Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Wittig Ylide Mediated Decomposition of N‑Sulfonylhydrazones to Sulfinates Deepika Choudhary,† Vineeta Khatri,† and Ashok K. Basak*,†,‡ †
Department of Chemistry, University of Rajasthan, JLN Marg, Jaipur, 302004, India Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
‡
S Supporting Information *
ABSTRACT: N-Sulfonylhydrazones generate sulfinates selectively when treated with a stabilized Wittig ylide in a polar aprotic solvent at elevated temperature. The transition metal and base free decomposition method is applicable to N-sulfonylhydrazones generated from a number of aromatic and heteroaromatic aldehydes and ketones. In the case of Ntosylhydrazones derived from O-allyl and O-propargyl salicylaldehydes, selective formation of sulfinate occurs over intramolecular [3 + 2]cycloaddition reaction. stoichiometric amount of BF3·OEt2.5b Pan et al. reported Cu(OTf)2 catalyzed aerobic oxidation of arylsulfonylhydrazides to sulfonyl radicals which couple with alcohols generating sulfinates in good yields.5c Jang and co-workers reported the formation of sulfinates from thiophenol via aerobic oxidation using CuI as a catalyst.5d In recent years, N-tosylhydrazones have emerged as important electrophilic coupling component in various crosscoupling reactions.6 The base mediated decomposition of Ntosylhydrazone in the presence of a transition metal generates metallocarbene complex which is responsible for effective crosscoupling reactions). However, transition metal free transformations have also gained considerable research interest after the reports of Barluenga et al.7 N-Tosylhydrazones have been utilized in various coupling reactions to generate new C−O,8 C−N,9 and C−S10 bonds under transition metal free conditions. Decomposition of N-tosylhydrazones in the presence of a base in appropriate solvents generates dialkylidenehydrazines and oximes.11 In the presence of a transition metal catalyst (Fe, Cu, or Rh), base mediated decomposition of N-tosylhydrazones yields sulfones (see Scheme 2).12 A report by Volk et al. showed that cyclic sulfinate could be obtained via NaHCO3 mediated decomposition of hydrazone under transition metal free conditions.13 This report describes the synthesis of sulfinates from Nsulfonylhydrazones via a stabilized Wittig ylide mediated decomposition in a polar aprotic solvent under neutral conditions. Recently, we reported the coupling of N-tosylhydrazones with 5,5-dimethyl cyclohexane 1,3-dione under transition metal free conditions.14 In the presence of a base, the coupling reaction generate C−O bond in a polar aprotic solvent. In the absence of base, the reaction follows a different pathway in
S
ulfinates are valuable intermediates in organic synthesis.1 In the case of coupling reactions, sulfinates behave as both nucleophilic and electrophilic reagents depending on the reaction conditions.2 Sulfinates are also known to exhibit important biological activity profiles. Wu et al. reported cytotoxic activity of a sulfinate against human leukemia cell lines.3 Chiral sulfinates provide convenient access to the chiral sulfur compounds including sulfoxide and sulfinamide.4 In light of the emergence of sulfinates as important synthetic intermediates, several methods have been reported for their synthesis. A review of recent synthetic methods for achiral sulfinates is summarized in Scheme 1. Wu and co-workers reported conversion of benzylic alcohols to sulfinates using TosMIC catalyzed by BiBr3 under mild acidic conditions.3 TosMIC was also utilized to generate sulfinates from alcohols under Mitsunobu conditions.5a Alcohols can also be converted to sulfinates by reaction with sodium sulfinate using a Scheme 1. Recent Methods for Achiral Sulfinate Synthesis
Received: December 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03953 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Synthesis of Sulfone and Sulfinate from NTosylhydrazone
To examine the effect of the size of the alkyl group on the reactivity, ylides having esters with varying size of alkyl groups were tested. The results, as listed in Table 2, reveal that ylides Table 2. Screening of Ylides for Decomposition of NTosylhydrazone to Sulfinate
