carmen nájera*, josé miguel sansano and enrique gómez...

Pure Appl. Chem. 2016; 88(6): 561–578

Conference paper

Carmen Nájera*, José Miguel Sansano and Enrique Gómez-Bengoa

Heterocycle-based bifunctional organocatalysts in asymmetric synthesisDOI 10.1515/pac-2016-0403

Abstract: Different chiral bifunctional organocatalysts derived from trans-cyclohexane-1,2-diamine bearing different types of guanidine units able to form-hydrogen bonding activation have been designed. Conforma-tional rigid 2-aminobenzimidazoles bearing a tertiary amino group have been used in enantioselective Michael type reactions of activated methylene compounds to nitroalkenes. The C2 symmetric bis(2-aminobenzimida-zole) derivatives the appropriate organocatalyst for the conjugate addition of 1,3-dicarbonyl compounds to maleimides as well as for the SN1 reaction of benzylic alcohols with carbon nucleophiles. 2-Aminobenzimi-dazoles bearing a primary amino group have shown excellent catalytic activity in the Michael reaction of aldehydes to maleimides and nitroalkenes. Diastereomeric 2-aminopyrimidines bearing a prolinamide unit have been incorporated in the trans-cyclohexane-1,2-diamine scaffold and have been used for the inter- and intra-molecular direct aldol reaction under solvent-free conditions. For the Michael reaction of aldehydes with maleimides the primary amine 2-aminopyrimidine has shown excellent efficiency as organocatalyst. The bifunctional character of these organocatalysts has been demonstrated by means of DFT calculations.

Keywords: aldols; asymmetric synthesis; bifunctional catalysis; carbenium ions; 1,3-dicarbonyl compounds; hydrogen bonding; nitro compounds; succinimides; TRAMECH VIII.

IntroductionThe crucial role of hydrogen-bonding (HB) interactions in biological systems have inspired the recent devel-opment of small organic molecules able to act as chiral hydrogen-bond donors and acceptors in asymmetric organocatalysis [1–5]. Chiral ureas [6–8] and thioureas [9–11] 1 with pKa = 27 and 21 in DMSO [12], respec-tively, have emerged as the most successful catalysts due to their ability to form two hydrogen bonds with nucleophiles and electrophiles (Fig. 1). Rigid guanidines have been employed as chiral bases also capable of forming hydrogen bonds [13–19]. However, acyclic guanidines due to conformational free rotation, according to DFT calculations, are able to form only one hydrogen bond with electrophiles [20–22]. Other systems able to form two-hydrogen bonds such as aminophosphonium [23–25], thioamides [26], squaramides [27, 28] and sulfonamides [29]. Concerning heterocyclic based organocatalysts 2-aminopyridinium ions 2 [30–35] with pKa = 6 in DMSO [36] have been used as chiral catalysts [26, 30–35]. Another 2-amino heterocyclic systems

Article note: A collection of invited papers based on presentations at the Trans Mediterranean Colloquium on Heterocylic Chemistry (TRAMECH VIII) in Anatalya, Turkey, 11–15 November 2015.

*Corresponding author: Carmen Nájera, Departamento de Química Orgánica and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain, e-mail: [email protected]é Miguel Sansano: Departamento de Química Orgánica and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante, SpainEnrique Gómez-Bengoa: Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, E-20018 San Sebastián, Spain

© 2016 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/ - 10.1515/pac-2016-0403

Downloaded from De Gruyter Online at 09/19/2016 09:17:09AMvia University of California - San Diego

mailto:[email protected]

http://creativecommons.org/licenses/by-nc-nd/4.0/

562 C. Nájera et al.: Heterocycle-based bifunctional organocatalysts in asymmetric synthesis

bearing a quinozaline 3 related to guanine, or benzothiadiazines 4 skeletons [37, 38] have shown excellent bifunctional catalytic properties acting as dual hydrogen-bond donors (Fig. 1). We envisaged that 2-amino-benzimidazoles and 2-aminopyrimidines can behave as rigid guanidines and should be appropriate units to form double hydrogen bonds. This article compiles our contribution on bifunctional heterocyclic organocata-lysts 5–8 (Fig. 1) by using the trans-cyclohexane-1,2-diamine as a chiral scaffold.

Chiral 2-aminobenzimidazoles2-Aminobenzimidazoles and 2-aminopyridines with similar pKa (7.0 and 6.2) have shown very good acid/base catalytic features substituting guanidinium moieties as phosphoryl transfer catalysts [39]. However, only tris(2-aminobenzimidazoles) 9 led to active RNA cleavers by means of HB with phosphates under neutral conditions being promising candidates as site specific artificial ribonucleases (Fig. 2). More recently, Moran et al. have designed a xanthenes-2-aminobenzimidazole receptor 10 able to form multiple hydrogen bonds with sulfoxides, ketones or alcohols and strongly with carboxylic acids and chloride anion [40]. The 2-amin-obenzimidazole is an important unit in medicinal chemistry due to the broad spectrum of pharmacologi-cal applications such as the antihelmintic mebendazole and albendazole and the antihistaminic astemizole [41–47]. Ganesh and Seidel [26] described a thiourea bearing a protonated 2-aminobenzimidazole unit 11, which has been used as chiral organocatalysts in the enantioselective addition of indole to nitroalkenes with amoderate 40 % ee. Further development of chiral 2-aminobenzimidazoles has demonstrated the outstand-ing ability of these units as dual HB donor [48].

