Synthesis of Terminal N-Vinylazoles from Aromatic Aldehydes, DMSO, and Azoles Based DMSO as Terminal Carbon Synthon

Article abstract of DOI:10.1002/adsc.202100663

A protocol for the synthesis of terminal N-vinylazoles from aromatic aldehydes, DMSO, and azoles has been reported. In this strategy, DMSO was involved in the construction of the C=C bond as a terminal carbon synthon. Both aromatic aldehydes and azoles could be well tolerated and give the corresponding terminal N-vinylazoles in 52–91% yields. Based on preliminary experiments, a plausible mechanism is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.202100663

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100663
Very Important Publication
Synthesis of Terminal N-Vinylazoles from Aromatic Aldehydes,
DMSO, and Azoles Based DMSO as Terminal Carbon Synthon
Zhiwen Nie,a Huifang Lv,a Hui Li,a Miaodong Su,a Tonglin Yang,a Weiping Luo,a
Qiang Liu,a,* and Cancheng Guoa,*
a
College of Chemistry and Chemical Engineering, Hunan University
Changsha 410082, People’s Republic of China
Fax: +86-731-88821488
Tel: +86-731-88821488
E-mail: fqiangliu@qq.com; ccguo@hnu.edu.cn
Manuscript received: May 31, 2021; Revised manuscript received: August 10, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100663
Abstract: A protocol for the synthesis of terminal N-vinylazoles from aromatic aldehydes, DMSO, and azoles
has been reported. In this strategy, DMSO was involved in the construction of the C=C bond as a terminal
carbon synthon. Both aromatic aldehydes and azoles could be well tolerated and give the corresponding
terminal N-vinylazoles in 52–91% yields. Based on preliminary experiments, a plausible mechanism is
proposed.
Keywords: Terminal N-vinylazoles; Aromatic Aldehydes; DMSO; Azoles; C=C and CÀ N bonds Formation
Introduction
methodology for the synthesis of terminal N-vinyl-
azoles by CuI-catalyzed cross-coupling between
Synthesis of terminal N-vinylazoles has attracted azoles and α-bromostyrene (Scheme 1, Eqn. 2).[5h]
considerable attention of the organic chemists because Besides, Pd-catalyzed cross-coupling of N-tosylhy-
the terminal N-vinylazole units widely existed in drazones with azoles to synthesize terminal N-vinyl-
natural
products,
pharmaceuticals,
and azoles has been reported by Cui and Alami group,
agrochemicals.[1] Futhermore, the terminal N-vinyl- respectively (Scheme 1, Eqn. 3).[6] These transition
azoles are also vital important intermediates in metal-catalyzed protocols are reliable and widely
synthetic chemistry[2] and materials science.[3] In the employed by many chemists, but most of these
past few decades, scientists have developed many elegant works suffer from certain limitations. Such as
strategies for the synthesis of the terminal N-vinyl- troublesome operation, expensive catalysts/ligands
azoles. In general, the intermolecular coupling or the especially raw materials requiring special structure.
intramolecular annulation is used to prepare of Recently, significant progress has been achieved in
terminal N-vinylazoles. Among these methods, the the synthesis of terminal N-vinylazoles via the
hydroamination of alkynes is the most straight cyclization reaction. For example, in 2007, Li group
forward approach for synthesizing terminal N- described a method to synthesize terminal N-vinyl-
vinylazole.[4] For example, the Koenigs group de- indoles via the intermolecular cyclization of o-
scribed an Au(I)-catalyzed hydroamination reaction alkynylanilines and alkynes (Scheme 1, Eqn. 4).[7]
of terminal alkynes with carbazoles to furnish Afterward, Fujioka group accomplished a similar
valuable terminal N-vinylcarbazoles (Scheme 1, transformation through the intermolecular cyclization
Eqn. 1).[4b] With the development of transition metal- of ketones and o-alkynylanilines (Scheme 1,
catalyzed reactions, Pd or Cu-catalyzed cross cou- Eqn. 5).[8] Besides, Xu group reported a method for
pling of azoles with olefin and its derivatives for the synthesis of terminal N-vinylindoles via the
preparation of terminal N-vinylazoles has been well- intramolecular annulation of N-(2-alkynylphenyl)
studied.[5] In 2009, Xi and co-workers reported a imine (Scheme 1, Eqn. 6).[9] However, these cycliza-
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Table 1. Optimization of reaction conditions.[a]
Entry
Base
Time
Temp.
