Copper-catalyzed aerobic oxidative transformation of ketone- Derived N-tosyl hydrazones: An entry to alkynes

Article abstract of DOI:10.1002/anie.201405058

A novel strategy involving Cu-catalyzed oxidative transformation of ketone-derived hydrazone moiety to various synthetic valuable internal alkynes and diynes has been developed. This method features inexpensive metal catalyst, green oxidant, good functional group tolerance, high regioselectivity and readily available starting materials. Oxidative deprotonation reactions were carried out to form internal alkynes and symmetrical diynes. Cross-coupling reactions of hydrazones with halides and terminal alkynes were performed to afford functionalized alkynes and unsymmetrical conjugated diynes. A mechanism proceeding through a Cu-carbene intermediate is proposed for the CC triple bond formation.

Full text of DOI:10.1002/anie.201405058

Angewandte
Chemie
DOI: 10.1002/anie.201405058
Synthetic Methods
Copper-Catalyzed Aerobic Oxidative Transformation of Ketone-
Derived N-Tosyl Hydrazones: An Entry to Alkynes**
Xianwei Li, Xiaohang Liu, Huoji Chen, Wanqing Wu, Chaorong Qi, and Huanfeng Jiang*
Abstract: A novel strategy involving Cu-catalyzed oxidative
transformation of ketone-derived hydrazone moiety to various
synthetic valuable internal alkynes and diynes has been
developed. This method features inexpensive metal catalyst,
green oxidant, good functional group tolerance, high regio-
selectivity and readily available starting materials. Oxidative
deprotonation reactions were carried out to form internal
alkynes and symmetrical diynes. Cross-coupling reactions of
hydrazones with halides and terminal alkynes were performed
to afford functionalized alkynes and unsymmetrical conju-
gated diynes. A mechanism proceeding through a Cu-carbene
applicability in synthetic chemistry. Another challenge faced
in ketone-to-alkyne transformations includes the selective
deprotonation of proximal hydrogen atoms.
In contrast, N-tosylhydrazones derived from simple
ketones, which were utilized as the precursors of diazo
compounds, have been widely exploited in modern synthetic
chemistry, especially in transition-metal-catalyzed reactions.[2]
Barluenga, Wang and others have demonstrated the synthetic
utility of metal/carbene species (derived from N-tosylhydra-
zones) in cross-coupling reactions. Such a methodology has
emerged as a powerful strategy for the construction of
structurally diverse molecules which might be difficult to
access by other cross-couplings.[3]
ꢀ
intermediate is proposed for the C C triple bond formation.
T
he hydration reaction of alkynes is a well-studied subject in
organic chemistry. However, the retrohydration reaction,
namely the conversion of ketones into alkynes, still remains
underdeveloped (Scheme 1). Previous synthetic protocols[1]
typically involved the enolization of the carbonyl group and
subsequent induced enol elimination induced by a sterically
ꢁ
hindered base to give the C C bond. These known methods
have drawbacks, such as low efficiency, requiring stepwise
a procedure, and harsh reaction conditions, which limit their
Scheme 2. Catalytic transformations of N-tosylhydrazones.
Despite these excellent developments, the cross-coupling
reactions involving N-tosylhydrazones as coupling partners
are still limited. Thus, developing new strategies combining
the chemistry of N-tosylhydrazones with other concepts, such
as aerobic oxidative transformations, might be one exciting
and desirable direction. However, the troublesome compat-
ibility of the stoichiometric amount of oxidant and harsh
reaction conditions in these processes might be the major
challenges.[4] During our search for more selective aerobic
oxidative transformations,[5] we reasoned that a copper/car-
bene species could be a versatile precursor in such conver-
sions. Herein, we would like to present an example of ketone-
to-alkyne (via hydrazones) transformation by selective depro-
tonation in the presence of O2.[3,6]
This copper-catalyzed selective oxidation of N-tosyl-
hydrazones occurs under an atmosphere of oxygen, thus
generating the corresponding internal alkynes or copper
acetylide intermediates in situ (Scheme 2), which could
subsequently participate in oxidative homocouplings, cross-
couplings with halides, and oxidative cross-couplings with
terminal alkynes to afford various symmetrical diynes,
internal alkynes, and unsymmetrical diynes. We speculate
Scheme 1. Retro alkyne hydration strategy: from ketones to alkynes.
