diastereoselective regiodivergent mannich versus tandem

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Diastereoselective Regiodivergent Mannich Versus TandemMannich-Cyclization Reactions

Wenzhong Zhang,a Xin Wang,a Biqing Zhu,a Di Zhu,a Jianlin Han,a,*Alicja Wzorek,b, d Azusa Sato,b, e Vadim A. Soloshonok,b, c,* Jie Zhou,a,* andYi Pana

a School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Jiangsu KeyLaboratory of Advanced Organic Materials, Nanjing University, 210093, People’s Republic of ChinaPhone: 86-25-83686133E-mail: [email protected]; [email protected]

b Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo ManuelLardiz�bal 3, 20018 San Sebasti�n, SpainE-mail: [email protected]

c IKERBASQUE, Basque Foundation for Science Department Alameda Urquijo 36–5, Plaza Bizkaia, 48011 Bilbao, Spaind Institute of Chemistry, Jan Kochanowski University in Kielce, Swietokrzyska 15G, 25-406 Kielce, Polande School of Medicine, Tokyo Women�s Medical University, 8-1Kawada-cho, Shinjuku-ku, 1628666 Tokyo, Japan

Received: August 15, 2017; Revised: September 23, 2017; Published online: October 16, 2017

Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201701066

Abstract: In the present work, we report theaddition reactions between (S)- and (R)-N-t-butyl-sulfinyl-3,3,3-trifluoro-acetaldimine and tertiaryenolates derived from a-thiocyanate ketones. Wedemonstrate that these reactions feature unusualregiodivergence, affording either the direct Man-nich adducts (NaOAc/THF) or the products oftandem Mannich addition-cyclization (Na2CO3/DMF) reactions. The latter represents a new classof spirocyclic trifluoromethyl-containing aziridinesunavailable by other approaches. The reactionsshow wide structural generality, rendering them ofcertain synthetic value for preparation of newfluorine-containing polyfunctional compounds ofbiological relevance. Mechanistic rationale for theobserved reactivity and stereochemical outcome isprovided.

Keywords: Mannich additions; asymmetric synthe-sis; cascade reaction; aziridines; spirocycles

Fluorine containing compounds are of vital impor-tance in the development of modern pharmaceuti-cals,[1] agrochemicals[2] and advanced materials.[3] Inparticular, fluorine containing amines,[4] amino acids[5]

and their analogs[6] serve as key structural units in thedesign of peptidic compounds with presupposed three-dimensional structure and enhanced bio-receptoraffinity. Thus, due to the innovative applications of

fluoro-organics, the synthetic methodology is focusedon preparation of structurally novel and functionallydiverse compounds with yet unexplored biologicaland/or physicochemical properties.[7] One of activedirections of the current research is the developmentof generalized approaches to fluorinated derivativesbearing keto/hydroxy/amino groups. The most chal-lenging aspect in this area is the control of absoluteand relative configurations of multiple stereogeniccenters, as well is the position of target functionalities.Consistent with our continuous interest in preparationof fluorinated amino compounds[8] our recent activitywas largely invested in the discovery of detrifluoroace-tylative in situ generation of fluoro-enolates[9] andchemistry of N-t-butylsulfinyl-3,3,3-trifluoro-acetaldi-mine 1 (Scheme 1).[10] We[11] and others[12] reportedMannich addition reactions of imine 1 with variousC�H acidic compounds, demonstrating remarkable

Scheme 1. Regiodivergent Mannich versus tandem Mannich-cyclization reactions between imine 1 and a-thiocyanateketones 2.

