Dimethylamine as the key intermediate generated in situ from dimethylformamide (DMF) for the synthesis of thioamides

Article abstract of DOI:10.3762/bjoc.11.187

An improved and efficient method for the synthesis of thioamides is presented. For this transformation, dimethylamine as the key intermediate is generated in situ from dimethylformamide (DMF). All the tested substrates produced the desired products with excellent isolated yields.

Full text of DOI:10.3762/bjoc.11.187

Dimethylamine as the key intermediate generated in situ from
dimethylformamide (DMF) for the synthesis of thioamides
Weibing Liu*1, Cui Chen1 and Hailing Liu*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1721–1726.
1College of Chemical Engineering, Guangdong University of
Petrochemical Technology, 2 Guandu Road, Maoming 525000, P. R.
China, Fax: +86-668-2923575; Tel: +86-668-2923956 and 2College
Analytical and Testing Centre, Beijing Normal University, No. 19,
Xinjiekouwai St., Haidian District, Beijing 100875, P. R. China; Tel:
+86-15010928428
doi:10.3762/bjoc.11.187
Received: 17 May 2015
Accepted: 04 September 2015
Published: 23 September 2015
Associate Editor: B. Stoltz
Email:
Weibing Liu* - liuhailing@bnu.edu.cn;
Hailing Liu* - liuhailing@bnu.edu.cn
© 2015 Liu et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aldehydes; dimethylformamide (DMF); elemental sulfur; ketones;
thioamides
Abstract
An improved and efficient method for the synthesis of thioamides is presented. For this transformation, dimethylamine as the key
intermediate is generated in situ from dimethylformamide (DMF). All the tested substrates produced the desired products with
excellent isolated yields.
Introduction
Thioamides, a well-known structural element of many sulfur- Consequently, a number of synthetic methods for the con-
containing molecules, synthetic agents [1,2], heterocycles, struction of this important unit have been established over
natural products and pharmaceuticals [3-8], have attracted the past decades [15-21]. However, some of these methods
considerable attention for their construction and use in organic have limited applications, because of harsh conditions, low
synthesis [9,10]. Many compounds containing a thioamide yields or the need of noble-metal catalysts. Therefore the devel-
motif are of medicinal significance and exhibit potent bio- opment of novel and efficient methods for the construction of
logical activities. These include for example opioid activity the thioamide motif is highly desirable. To avoid the disadvan-
[11], immunosuppressive activity and DHODH inhibitory prop- tages of the traditional methods, our group has developed
erties [12], activity against parasitic nematodes [13], and anti- an improved synthetic procedure to construct thioamides
tuberculotic activity [14].
(Scheme 1).
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Beilstein J. Org. Chem. 2015, 11, 1721–1726.
Table 1: Optimization studies.a
Entry Temp. ( °C) Base (0.2 equiv) Time (h) Yield (%)b
Scheme 1: Synthesis of thioamide derivatives.
1
2
120
120
120
120
120
120
120
120
120
100
rt
AcONa
AcONa
AcONa
Na2CO3
KOH
3
4
5
4
4
4
4
4
4
4
4
57
64
Results and Discussion
3
64
Our initial efforts focused on the optimization of the reaction
conditions by employing 4-methoxybenzaldehyde (1a) as a
model reactant to interact with elemental sulfur and DMF
(Table 1). The reaction is completed after 4 h at 120 °C, provid-
ing 4-methoxy-N,N-dimethylbenzothioamide (2a) with 64%
yield by using sodium acetate (AcONa) as the base (Table 1,
entry 2). With regard to the catalytic activity of different bases
(Table 1, entries 4–8), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) showed the highest activity and afforded the desired
product with 96% yield (Table 1, entry 7). It is worth
mentioning that this conversion does not take place in the
absence of a base (Table 1, entry 9). Lowering the temperature
4
25
5
15
6
DABCO
DBU
21
7
96
8
EtONa
none
17
9
none
79
10
11
DBU
DBU
none
aReaction conditions: 1a (0.25 mmol), S8 (1.2 equiv, based on 1/8 S8),
DMF (2.0 mL); bGC yield.
from 120 °C to 100 °C decreased the yield considerably gave the corresponding thioamides 2a–p exclusively in good to
(Table 1, entry 10). When the reaction was performed at room excellent isolated yields. It was also found that unsubstituted,
temperature no product was obtained at all (Table 1, entry 11). mono-, di- and trisubstituted substrates regardless of the pos-
