Aza-Henry Reactions on C-Alkyl Substituted

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Aza-Henry Reactions on C-Alkyl Substituted Aldimines Alessia Pelagalli, Lucio Pellacani, Elia Scandozza and Stefania Fioravanti * Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, I-00185 Roma, Italy; [email protected] (A.P.); [email protected] (L.P.); [email protected] (E.S.) * Correspondence: [email protected]; Tel.: +39-064-991-3098 Academic Editor: Alessandro Palmieri Received: 3 May 2016; Accepted: 26 May 2016; Published: 2 June 2016

Abstract: The reactivity of C-CH3 substituted N-protected aldimines in aza-Henry addition reactions was compared with that of the analogous trifluoromethylated compounds. C-Alkyl aldimines easily reacted with nitro alkanes under solvent-free conditions and in the absence of catalyst, despite being worse electrophiles than C-CF3 aldimines, they gave the aza-Henry addition only when ZrCl4 was added. The presence of a bulky group on the imine carbon deeply influenced the reactivity. Keywords: nitro compounds; amines; carbon–carbon bond formation

1. Introduction The development of stereoselective reactions to create carbon–carbon bonds between compounds bearing a heteroatom functionality can provide valuable building blocks for organic synthesis. Starting from this purpose and considering the importance of the 1,2-diamine structural motif in biologically active natural products, drugs, and more recently as chiral auxiliaries and chiral ligands in asymmetric catalysis, general methods to synthesize this class of compounds are most relevant. Among them, the aza-Henry reaction [1–4], also called nitro-Mannich reaction, involves the nucleophilic addition of nitro alkanes to aldimines and leads to the synthesis of β-nitro amines, valuable compounds containing two vicinal nitrogenated functionalities with different oxidation states. Also for this, the aza-Henry reaction presents important synthetic applications [5–8], providing access to a wide variety of other organic compounds by functional transformations of the nitro group into other chemical functionalities, such as amines, carbonyl groups, hydroxylamines, oximes, and nitriles. While only recently, C-CF3 substituted aldimines [9–11] are reported in the aza-Henry reactions as interesting trifluoromethyl nitrogen-containing starting materials; the reactivity of C-aryl analogues has been well documented in the literature, while very few data are reported on the reactivity of C-alkyl substituted aldimines [2]. Classically, non-enantioselective nucleophilic addition of nitro alkanes to C-aryl substituted aldimines usually required the presence of a base as catalyst [12]. On the contrary, the same reaction on C-trifluoromethyl imines takes place only in the presence of a Lewis acid, namely ZrCl4 , which was found to be the best catalyst for that reaction [9,10]. Stimulated by this difference of reactivity, we thought it might be interesting to deepen the study of the behavior of C-alkyl substituted aldimines in nitro-Mannich reactions, especially to compare their reactivity with that of fluorinated analogues. In fact, as is well known [13–20], the presence of fluorine atoms influences both the reactivity and biological properties of compounds in which they are present. 2. Results and Discussion Different C-alkyl substituted N-protected aldimines 3a–i were synthesized by solvent-free equimolar direct condensation reactions between primary amines 1a–c and aldehydes 2a–c (Table 1) following the methodology previously reported by us to obtain trifluomethylated substrates in high Molecules 2016, 21, 723; doi:10.3390/molecules21060723

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2. Results and Discussion 2. Results and Discussion Molecules 2016, 21, 723 2 of 11 Different C-alkyl substituted N-protected aldimines 3a–i were synthesized by solvent-free Different C-alkyl substituted N-protected aldimines 3a–i were synthesized by solvent-free equimolar direct condensation reactions between primary amines 1a–c and aldehydes 2a–c (Table 1) equimolar direct condensation reactions between primary amines 1a–c and aldehydes 2a–c (Table 1) following methodology previouslywith reported by us to obtain trifluomethylated high yields [21].the The reactions proceeded high stereoselectivity, leading, in high substrates yields andin purity, following the methodology previously reported by us to obtain trifluomethylated substrates in high yields [21]. The reactionswhich proceeded with high stereoselectivity, leading, in high yields and purity, only only to (E)-aldimines, can be used in the subsequent aza-Henry additions without further yields [21]. The reactions proceeded with high stereoselectivity, leading, in high yields and purity, only to (E)-aldimines, which can be used in the subsequent aza-Henry additions without further purification. purification. to (E)-aldimines, which can be used in the subsequent aza-Henry additions without further purification. Table Table 1. Solvent-free Solvent-free synthesis synthesis of C-alkyl substituted N-protected aldimines. Table 1. Solvent-free synthesis of C-alkyl substituted N-protected aldimines.

Entry 1 1 1 2 aa a 2 3 3 4 4 5 bb b 5 6 6 7 7 8 c c c 8 9 9

Entry Entry 1 1 1 2 3 4 5 6 7 8 9

R

RR

Bn Bn Bn Ph Ph Ph

2 22 a aa bb b bb b aa a bb b cc c aa a bb bc c c

R′ 1 Product 3 Yield (%) Product Yield (%) R′ R Product 3 3Yield (%) a Me 85 a a MeMe 85 85 b b Cy Cy 90 90 b Cy 90 c c t-But-Bu 95 95 c t-Bu 95 d d Me Me 78 78 d Me 78 e e Cy Cy 80 80 e Cy 80 83 f f t-But-Bu 83 f t-Bu 83 g g Me Me 80 80 g Me 80 88 h h Cy Cy 88 h i Cy 88 95 i t-But-Bu 95 i t-Bu 95

The The nitro-Mannich nitro-Mannich addition addition of of nitromethane nitromethane (4) (4) on on aldimine aldimine 3a, 3a, which which were were selected selected as as suitable suitable The nitro-Mannich addition of nitromethane (4) on aldimine 3a, which were selected as suitable reactants reactants to to fix the best reaction conditions, conditions, was was tested tested under under solvent-free solvent-free conditions conditions either either in in the the reactants to fix the best reaction conditions, was tested under solvent-free conditions either in the presence presence or or in the absence of a catalyst (base or acid). The The reactions reactions carried carried out out by by using using different different presence or in the absence of a catalyst (base or acid). The reactions carried out by using different organic organic (TEA, DABCO) or inorganic (K222CO CO33,,KF) KF)bases basesdid didnot not give give any any product product of of addition, addition, leading leading organic (TEA, DABCO) or inorganic (K2CO33, KF) bases did not give any product of addition, leading only only to to aa very complex complex reaction reaction mixture mixture with with the the disappearance disappearance of of all all reagent reagent signals signals in in the the NMR NMR only to a very complex reaction mixture with the disappearance of all reagent signals in the NMR spectra. spectra. On Onthe the contrary, contrary, performing performing the reaction with ZrCl444,, while while the the nitromethane nitromethane was quantitatively quantitatively spectra. On the111contrary, performing the reaction with ZrCl4, while the nitromethane was quantitatively recovered, recovered, the the H-NMR H-NMR spectrum spectrum of of the the crude crude mixture mixture showed showed only only the the disappearance disappearance of of the the imine imine recovered, the 1H-NMR spectrum of the crude mixture showed only the disappearance of the imine signals, signals, whose whose hydrolysis hydrolysis is is mainly mainly promoted promoted by by the presence of Lewis acid. Only Only working working without without signals, whose hydrolysis is mainly promoted by the presence of Lewis acid. Only working without added added catalyst, catalyst, the the expected expected product product5a 5a was was obtained obtained after after 11 hh of of stirring stirring at at room room temperature temperature by by aa added catalyst, the expected product 5a was obtained after 1 h of stirring at room temperature by a self-catalyzed self-catalyzed addition addition in in which which aldimine aldimine 3a 3a acts acts as as both both base base and and electrophile electrophile [22,23] [22,23] (Scheme (Scheme 1). self-catalyzed addition in which aldimine 3a acts as both base and electrophile [22,23] (Scheme 1).

