Copper(II)-acid co-catalyzed intermolecular substitution of electron-rich aromatics with diazoesters

Article abstract of DOI:10.1016/j.tetlet.2012.07.070

The intermolecular aromatic substitution of N,N-dialkylanilines and alkoxybenzenes with diazoesters is shown to proceed in the presence of catalytic amounts of both copper(II) salt and acid (Lewis or Br?nsted). This method is a mild and rare metal-free C-C bond formation reaction between aromatic (sp²) and aliphatic (sp³) carbons.

Full text of DOI:10.1016/j.tetlet.2012.07.070

Tetrahedron Letters 53 (2012) 5159–5161
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Tetrahedron Letters
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Copper(II)–acid co-catalyzed intermolecular substitution of electron-rich
aromatics with diazoesters
⇑
Eiji Tayama , Moe Ishikawa, Hajime Iwamoto, Eietsu Hasegawa
Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The intermolecular aromatic substitution of N,N-dialkylanilines and alkoxybenzenes with diazoesters is
shown to proceed in the presence of catalytic amounts of both copper(II) salt and acid (Lewis or
Brønsted). This method is a mild and rare metal-free C–C bond formation reaction between aromatic
(sp2) and aliphatic (sp3) carbons.
Received 4 June 2012
Revised 9 July 2012
Accepted 13 July 2012
Available online 22 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aromatic substitution
Co-catalysis
Synthetic method
Arene
Diazo compound
Transition metal-catalyzed aromatic substitution using a-diazo-
carbonyl compounds (formally, an aromatic C–H insertion) is a pow-
erful and efficient synthetic method that enables the formation of
C–C bonds between aromatic (sp2) and aliphatic (sp3) carbons under
mild conditions.1 These are several well-studied examples of suc-
cessful intramolecular benzofused-ring formations catalyzed by rho-
dium complexes; however, examples of the intermolecular version
are rare,2 except for some reactions with heteroaromatic com-
pounds.3 Furthermore, whereas rhodium complexes are among the
most efficient catalysts for the reactions, these complexes are too
expensive to use for large-scale synthesis. As such, it is important
to develop catalysts composed of earth-abundant metals such as
copper.4 Recently, we reported that the intermolecular aromatic sub-
stitution of N,N-disubstituted aniline 1 with diazoester 2 proceeded
in the presence of copper(II) triflate, [Cu(OTf)2] (Scheme 1).5,6 In the
course of our research, we found that co-catalysts derived from a
non-Lewis acidic copper(II) salt and a common acid catalyst also
accelerated the aforementioned intermolecular aromatic substitu-
tion.7,8 Herein, we report the development of the Cu(II)–acid co-cat-
alyzed version of the aromatic substitution reaction using
diazoesters. This method is a mild and rare metal-free C–C bond for-
mation reaction between aromatic (sp2) and aliphatic (sp3) carbons.
In our previous paper, we reported the intermolecular aromatic
substitution of N,N-dialkylaniline 1a with diazoester 2a catalyzed
by Cu(OTf)2 (Table 1, entries 1, 2). The reaction proceeded smoothly
in the presence of 2 mol % Cu(OTf)2 generating the desired
Scheme 1. The catalytic effect in the intermolecular aromatic substitution of N,N-
disubstituted aniline 1 with diazoester 2.
para-substituted adduct 3a in good yield. In contrast, the use of a
non-Lewis acidic copper(II) salt such as copper(II) acetylacetonate
[Cu(acac)2] resulted in a lower yield (entry 3). These results suggest
that a combination of a copper(II) salt (Catalyst A) and a common
Lewis acid (Catalyst B) might also catalyze the intermolecular aro-
matic substitution. Thus, we attempted the reaction in the presence
of a co-catalyst derived from 1 mol % Cu(acac)2 and 1 mol % boron
trifluoride diethyl etherate, (BF3ÁOEt2) (entry 4). As expected, the
reaction afforded the desired product with a yield similar to the ori-
ginal reaction with 2 mol % Cu(OTf)2. To clarify the effects of the
Cu(acac)2–BF3ÁOEt2 co-catalyst, we examined the reactions without
Cu(acac)2 and/or BF3ÁOEt2 (entries 5–7). These reactions were
unsuccessful. After further screening with a number of different
copper(II) salts, Lewis acids, and their catalytic amounts (entries
8–18), we found that the best yields were obtained from reactions
⇑
Corresponding author. Tel.: +81 25 262 7740; fax: +81 25 262 7741.
