Copper-catalyzed and iodide-promoted aerobic C-C bond cleavage/C-N bond formation toward the synthesis of amides

Article abstract of DOI:10.1039/c6ra02153k

A copper-catalyzed and iodide-promoted aerobic C-C bond cleavage/C-N bond formation reaction between ketone and simple amine was developed toward the synthesis of amides, which are useful synthetic intermediates in organic synthesis and important skeletons of biologically active molecules. Notably, the reaction conditions are very mild, and preliminary mechanistic investigations indicate that molecular oxygen might be involved in the C-C bond cleavage process.

Full text of DOI:10.1039/c6ra02153k

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Copper Catalyzed and Iodide Promoted Aerobic C-C
Bond Cleavage/C-N Bond Formation toward the
Synthesis of Amides
Cite this: DOI: 10.1039/x0xx00000x
Kun Wu,a Zhiliang Huang,a Yiyang Ma,a and Aiwen Leia,b*
Received 00th January 2014,
Accepted 00th January 2014
DOI: 10.1039/x0xx00000x
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generation of carbon–carbon and carbon–heteratom bonds.4 Of
A copper-catalyzed and iodide promoted aerobic C-C bond
cleavage/C-N bond formation reaction between ketone and
simple amine was developed toward the synthesis of amides,
which were useful synthetic intermediates in organic synthesis
and important skeletons of biologically active molecules. Notably,
the reaction conditions were very mild, and preliminary
mechanistic investigations indicated that molecular oxygen
might be involved in C-C bond cleavage process.
which, the selective oxidative cleavage of C–C single bonds still
remains a great challenge in chemistry and biology.5 In very recent
times, several achievements about the oxidative C(CO)–C(alkyl)
bond cleavage of ketones have been reported.6 With this strategy,
some kinds of amides could be synthesized from ketones and amines
via copper or iodine catalyzed (Scheme 1 (b)).7 However, in these
reactions, ammonia,7a, 7b, 7d azide,7f azoles7c or aminopyridine7e are
usually chosen as reagents, more universal amine rarely has been
reported up to now.8 Herein, we present a copperꢀcatalyzed and
iodide promoted aerobic CꢀC bond cleavage/CꢀN bond formation
reaction between ketone and simple amine toward the synthesis of
amides (Scheme 1 (c)).
Amides are one of the wellꢀknown and important classes of
compounds for life, which exhibit extraordinary properties in the
field of chemistry and biology.1 Especially, in recent years, with the
development of pharmaceutical industry, more and more researchers
project amidation as one of the most preferred reactions that require
universal and sustainable alternatives.2 To date, various amidation
reactions have been intensively investigated (Scheme 1 (a)).3
However, most of these methods involve corrosive reagents, toxic
gas, sensitivity toward moisture and highly harsh conditions.
Practical approaches to realize amidation under simple and mild
conditions are still desirable.
Table 1. Optimization of the reaction conditions.a
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), KI (0.6 mmol), NMP (0.75
mL), H2O (0.05 mL), 40 oC, 24 h, under O2 (1 atm); The yield was determined
b
Scheme 1. The synthesis of amides
by GC analysis, calibrated using biphenyl as the internal standard, the yield in
parenthesis was isolated yield.
During the past years, CꢀC bond activation and functionalization
have emerged as an attractive and powerful strategy for the
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DOI: 10.1039/C6RA02153K
The combination of CuI and KI in NMP and H2O (15:1) at
With the above optimized reaction conditions in hand, we
o
40 C gave the best result for the reaction between 1a and 2a subsequently tested the aerobic amidation of aryl ketones and
under 1 atm O2 (Table 1, entry 1). With these conditions, a 60% 2a, and the results are summarized in Table 2. All substrates
yield of morpholino(phenyl)methanone (3aa) was obtained. proceeded well and afforded corresponding products in
CuI played a critical role in the reaction, since no 3aa was moderate yields. Aryl methyl ketones with electronꢀdonating
formed without CuI. Other cuprous salts, such as CuCl, CuBr group such as methyl, methoxy (Table 2, 3fa
, 3ha) and
were also effective (Table 1, entries 2ꢀ4). As to additives, KI electronꢀwithdrawing group such as trifluoromethyl, cyano
gave the highest yield for this reaction (Table 1, entry 5), (Table 2, 3ba, 3ga) could react with 2a smoothly to afford the
nBu4NI was also effective and afforded 3aa in 55% yield (Table desired products in moderate yields. It is noteworthy that F, Cl,
1, entry 7), but I2 and NIS showed less efficiency in terms of Br and I substituents on the phenyl rings were well tolerated,
chemical yields (Table 1, entries 6 and 8). In addition, H2O was which enabled
beneficial for the reaction, the yield of desired product was functionalization (Table 2, 3ca
a
potential application in further
3da 3ea 3ja 3ka 3la). In
,
,
,
,
,
decreased to 38% without H2O, MeOH and EtOH could also addition, 1ꢀ(naphthalenꢀ2ꢀyl)ethanone was also suitable
promote the reaction (Table 1, entries 9ꢀ11). Notably, this substrate for this transformation (Table 2, 3ia).
