Copper(II)-catalyzed reactions of dimethylformamide with phenylacetonitrile and sulfur to form N,N-dimethylthioamides

Article abstract of DOI:10.1002/adsc.201300321

Novel copper-catalyzed three-component reactions of phenylacetonitrile, sulfur and DMF (dimethyformamide) for the selective preparation of N,N-dimethylthiobenzamide and N,N-dimethyl-2-phenylethanethioamides in yields of up to 96% are described. Copyright

Full text of DOI:10.1002/adsc.201300321

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DOI: 10.1002/adsc.201300321
Copper(II)-Catalyzed Reactions of Dimethylformamide with
Phenylacetonitrile and Sulfur to Form N,N-Dimethylthioamides
Yanyang Qu,a Zhengkai Li,a,* Haifeng Xiang,a and Xiangge Zhoua,b,*
a
Institute of Homogeneous Catalysis, College of Chemistry, Sichuan University, Chengdu 610064, Peopleꢀs Republic of
China
Fax : (+86)-28-8541-2904; e-mail: zhengkaili@scu.edu.cn or zhouxiangge@scu.edu.cn
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
b
Science, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
Received: April 17, 2013; Revised: September 2, 2013; Published online: November 4, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300321.
Abstract: Novel copper-catalyzed three-component
reactions of phenylacetonitrile, sulfur and DMF (di-
methyformamide) for the selective preparation of
N,N-dimethylthiobenzamide and N,N-dimethyl-2-
phenylethanethioamides in yields of up to 96% are
described.
applications. Moreover, the traditional syntheses of
N,N-disubstituted thioamides are rarely reported.[7]
In continuation of our studies on copper-catalyzed
coupling reactions, we recently described Cu-cata-
lyzed reactions involving nitriles or elemental sulfur.[8]
Following these works and based on literature re-
ports,[9] we envisioned that 3-phenylthiophene deriva-
tives might be obtained from the reaction between
phenylacetonitrile, elemental sulfur and an aldehyde
such as n-valeraldehyde as shown in Path A of
Scheme 1. However, after several trials, the desired
product was not found. On the contrary, N,N-dimeth-
yl-2-phenylethanethioamide was obtained as the main
Keywords: catalysis; copper; multi-component reac-
tions; sulfur; thioamides
Thioamides are a class of useful intermediates[1] in or- product when DMF was used as the solvent (Path B
ganic synthesis, and can be applied in the preparation in Scheme 1). Meanwhile, another interesting obser-
of a number of biologically relevant heterocyclic scaf- vation was that N,N-dimethylthiobenzamide was
folds as well as polypeptides in protein chemistry.[2] formed instead of the former product in the absence
Several protocols have been reported to obtain this of n-valeraldehyde under the same reaction condi-
kind of compound, including the reaction between an tions (Path C in Scheme 1). These observations inter-
amide and phosphorus pentasulfide[3] or Lawessonꢀs ested us as new methods to obtain N,N-disubstituted
reagent,[4] the Willgerodt–Kindler reaction,[5] the reac- thiobenzamides and derivatives.[7]
tion of hydrogen sulfide with nitrile or cyanogen or
At first, phenylacetonitrile, sulfur and DMF were
acryl chloride.[6] Meanwhile, some drawbacks such as selected as model substrates to optimize the reaction
difficulties in separation, high reaction temperatures, conditions based on Path C in Scheme 1 by using CuI
long reaction times and low yields have limited their as catalyst. As shown in Table 1, control experiments
Scheme 1. A new protocol for generating N,N-dimethylthiobenzamide and N,N-dimethylethanethioamides.
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Table 1. Selected results from an optimization of the reac-
Table 2. Copper-catalyzed synthesis of N,N-dimethylthiobenz-
tion conditions.[a]
amide derivatives.[a]
Entry Arylacetonitrile
1
Product
Yield [%][b]
89
Entry M (10%)
Solvent
Base
Yield [%][b]
1
–
DMF
DMF
H2O
K2CO3
–
K2CO3
8
5
–
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
3[c]
4[d]
5[e]
6[f]
7[g]
8
H2O:DMF K2CO3
55
68
63
56
73
38
54
62
32
89
16
75
35
24
2
3
4
91
92
81
toluene
dioxane
DMSO
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
Na2CO3
KOH
9
CuACHTUNGTRENNUNG(OAc)2 DMF
10
11
12
13
14
15
16
17
18
CuSO4
CuCl2
CuCl
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Cu
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
5
6
70
67
NaHCO3 21
[a]
Reaction conditions: phenylacetonitrile: 1.0 mmol, S8:
3.0 mmol, base: 3.0 mmol, copper source (10 mol%),
DMF: 2 mL at 1108C for 24 h.
