Nucleophilic additions to N-sulfinyl imines

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Additions of non-stabilized carbon nucleophiles to chiral N-sulfinyl imines involve the reaction of an organometallic reagent with a chiral N-sulfinyl imine to afford chiral amines in a highly stereoselective manner. Removal of the sulfinyl group, which acts as a chiral auxiliary in these reactions, yields chiral amines. The overall process exhibits high enantioselectivity in general and is a highly practical approach to the enantioselective synthesis of chiral branched amines.[1]


Approaches for enantioselective synthesis based on chiral auxiliaries make use of an easily cleavable group containing a stereogenic unit. Functionalization of a prochiral substrate with the auxiliary followed by diastereoselective reaction and removal of the auxiliary results in an overall process that is selective for a single enantiomer of product. Chiral sulfonamides and related compounds are an important class of chiral auxiliaries for enantioselective addition reactions. Chiral N-sulfinyl imines, derived most often from direct condensation of a ketone or aldehyde with a chiral sulfonamide, undergo diastereoselective addition reactions with organolithium, Grignard, and organozinc reagents. The sulfinyl group contains the key steroechemical element and activates the imine toward nucleophilic attack. Cleavage of the sulfinyl group, most commonly under acidic conditions, affords chiral branched amines (Eq. 1).


The observed sense of stereoinduction in a particular reaction depends on the organometallic reagent, the solvent, and the presence of coordinating groups in either substrate. A closed, chair-like transition state is invoked in non-coordinating solvents while an open transition state tends to prevail in polar solvents owing to the disruption of interactions between the N-sulfinyl imine and nucleophile by solvent molecules. Aldimines and ketimines commonly exhibit different behavior.

Mechanism and Stereochemistry

Prevailing Mechanism

Nucleophilic addition of the organometallic reagent to the imine carbon forges the stereocenter that is retained in the branched amine product after cleavage of the auxiliary. Stereochemical models that account for the observed sense of stereoinduction in this elementary step can be divided into closed and open types. In both models, it is assumed that the lone pair of electrons on nitrogen and the S–O bond in the N-sulfinyl imine are antiperiplanar.[2] In the closed transition state model, coordination between the sulfinyl oxgen and metal occurs and results in a chair-like six-membered transition state. The favored transition state 1 leads to product 2 and includes both the chiral group linked to sulfur and the larger group linked to the imine carbon in equatorial positions. In the open transition state model, direct coordination between the metal and N-sulfinyl imine is absent. In favored transition state 3, the conformation of the N-sulfinyl imine is enforced by the stereoelectronic effect described above and the nucleophilic group R3 approaches the imine carbon on the opposite face of auxiliary group R1. The product 4 is a diastereomer of 2; after removal of the sulfinyl group, the resulting products are enantiomers.


Solvent can have a profound effect on the observed sense of stereoinduction in these reactions. Non-coordinating solvents tend to favor closed transition states analogous to 1 while coordinating solvents tend to favor open transition states related to 2 (Eq. 2). However, the use of THF as solvent with Grignard reagents results in poor diastereoselectivity.[3][4]


Lewis acidic or basic additives can also enhance the diastereoselectivities of additions to chiral N-sulfinyl imines or alter their stereochemical outcomes. For example, coordination of an oxophilic Lewis acid to the sulfinyl oxygen can disrupt coordination of this oxygen to the metal, resulting in a switch in the observed sense of stereoinduction (Eq. 4).


Coordinating groups linked to the α-carbon of the imine can influence the outcomes of these reactions when such groups can coordinate to the metal in the organometallic reagent. For instance, under conditions that would otherwise promote the involvement of a closed transition state, Lewis basic groups linked to the α-position of the N-sulfinyl imine cause an inversion of the stereochemical outcome via involvement of an open transition state.[5] Stereogenic α-carbons also affect the outcomes of these reactions as the chiral auxiliary and α-stereocenter may either be "matched" (promoting formation of the same diastereomer) or "mismatched" (promoting formation of different diastereomers).[6] Finally, the presence of coordinating group in the nucleophile may alter the stereochemical outcome.[7]

Aldimines and ketimines react somewhat differently. The large steric difference between the hydrogen and carbon groups linked to the aldimine carbon commonly results in high diastereoselectivity in reactions of aldimines. However, ketimines containing two carbon groups of similar size can exhibit significantly lower diastereoselectivity. Mixtures of (E) and (Z) isomers of ketimines may be present in this case.

Scope and Limitations

Many N-sulfinyl aldimines and ketimines can be prepared via the direct condensation of an aldehyde or ketone with the corresponding sulfonamide.[8] An alternative approach for the synthesis of aldimines makes use of reduction of a nitrile followed by formation of an ate complex and trapping with Andersen reagent 9 (Eq. 5).[8]


The scope of the nucleophile includes organometallic reagents with carbon in any hybridization state, allylmetal reagents, propargylic reagents, and cyanide. Alkyl Grignard reagents are commonly employed when an alkyl nucleophile is desired (Eq. 6).[4] Primary Grignard reagents are most effective, as β-hydride transfer from secondary Grignard reagents can result in reduction of the imine. Although diorganozinc reagents do not add to N-sulfinyl imines, triorganozincate species formed by mixing a diorganozinc compound with an organomagnesium reagent do react.[9]


Because methyl groups in triorganozincates transfer relatively slowly, dimethylzinc can be applied for the selective addition of an alkenyl or alkynyl group via a triorganozincate intermediate (Eq. 7).[10] Interestingly, the sense of stereoinduction in this reaction is opposite that observed for reaction of vinylmagnesium bromide alone.


