Organocatalyzed Asymmetric Vinylogous Addition of Oxazole-2(3H

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Organocatalyzed Asymmetric Vinylogous Addition of Oxazole-2(3H)-Thiones to #,#-Unsaturated Ketones: An Additive Free Approach for Diversification of Heterocyclic Scaffold Sandrina Silva, Bianca T. Matsuo, Rodrigo C. da Silva, Lucas V Pozzi, Arlene G. Corrêa, Patrick Rollin, Julio Zukerman-Schpector, Marco Antonio Barbosa Ferreira, and Marcio W. Paixao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02236 • Publication Date (Web): 16 Jan 2018 Downloaded from http://pubs.acs.org on January 16, 2018

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The Journal of Organic Chemistry

Organocatalyzed Asymmetric Vinylogous Addition of Oxazole-2(3H)Thiones to α,β-Unsaturated Ketones: An Additive Free Approach for Diversification of Heterocyclic Scaffold Sandrina Silva,†* Bianca T. Matsuo,† Rodrigo C. da Silva,† Lucas V. Pozzi,† Arlene G. Correa,† Patrick Rollin,‡ Julio Zukerman-Schpector,† Marco A. B. Ferreira†* and Márcio W. Paixão†* †

Centre of Excellence for Research in Sustainable Chemistry (CERSusChem), Department of

Chemistry, Federal University of São Carlos – UFSCar, São Carlos, São Paulo, Brazil,13565905. ‡

Université d’Orléans et CNRS, ICOA, UMR 7311, BP 6759, F-45067 Orléans, France.

Corresponding

Authors

*emails:

[email protected]

(M.

W.

Paixão);

[email protected] (Sandrina Silva) and [email protected] (M. A. B. Ferreira) Tel. and Fax: +55-16-33518450.

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ACS Paragon Plus Environment

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Graphical Abstract S HN

O

R Chemoselectivity at C-5

NH2

N

O

S

N

O n R1

O

H NH

( 20 mol%)

+

R1

Via Chiral Ion Pair

Additive-free

N S

N

R

22 examples up to 99% yield up to 99% ee n

S

O N R

HN

+ NH2

N

O

R

N

re-face approach

Abstract A straightforward organocatalyzed asymmetric addition of oxazole-2(3H)-thiones to α,βunsaturated ketones is described. This additive-free Michael reaction in the presence of chiral cinchonine-derived primary amines as catalysts have proven to be highly effective for a wide range of cyclic and acyclic enones, leading to the Michael adducts in very good yields and excellent enantioselectivities. The absolute configuration (R) of compound 5j was unambiguous assigned by X-ray diffraction analysis. Furthermore, experimental and theoretical studies were performed and a mechanism is presented and discussed for this novel reaction.

Keywords: oxazole-2(3H)-thiones, organocatalysis, Michael addition, α,β–unsaturated ketones.

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Introduction The design and development of new stereoselective chemical transformations of carbonyl compounds is still a major challenge in contemporary organic synthesis. Undeniably, the creation of a stereogenic center at the β-position of a conjugated system is of fundamental interest and, therefore, has been the focus of numerous research efforts for decades. These reactions have emerged as elegant, versatile and atom-economic meaning for C-C or C-X bond construction.1 Over the last decade, asymmetric aminocatalysis2 has emerged as a powerful tool for chemical elaborations of carbonyl compounds. In this context, chiral amines3 have revealed an outstanding capacity to promote functionalization of aldehydes or ketones at their α-, β-, ɣand δ-positions.4 Particularly, the Michael addition on α,β-unsaturated ketones has largely been explored with a variety of C-, N-, O-, and S-centered nucleophiles.5 However, in almost all the related literature, a twofold excess of a strong acid co-catalyst should be employed along with the chiral primary amine organocatalyst (Fig 1a). Such reaction condition allows high levels of both reactivity and stereoselectivity, endorsed by the conformational flexibility and the multifunctional nature of the chiral iminium ion intermediate.5e More recently, the concept of vinylogy, introduced by Fuson6 has been explored for a wide range of organocatalyzed reactions, such as aldol, Mannich, Diels-Alder and vinylogous Michael addition reactions.7 In this regard, the activation of the pro-vinylogous nucleophiles (HOMO-raising activation) is usually performed by deprotonation under basic conditions. The LUMO lowering of the ketone electrophile combined with the HOMO raising of the vinylogous nucleophile maximize the energetic efficiency of these systems. Although some heterocycles e.g. γ-butenolides and other olefinic lactones, oxindoles, azlactones, furans and pyrroles have already been explored as vinylogous nucleophilic partners in asymmetric

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Michael addition,8 there is still a demand for the development of chiral heterocyclic scaffolds derivatives, with potential biological activity. In this regard, oxazole-2(3H)-thiones (OXTs) 9 have shown a unique chemical reactivity as well as interesting biological activity. In recent years, Rollin and co-workers have reported their studies related to the functionalization of OXTs at the sulphur and nitrogen atoms, as well as the exploitation of the thionocarbonyl moiety (Chart 1).10

Chart 1. Some N- and S-functionalizations previously reported for OXTs.

Although the reactivity of OXTs at the N- and S-centers has already been investigated, the reactivity of this pseudo-aromatic heterocycle at C-5 still remains unexplored. Regarding its versatility in both chemical and biological scenarios, we report herein, an efficient organocatalytic vinylogous Michael addition of OXTs to α,β-unsaturated ketones (Fig 1b). Besides the challenge of the regiochemical control (due to the poly-nucleophilic nature of the OXT nucleus), the nature of the enone acceptor was investigated as well. In addition, we carried out a theoretical study in order to understand the reactivity of OXTs and the origins of stereoselectivity by using density functional theory (DFT).

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Fig 1. 1a. Representation of Michael addition on α,β-unsaturated ketones with a variety of

nucleophiles; 1b. Present study. Results and Discussion In order to evaluate the reactivity of the catalytic system, we started our investigations by examining the model reaction involving the OXT 1a and the commercially available 2cyclohexen-1-one (2a), under various reaction conditions (table 1). When the model reaction was carried out in the presence of 20 mol% of 9-amino-9-deoxy-epi-cinchonine A and a twofold excess of trifluoroacetic acid (TFA, 40 mol%) at room temperature having DCM as solvent, an inseparable mixture of products was obtained (table 1, entry 1). A similar disappointing catalytic behaviour was observed when an equimolar amount of TFA (cocatalyst) was employed (1:1 ratio with 20 mol% of chiral amine, table 1, entry 2). However, performing the reaction in DCM without the presence of the co-catalyst, the desired product 3a was obtained in high ee, albeit in a low chemical yield (15% y, 95% ee, table 1, entry 3). Encouraged by this result, in which the catalytic cycle occurs without the need of a strong acid co-catalyst, we hereafter evaluated the influence of the solvent nature in the reaction outcome. When toluene was employed, the yield dropped slightly, however the ee raised to more than 99% (table 1, entry 4). Nevertheless, results proved to be more encouraging in the 5



