Letter Cite This: Org. Lett. 2019, 21, 279−282
pubs.acs.org/OrgLett
Sulfur-Promoted Decarboxylative Sulfurative Hexamerization of Phenylacetic Acids: Direct Approach to Hexabenzylidyne Tetrasulfides Thanh Binh Nguyen* and Pascal Retailleau Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Org. Lett. 2019.21:279-282. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/09/19. For personal use only.
S Supporting Information *
ABSTRACT: During our experiments aimed at understanding the reaction pathways by which arylacetic acids were oxidatively decarboxylated and condensed with different nucleophiles in the presence of elemental sulfur, these acids have been treated with sulfur powder in dimethyl sulfoxide (DMSO) and N-methylpiperidine in the absence of nucleophiles, producing a remarkable symmetrical sulfurated hexamer consisting of six benzylidyne moieties and four sulfur atoms.
T
resulted from the reduction of o-nitroaniline in this case), we wondered whether such an intermediate could be trapped as sulfur-containing compounds by the formation of oligomer molecules. Accordingly, we have reacted phenylacetic acid with 2 equiv of sulfur in dimethyl sulfoxide (DMSO) using Nmethylpiperidine3(NMP) as a sulfur activator in the absence of o-nitroaniline and iron salt. To our surprise, this reaction produced, along with various amounts of dithiobenzoate salt as orange crystals, a pale yellow solid, which is readily isolated by simply washing the reaction mixture with methanol and removing the remaining traces of sulfur in vacuo at 100−120 °C. In its pure state, this compound as well as its derivatives (vide infra) were found to be insoluble in most polar solvents such as methanol, DMSO, or DMF. Sparingly soluble in CDCl3, the molecules displayed an extremely simple 1H spectra with two sets of phenyl signals in a 2:1 ratio. Fortunately, we were able obtain its single crystals and consequently its molecular structure was readily determined by X-ray diffraction as depicted in Figure 1. Compound 2a crystallized in the monoclinic space group P21/ c, with a crystallographically imposed inversion center located at the midpoint of the C1C1 #1 bond (Csp3 ···Csp3 , 1.594(3)Å). This single bond links two 1,3-dithiole rings in an axially similar manner that the bi-1,3-dithiacyclopentyl4 and this dimer succeeded in fusing six phenyl groups into a hexamer (Figure 1). The phenyl at the equatorial position 2 covers the other thiol partner with a centroid−centroid distance of 3.625 Å, making a dihedral angle of 63.4°.
he transformation of simple molecules to yield more elaborate organic scaffolds in a single operation under simple reaction conditions is one of the important features of organic chemistry in the pursuit of the ideal synthesis. In line with this, we are focusing on the formation of several new sulfa heterocycles by direct incorporation of elemental sulfur to the organic scaffold with simultaneous formation of many C−C bonds.1 As part of an exploration of the reactivity of phenylacetic acids with various organic substrates, we have investigated their redox condensation with o-nitroanilines in the presence of catalytic amounts of sulfur and iron salts, leading to 2-arylbenzimidazoles.2 The formation of the benzimidazole products from oxidative decarboxylation of phenylacetic acids might be considered involving a sulfurated intermediate of the benzyl group from a mechanistic viewpoint (Scheme 1). In this transformation, the intermediate issued from phenylacetic acid was subsequently oxidized by the nitro group. In the absence of nucleophiles (o-phenylenediamine Scheme 1. Decarboxylative of Phenylacetic Acid
Received: November 21, 2018 Published: December 14, 2018 © 2018 American Chemical Society
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DOI: 10.1021/acs.orglett.8b03728 Org. Lett. 2019, 21, 279−282
Letter
Organic Letters
Table 1. Decarboxylative Sulfurative Hexamerization of Arylacetic Acid 2
Figure 1. Molecular structure of 2a (displacement ellipsoids drawn at the 30% probability level); H atoms are not shown for clarity; selected interatomic distances (Å) and angles (deg): C1S1, 1.835(2); C1 S2, 1.832(1); C1C1#1, 1.594(3); S1C2, 1.762(2); S2C3, 1.757(2); C2C3, 1.339(2); S1C1S2, 105.9(7); S1C1 C1 # 1, 110.2(1); S2C1C1 # 1, 108.7(1); C4C1C1 # 1; 113.3(2); S1C1C4, 108.9(1); S2C1C4, 109.6(1); C1 S1C2, 97.9(7); C1S2C3, 97.3(7). Symmetry transformations used to generate equivalent atoms: #1 −x + 1, −y + 1, −z + 1.
