Organocatalyzed Michael Addition to Nitroalkenes Via Masked Acetaldehyde

catalysts

Communication Organocatalyzed Michael Addition to Nitroalkenes via Masked Acetaldehyde

Giuliana Giorgianni 1, Valeria Nori 1 , Andrea Baschieri 1,2 , Laura Palombi 1 and Armando Carlone 1,*

1 Department of Physical and Chemical Sciences, Università degli Studi dell’Aquila, via Vetoio, 67100 L’Aquila, Italy; [email protected] (G.G.); [email protected] (V.N.); [email protected] (A.B.); [email protected] (L.P.) 2 Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy * Correspondence: [email protected]; Tel.: +39-0862433036

Received: 9 October 2020; Accepted: 4 November 2020; Published: 9 November 2020

Abstract: A novel and safe reaction protocol for the enantioselective enamine-catalysed addition of acetaldehyde to nitroalkenes is presented; this protocol makes use of a safe acetaldehyde precursor to access important intermediates to Active Pharmaceutical Ingredients (APIs), and allows the use of fewer equivalents of acetaldehyde and lower catalyst loadings. The reaction developed proved to be suitable to be performed on gram-scale and to produce key intermediates for the synthesis of pharmacologically active compounds such as pregabalin.

Keywords: acetaldehyde; asymmetric catalysis; Michael addition; organocatalysis; pregabalin

1. Introduction Nowadays, organocatalysis is a key technology platform and is routinely assessed in industry when taking a process to manufacture [1–4]. In fact, organocatalysis can bring many benefits to an industrial process; the catalysts are in general non-toxic, the reactions are robust, metals are avoided, and strictly controlled conditions are non-necessary. Organocatalysis can be employed to access very valuable γ-amino acids, such as pregabalin, and a great number of organocatalytic synthetic routes to this simple API has been disclosed [5]. Among these, the enamine-catalysed [6–9] addition of acetaldehyde to a nitroalkene holds high potential for a cost-efficient process; the raw materials are widely available at low prices and the catalyst needed can be accessed at a reasonable cost. Whereas different types of ketones and aldehydes have been activated as nucleophiles, few attempts of using acetaldehyde as nucleophile have been reported with aminocatalysis [10,11]. Controlling acetaldehyde’s reactivity is extremely challenging; in fact, it can easily undergo self-condensation reactions. Furthermore, the product of the enamine-mediated reaction of acetaldehyde is an aldehyde carrying a methylene group, which is still considerably reactive and could potentially react with either a nucleophile or an electrophile to give collateral products. Hayashi [12,13] and List [14] showed independently that, by carefully choosing the reaction conditions, an efficient aminocatalytic enantioselective addition of acetaldehyde to nitroalkenes can be accomplished (Scheme1a,b).

Catalysts 2020, 10, 1296; doi:10.3390/catal10111296 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 1296 2 of 7

Scheme 1. Literature-reported examples of enantioselective Michael addition of acetaldehyde to nitroalkenes compared to our synthetic strategy.

Despite the great advancement of the reports by Hayashi and List, the approach still suffers from the use of relatively high catalyst loading (10–20 mol%) and the use of a large excess of acetaldehyde; in fact, because of its high tendency to form oligomers, it was used in large excess and added slowly. Furthermore, by using two supported catalysts, Pericàs ingeniously employed paraldehyde to enable the same reaction and avoid the use of acetaldehyde [15] (Scheme1c). Nevertheless, they used 10 equivalents of masked acetaldehyde (i.e., 3.3 eq. of paraldehyde) and a relatively high catalyst loading of supported organocatalysts that, despite the potential recyclability, bring a considerable cost contribution to the manufacture process. Herein, we report the use of acetaldehyde dimethyl acetal in the aminocatalytic enantioselective addition to nitroalkenes. By employing a simple masked acetaldehyde, we could tackle the challenges that acetaldehyde brings to an industrial process, lower the catalyst loading, use fewer equivalents of acetaldehyde, and use affordable raw materials and catalyst. The desired γ-nitroaldehydes derivatives were obtained in high yields and enantioselectivities using a very simple, safe, and cost-efficient protocol.