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presence of polar protic solvents (table 1, entries 5-8). Effectively, the use of solvents that facilitate a proton transfer event, e.g. 2-propanol and trifluoroethanol, significantly improved the chemical yield with the persistent of high ee values (table 1, entries 5 and 6). Likewise, high chemical efficiency was observed by using MeOH as solvent: under such conditions, the desired adduct 3a was obtained in 65% isolated yield and 99% ee (table 1, entries 5 and 6 vs 7). Moreover, when EtOH was employed, the product was obtained in a shorter reaction time (6 hours) with no crucial change in both the chemical yield and ee (table 1, entry 8). Due to its sustainable nature and efficiency (reaction time), EtOH was therefore selected in order to pursue the optimization studies. In attempts to improve the catalytic course, we further screened the reaction concentration. In diluted solutions e.g. 0.5M, 0.25M and 0.1M respectively, the respective adducts 3a were isolated in better yields and excellent enantioselectivities (table 1, entries 9-11). However, when the concentration was even further decreased (0.05M), an erosion in terms of chemical efficiency was observed within a longer reaction time (table 1, entry 12). Furthermore, no improvements were observed by raising the reaction temperature up to 40ºC (entry 13). Table 1. Optimization of reaction conditions: solvent, concentration and temperature screening.

Entry[a] 1[d] 2[e] 3 4 5 6 7 8

Solvent [1a] (M) DCM 1 DCM 1 DCM 1 toluene 1 i-PrOH 1 TFE 1 MeOH 1 EtOH 1

time(h) 24 24 24 24 24 24 18 6

Yield (%)[b] n.r. n.r. 15 10 55 54 65 60

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ee (%)[c] ----95 99 95 99 99 99

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9 EtOH 0.5 15 66 93 10 EtOH 0.25 16 66 99 11 EtOH 0.1 24 79 96 12 EtOH 0.05 30 75 96 [f] 13 EtOH 0.1 15 76 90 [a] Unless otherwise specified, all reactions were performed using 1a (0.3 mmol), 2a (0.6 mmol), and organocatalyst (20 mol %), at room temperature. [b] Yields are for purified products. [c] Determined by chiral-phase HPLC analysis. [d] The reaction was performed in the presence 40 mol% of TFA as co-catalyst. [e] The reaction was performed in the presence of 20 mol% of TFA as co-catalyst. [f] The reaction was performed at 40ºC.

Having optimized solvent, concentration and temperature parameters, we turned our attention to the nature of the organocatalyst (scheme 1). As expected, primary amines such as 9-amino9-deoxy-epi-quinidine B and 9-amino-9-deoxy-epi-cinchonidine C gave rise to the Michael adduct 3a with similar results than catalyst A. Remarkably, organocatalyst A and its pseudoenantiomer C showed exactly the same stereoselectivity performance (96% ee) with opposite stereochemical bias (opposite sense of stereochemistry). The secondary amine L-proline D revealed to be stereoselective inadequate for this catalytic process, in spite of a good chemical yield (15% ee and 73% y). Finally, we evaluated the catalytic behaviour of chiral Brønsted bases e.g. cinchonine (E) or (DHQ)2Pyr (F) in the model reaction. However, by only raising the HOMO energy of the Michael donor, no consumption of the starting materials was observed in both aforementioned cases. These results suggested that an iminium ion is the key intermediate of this catalytic protocol – therefore, follows the common path previously reported in the literature.

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O S HN

O

O

Organocatalyst ( 20 mol%)

+

O

EtOH-[1a]0 = 0.1M rt, 24h

Me 1a

S

NH Me 3a

2a

Organocatalyst Screening N

N

N

NH2

NH2

NH2

O N H

MeO N

N A = 79% y, 96% ee

OH

N

B = 79% y, 94% ee

C = 75% y, - 96% ee

D = 73% y, 15% ee

N

Catalyst Loading

OH A = 73% y, 99% ee ( 10 mol%, 48h) (DHQ)2Pyr

A = 70% y, 89% ee ( 5 mol%, 72h) N E = n.r.

F = n.r.

Scheme 1. Screening of chiral organocatalysts for the enantioselective vinylogous addition of OXT (1a) to 2-cyclohexen-1-one (2a) as the reaction model.

Further studies revealed that the catalyst loading was also a key factor and strongly influenced the catalytic performance. Lowering the catalyst loading to 10 mol %, the desired product was obtained in a longer reaction time (48h) with a slightly lower yield, albeit in excellent ee (73% y and 99% ee). When the catalyst amount was further reduced to 5 mol %, even after 72h, the desired product 3a was obtained with an erosion in terms of chemical yield and stereocontrol (see supporting information, table S1). Having those results and taking into account the reaction time, catalyst amount, yield and ee, we have chosen 20 mol% of catalyst loading to carry on our study. In order to go further with the optimization studies, the stoichiometric amount of OXT 1a and enone 2a was changed from 1:2 to 2:1 and 1:1. However, no improvement was observed (see supporting information, table S5).

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Having the optimal reaction conditions in hand, the scope and limitations of this enantioselective vinylogous Michael addition of OXTs with respect to other α,β–unsaturated cyclic ketones derivatives were investigated (Scheme 2).

Scheme 2. Reactions were performed using 1 (0.3 mmol) and 2 (0.6 mmol). Yields refer to isolated compounds and the ee values were determined by chiral-phase HPLC analysis.

It appears from these results that the enantioselectivity is slightly affected by the ring size of the enone. Under the optimized reaction conditions, 2-cyclopenten-1-one 2b, 2-cyclohepten1-one 2c and 2-cycloocten-1-one 2d effectively underwent conjugated addition of OXT 1a, providing the respective adducts in good yields and excellent enantioselectivities (products 3b, 3c and 3d). Unfortunately, our attempts to extend this methodology for the heteroaryl functionalization of 3-ethyl-2-cyclohexenone – a β,β-disubstituted counterpart -

was

unsuccessful being both substrates completely recovered. Furthermore, the catalytic process could also be performed with sterically more demanding OXT frameworks. For example, the phenyl group attached at the C4 of the OXT core didn't

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influence the reactivity profile of the catalytic system, since the desired product 3e was formed in 73% chemical yield and good enantioselectivity (85% ee). In contrast, the C-4 unsubstituted OXT 1c underwent primary nucleophilic attack of the Ncenter and without enantiofacial differentiation (3f). This result corroborates the fact that OXT can act as a vinylogous Michael donor system. In order to further extend the scope of this protocol, α,β-unsaturated ketones were replaced by acyclic ones. However, by applying our optimized reaction conditions to the 4-phenyl-3buten-2-one 4a leads to poor enantioselection (Table 2, entry 1, 28% ee), therefore, further tuning on the conditions was required. In that way, we have modulated the concentration of the solution and from this study, it was observed that higher concentrations led to a high level of enantioselectivity (table 2, entries 2-6). Furthermore, the optimal reaction conditions were then achieved at -20º C, whereas the desired product 5a was delivered within 24h in excellent yield and enantioselectivity (table 2, entry 7, 95% y and 99% ee). Table 2. Optimization studies for the enantioselective reaction with acyclic α,β–unsaturated ketones.