Structurally, although only four sulfur atoms are required to form the hexamer 2a, the reaction is best performed with 2 equiv of atomic sulfur (Scheme 2). Indeed, lowering the sulfur
entrya
arylacetic acid 1
R
2, yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12
1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m
4-Me 4-t-Bu 4-MeO 3-MeO 3-F 3-Cl 3-CF3 3-CO2Me 3,4-(CH)4 2-Me 2-Cl 2-MeO
2b, 56 2c, 47 2d, 50 2e, 46 2f, 66 2g, 65 2h, 54 2i, 62 2j, 58 2k, 0c 2l, 0c 2m 0c
a
Scheme 2. Decarboxylative Sulfurative Hexamerization of Phenylacetic Acid
Reaction conditions: arylacetic acid (1 mmol), sulfur (2 mmol, 64 mg), NMP (1 mmol), DMSO (3 mmol, 0.2 mL), 80 °C, 16 h. b Isolated yield by filtration. cNo trace of hexamer was detected in the reaction mixture.
content to 1 equiv led to a significantly lower yield of the expected hexamer and resulted in unchanged phenylacetic acid. On the other hand, increasing the sulfur content to more than 2 equiv did not improve appreciably the yield of the hexamer. Other organic bases that were used in the related reactions involving elemental sulfur such as N-methylmorpholine, pyridine, and 3-methylpicoline5 failed to promote the reaction. In these cases, phenylacetic acid remained unchanged at 80 °C while increasing the reaction temperature to 130 °C led to its oxidation to a benzoate anion. The unique oxidative role of DMSO was confirmed by the fact that phenylacetic acid remained unchanged when DMSO was replaced by DMF or another polar aprotic solvent such as N,N-dimethylacetamide and N-methylpiperidone. The scope and limitation of this unusual sulfurative hexamerization reaction was next investigated with a range of substituted phenylacetic acid derivatives (Table 1). In general, the reaction was found to proceed in the same manner with phenylacetic acids substituted in the para or meta position by an alkyl, a halogen, an electron-donating group (methoxy), or an electron-withdrawing group (CO2Me, CF3). The reaction conditions were also applicable to 2-naphthylacetic acid. On the other hand, the reaction failed with osubstituted phenylacetic acids (o-methyl, o-chloro, o-methoxy) and resulted in the recovery of the starting materials and heating at higher temperature led only to their oxidation into the corresponding benzoates. This failure can be explained by the steric hindrance of these substituents. The structures of
2b−2d were also determined unambiguously by X-ray crystallography (see the Supporting Information). We emphasized that the solubility of this kind of compound is in general very low when the phenyl ring bears other para substituents. The reactions with p-fluoro-, p-chloro-, or pbromo-phenylacetic acid led to the expected hexamers (present in the crude mixtures by 1H NMR analysis). These hexamers could be isolated, but due their low solubilities, we could not record any 1H NMR. At this stage, we have little information about the reaction pathway of this sulfurative self-condensation described above. However, we supposed that the primary product of this transformation would have a sulfurated benzyl group. To confirm this hypothesis, the chemical behavior of dibenzyl disulfide 3, a stable derivative bearing both a benzyl group and sulfur atom, was considered under similar conditions. In the absence of elemental sulfur, this compound was essentially recovered unchanged, but comparable conversion into 2a was observed in the presence of 1 atomic equiv of sulfur (Scheme 3, eq 1). This observation suggested that elemental sulfur involved in the reaction was necessary for the formation of sulfurated benzyl derivatives and also for further oxidative hexamerization of these species. When benzyl mercaptan 4 was used as a possible sulfurated benzyl derivative, 0.5 equiv of elemental sulfur was used for oxidative coupling into dibenzyl disulfide even by simple mixing of the thiol compound with sulfur and NMP in DMSO at rt (Scheme 3, eq 2). Nevertheless, dibenzyl monosulfide 5 has proven to be totally inert, probably due to its highly stable C−S bonds (Scheme 3, eq 3). On the basis of the aforementioned results and our previously reported work,2a a plausible mechanism was 280