which two molecules of 1,3-dione undergo condensation with N-tosylhydrazone to generate tetraketo compound exclusively in a nonpolar solvent. Encouraged by these results, we screened several carbon nucleophiles and observed that N-tosylhydrazone 1a undergoes decomposition to generate sulfinate 3a in 51% yields when heated with Wittig ylide 2a in toluene at 95 °C for 3 h (entry a, Table 1). A short solvent screening revealed
solvent
2a (equiv)
a b c d e f g h i j k l
toluene Cl2(CH2)2 CH3CN 1,4-dioxane EtOH DMF DMSO NMP DMEU DMPU DMPU DMPU
1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.25 0.10
conditionsa 95 90 90 95 95 95 95 95 95 95 95 95
°C, °C, °C, °C, °C, °C, °C, °C, °C, °C, °C, °C,
3h 4h 3h 3h 10 h 15 min 20 min 25 min 15 min 10 min 10 min 30 min
ylide 2
a b c d e f
Ph3PCHCO2Et 2a Ph3PCHCO2Me 2b Ph3PCHCO2iPr 2c Ph3PCHCO2tBu 2d Ph3PCHCOCH3 2e Ph3PCHCN 2f
time 10 10 15 30 30 30
min min min min min min
yield (%)a 64 66 60 56 trace ND
a
All reactions were carried out using 1.0 equiv of 1a, 1.25 equiv of ylide in DMPU (0.5 M); ND = yield not determined.
Table 1. Optimization of Reaction Conditions for Transforming N-Tosylhydrazone to Sulfinate
entry
entry
incorporating esters with smaller alkyl groups provide better results (entries a−c, Table 2). The Wittig ylide generated from bromoacetone and bromoacetonitrile containing strong electron withdrawing groups were not effective. The optimized condition was tested on N-tosylhydrazones generated from several aldehydes and ketones. As presented in Scheme 3, the reactions were successful with N-tosylhydrazones synthesized from aryl and heteroaryl aldehyde and ketones. NTosylhydrazone generated from 3,4-dimethoxybenzaldehyde and 3,4,5-trimethoxybenzaldehyde produced the corresponding sulfinates 3b and 3c in 68% and 70% yields, respectively. 3Bromobenzaldehyde derived hydrazone provided sulfinate 3d in 60% yields. 3-Nitrobenzaldehyde derived hydrazone generated a complex reaction mixture in DMPU. However, sulfinate 3e could be obtained in 38% yield when the reaction was carried out in toluene at 90 °C. Sulfinate 3f and 3g having 4-chlorophenyl and 4-cyanophenyl groups were obtained in 59% and 57% yields, respectively. 2-Fluorobenzaldehyde derived hydrazone produced the sulfinate 3h in moderate yields (56%). 2-Naphthaldehyde derived hydrazone furnished sulfinate 3i in 68% yield. 4-Methoxyacetophenone derived hydrazone gave sulfinate 3j in 66% yield while benzophenone derived hydrazone generated the corresponding sulfinate 3k in 60% yield. Hydrazone derived from fluorenone gave sulfinate 3l in 64% yield. Among the heterocycles, pyridine 3-carboxaldehyde derived hydrazone gave sulfinate 3m in 66% yield whereas furan 2-carboxaldehyde derived hydrazone furnished the sulfinate 3n in 68% yield. Similarly, N-Boc-5-bromoindole 3carboxaldehyde derived N-tosylhydrazone furnished sulfinate 3o in 54% yield. No reaction was observed with Ntosylhydrazone derived from salicylaldehyde possibly due to acidic nature of the phenolic hydroxyl group. However, O-allyl, O-methyl acetate, and O-propargyl salicylaldehyde derived substrates showed very good reactivity and generated the corresponding sulfinates (3q−3s) selectively in good yields. NTosylhydrazone derived from cyclohexane carboxaldehyde did not react presumably due to higher pKa value of N−H proton. To study the effect of the substitution on the aryl groups attached to the S atom of the sulfonylhydrazones, we converted a few commercially available sulfonyl chlorides to the corresponding hydrazides15 and then treated with an aldehyde to generate the sulfonylhydrazones (see the Supporting
yield (%)c 51 45b 48b 44 NRb 54 52 53 56 60 64 ND
a All reactions were carried out in 200 mg scale using 1.0 equiv of 1a in appropriate solvent (0.5 M). bReactions were carried out in sealed vials. cFormation of sulfone was not observed under these conditions; NR = no reaction; ND = yield not determined; NMP = Nmethylpyrrolidinone; DMEU = N,N-dimethylethylene urea; DMPU = N,N-dimethylenepropylene urea.
