Copper(II)-catalyzed C-H (sp3) oxidation and C-N cleavage: Synthesis of methylene-bridged compounds using TMEDA as a carbon source in water

Article abstract of DOI:10.1039/c3ra40695d

A green, simple, and efficient protocol for the selective methylenation via CuCl₂/oxygen-mediated C-H (sp³) oxidation and C-N cleavage using tetramethylethylenediamine (TMEDA) as a carbon source has been developed. The reactions were achieved in green solvent water under atmospheric conditions. The protocol exhibited a broad substrate scope including indoles, anilines, pyrroles and 1,3-dicarbonyls. Furthermore, two key intermediates of the reaction were successfully identified and the mechanism was explored. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra40695d

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Copper(II)-catalyzed C–H (sp3) oxidation and C–N
cleavage: synthesis of methylene-bridged compounds
Cite this: RSC Advances, 2013, 3,
10272
using TMEDA as a carbon source in water3
Dan Zhao, Yue Wang, Min-Xue Zhu, Qi Shen, Lei Zhang, Yun Du and Jian-Xin Li*
A green, simple, and efficient protocol for the selective methylenation via CuCl2/oxygen-mediated C–H
(sp3) oxidation and C–N cleavage using tetramethylethylenediamine (TMEDA) as a carbon source has been
developed. The reactions were achieved in green solvent water under atmospheric conditions. The
protocol exhibited a broad substrate scope including indoles, anilines, pyrroles and 1,3-dicarbonyls.
Furthermore, two key intermediates of the reaction were successfully identified and the mechanism was
explored.
Received 20th October 2012,
Accepted 8th February 2013
DOI: 10.1039/c3ra40695d
www.rsc.org/advances
dehydrogenative-coupling (CDC) reaction in water was
reported in 2007 by Li.8
Introduction
With the concern about environmental impact, transition
metal-catalyzed C–H bond activation and subsequent C–C
bond formation without pre-functionalization of the sub-
strates and undesired byproducts have been a fascinating hot-
topic in organic synthesis.1 Recently, transition metal-cata-
lyzed oxidation of an sp3 C–H bond adjacent to a nitrogen
atom in a tertiary amine, followed through C–N bond cleavage
has emerged as a useful strategy for C–C bond construction.2
However, these protocols commonly required diethyl azodi-
carboxylate (DEAD) or tert-butyl hydrogen peroxide (TBHP) as
an oxidant and were also conducted in organic solvents.
Considering an environmentally benign and effective metho-
dology for oxidative transformation of amines, atmospheric
oxygen as a highly abundant and cheap resource3 in place of
DEAD or TBHP is still one of the most reasonable options. As a
unique solvent, water is a green, low cost, non-flammable,
non-toxic liquid with a wide temperature range. It also
possesses a high heat capacity making it inherently safe.4
Besides, transition metal catalysts can be separated from the
reaction mixture by simple phase separation because many
organic substrates are hydrophobic and insoluble in water.5
C–C bond formation through catalytic C–H bond activation
in water is one of the hotspots in organic synthesis.6 The
selective reaction of less reactive C–H bonds in the presence of
various functional groups and the stability of intermediates to
water make this subject highly challenging.7 The first C–C
coupling by the reaction of sp3 C–H bond via cross-
Indoles are important synthetic blocks in organic synthesis
and the chemical industry, and have been widely used in
medicinal chemistry.9 Alkylated indoles are usually synthe-
sized with strong acid- or base-mediated alkylation reactions,
in which highly air- and water-sensitive organometallic
reagents are essential.10 Thus, there still is a need to develop
a green method for the efficient synthesis of these compounds
under mild and green conditions.
Recently, we have reported a novel method for the synthesis
of 3,39-bisindolylmethane and 4,49-diaminodiphenylmethane
using TMEDA as methylene source catalyzed by CuCl2 in the
presence of atmospheric oxygen as an oxidant in acetonitrile.11
Encouraged by these results, we expect to broaden the scope of
functional group tolerance and decrease operating cost via
developing a milder and more environmentally friendly
procedure.