Scheme 1. Best for the aza-Henry addition. Scheme Best reaction reaction conditions conditions Scheme 1. 1. Best reaction conditions for for the the aza-Henry aza-Henry addition. addition.

To the best of our knowledge, neither the C-aryl nor the C-trifluoromethyl substituted aldimines To the the best best of of our our knowledge, knowledge, neither neither the the C-aryl C-aryl nor nor the the C-trifluoromethyl C-trifluoromethyl substituted substituted aldimines aldimines To have been reported to react in the absence of catalyst, thus confirming the strong influence of the imido thethe absence of catalyst, thusthus confirming the strong influence of the of imido have been been reported reportedtotoreact reactinin absence of catalyst, confirming the strong influence the carbon substituent on the reactivity of aldimines, that may affect the reaction outcome by influencing carboncarbon substituent on the reactivity of aldimines, that may affect the reaction outcome by influencing imido substituent on the reactivity of aldimines, that may affect the reaction outcome by the electrophilicity of the sp222 carbon and/or making the nitrogen lone pair more or less available. To 2 the electrophilicity of the sp carbon and/or making the nitrogen lone pair more or less available. To influencing the electrophilicity of the sp carbon and/or making the nitrogen lone pair more or less partially confirm this, we decided to test the reactivity of anil 3d. While similar N-aryl trifluoromethyl partially confirm this, we decided towe testdecided the reactivity anil 3d. While available. To partially confirm this, to testof the reactivity of similar anil 3d.N-aryl Whiletrifluoromethyl similar N-aryl aldimines did not give nitro-Mannich addition either without catalyst or in the presence of ZrCl44 [9], aldimines did not give nitro-Mannich addition eitheraddition withouteither catalyst or in catalyst the presence of ZrCl 4 [9], trifluoromethyl aldimines did not give nitro-Mannich without or in the presence N-phenyl C-methyl aldimine (3d) lead to the expected β-nitro amine 5d, in the absence of catalyst, N-phenyl C-methyl aldimine (3d) lead to(3d) the lead expected amine 5d,amine in the 5d, absence catalyst, of ZrCl4 [9], N-phenyl C-methyl aldimine to theβ-nitro expected β-nitro in theof absence of although in longer times and lower yields with respect to N-alkyl substituted 3a (Scheme 2). althoughalthough in longerintimes and lower yields with respect N-alkyl 3a (Scheme 2). catalyst, longer times and lower yields withto respect to substituted N-alkyl substituted 3a (Scheme 2).

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Scheme Scheme 2. 2. Aza-Henry Aza-Henry addition addition on on anil anil 3d. 3d. Scheme 2. Aza-Henry addition on anil 3d. Scheme 2. Aza-Henry addition on anil 3d.

The last result seems to confirm the relevant role of the substituent nature on imine carbon. The last result seems to confirm the relevant role of the substituent nature on imine carbon. In fact, Thethe last result seems to confirm the relevant role of the substituent nature on aromatic imine carbon. In fact, EDG methyl (electron donating group, EDG), counteracting the mesomeric effect The methyl last result seemsdonating to confirm the relevant role of the substituent nature on imine the EDG (electron group, EDG), counteracting the mesomeric aromatic effectcarbon. of the In the EDGresidue, methyl (electron EDG), counteracting the mesomeric aromatic effect of fact, the phenyl permitteddonating that thegroup, self-catalyzed addition reaction also takes place on an In fact, the EDG permitted methyl (electron donating group, EDG), counteracting thetakes mesomeric aromatic effect phenyl residue, that the self-catalyzed addition reaction also place on an aldimine of the phenyl residue, that the amine. self-catalyzed addition reaction also takes place on an aldimine derived from apermitted primary aromatic of the phenyl that the self-catalyzed addition reaction also takes place on an derived from a residue, primary permitted aromatic amine. aldimine derived from to a primary aromatic amine. Then, by turning match the diastereoselective reaction outcome, the chiral imine (R)-3g was aldimine fromto a primary aromatic amine. Then,derived by turning match the diastereoselective reaction outcome, the chiral imine (R)-3g was Then, bynitro turning to match reaction the chiral imine (R)-3g was reacted with alkanes 4 andthe 6 todiastereoselective study both the syn/anti andoutcome, the stereoselective facial outcome of Then, bynitro turning to match reactionand outcome, the chiral imine (R)-3g was reacted with alkanes 4 andthe 6 todiastereoselective study both the syn/anti the stereoselective facial outcome reacted with nitro alkanes 4 and 6 to studywere both compared the syn/antiwith and those the stereoselective facialfor outcome of the nitro-Mannich additions. The results already reported the same reacted with nitro alkanes 4 andThe 6 toresults study both syn/anti with and the stereoselective facialfor outcome of of the nitro-Mannich additions. werethe compared those already reported the same the nitro-Mannich additions. The were compared aldimine with those already for the same aza-Henry reactions performed onresults chiral trifluoromethyl 3j [9] (Tablereported 2). the nitro-Mannich additions. The results were compared with those already reported for the same aza-Henry reactions performed on chiral trifluoromethyl aldimine 3j [9] (Table 2). aza-Henry reactions performed on chiral trifluoromethyl aldimine 3j [9] (Table 2). aza-Henry reactions performed on chiral trifluoromethyl aldimine 3j [9] (Table 2). Table 2. Stereoselective comparison between the aza-Henry additions on C-alkyl substituted aldimines. Table 2. Stereoselective comparison between the aza-Henry additions on C-alkyl substituted aldimines. Table 2. Stereoselective comparison between the aza-Henry additions on C-alkyl substituted aldimines. Table 2. Stereoselective comparison between the aza-Henry additions on C-alkyl substituted aldimines.

