Copper-Catalyzed Reductive N-Alkylation of Amides with N-Tosylhydrazones Derived from Ketones

Article abstract of DOI:10.1002/asia.201600733

A CuI-catalyzed reductive coupling of ketone-derived N-tosylhydrazones with amides is presented. Under the optimized conditions, an array of N-tosylhydrazones derived from aryl–alkyl and diaryl ketones could couple effectively with a wide variety of (hete

Full text of DOI:10.1002/asia.201600733

DOI: 10.1002/asia.201600733
Communication
N-Alkylation
Copper-Catalyzed Reductive N-Alkylation of Amides with N-
Tosylhydrazones Derived from Ketones
Peng Xu,[a, b] Fu-Ling Qi,[b] Fu-She Han,*[a, b] and Yan-Hua Wang*[a]
lyzed[9] or by the oxidant-mediated[10] oxidative reactions
Abstract: A CuI-catalyzed reductive coupling of ketone-
derived N-tosylhydrazones with amides is presented.
(Scheme 1a and b). In such transformations, alcohols and alde-
hydes were converted into the acyl moiety of amides. Alterna-
Under the optimized conditions, an array of N-tosylhydra-
tively,
a transition-metal-catalyzed reductive coupling of
zones derived from aryl–alkyl and diaryl ketones could
couple effectively with a wide variety of (hetero)aryl as
well as aliphatic amides to afford the N-alkylated amides
in high yields. The method represents the very few exam-
ples for reliably accessing secondary and tertiary amides
through a reductive N-alkylation protocol.
amides with aldehyde or ketone derivatives with the assistance
of stoichiometric amounts of extraneous reductants has also
been investigated (Scheme 1c).[11] Such reactions afforded the
N-alkylated amides. However, to compare with the extensively
investigated oxidative N-acylation, the reductive N-alkylation
has been far less explored.
Secondary and tertiary amides are ubiquitous motifs in natural
products, synthetic bioactive compounds and materials.[1]
Therefore, the development of conceptually or methodologi-
cally new approaches toward efficient and versatile synthesis
of N-substituted amides has been a focus of contemporary or-
ganic chemistry. Traditional methods have mainly relied on the
condensation of carboxylic acids or their derivatives, such as
acyl chlorides, anhydrides, and esters with amines.[1b] Recent ef-
forts have been largely devoted to a Cu-[2] and Pd-catalyzed[3]
cross-coupling of aryl/alkenyl (pseudo)halides with amides. In
addition, a Pd-catalyzed aminocarbonylation of aryl halides
with a combination of water and isocyanides or nitriles, or
a combination of CO and amines has also been demonstrated
to be an alternative option.[4] Moreover, a report by Zhu[5]
showed that amides could be synthesized efficiently from aryl
diazonium salts and isocyanides under metal-free conditions.
Such advanced methods have enabled the versatile synthesis
of a rich variety of secondary and tertiary amides from aryl and
alkenyl substrates.
Scheme 1. Synthesis of amides from alcohol and aldehyde derivatives by ox-
idative amidation and reductive N-alkylation.
With the recent great advances in N-tosylhydrazone chemis-
try[12] involving a wide array of cross-couplings for CÀC,[13] CÀ
O,[14] CÀS,[15] CÀB,[16] CÀP,[17] CÀN,[18] and NÀN[19] bond-forma-
tions, as well as our constant interests in Cu-catalyzed CÀN
bond-forming reactions,[20] we have previously developed
a Cu-catalyzed reductive coupling of amides with aldehyde-de-
rived N-tosylhydrazones[20d] (Scheme 1d). The method provided
an alternative pathway for the synthesis of N-alkylated amides
and took advantage of carrying out the reaction by a one-pot
process without the need of external reductants.
