Copper-catalyzed cross dehydrogenative coupling reactions of tertiary amines with ketones or indoles

Article abstract of DOI:10.1021/ol102252n

A novel cross dehydrogenative coupling (CDC) reaction of N,N-dimethylanilines with methyl ketones by cooperative copper and aminocatalysis has been developed, which leads to the formation of β-arylamino ketones in 42-73% yields. Moreover, the copper-catal

Full text of DOI:10.1021/ol102252n

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5214-5217
Copper-Catalyzed Cross
Dehydrogenative Coupling Reactions of
Tertiary Amines with Ketones or Indoles
Fei Yang,† Jian Li,† Jin Xie,† and Zhi-Zhen Huang*,†,‡
Key Laboratory of Mesoscopic Chemistry of MOE, College of Chemistry, and
Chemical Engineering, Nanjing UniVersity, Nanjing 210093, P. R. China, and State
Key Laboratory of Elemento-organic Chemistry, Nankai UniVersity,
Tianjin 300071, P. R. China
huangzz@nju.edu.cn
Received September 20, 2010
ABSTRACT
A novel cross dehydrogenative coupling (CDC) reaction of N,N-dimethylanilines with methyl ketones by cooperative copper and aminocatalysis
has been developed, which leads to the formation of ꢀ-arylamino ketones in 42-73% yields. Moreover, the copper-catalyzed alkylation of free
(NH) indoles with N,N-dimethylanilines via CDC reaction is also presented, affording alkylated indoles in 52-78% yields.
It is known that transition-metal-catalyzed cross-coupling
reactions are among the most important methods for C-C
bond formation. However, these cross-coupling reactions
generally need functionalized substrates.1 Recently, much
attention has been focused on C-H bond activation and
subsequent C-C bond formation.2 Nevertheless, most of
them still require another functionalized substrate.1 Due to
direct use of C-H bonds, cross dehydrogenative coupling
(CDC) is a very promising method for the formation of a
C-C bond, which avoids the use of functionalized substrates
and is a more atom-economic and environmentally friendly
method.3 In recent years, several groups, especially Li’s
research group, have done excellent work on CDC reactions
of various sp3 C-H bonds, such as benzylic or allylic C-H,
R-C-H bonds of tertiary amines, R-C-H bonds of ethers,
or C-H bonds of alkanes with other C-H bonds. Among
them, great interest was paid to C-H activations of tertiary
amines and subsequent C-C formations with nucleophiles.1,4
(3) For reviews on CDC reactions: (a) Li, C.-J.; Li, Z.-P. Pure Appl.
Chem. 2006, 78, 935. (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (c)
Scheuermann, C.-J. Chem. Asian J. 2010, 5, 436.
(4) For representative papers on CDC reactions of tertiary amines, see:
(a) Li, Z.-P.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.-P.;
Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (c) Li, Z.-P.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 6968. (d) Murahashi, S.-I.; Komiya, N.; Terai, H.
Angew. Chem., Int. Ed. 2005, 44, 6931. (e) Catino, A.-J.; Nichols, J.-M.;
Nettles, B.-J.; Doyle, M.-P. J. Am. Chem. Soc. 2006, 128, 5648. (f)
Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008,
130, 11005. (g) Condie, A.-G.; Gonzalez-Gomez, J.-C.; Stephenson, C.-
R.-J. J. Am. Chem. Soc. 2010, 132, 1464. (h) Sud, D.; Sureshkumar, D.;
Klussmann, M. Chem. Commun. 2009, 3169. (i) Shen, Y.-M.; Li, M.; Wang,
S.-Z.; Zhan, T.-G.; Tan, Z.; Guo, C.-C. Chem. Commun. 2009, 953. (j)
Liu, P.; Zhou, C.-Y.; Xiang, S.; Che, C.-M. Chem. Commun. 2010, 2739.
(k) Shu, X.-Z.; Yang, Y.-F.; Xia, X.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M.
Org. Biomol. Chem. 2010, 8, 4077. (l) Wang, M.-Z.; Zhou, C.-Y.; Wong,
M.-K.; Che, C.-M. Chem.sEur. J. 2010, 16, 5723.
† Nanjing University.
‡ Nankai University.
(1) Li, Z.-P.; Bohle, D.-S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 8928.
(2) For a book and representative reviews on C-H activation and
subsequent C-C bond-forming reactions, see: (a) Dyker, G. Handbook of
C-H Transformations; Wiley-VCH: Weinheim, 2005. (b) Jia, C.-G.; Piao,
D.-G.; Oyamada, J.; Lu, W.-J.; Kitamura, T.; Fujiwara, Y. Science 2000,
287, 1992. (c) Chen, X.; Engle, K.-M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (d) Bellina, F.; Rossi, R. Chem. ReV. 2010,
110, 1082.
10.1021/ol102252n  2010 American Chemical Society
Published on Web 10/21/2010

