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`Angew Chem Int Ed Engl. Author manuscript; available in PMC 2015 March 24.
`Published in final edited form as:
`Angew Chem Int Ed Engl. 2014 March 24; 53(13): 3432–3435. doi:10.1002/anie.201310634.
`
`Aerobic Oxidation in Nanomicelles of Aryl Alkynes, in Water at
`Room Temperature**
`
`Sachin Handa, James C. Fennewald, Shane Rainey, and Bruce H. Lipshutz
`Department of Chemistry & Biochemistry, University of California Santa Barbara, California 93106
`USA
`
`Bruce H. Lipshutz: lipshutz@chem.ucsb.edu
`
`Abstract
`On the basis of the far higher solubility of oxygen gas inside the hydrocarbon core of
`nanomicelles, metal and peroxide free aerobic oxidation of aryl alkynes has been achieved in
`water at room temperature. Many examples are offered that illustrate broad functional group
`tolerance. The overall process is environmentally friendly, documented by the associated low E
`Factors.
`
`Keywords
`aerobic oxidation; TPGS-750-M; ATRA; micellar catalysis; E Factors; hydrophobic effect
`
`Reactions in alternative media represent one approach to decreasing the huge amounts of
`organic waste generated by use of organic solvents in organic chemistry.[1] While such
`options as ionic liquids, supercritical CO2, and fluorinated media, among others, have made
`important inroads in this regard, the most likely and perhaps logical choice, following
`Nature’s lead, is water.[2] Although we have investigated many processes enabled by
`designer surfactants where water serves as the gross reaction medium,[3] synthetic advantage
`has yet to be taken of the well established far greater solubility of gases in organic media
`than in water.[4] Since our reported cross-couplings and related reactions take place within
`the lipophilic cores of tailor-made micellar arrays, gases, as well as reactants and catalysts,
`should likewise co-exist in high concentrations and be available to participate in a given
`transformation. Surprisingly, there appears to be limited methodology[5] of synthetic utility
`focused on the use of gases in micellar catalysis. In this report we describe one such process
`involving dissolved oxygen serving as the stoichiometric oxidant, along with readily
`available aryl alkynes and sulfinic acids that leads to valuable β-ketosulfones under very
`mild, metal-free, and green conditions.
`
`**Financial support for this work was provided by the U.S. National Institutes of Health (******************* ).
`© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`Correspondence to: Bruce H. Lipshutz, lipshutz@chem.ucsb.edu.
`Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201xxxxxx
`
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`β-Ketosulfones can be derived from a radical reaction between an arylacetylene and a
`stoichiometric amount of a sulfinic acid. However, the short lifetime of the vinyl radical so
`generated[6] (Scheme 1) makes trapping with oxygen difficult and prevents the desired
`reaction from having any generality in a purely aqueous or wet organic solvent. On the other
`hand, by virtue of the hydrophobic effect[7] operating within the water-free lipophilic inner
`core of a nanomicelle, H-atom abstraction by a reactive vinyl radical by atom transfer
`radical addition (ATRA) from water or another molecule of alkyne should be minimized
`(path A). Rather, trapping of the vinyl radical by molecular oxygen is highly favored and
`ultimately leads to β-ketosulfone formation (path B). By contrast, related literature reports
`on this topic are far less environmentally friendly, as they take place in dry organic solvents
`at elevated temperatures with the use of metals and or peroxide initiators,[8] and offer no
`opportunities to recycle the reaction mixture. β-Ketosulfones are highly desirable materials,
`known to have fungicidal,[9] antibacterial, [10] as well as other biological properties.[11]
`Moreover, numerous derivatives, such as olefins, disubstituted alkynes, [12] allenes, [13] and
`chiral vinyl sulfones[14] and ketones[13, 14] have been prepared from such intermediates.