[*] X. Li, X. Liu, H. Chen, Dr. W. Wu, Dr. C. Qi, Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering, South China
University of Technology
Guangzhou 510640 (P.R. China)
E-mail: jianghf@scut.edu.cn
[**] We are grateful to Dr. Liangbin Huang for helpful suggestions and
comments on this manuscript. This work was supported by the
National Basic Research Program of China (973 Program)
(2011CB808600), the National Natural Science Foundation of China
(21172076), the Guangdong Natural Science Foundation
(10351064101000000), and the Fundamental Research Funds for
the Central Universities (2014ZP0004).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405058.
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that the key to the success of this transformation might be the
judicious choice of the base and oxidant molecular oxygen.
Based on the retro alkyne hydration strategy, the N-
tosylhydrazone of acetophenone 1a, a copper carbene
precursor[3] was employed to test ketone-to-alkyne trans-
formation. When Cu(OAc)2 was used as the catalyst, we
found the additives were quite important (Table 1, entries 1–
After optimal reaction conditions were established
(Table 1, entry 6), we investigated the scope of this oxidative
ꢁ
C C bond formation. As depicted in Table 2, substrates with
Table 2: Substrate scope of copper-catalyzed aerobic oxidation for diyne
formation.[a]
Table 1: Optimization of the reaction conditions.[a]
Entry
[Cu]
Additive
Oxidant
Yield [%][b]
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
–
–
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
BQ
DDQ
PIDA
N2
–
–
–
K2CO3
LiOtBu
DABCO
DABCO
DABCO
NEt3
78
83
98 (96)
<10
<10
12
81
10
–
–
–
–
–
Pyridine
DBU
9
10c
11d
12
13
14
15
16
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
O2
[a] Reaction conditions: hydrazone (1; 0.25 mmol), CuCl (10 mol%),
DABCO (0.25 mmol) in DMSO (2 mL), 1008C, O2 (1 atm), 12 h.
[b] Number within the parentheses is the yield of the isolated product on
a 1 mmol scale.
[a] Reaction conditions: 1a (0.25 mmol), [Cu] (0.025 mmol), additive
(0.25 mmol) in solvent (2 mL), 1008C, 12 h. [b] Yield was determined by
GC analysis. Number in parentheses is isolated yield. [c] DMF as the
solvent. [d] Toluene as the solvent.
electron-donating substituents on the phenyl ring showed
higher reactivity than those with electron-withdrawing ones.
Functional groups such as ethers (OMe, OCF3), halogens (F,
Cl, Br), nitriles, arenes, and CF3 on the benzene ring could be
compatible with this transformation. Sterically demanding
substituents (2o, 2p) were also tolerated. Notably, thienyl
(2n) and 1- and 2-naphthyl (2q, 2r) substituted 1,3-diynes,
which are potential monomers in luminescent materials, could
also be obtained in good yields.
4). The base additives such as K2CO3 and LiOtBu, which are
widely used in metal-mediated carbene transformations,
afforded (E)-but-2-ene-2,3-diyldibenzene, the major byprod-
uct derived from dimerization of the corresponding carbene
cuperate. It is delightful that the desired diyne product 2a was
obtained when DABCO was added to the reaction mixture.
Compared with other organic bases, DABCO displayed the
best efficiency (entry 6 versus entries 7–9). We suspected that
DABCO in our catalytic reaction system served both as base
and ligand to facilitate this reaction (see the Supporting
Information for more experimental recognition). Catalyst
investigation demonstrated that CuCl was the most efficient
(entries 4–6). Polar solvents were found to be critical for the
product formation (entries 10 and 11). Interestingly, other
oxidants such as BQ, DDQ, and PhI(OAc)2 could not afford
the desired 1,3-diynes, while molecular oxygen (1 atm) gave
the best result. Neither the diyne product nor phenylacetylene
(the monomer) could be obtained when the reaction was
performed under an N2 atmosphere (entry 15). The copper
catalyst was found to be essential for this transformation, with
(E)-but-2-ene-2,3-diyldibenzene detected as the side product,
which indicated that N-tosylhydrazones (1) could act as the
carbene precursors in this oxidative transformation
(entry 16).