Yield
(%)[b]
°
( C)
1
2
3
4
5
6
7
8
NaOH
\
30 min
30 min
30 min
30 min
30 min
20 min
40 min
30 min
30 min
30 min
30 min
80
80
80
80
80
80
80
70
90
80
80
18
0
K2CO3
tBuOK
KOH
KOH
KOH
KOH
KOH
KOH
KOH
trace
78
91
75
91
69
82
91
31
9
10[c]
11[d]
[a] Reaction conditions: benzaldehyde (1a, 0.5 mmol), indole
(2a, 1.0 mmol), base (2 mmol) and DMSO (2.5 mL).
[b] GC yield using 1,4-dichlorobenzene as an internal standard.
[c] Under O2 atmosphere.
[d] Under Ar atmosphere.
Scheme 1. Synthetic approaches toward terminal N-vinylazoles.
tion strategies are just applicable to synthesis of for 30 min in the presence of NaOH afforded the
terminal N-vinylindoles compounds. It is important to desired 3aa in 18% yield (Table 1, entry 1). Encour-
note that the C=C bond of the terminal N-vinylindoles aged by this result, we investigated other reaction
in all of the above methods is derived from the single conditions, including the variation of base, time, and
component, thus the raw materials requiring specific temperature. First, a series of inorganic base were
structures in these reactions.
screened and the results revealed that KOH was
Dimethyl sulfoxide (DMSO) is a cheap, versatile superior to other inorganic bases, such as NaOH,
t
solvent with low toxicity, great dissolving capacity, K2CO3 and BuOK. In addition, the 3aa could not be
and relative stability, which is used widely in organic obtained under a base-free condition (Table 1, En-
synthesis.[10] Moreover, DMSO as a carbon source for tries 2–5). Subsequently, we carried out a series of tests
the construction of organic molecules has received on reaction time. The test results showed that the
much attention in recent years.[11] With our continued benzaldehyde was consumed when the reaction time
interest in DMSO as a carbon synthon,[12] we herein was 30 minutes, and the yield was not improved by
report a strategy for the synthesis of terminal N- extending the reaction time (Table 1, Entries 6, 7).
vinylazoles via the three-component reaction of ar- Furthermore, we screened the reaction temperature.
omatic aldehydes, azoles, and DMSO (Scheme 1, Variation of the reaction temperature confirmed that
°
Eqn. 7). In this strategy, DMSO was involved in the 80 C was the optimal condition for this protocol, with
construction of the C=C bond as a terminal carbon lower and higher temperatures affording decreased
synthon. To our best knowledge, this is the first yields (Table 1, Entries 8, 9). Finally, the reactions
example of the synthesis of terminal N-vinylazoles via have been performed in Ar and O2 atmosphere,
the three-component reactions, and is also the first respectively (Table 1, Entries 10, 11). When reaction
example for the construction of C=C bond via the performed in O2 atmosphere, the similar result was
dual-component reactions.
obtained in contrast to in air. With the Ar replacing of
air, the yield of 3aa decreased significantly, which
indicated that O2 in air played a certain role in the
reaction.