Entry R R′ Product Time (h) Yield (%) b syn/anti a Dr a 1 a b a Entry R R3 R′ Product Time (h) (h) Yield syn/anti Dr Entry Product Yield syn/anti Dr 7/7′g 1 CH H R 1Time 90(%)(%) − 3:7aa Entry Rc R′ Product Time (h) Yield (%) syn/anti a Dr a b b 7/7′g 12 CH H 13 90 −− 3:7 7/7′j CF33 80 8:2 7/7′g 1 1 CHc3 H 1 90 − 3:7 CH 7/7 g 90 3:7 7/7′j 231 CF 3 3 3 CH3 38 1 80 −´ 8:2 syn-8/8′g; anti-9/9′g CH 84 1:1 2:8 c H 7/7′j 7/71 j 2 CF 3 c 3 3 80 80 −´ 8:2 CF 8:2 c 3 syn-8/8′g; anti-9/9′g 342 CH 3 CH 3 8 84 1:1 2:8 syn-8/8′j; anti-9/9′j CF3 18 70 3:7 7.2:2.8 1 g; anti-9/91 g syn-8/8′g; anti-9/9′g 3 CH 3 3 CH3 8 8 84 84 1:1 2:8 CH syn-8/8 1:1 c a4Determined 1 b anti-9/9′j CF3 cby H-NMR 18 3:7 CH3 syn-8/8′j; performed the crude mixtures. After 70 flash chromatography on 7.2:2.8 silica 1 on 1j CF syn-8/8 j; anti-9/9 3:7 7.2:2.8 syn-8/8′j; anti-9/9′j 44 c CF 3 c3 18 18 b 70 70 3:7 7.2:2.8 a 1 Determined H-NMRinperformed on the crude After flash chromatography on silica gel. Reactionby performed the presence of ZrCl 4 asmixtures. catalyst, see ref. [10]. a Determined b After c a Determined b After by 11H-NMR H-NMR performed thethe crude mixtures. flashflash chromatography on silicaon gel. by performedonon crude mixtures. chromatography silica c gel. Reaction performed in the presence of ZrCl 4 as see catalyst, see ref. [10]. Reaction performed in the presence of ZrCl as catalyst, ref. [10]. 4 gel. c Reaction performed in the presence of ZrCl4 as catalyst, see ref. [10].

The replacement of the −CF3 group with the −CH3 group on the imine carbon seems to partially The replacement of theof−CF 3 group (Table with the 3 group themuch iminemore carbon to partially influence time and yields additions 1, −CH entries 1, 3),on but theseems syn/anti reaction The replacement group with the ´CH group on theimine imine carbon carbon seems to partially replacement of of the the´CF −CF33 group −CH 33group on the seems influence time anddue yields of additions (Table 1, entries 1, 3), In butfact, much more thealkanes syn/antiadded reaction control, probably to the different involved mechanism. while nitro to influence time and yields of additions additions (Table (Table 1, 1, entries entries 1, 1, 3), 3), but but much much more morethe thesyn/anti syn/anti reaction control, dueintermolecular to the different involved mechanism. In fact, while nitro alkanesonly added to imine 3gprobably through an self-catalyzed reaction, imine 3j undergoes addition in the control, probably due to the the different different involved involved mechanism. mechanism. In fact, while nitro alkanes added to imine 3g through self-catalyzed reaction, imine 3j formation undergoesofaddition in the presence of ZrCl4 an by intermolecular an intramolecular process involving the in situ a chiral only zirconated imine 3g through an intermolecular self-catalyzed reaction, imine 3j undergoes addition only in the presence of ZrCl 4 by an intermediate (Figure 1). intramolecular process involving the in situ formation of a chiral zirconated presence of ZrCl ZrCl44 by an intramolecular process involving the in situ formation of a chiral zirconated intermediate (Figure 1). intermediate (Figure 1).

Figure 1. Different possible mechanisms. Figure Figure 1. 1. Different Different possible possible mechanisms. mechanisms. Figure 1. Different possible mechanisms.

As shown in Table 2, the chiral intermediate permits a partial control of the syn/anti As shown in that Table the chirallostintermediate permits reaction a partialapproach. control On of the contrary, syn/anti diastereoselectivity was2,completely by an intermolecular As shown in Table 2, the chiral intermediate permits a partial control of the syn/anti diastereoselectivity was completely lost intermolecular reaction On the contrary, the aldimine chiralthat resident center leads to by thean same stereoselective facialapproach. attack, the β-nitro amines diastereoselectivity that was completely lost by an intermolecular reaction approach. On the contrary, the aldimine resident leads stereoselective attack, the β-nitro amines always beingchiral obtained with center the same dr. to Bythe 2Dsame NOESY analyses (seefacial Supplementary Materials) [10] the aldimine chiral resident center leads to the same stereoselective facial attack, the β-nitro amines always being obtained with the same dr. By 2D NOESY analyses (see Supplementary Materials) [10] always being obtained with the same dr. By 2D NOESY analyses (see Supplementary Materials) [10]

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As shown in Table 2, the chiral intermediate permits a partial control of the syn/anti diastereoselectivity that was completely lost by an intermolecular reaction approach. On the contrary, the aldimine chiral Molecules 2016, 21, 723 resident center leads to the same stereoselective facial attack, the β-nitro amines 4 of 10 always obtained with the same dr. By 2D NOESY analyses (see Supplementary Materials)4 of [10] Molecules being 2016, 21, 723 10 1 g (entry 2), syn-8/81 g, and anti-9/91 g the R configuration to the new chiral center of major isomers 7 the R configuration to the new chiral center of major isomers 7′g (entry 2), syn-8/8′g, and anti-9/9′g the R assigned. configuration the newdata chiral centerthat of major isomers 7′g intermolecular (entry 2), syn-8/8′g, and anti-9/9′g The to obtained data showed that the nucleophilic nucleophilic intermolecular attack takes place were The obtained showed the attack takes place were assigned. obtained data showed that the2), nucleophilic takes place preferentially intramolecular attack addition proceeds preferentially onThe the methyl aldimine Si face (Figure just like theintermolecular intramolecular addition proceeds preferentially on the methyl aldimine Si face (Figure 2), just like the intramolecular addition proceeds preferentially on the analogous trifluoromethyl aldimine Si face. preferentially on the analogous trifluoromethyl aldimine Si face.

O O ON O Me N Me + R' H N + R' R H N Ph H R Ph H Si face Si face

Figure Figure 2. 2. Stereoselective Stereoselective intermolecular intermolecular attack. attack. Figure 2. Stereoselective intermolecular attack.