that the reaction occurred in several nonprotic solvents. Reaction in 1,2-dichloroethane generated sulfinate only in 45% yield (entry b, Table 1). In CH3CN, the reaction produced sulfinate 3a in 48% yields. The reaction produced a similar result in 1,4-dioxane as solvent. No reaction was observed in EtOH even after heating for 10 h. In polar aprotic solvents, a dramatic increase in the rate was observed (entries f−j, Table 1). In DMF, the reaction was complete within 15 min to generate 3a in 54% yields. Similar results were observed when the reaction was carried out in DMSO and NMP (entries g and h, Table 1). Improved yield was observed when the reaction was carried out in DMPU. The best yield for sulfinate 3a was obtained when the reaction was carried out using 1.25 equiv of ylide 2a in DMPU at 95 °C. Catalytic amount of 2a (10 mol %) gave very low conversion (entry l, Table 1) under the reaction conditions. B
DOI: 10.1021/acs.orglett.7b03953 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Synthesis of Sulfinates from N-Tosylhydrazonesa
Scheme 4. Synthesis of Sulfinates from Various NSulfonylhydrazonesa
a
All reactions were carried out in 100 mg scale using 1.0 equiv of Nsulfonylhydrazone, 1.25 equiv of 2b in DMPU (0.5 M) at 95 °C.
Scheme 5. Mechanism for the Ylide Mediated Decomposition of N-Sulfonylhydrazone and Controlled Experiments a All reactions were carried out in 100 mg scale using 1.0 equiv of Ntosylhydrazone, 1.25 equiv of 2b in DMPU (0.5 M) at 95 °C. NR = no reaction. bReaction was carried out in toluene (0.5 M) at 90 °C. c Reaction was carried out at 90 °C.
Information). As shown in Scheme 4, the sulfinate formation was effective with aryl, heteroaryl and benzyl group attached to S atom of hydrazones. Aryl rings having electron donating groups produced better results. Sulfinates 5b and 5c with 4methoxyphenyl and 3,4-dimethoxyphenyl group on the S atom were obtained in 66% and 68% yields, respectively. Sulfinate 5d and 5e, containing 3-(trifluoromethyl)phenyl and 4-bromophenyl groups on the S atom were obtained in 63% and 60% yields, respectively. Sulfinates 5f and 5g having mesityl and 4tert butylphenyl groups on S atom were also obtained in good yields. Sulfinate 5h containing benzyl group on the S atom was obtained in 68% yield. Sulfinates 5i and 5j having 5bromothiophene and 2-naphthyl group on the S atom were obtained in 58% and 65% yields, respectively. The possible mechanism for the ylide mediated decomposition of sulfonylhydrazone is depicted in Scheme 5. We believe that the reaction proceeds via proton abstraction as no reaction occurs with 1416 (Scheme 5b). N−H proton abstraction in 6 by ylide 2b triggers decomposition of the sulfonylhydrazone 6 to generate ionic intermediate 9. Rapid protonation of 9 leads to intermediate 11 which on C
DOI: 10.1021/acs.orglett.7b03953 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