At the same time, enamines as elegant nucleophiles have
become crucial reactive intermediates in organocatalysis for
C-C formations.5 However, there are only a few reports on
the application of aminocatalysis in the C-C bond formation
after C-H activation of tertiary amines by transition-metal
catalysis.4g,k In 2009, Klussmann’s research group revealed
a CDC reaction of tertiary amines with methyl ketones by
dual catalysis of the vanadium complex and proline, and
almost all tertiary amines employed efficiently in the CDC
reaction are limited to tetrahydroisoquinoline derivatives.4g
The investigation on the CDC reactions of tertiary amines
with ketones by cooperative metal and aminocatalysis,
including the use of common tertiary amines and cheap
metals, is a challenging subject. In this paper, we report a
CDC reaction of N,N-dimethylanilines with methyl ketones
by cooperative CuBr and pyrrolidine catalysis.
Table 1. Screening for the CDC Reaction of
N,N-Dimethylaniline with Ketone by Cooperative
Transition-Metal and Aminocatalysisa
entry
metal salt
organocatalyst
t (h)
yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuCl2
CuBr
Cu(acac)2
FeCl2
FeCl3
Fe(acac)3
CuBr
CuBr
1
8
8
8
4
4
4
4
4
4
8
4
4
8
4
4
0c
12
trace-17
23
36
18
42
35
53
2a
2b-4
5a
5b
5c
5b
5b
5b
5b
5b
5b
5b
5b
-
Initially, various aminocatalysts 1-5 (Figure 1) were tested
for the CDC reaction of N,N-dimethylaniline 6a with acetone
9
10
11
12
13
14
15
27
28
23
18
64d
trace
a Reaction conditions: amine (0.5 mmol), acetone (5.0 mmol), metal
salt (0.025 mmol), organocatalyst 1-5 (0.15 mmol), and TBHP-decane (0.75
mmol) at 70 °C. b Isolated yields. c MeOH (1.0 mL) as a solvent. d A small
amount of MeOH (0.2 mL) was added.
Figure 1. Organocatalysts 1-5.
7a in the presence of 5 mol % CuI and 1.5 equiv of tert-
butyl hydroperoxide (TBHP) as an oxidant (entries 1-6,
Table 1). When L-proline was employed as an organocatalyst,
no desired coupling product 8a was obtained (entry 1, Table
1). Gratifyingly, using diisopropylamine acetic salt 2a led
to the desired 8a in a 12% yield (entry 2, Table 1). After
screening of secondary amines and their salts 3-5, pyrro-
lidine benzoate 5b was found to be optimal with a 36% yield
of 8a (entry 5, Table 1, also see Supporting Information (SI)).
Then various metal salts, such as CuCl, CuCl2, CuBr,
Cu(acac)2, FeCl2, FeCl3, and Fe(acac)3, were examined. The
experiment indicated that CuBr was most effective among
the metal catalysts, which resulted in a 53% yield of 8a
(entries 7-13, Table 1). Oxidants including tert-butyl
peroxide (TBP), tert-butyl hydroperoxide, 70 wt % in water
(T-HYDRO), H2O2, and oxygen were also probed in the
reaction, which led to 8a in the lower yields of 0-48% as
compared to that of TBHP (for details, see SI). Finally,
various solvents were examined in the reactions, and the yield
of 8a was further improved to 64% by adding a small amount
of MeOH (entry 14, Table 1; also see SI). It is noteworthy
that only a trace amount of coupling product 8a was obtained
in the absence of pyrrolidine salt 5b (entry 15, Table 1).
This result demonstrates that the organocatalyst 5b is crucial
for the CDC reaction.
After screening of various organocatalysts, metal catalysts,
solvents, and oxidants, it can be concluded that the optimized
reaction should be performed under the cooperative catalysis
of 5 mol % CuBr and 30 mol % pyrrolidine salt 5b using
1.5 equiv of TBHP as an oxidant and methanol as a solvent.
Under the optimal reaction conditions, a set of N,N-
dimethylanilines were probed in the CDC reaction. It was
found that N,N-dimethylanilines bearing either electron-
donating or electron-withdrawing groups on the benzene
rings 6a-g could perform the CDC reaction with methyl
ketones 7a-c to give the desired ꢀ-arylamino ketones 8a-k
in satisfactory yields (42-73%). The coupling always occurrs
at the nonsubstituted R-position of the ketones 7, and no
coupling product was obtained using 3-pentanone or cyclo-
hexanone probably because the CDC reaction was sensitive
to steric hindrance.
Additionally, indole derivatives are also good nucleophiles
and have many important biological and pharmaceutical
activities.6 Recently, Li’s1 and Che’s4j research group
successively developed the CDC reaction of tetrahydroiso-
quinolines with indoles under the catalysis of copper(I)
bromide or silica-supported iron complex (Table 2), respec-
tively. In 2009, Che et al. found that N,N-dimethylanilines
could undergo a CDC reaction with N-aryl indoles by
ruthenium catalysts.4l However, the CDC reaction of N,N-
dimethylanilines with N-alkyl- or N-H-indoles did not
(5) For representative books and reviews on aminocatalysis, see: (a)
Berkessel, A.; Groger, H. Asymmetric Organocatalysis - From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim,
2005. (b) Dalko, P.-I. EnantionselectiVe Organocatalysis; Wiley-VCH:
Weinheim, 2007. (c) Mukherjee, S.; Yang, J.-W.; Hoffmann, S.; List, B.
Chem. ReV. 2007, 107, 5471.
(6) (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73. (b)
Kochanowska-Karamyan, A.-J.; Hamann, M.-T. Chem. ReV. 2010, 110,
4489.
Org. Lett., Vol. 12, No. 22, 2010
5215

