Copper(I)-Catalyzed Reductive Cross-Coupling of N-Tosylhydrazones with Amides: A Straightforward Method for the Construction of C(sp3)- N Amide Bonds from Aldehydes

Article abstract of DOI:10.1002/adsc.201500331

A method for the one-pot synthesis of substituted amides from aldehydes and amides is presented. Namely, condensation of aldehydes with N-tosylhydrazide generated the N-tosylhydrazones which were then reductively cross-coupled in situ with primary or secondary amides in the presence of a copper catalyst to afford secondary or tertiary amides, respectively. The reaction proceeded efficiently for a wide range of aldehydes and amides under the optimized conditions, i.e., 10 mol% of tetrakis(acetonitrile)copper(I) tetrafluoroborate [Cu(CH₃CN)₄BF₄], 1 mol% of tetra-n-butylammonium iodide [(n-Bu)₄NI], and sodium hydroxide [NaOH] as base in tetrahydrofuran (THF) at 80 C. As a result, the method provides a straightforward route for the synthesis of substituted amides from readily available aldehydes via a transition metal-catalyzed C(sp³)- N amide bond forming reaction.

Full text of DOI:10.1002/adsc.201500331

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DOI: 10.1002/adsc.201500331
Copper(I)-Catalyzed Reductive Cross-Coupling of N-Tosylhydra-
zones with Amides: A Straightforward Method for the Construc-
3
À
tion of C(sp ) N Amide Bonds from Aldehydes
Peng Xu,a,b Fu-She Han,a,b,* and Yan-Hua Wanga,*
a
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, Peopleꢀs Republic of China
E-mail: yhuawang@dlut.edu.cn
Key Lab of Synthetic Rubber, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin
b
Street, Changchun, Jilin 130022, Peopleꢀs Republic of China
Fax: (+86)-431-8526-2926; phone: (+86)-431-8526-2936; e-mail: fshan@ciac.ac.cn
Received: April 1, 2015; Revised: August 18, 2015; Published online: October 27, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500331.
Abstract: A method for the one-pot synthesis of
substituted amides from aldehydes and amides is
presented. Namely, condensation of aldehydes with
N-tosylhydrazide generated the N-tosylhydrazones
which were then reductively cross-coupled in situ
with primary or secondary amides in the presence
of a copper catalyst to afford secondary or tertiary
amides, respectively. The reaction proceeded effi-
ciently for a wide range of aldehydes and amides
under the optimized conditions, i.e., 10 mol% of
sis of amides from other types of readily available
substrates remains attractive. Moreover, the construc-
3
À
tion of C(sp ) N amide bonds by means of transition
metal-catalyzed cross-coupling has been largely unex-
plored.
Recently, intense interest has been directed to the
transition metal-catalyzed as well as the metal-free
cross-coupling of N-tosylhydrazones.[4] A wide variety
of synthetic methodologies has been developed
[5]
[6]
[7]
[8]
[9]
À
À
À
À
À
through various C C, C O, C N, C P, C S,
and N N
[7d,e]
À
tetrakis(acetonitrile)copper(I)
tetrafluoroborate
bond forming reactions. These results
[Cu(CH3CN)4BF4], 1 mol% of tetra-n-butylammo-
nium iodide [(n-Bu)4NI], and sodium hydroxide
[NaOH] as base in tetrahydrofuran (THF) at 808C.
As a result, the method provides a straightforward
route for the synthesis of substituted amides from
have demonstrated unambiguously the great impor-
tance of aldehydes and ketones in organic synthesis
since N-tosylhydrazones could be readily obtained
through the condensation of aldehydes or ketones
with N-tosylhydrazide.
readily available aldehydes via a transition metal-
catalyzed C(sp ) N amide bond forming reaction.