Entry[a] [1a] t(h) Yield[b] (%) ee[c] (%) 1 0.1M 72 55 28 2 0.25M 48 91 40 3 0.5M 36 90 62 4 1M 24 95 67 5 1.5M 18 96 70 6 2M 12 93 76 [d] 7 2M 24 95 99 [a] Unless otherwise noted reactions were performed using 1a (0.3 mmol) and 4a (0.6 mmol). [b] Isolated yield. [c] Determined by chiral-phase HPLC analysis. [d] Reaction performed at -20ºC.

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With the reaction conditions in hand, a plethora of acyclic enones was further investigated as Michael acceptors (Scheme 3). As depicted below, acyclic enones bearing aryl substituents with either electron-donating (methyl, hydroxyl, methoxyl) or electron-withdrawing groups (nitro, chloro, bromo, fluoro) were almost equally tolerated, thus delivering the desired Michael adducts in good to excellent chemical yields (88-99%) and high enantioselectivities (84-99%). However, a decrease in the stereochemical control was observed when electrondonating groups were present at the para position of the aryl substituent (5b and 5d). The methodology is still applicable even when a heteroaromatic–substituted enone is involved, affording the furan derivative 5k in 73% yield and 68% ee. Having completed the reaction scope for the β-monosubstituted enones, we turned our attention to the fewer explored β,βdisubstituted analogues. However, under the optimized reaction conditions the conjugated addition did not occur to trans-4-phenylpent-3-en-2-one. Surprisingly, trans-3-octen-2-one did not delivered the expected product when subjected to the reaction with both OXT 1a and 1b. Therefore, these substrate classes currently represent a limitation of the described methodology. As aforementioned, the use of OXT 1b, bearing a phenyl ring at C-4, led to the Michael adducts 5l-5o in high yields and good enantioselectivities. The vinylogous character of the nucleophile species was once more demonstrated when OXT 1c reacted with 4-phenyl-3buten-2-one 4a, providing the product 5p in high yield and total N-regioselectivity.

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Scheme 3. Reaction scope: acyclic enones and OXT variations –Reactions were performed using 1a (0.3 mmol) and 4a (0.6 mmol). Yields refer to isolated compounds and the ee values were determined by chiral-phase HPLC or UPC2 analysis.

The absolute configuration of the adduct 5j was unequivocally established to be (R) by X-ray analysis (Figure 2) and the remaining configurations were assumed by analogy.

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Fig 2. X-ray structure of compound 5j.

Mechanistic considerations With the intention to provide further insights into the reaction mechanism of this novel additive-free protocol, we performed additional controlled experiments (see Supporting Information for details). We first focused on discriminating the nature of the active iminium ion intermediate, particulary, whether one or more molecules of the chiral catalyst are involved in the reaction transition state.11 Therefore, for the non-linear effect (NLE) study, catalyst A was prepared in six different levels of enantiopurity and used to promote the reaction between OXT (1a) and commercially available 2-cyclohexen-1-one (2a) (Figure 3a). From this study, a negative NLE was observed, supporting a pathway in which more than one molecule of the chiral catalyst is likely to be involved in the transition state of the enantiofacial differentiation step. Another control experiment was conducted by evaluating the dependence of the enantioselectivity on the reaction time (Figure 3b).12 Accordingly, under the optimized reaction conditions, the enantiomeric excess of the adduct remained unchanged over a period of 24h. These results indicate a kinetic control on this vinylogous Michael addition within this reaction time.

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a)

100

b) 100

y = -2.321+0.4569x+0.0054x2 R2 = 0.99279

96

96

96

96

96

5

10

15

20

25

% ee product

80

% ee product

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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60 40 20

90

80

0

70 0

20

40

60

80

100

% ee catalyst

Reaction Time (h)

Fig 3. a) Non linear effect. b) Effect of the reaction time on the optical purity.

Based on our observations and on the literature precedents, a plausible mechanistic pathway is outlined in Figure 4. The catalytic process initiated by an acid-base equilibrium developed between the organocatalyst and the pronucleophile (OXT) to generate a chiral ion pair A’. Simultaneously, the condensation of the cinchona-based primary amine A with the α,βunsaturated ketone leads to the formation of the imine B. Sequentially, the imine is activated and positioned for the nucleophilic attack of the vinylogous OXT to the pro-chiral β-carbon though non-covalent intermolecular interactions, leading to the formation of a new stereocenter in a controlled way (C). Finally, the enamine (D) is in equilibrium with the iminium E and, after hydrolysis, the catalyst A is released from the intermediate, leading to the respective 1,4-Michael adducts. The absolute configuration of the newly formed stereogenic center was confirmed by the X-ray crystal structure analysis.

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Fig 4. Simplified catalytic cycle for the OXT addition to the α,β-unsaturated ketone.

Computational Studies Comparing our results with those by Rollin and co-workers, in which selectivity usually goes through the nucleophilic functionalization of the sulphur or nitrogen centers,10 we became interested on the origins of the C-5 regioselectivity of the OXTs under our reaction conditions. In order to better understand both reactivity and stereoselectivity of this reaction protocol, we carried out density functional theory (DFT) calculations. We firstly studied the molecular proprieties of OXTs, along with a full analysis of all possible reaction pathways and transition states (TS). We began our computational studies by investigating the hypothesis that the OXTs tautomeric equilibrium is related to it's vinylogous propriety. In principle, this equilibrium could be associated to the gain in energy upon aromatization of the enol-type isomer I and II. However, the computational calculations revealed that the tautomeric form II is 8.5 kcal.mol-1 higher in energy than I (Table 3, entry 1). This is not surprising in view of the lack of

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spectroscopic evidences for the presence of tautomer II. It is also important to emphasize that the low aromaticity character of the 1,3-oxazole rings - which are very close to the furan could drive the thermodynamics of the tautomeric equilibrium.13 In addition, a negative nucleus independent chemical shift (NICS) analysis was performed aiming to compare the relative aromaticity between these compounds.14 The NICS(1)ZZ values of -15.1, -21.8 and 19.9, for I, II and the deprotonated structure III, respectively, associates the level of electron delocalization due to the aromaticity of these rings (Table 3, entry 2). For reference, we calculated the NICS(1)ZZ value for the 1,3-oxazole (-28.5). In comparison to the 1,3-oxazole, it is unanticipated the relative lower level of aromaticity obtained for II and III, compared to the higher level observed for I (measured from NICS(1)ZZ). Afterwards, we interpreted these results based on natural resonance theory (NRT) analysis that provides an indicative of the influence of each contributing Lewis structures to the calculated wave function (Scheme 4, see the SI for full NRT analysis of each structure.).15 Table 3. Bond lengths (Å),a Wiberg bond indexes (bond orders),b NICS(1)ZZ,c and relative Free Energies (kcal.mol-1)b of isomers I, II, and 1,3-oxazole.

