Copper(I) chloride-catalyzed aerobic oxidative arylation of glycine ester and amide derivatives

Article abstract of DOI:10.1002/adsc.201300535

A simple and efficient copper(I) chloridecatalyzed aerobic oxidative coupling of glycine derivatives (glycine esters, glycine amides and short peptides) with indoles has been developed. The reaction is performed in the absence of any other additives under mild conditions and only requires simple copper salts as a catalyst and oxygen as a cooxidant.

Full text of DOI:10.1002/adsc.201300535

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DOI: 10.1002/adsc.201300535
Copper(I) Chloride-Catalyzed Aerobic Oxidative Arylation of
Glycine Ester and Amide Derivatives
Congde Huo,a,* Cheng Wang,a Mingxia Wu,a Xiaodong Jia,a Haisheng Xie,a
and Yong Yuana
a
Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education; College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, Peopleꢀs Republic of China
Fax : (+86)-931-797-1989; e-mail: Huocongde1978@hotmail.com
Received: June 18, 2013; Revised: November 4, 2013; Published online: January 31, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300535.
Abstract: A simple and efficient copper(I) chloride-
catalyzed aerobic oxidative coupling of glycine de-
rivatives (glycine esters, glycine amides and short
peptides) with indoles has been developed. The re-
action is performed in the absence of any other ad-
ditives under mild conditions and only requires
simple copper salts as a catalyst and oxygen as a co-
oxidant.
using a combination of visible-light photoredox and
Lewis acid catalysis.[3b,i]
However, there are deficiencies in both methods.
For the first one, a stoichiometric amount of tert-butyl
hydroperoxide (TBHP) was needed as the terminal
oxidant, which is potentially explosive and rather ex-
pensive.[4] Meanwhile, the substrate scope was limited
to glycine amides.[5] In the second one, their strategy
required very costly and toxic iridium or ruthenium
catalysts and light sources as well as long reaction
times. Very recently, we, for the first time, discovered
that a triarylaminium salt[6] could catalyze the reac-
tion of glycine derivatives with indoles in the absence
of any other additives and only required atmospheric
air as a co-oxidant.[7] However, an unstoppable cas-
Keywords: aerobic conditions; copper; glycine de-
rivatives; indoles; oxidative coupling
2
3
À
Csp Csp bond formation reactions, especially the cade aerobic double oxidative Friedel–Crafts alkyla-
Csp2
(aryl) Csp versions, are of fundamental interest tion reaction occurred and bisindolylmethane (BIM)
3
À
and among the most important processes in organic derivatives were obtained. Therefore, given the eco-
synthesis. In the past few years, oxidative dehydrogen- nomical and environmental factors, the development
ative coupling has gained significant attention because of a greener and more practical method using a low-
this strategy presents the prospect of the concise syn- cost catalyst with molecular oxygen as the terminal
thesis of complex molecules from simple starting ma- oxidant for the coupling of glycine derivatives with
terials, and is atom economical and environmentally electron-rich arenes is still highly desired. We report
benign.[1] Glycine derivatives and indoles are widely herein the first simple and efficient CuCl-catalyzed
existing substructures in natural products and bioac- aerobic oxidative coupling of glycine derivatives
tive compounds.[2] To bring these two skeletons to- under mild conditions. The use of cheap and non-
gether would not only offer significant potential bio- toxic simple copper salts as catalyst and atmospheric
logical applications but would also represent a signifi- air as environmentally benign oxidant with water as
cant contribution to synthetic chemistry. However, as the only waste product makes this reaction particular-
far as we know, until now, there have been only two ly attractive.
successful examples of the direct arylation of glycine
Liꢀs, Reupingꢀs and our previous studies all showed
derivatives.[3] In 2009, Liꢀs group first reported a that copper salts alone exhibited no activity in the re-
Cu-catalyzed coupling of glycine derivatives with in- action of glycine derivatives with indoles.[3,7] But very
ACHTUNGTRENNUNG
doles.[3a] In 2012, Liꢀs group reported a direct a-aryla- interestingly, we occasionally observed that the CuBr-
tion of a-amino carbonyl compounds with indoles catalyzed reaction between glycine ester 1a and
using visible light photoredox catalysis. In the same indole 2a actually occurred in 27% yield after 2 days
year, Ruepingꢀs group also reported a relay catalysis in an open flask under an air atmosphere. Although
protocol for the indolation of glycine derivatives the yield was low and the reaction time was long, this
initial result was quite exciting because the coupling
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Congde Huo et al.