While remarkable advances have been made, the
cross-coupling of N-tosylhydrazones with weak nucle-
ophiles remains difficult. Typically, the cross-coupling
of N-tosylhydrazones with amine derivatives has been
demonstrated.[7] However, a method for the coupling
with amides has not been reported, although there is
an alternative protocol by means of Co-catalyzed and
Et3SiH/TFA-mediated reductive N-alkylation of
amides with carbonyl compounds.[10] Based on the ob-
3
À
Keywords: aldehydes; amides; copper catalysts;
hydrazones; reductive cross-coupling
Due to the ubiquitous nature of amides, amidation servations in the literature,[5m,7b,c] this presumably re-
represents an important transformation in the area of sults from the electron-deficient nature of amides. For
synthetic organic chemistry.[1] The most commonly instance, conditions that have enabled the effective
used approaches included the condensation of a car- coupling of aliphatic amines were entirely ineffective
boxylic acid with an amine, the substitution of a car- for the relatively less nucleophilic anilines.[7b] Reac-
boxylic acid derivative such as acyl chloride, anhy- tion of the latter substrates required the assistance of
dride, or ester with an amine,[1c] and the Cu- or Pd- BINAP as supporting ligand combined with a harsher
2
catalyzed C(sp ) N cross-coupling of an aryl/alkenyl temperature.[7c]
À
(pseudo)halide with an amide.[2,3] A wide variety of
Despite the appreciable challenges, we were inter-
amides could be reliably prepared by employing these ested in investigating the cross-coupling of N-tosylhy-
methods. Nevertheless, the development of new pro- drazones with amides because this would provide
3
À
tocols which allow for an efficient and flexible synthe- a new pathway for the creation of C(sp ) N amide
Adv. Synth. Catal. 2015, 357, 3441 – 3446
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Peng Xu et al.
Table 1. Evaluation of the reaction conditions.[a]
of phase-transfer catalysts (PTCs) such as crown
ethers and tert-butylammonium salts was examined. It
was found that while most of the additives displayed
a detrimental effect to the reaction (data not shown),
the addition of 20 mol% of (n-Bu)4NI could improve
substantially the yield of 3a to about 70% in combina-
tion with an appropriate copper catalyst (entries 14–
16).
Entry [Cu]
Base
Additive
Yield
[%][b]
Here, to demonstrate the role played by (n-Bu)4NI,
some control experiments were carried out. The reac-
tion did not occur when (n-Bu)4NOH was used in-
stead of NaOH as base (Table 1, entry 17). This obser-
vation indicated that the increased coupling efficiency
of 1a and 2a was not a consequence of (n-Bu)4NOH
base generated in appreciable amounts from (n-
Bu)4NI and NaOH. On the other hand, benzyl iodide
4 which may be generated as an intermediate through
the substitution reaction of diazo ion species A[4b,9c]
with IÀ was not detected under the conditions other-
wise identical to those of entry 14 but just in the ab-
sence of amide 2a (Scheme 1). In addition, the reac-
tion of amide 2a with the freshly prepared benzyl
iodide 4[13] in the presence of NaOH afforded 3a in
lower than 10% yield. The results of these control ex-
periments indicate that (n-Bu)4NI may be acting to
serve as a PTC in the reaction system.
1
2
3
4
5
6
7
8
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
–
–
–
–
–
–
–
–
–
–
–
–
trace
20
21
15
21
Cu(acac)2
CuBr2
CuI
CuOAc
CuBr
14
25
5
Cu(CH3CN)4BF4 Cs2CO3
Cu Cs2CO3
9
Cu(CH3CN)4BF4 NaOAc
Cu(CH3CN)4BF4 K2CO3
Cu(CH3CN)4BF4 K3PO4
Cu(CH3CN)4BF4 NaOH
Cu(CH3CN)4BF4 t-BuOK
Cu(CH3CN)4BF4 NaOH
Cu(acac)2
CuBr2
Cu(CH3CN)4BF4 (n-Bu)4NOH
n.p[c]
n.p[c]
n.p[c]
50
10
11
12
13
14
15
16
17
45
(n-Bu)4NI 70[d]
(n-Bu)4NI 68[d]
(n-Bu)4NI 37[d]
NaOH
NaOH
–
trace
[a]
Reaction conditions (unless otherwise noted): N-tosylhy-
drazone 1a (0.5 mmol), benzamide 2a (0.75 mmol), [Cu]
(10 mol%), base (1.25 mmol), and additive in dioxane
(2.5 mL) at 1008C under an argon atmosphere for 3 h.