Finally, the temperature effect was considered. As previously reported [10], the stereoselective Finally, the effect considered. As reported [10], the stereoselective Finally, the temperature temperature effect was wason considered. As previously previously reported [10],by the stereoselective outcome of addition reactions carried out trifluoromethyl imines was not affected the temperature. outcome of addition reactions carried out on trifluoromethyl imines was not affected the outcome of addition reactions out on trifluoromethyl wasanot affected by the temperature. In fact, while working at lowcarried temperatures (from 0 to −20imines °C) only significant decrease in by yields ˝ temperature. Ininfact, while at low temperatures (from ´20 C) only a significant In fact, while working at lowworking temperatures (from 0 to −20 °C) only0high atosignificant decrease in yields and no changes diastereoselectivity was observed. Instead, a very complete stereoselectivity decrease in yields and no changes in diastereoselectivity was observed. Instead, a very and no changes in diastereoselectivity was observed. Instead, a very high complete stereoselectivity control was registered when the nitro-Mannich reactions were performed on (R)-3g under high low complete stereoselectivity control was registered when the nitro-Mannich reactions were performed control was registered when the nitro-Mannich reactions were performed on (R)-3g under low temperature and the chiral β-nitro amines 7′g and anti-9′g were obtained as diastereomerically pure 1 g and anti-91 g were obtained as on (R)-3g under low temperature and the chiral β-nitro amines 7 temperature and the chiral β-nitro amines 7′g and anti-9′g were obtained as diastereomerically pure compounds, although in lower yields and longer reaction times (Scheme 3). diastereomerically pureincompounds, in lower yields and longer 3). reaction times (Scheme 3). compounds, although lower yieldsalthough and longer reaction times (Scheme

Scheme 3. Temperature effect on the stereoselective aza-Henry additions. Scheme effect on on the the stereoselective stereoselective aza-Henry aza-Henry additions. additions. Scheme 3. 3. Temperature Temperature effect

The stereochemical results can be due to different steric and electronic effects of two considered TheInstereochemical results can be dueatom to different and effects of two groups. fact, the volume of the fluorine is closesteric to that of electronic the hydrogen atom and,considered above all, The stereochemical results can be due to different steric and electronic effects of two considered groups. In fact, the volume of the fluorine atom is close to that of the hydrogen atom and,the above all, the –CF3 group is one of the strongest electron-withdrawing groups able to increase carbon groups. In fact, the volume of the fluorine atom is close to that of the hydrogen atom and, above all, the –CF3 group[24–26]. is one of strongestconsequence, electron-withdrawing groups able difficult to increase the carbon electrophilicity Asthe a possible it seems to be more to control the the –CF3 group is one of the strongest electron-withdrawing groups able to increase the carbon electrophilicity [24–26]. As a possible consequence, it seems to be more difficult to control the nucleophilic attack rate and even stereoselectivity starting from trifluoromethyl aldimine 3j. electrophilicity [24–26]. As a possible consequence, it seems to be more difficult to control the nucleophilic attack rate and even stereoselectivity starting from trifluoromethyl aldimine 3j. Continuing our study, we decided to consider the influence of two other different alkyl groups nucleophilic attack rate and even stereoselectivity starting from trifluoromethyl aldimine 3j. Continuing our study,substituted we decidedaldimines to consider thenitro influence of two other different alkyl groups on the reactivity of C-alkyl with alkanes. Continuing our study, we decided to consider the influence of two other different alkyl groups on on the reactivity of C-alkyl substituted aldimines with nitro alkanes. Therefore, imines 3b,e derived from cyclohexanecarbaldehyde and imines 3c,f, derived the reactivity of C-alkyl substituted aldimines with nitro alkanes. imines 3b,e1) derived from under cyclohexanecarbaldehyde andwith imines 3c,f, derived from Therefore, pivalaldehyde (Table were reacted solvent-free conditions nitromethane (4). Therefore, imines 3b,e derived from cyclohexanecarbaldehyde and imines 3c,f, derived from pivalaldehyde 1) imines were reacted solvent-free conditions nitromethane (4). Unexpectedly, while (Table C-hexyl reactedunder without catalyst giving the with corresponding β-nitro from pivalaldehyde (Table 1) were reacted under solvent-free conditions with nitromethane (4). Unexpectedly, while C-hexyl imines reacted without catalyst giving the corresponding β-nitro amines 5b,e (Scheme 4, A), the presence of the tert-butyl group on the imine carbon required ZrCl4 as Unexpectedly, while C-hexyl imines reacted without catalyst giving the corresponding β-nitro amines amines 5b,e (Scheme A), the presence of the tert-butyl the no imine carbon required ZrCl 4 as catalyst to lead to the4,expected compounds 5c,f (Schemegroup 4, B),on with reaction taking place either 5b,e (Scheme 4, A), the presence of the tert-butyl group on the imine carbon required ZrCl4 as catalyst catalyst to lead to the expected compounds 5c,f (Scheme 4, B), with no reaction taking place either without catalyst or in the presence of a base (K2CO3 or Et3N), or also by changing other reaction to lead to the expected compounds 5c,f (Scheme 4, B), with no reaction taking place either without 3 or presence Et3N), orofalso by changing other without catalyst in thetemperature presence of(from a base parameters (molarorratios, 25(K to2CO 60 °C), a solvent (THF, CH 2Cl2reaction )). catalyst or in the presence of a base (K2 CO3 or Et3 N), or also by changing other reaction parameters parameters (molarreactivity ratios, temperature (from 25 to 60 °C), presence of a solvent (THF, CH 2intriguing. Cl 2)). The different of aldimines 3c,f, derived from pivalaldehyde appeared very (molar ratios, temperature (from 25 to 60 ˝3c,f, C), presence of a solvent (THF, CH 2 Cl2 )). very intriguing. The different reactivity of aldimines derived from pivalaldehyde appeared In fact, the tert-butyl group, characterized by an electron-donating effect but even by a strong steric In fact, the seems tert-butyl group, characterized by an electron-donating but even by a strong hindrance, to influence the C=N reactivity in the same wayeffect of the −CF 3 group, that onsteric the hindrance,asseems to influence C=N reactivity in the same(electron way of the −CF3 group, that on the contrary, reported before, isthe a well-known strong EWG withdrawing group, EWG) contrary, as reported before, is a well-known strong EWG (electron withdrawing group, EWG) although with limited steric hindrance. Therefore, trifluoromethyl aldimines can be considered good although withunlike limited steric hindrance. Therefore, electrophiles, their unfluorinated analogues.trifluoromethyl aldimines can be considered good electrophiles, unlike their unfluorinated analogues.