2. Results and Discussion A range of organic, inorganic, and immobilized acids were tested on the in-situ deprotection of acetaldehyde dimethyl acetal 5 (Table1). While organic acids a ﬀorded negligible amounts of 1

Catalysts 2020, 10, x FOR PEER REVIEW 3 of 7 similar conversion, was discarded for further screening given its higher cost and the challenges that a polymericCatalysts 2020 sheet, 10, 1296brings in a process. 3 of 7

Table 1. Results of the acid-catalysed deprotection of acetaldehyde dimethyl acetal 1. deprotected products (Table1, entries 1–4), encouraging results were obtained with inorganic acids Catalystsand 20 acidic20, 10, x resins FOR PEER (Table REVIEW1, entries 5–6 and 7–8 and 10) and triﬂuoroacetic acid (Table1, entry 9). 3 of 7 The most promising acids proved to be TFA and Amberlyst-15, providing the deprotected acetaldehyde similar2 in conversion, 16% and 18% was conversion, discarded respectively for further (Table screening1, entry given 9–10). its Naﬁon higher NRE cost 212, and albeit the challenges showing a that a polymericsimilar conversion, sheet brings was in discarded a process. for further screening given its higher cost and the challenges that a polymeric sheet brings in a process. 2 Table 1. ResultEntrys of the acid-catalysedAcid deprotection of acetaldehydeConv. (%) dimethyl acetal 1. Table 1. Results1 of the acid-catalysedBenzoic deprotection Acid of acetaldehyde0 dimethyl acetal 1. 2 AcOH 1 3 p-NO2-C6H4CO2H 0 4 pTSA 0

Entry5 HCl Acid 14Conv. (%) 2 Entry Acid Conv. (%) 2 16 H Benzoic2SO4 Acid14 0 271 AmberlystBenzoic AcOH Acid-36 120 1 382 Nafionp-NOAcOH 2NRE-C6H 4 212CO2 H151 0 4 pTSA 0 3 p-NO2-C6H4CO2H 0 59 TFA HCl 16 14 4 pTSA 0 610 Amberlyst H2SO-415 18 14 75 Amberlyst-36HCl 14 12 1 Acetaldehyde dimethyl acetal (0.8 mmol) and acid (10 mol%) were mixed in CDCl3 for 2 h. 2 8 Nafion NRE 212 15 6 H2SO4 14 Conversion of acetaldehyde9 dimethyl acetal 5 in TFAto acetaldehyde 2. 16 107 Amberlyst Amberlyst-15-36 12 18 Encouraged by these results,8 we furtherNafion optimized NRE 212 the reaction15 conditions between nitrostyrene 1 2 Acetaldehyde dimethyl acetal (0.8 mmol) and acid (10 mol%) were mixed in CDCl3 for 2 h. Conversion of 1a and acetaldehydeacetaldehyde dimethyl dimethyl acetal9 5 acetalinto acetaldehyde 5 in theTFA2 . presence of a catalytic16 amount of Hayashi/Jørgensen catalyst 6, by employing Amberlyst10 -15Amberlyst as a catalyst-15 to effect the18 deprotect ion (Table 2, see also Supplementary1 AcetaldehydeEncouraged Materials dimethylby these); the results, acetal use we (0.8of furtherTFA mmol) was optimized and discarded acid the (10 reaction asmol% no )7 conditions wereis formed mixed between in in the CDCl nitrostyrenepresence3 for 2 hof.1a 2TFA, 1a, 6and Conversionand acetaldehyde 5 in CHCl of acetaldehyde3.dimethyl Adventitious acetal dimethyl 5winater theacetal is presence not 5 in enoughto ofacetaldehyde a catalytic to afford amount 2. a high of Hayashiconversion/Jørgensen and the catalyst addition of water6, by is employing needed ( Amberlyst-15Table 2, entries as a1 catalyst–2). A solvent to effect screening the deprotection was carried (Table2 ,out see with also Supplementary5 eq. of 5, 10 eq. of waterMaterials);Encouraged (i.e., 2 eq. the with by use these ofrespect TFA results, was to discarded5 )we over further 7 as2 h no optimized(Table7 is formed 2, entries the in thereaction 2 presence–9). Chloroform conditions of TFA, 1a between,afforded6 and 5 in nitrost the CHCl desired3y.rene product1a andAdventitious acetaldehyde 3a in 94% water conversion dimethyl is not enough and acetal 93% to 5ee a ffin (ordTable the a presence high 2, entry conversion 2).of Solventsa catalytic and the such additionamount as ethyl of acetate, waterHayashi is acetonitrile, needed/Jørgensen andcatalyst (Tableacetone 6,2 ,by entriesshowed employing 1–2). lower A solvent Amberlyst conversion screening-15 and as was aenantioselectivity catalyst carried out to witheffect 5( Table eq.the ofdeprotect 2,5, entries 10 eq.ion of 3 – water(Table5), while (i.e., 2, 2toluene see eq. also, with respect to 5) over 72 h (Table2, entries 2–9). Chloroform a fforded the desired product 3a in 94% diethylSupplementary ether, and Materials dichloromethane); the use of provided TFA was lower discarded conversion as no 7with is formed enantioselectivity in the presence comparable of TFA, conversion and 93% ee (Table2, entry 2). Solvents such as ethyl acetate, acetonitrile, and acetone 3 to1a ,CHCl 6 and3 (5Table in CHCl 2, entries. Adventitious 6–8). The wuseater of isdi notoxane enough provided to afford similar a high conversion conversion and eeand to the CHCl addition3 over showed lower conversion and enantioselectivity (Table2, entries 3–5), while toluene, diethyl ether, 7of2 waterh (Table is needed2, entry ( Table9). However 2, entries, when 1–2). the A solventreaction screening time was was shortened carried to out 24 with h, CHC 5 eq.l3 ofproved 5, 10 eq.to beof and dichloromethane provided lower conversion with enantioselectivity comparable to CHCl3 (Table2, water (i.e., 2 eq. with respect to 5) over 72 h (Table 2, entries 2–9). Chloroform afforded2 the desired a betterentries solvent 6–8). than The usedioxane of dioxane both providedwith 10 eq. similar (Table conversion 2, entries and 10 ee–11 to) CHCland 153 over eq. 72of hH (TableO (Table2, 2, product 3a in 94% conversion and 93% ee (Table 2, entry 2). Solvents such as ethyl acetate, acetonitrile, entriesentry 12– 9).13 However,). when the reaction time was shortened to 24 h, CHCl3 proved to be a better solvent and acetone showed lower conversion and enantioselectivity (Table 2, entries 3–5), while toluene, than dioxane both with 10 eq. (Table2, entries 10–11) and 15 eq. of H 2O (Table2, entries 12–13). diethyl ether, and dichloromethaneTable 2. Optimization provided of conditions lower conversion for the Mich withael addition enantioselectivity 1. comparable 1. to CHCl3 (Table 2, entriesTable 6–8). 2. TheOptimization use of d ofioxane conditions provided for the Michaelsimilar addition conversion and ee to CHCl3 over 72 h (Table 2, entry 9). However, when the reaction time was shortened to 24 h, CHCl3 proved to be a better solvent than dioxane both with 10 eq. (Table 2, entries 10–11) and 15 eq. of H2O (Table 2, entries 12–13).