For an amide synthesis from alkyl substrates, a direct amida-
tion of alcohols or aldehydes with amines has been successful-
ly established either by the Ru-,[6] Rh-,[7] Ag-,[8] and Cu-cata-
[a] P. Xu, Dr. F.-S. Han, Prof. Y.-H. Wang
State Key Laboratory of Fine Chemicals
Dalian University of Technology
Dalian 116024 (China)
Unfortunately, when N-tosylhydrazones derived from ke-
tones were employed to couple with amides, the reaction did
not proceed under the identical conditions for coupling the al-
dehyde-derived N-tosylhydrazones (10 mol% of Cu(CH3CN)4BF4,
1 mol% of nBu4NI, and NaOH base in THF). This presumably re-
sulted from the steric hindrance of ketones as well as the weak
nucleophilic nature of amides as implied by the reported CÀN
bond-forming reactions of N-tosylhydrazones with amines.[18]
E-mail: yhuawang@dlut.edu.cn
[b] P. Xu, Dr. F.-L. Qi, Dr. F.-S. Han
Key Lab of Synthetic Rubber
Changchun Institute of Applied Chemistry
Chinese Academy of Sciences
5625 Renmin Street, Changchun, Jilin, 130022 (China)
E-mail: fshan@ciac.ac.cn
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201600733.
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Thus, we initiated a study aimed at establishing a method for
effectively coupling the ketone-derived N-tosylhydrazones with
amides. The successful results are presented herein.
(entry 1). Other combinations of copper catalysts and bases
were ineffective (data not shown). The yield could be im-
proved to 63% with 15 mol% of CuI loading (entry 3). Howev-
er, further attempts toward improving the yield of 3a by in-
creasing the catalyst loading (entry 4) or varying the reaction
temperature (entries 4–7) proved to be futile even in the pres-
ence of a large excess amount of 2a (2.5 equiv) and a base (ca.
6.25 equiv). The key problems involved in this transformation
are the production of side products 4a and 5a (Figure 1)
formed through the Cu-catalyzed competitive homocoupling[21]
and denitrogenation[15a] of tosylhydrazone 2a, respectively, at
a temperature higher than the boundary temperature for gen-
erating the reactive diazo intermediate 6a (>608C based on
the control experiment in entry 7). We then examined the
effect of a phase-transfer catalyst (PTC) on the transformation,
because it was found to be crucial for a Cu-catalyzed coupling
of aldehyde-derived N-tosylhydrazones with amides.[20d] De-
lightedly, addition of 10 mol% of nBu4NI improved substantial-
ly the reaction efficiency, the yield of 3a could be increased to
77% (entry 8). In addition, both the molar equivalents of 2a
and tBuOLi base could be markedly decreased from 2.5 and
6.25 equiv to 1.5 and 3.0 equiv, respectively. A further optimiza-
tion of PTC loading showed that the use of 25 mol% of nBu4NI
was optimal, affording 3a in 87% yield (entry 11).
Benzamide (1a) and tosylhydrazone 2a were used as the
model substrates to optimize the reaction conditions (Table 1).
Table 1. Optimization of reaction conditions.
Entry
CuI [mol%]
T [8C]
Additive [mol%]
Yield [%][c]
1[a]
5
80
80
80
80
100
70
60
80
80
80
80
80
–
–
–
–
–
–
–
44
56
63
61
60
49
trace
77
80
83
87
89
2[a]
10
15
20
20
20
20
15
15
15
15
15
3[a]
4[a]
5[a]
6[a]
7[a]
8[b]
9[b]
10[b]
11[b]
12[b]
nBu4NI (10)
nBu4NI (15)
nBu4NI (20)
nBu4NI (25)
nBu4NI (50)
[a] Reaction conditions: benzamide 1a (0.4 mmol), N-tosylhydrazone 2a
(1.0 mmol), CuI (x mol%), and tBuOLi (2.5 mmol) in THF (5.0 mL) under
argon atmosphere for 6 h. [b] Reaction conditions: benzamide 1a
(0.4 mmol), N-tosylhydrazone 2a (0.6 mmol), CuI (15 mol%), tBuOLi
(1.2 mmol), and nBu4NI ( mol%) in THF (5.0 mL) at 808C under argon at-
mosphere for 6 h. [c] Isolated yields.