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13

I

∆∆Grel NICS(1)ZZ Bond length

Bond order

r(O1-C2) r(C2-C3) r(C3-N4) r(N4-C5) r(C5-S6) r(O1-C5) r(N4-H) r(S6-H) O1-C2 C2-C3 C3-N4

II

0.0 kcal.mol -15.1 1.372 1.346 1.394 1.349 1.661 1.342 1.014 0.996 1.71 1.09

-1

-1

8.5 kcal.mol -21.8 1.368 1.357 1.394 1.290 1.753 1.338 1.356 1.01 1.67 1.17

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III

1,3-oxazole

-19.9 1.363 1.356 1.384 1.315 1.713 1.371 1.02 1.65 1.20

-28.5 1.355 1.357 1.385 1.290 1.340 -

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14 15 16 17 18 19 20 21 a)

N4-C5 C5-S6 O1-C5 N4-H S6-H

1.24 1.46 1.07 0.769 -

1.60 1.09 1.07 0.953

1.51 1.26 1.01 -

Calculated at M06-2X/def2-svp. b) Calculated at M06-2X/def2-tzvp/IEF-PCM//M06-2X/def2-svp/IEFPCM. c) Calculated at B3LYP/6-311+G(d,p)/IEF-PCM//M06-2X/def2-svp/IEF-PCM.

Scheme 4. NRT analysis for structures I-III calculated at M06-2X/def2-tzvp/IEF-PCM// M062X/def2-svp/IEF-PCM.

It is remarkable that the Kekulé structure Ia contributes only with 29.9% to the molecular electron density (Scheme 4) and, the structures IIb (27.2%) and IIc (16.4%) are similar in terms of resonance contribution, 43.6% in total, giving the aromatic character to this molecule. The observed increase in bond order of C5-N4 and decrease of C5-S6 are in agreement with this scenario (Table 3). Considering the tautomer II, the aromatic Kekulé

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structures IIa and IIb accounts for 69% while the structure IIc (5.7% weight) might be responsible for the decrease of its aromatic character compared to the 1,3-oxazole. For tautomer II, 50% of resonance structures correspond to “non-Kekulé” (or charge-separated) ressonance type, a particularly interesting result reveals the disturbance of ring electron density by the exocyclic conjugated sulfur. Similar NRT analysis for unsubstituted fivemembered heteroaromatic compounds discloses no more than 30% of charge-separated resonance structures.15 An analogous trend was observed for the anion III, in which IIIa possesses the highest resonance weight (41.2%). Observed chemical bonds and bond orders (Table 3) for I, II and III are in perfect agreement with the previous NRT analysis. Therefore, from the analysis of Scheme 4 and the observed similarity in the degree of aromaticity among isomers I and II, the differences in energy between both compounds are mainly due to the binding energies, in analogy to a keto-enol tautomerism. Finally, on the basis of the aforementioned results, we were able to rationalize that the vinylogy of OXTs appears only in its anionic form. Furthermore, with the intent of understanding the reactivity of the OXTs, analysis of Frontier Molecular Orbital (FMO) of these species have been carried out. As can be seen in Figure 5, the HOMO of I and III are very similar, and the higher orbital coefficients are concentrated on S6 and C2, suggesting that these two atoms are the most reactive centers. Other important orbitals involve the non-conjugated lone pairs of sulfur (HOMO-1) and nitrogen (HOMO-3).

FMO

I

III

0.122 eV

0.063 eV

LUMO

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HOMO

-0.314 eV

-0.224 eV

-0.352 eV

-0.254 eV

HOMO-1

HOMO-3

-0.310 eV

Fig 5. LUMO and HOMO of I and III calculated at HF/def2-tzvp/IEF-PCM//M06-2X/def2-svp/IEFPCM.

Subsequently, we explored the acid-base equilibrium between the organocatalyst and the pronucleophile (I) to generate the chiral ion-pair A’ (Figure 4a) – in this regard, a simpler catalyst model has been evaluated, therefore avoiding the conformational possibilities presented in the cinchona derived catalyst. Thus, our calculation started by using isopropylamine as the primary amine and quinuclidine as a portion of the tertiary amine. Using the quinuclidine, acting as a base, we could characterize the coordination centers on the OXT as being the nitrogen atom, arising the ion-pair III’, and the sulfur, forming the ion-pair III’’ (Scheme 5a). Compared to the complex III’’, we observed a slight preference for ionpair III’ involving the nitrogen center, probably due to its ionic hydrogen bond (HB) presenting the higher stabilizing interaction (71.1 kcal/mol) measured by natural bond orbital

19



(NBO) analysis.16 Both ion-pair III’’ and the separated ion-pair (III + VI) showed higher relative energies. A striking feature was exposed by the NRT analysis (Scheme 5b), which revealed that less than 30% of weight for the aromatic Kekulé structures III’a and III’’a are responsible for the vinylogy already pointed to anionic OXT.

Scheme 5. a) Tautomeric equilibrium developed between I and quinuclidine IV. b) NRT analysis for structures III’ and III’’ calculated at M06-2X/def2-tzvp/IEF-PCM//M06-2X/def2-svp/IEF-PCM .

Aiming to elucidate the origins of regioselectivity, in which leads to the C-C bond formation instead of C-N or C-S bonds on the OXT addition to the α,β-unsaturated ketone, the relative 20


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Gibbs Free Energies were carefully calculated (Scheme 6, represents all feasible paths involved in this conjugation addition protocol). After generation of close ion-pair III’ and iminium X, the reaction may undergo through four different pathways (Scheme 6). We did not consider a closer ion-pair between the activated imine X and III, aiming to prevent possible repulsive interactions with fragments of the catalyst structure. The nitrogen attack of ion-pair III’ to the conjugated system through TS1 (barrier of 19.7 kcal/mol), with an orientation that prevents steric repulsions between the methyl group of the oxazole and the catalyst portion of iminium ion, therefore, producing the C-N bond of XI, in a low thermodynamic preference (0.4 kcal/mol). The sulfur nucleophilic attack to X - represented as TS2 - after the cation counter ion reorganization of ion-pair III’, showed the lowest barrier (14.7 kcal/mol) among all calculated TS. However, the C-S bond formation (XII) leads to a product 4.3 kcal/mol less stable than the starting materials, consequently, revealing an unfavorable path. The stronger C-C bond on compound 3a provides a stabilization energy of 6.8 kcal/mol proceeding from TS3 or TS3’, with barriers of 24.3 and 18.8 kcal/mol, respectively. The differences between TS3 and TS3’ are related to the face attack of III’. The orientation of OXT moiety and the unsaturated iminium π system in TS3’ lead to strong secondary interactions that are responsible for its lower relative energy.17 From the noncovalent interaction (NCI) analysis, we were able to visualize the erstwhile observation and others strong attractive interactions regions (in blue), together with weak van der Waals attractive forces (in green) and strong repulsive interactions (in red) (Scheme 6).18 Both XIII and XIII’ provide 3a after tautomeric equilibration to oxazole ring, and enamine-imine equilibration followed by hydrolysis, releasing the catalyst. From these results it is possible to observe the preference for C-C regioisomer formation using the OXT I under both kinetic and thermodynamic conditions.