Table 2. Optimization of conditions for the Michael addition 1.

2 3 Entry 5 (eq) H2O (eq) Solvent t (h) Conv. [%] ee (%) Entry 5 (eq) H2O (eq) Solvent t (h) Conv. [%] 2 ee (%) 3 1 5 0 CHCl3 72 46 96 1 5 0 CHCl3 72 46 96 2 5 10 CHCl3 72 94 93 2 35 510 10CHCl AcOEt3 72 72 3294 88 93 3 45 510 10AcOEt MeCN 72 72 532 44 88 4 5 10 MeCN 72 5 44

5 5 10 Acetone 72 75 87 2 3 Entry6 5 (eq)5 H2O10 (eq) TolueneSolvent t 72(h) Conv.85 [%] ee 94(%) 3 71 5 100 CHClEt2O 72 7146 9496 2 5 10 CHCl3 72 94 93 3 5 10 AcOEt 72 32 88 4 5 10 MeCN 72 5 44 5 5 10 Acetone 72 75 87 6 5 10 Toluene 72 85 94 7 5 10 Et2O 72 71 94

Catalysts 2020, 10, 1296 4 of 7

Table 2. Cont.

2 3 Entry 5 (eq) H2O (eq) Solvent t (h) Conv. [%] ee (%) 5 5 10 Acetone 72 75 87 6 5 10 Toluene 72 85 94 7 5 10 Et2O 72 71 94 8 5 10 CH2Cl2 72 61 92 9 5 10 Dioxane 72 93 94 10 5 10 Dioxane 24 71 93 11 5 10 CHCl3 24 93 93 12 5 15 Dioxane 24 84 95 13 5 15 CHCl3 24 97 93 14 1.2 3.6 CHCl3 24 57 91 15 2 6 CHCl3 24 74 90 16 3 9 CHCl3 24 81 92 4 17 3 9 CHCl3 24 >99 94 4 18 2 6 CHCl3 24 81 92 5 19 2 6 CHCl3 24 94 90 5,6 20 2 6 CHCl3 24 91 90 5,7 21 2 6 CHCl3 24 10 93 5,8 22 2 6 CHCl3 24 0 n.d 9 23 2 6 CHCl3 24 48 91 24 5 2 6 Dioxane 24 65 92 1 Reactions performed with catalyst 6 (7.5 mg, 0.02 mmol, 0.05 eq), trans-β-nitrostyrene 1a (60 mg, 0.4 mmol, 1 eq.), acetaldehyde dimethyl acetal 5, water, Amberlyst-15 (10 mol%) and solvent (1 mL, 0.4 M) at room temperature. 2 Measured by 1H NMR spectroscopy. 3 Determined by chiral HPLC analysis after conversion of the aldehyde into the 4 corresponding alcohol by reduction with NaBH4. See the Supporting Information for details. 0.5 mL of solvents were used, M = 0.8 mol/L. 5 0.25 mL of solvents were used, M = 1.6 mol/L. 6 7 mg of Amberlyst-15 were used. 7 28 mg of Amberlyst-15 were used. 8 L-proline was used as a catalyst. 9 (S)-α,α-Bis [3,5-bis(triﬂuoromethyl)phenyl]-2- pyrrolidinemethanol trimethylsilyl ether (Jørgensen catalyst) was used as a catalyst.

Lowering the equivalents of 5 afforded a more sluggish reaction (Table2, entries 14–16); the reactivity at 3 eq. could be restored by increasing the concentration to 0.8 M (Table2, entry 17), while the use of 2 eq. called for 1.6 M conditions (Table2, entries 18–19). Using different amounts of Amberlyst-15 proved detrimental to the reaction (Table2, entries 20–21), slowing it down dramatically in case of a larger amount, probably because the acetaldehyde was released too quickly, giving rise to oligomers (Table2, entry 21). Variation of the catalyst (Table2, entries 22–23) and testing dioxane, one of the promising solvents, in the conditions of entry 19 (Table2, entry 24), did not bring any improvement. Based on the results, we chose the conditions in Table2, entry 19, to evaluate the generality of the reaction (Table3, see also Supplementary Materials). As expected, and in agreement with the previous reports [13–15], other nitroalkenes are less reactive than nitrostyrene. Nevertheless, nitrostyrene derivatives, having either electron-rich or electro-deficient substituents, successfully afforded the desired Michael adducts in high yields and enantioselectivity (Table3, entries 1–4). The protocol developed proved to be successful also with alkyl-substituted nitroalkenes to give the desired products in high yields and optical purity (Table3, entries 5–8). Catalysts 2020, 10, x FOR PEER REVIEW 4 of 7

8 5 10 CH2Cl2 72 61 92 9 5 10 Dioxane 72 93 94 10 5 10 Dioxane 24 71 93 11 5 10 CHCl3 24 93 93 12 5 15 Dioxane 24 84 95 13 5 15 CHCl3 24 97 93 14 1.2 3.6 CHCl3 24 57 91 15 2 6 CHCl3 24 74 90 16 3 9 CHCl3 24 81 92 17 4 3 9 CHCl3 24 >99 94 18 4 2 6 CHCl3 24 81 92 19 5 2 6 CHCl3 24 94 90 20 5,6 2 6 CHCl3 24 91 90 21 5,7 2 6 CHCl3 24 10 93 22 5,8 2 6 CHCl3 24 0 n.d 23 9 2 6 CHCl3 24 48 91 24 5 2 6 Dioxane 24 65 92 1 Reactions performed with catalyst 6 (7.5 mg, 0.02 mmol, 0.05 eq), trans-β-nitrostyrene 1a (60 mg, 0.4 mmol, 1 eq.), acetaldehyde dimethyl acetal 5, water, Amberlyst-15 (10 mol%) and solvent (1 mL, 0.4 M) at room temperature. 2 Measured by 1H NMR spectroscopy. 3 Determined by chiral HPLC analysis

after conversion of the aldehyde into the corresponding alcohol by reduction with NaBH4. See the Supporting Information for details. 4 0.5 mL of solvents were used, M = 0.8 mol/L. 5 0.25 mL of solvents were used, M = 1.6 mol/L. 6 7 mg of Amberlyst-15 were used. 7 28 mg of Amberlyst-15 were used. 8 L- proline was used as a catalyst. 9 (S)-α,α-Bis [3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether (Jørgensen catalyst) was used as a catalyst.