`
`A model reaction between phenylacetylene 1 with p-toluene-sulfinic acid sodium salt 2 was
`run at ambient temperature in an aqueous medium containing 2 wt. % TPGS-750-M
`(Scheme 2).[15] The acid was generated in situ by the reaction of inexpensive 2 and HCl.
`Only traces of the desired product, however, were observed after 24 hours. A large amount
`of unreacted phenylacetylene was recovered, along with byproducts, most likely due to rapid
`autoxidation of p-tolylsulfinc acid to the sulfonic acid and quenching of the vinyl radical by
`ATRA.[6b,16] Preventing autoxidation of a sulfinic acid to a sulfonic acid by introducing 2,6-
`lutidine into the reaction medium greatly improved formation of the desired product.[17]
`After stirring at room temperature for eight hours, β-ketosulfone 3a was isolated in 70%
`yield, to the complete exclusion of the corresponding vinylsulfone.
`
`Optimization of this conversion documented its dependence on several reaction variables,
`including (1) the choice of surfactant; (2) source of oxygen; (3) temperature; (4) base; (5)
`conditions for neutralization of the sodium arylsulfinate with HCl; (6) ratio of arylsulfinic
`acid to base; (7) equivalents of sulfinic acid needed to drive the reaction to completion; (8)
`surfactant concentration in water; (9) arylacetylene concentration in the surfactant; and (10)
`portion-wise addition of reagents. After extensive screening (see Supporting Information),
`the optimum conditions were determined to be: TPGS-750-M (2% weight percent) as
`surfactant in water, 2,6-lutidine as base, 4.0 equivalents of arylsulfinic acid, 0.3 M
`arylacetylene in the aqueous medium, along with ambient temperature and light.
`
`Substrate scope was next explored (Table 1). Good-to-excellent yields were obtained with
`electron-donating substituents on the aryl ring of the alkynes, leading to products 4, 5 and
`18. Heteroaromatic and sensitive nitrile functional groups were all well tolerated, and 69–
`78% yields were obtained for aducts 6–8. Challenging electron-withdrawing groups in the
`educts, nonetheless, afforded products bearing bromo (9 and 10), acetyl (11), ethynyl (12),
`cyano (7 and 8), and amide (25 and 26) residues, Similarly, a representative alkylsulfinic
`acid also led to the desired sulfone 17. Electronic rather than steric effects were found to be
`of greater consequence, as no reaction was observed with a substrate containing CF3 groups
`in the 3- and 5-positions of the aromatic ring of an arylacetylene. It is noteworthy that only
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`one ethynyl group showed reactivity in 3-ethynyl phenylacetylene to afford product 12. A
`cycloalkenyl group was also well tolerated (14)[18]
`
`Sequential reactions involving initial β-ketosulfone formation are also possible. For
`example, after an initial reaction giving β-ketosulfone 10, Suzuki-Miyaura couplings with
`either an arylboronic acid or MIDA boronate[19] within the same pot led to final products 15
`and 20 in 62% and 55% overall yields, respectively (Scheme 3).
`
`To gain insight regarding the location of the reaction under micellar conditions, an
`arylalkyne 21 bearing a p-dimethylamino group on the aryl ring of the alkyne was subjected
`to protonation (aq. HCl) under aerobic oxidation conditions (Scheme 4A). Rather than the
`expected β-ketosulfone, only arylvinylsulfone 22 was obtained (89%). The water-soluble
`ammonium salt is unlikely to enter the oxygen-rich nonpolar lipophilic core of the micelle
`and hence, dioxygen trapping is precluded. Instead, the vinyl radical is converted to the
`corresponding olefin 22 by an ATRA process. In the presence of twice the typical amount of
`sulfinic acid, a second addition of arylsulfonyl to 22 ensues forming 23 in 81% yield.