F.; Hernandez Linares, A.; Mastranzo, V. M.; Ortiz, B.; SanchezObregon, R.; Fraile, A.; Garcia Ruano, J. L. J. Org. Chem. 2011, 76, 4635. (c) Aziz, J.; Messaoudi, S.; Alami, M.; Hamze, A. Org. Biomol. Chem. 2014, 12, 9743. (d) Lujan-Montelongo, J. A.; Estevez, A. O.; Fleming, F. F. Eur. J. Org. Chem. 2015, 2015, 1602. (3) Li, H. J.; Wang, R.; Gao, J.; Wang, Y. Y.; Luo, D. H.; Wu, Y. C. Adv. Synth. Catal. 2015, 357, 1393. (4) For leading references, see (a) Zhang, Y.; Chitale, S.; Goyal, N.; Li, G.; Han, Z. S.; Shen, S.; Ma, S.; Grinberg, N.; Lee, H.; Lu, B. Z.; Senanayake, C. H. J. Org. Chem. 2012, 77, 690. (b) Fernández, I.; Khiar, N. Chem. Rev. 2003, 103, 3651. (5) (a) Kadari, L.; Radha Krishna, P.; Prapurna, Y. L. Adv. Synth. Catal. 2016, 358, 3863. (b) Huang, M.; Hu, L.; Shen, H.; Liu, Q.; Hussain, M. I.; Pan, J.; Xiong, Y. Green Chem. 2016, 18, 1874. (c) Du, B. N.; Li, Z.; Qian, P.; Han, J. L.; Pan, Y. Chem. - Asian J. 2016, 11, 478. (d) Shyam, P. K.; Kim, Y. K.; Lee, C.; Jang, H.-Y. Adv. Synth. Catal. 2016, 358, 56. (6) For recent reviews, see (a) Barluenga, J.; Valdés, C. Angew. Chem., Int. Ed. 2011, 50, 7486. (b) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560. (c) Xiao, Q.; Zhang, Y.; Wang, J. B. Acc. Chem. Res. 2013, 46, 236. (d) Jadhav, A. P.; Ray, D.; Rao, V. U. B.; Singh, R. P. Eur. J. Org. Chem. 2016, 2016, 2369. (7) Barluenga, J.; Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Nat. Chem. 2009, 1, 494. (8) For a selected example, see Barluenga, J.; Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Angew. Chem., Int. Ed. 2010, 49, 4993. (9) (a) Hamze, A.; Tréguier, B.; Brion, J.-D.; Alami, M. Org. Biomol. Chem. 2011, 9, 6200. (b) Aziz, J.; Brion, J. D.; Hamze, A.; Alami, M. Adv. Synth. Catal. 2013, 355, 2417. (c) Roche, M.; Frison, G.; Brion, J. D.; Provot, O.; Hamze, A.; Alami, M. J. Org. Chem. 2013, 78, 8485. (d) Roche, M.; Bignon, J.; Brion, J. D.; Hamze, A.; Alami, M. J. Org. Chem. 2014, 79, 7583. (10) For selected examples, see (a) Feng, X.-W.; Wang, J.; Zhang, J.; Yang, J.; Wang, N.; Yu, X.-Q. Org. Lett. 2010, 12, 4408. (b) Ding, Q.; Cao, B.; Yuan, J.; Liu, X.; Peng, Y. Org. Biomol. Chem. 2011, 9, 748. (c) Lin, Y.; Luo, P.; Zheng, Q.; Liu, Y.; Sang, X.; Ding, Q. RSC Adv. 2014, 4, 16855. (d) Mao, S.; Gao, Y.-R.; Zhu, X. Q.; Guo, D.-D.; Wang, Y.-Q. Org. Lett. 2015, 17, 1692. (e) Li, L.-L.; Gao, L.-X.; Han, F.-S. RSC Adv. 2015, 5, 29996. (f) Tsai, A. S.; Curto, J. M.; Rocke, B. N.; Dechert-Schmitt, A. M. R.; Ingle, G. K.; Mascitti, V. Org. Lett. 2016, 18, 508. (11) Sha, Q.; Wei, Y. Tetrahedron 2013, 69, 3829. (12) (a) Zhao, J. L.; Guo, S.-H.; Qiu, J.; Gou, X.-F.; Hua, C.-W.; Chen, B. Tetrahedron Lett. 2016, 57, 2375. (b) Barluenga, J.; TomásGamasa, M.; Aznar, F.; Valdés, C. Eur. J. Org. Chem. 2011, 2011, 1520. (c) Feng, X. W.; Wang, J.; Zhang, J.; Yang, J.; Wang, N.; Yu, X. Q. Org. Lett. 2010, 12, 4408. (d) Zhang, J. L.; Chan, P. W. H.; Che, C. M. Tetrahedron Lett. 2003, 44, 8733. (13) Bertha, F.; Kégl, T.; Fetter, J.; Molnár, B.; Dancsó, A.; Németh, G.; Simig, G.; Volk, B. J. Org. Chem. 2017, 82, 1895. (14) Choudhary, D.; Agrawal, C.; Khatri, V.; Thakuria, R.; Basak, A. K. Tetrahedron Lett. 2017, 58, 1132. (15) Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. J. Org. Chem. 2014, 79, 328. (16) Kong, Y.; Zhang, W.; Tang, M.; Wang, H. Tetrahedron 2013, 69, 7487. (17) (a) Zheng, Y.; Zhang, X.; Yao, R.; Wen, Y. C.; Huang, J.; Xu, X. J. Org. Chem. 2016, 81, 11072. (b) Divya, K. V. L.; Meena, A.; Suja, T. D. Synthesis 2016, 48, 4207.