Lowering the equivalents of 5 afforded a more sluggish reaction (Table 2, entries 14–16); the reactivity at 3 eq. could be restored by increasing the concentration to 0.8 M (Table 2, entry 17), while the use of 2 eq. called for 1.6 M conditions (Table 2, entries 18–19). Using different amounts of Amberlyst-15 proved detrimental to the reaction (Table 2, entries 20– 21), slowing it down dramatically in case of a larger amount, probably because the acetaldehyde was released too quickly, giving rise to oligomers (Table 2, entry 21). Variation of the catalyst (Table 2, entries 22–23) and testing dioxane, one of the promising solvents, in the conditions of entry 19 (Table 2, entry 24), did not bring any improvement. Based on the results, we chose the conditions in Table 2, entry 19, to evaluate the generality of the reaction (Table 3, see also Supplementary Materials). As expected, and in agreement with the previous reports [13–15], other nitroalkenes are less reactive than nitrostyrene. Nevertheless, nitrostyrene derivatives, having either electron-rich or electro-deficient substituents, successfully afforded the desired Michael adducts in high yields and enantioselectivity (Table 3, entries 1–4). The protocol developed proved to be successful also with alkyl-substituted nitroalkenes to give the Catalystsdesired2020 products, 10, 1296 in high yields and optical purity (Table 3, entries 5–8). 5 of 7

Table 3. Catalytic Michael addition of acetaldehyde dimethyl acetal 5 with various nitroalkenes 1. Table 3. Catalytic Michael addition of acetaldehyde dimethyl acetal 5 with various nitroalkenes 1.

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 7 Catalysts 2020, 10, x FOR PEER REVIEW 5 of 7 Catalysts 2020, 10, x FOR PEER REVIEW 5 of 7 Catalysts 2020, 10, x FOR PEER REVIEW 5 of 7 Catalysts 20202020,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 55 of 77 Entry R 3 t (h) Yield (Conv.) (%) 2 ee (%) 3 Entry R 3 t (h) Yield (Conv.) (%) 2 ee (%) 3 1 3a 24 90 (94) 95 1 3a 24 90 (94) 95 1 1 3a3a 24 24 9090 (94) (94)(94) 95 95

2 3b 72 62 (65) 94 2 3b 72 62 (65) 94 2 2 3b3b 72 72 6262 (65) (65)(65) 94 94

3 3c 72 76 (80) 92 3 3c 72 76 (80) 92 3 3 3c3c 72 72 7676 (80) (80) 92 92 3 3c 72 76 (80)(80) 92

4 3d 48 83 (85) 93 4 4 3d3d 48 48 8383 (85) (85) 93 93 4 3d 48 83 (85)(85) 93

5 3e 48 75 (78) 96 5 5 3e3e 48 48 7575 (78) (78) 96 96 5 3e 48 75 ((78) 96

4 5 6 4 4 3f 48 89 (92) 5 −95 5 6 4 6 3f3f 48 48 8989 (92) (92) 95 −95 5 6 4 3f 48 89 (92) −95 5 6 4 3f 48 89 (92) − −95 5 6 4 3f 48 89 (92)(92) −95 5

7 4 4 3g 72 93 (94) 93 7 47 3g3g 72 72 9393 (94) (94) 93 93 7 4 3g 72 93 (94) 93 7 4 3g 72 93 (94) 93 7 4 3g 72 93 (94) 93 7 4 3g 72 93 (94)(94) 93