21



Scheme 6. Reaction free energy and NCI analysis for TS3’ involving the C-C, C-N and C-S bond formation at M06-2X/def2-tzvp/IEF-PCM//M06-2X/def2-svp/IEF-PCM. In red, relative Gibbs Free Energies [barriers in brackets]. 22


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Additionally, the N-regioselectivity observed on the formation of products 3f and 5p was also computationally investigated (see SI, section 5 for complete details). By removing the methyl group in the OXT core, reduces the free energy of the transition state in favour to the nitrogen attack (TS1-S). The significant free energy difference between TS1-S (N-attack) and TS3’-S (C-attack) shuttle 3 kcal.mol-1 and, therefore explains the experimental regioselectivity. Another point to be highlighted was the absence of stereodifferentiation in both of these examples. Although no experimental proof have been obtained, regarding the application of the OXT 1c, the model illustrated in the scheme 6 can serve as a useful guide to explain this behaviour. Analysing the transition states TS1 and TS3' it is possible to rationalize that the Cattack drives the OXT and its ionic pair closer to the catalyst (TS3'), whereas the N-attack (TS1) directs the nucleophilic approach towards an axial orientation, reducing the chiral environmental of both faces. We then turned our attention to the stereoselective aspects for the C-C bond formation step. The main component that directs the enantioselection in our system is located on the cinchona portion of the iminium ion intermediated, which are in agreement with similar reports.17 Notwithstanding, quinuclidine continued to be used as a counter ion of OXT on this part of computational studies aiming the simplification and reduction in computational costs. To understand the role of the iminium ion structure XIV on the enantioselection event (Scheme 7), we obtained an accurate description of the conformational space varying relevant dihedral angles of Z-configured C=N bond (see SI for further details).19 The adopted lowest energy conformation involves an internal HB between quinuclidine nitrogen and iminium N-H bond (6.4 kcal/mol) and thus shield the Si-face of reactive double-bond of iminium XIV by the quinoline ring, and inducing the attack of chiral ion-pair by the Re-face. The formation of enantiomer 3a is assessed by the computed most stable TS5 (barrier of 17.2 kcal/mol) and the

23



conformational accessible TS5’, only 0.4 higher in energy, which is now engaged in an ionic HB with sulfur oxazole atom. The opposite enantiomeric product ent-3a would be obtained from the OXT addition in Si-face of the iminium by TS4 (Scheme 7), approximately 2.0 kcal/mol higher in energy than TS5. This energy difference provides a theoretical enantiomeric excess of 93% for 3a at 25 ºC, in excellent agreement with the experimental result (96%). Finally, the Figure 6 shows the results of NCI analysis for TS4, TS5 and TS5’. Overall, large green weak interactions occur in TS5 and TS5’, clearly related with van der Waals and nonclassical CH⋯X interactions. In a different way, a disappearance of the green surfaces is associated with competing transition structure TS4. Unambiguously, the stabilizing secondary interactions appears in light blue only in between the iminium and the nucleophile of TS5 and TS5’, while only weak van der Waals interactions appear for TS4.

24


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Scheme 7. Reaction free energy involving the enantioselective C-C bond forming step at M062X/def2-tzvp/IEF-PCM//M06-2X/def2-svp/IEF-PCM. In red, relative Gibbs Free Energies [barriers in brackets].

25



Page 26 of 42

TS5

TS5'

TS4

Fig 6. NCI analysis for TS4, TS5 and TS5’.

Conclusions In summary, we have developed a highly regio- and stereoselective organocatalytic vinylogous Michael addition of oxazole-2(3H)-thiones (OXTs) to α,β–unsaturated ketones. This co-catalyst-free protocol smoothly performs conjugate addition of the OXT framework in the presence of chiral primary amines with a wide range of cyclic and acyclic enones. The functional-group tolerance allied to the employment of readily available starting materials, substantiate the versatility of this method, making it attractive for biological applications. Furthermore, experimental and theoretical studies were performed and mechanistic proposal for this novel reaction was outlined. Studies along these lines, including reactions with different Michael acceptors, are underway and will be reported in due course. General The 1H and

13

C NMR spectra were recorded at 400 MHz for 1H and at 100 MHz for

respectively. The chemical shifts (δ) for 1H and

constants (J) are given in hertz.

C,

13

C are given in ppm relative to residual

7.26 ppm 1H NMR, 77.16 ppm

signals of the solvents (CHCl3

13

13

C NMR). Coupling

The following abbreviations are used to indicate the

multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd = doublet of 26


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doublet; dt = doublet of triplet. High-resolution mass spectra (HRMS) were recorded using electrospray ionization (ESI) (Hybrid linear ion trap–orbitrap FT-MS and QqTOF/MS – Microtof – QII models). The compounds were purified by flash chromatography (n-hexane/ EtOAc) using silica gel 60 (230-400 mesh) and analytical thin layer chromatography was carried out on silica gel aluminum sheets, visualized with UV light and stained with iodine vapor or acidic vanillin.

X-ray data were collected using the Bruker APEX-II CCD

diffractometer of the IQSC-USP. Optical rotations were measured with a Polarimeterat 589 nm, 20 °C. Determination of Enantiomeric Purity.

HPLC chromatograms were obtained on an

apparatus with a LC-10AT pump, SPD-10AUV-Vis detector, SCL-10A System Controller, using a Chiralpak AD-H (4,6 mmØ x 250 mmL, particle size 5 µm), Chiralpak OD-H (4,6 mmØ x 250 mmL, particle size 5 µm), Chiralpak OJ-H (4,6 mmØ x 250 mmL, particle size 5 µm), Chiralpak AS-H (4.6 mmØ x 250 mmL, particle size 5 µm). Ultrafast chromatography was performed on a Waters ACQUITY UPC2 system using a Trefoil CEL1 column (2.5 µm, 3 mm x 150 mm). Materials. Commercial grade reagents and solvents were purchased from Sigma Aldrich and used without further purification; when necessary, they were purified as recommended.20 The chiral primary amine catalysts were synthesized following the general procedure described in the literature,21 purified by flash column chromatography and stored at 4°C under argon atmosphere. General procedure for the 1,4-addition of OXTs to cyclic α,β-unsaturated ketones: The α,β-unsaturated ketone (0.6 mmol – 2 eq.), catalyst (20 mol %, 0.06 mmol) and OXT (0.3 mmol – 1 eq.) were mixed in 3 mL of ethanol at room temperature. The solution was stirred until complete consumption of the starting material, being monitored by TLC (24 hours). The mixture was then concentrated under reduced pressure and the resulting crude mixture was

27



purified by flash column chromatography using n-hexane/EtOAc as eluent. The enantiomeric excess was determined by chiral-phase HPLC analysis through comparison with the authentic racemic material. Compound 3a: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 79% (0.24 mmol, 50.02 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 3.01 – 2.94 (m, 1H), 2.70 – 2.63 (m, 1H), 2.48 – 2.41 (m, 2H), 2.39 – 2.30 (m, 1H), 2.19 – 2.11 (m, 1H), 2.06 (s, 3H), 2.03 – 1.98 (m, 1H), 1.96 – 1.89 (m, 1H), 1.76 – 1.64 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 209.5, 177.2, 146.7, 120.1, 45.5, 41.0, 35.0, 29.6, 25.0, 8.1. The enantiomeric excess was determined to be 96% by HPLC analysis on a Daicel Chiralpak AS-H column: 80:20 hexane/iPrOH, flow rate 1.0 mL/min, λ = 270 nm minor = 69.8 min., major = 44.6 min.; [] = -14.2 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H13NO2SNa 234.0565; Found 234.0559.