we wish to present our recent results on this CDC reaction
catalyzed by CuBr.
Table 2. CDC Reaction of N,N-Dimethylanilines 6 with Methyl
Ketone 7 under the Cooperative Catalysis of CuBr and
Pyrrolidine Salt 5ba
Considering that some CDC reactions of tetrahydroiso-
quinolines with indoles or ketones proceed smoothly under
neat conditions,1,4i the reaction of N,N-dimethylaniline 6a
with indole 9a was initially tested in the presence of 5 mol
% CuBr and 1.0 equiv of TBHP at 40 °C under neat
conditions. To our delight, the desired product 10a was
formed in 38% yield (entry 1, Table 3). Then, other copper
Table 3. Screening of Reaction Conditions for the CDC
Reaction of N,N-Dimethylaniline with Indolea
entry metal salt TBHP (equiv) t (h) solvent yield (%)b
1
2
3
4
5
6
7
8
CuBr
CuCl
CuCl2
CuI
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
3
3
3
3
3
3
12
3
12
12
12
neat
neat
neat
neat
neat
neat
neat
neat
38
26
16
25
18
52
17c
22d
9
9
10
11
CH3CN
hexane
toluene
18
25
a Reaction conditions: N,N-dimethylaniline (1.0 mmol), indoles (0.5
mmol), metal catalyst (0.025 mmol), 40 °C. b Isolated yields. c The reaction
was performed at rt. d The reaction was performed at 50 °C.
salts, such as CuCl, CuCl2, CuI, and Cu(OAc)2, were
examined, and it was found that CuBr was the most effective
metal catalyst (entries 2-5, Table 3). The optimizing
experiment also indicated that increasing the amount of
TBHP from 1.0 to 1.5 equiv improved the yield of 10a
(compare entry 1 with 6, Table 3). Among the reaction
temperatures tested, 40 °C was the most suitable temperature
(entries 6-8, Table 3). After further screening of solvents
such as toluene, hexane, and CH3CN, the neat conditions
were still optimal for the CDC reaction.
On the basis of screening the above CDC reaction
conditions, it can be concluded that the optimized reaction
should be performed in the presence of 5 mol % CuBr
and 1.5 equiv of TBHP at 40 °C under neat conditions.
Under the optimal conditions, it was found that different
N,N-dimethylanilines 6a-c and free (NH)-indoles 9a-d
could undergo the CDC reaction smoothly to afford the
corresponding alkylated indoles, N-indolylmethyl-N-me-
thylbenzenamine 10a-g in 52-78% yields (entries 1-7,
Table 4). The 4-substituted N,N-dimethylanilines 6b,c led
to higher yields of 10b-d than those resulting from 6a
probabaly because 6a with indole 9a could form 4-in-
dolylmethyl N,N-dimethylbenzenamine as a byproduct
a Reaction conditions: amine (0.5 mmol), ketone (5.0 mmol), CuBr
(0.025 mmol), organocatalyst 5b (0.15 mmol), TBHP-decane (0.75 mmol),
MeOH (0.20 mL), 70 °C. b Isolated yields. c The reaction was performed
at 50 °C.
perform smoothly. At the same reaction conditions, using
N-H- or N-alkyl-indoles efficiently resulted in dimethylami-
nobenzyl indoles rather than the expected CDC products with
N,N-dimethylanilines.4l To the best of our knowledge, no
literature was disclosed on the CDC reaction of N,N-
dimethylanilines with free (NH)-indole derivatives. Herein,
5216
Org. Lett., Vol. 12, No. 22, 2010