6 8 8 3h3h 72 72 8383 (86) (86) 94 94 6 8 3h 72 83 (86) 94 6 8 3h 72 83 (86) 94 6 8 3h 72 83 (86) 94 6 8 3h 72 83 (86) 94 6 8 3h 72 83 (86) 94 6 18 3h 72 83 (86) 94 1 1 The reaction was performed with nitroalkenes (0.7 mmol, 1 eq), acetaldehyde dimethyl acetal 5 (1.4 The reaction1 The reaction was performed was performed with nitroalkenes with nitroalkenes (0.7 mmol, 1 ( eq),0.7 m acetaldehydemol, 1 eq), dimethylacetaldehyde acetal 5dimethyl(1.4 mmol, acetal 2 eq), 5 (1.4 1 The reaction was performed with nitroalkenes (0.7 mmol, 1 eq), acetaldehyde dimethyl acetal 5 (1.4 1mmol, The reaction 2 eq), catalyst was performed 6 (0.035 mmol, with nitroalkenes0.05 eq), Amberl (0.7 ymstmol-15 ,( 101 eq), mol% acetaldehyde), water (4.2 dimethylmmol, 6 eq) acetal in CHCl 5 (1.43 catalystmmol,1 T6he(0.035 reaction 2 eq), mmol, catalyst was 0.05 performed eq), 6 (0.03 Amberlyst-155 mmol, with nitroalkenes0.05 (10 eq), mol%), Amberl water (0.7 y mst (4.2mol-15 mmol, ,(, 101 eq), mol% 6 eq)acetaldehyde), in water CHCl (4.23 (0.44 dimethylmmol, mL, 6 1.6 eq) acetal M) in at CHCl 5 ((1.43 mmol, 2 eq),2 catalyst 6 (0.035 mmol, 0.053 eq), Amberlyst-15 (10 mol%), water (4.2 mmol, 6 eq) in CHCl3 room temperature.mmol,(0.44 mL, 2 eq), 1.6 catalyst YieldM) at of room isolated6 (0.03 temperature.5 product. mmol, 0.05Optical 2 Yieldeq), A purity ofmberl isolated wasyst determined-15 product (10 mol%. by3 Optical) chiral, water HPLC purity (4.2 /mmol,GC was analysis determined 6 eq) after in CHCl by3 mmol,(0.44 mL, 2 eq), 1.6 catalyst M) at room 6 (0.03 temperature.5 mmol, 0.05 2 Yieldeq), A ofmberl isolatedyst-15 product (10 mol%. 3 Optical), water purity (4.2 mmol, was determined 6 eq) in CHCl by3 conversionmmol, of the2 eq), aldehyde catalyst into 6 (0.03 the corresponding5 mmol, 0.052 alcohol eq), A bymberl reductionyst-15 with (10 mol% NaBH3 )., 4waterAmberlyst-15 (4.2 mmol, (5 mol%) 6 eq) wasin CHCl3 (chiral0.44 mL, HPLC 1.6 M)/GC at analysisroom temperature. after conversion 2 Yield of of isolated the aldehyde product into. 3 Optical4 the correspondingpurity was determined alcohol by 5(chiral0.44 mL, HPLC 1.6 M)/GC at analysisroom temperature.6 after conversion 22 Yield of of isolated the aldehyde product into. 33 Optical the correspondingpurity was determined alcohol by used. chiral(0.44(R)-6 mL, was HPLC 1.6 used /GCM) as ata analysis catalyst.room temperature. Optical after conversion purity Yield was determined of of isolated the aldehyde after product conversion into. Optical the of the corresponding purity corresponding was determined alcohol alcohol by chiralreduction HPLC with/GC NaBH analysis4. 4 Amberlyst after conversion-15 (5 mol%) of thewas aldehyde used. 5 ( R into)-6 was the used corresponding as a catalyst alcohol. 6 Optical by into thereduction tosylate derivative. with NaBH4. 4 Amberlyst-15 (5 mol%) was used. 5 (R)-6 was used as a catalyst. 6 Optical chiralreductionchiral HPLC HPLC with/GC/GC NaBH analysis. 4 Amberlyst after conversion-15 (5 mol%) of thewas aldehyde used. 5 ( R into)-6 was the used corresponding as a catalyst alcohol. 6 Optical by reduction with NaBH4. 4 Amberlyst-15 (5 mol%) was used. 5 (R)-6 was used as a catalyst. 6 Optical reductionpurity was with determined NaBH4. after4 Amberlyst conversion-15 (5of mol%)the corresponding was used. 5 alcohol(R)-6 was into used the tosas ya latecatalyst derivative. 6 Optical. reductionpurityreduction was withwith determined NaBHNaBH44.. after4 Amberlyst conversion--15 (5of mol%)the corresponding was used. 5 alcohol((R))--6 was into used the tosas ya latecatalyst derivative.. 