[122833-58-3]  · C8H18N2O4S2  · (270.36)

(catalyst for organozinc-mediated additions to aldehydes,1 catalyst for Simmons-Smith type cyclopropanation of allylic alcohols2)

Physical Data: mp 157 °C; [a]D20 -20.1 (c 3.07, pyridine).

Solubility: soluble in most organic solvents except hydrocarbons.

Form Supplied in: white solid.

Preparative Methods: The enantiopure sulfonamide 1a is prepared via sulfonylation of (R,R)-1,2-diaminocyclohexane 2 in the presence of an excess of triethylamine (1).3 Use of excess amine base is essential for obtaining a high yield of the bis-sulfonamide. Synthesis of related bis-sulfonamides is easily accomplished by substituting the desired sulfonyl chloride in the former procedure. Recrystallization of the bis-sulfonamide 1a from hexane/ethyl acetate and drying over P2O5 allows for isolation of the analytically pure reagent. Methanesulfonyl chloride and (R,R)-1,2-diaminocyclohexane 2 are commercially available from a number of sources. However it should be noted that racemic 1,2-diaminocyclohexane 2 can be resolved via formation of the tartrate salt.4 Typically, the diamine can be obtained in >99:1 enantiomeric ratio (er) after two crystallizations from water. Determination of the enantiopurity of the diamine is accomplished via formation of the bis-3-toluyl amide and analysis via chiral stationary phase HPLC (Chiralcel AD; hexane/i-PrOH; 95:5, 1.0 mL min-1).

Handling, Storage, and Precautions: The sulfonamide is a shelf-stable, non-hygroscopic compound which does not require special precautions for storage or handling.


The 1,2-bis-(methanesulfonamido)-cyclohexane 1a is an important member of a larger class of C2-symmetric bis-sulfonamide ligands which have had a powerful impact on the field of organozinc chemistry.1,2 The success of these ligands is, in part, due to the straightforward installation of a variety of sulfonamide groups, providing access to a wide array of sterically and electronically diverse ligands.

Additions to Aldehydes

Alkylation of aromatic and aliphatic aldehydes with a combination of titanium tetraisopropoxide, Ti(O-i-Pr)4, and diethylzinc, ZnEt2, in the presence of a catalytic amount of the bis-sulfonamide 1a leads to formation of (S)-1-phenyl-1-propanol 4 with high enantioselectivity (2, 1).5 Use of the (R,R)-1,2-(trifluoromethanesulfonamido)-cyclohexane 1b [CAS 122833-60-7] allows for an equally selective reaction, but at exceptionally low catalyst loadings. In the case of aromatic aldehydes, these reactions are fairly rapid, requiring at most 2 hours to reach full conversion.

Through the use of the bis-sulfonamide 1b, the scope of the reaction has been expanded to include a larger number of aldehydes and organozinc reagents (Table 2). High yields and selectivities are obtained in the alkylations of conjugated aldehydes (5) as well as simple aliphatic aldehydes (7,9). The broad scope of this reaction with respect to the electrophile contrasts the slightly limited scope of the reaction when considering the structure of the nucleophile. The use of small alkylzinc reagents, such as dimethylzinc, leads to a depressed selectivity (entry 4). However, the use of larger alkylzinc reagents still provides the exceptional selectivity observed in the case of diethylzinc (entries 5 and 6).

The scope of the reactive partners has been fully explored and expanded to include a diversity of functionalized organozinc reagents. Preparation of the functionalized organozinc reagent proceeds via hydroboration and boron-zinc exchange of a simple terminal alkene. The resulting organozinc reagent can then be used in an identical manner to that shown above. In the presence of <10 mol % of catalyst 1b, high yields and selectivities can be obtained (4).6 One drawback of this method is that 50% of the starting alkene must be sacrificed. However, recent reports have revealed that use of a mixed organozinc species, which is accessible by disproportionation of two symmetric organozinc reagents, obviates this wasteful complication (5).7

Comparable selectivity can be obtained in the alkylation of benzaldehyde 3 with diethylzinc using the titanium TADDOL complex 20 (>99:1 er) or 3-exo-(dimethylamino)isoborneol, 21 (>99:1 er), although both methods employ higher catalyst loadings.8,9 While benzaldehyde is illustrative, the substrate scope is equally broad in the case of these two catalysts.

Cyclopropanation of Allylic Alcohols

Simmons-Smith type cyclopropanation of the allylic alcohol 22 in the presence of a catalytic amount of the bis-sulfonamide 1a leads to formation of the corresponding cyclopropane 23 in high yield and selectivity (6, Table 3).10 The reaction is rapid (<1 h) and can be performed at low temperature (either 0 °C or -20 °C). Substrate scope encompasses both di- and tri-substituted allylic alcohols (24 and 26). However, substitution at the 2 position, as in 28, leads to a drastic decrease in selectivity. The presence of additional oxygenated functionality (30) in the proximity of the alkene also lessens selectivity.11 The method is limited to the cyclopropanation of allylic alcohols. Other alkene-containing substrates, such as allylic ethers, homo-allylic alcohols and allylic carbamates, do not react with high selectivity.