Isolated yield based on 1a.
[b]
[c]
[d]
No product was detected.
20 mol% of additive was used.
bonds. In addition, it would also expand greatly the
scope for accessing amides since aldehydes and ke-
tones are abundant chemicals. As a result of our ex-
[11]
À
periences in Cu-catalyzed C N coupling reactions,
Scheme 1. Control experiments.
we set out to study the cross-coupling of N-tosylhy-
drazones and amides by using copper-based catalysts.
The successful demonstration of this transformation
will be presented herein.
Having defined the catalyst, base, and PTC in this
Optimization of the reaction parameters was car- way, we carefully optimized other parameters. Repre-
ried out by employing N-tosylhydrazone 1a and ben- sentative data are shown in Table 2. An evaluation of
zamide 2a as substrates.[12] Some representative data the molar ratio of N-tosylhydrazone 1a to benzamide
are summarized in Table 1. Initial trials showed that 2a, and the loading amount of Cu(CH3CN)4BF4 cata-
the reaction was ineffective under metal-free condi- lyst and NaOH base showed that the yield of 3a could
tions (entry 1). In comparison, the copper-catalyzed be improved to 83% when the molar ratio of 1a:2a
couplings could proceed to deliver the desired prod- was changed from 1:1.5 to 1.5:1 associated with the
uct 3a. However, poor yields were obtained in the presence of 10 mol% copper catalyst and 3.75 equiv.
presence of a range of copper salts having different of base (2.5 equiv. relative to 2a) (entry 1). A brief ex-
redox states [i.e., Cu(0) to Cu(II)] and counter ions amination of the temperature showed that the reac-
(entries 2–8). Screening of bases showed that the tion also proceeded smoothly at 808C (entry 2). Sur-
yields could be improved to moderate by replacing prisingly, only a trace amount of 3a was detected at
Cs2CO3 with a strong base such as NaOH or t-BuOK 708C (entry 3). Such a dramatic effect of temperature
associated with the use of Cu(CH3CN)4BF4 as catalyst has not been noted in previous reports because most
(entries 12 and 13). Next, with the aim of increasing of the reported reactions were performed at above
the solubility of inorganic bases, the effect of a range 1008C. Our control experiments showed that N-tosyl-
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Copper(I)-Catalyzed Reductive Cross-Coupling of N-Tosylhydrazones
Table 2. Screening of the additives.[a]
Entry (n-Bu)4NI
Temp.
[oC]
Solvent Yield
[%][b]
(mol%)
1
2
3
4
5
6
7
8
20
20
20
10
5
1
1
1
1
1
1
1
1
100
80
70
80
80
80
80
80
80
80
80
80
80
dioxane 83
dioxane 89
dioxane trace
dioxane 83
dioxane 80
dioxane 86
DME
THF
83
99
9
MeCN 39
10
11
12
13
PhF
trace
toluene trace
THF
THF
99[c]
96[c,d]
Scheme 2. Proposed mechanism.
[a]
Reaction conditions: benzamide 2a (0.5 mmol), N-tosyl-
hydrazone 1a (0.75 mmol), Cu(CH3CN)4BF4 (10 mol%),
NaOH (1.88 mmol), and (n-Bu)4NI (x mol%) in solvent
(2.5 mL) under an argon atmosphere for 3 h.
To get an in-depth understanding of the reaction
mechanism, we investigated the reaction by using
diazo compound 7[15] instead of 1a as starting materi-
al. Product 3a was obtained in 79% and 72% yields at
808C and 708C, respectively, accompanied by forma-
tion of small amounts of side-product 8 (Figure 1).