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Scheme 4. 4. Reactivity of different different C-alkyl C-alkyl substituted substituted aldimines aldimines with with CH CH33NO22 (4). Scheme

A possible explanation this unexpected similarfrom reactivity can be proposed. The different reactivity for of aldimines 3c,f, derived pivalaldehyde appeared very intriguing. As already reported by us [10] in the reaction of trifluoromethyl aldimine 3j the catalyst is In fact, the tert-butyl group, characterized by an electron-donating effect but even by a strong steric required to increase the acidity of the nitro alkane α-proton by ZrCl 4-coordination, since the presence hindrance, seems to influence the C=N reactivity in the same way of the ´CF3 group, that on the of the −CF3 group increases the C=N double bond electrophilicity, but at the same time drastically contrary, as reported before, is a well-known strong EWG (electron withdrawing group, EWG) decreases the lone pair nitrogen availability so that the nucleophile may not be formed. although withScheme limited steric hindrance. trifluoromethyl can be considered 4. Reactivity of differentTherefore, C-alkyl substituted aldimines aldimines with CH3NO 2 (4). On the contrary, the presence of a tert-butyl group in 3c,f favors the nitronate formation but good electrophiles, unlike their unfluorinated analogues. could decrease the reactivity of the C=N carbon due to both steric and electronic effects. Therefore, A possible explanation for this unexpected similar reactivity reactivity can can be be proposed. proposed. the ZrCl4-coordination with aldimine 3 and nitromethane 4 (I) increases the sp2 carbon reactivity but, As already us us [10][10] in the of trifluoromethyl aldimine 3j the catalyst required alreadyreported reportedbyby in reaction the reaction of trifluoromethyl aldimine 3j the is catalyst is above all, allows the reaction to be able to occur through an intramolecular addition (Figure 2), as to increase the acidity of the nitro alkane α-proton by ZrCl -coordination, since the presence of the required to increase the acidity of the nitro alkane α-proton by 4 ZrCl4-coordination, since the presence already proposed to explain the reactivity of C-CF3 substrates, thereby probably minimizing the ´CF increases the C=N bond electrophilicity, but at thebut same timesame drastically decreases of the −CF3 group increases thedouble C=N double bond electrophilicity, at the time drastically 3 group tert-butyl steric effect. the lone pair nitrogen availability so that the nucleophile may not be formed. decreases the lone pair nitrogen availability so that the nucleophile may not be formed. On the contrary, the presence of a tert-butyl group in 3c,f favors favors the nitronate formation but could decrease the reactivity of the C=N carbon due to both steric and electronic effects. Therefore, Therefore, 2 carbon reactivity 2 the ZrCl ZrCl44-coordination -coordinationwith withaldimine aldimine3 and 3 and nitromethane 4 (I) increases the sp nitromethane 4 (I) increases the sp carbon reactivity but, but, above all, allows the reaction be able to occur through an intramolecular addition (Figure above all, allows the reaction to betoable to occur through an intramolecular addition (Figure 2), 3), as as already proposed explainthe thereactivity reactivityofofC-CF C-CF3 3substrates, substrates,thereby thereby probably probably minimizing minimizing the already proposed to to explain tert-butyl steric effect.

Figure 2. Proposed outcome for the ZrCl4-catalyzed addition.

Finally, the stereoselective reaction outcome was even studied on C-alkyl substituted (E)-aldimines 3h,i. The reactions were performed at low temperature and starting from 3i in the presence of ZrCl4 as catalyst. The results are reported in Table 3. The increase of steric hindrance on the imine carbon influenced the course of the aza-Henry additions. Besides determining an increase of reaction time and a decrease in the yields, the addition Figure 3. 2. Proposed Proposed outcome outcome for for the the ZrCl ZrCl4-catalyzed addition. Figure addition. of 6 failed in the syn/anti stereocontrol on the aldimine 3h (entry 2) and does not take place starting 4 -catalyzed from the highly hindered tert-butyl aldimine 3i (entry 3). Only the stereoselectivity of attack remains Finally, the stereoselective reaction outcome was even studied on C-alkyl substituted (E)-aldimines very high giving only one diastereomer by addition of nitromethane (4) (entries 1, 3). The same 3h,i. The reactions were performed at low temperature and starting from 3i in the presence of ZrCl4 selectivity was observed in the reaction of 6 with aldimine 3g (entry 3), with only one diastereomer as catalyst. The results are reported in Table 3. of syn/anti geometric isomers being formed. The increase of steric hindrance on the imine carbon influenced the course of the aza-Henry additions. Besides determining an increase of reaction time and a decrease in the yields, the addition of 6 failed in the syn/anti stereocontrol on the aldimine 3h (entry 2) and does not take place starting

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Finally, the stereoselective reaction outcome was even studied on C-alkyl substituted (E)-aldimines 3h,i. The reactions were performed at low temperature and starting from 3i in the presence of ZrCl4 as catalyst. The results are reported in Table 3. Molecules 2016, 21, 723 6 of 10 Table 3. 3. Diastereoselective Diastereoselective additions additions on on different different C-alkyl C-alkyl substituted substituted aldimines. aldimines. Table

a a b b syn/anti Entry Product Time (h) (h) Yield Entry RR R' R' Product Time Yield syn/anti (%)(%) 7/7′h 11 H H 7/71 h 24 24 4545 ´− CyCy 1 syn-8/8 h; anti-9/9′h 22 CH3 CHsyn-8/8′h; 48 56 1:1 48 56 1:1 3 anti-9/91 h 7/7′i H 8 55 − 3 t-Bu c 1i 3 H 7/7 8 55 ´ 4 − − − − c CH3

Dr Dra a

99:1 99:1 99:1 99:1 99:1 −

99:1

t-Bu 4 CH3 ´ ´ ´ ´ ´ Determined by 1H-NMR performed on the crude mixtures; b After purification on silica gel; c Reaction a Determined by 1 H-NMR performed on the crude mixtures; b After purification on silica gel; c Reaction performed in the presence of ZrCl4 (50 mol %). a

performed in the presence of ZrCl4 (50 mol %).

