β,β-Disilylated Sulfones as Versatile Building Blocks in Organic Chemistry - A New Sulfonyl Carbanion Transmetalation

Abstract

1,3-Bis(trimethylsilyl)propyl phenyl sulfone undergoes, in contrast to all reported sulfones bearing α-hydrogen atoms, an initial ortho metalation to an aryllithium at low temperature, which transmetalates quantitatively to the corresponding α-sulfonyl organolithium intermediate. Both organolithiums react selectively with aldehydes to give the corresponding products in good to excellent yields with high selectivity.

The formation of carbon-carbon double bonds is one of the most important reactions in organic synthesis, since olefins are prevalent in many naturally occurring and biologically active molecules, polymer precursors, and organic materials. Numerous methods ranging from Wittig and related reactions, through Peterson- or Tebbe-type olefinations to cross-metathesis were developed over the years. Among those, the Julia olefination and its variants [¹] represents one of the most powerful tools of organic chemistry, since it is known to be E-selective, well controlled, and easy to perform.

In a recent total synthesis of dihydronepetalactone, [²] a Wittig reaction using phosphorane A was applied to construct the pivotal trisubstituted allylsilane cyclization precursor B (Scheme  [¹] , X = H). This reaction was plagued by low yield and the formation of side products. Thus, an alternative selective approach to allylsilanes of type B (X = H) or 2 (X = TMS) was highly needed. Since known methods [³] to access compounds of type 2 were not applicable with respect to functional-group tolerance and ease of precursor synthesis, we aimed for the development of a Julia olefination using unknown silylated sulfones 1.

We present herein, initial results of a reactivity study of the so far unknown bissilylated sulfone 1 (Scheme  [¹] ). This sulfone proves to be a true synthetic chameleon because of its distinct behavior under defined metalation conditions, but also since the resulting anions can be recognized easily visually by their colors. Not less than three classes of so far more or less explored compound classes, compounds 2-4 can be synthesized with a good substrate scope in good to excellent yield applying defined metalation conditions. This reactivity diversity is based on a new sulfonyl carbanion transmetalation.

Bis(trimethylsilylmethyl)methyl phenyl sulfone (1) was prepared by successive alkylation of methyl phenyl sulfone with (chloromethyl)trimethylsilane in the presence of TMEDA in excellent yield in a one-pot process (Scheme  [²] ). It is worth underlining that a single addition of two equivalents of n-BuLi and (chloromethyl)trimethylsilane does not lead to compound 1, but gives only the monoalkylated product even after long reaction time at elevated temperature.

Initial experiments of 1 with benzaldehyde using standard Julia olefination conditions (n-BuLi, -78 ˚C) furnished ortho-substituted 3a instead of the expected olefination product (Scheme  [³] ). Addition of TMEDA leads to the same result. This was surprising, since directed ortho metalation was never observed before as the initial event for sulfones bearing α-hydrogens. [4] [5] On the other hand, allylic silyl ether 4a was obtained as the only product using HMPA as an additive.

These results indicated that the ortho- or the α-carbanions 1a-Li or 1b-Li were either selectively generated or that a rearrangement between them took place (Scheme  [4] ). To distinguish these options, the deprotonation of 1 using different bases and additives was monitored by keeping the reaction mixtures for 30 minutes at the given temperatures, taking aliquots, quenching them by D₂O, and analyzing the products by ^¹H NMR (Scheme  [4] , Table  [¹] ). Using n-BuLi as a base in THF at -78 ˚C, 1a-D and 1b-D were formed in a 2.3:1 ratio (entry 1). Warming successively to -40 ˚C, 0 ˚C, and 20 ˚C leads to a reversed ratio of 1a-D/1b-D of 1:24. The course of the transmetalation of the ortho- to the α-carbanion can be monitored even visually, since 1a-Li is pale yellow while 1b-Li appears red in solution. The initial 1a-Li/1b-Li selectivity is better with TMEDA (entry 2) and especially in DME (entry 3). Immediate α-deprotonation to 1b-Li was predominant with HMPA even at -78 ˚C (entry 4). LDA deprotonated 1 less selectively to 1a-Li at -78 ˚C, but rearrangement to 1b-Li took place smoothly (entry 5). The conversion was quantitative for all entries. In contrast, widely used ­KHMDS was completely ineffective as a base (entry 6).