`Similar results were obtained when 22 was isolated and re-subjected to the optimized
`reaction conditions, leading to 23 in 84% isolated yield. Protection of the amine
`functionality in 21 (X = NH) as the derived acetamide 24 (X = NHCO) negated salt
`formation and led, exclusively, to β-ketosulfone 25 in 69% yield. Inverting the location of
`the acetamide group from arylacetylene 24 to the arylsulfinic acid coupling partner gave
`similar results (Scheme 4B): β-ketosulfone product 26 was isolated in 72% yield. Replacing
`nitrogen in the arylalkyne with oxygen (i.e., 27, X = O) afforded results similar to those
`from 24, again suggesting that the reaction is taking place within the micellar core. In this
`case, β-ketosulfone 28 was obtained in 70% isolated yield (91% yield based on recovered
`starting material; brsm).
`
`Additional evidence regarding the likely location of these reactions could be obtained by
`altering the reaction medium such that the conversion of p-dimethylaminophenylacetylene
`21 to the corresponding β-ketosulfone could be realized (Scheme 5). To achieve salt-free
`conditions, the stronger base N,N-diisopropyl-ethylamine (DIPEA) was used in place of 2,6-
`lutidine. As postulated, DIPEA inhibited formation of salt 21a thereby allowing uncharged
`21 to gain entry to the micellar core facilitating generation of the desired product 29 (path
`II). Variable yields were obtained depending upon the reaction temperature (e.g., 61% at
`room temperature, 78% at 40 °C). Comparatively weaker bases such as pyridine, 2,4,6-
`collidine, and 4-picoline gave the same undesirable results seen with 2,6-lutidine, where
`protonation took place leading to a polar intermediate that remains in the poorly oxygenated
`water and produces an olefinic product (path I).
`
`To confirm that air, rather than water, was the source of oxygen in the products, a reaction in
`2% TPGS-750-M in 18O-labelled water was conducted. As expected, no incorporation
`of 18O was observed in the product (Scheme 6, top). The radical nature of these reactions
`was further confirmed by inclusion of catalytic amounts of inhibitors BHT or TEMPO;
`product 13a was formed only to the extent of 7 and 9%, respectively (Scheme 6, bottom).
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`A plausible mechanism for the overall sequence starts from in situ generation of free
`arylsulfinic acid 30 from its sodium salt and HCl (Scheme 7). No aerobic oxidation reaction
`occurs without this initial neutralization, followed by exposure to 2,6-lutidine as base. Thus,
`generation of sulfonyl radical 31 requires a lutidinium salt under ambient light, rather than
`the corresponding sodium salt. An aryl sulfonyl radical is then generated after single
`electron transfer (SET) to oxygen that is highly localized within the micelle. Radical 31 then
`adds to arylacetylene 1 to give vinyl radical 32 which is then trapped by oxygen to generate
`intermediate 33. SET from another molecule of arylsufinate to 33 generates arylperoxide
`anion 34. The newly generated arylsulfonyl radical enters the next cycle, while 34 undergoes
`protonation either by water or a pyridinium cation to form arylhydroperoxide species 35.
`Oxidation of arylsulfinate to arylsulfonate by 36 generates an enol that tautomerizes to final
`product 36. The arylsulfonic acid generated as a byproduct remains in the aqueous phase,
`while the organic product can be isolated by extraction.
`
`An E Factor[20] of 5.3 was determined on the basis of organic solvent utilized for the model
`system (Scheme 8)..[21] This value compares quite favorably with those typical of the
`pharma and fine chemicals industries,[22] as well as related literature.[8, 23] Moreover,
`recycling of the aqueous mixture led to good-to-excellent yields being obtained over three
`reaction cycles. The yield for the third cycle was noticeably lower, but this was due to
`practical considerations, as buildup of the sulfonic acid salt caused thickening and, therefore,
`problems with stirring on the scale at which the reaction was run.