6 Optical. purity was determined after conversion of the corresponding alcohol into the tosylate derivative. As anticipatedpurity was atdetermined the outset, after the conversion catalytic Michael of thethe correspondingcorresponding reaction aﬀords alcoholalcohol nitroaldehydes intointo thethe tostosylatelate that derivative are versatile.. As anticipated at the outset, the catalytic Michael reaction affords nitroaldehydes that are and key intermediatesAs anticipated to access at the important outset, the APIs, catalytic such as Michael pregabalin reaction [16], aaffords widely nitroaldehydes used anti-epileptic that are versatileAs anticipatedand key intermediates at the outset, to access the catalytic important Michael APIs, reaction such as affordspregabalin nitroaldehydes, a widely used that anti are- drug.versatile TheAs developed anticipatedand key protocolintermediates at the was outset, tested to access the on catalytic> important1 g scale Michael of APIs, the reaction starting such as nitroalkene affords pregabalin nitroaldehydes, 1ha widelyto provide used thatthat a anti are are- versatileepileptic and drug key. The intermediates developed protocolto access was important tested onAPIs, >1 gsuch scale as ofpregabalin the starting, a widely nitroalkene used 1hanti to- moreversatileepileptic reliable expectation and drug key. The intermediates ofdeveloped how it should protocol to access behave was important on tested bigger onAPIs, scales >1 gsuch (Schemescale as of pregabalin2 the, see starting also,, Supplementaryaa widelywidely nitroalkene usedused 1h antianti to-- epilepticprovide a drug more. The reliable developed expectation protocol of how was it tested should on behave >1 g scale on bigger of the scales starting (Scheme nitroalkene 2, see 1h also to Materials).epilepticprovide The a drug more reaction.. The reliable was developed stoppedexpectation protocol after of 72 how wash; the it tested yieldshould on proved behave >1 g toscale beon in bigger of line the withscales starting the (Scheme smaller nitroalkene 2 scale,, see 1h also toto provideSupplementary a more Materialsreliable expectation) [16]. The reactionof how itw shouldas stopped behave after on 7 2bigger h; the scalesyield p(Schemeroved to 2 be, see in alsoline whileprovideSupplementary the enantioselectivity a more Materialsreliable was expectation) [16] higher. The than reactionof onhow a smaller itw shouldas stopped scale behave and after nearly on 7 2bigger h complete; the scalesyield (> p(Scheme(Scheme99%),roved pointing to 22 be,, seesee in alsoalsoline Supplementarywith the smaller Materials scale, while) [16] the. The enantioselectivity reaction was stopped was higher after 7than2 h; onthe ayield smaller proved scale to and be innearly line to theSupplementarywith fact thatthe smaller the protocol Materials scale is, while very)) [16][16] promisingthe.. The enantioselectivity reaction for further was stopped development. was higher after 7than2 h;; onthethe a yieldyield smaller provedroved scale toto and bebe innearlyin lineline withcomplete the smaller(>99%), scalepointing, while to thethe fact enantioselectivity that the protocol was is veryhigher promising than on fora smaller further scaledevelopment. and nearly withcomplete thethe smaller(>99%), scalepointing,, whilewhile to the thethe fact eenantioselectivity that the protocol was is veryhigher promising than on fora smaller further scaledevelopment. and nearly complete (>99%), pointing to the fact that the protocol is very promising for further development. complete (>99%),, pointing to the fact that the protocol is very promising for further development.