nucleophilic displacement by the sulfonyl group 12 generates sulfinate 13. In DMPU, which is known to stabilize ion-pairs and increase the nucleophilicity of anions, the decomposition of 1s leads to sulfinate 3s exclusively whereas in toluene the decomposition yields 12% of pyrazole 15 generated via intramolecular [3 + 2]-cycloaddition17 reaction along with the sulfinate 3s. This suggests that the sulfinate formation occurs via rapid protonation of intermediate 9. In the cross over experiment between N-sulfonylhydrazones 1f and 4f, cross over products were observed suggesting that the reaction is likely intermolecular in nature. Although ylide 2b could be recovered partly after the reaction, the catalytic amount of the ylide is not sufficient for effective transformation under the present reaction conditions. Reaction of the N-sulfonylhydrazone 1a in the presence of a phosphazene base, tert-butylimino-tri(pyrrolidino)phosphorane and sulfur ylide, methyl 2-(diphenyl-λ4-sulfanylidene)acetate did not yield sulfinate. Transition of the phosphorus ylide 2b to its salt and vice versa is believed to be responsible for the effective conversion of N-sulfonylhydrazones to sulfinates. In summary, a convenient method for the decomposition of N-sulfonylhydrazones to the corresponding sulfinates is developed under neutral reaction conditions. The transition metal and base free decomposition method is compatible with other functional groups and generates sulfinates in good yields. The O-allyl and O-propargyl salicylaldehyde derived Ntosylhydrazones selectively generated the sulfinates and did not produce [3 + 2]-cycloadducts, which are obtained exclusively in the presence of a base. A more detailed investigation on this method is going on in our laboratory.
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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.7b03953. Typical experimental procedure, characterization data and copies of 1H NMR and 13C NMR spectra for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] ORCID
Ashok K. Basak: 0000-0002-1142-1324 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Research grants from SERB (Grant YSS/2014/000957) and UGC (F.4-5/2006(BSR)), New Delhi, is gratefully acknowledged. We thank MRC, MNIT Jaipur for recording the NMR spectra. We also thank USIC, University of Rajasthan, Jaipur, for the high-resolution mass spectrometry (HRMS) data.
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REFERENCES
(1) For reviews on the synthesis and applications of sulfinates, see (a) Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651. (b) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600. (2) (a) Tapia-Pineda, A.; Perez-Arrieta, C.; Silva-Cuevas, C.; Paleo, E.; Lujan-Montelongo, J. A. J. Chem. Educ. 2016, 93, 1470. (b) Yuste, D
DOI: 10.1021/acs.orglett.7b03953 Org. Lett. XXXX, XXX, XXX−XXX