Yield of isolated product.
DMF 1.5 mmol, Et4NI: 1.0 mmol.
[b]
[c]
[d]
[e]
[f]
7
8
65
94
H2O:DMF=1 mL:1 mL as solvent.
Toluene:DMF=1 mL:1 mL as solvent.
Dioxane:DMF=1 mL:1 mL as solvent.
DMSO:DMF=1 mL:1 mL as solvent.
[g]
revealed that a metal catalyst and a base were essen-
tial to the catalysis, and only an 8% or 5% yield was
obtained in the absence either of them (Table 1, en-
tries 1 and 2). A series of different solvents including
water, toluene, dimethyl sulfoxide (DMSO) and 1,4-
dioxane was tested, and DMF itself was found to be
more suitable for the reaction than others giving yield
of 73%, while almost no conversion was found in the
case of water (Table 1, entries 3–8). Subsequent stud-
9
96
68
42
10
11
ies revealed that Cu
source to give an 89% yield of the product (Table 1,
entry 13). Other copper salts, such as CuI, Cu(OAc)2,
CuSO4, CuCl2 and CuCl resulted in lower yields rang-
ing from 32% to 73% (Table 1, entries 9–12). The test
of different bases indicated K2CO3 to be a good
choice (Table 1, entries 13–18). Thus, the optimized
reaction conditions consist of phenylacetonitrile
ACHTUNGTNER(NNUG acac)2 was the best copper
AHCTUNGTRENNUNG
12
trace
[a]
Reaction conditions: aryl acetonitrile 1.0 mmol, S8
3.0 mmol, K2CO3 3.0 mmol, DMF 2 mL, at 1108C for
24 h.
[b] Yield of isolated product.
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Copper(II)-Catalyzed Reactions of Dimethylformamide with Phenylacetonitrile and Sulfur
Scheme 2. Exploring the mechanism of formation of N,N-dimethylthiobenzamide.
(1.0 mmol), S8 (3.0 mmol), K2CO3 (3.0 mmol), and (Scheme 2B), which indicated that the desired prod-
CuACHTUNGTRENNUNG(acac)2 (10 mol%) in 2 mL DMF at 1108C for uct might be generated from the reaction between 2
À
a time period of 24 h.
and phenylacetonitrile involving a C C bond cleav-
To extend the substrate scope, different phenylace- age. Thus, 2,2,6,6-tetramethylpiperidine 1-oxyl
tonitriles were investigated. As shown in Table 2, (TEMPO) was added to trap the possible free radical
functional groups including methoxy, trifluoromethyl, intermediate. As shown in Scheme 2C, the corre-
trifluoromethoxy, amino, chloro etc. were all well tol- sponding product 4 was successfully obtained in
erated during reaction to give the corresponding a high yield of 87%.
products in moderate to excellent results ranging
According to the above observations, a tentative
from 42% to 96%. Meanwhile, ortho substituents fur- mechanism was proposed as shown in Scheme 3. First-
À
nished lower yields compared with para or meta ones, ly, copper-catalyzed C C bond cleavage of phenylace-
which might be caused by steric hindrance. For exam- tonitrile forms a benzene radical intermediate I,
ple, 4- or 3-methylphenylacetonitrile gave the corre- which then reacts with the N,N-dimethyl sulfide
sponding products in 91% or 92% yields respectively, amide 2 generated from the reaction of elemental
while 2-methylphenylacetonitrile resulted in only sulfur and DMF to give the final target product thio-
81% yield (Table 2, entries 2–4). Furthermore, elec-
tron-donating groups seemed to be more beneficial to
ACHTUNGTRENNUNG
the catalysis than electron-withdrawing groups. For phenylethanethioamides by using n-valeraldehyde as
example, p-methylphenylacetonitrile gave 91% yield, additive according to the path B in Scheme 1. Further
while the trifluoromethyl counterpart resulted in only studies indicated that 1.0 equiv. of n-valeraldehyde
70% yield (Table 2, entries 2 and 5). And the highest was satisfactory for the reaction and the product
yield was obtained in the case of 1,2- could be obtained in 82% yield.[11]
dimethoxyphenyl
acetonitrile, namely 96% (Table 2,
Then, different phenylacetonitriles were also
screened for this reaction. As illustrated in Table 3,
entry 9).[10]
In order to explore the catalytic mechanism, some
control experiments were then performed as shown in
Scheme 2. When phenylacetonitrile was reacted with
DMF in the absence of sulfur, only a small amount
of N,N-dimethylbenzamide (1) was generated
(Scheme 2A). Meanwhile, isolated 1 could not afford
the desired product 3 when reacted with sulfur under
the same conditions. On the contrary, N,N-dime-
thylthioamide 2 was obtained as the main product
Scheme 3. Possible mechanism for the Cu-catalyzed three-
from the reaction between DMF and sulfur component synthesis of N,N-dimethylthiobenzamide.