Scheme 2. Application of the developed protocol on >1 g scale to afford synthetically useful Scheme 2. Application of the developed protocol on >1 g scale to afford synthetically useful Scheme 2. Application of the developed protocol on >1 g scale to afford synthetically useful Schemeintermediateintermediate 2.. A 3hpplication.. of the developedloped protocol protocol on on >1 g scalescale to to afford synthetically useful intermediate 3h. intermediateintermediate 3h..

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 7

1 3a 24 90 (94) 95

2 3b 72 62 (65) 94

3 3c 72 76 (80) 92

4 3d 48 83 (85) 93

5 3e 48 75 (78) 96

6 4 3f 48 89 (92) −95 5

7 4 3g 72 93 (94) 93

8 3h 72 83 (86) 94 6

1 The reaction was performed with nitroalkenes (0.7 mmol, 1 eq), acetaldehyde dimethyl acetal 5 (1.4

mmol, 2 eq), catalyst 6 (0.035 mmol, 0.05 eq), Amberlyst-15 (10 mol%), water (4.2 mmol, 6 eq) in CHCl3 (0.44 mL, 1.6 M) at room temperature. 2 Yield of isolated product. 3 Optical purity was determined by chiral HPLC/GC analysis after conversion of the aldehyde into the corresponding alcohol by reduction with NaBH4. 4 Amberlyst-15 (5 mol%) was used. 5 (R)-6 was used as a catalyst. 6 Optical purity was determined after conversion of the corresponding alcohol into the tosylate derivative.