reaction did not proceed in the absence of molecular oxygen
(Table 1, entry 12).
Furthermore, we explored the reactions between
acetophenone with other secondary amines. Preliminary results
showed that piperidine 2b and
good substrates, generating the target amides in 50% and 53%
yields, respectively (Table 2, 3ab 3ad). Diꢀnꢀbutylamine 2c
could also obtain desired product smoothly (Table 2, 3ac).
Besides, primary amines such as ꢀbutyl amine and aniline
Nꢀmethyl benzylamine 2d were
Table 2. Copper catalyzed aerobic CꢀC bond cleavage/CꢀN bond formation
reaction from
1 .
with 2 a
,
n
were also tested, but they were not compatible with this
reaction.
Scheme 2. Control Experiments.
To explore the mechanism of this transformation, some
potential intermediates were subjected to the reaction system
(Scheme 2). When benzaldehyde (
employed to react with 2a under the standard conditions, no
3aa was detected, which suggested that and were not the
active intermediates for this reaction (eqn. (1), (2)). In addition,
the reactions of the intermediates and with morpholine (2a
4) and benzoic acid (5) were
4
5
6
8
)
afforded amides in a very low yields (eqn. (3), (5)). These
results indicated that they might not be involved in the
transformation. Furthermore, 2ꢀiodoꢀ1ꢀphenylethanone (
7) was
also investigated and the desired product was afforded in 30%
yield, demonstrating that
(eqn. (4)).
7 might be an alternative intermediate
a 1 (0.5 mmol),
2 (1.0 mmol), KI (0.6 mmol), NMP (0.75 mL), H2O (0.05 mL), 40
b
oC, 24 h, under O2 (1 atm); Yields shown are of isolated products. GC yields,
To further elucidate the mechanism, 18O isotope labeling
experiments were performed. As shown in Scheme 3, only 1%
of 18Oꢀlabeled 3aa was obtained when the reaction was
calibrated using biphenyl as the internal standard.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA02153K
performed under 1 atm 18O2 (eqn. (6)). 9% of 18Oꢀlabeled 3aa
In conclusion, we have demonstrated a novel copperꢀ
was observed when H218O instead of H2O was employed for the catalyzed and iodide promoted aerobic CꢀC bond cleavage/CꢀN
transformation (eqn. (7)). In addition, when the reaction was bond formation reaction between ketone and amine under
performed under both 18O2 and H218O, also only 7% of 18Oꢀ simple and mild conditions. Preliminary mechanistic
labeled 3aa was detected (eqn (8)). These results indicated that investigations indicated that molecular oxygen might be
the carbonyl oxygen atom of products should be from the involved in CꢀC bond cleavage process, but not be a part of the
ketones, rather than O2 or H2O.
desired amides. Detailed mechanism research and the synthetic
applications of this methodology are currently ongoing in our
laboratory.
Scheme 4. Proposed mechanism.
Scheme 3. Isotope labeled control experiments.
Acknowledgement
Besides, when amine 2d was subjected to the standard
conditions under 1 atm 18O2 in the absence of H2O, some
interesting results were observed (eqn. (9)). Firstly, except for
This work was supported by the 973 Program
(2012CB725302), the National Natural Science Foundation of
China (21390400, 21520102003, 21272180, 21302148), the
Hubei Province Natural Science Foundation of China
(2013CFA081), the Research Fund for the Doctoral Program of
Higher Education of China (20120141130002), and the
the desired product 3ad, compound
9 was also detected by GCꢀ
MS, which was believed to be a cleavage byproduct in this
transformation. Then, 2% of 18Oꢀlabeled 3ad and 84% of 18Oꢀ
labeled
might be involved in CꢀC bond cleavage process, but not be a
part of the desired amides 3ad
9 were detected, indicating that molecular oxygen
Ministry
of
Science and
Technology
of
China
.
(2012YQ120060). The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also
appreciated.
Notes and references
a
College of Chemistry and Molecular Sciences, the Institute for
Advanced Studies (IAS), Wuhan University, Wuhan, Hubei 430072, P. R.
China. Fax: (+86)-27-68754067; Tel: (+86)-27-68754672; E-mail:
aiwenlei@whu.edu.cn;
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, 730000, P. R. China;
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/c000000x
Based on the results of mechanistic investigations and
literature reports,9 two possible pathways were proposed in
Scheme 4. In the Path A, initially, three sequential αꢀ
halogenations took place to afford the triiodoacetophenone
the presence of Cu/O2/KI. Then the compound was attacked
by the amines to form the intermediate II. Finally, the product
was obtained via the CꢀC bond cleavage and electron transfer of
intermediate II. Alternatively, in Path B, the intermediate III
was formed by the nucleophilic addition of ketone with amine,
which could further transform into the radical intermediate IV
in the presence of Cu(II) and O2 via a single electron transfer
(SET) process. Subsequently, the SET reduction and
protonation of intermediate IV by Cu(I) and base(H+) generated
I in
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DOI: 10.1039/C6RA02153K
A copper-catalyzed and iodide promoted aerobic C-C bond cleavage/C-N bond formation reaction between
ketone and simple amine was developed toward the synthesis of amides.