Based on these results and the literature concerning
N-tosylhydrazones,[4] we could propose a plausible
mechanism (Scheme 2). The reaction starts with the
thermal decomposition of 1a in the presence of base
to deliver diazo compound 7, which then forms
a Cu(I) carbene 9. Nucleophilic attack of anion 10 to
9 generates the copper species 11. Finally, hydrogen
transfer of 11 produces the coupled product 3a. The
results also revealed that, in the reaction cycle, the
thermal decomposition of N-tosylhydrazone 1a for
the formation of diazo compound 7 requires a higher
[b]
[c]
[d]
Isolated yield based on benzamide 2a.
The reaction was performed via a one-pot operation.
(n-Bu)4Br was used instead of (n-Bu)4NI. DME=1,2-di-
methoxyethane; THF=tetrahydrofuran.
Figure 1. Structures of by-products and intermediates.
hydrazone 1a decomposed rapidly at above 808C to temperature than the generation of the Cu(I) carbene
form the diazo compound 5[14] and sulfone 6[9a] as the since only a trace amount of product was detected at
major by-products (Figure 1). As a comparison, 1a re- 708C with 1a as substrate (Table 2, entry 3). In con-
mained almost intact at 708C. These results, in combi- trast, 72% of 3a could be obtained at the same tem-
nation with the generally proposed mechanism con- perature when diazo 7 was used as reactant.
cerning the cross-coupling of N-tosylhydrazone,[4] sug-
With robust one-pot reaction conditions established
gest that there exists a boundary temperature for the (Table 2, entry 12), we examined the general applica-
generation of the reactive diazo intermediate 7 from bility of the method. First, the scope of a wide variety
N-tosylhydrazone. Finally, an evaluation on the load- of aldehydes was evaluated (Table 3). The mono-sub-
ing amounts of (n-Bu)4NI (entries 4–6) and solvents stituted benzaldehydes and ring-fused aryl aldehydes
(entries 6–11) showed that the reaction proceeded could couple efficiently with benzamide 2a to afford
well even with the presence of 1 mol% of (n-Bu)4NI secondary amides 3 in high yields under the optimized
in ether solvents such as dioxane, DME, and THF conditions (3b–3k). The reaction was less affected by
(entries 6–8). Almost a quantitative yield was ob- the electronic nature and the position of substituents
tained in THF either by a stepwise or one-pot proce- in aldehydes. In addition, a couple of disubstituted
dure (entry 8 vs. 12). To further clarify that (n-Bu)4NI benzaldehydes reacted with 2a to afford the cross-
acts as a PTC under the optimized conditions, we ex- coupled products in moderately high yields (3l and
amined the reaction by replacing (n-Bu)4NI with (n- 3m). It should be mentioned that the relatively mild
Bu)4NBr. An almost identical yield was obtained conditions and fast reactions avoid the possible com-
À
(entry 13). This result together with those in entry 17 petitive cross-couplings of C X (X=Cl and Br, 3d–
of Table 1 and in Scheme 1 clearly confirm that the 3h) bonds with amides.[1a,e,2] Finally, the aliphatic alde-
tert-butylammonium salt plays the role of a PTC.
hydes were less reactive under the standard condi-
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Table 3. Substrate scope by the varying aldehydes.[a,b]
Table 4. Substrate scope by varying the amides.[a,b]
[a]
Reaction conditions (unless otherwise noted): aldehyde
12a (0.75 mmol) and N-tosylhydrazide (0.75 mmol) in
THF (2.5 mL) were stirred at 408C until the completion
of condensation as monitored by TLC. Then benzamide
2
(0.5 mmol), NaOH (1.88 mmol), Cu(CH3CN)4BF4
(10 mol%), and (n-Bu)4NI (1 mol%) were charged. The
mixture was stirred at 808C under an argon atmosphere
for 3 h.
[b]
[c]
Isolated yield based on benzamide 2.
Dioxane was used as solvent.