E-mail address: tayama@chem.sc.niigata-u.ac.jp (E. Tayama).
with
1 to 2 mol % (total amount) co-catalyst derived from
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.070

5160
E. Tayama et al. / Tetrahedron Letters 53 (2012) 5159–5161
Table 1
Table 2
Screening of Cu(II) and Lewis acid catalysts for the intermolecular aromatic
Cu(II)–Lewis acid co-catalyzed intermolecular aromatic substitution of various types
substitution of 1a with 2a
of 1 with 2
Entry
Catalyst A (mol %)
Catalyst B (mol %)
Time (h)
3aa (%)
1
2
3
4
5
6
7
Cu(OTf)2 (2)
Cu(OTf)2 (1)
Cu(acac)2 (1)
Cu(acac)2 (1)
—
—
—
—
12
12
12
6
6
24
6
89b
53b
31
89
31
53
0
Entry
R1
R2
Product
Method, yielda
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
—
A (%)
B (%)
—
—
1
2
3
4
5
6
7
8
CONEt2 (1b)
COt-Bu (1c)
COPh (1d)
CH2OBn (1e)
CH2OMe (1f)
Ph (1g)
p-Cl-Ph (1h)
p-MeO-Ph (1i)
Ph (1g)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
Cl (2b)
OMe (2c)
H (2a)
H (2a)
3b
3c
3d
3e
3f
3ga
3h
3i
3gb
3gc
3j
41
54
76
90
92
78
79
89
90
78
4
42b
68b
0b
8
9
Cu(acac)2 (0.5)
Cu(acac)2 (2)
Cu(acac)2 (1)
Cu(acac)2 (2)
Cu(OAc)2ÁH2O (1)
Cu(OAc)2 (1)
Cu(hfacac)2ÁnH2O (1)
Cu(phen)Cl2 (1)
Cu(acac)2 (1)
Cu(acac)2 (1)
Cu(acac)2 (1)
BF3ÁOEt2 (0.5)
BF3ÁOEt2 (2)
BF3ÁOEt2 (2)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
Sc(OTf)3 (1)
Zn(OTf)2 (1)
Sn(OTf)2 (1)
6
6
6
6
6
6
6
6
92
70
84
76
88
86
42
38
65
29
67
59b
59b
35b
40
28
36
86
2
10
11
12
13
14
15
16
17
18
9
6
6
6
10
11
12
Ph (1g)
H (1j)
H (1j)
3j
25c
—
a
a
b
c
Isolated yield.
Reported data in Ref. 5.
Isolated yield.
b
Reported data in Ref. 5.
100 mol % BF3ÁOEt2 was used.
Table 3
The intermolecular aromatic substitution of alkoxybenzenes 4 with 2a
Cu(acac)2–BF3ÁOEt2.9 The use of other common copper(II) salts,
such as copper(II) acetate, hexafluoroacetylacetonate [Cu(hfacac)2],
dichloro(1,10-phenanthroline)copper(II) [Cu(phen)Cl2], or Lewis
acids showed no further improvement on the yield.