Compound 3b: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 75% (0.22 mmol, 44.35 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.51 (s, 1H), 3.37 – 3.28 (m, 1H), 2.55 – 2.42 (m, 2H), 2.32 – 2.25 (m, 2H), 2.23 – 2.13 (m, 2H), 2.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 216.0, 145.7, 120.8, 42.6, 38.2, 32.6, 28.2, 8.3. The enantiomeric excess was determined to be 95% by HPLC analysis on a Daicel Chiralpak AS-H column: 80:20 hexane/iPrOH, flow rate 1.0 mL/min, λ = 270 nm: τminor = 73.8 min., τmajor = 41.9 min; [] = -21.8 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H12NO2S 198.0589; Found 198.0583.

Compound 3c: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 68% (0.20 mmol, 45.91 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 3.03 (dd, J = 13.7, 11.8 Hz, 1H), 2.85 (tt, J = 11.5, 2.7 Hz, 1H),

28


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2.66 – 2.59 (m, 1H), 2.54– 2.45 (m, 2H), 2.06 (s, 3H), 2.00 – 1.94 (m, 2H), 1.92 – 1.82 (m, 2H), 1.76 – 1.65 (m, 1H), 1.45 – 1.36 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 212.1, 177.2, 148.6, 119.0, 47.7, 44.0, 35.8, 33.2, 28.3, 23.5, 8.2. The enantiomeric excess was determined to be 99% by HPLC analysis on a Daicel Chiralpak AS-H column: 80:20 hexane/iPrOH, flow rate 1.0 mL/min., λ = 270 nm: major = 52.1. min.; [] = -1.85 (c 0.1, EtOAc); HRMS (ESITOF) m/z: [M + H]+ Calcd for C11H16NO2S 226.0902; Found 226.0896.

Compound 3d: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 72% (0.21 mmol, 51.64 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H), 3.16 – 3.10 (m, 1H), 3.09 – 3.02 (m, 1H), 2.49 – 2.35 (m, 2H), 2.32 – 2.25 (m, 1H), 2.21 – 2.12 (m, 1H), 2.09 (s, 3H), 1.92 – 1.64 (m, 6H), 1.55 – 1.48 (m, 1H), 1.29 – 1.17 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 214.9, 177.2, 148.8, 119.0, 43.9, 35.8, 31.5, 28.0, 23.5, 23.1, 8.2. The enantiomeric excess was determined to be 95% by HPLC analysis on a Daicel Chiralpak AS-H column: 80:20 hexane/iPrOH, flow rate 1.0 mL/min., λ = 270 nm minor = 21.6 min, major = 25.1 min.; [] = -26.4 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H17NO2SNa 262.0878; Found 262.0875.

Compound 3e: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 73% (0.22 mmol, 59.80 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 7.48 – 7.40 (m, 3H), 7.38 – 7.35 (m, 2H), 3.22 (tt, J = 12.2, 3.9 Hz, 1H), 2.77 (t, J = 13.6, 1H), 2.55 – 2.50 (m, 1H), 2.46 – 2.32 (m, 2H), 2.20 – 1.99 (m, 3H), 1.75 – 1.64 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 209.1, 177.6, 146.6, 129.9, 129.6, 127.3, 125.2, 125.1, 45.5, 40.9, 35.5, 29.8, 25.0. The enantiomeric excess was determined to be 85% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.6 mL/min, λ = 270 nm: minor = 9.3 min, major = 11.8 min.; [] = -

29



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13.9 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H15NO2SNa 296.0721; Found 296.0729.

Compound 3f: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 73% (0.22 mmol, 43.15 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 1.5 Hz, 1H), 6.95 (d, J = 1.5 Hz, 1H), 4.93 – 4.85 (m, 1H), 2.90 – 2.85 (m, 1H), 2.54 – 2.48 (m, 2H), 2.40 – 2.32 (m, 1H), 2.27 – 2.23 (m, 1H), 2.13 – 2.05 (m, 1H), 2.01 – 1.92 (m, 1H), 1.87 – 1.76 (m, 1H);

13

C NMR (101 MHz, CDCl3) δ

206.4, 177.8, 136.1, 115.5, 56.1, 45.7, 40.6, 29.4, 21.7. The compound was obtained as a racemic mixture. HPLC analysis on a Daicel Chiralpak AS-H column: 80:20 hexane/iPrOH, flow rate 1.0 mL/min, λ = 270 nm: minor = 53.9 min, major = 69.2 min.; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H12NO2S 198.0589; Found 198.0576.

General procedure for the 1,4 addition of OXTs to acyclic α,β-unsaturated ketones: The α,β-unsaturated ketone (0.6 mmol – 2 eq.), catalyst (20 mol %, 0.06 mmol) and OXT (0.3 mmol – 1 eq.) were solubilized in 150 µL of ethanol at -20ºC. The system was stirred until complete consumption of the starting material, as monitored by TLC (24 hours). The mixture was then concentrated under reduced pressure and the resulting crude product was purified by flash column chromatography using n-hexane/EtOAc as eluent. The enantiomeric excess was determined by chiral-phase HPLC or UPC2 analysis through comparison with the authentic racemic material.

Compound 5a: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 95% (0.28 mmol, 74.41 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.19 (s, 1H), 7.32-7.28 (m, 5H), 4.43 (dd, J = 8.7, 5.5 Hz, 1H),

30


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3.35 (dd, J = 17.9, 8.7 Hz, 1H), 3.01 (dd, J = 18.0, 5.6 Hz, 1H), 2.13 (s, 3H), 2.04 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.8, 176.8, 146.2, 139.7, 129.0, 127.5, 127.5, 121.1, 46.9, 36.2, 30.5, 8.0. The enantiomeric excess was determined to be 99% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = + 24.4 min, major = 21.5 min.; [] = -161.1 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]

Calcd for C14H16NO2S 262.0902; Found 262.0896.

Compound 5b: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 88% (0.26 mmol, 72.63 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 4.40 (t, J = 7.0 Hz, 1H), 3.31 (dd, J = 17.9, 8.5 Hz, 1H), 3.00 (dd, J = 17.9, 5.9 Hz, 1H), 2.29 (s, 3H), 2.12 (s, 3H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.9, 176.9, 146.4, 137.2, 136.8, 129.7, 127.4, 120.9, 47.0, 35.9, 30.5, 21.1, 8.0. The enantiomeric excess was determined to be 86% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 20.3 min., major = 22.3 min.; [] = -141.3 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H18NO2S 276.1058; Found 276.1053.

Compound 5c: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 85% (0.25 mmol, 70.15 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.20 – 7.15 (m, 1H), 7.14 – 7.12 (m, 2H), 4.68 (dd, J = 8.8, 5.3 Hz, 1H), 3.37 (dd, J = 18.0, 8.8 Hz, 1H), 2.97 (dd, J = 18.0, 5.3 Hz, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 1.99 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ

205.8, 177.0, 145.9, 137.6, 135.2, 130.8, 127.4, 127.4, 126.9, 121.0, 46.8, 31.9, 30.5, 19.7, 8.2. The enantiomeric excess was determined to be 94% by HPLC analysis on a Daicel

31



Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 21.1 + min., major = 27.2 min.; [ ] = -143.9 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H] Calcd

for C15H18NO2S 276.1058; Found 276.1064.