[a]
Reaction conditions (unless otherwise noted): aldehyde 12
(0.75 mmol) and N-tosylhydrazide (0.75 mmol) in THF
(2.5 mL) were stirred at 408C until the completion of
condensation as monitored by TLC. Then benzamide 2a
(0.5 mmol), NaOH (1.88 mmol), Cu(CH3CN)4BF4
(10 mol%), and (n-Bu)4NI (1 mol%) were charged. The
mixture was stirred at 808C under an argon atmosphere
for 3 h.
combination of several different aldehydes and
amides (Table 5). In general, effective couplings were
observed for an array of combinations to afford the
products in good yields (3aa–3al). Notably, halogen
functional groups such as F, Cl, and Br either in the
aldehyde or in the amide component were tolerated
under the conditions. This provides an opportunity for
flexible modification of the products when a particular
application is considered.
[b]
Isolated yield based on benzamide 2a.
20 mol% of (n-Bu)4NI was used.
[c]
tions. However, satisfactory yields were obtained
when 20 mol% of (n-Bu)4NI was loaded (3n–3p).
In conclusion, we have developed an efficient and
general Cu(I)-catalyzed reductive cross-coupling of
We also evaluated the generality of this methodolo- N-tosylhydrazones with amides. This method has uti-
gy by varying the amide component (Table 4). The re- lized the conveniently available aldehydes as starting
action proceeded well for aryl amides modified by substrates via a one-pot operation, and thereby offer-
weak electron-donating (3q) or by electron-withdraw- ing not only a straightforward but also an alternative
ing groups (3r and 3s). As a comparison, the yield for channel for flexibly accessing substituted amides.
an electron-rich amide was somewhat diminished (3t). More significantly, the method has realized the transi-
3
À
In addition, a secondary amide also reacted unevent- tion metal-catalyzed C(sp ) N amide bond forming
fully to give the coupled product in moderately high reaction. As a result, this method, together with those
2
À
yield (3u). Finally, except for the sterically bulky tert- of transition metal-catalyzed C(sp ) N bond cross-
butyl amide (3z), an array of aliphatic amides was coupling of aryl (pseudo)halides with amides are
also viable substrates, affording the desired products agreeably complementary for the flexible synthesis of
in high yields (3v–3y).
amides with structural diversity.
To expand the utility of this method, the coupling
efficiency was further examined by means of a free
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Copper(I)-Catalyzed Reductive Cross-Coupling of N-Tosylhydrazones
Table 5. Substrate scope by a free combination of various al-
ed 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 pro-
duct 3.
dehydes and amides.[a,b]
Acknowledgements
Financial support from State Key Laboratory of Fine Chemi-
cals (KF 1201) is acknowledged.
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[a]
Reaction conditions (unless otherwise noted): aldehyde 12
(0.75 mmol) and N-tosylhydrazide (0.75 mmol) in THF
(2.5 mL) were stirred at 408C until the completion of
condensation as monitored by TLC. Then benzamide 2
(0.5 mmol), NaOH (1.88 mmol), Cu(CH3CN)4BF4
(10 mol%), and (n-Bu)4NI (1 mol%) were charged. The
mixture was stirred at 808C under an argon atmosphere
for 3 h.
[b]
Isolated yield based on benzamide 2.
Experimental Section
General Procedure for the One-Pot Synthesis of
Amides
A
mixture of aldehyde 8 (0.75 mmol) and TsNHNH2
(0.75 mmol) in THF (2.5 mL) was stirred at 408C until the
condensation had been completed as monitored by TLC.
Then, benzamide
2
(0.5 mmol), NaOH (1.88 mmol),
Cu(CH3CN)4BF4 (10 mol%), and (n-Bu)4NI (1 mol%) were
recharged into the reaction vessel. The resulting mixture
was then stirred vigorously at 808C for 3 h in the sealed
vessel under an argon atmosphere. After the completion of
the reaction as monitored by TLC, the mixture was cooled
to room temperature and diluted with CH2Cl2 (20 mL). The
reaction mixture was washed with water. The organic layer
was dried over anhydrous Na2SO4, filtered, and concentrat-
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Adv. Synth. Catal. 2015, 357, 3441 – 3446
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