Results and Discussion
Initially, we explored benzaldehyde (1a) and indole
Having established the optimized reaction condi-
(2a) as a model reactant and the results are summar- tions, the substrate scope of aldehydes was explored
°
ized in Table 1. Heating reactants with DMSO at 80 C firstly and the results are summarized in Table 2. For
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5-OCH3), and electron-deficient group (4-F and 5-Br)
were tolerated, affording the corresponding products in
moderate to good yields (3ab–3af). Delightfully, other
azaindole substrates such as 5-azaindole and 7-
azaindole also be employed to form the corresponding
products without any difficulties (3ag–3ah). Encour-
aged by the results obtained with substituted indoles,
we proceeded to apply this catalytic system to other
azoles. To our delight, other azoles, such as pyrrole,
carbazole, pyrazole, indazole, imidazole, benzimida-
zole, 1H-1,2,3-triazole, and 1H-1,2,4-triazole also
produced the corresponding terminal N-vinylazoles
products (3ai–3hi) with moderate to good yields,
many of which are not readily accessible by conven-
tional methods.
Table 2. The scope of aldehydes and azoles for preparation of
terminal N-vinylazoles.[a,b]
Enamides constitute the core structure of many
functional materials[13] and natural products of bio-
logical significance.[14] Encouraged by the above
results, we speculated that using amides instead of
azoles could efficient synthesis of enamides by this
strategy. Therefore, we tested the reaction of benzalde-
hyde with caprolactam by slightly modifying the
reaction conditions. Fortunately, the reaction was
proceeded smoothly at room temperature and the
desired product 5aa was obtained with a yield of 86%
(Table 3). Furthermore, other aromatic aldehydes and
amides could also produce the corresponding enamides
under the same conditions with good yields (5da–
5ac). Besides, we also tried to use phthalimide as a
substrate in this method. Unfortunately, the desired
product was not detected.
More practically, a gram-scale reaction involving
10.0 mmol benzaldehyde, 15.0 mmol indole and
20.0 mmol KOH has also been conducted in this work.
As a result, 76% yield of 3aa (1664.4 mg) was
[a] Reaction conditions: aldehydes (1, 0.5 mmol), azoles (2,
°
1.0 mmol), KOH (2 mmol), DMSO (2.5 mL), at 80 C for
30 min.
[b] Isolated yield.
Table 3. The scope of aldehydes and amides for preparation of
enamides.[a,b]
example, aryl aldehydes bearing an electron-rich group
(2-Me, 4-OMe, 3-OMe and 3,4-(OMe)2) as well as an
electron-deficient group (3-CF3) all reacted smoothly,
providing products 3ba–3da and 3ha in moderate to
good yields (77%–87%). An array of halogen sub-
stituents (4-F, 3-Cl, and 4-Br) were also compatible
with the reaction to furnish products 3ea–3ga in 74%–
78% yields, therefore providing the possibility for
synthetic derivatization. Gratifyingly, 2-naphthalde-
hyde also provided the N-vinylindole in 83% yield
(3ia). Furthermore, thiophene-2-carbaldehyde readily
underwent the reaction to generate the expected
product in high yield (3ja). However, when aryl
aldehydes were replaced by aliphatic aldehydes, the
corresponding products could not be gained. Subse-
quently, the scope of the reaction was further explored
using a variety of substituted indoles. For example,
indoles bearing electron-rich group (2-Me, 3-Me and
[a] Reaction conditions: aldehydes (1, 0.5 mmol), amides (4,
1.0 mmol) KOH (2 mmol), DMSO (2.5 mL), at room
temperature for 2 h.
[b] Isolated yield.
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obtained using flash column chromatography on silica, 93% and 95% yields, respectively (eq. 3 and 4). These
that clearly showing its potential application in organic results further proved that A and B would be the key
synthesis (Scheme 2).
intermediates in this reaction. Intermediate B was used
To further understand the reaction mechanism, to react with 2a under standard conditions, when the
several control experiments were conducted reaction stoped at 3 min, ca. 10% intermediate C and
(Scheme 3). By addition of 2 equiv. radical inhibitor 32% 3aa were detected. When the reaction was
TEMPO or BHT, product 3aa was still obtained in stopped at 30 min, C disappeared, whereas the yield of
high yields under standard reaction conditions, indicat- 3aa was increased to 95%. The deuterium-experiments
ing that this reaction may not proceed via a radical were also carried out. By using DMSO-d6 instead, the
process (eq. 1). When the model reaction was stopped partially deuterated product 3aa-d3 was isolated, which
at 5 min, ca. 82% (methylsulfinyl)vinyl)benzene (A), showing that DMSO was a source of methine units. In
4% (E)-(2-(methylsulfonyl)vinyl)benzene (B) and 6% addition, there have hydrogen exchange reaction in the
3aa were detected by GC-MS. By further heating the C3-H and NÀ H of indoles (eq. 5 and 6). Finally, our
reaction mixture to 15 min, ca. 21% A, 5% B and 62% conclusion was confirmed by using 3-methylindole
3aa were detected. When the model reaction was instead of indole (eq. 7).