As anticipated at the outset, the catalytic Michael reaction affords nitroaldehydes that are versatile and key intermediates to access important APIs, such as pregabalin, a widely used anti- epileptic drug. The developed protocol was tested on >1 g scale of the starting nitroalkene 1h to provide a more reliable expectation of how it should behave on bigger scales (Scheme 2, see also Supplementary Materials) [16]. The reaction was stopped after 72 h; the yield proved to be in line Catalystswith 2020the , smaller10, 1296 scale, while the enantioselectivity was higher than on a smaller scale and nearly6 of 7 complete (>99%), pointing to the fact that the protocol is very promising for further development.

Scheme 2. Application of the developed protocol on >1 g scale to afford synthetically useful intermediate 3h. Scheme 2. Application of the developed protocol on >1 g scale to afford synthetically useful 3. Conclusionsintermediate 3h. In conclusion, we have developed an industrially interesting protocol for the Michael addition of acetaldehyde to nitroalkenes, aﬀording the corresponding products in high yields and ee. A current limitation of the presented reaction is the use of a class 2 solvent; however, we believe that further R&D can tackle this issue. The presented reaction makes use of a masked acetaldehyde to avoid the use of a highly toxic and reactive intermediate. Furthermore, the use of an acidic resin and low amounts of an aﬀordable organocatalyst make the overall protocol appealing for more in-depth studies to assess its application in manufacture.

4. Materials and Methods Typical procedure: acetaldehyde dimethyl acetal 5 (148 µL, 1.4 mmol) was added to a mixture of (S)-diphenyltrimethylsiloxymethyl pyrrolidine 6 (11.4 mg, 0.035 mmol), trans-β-nitrostyrene 1a (105 mg, 0.7 mmol), Amberlyst-15 (10 mol%, H+ exchange capacity (4.7 meq/g)), water (76 µL, 4.2 mmol) and CHCl3 (0.44 mL). The reaction mixture was stirred at room temperature for 24 h and then quenched with 1 mL 1M HCl. Then, the aqueous mixture was extracted with ethyl acetate (3 3 mL). The combined organic layers were dried over anhydrous MgSO , filtered and concentrated × 4 in vacuo. Purification by flash chromatography on silica gel (petroleum ether/ethyl acetate = 90:10) gave (S)-4-nitro-3-phenylbutanal 3a (122 mg, 0.63 mmol) in 90% yield and 95% ee. The enantiomeric excess was determined by chiral HPLC analysis after conversion of the aldehyde into the corresponding alcohol by reduction with NaBH4.

Supplementary Materials: General procedures, preparation of starting materials, characterization of compounds, 1H and 13C NMRs, and HPLC traces are available online at http://www.mdpi.com/2073-4344/10/11/1296/s1. Author Contributions: Methodology, investigation, analysis, data curation, writing—original draft preparation: G.G. and V.N. Writing—review and editing, supervision and funding acquisition: L.P., A.B. and A.C. Conceptualisation and project administration: A.C. All authors have read and agreed to the published version of the manuscript. Funding: G.G. is grateful to PON—DOT13OV2OC for an industrial PhD fellowship. A.B. acknowledges PON—AIM1842894, CUP E18D19000560001 for support. A.C. and A.B. acknowledge Royal Society of ChemistryResearchFund (RF19-5583 and R19-3106) for support. Acknowledgments: A.C. is extremely grateful to Fred Cederbaum and Nikola Kokosar, Syngenta Crop Protection Research Center—Stein (CH), Angelini Fine Chemicals Process Development—Aprilia (I), Reddy’s—Cambridge (UK), and Discovery Department, Dompè farmaceutici SpA—L’Aquila (I), for their generous support. Francesco Fini (Università di Modena e Reggio Emilia) is acknowledged for HRMS analysis. Giorgio Bencivenni (Alma Mater Studiorum—Università di Bologna) is acknowledged for help with chiral HPLC analysis of 3e. Conﬂicts of Interest: The authors declare no conﬂict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Catalysts 2020, 10, 1296 7 of 7

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