COMMUNICATIONS DOI: 10.1002/adsc.201701066

Adv. Synth. Catal. 2017, 359, 4267 – 4273 4267 � 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

https://doi.org/10.1002/adsc.201701066

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synthetic value of reagent 1 for preparation of b-trifluoromethyl-b-amino keto-compounds.[10] How-ever, the reactivity of imine 1 with tertiary enolatesbearing additional functional groups, except for afluorine atom,[13] still remains unexplored area ofresearch. Searching for this type of structurally newand interesting enol substrates, our attention wasattracted by the chemistry of a-thiocyanate ketones2.[14]

In particular, a thiocyanate functionality is foundin numerous naturally occurring compounds, isolatedmostly form marine sources,[15] and carries certainbiological activity.[16] Furthermore, the thiocyanategroup displays versatile reactivity rendering it veryvaluable in synthesis of biologically relevant sulfurand heterocyclic compounds.[17] On the other hand,literature examples of asymmetric preparation ofcompounds featuring thiocyanate group attacheddirectly to a stereogenic carbon are virtually unknown,suggesting an appreciable synthetic challenge.[18] Beingmotivated by a chance to explore these novel facets ofreactivity of both imine 1 and a-thiocyanate ketones2, we initiated the present research project into thecorresponding Mannich addition reactions. As shownin Scheme 1, besides the original targets of this work,adducts 3, we discovered an additional synthetic bonusallowing preparation of spirocyclic aziridines 4. Bothstructural types of compounds 3 and 4 are new and ofhigh complexity, possessing consecutive stereogeniccenters and multiple functionalities. Here we discloseexperimental details and discuss plausible mechanisticrationale for the observed reactivity and stereochem-ical outcome.

Drawing from our experience in the chemistry ofimine 1[19] and literature data[20] on chemical liabilityof a-thiocyanates, our design of the reactions between1 and 2 was based on application of as mild reactionconditions as possible. Major results (for the fulldetails, see SI) are presented in Table 1.

Initially, we conducted a series of pilot experimentsin THF which revealed that relatively weak organic(of triethylamine type) bases are inadequate tocatalyze the Mannich addition. On the other hand,strong bases (of t-BuOK type) caused virtually com-plete decomposition of starting compounds. Somebreakthrough in controlling the reactivity wasachieved with application of Na2CO3 as a base(entry 1). In this case the target product 3 a wasisolated with 43% chemical yield and of appreciablediastereoselectivity. One should keep in mind thatformation of two new stereogenic centers in 3a couldlead to up to four stereoisomers; therefore observationof only two diastereomers in 84/16 ratio, we consid-ered as a good starting point. Also we found thatbesides the expected compound 3 a, the reactionmixture contained up to 5% cyclic derivative 4 andnoticeable amounts of byproducts, resulting, likely,form chemically liable[20] nature of the SCN group.Interestingly, the use of K2CO3 (entry 2) led toexcellent diastereoselectivity of the Mannich addition,but product 3 a was isolated with low yield. On theother hand, application of sodium acetate (entry 3)allowed increasing both the isolated yield of product3 a and the stereochemical outcome. By contrast,lithium acetate (entry 4) gave subpar results in bothchemical yield and diastereoselectivity. Among other

Table 1. Optimization of the reaction conditions for the Mannich additions between imine (Rs)-1 and a-thiocyanate 2.[a]

Entry Base Solvent T (oC) Time (h) 3 a/4a Yield (%)[b] Dr[c]

1 Na2CO3 THF rt 16 90:10 43 84:162 K2CO3 THF rt 16 76:24 20 >98:23 NaOAc THF rt 16 99:1 45 91:94 LiOAc THF rt 16 96:4 38 81:195 Na3PO4 THF rt 16 64:36 30 98:26 PhCO2Na THF rt 16 96:4 33 85:157 CF3CO2Na THF rt 16 97:3 35 83:178 NaOAc 2-Me-THF rt 16 95:5 31 82:189 NaOAc THF �20 96 99:1 84 91:910 NaOAc THF �40 120 >99:1 76 91:9[a] Reaction conditions: 2 a (0.2 mmol), imine 1 (0.24 mmol) and base (0.24 mmol) in the solvent (2 mL).[b] Isolated yields of 3 a.[c] Dr of 3 a determined by 19F NMR analysis.