stopped at 30 min, A and B disappeared, whereas the
On the basis of the above experimental results and
yield of 3aa was increased to 91%, implying that A in combination with previous literature,[15–18] a reason-
and B would be the key intermediates in this reaction able reaction mechanism was proposed using benzalde-
(eq. 2). Pure A and B were synthesized following the hyde 1a and indole 2a as an example and outlined in
established procedure. Under the standard reaction Scheme 4. Initially, benzaldehyde 1a reacted with
conditions, both A and B could be converted to 3aa in DMSO under base conditions to give the styryl
sulfoxide A through an aldol condensation reaction. In
the presence of O2, styryl sulfoxide A underwent
oxidation to generate styryl sulfone B, followed by
addition with indole 2a to form C. Subsequently,
intermediate C by the base-assisted deprotonation yield
an anion D with one molecule of water been released.
Finally, the intermediate D underwent β-elimination to
afford the final product 3aa.
Scheme 2. Gram-scale reactions.
Conclusion
In summary, we have disclosed a three-component
assembly reaction between aromatic aldehydes,
DMSO, and azoles/amides. Various terminal N-vinyl-
azoles and enamides were synthesized in good yields.
What’s more, this reaction could be conducted on a
10 mmol scale, clearly showing the potential practical-
ity of this reaction in organic synthesis. On the basis of
control experiments and literature precedents, a plau-
sible reaction path accounting well for the single
carbon transfer as well as C=C and CÀ N bond
formations.
Scheme 3. Control experiments.
Scheme 4. Proposed mechanism.
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Chem. Int. Ed. 2017, 56, 1120–1124; Angew. Chem.
Experimental Section
2017, 129, 1140–1144; f) D. Takeda, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2013, 15, 1242–1245; g) G.
Wu, W. Su, Org. Lett. 2013, 15, 5278–5281; h) Q. Liao,
Y. Wang, L. Zhang, C. Xi, J. Org. Chem. 2009, 74,
6371–6373.
In a Schlenk tube of 25 mL, KOH (1.0 mmol, 56 mg), DMSO
(2.5 mL), aldehydes (1, 0.5 mmol), azoles (2, 1.0 mmol) were
added. The mixture was stirred at 80 C for 30 min. After
completion of the reaction, the resulting solution was cooled to
room temperature; then it was diluted with ethyl acetate (6 mL),
washed with water (6 mL), extracted with ethyl acetate (6×
3 mL), and dried over anhydrous Na2SO4 and concentrated in
vacuo. The crude product was purified by flash column
chromatography on silica gel to give the desired product final
product.
°
[6] For some examples, see: a) M. Roche, J. Bignon, JÀ D
Brion, A. Hamze, M. Alami, J. Org. Chem. 2014, 79,
7583–7592; b) X. Zeng, G. Cheng, J. Shen, X. Cui, Org.
Lett. 2013, 15, 3022–3025; c) M. Roche, G. Frison, J. D.
Brion, O. Provot, A. Hamze, M. Alami, J. Org. Chem.
2013, 78, 8485–8495.
[7] Y. Zhang, J. P. Donahue, C. J. Li, Org. Lett. 2007, 9,
627–630.
Acknowledgements
[8] K. Murai, S. Hayashi, N. Takaichi, Y. Kita, H. Fujioka, J.
Org. Chem. 2009, 74, 1418–1421.
[9] a) Z. Q. Wang, X. Zhang, L. T. Yu, W. T. Mao, C. Z.