The optimal procedure calls for a three-flask protocol which segregates the individual reactive components. Pre-formation of the zinc alkoxide, zinc sulfonamide complex and the cyclopropanation reagent, Zn(CH2I)2, by combination of diethylzinc with the allylic alcohol, bis-sulfonamide and diiodomethane, respectively, is essential for high selectivity and reproducibility. While the individual reaction components are soluble in halogenated solvents such as dichloromethane, the zinc sulfonamide complex is a highly insoluble species which is prone to aggregation. Because of the nature of the zinc carbenoid, a heterogenous reaction is always observed. None of the related bis-sulfonamide catalysts shown in Table 4 are able to dissolve the precipitate. Still, a survey of catalyst structure reveals that large variations in sulfonamide structure can be tolerated without compromising selectivity (entries 1 and 2).10,12 Bulky sulfonamide groups, however, clearly interfere with the selective cyclopropanation process (entries 3 and 4).

This method is comparable to similar, catalytic Simmons-Smith-type methods employing the titanium TADDOL catalyst 20 (95:5 er) or the C1-symmetric bis-sulfonamide catalyst 32 (93:7 er) for the cyclopropanation of the allylic alcohol 22 (6).13,14 However, due to the preliminary nature of these earlier investigations, substrate scope and generality have not been extensively documented. All of the aforementioned methods are limited by their dependence on the allylic alcohol functionality. Only one method for Simmons-Smith-type cyclopropanation of other substrate classes has been developed. Use of a stoichiometric, chiral dioxaborolane [CAS 161344-85-0] additive allows for selective cyclopropanation of allylic ethers, homo-allylic alcohols and allylic carbamates.15

1. (a) Pu, L.; Yu, H. B., Chem. Rev. 2001, 101, 757. (b) Soai, K.; Shibata, T. In Comprehensive Asymmetric Catalysis II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer Verlag: Heidelberg, 1999, Ch. 26.1, pp 911-922.
2. (a) Charette, A. B.; Beauchemin, A., Org. React. 2001, 58, 1-415. (b) Charette, A. B.; Lebel, H. In Comprehensive Asymmetric Catalysis II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer Verlag: Heidelberg, 1999, Ch. 16.3, p 581-603.
3. Denmark, S. E.; Christenson, B. L.; O'Connor, S. P., Tetrahedron Lett. 1995, 36, 2219.
4. (a) Glasbøl, F.; Steenbøl, P.; Søndergaard-Sørenson, B., Acta Chem. Scand. 1972, 26, 3605. (b) Whitney, T. A., J. Org. Chem. 1980, 45, 4214.
5. (a) Yoshioka, M.; Kawakita, T.; Ohno, M., Tetrahedron Lett. 1989, 30, 1657. (b) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S. Tetrahedron 1992, 48, 5691.
6. Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P-Y.; Knochel, P., J. Org. Chem. 1996, 61, 8229.
7. (a) Lutz, C.; Knochel, P., J. Org. Chem. 1997, 62, 7895-7898. (b) Lutz, C.; Jones, P.; Knochel, P., Synthesis 1999, 312.
8. (a) Schmidt, B.; Seebach, D., Angew. Chem., Int. Ed. Eng. 1991, 30, 99. (b) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M., Tetrahedron 1994, 50, 4363.
9. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R., J. Am. Chem. Soc. 1986, 108, 6071.
10. (a) Denmark, S. E.; O'Connor, S. P., J. Org. Chem. 1997, 62, 3390. (b) Denmark, S. E.; O'Connor, S. P., J. Org. Chem. 1997, 62, 584.
11. Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai, N.; Kobayahsi, S., Tetrahedron 1995, 51, 12013.
12. Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S., Tetrahedron Lett. 1992, 33, 2575.
13. Charette, A. B.; Brochu, C., J. Am. Chem. Soc. 1995, 117, 11367.
14. Imai, N.; Sakamoto, K.; Maeda, M.; Kouge, K.; Yoshizane, K.; Nokami, J. Tetrahedron Lett. 1997, 38, 1423.
15. (a) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C., J. Am. Chem. Soc. 1998, 120, 11943. (b) Charette, A. B.; Lebel, H.; Gagnon, A., Tetrahedron 1999, 55, 8845.

Scott E. Denmark & Gregory Beutner

University of Illinois, Urbana, IL, USA

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