`
`In summary, an environmentally friendly aerobic oxidation has been developed for
`converting arylalkynes and arylsulfinate salts to β-ketosulfones. This process relies on the
`far greater solubility of oxygen in hydrocarbon media as found within micellar arrays than in
`the surrounding water. The process, enabled by a commercially available designer
`surfactant, is metal-free, takes place in water at room temperature using air as the
`stoichiometric oxidant, and is amenable to recycling of the aqueous reaction medium in
`which the amphiphile remains. Minimal amounts of organic solvent can be used to recover
`the desired product, which leads to a low E Factor. Experiments supporting a radical-based
`process are provided, along with data suggesting that the oxidation is taking place within the
`lipophilic core of the nanomicelles present in aqueous solution.
`
`Supplementary Material
`
`Refer to Web version on PubMed Central for supplementary material.
`
`References
`
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`Gadwood RC. J Org Chem. 2011; 76:4379–4391. Sigma-Aldrich catalog # 733857. [PubMed:
`21548658]
`16. For details about ATRA processes, see; Jasperse CP, Curran DP, Fevig TL. Chem Rev. 1991;
`91:1237–1286.Majumdar KC, Debnath P. Tetrahedron. 2008; 64:9799–9820.Bałczewski P,
`Szadowiak A, Białas T. Heteroatom Chem. 2006; 17:22–35.
`17. For detailed optimization studies and procedures, see the SI.
`18. Neither terminal alkylacetylenes, nor aryl alkyl alkynes reacted under these conditions.
`19. Isley NA, Gallou F, Lipshutz BH. J Am Chem Soc. 2013; 135:17707–17710. [PubMed: 24224801]
`20. a) Sheldon RA. Green Chem. 2007; 9:1273–1283.b) Bonollo S, Lanari D, Longo JM, Vaccaro L.
`Green Chem. 2012; 14:164–169.c) Kirchhoff MM. J Chem Educ. 2013; 90:683–684.
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`22. Sheldon, RA.; Arends, IWCE.; Hanefeld, U. Green Chemistry and Catalysis. Wiley-VCH, Verlag
`GmbH & Co; KGaA: 2007.
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`Scheme 1.
`Aerobic oxosulfonylation of arylacetylenes within nanomicelles in water.
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`Scheme 2.
`Aerobic difunctionalization of an arylacetylene.
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`Scheme 3.
`Sequential 1-pot aerobic oxidation/Suzuki-Miyaura coupling.
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`Scheme 4.
`Sequence of events within micelles leading to products.
`Conditions: a) 1 mmol, 0.3 M arylacetylene in 2 wt. % TPGS-750-M, 4.0 mmol sodium p-
`toluenesulfinate in Scheme 5A while sodium 4-(N-acetylamino)benzenesulfinate in Scheme
`5B, 4.0 mmol aq. HCl, 3.5 mmol 2,6-lutidine (all reagents were added in two portions in 80
`min intervals), RT, air balloon, up to 24 h. After HCl addition to the solution of sodium p-
`toluenesulfinate in TPGS-750-M, the mixture was stirred for 2–3 min. before addition of
`2,6-lutidine (see SI). b) addition of extra 4.0 (1 × 4) equivalents of arylsulfinic acid at 1.5 h
`intervals. †Yield 84% when reaction run with 22 as SM.
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`Scheme 5.
`Use of base strength to determine reaction pathway.
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`Scheme 6.
`Isotopic labeling and radical quenching experiments.
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`Scheme 7.
`Mechanistic rationale for the conversion of 1 to β-ketosulfone 37.
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`Scheme 8.
`E Factor and recycling studies.
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`Substrate scope of micellar aerobic difunctionalization of aryl acetylenes
`
`Table 1
`
`Conditions: 1 mmol, 0.3 M phenylacetylene in 2 wt. % TPGS-750-M in water, 4.0 mmol sodium p-toluenesulfinate, 4.0 mmol aq. HCl*, 3.5 mmol
`2,6-lutidine (all these reagents were added in two portions in 80 min intervals), RT, air balloon. *After HCl addition to the solution of sodium p-
`toluenesulfinate in TPGS-750-M, the mixture was stirred for 2–3 min before addition of 2,6-lutidine (for details, see the SI).
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