Chena, K. Xu, Org. Biomol. Chem. 2015, 13, 6931–
6934.
Support for this research from National Natural Science
Foundation of China (No. 21572049) is gratefully acknowl-
edged.
References
[10] D. Martin, A. Weise, H. J. Niclas, Angew. Chem. Int. Ed.
1967, 6, 318–334; Angew. Chem. 1967, 79, 340–357.
[11] For some examples, see: a) Z. Tashrifi, M. M. Khana-
poshtani, B. Larijani, M. Mahdavi, Adv. Synth. Catal.
2020, 362, 65–86; b) X. F. Wu, K. Natte, Adv. Synth.
Catal. 2016, 358, 336–352; c) C. Xu, S. F. Jiang, X. H.
Wen, Q. Zhang, Z. W. Zhou, Y. D. Wu, F. C. Jia, A. X.
Wu, Adv. Synth. Catal. 2018, 360, 2267–2271; d) P.
Yadav, A. Awasthi, S. Gokulnath, D. K. Tiwari, J. Org.
Chem. 2021, 86, 2658–2666; e) E. J. Mensah, M. Karki,
J. Magolan, Synthesis. 2016, 48, 1421–1436.
[12] a) H. Li, H. Liu, Y. Liu, Z. Cao, M. Su, M. Fu, W. Luo,
Q. Liu, C. Guo, Adv. Synth. Catal. 2019, 361, 5392–
5399; b) Y. F. Liu, P. Y. Ji, J. W. Xu, Y. Q. Hu, Q. Liu,
W. P. Luo, C. C. Guo, J. Org. Chem. 2017, 82, 7159–
7164; c) H. Li, M. Su, Z. Nie, T. Yang, W. Luo, Q. Liu,
C. Guo, Adv. Synth. Catal. 2021, 363, 3127–3137.
[13] For some examples, see: a) L. Yet, Chem. Rev. 2003,
103, 4283–4306; b) K. Gopalaiah, H. B. Kagan, Chem.
Rev. 2011, 111, 4599–4657; c) N. H. Tan, J. Zhou, Chem.
Rev. 2006, 106, 840–895; d) K. C. Nicolaou, G. Y. C.
Leung, D. H. Dethe, R. Guduru, Y. P. Sun, C. S. Lim,
D. Y. K. Chen, J. Am. Chem. Soc. 2008, 130, 10019–
10023.
[14] For some examples, see: a) J. Kohno, Y. Koguchi, M.
Nishio, K. Nakao, M. Kuroda, R. Shimizu, T. Ohnuki, S.
Komatsubara, J. Org. Chem. 2000, 65, 990–995; b) B.
Kunze, R. Jansen, G. Höfle, H. Reichenbach, J. Antibiot.
1994, 47, 881–886; c) S. Ghosh, D. Bhusan, D. N. Sen,
Synth. Commun. 1987, 17, 299–307; d) A. Maxwell, D.
Rampersad, J. Nat. Prod. 1989, 52, 411–414; e) K. C.
Nicolaou, Y. P. Sun, R. Guduru, B. Banerji, D. Y. K.
Chen, J. Am. Chem. Soc. 2008, 130, 3633–3644; f) K. C.
Nicolaou, R. Guduru, Y. P. Sun, B. Banerji, D. Y. K.
Chen, Angew. Chem. Int. Ed. 2007, 46, 5896–5900;
Angew. Chem. 2007, 119, 6000–6004; g) A. B. Smith,
M. O. Duffey, K. Basu, S. P. Walsh, H. W. Suennemann,
M. Frohn, J. Am. Chem. Soc. 2008, 130, 422–423.
[1] For some examples, see: a) M. Ogata, H. Matsumoto, S.
Shimizu, S. Kida, M. Shiro, K. Tawara, J. Med. Chem.
1987, 30, 1348–1354; b) A. G. Schultz, W. P. Malachow-
ski, Y. Pan, J. Org. Chem. 1997, 62, 1223–1229; c) H.