Organolithium reagents often react through an open transition state structure; the reaction of phenyllithium with an aryl-substituted aldimine shown in Eq. 7 is a typical example.[11] Product 10, derived from an open transition state (see Eq. 2), predominates over product 1 derived from a chair-like closed transition state. Aryllithium reagents are also effective in additions to ketimines.[4]


Addition of allylic nucleophiles to N-sulfinyl aldimines is an important method for the asymmetric synthesis of homoallylic amines. Organomagnesium, organozinc, and organoindium reagents may be applied in this context. Additions of allylindium reagents may be carried out in THF (Eq. 8)[12] or in saturated aqueous sodium bromide.


Among alkynyl nucleophiles, alkynylaluminum reagents represent a potentially cost-effective source of sp-hybridized carbon nucleophiles. Although this class of reagents is effective in additions to N-sulfinyl aldimines, a large excess of the nucleophile is required (Eq. 10).[13]


Synthetic Applications

Additions to chiral N-sulfinyl imines have been applied toward the synthesis of enantiomerically enriched amino acids, active pharmaceutical agents, and natural products. For example, the addition of methylmagnesium chloride to an aldimine set the configuration of the lone stereocenter in a series of bradykinin B1 antagonists (Eq. 11).[14]


An inhibitor of plasmodium dipeptidyl aminopeptidase (DPAP) effective in the treatment of malaria was synthesized using a sequence with addition of an alkynylaluminum species to a ketimine as a key step (Eq. 12).[15]


Comparison to Other Methods

Approaches for the synthesis of chiral branched amines can be divided into aminations, which involve the formation of a carbon–nitrogen bond, and additions, which involve the formation of a carbon–carbon bond via reaction of an electrophile containing a carbon–nitrogen double bond. Additions to N-sulfinyl imines naturally fall into the latter category. Alternatives in this class make use of either enantioselective catalysts or other chiral auxiliaries. Nucleophilic additions to so-called RAMP and SAMP hydrazones are an example of the latter approach (Eq. 13).[16]


A number of catalytic, enantioselective additions to achiral imines have been developed. Although the class of reactions as a whole has broad scope, the particular catalyst system that is most effective for a particular combination of imine and nucleophile can vary. One of the most general approaches involves the use of a zirconium catalyst and peptidic Schiff base ligand for additions of diorganozinc nucleophiles to N-aryl imines (Eq. 14).[17] Both alkynyl- and alkylzinc reagents can be used.


Catalytic, enantioselective hydrogenation of imines furnishes chiral branched amines, but these reactions cannot be used to forge quaternary stereocenters. A recent report on the hydrogenation of N–H imines is remarkable because the reaction described, which involves an iridium catalyst with chiral phosphine ligand, does not require the installation and removal of a protecting group in the imine (Eq. 15).[18]


Experimental Conditions and Procedure

Typical Conditions

Beyond the typical care that should be taken in the handling of highly reactive organometallic reagents, nucleophilic additions to N-sulfinyl imines are not associated with major safety concerns. However, many of the nucleophiles employed are pyrophoric and should be transferred via cannula under an inert atmosphere. Reagents containing cyanide should be handled exclusively in a fume hood and cyanide-containing waste should be kept at basic pH to avoid the formation of extremely toxic hydrogen cyanide gas.

Example Procedure[19]


To a solution of (R)-N-benzylidene-2-methylpropane-2-sulfinamide (200 mg, 0.96 mmol) in CH2Cl2 (5.8 mL) at ‒48 °C was added MeMgBr (0.64 mL, 1.92 mmol, 2.0 equiv, 3 M in Et2O). The mixture was stirred at ‒48 °C for 6 h, after which it was warmed to rt and was stirred overnight. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (2 mL). The aqueous layer was extracted with EtOAc (3 × 3 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (207 mg, 96%, dr 97:3). The diastereomeric ratio was determined by GC analysis of α-methoxy-α-trifluoromethylphenylacetyl (MTPA) derivatives of (S)-1-phenylethylamine:[20] tR (R) 16.3 min, tR (S) 16.7 min (HP Ultra II, 20 psi, 5 °C/min, 150–250 °C); 1H NMR (CDCl3, 300 MHz) δ 7.33–7.25 (m, 5H), 4.58–4.56 (m, 1H), 3.32 (br s, 1H), 1.47 (d, J = 10.3 Hz, 3H), 1.27 (s, 9H). Anal. Calcd for C12H19NSO: C, 63.96; H, 8.50; N, 6.22. Found: C, 64.07; H, 8.18; N, 6.27.


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