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Yanyang Qu et al.
Table 3. Copper-catalyzed synthesis of N, N’-dimethyl-2-phenylethanethioamides derivatives.[a]
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[a]
Reaction conditions: aryl acetonitrile 1.0 mmol, S8 3.0 mmol, K2CO3 3.0 mmol, DMF 2 mL,
at 1108C for 24 h. Yield of isolated product.
the reaction proceeded smoothly to afford N,N-di- benzene radicals according to the literature[12] and our
methyl-2-phenylethanethioamides in moderate to experiments. As shown in Scheme 4, when benzoni-
good yields from 40% to 89%. Again, electron-with- trile or phenylpropionitrile was used as substrate in-
drawing substituents and steric hindince were not stead of phenylacetonitrile, N,N-dimethylthiobenz-
beneficial to the catalysis, and low yields of 40% and
44% were obtained in the case of 4-nitro- and 2- could be obtained in 56% and 71% yields in the pres-
chlorophenylacetonitrile, while the highest yield 89% ence of aldehyde, respectively [Scheme 4 Eq. (2) and
was obtained when 3,4-dimethoxylphenylacetonitrile Eq. (3)]. Meanwhile, only 6% dimethylthiobenzamide
was the substrate (Table 3). was formed without addition of the aldehyde
ACHTUNGTRENaNGNU mide or N,N-dimethyl-3-phenylpropanethioamide
ACHTUNGTRENNUNG
Although the actual role of aldehyde during the re- [Scheme 4 Eq. (1)]. This might also suggest that the
À
action is still unclear at present, we assume that the existence of aldehyde would favor the C CN bond
existence of aldehyde might prevent the formation of
Scheme 4. Use of other nitriles for this reaction.
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Copper(II)-Catalyzed Reactions of Dimethylformamide with Phenylacetonitrile and Sulfur
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In summary, we have discovered a novel protocol
for generating N,N-dimethylthiobenzamide and N,N-
dimethyl-2-phenylethanethioamides, respectively, by
a one-pot procedure using phenylacetonitrile, sulfur
and DMF with or without addition of n-valeralde-
hyde. The relatively inexpensive copper catalyst and
solvent-free system in this reaction exhibits the ad-
vantages of this reaction. The high yields of up to
96% obtained in this method show promise for appli-
cations in organic synthesis. Mechanistic studies are
still underway in this laboratory.
Experimental Section
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Typical Procedure for the Preparation of N,N-
Dimethylthiobenzamide
CuACHTUNGTRENNUNG(acac)2 (26.1 mg, 0.1 mmol), K2CO3 (0.4 g, 3 mmol), ele-
mental sulfur (96 mg, 3 mmol), phenylacetonitrile (117 mg,
1.0 mmol), and DMF (2 mL) were added to a Schlenk tube
(25 mL) equipped with a magnetic stirrer bar. The Schlenk
tube was then closed and the resulting mixture was stirred
at 1108C for 24 h. After cooling down to room temperature,
the reaction mixture was filtered with celite and washed
with CH2Cl2. The filtrate was evaporated under vacuum.
The residue was purified by silica gel column chromatogra-
phy with petroleum ether/EtOAc (4:1) to give the product
as a dark green solid; yield: 147 mg (89%).
Typical Procedure for the Synthesis of N,N-Dimethyl-
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2-phenylethanethioamides
CuACHTUNGTRENNUNG(acac)2 (26.1 mg, 0.1 mmol), K2CO3 (0.4 g, 3 mmol), ele-
mental sulfur (96 mg, 3 mmol), phenylacetonitrile (117 mg,
1.0 mmol), n-C4H9CHO (86 mg, 1 mmol) and DMF (2 mL)
were added to a Schlenk tube (25 mL) equipped with a mag-
netic stirrer bar. The Schlenk tube was then closed and the
resulting mixture was stirred at 1108C for 24 h. After cool-
ing down to room temperature, the reaction mixture was fil-
tered with celite and washed with CH2Cl2. The filtrate was
evaporated under vacuum. The residue was purified by
silica gel column chromatography with petroleum ether/
EtOAc (4:1) to give product as a dark green solid; yield:
147 mg (82%).
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We appreciate the Natural Science Foundation of China (No.
21072132, 21272161, 21372163) and the Ministry of Educa-
tion of China (No. 20120181110050) for financial support.
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