3. Experimental Section The increase of steric hindrance on the imine carbon influenced the course of the aza-Henry solvent. IR spectra were recorded on Perkin-Elmer 1600time FT/IR spectrophotometer in CHCl additions. Besides determining anaincrease of reaction and a decrease in the yields, the3 as addition of 1H-NMR and 13C-NMR spectra were recorded on a VARIAN XL-300 spectrometer at 300 and 75 MHz 6 failed in the syn/anti stereocontrol on the aldimine 3h (entry 2) and does not take place starting from or a Bruker Avance III at 400aldimine and 1013i MHz, respectively, atstereoselectivity room temperature. CDCl3remains was used as theon highly hindered tert-butyl (entry 3). Only the of attack very 1 13 solvent and CHCl anddiastereomer CDCl3 as internal standard H and C, respectively. experiments high giving only 3one by addition offor nitromethane (4) (entries 1,The 3). NOESY The same selectivity were performed with a Bruker Avance III spectrometer at 400 MHz using CDCl 3 as solvent and was observed in the reaction of 6 with aldimine 3g (entry 3), with only one diastereomer of syn/anti CHCl 3 as internal standard and used to assist in structure elucidation [27]. HPLC analyses were geometric isomers being formed. performed with a Varian 9001 instrument using an analytical column (3.9 × 300 mm, flow rate 1.3 detector: 254 nm) equipped with a Varian RI-4 differential refractometer, or a Varian 9050 3. mL/min; Experimental Section UV/VIS detector. Eluents were HPLC grade. HR-MS analyses were performed using a Micromass IR spectra were recorded on a Perkin-Elmer 1600 FT/IR spectrophotometer in CHCl3 as solvent. Q-TOF Micro quadrupole-time of flight (TOF) mass spectrometer equipped with an ESI source and a 1 H-NMR and 13 C-NMR spectra were recorded on a VARIAN XL-300 spectrometer at 300 and 75 MHz syringe pump. The experiments were conducted in the positive ion mode. Optical rotation was or on a Bruker Avance III at 400 and 101 MHz, respectively, at room temperature. CDCl3 was used determined at 25 °C with a JASCO DIP-370 polarimetry at a1wavelength of 589 nm, using a quartz as solvent and CHCl3 and CDCl3 as internal standard for H and 13 C, respectively. The NOESY cell of 1 cm length. experiments were performed with a Bruker Avance III spectrometer at 400 MHz using CDCl3 as solvent and CHCl3 as internal standard and used to assist in structure elucidation [27]. HPLC analyses 3.1. General Procedure for the Synthesis of C-alkyl Imines (3a–i) were performed with a Varian 9001 instrument using an analytical column (3.9 ˆ 300 mm, flow rate Equimolar amounts254 (5 mmol) of aldehyde and amine RI-4 weredifferential reacted under solvent free or conditions. 1.3 mL/min; detector: nm) equipped with a Varian refractometer, a Varian The stirred atHPLC room temperature foranalyses 15 min, then 2Cl2 (3 mL) anda anhydrous 9050reaction UV/VISmixtures detector.were Eluents were grade. HR-MS wereCH performed using Micromass sodium sulfatequadrupole-time (Na2SO4) were added and the mixtures were filtered off. The organic Q-TOF Micro of flight (TOF) mass spectrometer equipped with an ESIsolvent source was and evaporated under vacuum to give the expected aldimines which were used without further a syringe pump. The experiments were conducted in the positive ion mode. Optical rotation was purification. 3a–i known compounds. determined at 25 ˝[28–35] C with are a JASCO DIP-370 polarimetry at a wavelength of 589 nm, using a quartz cell of 1 cm length. 3.2. General Procedure for the Synthesis of C-alkyl β-nitro Amines 3.1. General Procedure for the Synthesis of C-alkyl Imines (3a–i) Procedure A. (E)-Aldimines 3 (1 mmol) were stirred at room temperature (1–18 h) with a five-fold amounts (54mmol) of aldehyde and amine were reacted undersolvent-free solvent freeconditions. conditions. excessEquimolar of nitro compound (eight-fold excess of nitro compound 6) under The reaction mixtures stirred at roomunder temperature for the 15 min, then CH2 Cl2were (3 mL) and anhydrous After removal of nitrowere compound excess vacuum, crude mixtures purified by flash sodium sulfate (Na SO4 ) gel. were added and the mixtures were filtered off. The organic solvent was chromatography on 2silica Procedure B. As procedure A, but at −20 °C. Procedure C. ZrCl4 (0.5 mmol) was added to a mixture of (E)-aldimine 3i (1 mmol) and nitro compound 4 (5 mmol) or 6 (8 mmol). The reactions were performed under solvent-free conditions and stirred at room temperature (1–2 h). Then, after addition of water (5 mL), the crude mixtures were extracted three times with Et2O. The collected organic layers were dried over anhydrous Na2SO4 and the solvent evaporated under vacuum. The crude mixtures were purified by flash chromatography

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evaporated under vacuum to give the expected aldimines which were used without further purification. 3a–i [28–35] are known compounds. 3.2. General Procedure for the Synthesis of C-alkyl β-nitro Amines Procedure A. (E)-Aldimines 3 (1 mmol) were stirred at room temperature (1–18 h) with a five-fold excess of nitro compound 4 (eight-fold excess of nitro compound 6) under solvent-free conditions. After removal of nitro compound excess under vacuum, the crude mixtures were purified by flash chromatography on silica gel. Procedure B. As procedure A, but at ´20 ˝ C. Procedure C. ZrCl4 (0.5 mmol) was added to a mixture of (E)-aldimine 3i (1 mmol) and nitro compound 4 (5 mmol) or 6 (8 mmol). The reactions were performed under solvent-free conditions and stirred at room temperature (1–2 h). Then, after addition of water (5 mL), the crude mixtures were extracted three times with Et2 O. The collected organic layers were dried over anhydrous Na2 SO4 and the solvent evaporated under vacuum. The crude mixtures were purified by flash chromatography on silica gel. Procedure D. Same as procedure C, but at ´20 ˝ C. N-Benzyl-1-nitropropan-2-amine (5a, Procedure A). Yellow oil; (0.165 g, 85%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR νmax 3355, 1571 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.31–7.18 (5H, m), 4.37–4.26 (m, 2H), 3.83–3.67 (2H, m), 3.43–3.32 (1H, m), 1.59 (1H, br), 1.15 (3H, d, J = 6.6 Hz); 13 C-NMR (CDCl3 , 75 MHz) δ 139.6, 128.4 (2C), 127.9 (2C), 127.1, 80.2, 51.2, 50.8, 18.2; HRMS m/z [M + H]+ 195.1139 (calcd for C10 H15 N2 O2 , 195.1134). N-Benzyl-1-cyclohexyl-2-nitroethanamine (5b, Procedure A). Yellow oil; (0.223 g, 85%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR νmax 3353, 1562 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.31–7.18 (5H, m), 4.43 (1H, dd, J = 11.5, 5.0 Hz), 4.34 (1H, dd, J = 11.7, 7.8 Hz), 3.75 (2H, s, J = 10.3 Hz), 3.14–3.08 (1H, m), 1.78–1.45 (7H, m), 1.25–0.90 (5H, m); 13 C-NMR (CDCl3 , 75 MHz) δ 139.8, 128.3 (2C), 128.0 (2C), 127.0, 77.1, 60.8, 51.5, 39.7, 29.0, 28.8, 26.2, 26.1 (2C); HRMS m/z [M + H]+ 263.1758 (calcd for C15 H23 N2 O2 , 263.1760). N-Benzyl-3,3-dimethyl-1-nitrobutan-2-amine (5c, Procedure C). Pale yellow oil; (0.189 g, 80%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR νmax 3359, 1571 cm´1 ; 1 H-NMR (CDCl , 300 MHz) δ = 7.35–7.22 (5H, m), 4.59 (1H, dd, J = 11.8, 4.0 Hz), 4.32 (1H, dd, J = 11.8, 3 8.8 Hz), 3.87–3.77 (2H, m,), 3.16 (1H, dd, J = 8.8, 4.0 Hz), 1.75 (1H, br), 0.97 (9H, s); 13 C-NMR (CDCl3 , 75 MHz) δ 140.1, 128.4 (2C), 128.3 (2C), 127.2, 78.3, 65.5, 54.5, 35.4, 26.6 (3C); HRMS m/z [M + H]+ 237.1601 (calcd for C13 H21 N2 O2 , 237.1603). N-(1-Nitropropan-2-yl)aniline (5d, Procedure A). Yellow oil; (0.09 g, 50%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR νmax 3355, 1567 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 1 H NMR (CDCl3 , 300 MHz) δ 7.22 (2H, t, J = 7.8 Hz) 6.79 (1H, t, J = 7.3 Hz), 6.67 (2H, d, J = 7.9 Hz), 4.58 (1H, dd, J = 12.2, 4.5 Hz), 4.38 (1H, dd, J = 11.7, 8.3 Hz), 4.26–4.20 (1H, m), 3.71 (1H, br), 1.38 (3H, d, J = 6.3 Hz); 13 C-NMR (CDCl3 , 75 MHz) δ 145.6, 129.6 (2C), 118.9, 113.7 (2C), 79.2, 47.8, 18.6; HRMS m/z [M + H]+ 181.0982 (calcd for C9 H13 N2 O2 , 181.0977). N-(1-Cyclohexyl-2-nitroethyl)aniline (5e, Procedure A). Pale yellow oil; (0.134 g, 54%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR νmax 3356, 1564 cm´1 ; 1 H NMR (CDCl3 , 300 MHz) δ 7.19 (2H, t, J = 7.8 Hz), 6.75 (1H, t, J = 7.3 Hz), 6.66 (2H, d, J = 7.9 Hz), 4.63–4.39 (2H, m), 4.12–3.88 (1H, m), 3.72 (1H, br), 1.98–1.50 (6H, m), 1.38 –0.95 (5H, m); 13 C NMR (CDCl3 , 75 MHz) δ 146.5, 129.5 (2C), 118.4, 113.4 (2C), 76.4, 56.9, 40.6, 29.6, 28.8, 26.1, 25.9 (2C); HRMS m/z [M + H]+ 249.1601 (calcd for C14 H21 N2 O2 , 249.1603). N-(3,3-Dimethyl-1-nitrobutan-2-yl)aniline (5f, Procedure C). Pale yellow oil; (0.122 g, 55%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 90:10); IR νmax 3350, 1563 cm´1 ;

