields of 3c, 3e,
(BF3·OEt2) did not show any catalytic activity (Entry 10). and 3g were not improved (Entries 1–3), the reactions of
However, reaction in the presence of a stoichiometric 1h were accelerated, and the yields of 3h were improved
amount of BF3·OEt2 proceeded in reasonable yields at remarkably by addition of ligands 4a or 4b (Entry 4, 71%;
room to reflux temperature (Entry 11, 47%; Entry 12, Entry 5, 73%). Ligand 4c did not accelerate the reaction of
70%).[5] Other Lewis acids such as tin(II) or scandium(III) 1h (Entry 6, 29%). A reaction of N,N-dimethylaniline (1i)
triflate did not give any product (Entries 13, 14). It is worth failed though in the presence of 4a (Entry 7, 2%). Although
noting that use of rhodium(II) acetate dimer [Rh2(OAc)4], the exact reason is presently unknown, it is safe to say that
which is usually the preferred catalyst in diazo carbonyl the initial ligand 4a or 4b might be exchanged by excess
aromatic substitution reactions, resulted in a modest yield amounts of substrates 1c, 1e, 1g, or 1i, and their reactions
(Entry 15, 39%).
This method was used to carry out reactions of various
types of N-(β-carbonylmethyl)-N-methylaniline derivatives
1 with 2a, that might afford the corresponding intermo-
lecular aromatic substitution products 3 (Table 2). As ex-
pected, reaction of benzyl ester (1b) and tert-butyl ketone
(1c) derivatives proceeded smoothly to give 3b and 3c,
respectively, in reasonable yields (Entry 1, 85%; Entry 2,
68%); however, phenyl ketone derivative 1d did not give the
expected product at all (Entry 3, 0%). A complex mixture
of unidentified products was obtained. The acidic α-proton
of 1d might inhibit the reaction. Use of other analogs, such
as the amide-type substrate 1e, gave the adduct 3e in lower
yield (Entry 4, 42%). To determine the scope and limita-
tions of the present method, we examined the reactions of
N-alkyl-N-methylanilines under the same conditions. Inter-
Figure 1. Structure of ligands 4a–4c.
Table 3. Intermolecular aromatic substitution of 1 in the presence
of ligand 4.[a]
Entry
Aniline 1
R1
Diazo ester 2
Product 3
R2
R3
R4
Yield [%][d]
1
2
3
COtBu
CONEt2
CH2OMe
Ph
Me (1c)
Me (1e)
Me (1g)
Me (1h)
Me (1h)
Me (1h)
Me (1i)
Me (1j)
H
H
H
H
H
H
H
H
H
H
H
Cl
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2b)
60 (3c)
25 (3e)
63 (3g)
71 (3h)
73 (3h)
29 (3h)[e]
2 (3i)
64 (3j)
46 (3k)
62 (3l)
72 (3m)
36 (3n)
86 (3o)
64 (3p)
31 (3q)
Table 2. Intermolecular aromatic substitution of 1b–1i.
4
5[b]
6[c]
7
Ph
Ph
H
8
9
p-ClC6H4
p-MeOC6H4 Me (1k)
Entry
R1
Compound
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
CO2Bn
COtBu
COPh
CONEt2
CH2OBn
CH2OMe
Ph
b
c
d
e
f
g
h
i
12
12
12
12
12
12
12
24
85
68
0
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
Et (1l)
Bn (1m)
Me (1h)
Me (1h) OMe Me (2c)
Me (1h)
Me (1h)
42[b]
59
59
35
2
H
H
Et (2d)
Bn (2e)
[a] Unless otherwise noted, 4a was used as a ligand. [b] 4b was used
as a ligand. [c] 4c was used as a ligand. [d] Isolated yield unless
otherwise noted. [e] Determined by 1H NMR assay using aceto-
phenone as an internal standard.
H
[a] Isolated yield unless otherwise noted. [b] Determined by 1H
NMR assay using acetophenone as an internal standard.
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Eur. J. Org. Chem. 2010, 6719–6721

Aromatic Substitution of N,N-Disubstituted Anilines
the residue by chromatography on silica gel (hexane/ethyl acetate,
15:1 to 10:1) afforded 3h (74 mg, 71% yield) as a pale yellow oil.
are not accelerated. However, substrate 1h would not ex-
change with the initial ligand 4a or 4b, and its reaction was
accelerated, because both 4a and 4b are able to work as
chelating ligands to stabilize the complexes or intermedi-
ates.[6] Ligand 4c might be liberated by 1h due to its lower
chelating ability. Sterically less demanding 1i would coordi-
nate to Cu(OTf)2 strongly and deactivate the catalyst. In
fact, when the reaction of 1a with 2a catalyzed by 2 mol-%
of Cu(OTf)2 (Table 1, Entry 8, 89%) was carried out in the
presence of catalytic amounts of 1i (2–10 mol-%), the yields
of 3a were decreased (2 mol-%: 63%; 5 mol-%: 31%;
10 mol-%: 8%).