With reliable conditions in hand to generate anions 1a-Li and 1b-Li selectively, the scope of their reactivity toward aldehydes was explored. Deprotonation of 1 with n-BuLi/TMEDA in THF at -78 ˚C for 30 minutes, followed by addition of aldehydes gave ortho-(hydroxyalkyl)phenyl sulfones 3a-d in excellent yield (Scheme  [5] , Table  [²] , entries 1-4). This method is also applicable to ketones such as cyclohexanone or benzophenone to provide alcohols 3e-f (entries 5 and 6).

When the reaction mixture of 1, n-BuLi, and TMEDA was allowed to warm to room temperature followed by addition of structurally different aldehydes, very unstable alcohols 6 resulted (Scheme  [6] ). To circumvent isolation of 6, benzoyl chloride [6] was added immediately after consumption of the aldehyde providing the more stable β-benzoyloxy sulfones 7a-e in good yields (Table  [³] ). The reagent used for the subsequent conversion of 7a-e to allylic bissilanes 2a-e in high yields was SmI₂ (0.1 M in THF; entries 1-5). Some isomerization was observed during reduction of 7b (E/Z ratio = 4:1, entry 2). Even brominated compound 2e was obtained in excellent yield (entry 5).

Deprotonation of 1 in the presence of HMPA as an additive and subsequent reaction with aldehydes at low temperature furnished the allylic silyl ethers 4a-f in good yield (Scheme  [7] , Table  [4] ). These compounds are very valuable as substituted allylic silane nucleophiles [7] or trimethylene methane precursors after conversion of the ­silyl ether unit to a triflate. [8]

This divergent reactivity can be rationalized as follows at the current stage: Initial ortho deprotonation of 1 with n-BuLi is strongly kinetically favored at low temperature. The resulting anion 1a-Li is stable at low temperature and reacts selectively with electrophiles to benzylic alcohols 3. On warming, the aryllithium transmetalates to thermodynamically favored α-sulfonyllithium 1b-Li and provides Julia olefination products 2. Immediate α-deprotonation to 1b-Li seems to prevail in the presence of HMPA, suggesting that good ligands for the lithium ion prevent precoordination of BuLi to the sulfone necessary for the formation of 1a-Li more effectively. This fact together with the synergistic facilitation of the Brook rearrangement [9] leads to silyl ethers 4 and contributes favorably to the diversity of the reactivity of 1.

How general is the sulfonyl anion transmetalation? It is known that deprotonation of isopropyl phenyl sulfone 8 occurs exclusively in α-position at room temperature (Scheme  [8] ). [¹0] To shed more light on a potentially similar initial metalation selectivity, orienting deprotonation/deuteration experiments were performed with 8 and phenyl (2,2,6,6-tetramethylhept-4-yl)phenyl sulfone (9), the carbon analogue of 1. For 8, exclusive but common α-deprotonation was found at -78 ˚C even after short deprotonation times. Compound 9, which was obtained by twofold alkylation of methyl phenyl sulfone with neopentyl iodide (see the Supporting Information), gave ortho-deuterated product 9a exclusively after five minutes deprotonation time. The lower D incorporation of 65% into 9 may be due to incomplete deprotonation of this even more hindered sulfone after the short metalation time. This result demonstrates that the initial ortho deprotonation and the subsequent rearrangement may be a more general process even when more acidic α-protons are available. The results of 8 and 9 vs. 1 point to steric reasons being responsible for the divergent deprotonation behavior. A potential kinetically destabilizing β-silyl carbanion effect [¹¹] can be excluded based on the common reactivity of 1 and 9. Future studies must determine how far the steric hindrance of the sulfones can be reduced to still allow initial ortho deprotonation. Other factors such as whether the transmetalation is inter- or intramolecular must be studied in detail.

In summary, a new sulfonyl carbanion transmetalation was discovered. It seems to be based on the limited accessibility of the α-proton in sulfones such as 1 or 9. A selective rich reactivity of bissilylated sulfone 1 based on its carbanion chemistry was uncovered. Directed ortho metalation/nucleophilic additions, Julia olefinations and Brook rearrangements can be selectively addressed. All products 2-4 are synthetically interesting in their own right. Especially the bis(allylic) silanes 2 will be interesting functional dinucleophiles and radical acceptors for future applications. Compounds 4 represent nucleophiles, which are applicable in Sakurai reactions or as substituted trimethylenemethane synthons after conversion of the silyl ether to a triflate. The synthetic potential and structural prerequisites of the new transmetalation must be explored in future studies. On this basis, many applications of 1 and other similar compound classes can be foreseen. Research along these lines is under way in this laboratory.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

We gratefully acknowledge generous funding by a grant of the Academy of Sciences of the Czech Republic (Z4 055 0506).