5-electron-donating group substituted indoles led to no
coupling product.
Table 4. CDC Reaction of N,N-Dimethylanilines 6 with Indoles
9 Catalyzed by CuBra
Furthermore, it was found that when 2,6-di-tert-butyl-4-
methyl phenol (BHT), a radical inhibitor, was added into
the above CDC reaction systems of N,N-dimethylaniline 6a
with acetone 7a or indole 9a the yield of the coupling product
8a was decreased dramatically to 18%, or no coupling
product 10a was observed under the optimal conditions.
Therefore, the mechanism of the two CDC reactions may
undergo radical pathways. As shown in Scheme 1, a tert-
Scheme 1. Depiction of Plausible Mechanism
butoxyl radical generateded by copper-catalyzed decomposi-
tion of TBHP initially abstracts an R-hydrogen to form
radical 11, followed by a single electron transfer (SET) to
generate imine cation 12.1 Then, 12 may undergo a nucleo-
philic attack by an enamine formed from ketone and
pyrrolidine in situ or by an indole derivative, affording the
coupling product 8 after hydrolysis or 10, respectively.
In conclusion, we have developed a novel CDC reaction
of N,N-dimethylanilines 6 with methyl ketones 7 by the
cooperative catalysis of 5 mol % CuBr and 30 mol %
pyrrolidine benzoate 5b in the presence of TBHP, affording
ꢀ-arylamino ketones 8a-k in 42-73% yields. Moreover,
we also found that under the catalysis of 5 mol % CuBr and
in the presence of TBHP N,N-dimethylanilines 6 could
undergo CDC reaction with free (NH)-indoles 9 smoothly
to afford the alkylated indoles 10 in 52-78% yields. Further
investigations on the extension of substrate scopes are
currently underway in our laboratory.
a Reaction conditions: amine (1.0 mmol), indole (0.5 mmol), CuBr (0.025
mmol), TBHP-decane (0.75 mmol), 40 °C, 3 h. b Isolated yields. c The
reaction time is 12 h.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 20872059 and
21072091)andMOSTofChina(973program2011CB808600)
is gratefully acknowledged.
(compare entries 2-4 with 1, Table 4).4l,7 When 5-meth-
ylindole was employed, we could not isolate the pure
coupling product due to its instability, and using other
Supporting Information Available: Experimental pro-
1
cedures, spectroscopic data, and spectra of H NMR, 13C
NMR, and MS for coupling products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(7) We also isolated 4-indolymethyl N,N-dimethylbenzenamine as a
byproduct.
OL102252N
Org. Lett., Vol. 12, No. 22, 2010
5217