N-Tosylhydrazones of ketones bearing two kinds of
ꢁ
hydrogen atoms available for deprotonation for C C bond
formation were also compatible with these reaction condi-
tions, thus affording the corresponding internal alkynes[7]
instead of diynes (Table 3). The formation of the desired
products was observed with great regioselectivty in moderate
to good yields using N-tosyl hydrazones of 1-aryl- or 1-alkyl-
substituted acetones (1). The exclusive formation of internal
alkyne products (3a–h) may be attributed to the lower bond-
ꢀ
dissociation energy of secondary C H groups than its primary
counterpart. And the transformation was prone to giving the
conjugated products (3i–k) because of their stability when the
ꢀ
substrates have only secondary C H.
Interestingly, N-tosylhydrazones of 1-phenyl-1-ones 1’
could be also converted into 3, albeit with lower efficiency
(3a, 3b) [Eq. (1)]. Moreover, when N-tosylhydrazone of 1,2-
diphenylethanone 1’’ was used as the substrate, the trans-
2
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Table 3: Copper-catalyzed aerobic oxidation for the internal alkyne
Table 4: Oxidative cross-couplings of 1 with RX to afford alkyne
formation.[a]
derivatives.[a]
[a] Reaction conditions: hydrazone (1; 0.25 mmol), CuCl (10 mol%),
DABCO (0.25 mmol) in DMSO (2 mL), 1008C, O2 (1 atm), 12 h.
formation afforded 1,2-diphenylethyne (4a) in moderate
yield [Eq. (2)].
The results above are reminiscent of Glaser–Hay coupling
reactions.[8] To investigate whether acetylene cuprates were
[a] Reaction conditions: 1 (0.25 mmol), RX (0.25 mmol), CuCl
(10 mol%), DABCO (0.25 mmol), DMSO (2 mL) at 1008C under O2
(1 atm), 12 h.
summarized in Table 5, both aromatic and aliphatic terminal
ꢀ
alkynes could serve as the proper C H nucleophile to
undergo aerobic oxidative cross-coupling reactions. In gen-
eral, this method provides an alternative to the Cadiot–
Table 5: Copper-catalyzed oxidative cross-coupling of 1 with terminal
generated in situ during this transformation, we performed
a Castro–Stephens coupling reaction[9] by adding another
equivalent of R2I into the standard reaction system. To our
delight, disubstituted acetylenes were obtained with excellent
efficiency. The scope of oxidative cross-coupling of the
hydrazones 1 with RX affording various functionalized
acetylenes, enynes, and ynones is depicted in Table 4. Notably,
when using 2-iodoaniline as the coupling partner, a cascade
reaction involving cross-coupling and cyclization took place
under the optimal reaction conditions to afford the corre-
sponding indole product 4h.[10] These observations indicated
that cuprous acetylides species might be generated in situ
during the process, and more importantly, cross-coupling of
cuprous acetylides with RX proceeded much faster than
oxidative dimerization of acetylene cuprates under these
reaction conditions.
alkynes.[a]
[a] Reaction conditions: 1 (0.25 mmol), terminal alkynes (0.375 mmol),
CuCl (10 mol%), DABCO (0.25 mmol), DMSO (2 mL) at 1008C under
O2 (1 atm), 12 h.
Our next target is to provide a complementary protocol
for the synthesis of unsymmetrical conjugated diynes by
introducing another terminal alkyne using the oxidative cross-
coupling strategy.[11] It should be noted that significant
challenges are still present in the cross-coupling reactions
employing terminal alkynes as the coupling partners.[12]
Indeed, the unsymmetrical alkynes 7 were formed in moder-
ate yields by introducing another terminal alkyne (1.5 equiv)
as the nucleophile into the optimal reaction system. As
Chodkiewicz coupling.[13] Intriguingly, a related copper(I)-
catalyzed cross coupling between 1 and terminal alkynes
afforded internal alkynes (versus the diyne species in current
system),[14] thus highlighting the critical role of molecular
oxygen in our reaction system.[15]
We then applied the present protocol to the functional-
ization of cholesteryl derivatives.[7f,16] The steroid 8, which was
derived from biologically active cholesteryl bromide (see the
Supporting Information), could undergo further modification
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ꢁ
smoothly and the C C-containing alkylated cholesteryl 9 was
successfully constructed (Scheme 3).
To gain more insight to this transformation, we conducted
radical capture reactions by adding a radical inhibitor (BHT)
Scheme 3. Further modification on drug derivatives. Reaction condi-
tions: 1) NH2NHTs (1 equiv), MeOH, 608C, 2 h. (ii) CuCl (10 mol%),
DABCO (1 equiv) in DMSO (2 mL), 1008C under O2 (1 atm), 12 h.