We report herein a CuCl2/oxygen-mediated, mild and
efficient transformation for the synthesis of methylene-
bridged indole derivatives in water using tetramethylethylene-
diamine (TMEDA) as methylene donor. To the best of our
knowledge, this is the first example of C–C bond formation via
C–H and C–N bonds cleavage in water. The success of indoles
methylenation inspired us to further extend the substrate
scope beyond indoles. Very meaningfully, the optimized
reaction conditions were also available in the transformation
of anilines, pyrroles, and even 1,3-dicarbonyl derivatives.
State Key lab of Analytical Chemistry for Life Science, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China.
E-mail: lijxnju@nju.edu.cn; Fax: +86-25-83686419; Tel: +86-25-83686419
Results and discussion
With continuous interest in developing environmentally
benign and efficient reaction conditions for C(aryl) –C(aryl)
Electronic supplementary information (ESI) available: Experimental section,
3
spectral data and other information. See DOI: 10.1039/c3ra40695d
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Table 1 Optimization of reaction conditionsa
Entry Cat.
T (uC) t (h) Additive (equiv.)
Yield (%)b
1
2
3
4
5
6
7
8
CuCl2
CuCl2
FeCl3
90
90
90
5
—
—
—
—
—
—
—
—
20
42
0
23
10
17
Trace
15
8
55
35
51
33
12
12
12
12
12
12
12
12
5
5
5
5
5
Cu(OAc)2 90
ZnCl2
NiCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
90
90
20
50
90
90
90
90
90
90
90
90
9c
10
11
12
13
14
15
16
—
CH3CO2H (1.0)
CF3CO2H (1.0)
C6H5CO2H (1.0)
HCO2H (1.0)
HO2CCH2CH2CO2H (1.0) 45
CH3CO2H (1.0)
CH3CO2H (3.0)
12
12
88
76
a
Reaction conditions: 1a (1.0 mmol) was added to a mixture of
catalyst, 2, and water (10 mL), then heated to indicated temperature
b
c
and time under air conditions. Isolated yield. Catalyst (10 mol%).
bond formation,12 a reaction of 1-ethyl-1H-indole (1a) and
TMEDA (2) was selected as a model one. In the reaction, the
bisindole was synthesized through direct arylation catalyzed
by some abundant and cheap metal salts.13 As shown in
Table 1, when water was chosen as a solvent, treatment of 1a
and 2 with CuCl2 at 90 uC for 5 h afforded the desired product
3a in only 20% yield (entry 1). As usual, we prolonged the
reaction time, the yield was increased, but just to 42% (entry
2). Next, a series of other transition metal catalysts including
FeCl3, Cu(OAc)2, ZnCl2 and NiCl2 were tested (entries 3–6),
unfortunately, all were inferior to CuCl2. When CuCl2 was
reduced to 10 mol%, product yield was lowered to 8% (entry 9).
Further screening of the reaction temperature revealed that
the reaction at 90 uC gave the best results (entries 2, 7 and 8),
but the yields were still dissatisfied. To our delight, when the
same starting materials of entry 1 were treated with 1.0 equiv
of acetic acid, 3a was provided in 55% yield (entry 10) within 5
h. Excitedly, 3a was obtained in 88% yield (entry 15) when
reaction time prolonged to 12 h. However, as acetic acid was
increased to 3.0 equiv the yield declined to 76% (entry 16).
Other carboxylic acids such as benzoic acid, formic acid,
succinic acid were also evaluated. Although each yield was
different, all of the tested acids showed promotive activity
(entries 11–14). It was noticed that tris(1-ethyl-1H-indol-3-
yl)methane 3aa (,5%) was isolated as a byproduct in the
reactions (Table 1). For the methylene donor, another tertiary
Scheme 1 Scope of synthesis of bisindolylmethane using TMEDA as methylene
donor.a
amine N,N9-dimethylpiperazine was also available and
afforded the desired product in 61% yield under the same
reaction conditions as entry 15.