Having established the optimized conditions (Table 1,
entry 11), we examined the general applicability of the
method. Firstly, the reaction of benzamide (1a) and an array of
N-tosylhydrazones were investigated (Table 2). The reaction
Table 2. Substrate scope by varying N-tosylhydrazones.[a]
An extensive screening of various conditions by means of
a free combination of an array of copper catalysts (e.g., Cu
powder, Cu(acac)2, CuBr2, CuOAc, CuBr, Cu(CH3CN)4BF4, and
CuI) and bases (e.g., Na2CO3, K2CO3, K3PO4, NaOH) showed that
the reaction did not proceed or gave only a trace amount of
products. In most cases, 1a remained intact, but 2a was de-
composed to form a mixture of 4a and 5a[21] (Figure 1). Based
Figure 1. Structures of byproducts and a diazo intermediate.
on these observations and the proposed mechanism in our
previous study,[20d] tBuOM (M=Li and K) was employed as base
to screen the catalysts and solvents. We assumed that the use
of such strong and sterically hindered bases would allow for
the amide 1a to generate an amido anion more efficiently,
which could serve as a stronger nucleophilic species than 1a
itself in the reaction system. Thus, after a brief evaluation of
the reaction parameters, we found that CuI and tBuOLi would
be a promising combination. The reaction proceeded to give
product 3a in 44% yield with 5 mol% of CuI in THF at 808C
[a] Unless otherwise noted, the reaction conditions were: benzamide 1a
(0.4 mmol), N-tosylhydrazones (0.6 mmol), CuI (15 mol%), tBuOLi
(1.2 mmol), nBu4NI (25 mol%) in THF (5.0 mL) at 808C under argon atmos-
phere for 6 h; isolated yields. [b] The reaction was carried out at 1008C.
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proceeded well with an array of N-tosylhydrazones prepared
from various alkyl–aryl ketones, such as acetophenone (3a–3 f)
and acetonaphthone derivatives (3g and 3h). Notably, halogen
functionalities in the aryl ring periphery were well tolerated
under the conditions (3d and 3e). In addition, N-tosylhydra-
zones formed from diaryl ketones were also viable substrates,
affording the corresponding products in high yields (3i and
3j). However, the method was incompatible with dialkyl
ketone-derived N-tosylhydrazones (3k and 3l) due to the de-
composition of the corresponding N-tosylhydrazones under
the standard conditions.
3y). However, the reaction of an N-alkyl-modified derivative
was sluggish (3z).
Finally, we further inspected the reaction by varying both
the amide and N-tosylhydrazone partners to showcase the ro-
bustness of the methodology (Table 4). The results showed
that the reaction proceeded uneventfully for various combina-
tions of amides and N-tosylhydrazones to afford the cross-cou-
pled products in high yields.
Table 4. Substrate scope by varying amides and N-tosylhydrazones.[a]
Next, the scope of amides was evaluated. A broad range of
amides 1 reacted smoothly with N-tosylhydrazone 2a. As
shown in Table 3, aryl amides modified by electron-withdraw-
ing (3n and 3o) and -donating (3p) groups were coupled effi-
ciently to afford the N-alkylated products in high yields. Impor-
Table 3. Substrate scope by varying amides.[a]
[a] Unless otherwise noted, the reaction conditions were: Amides
(0.4 mmol), N-tosylhydrazones (0.6 mmol), CuI (15 mol%), tBuOLi
(1.2 mmol), and nBu4NI (25 mol%) in THF (5.0 mL) at 808C under argon
atmosphere for 6 h; isolated yields. [b] The reaction was carried out at
1008C.
[a] Unless otherwise noted, the reaction conditions were: Amides
1 (0.4 mmol), N-tosylhydrazone 2a (0.6 mmol), CuI (15 mol%), tBuOLi
(1.2 mmol), and nBu4NI (25 mol%) in THF (5.0 mL) at 808C under argon
atmosphere for 6 h; isolated yields.