With the method in hand, we investigated the reactions of var-
ious types of N,N-dialkylanilines 1 with 2 in the presence of Cu(a-
cac)2–BF3ÁOEt2 co-catalyst (Method A) and compared the catalytic
activity with Cu(OTf)2 (Method B) (Table 2). The reaction of N,N-
diethylamide 1b and tert-butylketone derivatives 1c under co-cat-
alyzed conditions afforded 3b and 3c, respectively, in yields similar
to those reactions using only Cu(OTf)2 (entries 1, 2). Interestingly,
the reaction of phenylketone derivative 1d proceeded without
unfavorable side reactions under co-catalyzed conditions (entry
3); the yield of the desired product 3d was improved to 76% (Meth-
od A) from 0% (Method B). Favorable effects of the Cu(acac)2–
BF3ÁOEt2 co-catalyst were also observed in the reactions of
substrates 1e–1i with 2a–2c10 (entries 4–10); however, the reac-
tions of N,N-dimethylaniline (1j) failed (entry 11), even with stoi-
chiometric amounts of BF3ÁOEt2 (entry 12). Any C–H insertion
products into the N-methyl group2b as in 1 were not obtained.11
To expand the scope of Cu(acac)2–BF3ÁOEt2 co-catalyzed inter-
molecular aromatic substitution, we examined reactions of alkoxy-
benzenes 4, which, due to their alkoxy substituents, are poorer
electron donors and thus potentially less reactive (Table 3). First,
we selected 1,2-dimethoxybenzene (4a) as a substrate and carried
out the reactions in the presence of either Cu(II)–BF3ÁOEt2 co-cata-
lyst or Cu(OTf)2 alone. Unfortunately, these reactions were unsuc-
cessful (entries 1–3). We tested a variety of Cu(II) salts for this
reaction and found that 1,10-phenanthroline Cu(II) complexes,
[Cu(phen)mCln], gave the desired adduct 5a in low yields (entries
4–6). Increasing the amount of catalyst to 5 mol % BF3ÁOEt2 with
1 mol % Cu(phen)mCln produced 5a in acceptable yields (entries
7, 8). The analagous 1,3-dimethoxybenzene (4b) showed similar
reactivity (entry 9); however, a reaction of mono-alkoxybenzene,
Entry
R of 4
Catalyst Aa (mol %)
Catalyst B (mol %)
5b (%)
1
2
3
4
5
6
7
8
9
10
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
3-OMe
H
a
a
a
a
a
a
a
a
b
c
Cu(OTf)2 (2)
Cu(acac)2 (1)
Cu(OAc)2 (1)
Cu(phen)Cl2 (1)
[Cu(phen)2Cl]Cl (1)
[Cu(phen)3]Cl2 (1)
Cu(phen)Cl2 (1)
[Cu(phen)2Cl]Cl (1)
[Cu(phen)2Cl]Cl (1)
[Cu(phen)2Cl]Cl (1)
—
6
17
19
53
51
40
66
60
56
35
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (1)
BF3ÁOEt2 (5)
BF3ÁOEt2 (5)
BF3ÁOEt2 (5)
BF3ÁOEt2 (5)
a
phen = 1,10-phenanthroline.
Isolated yield.
b
specifically anisole (4c), resulted in
a low yield (entry 10).
Previously, we reported that substrates such as 1 function as li-
gands of Cu(II) salts, and the catalytic activity is determined by
the structure of the complexes.5 1,2-Dimethoxybenzene 4a also
function as ligands; however, the catalytic activity is lowered (en-
try 1–3). 1,10-Phenanthroline, as in Cu(phen)mCln may not ex-
change with 4a because of its higher chelating ability and the
catalytic activity may be maintained.
We expected that the reaction might be accelerated with a
Brønsted acid instead of a Lewis acid catalyst. Thus, we attempted
the Cu(II)–acid co-catalyzed intermolecular aromatic substitution
of 1a with 2a in the presence of 1 mol % common sulfonic acid as

E. Tayama et al. / Tetrahedron Letters 53 (2012) 5159–5161
5161
Table 4
Cu(II)–Brønsted acid co-catalyzed intermolecular aromatic substitution of 1 with 2a
Acknowledgment
This work was supported by Grant for Basic Science Research
Projects from The Sumitomo Foundation (110187).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.070.
Entry
R1
x
Brønsted acid
Time (h)
Product
3a (%)
1
2
3
4
5
6
7
8
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CONEt2
CONEt2
CH2OMe
CH2OMe
Ph
1
1
1
1
0
1
0
1
0
1
0
1
1
0
1
1
1
TsOHÁH2O
DL-CSAb
PPTS
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
24
24
24
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3a
3a
3a
3a
3a
3b
3b
3f
30
37
6
86
91
69
0
78
6
85
61
5
77
51
11
28
27
References and notes
1. For reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998;
(b) Davies, H. M. L. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 4,. Chapter 4.8.
2. (a) Park, C. P.; Nagle, A.; Yoon, C. H.; Chen, C.; Jung, K. W. J. Org. Chem. 2009, 74,
6231–6236; (b) Davies, H. M. L.; Jin, Q. Org. Lett. 2004, 6, 1769–1772; (c) Davies,
H. M. L.; Smith, H. D.; Hu, B.; Klenzak, S. M.; Hegner, F. J. J. Org. Chem. 1992, 57,
6900–6903; (d) Toda, M.; Hattori, M.; Okada, K.; Oda, M. Chem. Lett. 1987, 16,
1263–1266; (e) Ledon, H.; Linstrumelle, G.; Julia, S. Bull. Soc. Chim. Fr. 1973,
2065–2071.