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basic salts which can be used to catalyze this additionwe would like to mention Na3PO4 (entry 5), PhCO2Na(entry 6) and CF3CO2Na (entry 7). These reactionsgave somewhat similar results in terms of chemicalyield, pointing to NaOAc (entry 3) as the mostoptimal base. Further attempts to improve the reac-tion performance by screening various solvents weremostly unsuccessful. Actually, the reactions conductedin ethyl acetate, methanol, DMF, dioxane, acetonitrile,DCM and chlorobenzene did not proceed at all,resulted in increased the amounts of cyclized by-product 4 a, or led to sizable decomposition. Further-more, close analog of THF, 2-Me-THF (entry 8), gavenoticeably lower values of chemical yield and diaster-eoselectivity. On the other hand, the variation of thereaction temperature gave very positive outcome.Thus, the addition conducted at �20 8C (entry 9)allowed improving the yield to 84% with appreciableselectivity of 91/09, albeit the completion of thereaction required about 4 days. Unfortunately furtherimprovement of the stereochemical outcome bydecreasing the reaction temperature to �40 8C was notachieved (entry 10). Product 3a was prepared indiastereomerically pure form by column chromatog-raphy and its absolute configuration was determinedby the crystallographic analysis (see SI file).[21] Ac-cording to the X-ray data, the configurations of thetwo newly generated stereogenic carbons are (2R,1’S).

Using these optimized reaction conditions, webriefly explored the generality of these Mannichadditions, as presented in Scheme 2.

Under the standard conditions, the correspondingaddition products bearing halogen atoms 3 b,c,f,methyl 3 d and methoxy groups 3 e, were preparedwith variable chemical yields, reflecting rather differ-ences in physicochemical properties during isolation

procedure than structural limitations of the method.Most significantly, the diastereoselectivity, as deter-mined on the crude reaction mixtures, was virtuallyconstant in all cases, giving preference (~90/10) forthe (2R,1’S,Rs) stereochemistry. Also importantly, allmajor diastereomers 3 a–f can be readily prepared indiastereomerically pure form by routine columnchromatography, rendering them available for bio-logical studies or synthetic elaborations. In this regard,we decided to demonstrate the removal of the sulfinylauxiliary as presented in Scheme 3. Thus, usingstandard conditions[22] the sulfinyl group was cleanlycleaved at ambient temperature and free aminocompound 5 a was isolated with 73% yield in diaster-eomerically pure form. It is interesting to note that,despite the presence of the free amino group and theSCN functionality,[20b] product 5 is relatively stable andcan be stored, which is probably due to the lowbasicity/nucleophilicity of the amino group in the a-position to CF3.

[23]

Having accomplished the investigation of Mannichaddition reactions, we decided to turn out attention tocyclized compound 4 a (Table 1) which was alwaysobserved as a byproduct in the reactions understudy.Trifluoromethyl-aziridines, especially in enantiomeri-cally pure form, are extremely synthetically challeng-ing compounds.[24] Therefore, the prospect to developa new procedure for their preparation was particularlymotivating. To this end we conducted yet anotheroptimization study, targeting this time the formationof spirocyclic compound 4. The major results arepresented in Table 2 (for the full details, see SI).

While THF was a solvent of choice for the directMannich additions (Table 1), it was found unsuitablefor the tandem addition-cyclization pathway requiringthe intramolecular nucleophilic substitution step. Ac-cordingly, we focused our attention on more polarsolvents. First promising result was achieved usingsodium acetate as a base and ethyl acetate as a solvent(entry 1). In this case target bicyclic product 4 a wasisolated in diastereomerically pure state with 30%yield. Interestingly, other polar or non-polar solvents(methanol, DCE, dioxane, CCl4, acetonitrile) did notfavor the formation of compound 4 a with the notice-able exception of DMF. Thus, the reaction conductedin DMF (entry 2) afforded aziridine 4 a with appreci-able 64% yield and excellent diastereoselectivity of

Scheme 2. Substrate generality of Mannich additions be-tween imine (R)-1 and substituted a-thiocyanates 2.

Scheme 3. Preparation of free amino derivative 5 a.




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92/8. Application of different and a bit stronger, thanNaOAc, bases (entries 3–7) allowed us to identifyNa2CO3 (entry 6) as the most optimal, giving rise tocyclized product 4a in 90/10 diastereomeric ratio andwith 67 chemical yield. In contrast to the directMannich addition, the modification of the reactiontemperature (entries 8, 9) had virtually no effect onthe stereochemical outcome. Spirocyclic 4 a was pre-pared in diastereomerically pure form by columnpurification and its absolute stereochemistry wasdetermined as (2S,2’S,Ss) by single crystal X-rayanalysis.[21] It should be emphasized that in this series,as compared with the direct Mannich additions, weused starting chiral imine 1 of (Ss) configuration.