References

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References

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• 1b El-Awa A. Noshi MN. Mollat XJ. Fuchs PL. Chem. Rev.  2009,  109:  2315 
  Search in Google Scholar
• 1c Dumeunier R. Markó IE. In Modern Carbonyl Olefination   Takeda T. Wiley-VCH; Weinheim: 2004.  p.104 
• 1d Blakemore PR. J. Chem. Soc., Perkin Trans. 1  2002,  2563 
• 1e Kociensky PJ. In Comprehensive Organic Synthesis   Vol. 6:  Trost BM. Fleming I. Pergamon; New York: 1991.  p.987 
  Search in Google Scholar
• 2 Jahn U. Hartmann P. Kaasalainen E. Org. Lett.  2004,  6:  257 
  CrossrefSearch in Google Scholar
• For other methods, see:
• 3a Uenishi J. Iwamoto T. Ohmi M. Tetrahedron Lett.  2007,  48:  1237 
  Search in Google Scholar
• 3b Uenishi J. Ohmi M. Angew. Chem. Int. Ed.  2005,  44:  2756 
  Search in Google Scholar
• 3c Kercher T. Livinghouse T. J. Org. Chem.  1997,  62:  805 
  Search in Google Scholar
• 3d Kercher T. Livinghouse T. J. Am. Chem. Soc.  1996,  118:  4200 
  Search in Google Scholar
• 3e Wang KK. Dhumrongvaraporn S. Tetrahedron Lett.  1987,  28:  1007 
  Search in Google Scholar
• 4a Iwao M. Iihama T. Mahalanabis KK. Perrier H. Snieckus V. J. Org. Chem.  1989,  54:  24 
  Search in Google Scholar
• 4b MacNeil SL. Familoni OB. Snieckus V. J. Org. Chem.  2001,  66:  3662 
  Search in Google Scholar
• In a single example of a ortho metalation, but after α-deprotonation, the resulting dianion rearranges under harsh conditions:
• 5a Vollhardt J. Gais H.-J. Lukas KL. Angew. Chem., Int. Ed. Engl.  1985,  24:  610 
  Search in Google Scholar
• Application:
• 5b Gais H.-J. Ball WA. Bund J. Tetrahedron Lett.  1988,  29:  781 
  Search in Google Scholar
• 6a Pospíšil J. Pospíšil T. Markó IE. Org. Lett.  2005,  7:  2373 
  Search in Google Scholar
• 6b Markó IE. Murphy F. Dolan S. Tetrahedron Lett.  1996,  37:  2089 
  Search in Google Scholar
• 7 For a recent application, see: Yang D. Micalizio GC. J. Am. Chem. Soc.  2009,  131:  17548 
  CrossrefSearch in Google Scholar
• Recent reviews:
• 8a Le Marquand P. Tam W. Angew. Chem. Int. Ed.  2008,  47:  2926 
  Search in Google Scholar
• 8b Chan DMT. In Cycloaddition Reactions in Organic Synthesis   Kobayashi S. Jørgensen KA. Wiley-VCH; Weinheim: 2002.  p.57 
• 8c Frühauf H.-W. Chem. Rev.  1997,  97:  523 
  Search in Google Scholar
• 8d Trost BM. Angew. Chem., Int. Ed. Engl.  1986,  25:  1 
  Search in Google Scholar
• Recent reviews:
• 9a Smith AB. Wuest WM. Chem. Commun.  2008,  5883 
• 9b Schaumann E. Kirschning A. Synlett  2007,  177 
• 9c Moser WH. Tetrahedron  2001,  57:  2065 
  Search in Google Scholar
• 9d Brook AG. Bassendale AR. In Rearrangements in Ground and Excited States   Vol. 2:  de Mayo P. Academic Press; New York: 1980.  p.149 
  Search in Google Scholar
• ortho-Deprotonation is also observed for 8, but only after α-deprotonation:
• 10a Cabiddu S. Fattuoni C. Floris C. Gelli G. Melis S. Synthesis  1993,  41 
• 10b Cabiddu M. Cabiddu S. Fattuoni C. Floris C. Gelli G. Melis S. Phosphorus, Sulfur Silicon Relat. Elem.  1992,  70:  139 
  Search in Google Scholar
• 11 Engel W. Fleming I. Smithers RH. J. Chem. Soc., Perkin Trans. 1  1986,  1637 
  Crossref

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