The scope of substrates was further explored as shown
in Entries 8–15. N-Alkyl-N-benzylanilines 1j–1m reacted
with 2a in 46–72% yield (Entries 8–11). This reaction is sen-
sitive to the structural and electronic properties of the diazo
esters. Whereas a reaction of p-chlorophenyl diazo ester 2b
with 1h gave a lower yield (Entry 12, 36%), a reaction of p-
methoxyphenyl diazo ester 2c afforded 3o in excellent yield
(Entry 13, 86%). In addition, a reaction of ethyl diazo ester
2d with 1h proceeded in moderate yield (Entry 14, 64%),
but benzyl diazo ester 2e did not (Entry 15, 31%).[7]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details; spectroscopic characterization data for
1
all compounds; copies of the H and 13C NMR spectra of 3a–q.
Acknowledgments
This work was supported by the Union Tool Scholarship Founda-
tion.
[1] a) M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, Wiley,
New York, 1998; b) H. M. L. Davies, in Comprehensive Organic
Synthesis, vol. 4 (Eds: B. M. Trost, I. Fleming), Pergamon, Ox-
ford, 1991, chapter 4.8.
[2] a) C. P. Park, A. Nagle, C. H. Yoon, C. Chen, K. W. Jung, J.
Org. Chem. 2009, 74, 6231–6236; b) H. M. L. Davies, Q. Jin,
Org. Lett. 2004, 6, 1769–1772; c) H. M. L. Davies, H. D. Smith,
B. Hu, S. M. Klenzak, F. J. Hegner, J. Org. Chem. 1992, 57,
6900–6903; d) M. Toda, M. Hattori, K. Okada, M. Oda, Chem.
Lett. 1987, 16, 1263–1266; e) H. Ledon, G. Linstrumelle, S.
Julia, Bull. Soc. Chim. Fr. 1973, 2065–2071.
[3] Examples of intermolecular aromatic substitution by using het-
eroaromatic substrates: a) W.-W. Chan, S.-H. Yeung, Z. Zhou,
A. S. C. Chan, W.-Y. Yu, Org. Lett. 2010, 12, 604–607; b)
H. M. L. Davies, S. J. Hedley, Chem. Soc. Rev. 2007, 36, 1109–
1119, and references cited therein.
[4] F. G. West, J. S. Clark, in Nitrogen, Oxygen and Sulfur Ylide
Chemistry (Ed.: J. S. Clark), Oxford University Press, Oxford,
2002, chapter 2.1.
[5] Previous examples of acid-promoted intramolecular aromatic
substitution reactions: a) M. P. Doyle, M. S. Shanklin, H. Q.
Pho, S. N. Mahapatro, J. Org. Chem. 1988, 53, 1017–1022; b)
D. W. Johnson, L. N. Mander, Aust. J. Chem. 1974, 27, 1277–
1286; c) M. S. Newman, G. Eglinton, H. M. Grotta, J. Am.
Chem. Soc. 1953, 75, 349–352.
[6] Davies et al. reported that the aromatic substitution reaction,
which is promoted by electron-deficient rhodium catalysts, pro-
ceeds by formation of zwitterionic intermediate A (ref.[2b]). Cu-
(OTf)2 also works as an electron-deficient catalyst. However,
substrates (ligands) work as electron-donors, and some of them
might inhibit the formation of A. Although chelating ligands
4a or 4b coordinate to Cu(OTf)2 efficiently, the ability as elec-
tron-donors might be lower than 1h.
Conclusions
We have demonstrated the versatility of an intermo-
lecular aromatic substitution reaction, which employs N,N-
disubstituted anilines and diazo esters as substrates. The re-
action is shown to proceed under mild conditions in the
presence of catalytic amounts of copper(II) triflate–ligand
complexes. The scope and limitations regarding substrates,
diazo esters, and ligands has been described. Further work
to develop an asymmetric reaction by using chiral ligands
is in progress in our laboratory.
Experimental Section
An off-white suspension of copper(II) triflate (22 mg, 0.06 mmol)
in dichloromethane (15 mL) was added to a flask containing 4a
(12 mg, 0.06 mmol) at room temperature with stirring under nitro-
gen. The mixture was stirred at the same temperature for over 3 h,
and part of the resulting solution (1.5 mL, 0.006 mmol) was added
to 1h (89 mg, 0.45 mmol) with stirring at room temperature. Then,
a solution of 2a (53 mg, 0.30 mmol) in dichloromethane (1.5 mL)
was added dropwise successively. After stirring for 12 h at the same
temperature, the reaction was quenched with saturated aqueous so-
dium hydrogen carbonate. Extractive workup and purification of
[7] We attempted reactions using diazo esters without an α-aryl
substituent. However, the reactions did not succeed.
Received: August 2, 2010
Published Online: November 2, 2010
Eur. J. Org. Chem. 2010, 6719–6721
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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