Using the optimized conditions, as presented inTable 2, entry 6, we performed substrate generalitystudy summarized in Scheme 4.

For example, series of halogen substituted bicyclicproducts 4 b–h were prepared with decent chemicalyields and with diastereoselectivity generally betterthan 90/10. Most likely fluorine (4 b,e), chlorine (4 d,f)and bromine (4 c,g,h) atoms in various positions onthe phenyl ring in starting ketones 2 do not influencethe stereochemical outcome of this reaction in anynoticeable way. Aziridines 4 i and 4 j, containingmethyl and methoxy groups respectively, were alsoobtained with expected values of chemical yield andstereoselectivity. Of particular significance are spiro-cyclic derivatives 4k-m, containing six-membered ring,and 4 n, comprised of seven-membered cycle. Quiteremarkably, in these cases the diastereoselectivity was

nearly perfect registering uniformly the 99/1 value.Furthermore, sulfur 4 o and oxygen 4 q, containingheterocyclic type of products, highlight yet anotherfacet of the structural generality of this method.Finally, we prepared compounds 4p–s bearing CHF2,CBrF2 and C2F5 groups, respectively, using the corre-sponding analogs[25] of imine 1. One may agree thatexamples collected in Scheme 3 clearly underscore thestructural generality of this approach and its syntheticvalue for preparation of fluorinated spirocyclic azir-idines.

As we did in the case of direct Mannich adducts(Scheme 3), we decided to make sure that the removalof chiral axillary does not interfere with the spirocyclicaziridine moiety. To this end, we performed trans-formation depicted in Scheme 5. The hydrolysis of thesulfinyl group in diastereomerically pure 4a wasconducted under the standard conditions using meth-anol solution of HCl. After neutralization with

Table 2. Optimization of the reaction conditions for thetandem Mannich-cyclization additions between imine (Ss)-1and a-thiocyanate 2 a.[a]

Entry Base Solvent T (oC) 4 a/3 a Yield (%)[b] Dr[c]

1 NaOAc EtOAc rt >99:1 30 >99:12 NaOAc DMF rt 96:4 64 92:83 KOAc DMF rt 90:10 36 92:84 K2CO3 DMF rt >99:1 59 90:105 Cs2CO3 DMF rt >99:1 41 90:106 Na2CO3 DMF rt 99:1 67 90:107 NaOH DMF rt >99:1 61 90:108 Na2CO3 DMF 0 97:3 62 93:79 Na2CO3 DMF 40 >99:1 67 89:11[a] Reaction conditions: 2 a (0.2 mmol), imine 1 (0.24 mmol)

and base (0.24 mmol) in the solvent (2 mL) for 16 h.[b] Isolated yields of 4 a.[c] Dr of 4 a determined by 19F NMR analysis.

Scheme 4. Substrate generality of the tandem Mannich-cyclization additions between imine (S)-1 and a-thiocyanate2.

Scheme 5. Preparation of free amino derivative of spirocyclicaziridine 6a.




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triethylamine, free aziridine 6 a was isolated withexcellent 91% yield.

To account for the observed stereochemical out-come and reactivity in these Mannich and tandemMannich-cyclization reactions, we can propose thetransition states (TSs A–C) presented in Figure 1.