With the optimized conditions in hand, a series of
3,39-bisindolylmethane (3a–p) were generated by this novel
protocol (Scheme 1). The Cu-catalyzed C3-selective transfor-
mation of indoles was compatible with a range of substituents
in all positions of the indole ring, and generated the
corresponding products in reasonable to excellent yields. For
N-protecting groups, the N–Et group delivered a good result
(3a), while N–Bn group gave moderate yield (3b). In indole
ring, substituents such as Me, CN, and MeO were well
tolerated, and the positions of substituents did not appear to
exert much appreciable influence on the efficiency (3d–h).
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Scheme 3 Scope of synthesis of bispyrrolylmethane using TMEDA as methylene
donor.a
interesting chemical properties.14 As shown in Schemes 2 and
3, 4,49-diaminodiphenylmethane were prepared in good to
excellent yields. 2,29-Bispyrrolylmethanes were also synthe-
sized although the yields were relatively low. It should be
indicated that regioselectivity of these transformations for
diaminodiphenylmethane was excellent. Only 4,49-diaminodi-
phenylmethane was isolated in the reactions, no 4,29- or
4,39-diaminodiphenylmethane
was
observed.
Notably,
Scheme 2 Scope of synthesis of 4,49-diaminodiphenylmethane using TMEDA as
N-protecting groups also showed an influence on reactivity of
substrates (5a and 5b). Besides, the same as indoles, the
electronic nature of the substituents affected the transforma-
tion. For example, m-Me- and m-OMe-substituted aniline
reacted smoothly to furnish desired products (5c and 5d) in
better yields than that of 5b. Gratifyingly, naphthylamine and
cyclic amine selectively underwent the target coupling reaction
in moderate yields (5e and 5f). As bispyrrolylmethane have
been synthesized using a variety of procedures in organic
solvents,15 with the optimized reaction conditions, a series of
methylene donor.a
Notably, C–Cl bond remained intact during the reaction (3c),
which provided an additional handle for further elaboration of
product. For electron-withdrawing groups such as COOMe and
NO2 in indole ring and azaindole, the reactions were still
practical although the yields were low (3i–k), however, they
were unavailable in our previous works.11 Moreover, four aza-
macrocyclic compounds were successfully constructed in the
reaction system when 80% acetonitrile aqueous solution was
used as a solvent (3m–p). Very interestingly, when conducted
in pure water, those reactions mainly provided intermolecular
methylene-bridged compounds. While in pure acetonitrile, the
main products were C3-formylation indoles. The reason might
be presumably due to the concentration inequality caused by
bad solubility of substrates in water. It is worth mentioning
that tert-butyl carbonate (Boc)-protected indole reacted with
TMEDA affording the N-free compound (3l) that was unavail-
able to be obtained with other N–Et protected or non-protected
indoles. The result makes this protocol more useful for the
introduction of new N-functional groups. As a summary, the
electronic nature of the substituents in the indole ring affected
this transformation, the reactivity of electron-donating groups
was superior to that of the electron-withdrawing groups, which
might be due to the higher nucleophilicity of electron rich
indoles.
2,29-bispyrrolylmethanes
(7a–d)
were
also
prepared
(Scheme 3). However, pyrroles with N-protecting groups, e.g.,
Me, Ph, Bn and 4-methylbenzyl (PMB), gave relatively low
yields.
The results above mainly focused on sp2 C–H and sp3 C–H
cross-coupling reactions. To address the even more challen-
ging reactions under current conditions, we expanded our
substrates to sp3 C–H and sp3 C–H cross-couplings to generate
methylene-bridged compounds. An iron-catalyzed protocol for
the synthesis of methylene-bridged bis-1,3-dicarbonyls was
initially reported by Li et al.,2b and further several synthetic
procedures have been created.16 Considering the valuableness,
1,3-dicarbonyl compounds were used to investigate the
availability of our protocol (Scheme 4). Very interestingly, the
desired products were successfully obtained although the
yields were low. To improve the yields, a different catalytic
system might be desired, and further effort is essential.