Compound 5d: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 1:1) in 99% (0.29 mmol, 82.29 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 4.35 (dd, J = 8.6, 5.8 Hz, 1H), 3.29 (dd, J = 17.9, 8.6 Hz, 1H), 2.98 (dd, J = 17.9, 5.8 Hz, 1H), 2.13 (s, 3H), 2.00 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 206.6, 177.0, 155.4, 146.6, 131.5, 128.8, 120.7, 116.0, 47.2, 35.6, 30.6, 8.1. The enantiomeric excess was determined to be 84% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 69.2 min., major = 51.6 min.; [] = -122.1 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16NO3S 278.0851; Found 278.0879.

Compound 5e: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 1:1) in 94% (0.28 mmol, 82.09 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.79 (s, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.79 – 6.78 (m, 1H), 6.76-6.73 (m, 1H), 4.39 (dd, J = 8.6, 5.6 Hz, 1H), 3.76 (s, 3H), 3.31 (dd, J = 18.0, 8.6 Hz, 1H), 3.00 (dd, J = 18.0, 5.7 Hz, 1H), 2.12 (s, 3H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.8, 176.8, 159.9, 146.0, 141.2, 130.0, 121.1, 119.8, 113.6, 112.5, 55.3, 46.7, 36.2, 30.4, 8.0. The enantiomeric excess was determined to be 88% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min., λ = 270 nm: minor = 27.2 min., major = 33.5 min.; [] = -128.9 (c 0.1, EtOAc); HRMS (ESITOF) m/z: [M + H]+ Calcd for C15H18NO3S 292.1007; Found 292.1011.

32


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Compound 5f: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 1:1) in 99% (0.29 mmol, 91 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 7.82 (dd, J = 8.1, 0.9 Hz, 1H), 7.68 (dd, J = 7.8, 0.9 Hz, 1H), 7.63 – 7.55 (m, 1H), 7.44 – 7.36 (m, 1H), 5.18 (dd, J = 8.0, 6.0 Hz, 1H), 3.34 (dd, J = 18.3, 8.1 Hz, 1H), 3.12 (dd, J = 18.3, 5.9 Hz, 1H), 2.16 (s, 3H), 2.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 204.5, 177.2, 148.9, 144.2, 134.0, 133.4, 129.8, 128.3, 124.7, 122.6, 47.1, 30.3, 29.96, 8.1. The enantiomeric excess was determined to be 93% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm:

minor = 34.2 min., major = 48.2 min.; [ ] = -141.3 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H15N2O4S 307.0752; Found 307.0756.

Compound 5g: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 93% (0.28 mmol, 82.32 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.33 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 4.55 (dd, J = 8.3, 5.7 Hz, 1H), 3.36 (dd, J = 18.2, 8.4 Hz, 1H), 3.05 (dd, J = 18.3, 5.7 Hz, 1H), 2.16 (s, 3H), 2.10 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 204.7, 177.6, 147.3, 147.0, 144.4, 128.7, 124.4, 121.8, 46.7, 35.9, 30.4, 8.2. The enantiomeric excess was determined to be 91% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min., λ = 270 nm: minor = 22.4 min., major = 24.4 min.; [] = -155.0 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H15ClNO2S 296.0512; Found 296.0506.

Compound 5h: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 92% (0.28 mmol, 93.56 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.71 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.39 (dd, J = 8.2, 5.9 Hz, 1H), 3.30 (dd, J = 18.1, 8.4 Hz, 1H), 2.99 (dd, J = 18.1, 5.8 Hz, 1H), 2.13 (s, 3H), 2.04 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.4, 177.1, 145.6, 138.8, 132.1, 129.3, 121.5, 121.3, 46.8, 35.6, 30.5, 8.1. The enantiomeric excess was determined to be 92% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 33



mL/min, λ = 270 nm: minor = 24.1 min., major = 25.7 min.; [] = -146.5 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H14BrNO2SNa 361.9826; Found 361.9821.

Compound 5i: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 98% (0.29 mmol, 82.05 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.77 (s, 1H), 7.25 – 7.17 (m, 2H), 6.97 – 6.88 (m, 2H), 4.41 (dd, J = 8.3, 5.9 Hz, 1H), 3.29 (dd, J = 18.1, 8.5 Hz, 1H), 2.98 (dd, J = 18.1, 5.9 Hz, 1H), 2.11 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 205.6, 177.0, 161.8, 145.8, 135.5, 135.1, 129.2, 129.1, 115.9, 115.7, 47.0, 35.4, 30.4, 8.00. The enantiomeric excess was determined to be 89% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 22.7 min., major = 25.1 min.; [] = -123.0 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H15FNO2S 280.0808; Found 280.0811.

Compound 5j: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 7:3) in 90% (0.27 mmol, 75.35 mg) isolated yield. 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.27 (m, 1H), 7.18 – 7.13 (m, 1H), 7.05 – 7.03 (m, 1H), 6.98 – 6.93 (m, 1H), 4.74 (dd, J = 9.3, 5.1 Hz, 1H), 3.32 (dd, J = 18.1, 9.3 Hz, 1H), 2.94 (dd, J = 18.1, 5.1 Hz, 1H), 2.09 (s, 3H), 2.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.8, 176.8, 146.3, 137.1, 136.7, 129.6, 127.4, 126.8, 120.9, 47.8, 46.9, 35.81, 31.0, 30.5, 21.0, 7.9. The enantiomeric excess was determined to be 90% by HPLC analysis on a Daicel Chiralpak ODH column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: λ = 270 nm: minor = 22.7 + min, major = 26.2 min.; [] = -125.4 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]

Calcd for C14H15FNO2S 280.0808; Found 280.0805.

34


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Compound 5k: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 73% (0.22 mmol, 54.98 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.49 (s, 1H), 7.24 (dd, J = 1.8, 0.7 Hz, 1H), 6.22 (dd, J = 3.2, 1.9 Hz, 1H), 6.05 (d, J = 3.3 Hz, 1H), 4.50 (dd, J = 8.3, 5.8 Hz, 1H), 3.17 (dd, J = 18.1, 8.4 Hz, 1H), 3.06 (dd, J = 18.1, 5.8 Hz, 1H), 2.11 (s, 3H), 1.99 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.0, 177.0, 151.7, 143.8, 141.9, 133.1, 122.0, 110.6, 106.7, 44.3, 30.2, 7.8. The enantiomeric excess was determined to be 68% by HPLC analysis on a Daicel Chiralpak ODH column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 25.5 min., major = + 28.1 min.; [] = -40.4 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H] Calcd for

C12H14NO3S 252.0694; Found 252.0699.