One may agree that in TSs A and B, thetrifluoromethyl group is, most likely, involved in stericand electrostatic[26] repulsive interactions with thephenyl and the enolate oxygen, respectively. Bycontrast, in TS-C, the imine nitrogen and the enolateoxygen are located in close proximity to each other tocomply with the principle of the minimum chargeseparation[27] allowing for the concerted oxygen–nitro-gen charge transfer. Accordingly, TS-C, leading to themajor diastereomeric products, might be considered asthe most plausible. Considering the absolute config-uration of the CF3 bearing carbon (1’S) in 3 and (2’R)in 4, one should take a note that these two arestereochemically equivalent and the difference in theassignment arises only due to CIP priority rules[28] as aSCN overtakes in priority a CF3. Therefore, we canassume that TS-C operates in both direct Mannichand tandem Mannich-cyclization addition reactions.Consequently, the nitrogen-ionized intermediate of 3can undergo intramolecular SN2 substitution of theSCN group affording spirocyclic product 4.[29] Thus,upon this cyclization the stereogenic carbon in a-position to the keto group undergoes the inversionform (2R) to (2S) and the CF3-bearing carbon changesthe assignment from (1’S) to (2’R).

In conclusion, we found that the reactions of (S)-and (R)-N-t-butylsulfinyl-3,3,3-trifluoro-acetaldiminewith tertiary enolates derived from a-thiocyanateketones show unusual regiodivergence as a function ofthe reaction conditions. In particular, application ofNaOAc as a base and THF as a solvent leads tonormal Mannich addition products. On the otherhand, the use of Na2CO3 as a base and DMF as asolvent give preference for the tandem Mannich-

cyclization process affording an exceptional type ofstructurally new spirocyclic aziridines. Both processesproceed with appreciable chemical yields and diaster-eoselectivity, boding well with high synthetic value ofthese methods for preparation of new fluorine con-taining compounds of biological importance. Mecha-nistic rationale for the observed reactivity and stereo-chemical outcome involves, most likely, the sametransition state followed by intramolecular SN2 cycli-zation of the nitrogen-ionized intermediate undermore basic reaction conditions.

Experimental SectionGeneral Procedures for the Reaction for the MannichAdditions Between Imine (R)-1 and a-Thiocyanate 2

An oven-dried reaction vial containing a-thiocyanate 2(0.2 mmol) and NaOAc (0.24 mmol, 1.2 equiv) was evac-uated and purged with argon three times. Then THF (2 mL)as solution and imine (R)-1 (0.24 mmol, 1.2 equiv.) wereadded via syringe at �20 8C, respectively. The reactionmixture was stirred for 96 h at �20 8C, and then the reactionwas quenched with NH4Cl (5 mL). The organic layer wasremoved, and the aqueous layer was extracted with EtOAc(2 3 5 mL). The combined organic layers were washed withH2O (2 3 10 mL) and brine solution (10 mL) and dried overanhydrous Na2SO4. The solvent was evaporated to give thecrude product 3, which was purified by flash chromatogra-phy.

General Procedures for the Reaction for the TandemMannich-Cyclization Additions Between Imine (S)-1and a-Thiocyanate 2

An oven-dried reaction vial containing a-thiocyanate 2(0.2 mmol) and Na2CO3 (0.24 mmol, 1.2 equiv.) was evac-uated and purged with argon three times. Then DMF (2 mL)as solution and imine (S)-1 (0.24 mmol, 1.2 equiv.) wereadded via syringe, respectively. Then the reaction mixturewas stirred for 16 hours at room temperature, and then thereaction was quenched with NH4Cl (5 mL). The organic layerwas removed, and the aqueous layer was extracted withEtOAc (2 3 5 mL). The combined organic layers werewashed with H2O (2 3 10 mL) and brine solution (1 3 10 mL)and dried over anhydrous Na2SO4. The solvent was evapo-rated to give the crude product 4, which was purified by flashchromatography.

AcknowledgementsWe gratefully acknowledge the financial support from theNational Natural Science Foundation of China(No. 21472082). The Jiangsu 333 program (for Pan), IKER-BASQUE, Basque Foundation for Science (for Soloshonok)and Changzhou Jin-Feng-Huang program (for Han) are alsoacknowledged.

Figure 1. Plausible transition states (TS) A–C accounting forthe observed stereochemical outcome and reactivity.




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[29] Following a request of one of the referees, diastereo-merically pure compound 3 a was subjected to theoptimized reaction conditions (DMF, Na2CO3) tofurnish product 4 a with 60% isolated yield and of 53/47diastereomeric ratio.




diastereoselective regiodivergent mannich versus tandem

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