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1 H-NMR

(CDCl3 , 400 MHz) δ 7.16 (2H, t, J = 7.9 Hz), 6.72 (1H, t, J = 7.3 Hz), 6.67 (2H, d, J = 7.8 Hz), 4.63 (1H, dd, J = 12.1, 4.8 Hz), 4.36 (1H, dd, J = 12.1, 8.6 Hz), 4.10 (1H, m), 3.63 (1H, br), 1.02 (9H, s); 13 C-NMR (CDCl , 100 MHz) δ 147.4, 129.5 (2C), 118.4, 113.4 (2C), 77.2, 61.2, 29.8, 26.6 (3C); HRMS m/z 3 [M + H]+ 223.1451 (calcd for C12 H19 N2 O2 , 223.1447).

(S)-1-Nitro-N-[(R)-1-phenylethyl]propan-2-amine (7g, Procedure A). Yellow oil; (0.135 g, 65%); separated by HPLC (eluent: hexane/ethyl acetate = 90:10); [α]D : ´55.4 (c = 40 g/100 mL, CHCl3 ); IR νmax 3358, 1555 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.37–7.27 (5H, m), 4.41 (1H, dd, J = 11.4, 5.4 Hz), 4.23 (1H, dd, J = 11.4, 5.4 Hz), 3.93 (1H, q, J = 6.5 Hz), 3.28–3.14 (1H, m), 1.79 (1H, br), 1.34 (3H, d, J = 6.5 Hz), 1.15 (3H, d, J = 6.6 Hz); 13 C-NMR (CDCl3 , 75 MHz) δ 144.7, 128.6 (2C), 127.2, 126.5 (2C), 81.2, 55.3, 49.2, 25.1, 17.6; HRMS m/z [M + H]+ 209.1297 (calcd for C11 H17 N2 O2 , 209.1290). (R)-1-Nitro-N-[(R)-1-phenylethyl]propan-2-amine (71 g, Procedure B). Yellow oil; (0.168 g, 81%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 90:10); [α]D : -70.4 (c = 40 g/100 mL, CHCl3 ); IR νmax 3358, 1555 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.37–7.22 (5H, m), 4.42 (1H, dd, J = 11.4, 5.4 Hz), 4.33 (1H, dd, J = 11.3, 5.3 Hz), 3.90 (1H, q, J = 6.5 Hz), 3.32–3.14 (1H, m), 1.58 (1H, br), 1.33 (3H, d, J = 6.5 Hz), 1.12 (3H, d, J = 6.6 Hz); 13 C-NMR (CDCl3 , 75 MHz) δ 145.1, 128.6 (2C), 127.2, 126.4 (2C), 79.63, 55.4, 49.5, 24.6, 19.2; HRMS m/z [M + H]+ 209.1288 (calcd for C11 H17 N2 O2 , 209.1290). (S)-1-Cyclohexyl-2-nitro-N-[(R)-1-phenylethyl]ethanamine (7h, Procedure A). Pale yellow oil; (0.153 g, 55.3%); separated by HPLC (eluent: hexane/ethyl acetate = 85:25); [α]D : +13.8 (c = 40 g/100 mL, CHCl3 ); IR νmax 3361, 1558 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.38–7.20 (5H, m), 4.28 (1H, dd, J = 11.6, 5.1 Hz), 4.19 (1H, dd, J = 11.6, 8.0 Hz), 3.87 (1H, q, J = 6.5 Hz), 3.07–2.99 (1H, m), 1.86–0.87 (12H, m), 1.31 (3H, d, J = 6.5 Hz); 13 C-NMR (CDCl3 , 75 MHz) δ 145.0, 128.4 (2C), 127.2, 126.7 (2C), 77.6, 58.8, 55.5, 39.3, 29.2, 28.3, 26.4, 26.3 (2C), 24.6; HRMS m/z [M + H]+ 277.1923 (calcd for C16 H25 N2 O2 , 277.1916). (R)-1-Cyclohexyl-2-nitro-N-[(R)-1-phenylethyl]ethanamine (71 h, Procedure B). Pale yellow oil; (0.065 g, 23.7%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 85:25); [α]D : +18.5 (c = 40 g/100 mL, CHCl3 ); IR νmax 3361, 1558 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.37–7.19 (5H, m), 4.51 (1H, dd, J = 11.6, 5.0 Hz), 4.40 (1H, dd, J = 11.5, 5.6 Hz), 3.88 (1H, q, J = 6.5 Hz), 2.86 (1H, q, J = 5.5 Hz), 1.32 (3H, d, J = 6.5 Hz), 1.97–0.81 (12H, m); 13 C -NMR (CDCl3 , 75 MHz) δ 145.1, 128.4 (2C), 127.2, 126.8 (2C), 76.1, 58.8, 55.5, 40.2, 29.3, 29.0, 26.3, 26.1 (2C), 24.7; HRMS m/z [M + H]+ 277.1913 (calcd for C16 H25 N2 O2 , 277.1916). (S)-3,3-dimethyl-1-nitro-N-[(R)-1-phenylethyl]butan-2-amine (7i, Procedure C). Pale yellow oil; (0.063 g, 25%); separated by HPLC (eluent: hexane/ethyl acetate = 85:25); [α]D : ´85.4 (c = 40 g/100mL, CHCl3 ); 1 H-NMR (CDCl , 300 MHz) δ 7.29–7.18 (5H, m), 4.33 (1H, dd, J = 11.9, 4.6 Hz), 4.06 (1H, dd, J = 11.9, 3 7.5 Hz), 3.75 (1H, q, J = 6.5 Hz), 3.05 (1H, dd, J = 7.5 Hz, 4.6 Hz), 1.25 (3H, d, J = 6.5 Hz), 1.20 (1H, br, J = 2.1 Hz), 0.90 (9H, s); 13 C NMR (CDCl3 , 75 MHz) δ 145.7, 128.5 (2C), 127.4, 126.9 (2C), 78.3, 63.2, 57.4, 35.7, 26.7 (3C), 23.6; HRMS m/z [M + H]+ 251.1765 (calcd for C14 H23 N2 O2 , 251.1760). (R)-3,3-dimethyl-1-nitro-N-[(R)-1-phenylethyl]butan-2-amine (71 i, Procedure D). Pale yellow oil; (0.138 g, 55%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 85:25); [α]D : ´43.6 (c = 40 g/100 mL, CHCl3 ); IR νmax 3359 1553 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.33–7.24 (5H, m), 4.59 (1H, dd, J = 11.8, 4.5 Hz), 4.34 (1H, dd, J = 11.7, 6.4 Hz), 3.82 (1H, q, J = 6.5 Hz), 2.86 (1H, dd, J = 6.3 Hz, 4.6 Hz), 1.59 (1H, br), 1.32 (3H, d, J = 6.5 Hz), 0.85 (9H, s); 13 C-NMR (CDCl3 , 75 MHz) δ 144.9, 128.3 (2C), 127.2 (2C), 127.1, 77.5, 62.7, 56.3, 35.1, 26.4 (3C), 24.5; HRMS m/z [M + H]+ 251.1763 (calcd for C14 H23 N2 O2 , 251.1760). 3-Nitro-N-[(R)-1-phenylethyl]butan-2-amine (syn-8g/81 g;anti-9g/91 g, Procedure A) Yellow oil; (0.186 g, 84%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR νmax 3355, 1567 cm´1 ; 1 H -NMR (CDCl3 , 300 MHz) δ 7.48–7.07 (20H, m), 4.76–4.62 (2H, m), 4.56–4.30 (2H, m), 3.99–3.86 (3H, m), 3.87–3.70 (1H, m), 3.24–3.08 (1H, m), 3.03–2.83 (3H, m), 1.54–1.35 (4H, m),