To exemplify the straightforwardness of the methodolgy, we
briefly investigated the feasibility of the reaction through
a one-pot operation (Scheme 2). The reaction proceeded well
without an apparent erosion of the yields as compared to the
stepwise operation.
tantly, halogen substituents remained intact under the reaction
conditions. In addition, high yield was observed for a heteroaryl
amide (3q). Moreover, the method was also exemplified to be
applicable for various aliphatic amides (3r–3w), including
a sterically hindered pivalamide (3v). We also examined the re-
action of secondary amides, the results showed that the N-aryl-
substituted amides could react with N-tosylhydrazone 2a to
afford the desired products in moderate to high yields (3w–
Scheme 2. N-alkylation of benzamide through a one-pot procedure.
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few examples for reductive N-alkylation of amides. As a result,
the method would highly complement with the oxidative ami-
dation for the flexible synthesis of amides with structural diver-
sity.
Experimental Section
General procedure for the coupling of amides with N-tosyl-
hydrazones
To a 25 mL oven-dried Schlenk tube equipped with a magnetic bar
was added amide (0.4 mmol), N-tosylhydrazone (0.6 mmol,
1.5 equiv), CuI (15 mol%), LiOtBu (1.2 mmol, 3.0 equiv), and nBu4NI
(25 mol%). The reaction vessel was evacuated and backfilled with
argon three times. Dried THF (5.0 mL) was then injected using a sy-
ringe. The tube was sealed with a Teflon screwcap, and the result-
ing reaction mixture was stirred vigorously at 808C for 6 h. After
the completion of the reaction as monitored by TLC, the reaction
mixture was cooled to room temperature and diluted with ethyl
acetate (20 mL). The reaction mixture was washed with water for
three times. The organic layer was dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude mix-
ture was purified by flash chromatography on silica gel with
a mixed solvent of ethyl acetate and petroleum ether as eluent to
afford product 3.
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General procedure for the one-pot reaction of amides and
ketones
A mixture of ketones 7 (0.6 mmol) and TsNHNH2 (0.6 mmol) in THF
(5.0 mL) was stirred at 808C until the condensation had completed
as monitored by TLC. Then, benzamide 1a (0.4 mmol), CuI
(15 mol%), LiOtBu (1.2 mmol, 3.0 equiv), and nBu4NI (25 mol%)
were recharged in situ to the reaction vessel. The resulting mixture
was then stirred vigorously at 808C for 6 h in the sealed vessel
under argon atmosphere. After the completion of the reaction as
monitored by TLC, the mixture was cooled to room temperature
and diluted with ethyl acetate (20 mL). The reaction mixture was
washed with water for three times. The organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel by using a mixed solvent of EtOAc and petroleum ether
as eluent to afford product 3.
Acknowledgements
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Financial support from State Key Laboratory of Fine Chemicals
(KF1515) is acknowledged.
Keywords: amides
·
copper catalysts
·
ketones
·
N-
tosylhydrazones · reductive coupling
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Manuscript received: May 25, 2016
Final Article published: && &&, 0000
Chem. Asian J. 2016, 00, 0 – 0
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
N-Alkylation
Peng Xu, Fu-Ling Qi, Fu-She Han,*
Yan-Hua Wang*
&& – &&
A CuI-catalyzed reductive coupling of
ketone-derived N-tosylhydrazones with
amides has been developed (see
riety of (hetero)aryl as well as aliphatic
amides to afford the N-alkylated amides
in high yields. The method represents
the very few examples for reliably ac-
cessing secondary and tertiary amides
through a reductive N-alkylation proto-
col.
Copper-Catalyzed Reductive N-
Alkylation of Amides with N-
Tosylhydrazones Derived from
Ketones
scheme). Under the optimized condi-
tions, an array of N-tosylhydrazones de-
rived from aryl–alkyl and diaryl ketones
could couple effectively with a wide va-
&
&
Chem. Asian J. 2016, 00, 0 – 0
www.chemasianj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!