DOI: 10.1021/acs.orglett.8b03728 Org. Lett. 2019, 21, 279−282
Letter
Organic Letters
nucleophilicity and oxidizing ability compared to elemental sulfur. Consequently, polysulfide A was capable of oxidatively decarboxylating phenylacetate B to provide benzyl polysulfide C, existing in equilibrium with dibenzyl disulfide D via sulfur exchange with A. The oxidative fragmentation of D promoted by A would provide two molecules of thiobenzaldehyde E, which could be considered as a principal monomer for the subsequent hexamerization process. The dimerization of thiobenzaldehyde E into dithiobenzoin J could proceed in a similar manner to classical benzoin condensation reaction. Indeed, intermediate F or G, which derived from addition of one or two polysulfide chains to thiobenzaldehyde E, could be deprotonated to give carbanion H stabilized by gem-disulfur atoms and subsequently added to another thiobenzaldehyde molecule E to provide dithiobenzoin J. Its vic-dimercaptostilbene tautomer K could condense with thiobenzaldehyde E to generate trimer L. Subsequent transformation of trimer L into hexamer 2a could occur via radical oxidative dimerization. Alternatively, we proposed also a stepwise pathway starting with a base-catalyzed benzoin condensation type reaction with thiobenzaldehyde E, followed by an oxidation of the resulting thiol M into thioketone N. Final condensation of tetramer N with dimer J would give hexamer 2a. In summary, we have shown that elemental sulfur in the presence of N-methylpiperidine in DMSO effects the decarboxylative sulfurative self-condensation of phenylacetic acids to produce a range of unusual sulfa heterocycles. These cascade transformations are reminiscent of, but go beyond, the sulfur-mediated oxidative oligomerization reactions of small molecules.6 We strongly believe that the practical and chemical value of this stable and symmetrical skeleton will be extremely interesting, for example as an excellent scaffold for catalyst design and development of new functional materials. One can readily conceive of different modes of desymmetrization of these molecules which could lead to a huge number of possibilities. We also have evidence that this unusual structure could be obtained from other kinds of readily available functional groups.
Scheme 3. Control Experiments
depicted in Scheme 4. First, cyclooctasulfur was activated by a ring opening reaction with NMP to provide piperidinium polysulfide A with various chain lengths and enhanced Scheme 4. Proposed Mechanism
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03728. Experimental procedures, characterizations of new compounds, and copies of their NMR spectra (PDF) Accession Codes
CCDC 1874679 and 1875507−1875509 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Thanh Binh Nguyen: 0000-0001-8779-9641 281
DOI: 10.1021/acs.orglett.8b03728 Org. Lett. 2019, 21, 279−282
Letter
Organic Letters Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank ICSN-CNRS for financial support and Dr. A. Marinetti (ICSN-CNRS) for her helpful support. REFERENCES
(1) (a) Nguyen, T. B.; Retailleau, P. Green Chem. 2018, 20, 387. For reviews on recent advances in organic chemistry using elemental sulfur, see: (b) Nguyen, T. B. Adv. Synth. Catal. 2017, 359, 1066. (c) Nguyen, T. B. Asian J. Org. Chem. 2017, 6, 477. (2) (a) Nguyen, T. B.; Ermolenko, L.; Corbin, M.; Almourabit, A. Org. Chem. Front. 2014, 1, 1157. For a similar reaction of decarboxylative coupling of phenylacetic acids with sulfur and amines leading to thiobenzamides, see: (b) Guntreddi, T.; Vanjari, R.; Singh, K. N. Org. Lett. 2014, 16, 3624. (3) Nguyen, T. B.; Retailleau, P. Org. Lett. 2017, 19, 3887. (4) Brahde, L. B. Acta Chem. Scand. 1954, 8, 1145. (5) (a) Nguyen, L. A.; Ngo, Q. A.; Retailleau, P.; Nguyen, T. B. Green Chem. 2017, 19, 4289. (b) Nguyen, T. B.; Retailleau, P. Org. Lett. 2017, 19, 3879. (c) Guntreddi, T.; Vanjari, R.; Singh, K. N. Org. Lett. 2015, 17, 976. (6) (a) Nguyen, T. B.; Ermolenko, L.; Almourabit, A. Org. Lett. 2012, 14, 4274. (b) Nguyen, T. B.; Retailleau, P. Green Chem. 2018, 20, 387.
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DOI: 10.1021/acs.orglett.8b03728 Org. Lett. 2019, 21, 279−282