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1.48 (3H, d, J = 7.0 Hz), 1.44 (6H, d, J = 6.6 Hz), 1.40 (3H, d, J = 6.4 Hz), 1.33 (9H, d, J = 6.4 Hz), 1.30 (3H, d, J = 6.5 Hz), 1.12 (3H, d, J = 6.5 Hz), 1.11 (3H, d, J = 6.4 Hz), 1.01 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.8 Hz); 13 C-NMR (CDCl3 , 75 MHz) δ 145.5, 145.2, 144.7, 144.6, 128.4 (4C), 128.3, 128.2 (4C), 126.9 (4C), 126.6, 126.5, 126.3 (4C), 126.2, 87.8, 87.3, 87.0, 84.4, 55.7, 55.1, 54.9, 53.8 (2C), 53.7, 53.1, 52.9, 25.1, 24.7, 24.4, 23.7, 16.6, 16.5 (2C), 15.8, 15.6, 15.3, 14.5 (2C); HRMS m/z [M + H]+ 223.1450 (calcd for C12 H19 N2 O2 , 223.1447). (2R,3S)-3-Nitro-N-[(R)-1-phenylethyl]butan-2-amine (anti-91 g, Procedure B). Yellow oil; (0.133 g, 60%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); [α]D : ´9.9 (c = 40 g/100 mL, CHCl3 ); IR νmax 3353, 1566 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.37–7.22 (5H, m), 4.75–4.63 (1H, m), 3.94 (1H, q, J = 6.5 Hz), 2.95 (1H, m), 2.00 (1H, br), 1.44 (3H, d, J = 6.7 Hz), 1.32 (3H, d, J = 6.5 Hz), 1.00 (3H, d, J = 6.6 Hz); 13 C-NMR (CDCl3 , 75 MHz) δ 145.3, 128.5 (2C), 127.1, 126.4 (2C), 84.5, 55.2, 54.0, 24.5, 16.7, 14.7; HRMS m/z [M + H]+ 223.1445 (calcd for C12 H19 N2 O2 , 223.1447). (R)-1-Cyclohexyl-2-nitro-N-[(R)-1-phenylethyl]propan-1-amine (syn-8'h/anti-9'h, Procedure B). Pale yellow oil; (0.162 g, 56%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR νmax 3357, 1568 cm´1 ; 1 H-NMR (CDCl3 , 300 MHz) δ 7.36–7.21 (10H, m), 4.62 (1H, q, J = 6.9 Hz, syn), 4.25 (1H, q, J = 6.5 Hz, anti), 3.76 (1H, q, J = 6.8 Hz, anti), 3.74 (1H, q, J = 6.2 Hz, syn), 2.93 (1H, dd, J = 5.9 Hz, 4.2 Hz, anti), 2.83 (1H, dd, J = 7.5 Hz, 4.1 Hz, syn), 1.52 (3H, d, J = 3.9 Hz, syn), 1.48 (3H, d, J = 6.8 Hz, anti), 1.83–0.94 (24H, m), 1.27 (6H, d, J = 6.5 Hz); 13 C NMR (CDCl3 , 75 MHz) δ 145.4, 145.2, 128.4 (2C), 128.3 (2C), 127.2, 127.1, 126.9 (2C), 126.5 (2C), 86.6, 83.8, 69.4, 62.8, 57.0, 56.7, 41.1, 40.2, 30.8, 30.7, 29.8 (2C), 26.1 (2C), 25.4 (2C), 24.7, 23.9, 21.7, 21.4, 16.8, 13.5; HRMS m/z [M + H]+ 291.2074 (calcd for C17 H27 N2 O2 291.2073). 4. Conclusions In summary, a first direct comparison in aza-Henry addition reactions between the C-CF3 and C-CH3 substituted N-protected aldimines was reported. The different inductive effect of the two groups greatly influence the reaction outcome acting both on the electrophilicity of the imino carbon and on the nitrogen lone pair availability. The presence of a strong steric hindrance on the imine carbon due to the tert-butyl group unexpectedly required the reaction conditions already fixed for trifluoromethyl aldimines, although for different reactivity reasons. Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/ 21/6/723/s1. Acknowledgments: We thank the Università degli Studi di Roma “La Sapienza” for financial support. Author Contributions: S.F. and A.P. conceived and designed the experiments, A.P. and E.S. performed the experiments, and S.F. and L.P. analyzed the data and wrote the paper. All authors discussed the results and approved the final version. Conflicts of Interest: The authors declare no conflict of interest.

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