Table 1. Screening of reaction conditions.
reaction of glycine esters with nucleophiles did not
occur using the CuBr/TBHP catalytic system.[3a,5] Also
the use of atmospheric air as oxidant offered a safer
and more practical process. This encouraged us to op-
timize the reaction conditions. Various copper and
iron salts were examined as catalysts for the indola-
tion of 1a. CuCl proved to be the best catalyst. No re-
action was observed in the absence of a copper cata-
lyst. Different solvents were then investigated. The re-
action was highly dependent on the solvent choice.
THF was found to be the most effective solvent. Sur-
prisingly, when commercial THF was switched to very
highly dried THF, the efficiency of the reaction dra-
matically decreased, providing the designed product
only in trace yield. We then discovered the critical
role of water in this oxidative coupling reaction.[8] To
improve the yields, various ratios of water were exam-
ined. The best yield was obtained when the THF/H2O
ratio was 10:1. Since we found that the solvent em-
ployed plays an important role, other copper and iron
salts were rechecked in the optimized mixture of
THF-H2O (10:1) under air (Table 1, entries 18–22).
CuCl was proved to still be the best catalyst.
Under the optimized conditions (Table 1, entry 16),
we probed the scope and generality of both glycine
derivatives and indoles for the CuCl-catalyzed aerobic
a-arylation (Table 2). Initially, different glycine esters
were investigated and the reaction proceeded smooth-
ly to afford the desired products in high yields
(Table 2, 3aa–3ia). The allyl group was tolerated in
this reaction (Table 2, 3ea). The scope of the indole
counterpart in this reaction has also been evaluated.
Indoles with electron-donating groups or electron-
withdrawing groups on C-6, C-5, C-4, C-2, and/or N-
1 all worked well with glycine esters under the pres-
[a]
[b]
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), sol-
vent (1 mL), air (1 atm), room temperature, 6 h.
Yields were determined by NMR spectroscopy.
ent reaction conditions (Table 2, 3ba–3bj). The intro- cates that our protocol not only is atom-efficient and
duction of a halogen atom into this system makes this environmentally benign but also could be convenient-
methodology more useful for further transformations ly scaled up in industry. Further studies on the cou-
(Table 2, 3bc). N-Me and N-Bn protected indoles also pling reactions of glycine derivatives with different
gave the corresponding products in high yields kind of nucleophiles under Cu-catalyzed aerobic con-
(Table 2, 3bg, 3bh). Under similar reaction conditions, ditions are ongoing in this laboratory.
various glycine amides were effective substrates in
Some control experiments were carried out in
this system. The secondary and tertiary amides all re- order to reveal the mechanism of this transformation
acted well (Table 2, 3ja–3ma). An aromatic amide (Scheme 1). Firstly, the reaction of 1a with indole in
also afforded the corresponding product in high yield an argon atmosphere (in the absence of molecular
(Table 2, 3na). To establish the scope of this transfor- oxygen) furnished no product [Eq. (1)], indicating
mation further, short peptides were next investigated. that molecular oxygen is definitely crucial for the re-
Dipeptides were also suitable substrates and afforded action. Secondly, a stoichiometric amount of TEMPO
the corresponding products in high yields (Table 2, was employed in the standard reaction as radical scav-
3oa–3oh). It is worth mentioning that no peptide deg- enger; a significant drop in yield was observed [Eq.