Further experiments have been performed to obtain the
insight into the mechanism. Based on our previous research
and reported data, we speculated formaldehyde might be the
key intermediate of the reaction. Therefore, a reaction of 1a
The success of indoles methylenation encouraged us to
further extend the substrate scope beyond indoles. Anilines
and pyrroles are structurally unique and possess a variety of
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Scheme 4 Scope of synthesis of bis-1,3-dicarbonylmethane using TMEDA as
methylene donor.a
with an aqueous solution of formaldehyde was carried out
using the CuCl2/AcOH/H2O system [eqn (1)]. As expected, the
desired product 3a was generated in 89% yield, which
suggested that formaldehyde was most likely a possible
intermediate for the present transformation. To confirm the
presence of formaldehyde, Nash reagent as a capturing tool
was applied.17 Fortunately, formaldehyde was successfully
identified in the CuCl /AcOH/H O system (see ESI ). For the
Scheme 5 Proposed reaction mechanism.
3
2
2
byproduct 3aa, a reaction of 1a and 3-formylindole (1q) gave
3aa in 18% yield [eqn (2)], suggesting that 1q should be
important in the formation of the byproduct generated from
ascribed to trapping of intermediate B by coordinated OH or
by water, to give a-hydroxylated amine C, which subsequently
decomposes to give formaldehyde and N-demethylation
product.19 In the presence of Lewis acid, two molecules of
indoles react with one molecule of formaldehyde to afford
bisindolylmethane (pathway A).20 In view of pathway B,
nucleophilic addition of indole affords the oxidative
Mannich-type product D,21 which undergoes further oxidation
to the second iminium ion E, followed by hydrolysis to
generate 3-formylindole (1q).2f Next, nucleophilic substitution
of 1q with two molecules of indoles afforded byproduct via
protonation and elimination of one molecule of H2O.22 The
final step of the catalytic cycle is oxidation of Cu(I) to Cu(II),
using O2 as terminal oxidant in presence of H+,23 which might
be the reason why acetic acid elevated reaction yields. Notably,
relatively strong acid such as CF3COOH was not conducive to
methylenation as shown in Table 1 (entries 11–14). We
postulated that this is attributed to the formation of an ion
pair consisting of TMEDA cation and strong acid anion, which
weakens the coordination of TMEDA and the catalyst.
three-component couplings (Table 1). Expectedly, 1q was
1
exactly detected via H NMR in the reaction system (see ESI ).
3
(1)
(2)
With above evidences and reported information in hand,
we proposed a tentative mechanism as shown in Scheme 5.
Initially, TMEDA coordinated with CuCl2 affording Cu(II)–
TMEDA complex A. Iminium ion B is generated in the reaction
system via the general accepted mechanism as follows:18 one-
electron oxidation of nitrogen, deprotonation of C–H adjacent
to a nitrogen atom, and second one-electron oxidation.
Following this, the formation of formaldehyde could be
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9 D. J. Faulkner, Nat. Prod. Rep., 2001, 18, 1–49.
10 (a) F. Andreani, R. Andrisano, C. D. Casa and
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Conclusions
In summary, we have successfully developed a carboxylic acid-
promoted CuCl2/oxygen-mediated method for the synthesis of
methylene-bridged compounds using TMEDA as methylene
source in water. The electronic properties of the N-protecting
groups and substituents impacted the reactivity of the
methylenation. The current protocol showed a broad substrate
scope, not only indoles, but also anilines, pyrroles and 1,3-
dicarbonyls. Notably, two key intermediates of the reaction
were identified and a mechanism was proposed. Moreover,
green solvent might decrease operation cost for large scale
preparation of the regioselective synthesis of methylene-
bridged compounds. Further study on TMEDA reacting with
other nucleophiles is currently underway in our laboratory.
13 (a) Y. Kuninobu, M. Nishi and K. Takai, Chem. Commun.,
2010, 46, 8860–8862; (b) Z. Li and C.-J. Li, J. Am. Chem. Soc.,
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21272114, 90913023), and the National
Natural Science Fund for Creative Research Groups
(21121091).
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