Li, N. Boonnak, A. Padwa, J. Org. Chem. 2011, 76,
9488–9496; d) W. J. Ross, W. B. Jamieson, M. C. McCo-
wen, J. Med. Chem. 1973, 16, 347–352.
[2] a) A. Ghosh, L. M. Stanley, Chem. Commun. 2014, 50,
2765–2768; b) F. Li, C. Shen, J. Zhang, L. Wu, X. Zhuo,
L. Ding, G. Zhong, Adv. Synth. Catal. 2016, 358, 3932–
3937; c) A. Ghosh, D. T. Bainbridge, L. M. Stanley, J.
Org. Chem. 2016, 81, 7945–7951; d) J. A. Walker, L. M.
Stanley, Org. Biomol. Chem. 2016, 14, 9981–9984.
[3] For some examples, see: a) Y. Oshiro, Y. Shirota, H.
Mikawa, J. Polym. Sci. Polym. Chem. Ed. 1974, 12,
2199–2206; b) A. Priola, G. Gatti, S. Cesca, Makromol.
Chem. 1979, 180, 1–11; c) E. Gipstein, W. A. Hewett,
Macromolecules. 1969, 2, 82–85; d) Y. Maki, H. Mori,
T. Endo, Macromolecules. 2007, 40, 6119–6130.
[4] For some examples, see: a) H. J. Kang, J. H. Lee, D. H.
Kim, C. G. Cho, Org. Lett. 2020, 22, 7588–7593; b) S.
Jana, F. He, R. M. Koenigs, Org. Lett. 2020, 22, 4873–
4877; c) V. Garg, P. Kumar, A. K. Verma, J. Org. Chem.
2018, 83, 11686–11702; d) M. Patel, R. K. Saunthwal,
A. K. Verma, Acc. Chem. Res. 2017, 50, 240–254; e) T.
Mahdi, D. W. Stephan, Angew. Chem. Int. Ed. 2013, 52,
12418–12421; Angew. Chem. 2013, 125, 12644–12647;
f) T. Tsuchimoto, K. Aoki, T. Wagatsuma, Y. Suzuki,
Eur. J. Org. Chem. 2008, 4035–4040.
[5] For some examples, see: a) C. S. Sevov, J. Zhou, J. F.
Hartwig, J. Am. Chem. Soc. 2014, 136, 3200–3207; b) V.
Motornov, G. V. Latyshev, Y. N. Kotovshchikov, N. V.
Lukashev, I. P. Beletskaya, Adv. Synth. Catal. 2019, 361,
3306–3311; c) M. Zhou, X. Tan, Y. Hu, H. C. Shen, X.
Qian, J. Org. Chem. 2018, 83, 8627–8635; d) Y. Obora,
Tetrahedron Lett. 2018, 59, 167–172; e) H. Yi, L. Niu,
C. Song, Y. Li, B. Dou, A. K. Singh, A. Lei, Angew.
Adv. Synth. Catal. 2021, 363, 1–7
5
© 2021 Wiley-VCH GmbH
��
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RESEARCH ARTICLE
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[15] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, [17] Q. Zhang, S. Cai, L. Li, Y. Chen, H. Rong, Z. Niu, J.
1345–1353. Liu, W. He, Y. Li, ACS Catal. 2013, 3, 1681–1684.
[16] P. Yang, W. Xu, R. Wang, M. Zhang, C. Xie, X. Zeng, [18] Q. Xu, J. Chen, H. Tian, X. Yuan, S. Li, C. Zhou, J. Liu,
M. Wang, Org. Lett. 2019, 21, 3658–3662.
Angew. Chem. Int. Ed. 2014, 53, 225–229; Angew. Chem.
2014, 126, 229–233.
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RESEARCH ARTICLE
Synthesis of Terminal N-Vinylazoles from Aromatic
Aldehydes, DMSO, and Azoles Based DMSO as Terminal
Carbon Synthon
Adv. Synth. Catal. 2021, 363, 1–7
Z. Nie, H. Lv, H. Li, M. Su, T. Yang, W. Luo, Q. Liu*, C.
Guo*