radation has been observed with our protocol and the (2)]. This result suggested that the present reaction
reaction occurred exclusively at the N terminus of the includes a radical process. Thirdly, as expected, the
peptides. To evaluate the practicability of our treatment of ethyl 2-(para-tolylimino)acetate 4 of-
method, the reaction between glycine ester 1a and fered the desired product 3aa under identical reaction
indole has been performed on a 52-mmol scale (> conditions [Eqs. (3) and (4)]. Consequently, based on
10 g) in a single batch. To our delight, no obvious loss experimental observations, a plausible mechanism for
of yield was observed (isolated yield: 75%). This indi- this Cu-catalyzed aerobic transformation is illustrated
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Copper(I) Chloride-Catalyzed Aerobic Oxidative Arylation
Table 2. Scope of the CuCl-catalyzed aerobic oxidative coupling reaction.[b]
[a]
Standard reaction conditions for glycine esters: 1 (1.0 mmol), 2 (1.0 mmol), THF/H2O (10:1, 10 mL), air
(1 atm), room temperature, 4–8 h. Standard reaction conditions for glycine amides: 1 (1.0 mmol), 2
(1.0 mmol), THF/H2O (10:1, 10 mL), O2 (1 atm), room temperature, 8–16 h. Standard reaction conditions
for short peptides: 1 (1.0 mmol), 2 (1.0 mmol), THF/H2O (10:1, 10 mL), O2 (1 atm), 408C, 10–16 h.
Yields of the isolated products.
Reaction on a 52-mmol scale.
[b]
[c]
Scheme 1. Control experiments.
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Congde Huo et al.
Scheme 2. Proposed reaction mechanism.
in Scheme 2. Initially, a copper(II) peroxide radical[9]
generated by a combination of molecular oxygen with
copper(I) might abstract an a hydrogen atom of gly-
cine derivatives 1 to form radical intermediate A sta-
bilized by the push-pull effect. The iminium type in-
termediate B could then be formed through a single-
electron transfer (SET) from A. Subsequently, cou-
pling of B with indoles results in the desired product
3.
In summary, we have demonstrated a simple
copper salt-catalyzed, aerobic oxidative coupling reac-
tion of glycine derivatives with indoles. The use of
cheap and non-toxic simple copper salts as the cata-
lyst and molecular oxygen as the oxidant makes this
transformation sustainable and practical. It is note-
worthy that a broad scope of glycine derivatives such
as esters, amides and short peptides are all suitable in
this transformation. Using free (NH) indoles and
free-(NH) peptides directly would eliminate the pro-
tection-deprotection process.
General Procedure for CuCl-Catalyzed Reaction of
Glycine Amides with Indoles
Glycine amides (1, 1 mmol) and indoles (2, 1 mmol) were
dissolved in THF/H2O (10:1, 10 mL) at ambient tempera-
ture; CuCl (0.05 mmol) was then added in one portion
under stirring. The reactions were performed under an
oxygen atmosphere (oxygen balloon) at room temperature
and were complete within 8–16 hour as monitored by TLC.
Then the reaction mixtures were concentrated on a rotary
evaporator. The resulting residues were purified by column
chromatography to afford the desired compounds.
General Procedure for CuCl-Catalyzed Reaction of
Short Peptides with Indoles
Short peptides (1, 1 mmol) and indoles (2, 1 mmol) were dis-
solved in THF/H2O (10:1, 10 mL) at ambient temperature;
CuCl (0.05 mmol) was then added in one portion under stir-
ring. The reactions were performed under an oxygen atmos-
phere (oxygen balloon) at 408C and were complete within
10–16 hour as monitored by TLC. Then the reaction mix-
tures were concentrated on a rotary evaporator. The result-
ing residues were purified by column chromatography to
afford the desired compounds.
Experimental Section
General Procedure for CuCl-Catalyzed Reaction of
Glycine Esters with Indoles
Acknowledgements
Glycine esters (1, 1 mmol) and indoles (2, 1 mmol) were dis-
solved in THF/H2O (10:1, 10 mL) at ambient temperature;
CuCl (0.05 mmol) was then added in one portion under stir-
ring. The reactions were performed under an air atmosphere
(open flask) at room temperature and were complete within
5–8 hour as monitored by TLC. Then the reaction mixtures
were concentrated on a rotary evaporator. The resulting res-
idues were purified by column chromatography to afford
the desired compounds.
We thank the National Natural Science Foundation of China
(21262029, 21002080) and the Natural Science Foundation of
Gansu Province (1107RJYA026) for financially supporting
this work.
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