3. Examples of intermolecular aromatic substitution using heteroaromatic
compounds, see: (a) Chan, W. W.; Yeung, S. H.; Zhou, Z.; Chan, A. S. C.; Yu,
W. Y. Org. Lett. 2010, 12, 604–607; (b) Davies, H. M. L.; Hedley, S. J. Chem. Soc.
Rev. 2007, 36, 1109–1119. and references therein.
4. An example of rhodium and copper catalyzed intramolecular aromatic
substitution and their mechanistic studies, see: Kim, J.; Ohk, Y.; Park, S. H.;
Jung, Y.; Chang, S. Chem. Asian J. 2011, 6, 2040–2047.
9
3f
10
11
12
13
14
15
16
17
3ga
3ga
3j
3a
3a
3b
3f
Ph
H
CO2Et
CO2Et
CONEt2
CH2OMe
Ph
3ga
a
Isolated yield.
b
CSA = camphorsulfonic acid.
5. Tayama, E.; Yanaki, T.; Iwamoto, H.; Hasegawa, E. Eur. J. Org. Chem. 2010, 6719–
6721.
6. Previous examples of acid-promoted intramolecular aromatic substitution, see:
(a) Wang, H. L.; Li, Z.; Wang, G. W.; Yang, S. D. Chem. Commun. 2011, 47, 11336–
11338; (b) Doyle, M. P.; Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N. J. Org.
Chem. 1988, 53, 1017–1022; (c) Johnson, D. W.; Mander, L. N. Aust. J. Chem.
1974, 27, 1277–1286; (d) Newman, M. S.; Eglinton, G.; Grotta, H. M. J. Am.
Chem. Soc. 1953, 75, 349–352.
7. For a review of Brønsted acid catalyzed reaction using diazo compounds, see:
Johnston, J. N.; Muchalski, H.; Troyer, T. L. Angew. Chem., Int. Ed. 2010, 49, 2290–
2298.
8. Examples of transition metal–acid co-catalyzed reaction using diazo
compounds, see: (a) Xu, X.; Zhou, J.; Yang, L.; Hu, W. Chem. Commun. 2008,
6564–6566; (b) Hu, W.; Xu, X.; Zhou, J.; Liu, W. J.; Huang, H.; Hu, J.; Yang, L.;
Gong, L. Z. J. Am. Chem. Soc. 2008, 130, 7782–7783.
9. Although the reactions of entry 4 (total 2 mol %) and entry 8 (total 1 mol %) in
Table 1 were quenched for 1 h, a remarkable difference between the yields was
not observed (entry 4: 38%, entry 8: 30%).
an acid component (Table 4, entries 1–4). The use of a strongly
acidic Brønsted acid such as triflic acid afforded the adduct 3a in
excellent yield (entry 4). Interestingly, the reaction of 1a proceeded
smoothly without Cu(II) salts (entry 5). When reactions of the less-
reactive substrate 1 were examined, the addition of Cu(acac)2 was
necessary to obtain adduct 3 in acceptable yields (entries 6–11).
Again, the reaction of N,N-dimethylaniline (1j) did not proceed un-
der these conditions (entry 12). The analogue of triflic acid, bistri-
flimide (Tf2NH), also worked as a Brønsted acid catalyst; however,
the catalytic activity was lowered (entries 13–17).
10. We attempted reactions using diazoesters without an a-aryl substituent such
In conclusion, we have demonstrated the Cu(II)–acid co-cata-
lyzed intermolecular aromatic substitution of N,N-dialkylanilines
or alkoxybenzenes with diazoesters. This method is a mild and rare
metal-free C–C bond formation reaction between aromatic (sp2)
and aliphatic (sp3) carbons.
as cyclohexyl 2-diazoacetate or cyclohexyl 2-diazo-3-oxobutanoate; however,
the corresponding products were not obtained.
11. Davies et al. reported that the electrophilic aromatic substitution reaction
proceeds in the presence of electron-deficient rhodium catalysts (Ref. 2b). Acid
catalysts may interact with the ligands around Cu(II), leading to more electron-
deficient catalysts.