ꢁ
Scheme 4. A tentative pathway to rationalize the oxidative C C bond
formation.
or a radical-trapping reagent (TEMPO) to the reaction
system, and the formation of the product 2a was completely
inhibited. When diallyl ether was subjected to the standard
reaction conditions, the corresponding cyclization product
was detected (see the Supporting Information). These obser-
vations supported a radical pathway in this reaction.
Meanwhile, styrene could not afford 2a under the
standard reaction conditions, and means that Shapiro reac-
tion[17] might not be involved in this process. Thus, these
results were in accordance with the formation of a carbene
cuprate. Furthermore, as mentioned above (Table 1,
entry 15), molecular oxygen might not only contribute to
the homocoupling of in situ generated phenylacetyenes to the
corresponding diynes, but also play a vital role in the aerobic
oxidation of copper carbene into acetylene cuprate.
partners. Comparative experiments using phenylacetylene as
the substrate to perform the cross-coupling reactions in
Table 4 (see the Supporting Information for details) led to
lower reactivity and selectivity, which highlighted the poten-
tial synthetic utility of the in situ generated copper acetylide
derived from N-tosylhydrazones under this Cu/O2 catalytic
system.
In summary, copper-catalyzed selectively oxidative trans-
formation of ketone-derived N-tosyl hydrazones to alkynes
and diynes was developed. The significant features of this
chemistry are as follows: 1) inexpensive metal catalyst, green
oxidant, readily available starting materials and good func-
3
ꢀ
tional group tolerance; 2) good reactivity towards C(sp ) H
bond of N-tosylhydrazones of ketones under this Cu/O2
catalytic system, and great regioselectivity towards the
ꢀ
Taking into account the experimental results, we propose
substrates bearing more than one available C H bond for
the following rationale for the mechanism of this copper(I)-
aerobic oxidation; 3) a variety of alkynes and diynes obtained
conveniently by selective oxidative deprotonations as well as
cross-coupling reactions of in situ generated copper acetylides
with halides or terminal alkynes. We anticipate this work
could provide some synthetic applications and insight to
copper and alkyne chemistry, specifically, in selective aerobic
oxidations. Further studies to expand the synthetic scope of
this reaction and address further mechanistic details will be
reported in due course.
[18]
ꢁ
catalyzed aerobic oxidative C C formation in Scheme 4.
Initially, the diazo substrate A is generated in situ from the N-
tosylhydrazone in the presence of DABCO, which reacted
with CuI to give the copper carbene species B. Subsequent
oxidation and dehydrogenation of B with the assistance of O2
and base[19] to generate the internal alkynes 3 (when R2 ¼ H)
or the terminal alkynes in situ (R2 = H), together with the
release of HX, H2O, or [CuII-OH].[19] We suspect that the
in situ formed terminal alkyne can be readily deprotonated by
the coordinating copper (an alkyne-coordinated copper
species was proposed as an intermediate in the Glaser
reaction),[6d,20] thus promoting the selectivity for cross-cou-
pling in the reactions, such as the heteroselective cross-
couplings with terminal alkynes to deliver the unsymmetrical
diynes 7. In contrast, internal alkynes can be released upon
the formation of the copper-coordinated alkyne. Upon the
in situ formation of terminal alkynes, Glaser coupling pro-
ceeds to give the corresponding conjugated diynes 2 with the
assistance of DABCO as the base and/or ligand.[21] Further-
more, a Castro–Stephens-type coupling product internal
alkynes 4, 5 and 6 were obtained using R’I as the coupling
Received: May 7, 2014
Published online: && &&, &&&&
Keywords: aerobic oxidation · alkynes · copper-catalyzed ·
.
cross-coupling · ketones
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Communications
Synthetic Methods
X. Li, X. Liu, H. Chen, W. Wu, C. Qi,
H. Jiang*
&&&& — &&&&
Copper-Catalyzed Aerobic Oxidative
Transformation of Ketone-Derived N-
Tosyl Hydrazones: An Entry to Alkynes
The ynes: The title reaction leads to
synthetically valuable internal alkynes and
diynes. This method features an
inexpensive catalyst, O2 as the oxidant,
good functional-group tolerance, high
regioselectivity, and readily available
starting materials. DABCO=1,4-
diazabicyclo[2.2.2]octane, Ts=4-toluene-
sulfonyl.
6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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