ition (o-, m-, or p-) and the electronic properties of the
Once the optimal conditions had been identified (Table 1, entry substituents (electron-donating or –withdrawing) on the
7), next the scope of the reaction was investigated. Sixteen benzene ring were all compatible with the standard conditions.
substrates including 12 substituted aldehydes and 4 ketones For example, methoxy-, o-, m-, and p-methyl-, fluoro-, chloro-,
were screened and the results are presented in Table 2. As can or hydroxy-substituted aromatic aldehydes and ketones were all
be seen from the Table, all reactions proceeded smoothly and converted to their corresponding thioamides with excellent
Table 2: Scope of the reaction.a
Entry
1
Educt 1a–p
Product 2a–p
Yield (%)b
90 (88)
1a
1b
2a
2b
2
84
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Beilstein J. Org. Chem. 2015, 11, 1721–1726.
Table 2: Scope of the reaction.a (continued)
3
82
82
1c
2c
4
1d
1e
2d
2e
2f
5
6
83
80
1f
7
8
80
89
1g
2g
2h
1h
1i
9
83
88
80
2i
2j
10
11
1j
1k
2k
12
13
84
77
1l
2l
2i
1m
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Beilstein J. Org. Chem. 2015, 11, 1721–1726.
Table 2: Scope of the reaction.a (continued)
14
79
2n
1n
1o
15
16
63
67
2o
2p
1p
aReaction conditions: 1 (1.0 mmol), S8 (1.2 equiv, based on 1/8 S8); bisolated yield. Number in parentheses is the isolated yield of 1 (10.0 mmol
scale) after purification by column chromatography.
isolated yields. Finally, some aliphatic aldehydes such as able to promote the reaction. However, repeating the reaction in
phenylacetaldehyde (Table 2, entry 9), butyraldehyde (Table 2, DMA in the presence of N,N-dimethylamine the desired prod-
entry 15) and pentanal (Table 2, entry 16) were subjected to the uct 2a was obtained in 98% yield. These results are proving the
reaction. They were also found compatible with the standard involvement of dimethylamine in this transformation and that it
conditions, and the corresponding products were isolated in is in situ generated from N,N-dimethylformamide under the
moderate to good yields.
reaction conditions.
In order to expand the scope and to get insight into the reaction Based on the above experiments and the existing literature [22-
mechanism of this protocol, three control experiments were 24], a suggested mechanism is outlined in Scheme 3. The reac-
conducted (Scheme 2). In the first two experiments the reaction tion starts with a base-induced cleavage of DMF to form the
was performed with N,N-dimethylacetamide (DMA) and N,N- required dimethylamine according to the mechanism suggested
dimethylacrylamide instead of DMF under the standard condi- by Van der Eycken, Hallberg and co-workers [25,26]. The
tions. In both cases no product formation was observed, subsequent step involves the classical Willgerodt–Kindler reac-
suggesting that neither DMA nor N,N-dimethylacrylamide is tion as described by Amupitan and Darabi [27,28].
Scheme 2: Control experiments.
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Beilstein J. Org. Chem. 2015, 11, 1721–1726.
Scheme 3: A mechanistic rationale for the synthesis of thioamides.
9. Goldberg, J. M.; Chen, X.; Meinhardt, N.; Greenbaum, D. C.;
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Conclusion
In summary, an improved synthetic procedure for the synthesis
of thioamides has been established. This protocol is applicable
to a wide range of aldehydes and ketones yielding the
thioamides with excellent isolated yields. For this transforma-
tion, DMF works not only as the solvent but also as the source
of dimethylamine. The present method is more practical
compared to the traditional strategies and complements the clas-
sical methods for the rapid construction of thioamides.
10.Goldberg, J. M.; Batjargal, S.; Chen, B. S.; Petersson, E. J.
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Supporting Information
14.Cynamon, M. H.; Gimi, R.; Gyenes, F.; Sharpe, C. A.; Bergmann, K. E.;
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Supporting Information File 1
Full experimental details and copies of NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-187-S1.pdf]
16.Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P. H.
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Acknowledgements
We thank the Excellent Young Scientist Fund of Guangdong
Province Education Department (No.2013LYM_0059) for
financial support.
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