Compound 5l: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 85% (0.25 mmol, 82.39 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 7.43 – 7.38 (m, 2H), 7.37 – 7.27 (m, 3H), 7.25 – 7.21 (m, 3H), 7.20 – 7.08 (m, 2H), 4.62 (dd, J = 8.5, 5.9 Hz, 1H), 3.33 (dd, J = 18.0, 8.5 Hz, 1H), 3.01 (dd, J = 18.0, 5.9 Hz, 1H), 2.04 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 205.7,

177.3, 146.0, 140.1, 129.5, 129.3, 129.1, 128.7, 128.2, 127.6, 127.5, 127.3, 125.7, 125.3, 47.5, 36.8, 30.4. The enantiomeric excess was determined to be 87%, measured by ACQUITY UPC2 system (Waters Corp., Milford, MA, USA). Separation was performed on an ACQUITY UPC2 Trefoil AMY1 column AD (2.5µm, 3 mm x 150 mm) using a method with the mobile phase containing SCCO2 (purity ≥ 99.99%) and EtOH (80:20) delivered at a flow rate of 0.8 mL/min., λ = 270 nm: inor = 3.71 min., jor = 4.00 min.; [] = -26.5 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H18NO2S 324.1058; Found 324.1073.

35



Compound 5m: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 89% (0.27 mmol, 90.01 mg) isolated yield; 1H NMR (400 MHz, ) δ 11.89 (s, 1H), 7.50 – 7.47 (m, 2H), 7.44 – 7.42 (m, 1H), 7.40 – 7.38 (m, 2H), 7.19 – 7.15 (m, 1H), 7.14 – 7.07 (m, 3H), 4.92 (dd, J = 9.5, 4.7 Hz, 1H), 3.49 (dd, J = 18.0, 9.6 Hz, 1H), 2.94 (dd, J = 18.1, 4.7 Hz, 1H), 2.16 (s, 3H), 2.10 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.9, 177.4, 146.1, 138.5, 134.8, 130.9, 129.6, 129.3, 128.7, 128.2, 127.4, 127.0, 125.7, 125.5, 46.9, 32.6, 30.4, 19.5. The enantiomeric excess was determined to be 86% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: 7.8 min., major = 9.4 min.; [] = -114.5 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H20NO2S 338.1215; Found 338.1217.

Compound 5n: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 88% (0.26 mmol, 89.00 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 7.49 – 7.47 (m, 2H), 7.45 – 7.41 (m, 2H), 7.40 – 7.38 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.65 (dd, J = 8.3, 5.9 Hz, 1H), 3.38 (dd, J = 18.0, 8.4 Hz, 1H), 3.07 (dd, J = 18.0, 6.0 Hz, 1H), 2.30 (s, 3H), 2.11 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 205.8, 177.4, 146.4, 137.3, 137.2, 129.8, 129.6, 129.4,

127.4, 127.4, 125.6, 125.5, 47.6, 36.5, 30.5, 21.1. The enantiomeric excess was determined to be 86% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 8.6 min, major = 10.1 min.; [ ] = -44.9 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H20NO2S 338.1215; Found 338.1219.

Compound 5o: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 90% (0.27 mmol, 92.09 mg) isolated yield; 1H

36


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NMR (400 MHz, CDCl3) δ 7.52 – 7.50 (m, 2H), 7.46 – 7.44 (m, 1H), 7.42 – 7.37 (m, 3H), 7.24 – 7.20 (m, 1H), 7.11 (td, J = 7.6, 1.1 Hz, 1H), 7.04 – 6.99 (m, 1H), 5.06 (dd, J = 9.2, 5.1 Hz, 1H), 3.43 (dd, J = 18.2, 9.4 Hz, 1H), 3.05 (dd, J = 18.1, 5.2 Hz, 1H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.1, 177.6, 159.8, 144.9, 129.7, 129.4, 129.3, 129.1, 127.4, 126.8, 125.7, 124.9, 115.9, 115.9, 46.3, 30.2, 29.7. The enantiomeric excess was determined to be 89% by HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 9.3 min., major = 10.8 min.; [] = -99.0 (c 0.1, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H17FNO2S 342.0964; Found 342.0951.

Compound 5p: Synthesized according to the general procedure and purified by flash column chromatography (n-hexane: EtOAc 6:4) in 73% (0.22 mmol, 54.11 mg) isolated yield; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.31 (m, 5H), 7.19 (d, J = 1.7 Hz, 1H), 6.77 (d, J = 1.7 Hz, 1H), 6.22 (t, J = 7.4 Hz, 1H), 3.36 (qd, J = 16.8, 6.7 Hz, 2H), 2.22 (s, 3H);

13

C NMR (101

MHz, CDCl3) δ 204.3, 178.1, 135.6, 129.3, 129.1, 127.5, 117.1, 116.2, 57.2, 45.6, 30.1. The compound was recovered as a racemic mixture. HPLC analysis on a Daicel Chiralpak OD-H column: 90:10 hexane/iPrOH, flow rate 0.4 mL/min, λ = 270 nm: minor = 17.1 min., major = 20.3 min.; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H14NO2S 248.0745; Found 248.0743.

Computational Details: All DFT calculations were performed with Gaussian 09 suit of programs using a ultrafine grid.22 Full optimization were conducted with Truhlar M06-2X functional23 and def2-svp basis set. The IEF-PCM [ethanol] was used for inclusion of the solvent effect for all optimizations. All Cartesian coordinates are supplied in the SI. isualizations were done with the beta version of CYLview.24 Frequency calculations at 295.15

37



K (1 atm) ensured that the stationary points represent either minima (no imaginary frequency) or transition states (single imaginary frequency) on the potential-energy surface, furnishing also the zero-point vibrational energies, the thermal and entropic correction from which the Gibbs free energies were determined. To refine the electronic energy, single-point calculations were performed at M02X/def2-tzvp/IEF-PCM level of theory employing the M02X/def2-svp/IEF-PCM geometries. The IRC calculations were done ensuring that each transition state connects reagents and products. The natural bond orbital (NBO) analysis was calculated at M02X/def2-tzvp/IEF-PCM level using NBO 6.0 program.25 The frontier molecular orbitals (FMO) were plotted at HF/def2-tzvp/IEF-PCM//M06-2X/def2-svp/IEFPCM level of theory, isodensity of 0.02 with the GaussView05 software. The Non Covalent Interaction (NCI) analysis was carried out with the NCIplot 3.0 software,26 with VMD27 as visual interface.

Acknowledgements Authors acknowledge CNPq, CAPES while S. Silva cordially acknowledges FAPESP (2012/04986-5) for the fellowships conceded. We also gratefully acknowledge financial support from CNPq (INCT-Catálise) and FAPESP (14/50249-8, 15/08541-6, and 15/171411). We also thank Prof. Regina H.A. Santos, from IQISC-USP for the RX data collection. We are in debit to Prof. Claudio Tormena for computational facilities support. Supporting Information. 1H,

13

C NMR, chiral-phase HPLC and UPC2 analysis of Michael

adducts. X-ray crystallography data of compound 5j and DFT computational details. This material is available free of charge via the Internet at http://pubs.acs.org. References 1

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Organocatalyzed Asymmetric Vinylogous Addition of Oxazole-2(3H

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