We initially designed and synthetized different 2-aminobenzimidazoles 5 starting from both enantiomers of trans-cyclohexane-1,2-diamine by reaction with 2-chlorobenzimidazole [49]. From X-ray diffraction analy-sis data and DFT calculations the distances of both hydrogens in the NH groups could be determined. They are in the range of 2.41–2.61 Å, whereas in related thiourea 12 [9–11] and squaramide 13 [27] are 2.13 Å and 2.72 Å, respectively (Fig. 3).

As a benchmark reaction the conjugate addition of diethyl malonate to β-nitrostyrene catalyzed by com-pounds 5 bearing a primary amine 5a (R = H, X = H), a tertiary amine 5b (R = Me, X = H), 5c (R = Et, X = H) and 5d (R = Me, X = 6-CF3) in different solvents and in the presence and absence of trifluoroacetic acid (TFA) as cocatalyst was studied [49]. From the screening of these reaction conditions it could be deduced that toluene as a solvent, organocatalysts 5b (10 mol %), TFA (10 mol %) at room temperature during 2 days gave the best performance (Scheme 1). This organocatalyst could be recovered in 94 % yield by extractive work-up with 10 % aqueous NaOH. The Michael adducts were obtained in 95–98 % yield and 87–94 % ee (Scheme 1). When β-keto esters were used as nucleophiles moderate to high diatereoselectivities were observed (up to 82 %) with in general high enantioselectivity for each diastereomer (70–93 % ee). Acetylacetone afforded the cor-responding Michael adducts in 93–96 % yield and 86–99 % ee under the same reaction conditions.

R2N

N N

NNH

NH N

H

N

N

NH

RN N

RX

HH

X = O, S, NH

1

N+NR

H H

2

N

N

N

O

HX

3

H NMe2

N

NS

N

O

HX

4

H NMe2

O

H H

5 6

NH2

N

H

7

N

NX

NH

N

H

8

N

N

O

NH

Fig. 1: Dual hydrogen-bonding systems.

- 10.1515/pac-2016-0403Downloaded from De Gruyter Online at 09/19/2016 09:17:09AM

via University of California - San Diego

C. Nájera et al.: Heterocycle-based bifunctional organocatalysts in asymmetric synthesis 563

From DFT calculations at the B3LYP/6-311++G∗∗//B3LYP/6-31G∗ level for the conjugate addition of dimethyl malonate or acetylacetone to β-nitrostyrene two possible activation modes were considered with the neutral and the protonated organocatalyst (Fig. 4). The most favored activation mode is in agreement with Papai et al. calculations for the same reaction catalyzed by thiourea 12 [50], the formation of the two hydrogen bonds from the 2-aminobenzimidazole unit with the 1,3-dicarbonyl compound.

Transition state TSa for the R-enantiomer in the case of malonate is 1.9 kcal/mol more stable than for the S-enantiomer. However, the other interaction gave the opposite enantioselection and only a 0.6 kcal/mol difference in energy for both TS producing quasi-racemic products [49] (Fig. 5). These calculations not only supported the dual HB but also the bifunctional character of this catalyst and the participation of TFA as a cocatalyst. On the other hand, the protonated dimethylamino group form a hydrogen bond with one of the oxygen of the nitro group.

N

N

NH

H

N

HN

NH N

H

N

NH

N

9

O

NH HN

Cl Cl

O

NH

NHN

NH

N

10

N N

S

N

N+H

HHHOH

11

Fig. 2: Selected 2-aminobenzimidazoles.

R2N

N N

N

H H

2.41–2.61 Å 2.13 Å

NH

NH

NMe2

S

CF3

F3C

O O

NNF3C

CF3

N

N

HH

2.72 Å

X

12 135

Fig. 3: Hydrogen distances for organocatalysts 5, 12 and 13.

Me2N

N N

N

H H

5b

NO2+RO OR

O O 5b (10 mol %)

Toluene, rtAr NO2Ar

RO2C CO2RTFA (10 mol %)

95–98 %87–94 % eeR = Me, Et, Pri

Ar = Ph, 4-ClC6H4, 2-CF3C6H4,2,4-Cl2C6H3, 4-MeOC6H4,4-Tol, 2-thienyl

Scheme 1: Conjugate addition of malonates to nitrostyrenes.




Independently, the Park and Jew groups [51] described that related 2-aminobenzimidazoles 14 and 15 (Fig. 6), derived from dihydroquinidine and quinidine as chiral bases, were very efficient organocatalysts for the Michael addition of dimethyl malonate to nitroalkenes. Under neutral conditions by using 2 mol %

N

O

O

PhMeO OMe

O O

NMe2N

N

NH

H

H

+

N

O

O

PhMeO OMe

O O

NMe2N N

N

HH

H

+

MeO OMe

O O

NNMe2

N

N

H H

NO

Ph

OH

+

TSb-R

TSb-S

TSa-S

TSa-R

1.9

0.0

2.9

2.3

H

H

H

OMe

OMe

O

O

N

Me2N

N

N

HH

NOOH

+

Ph

H

–

– –

–

Fig. 5: Energy differences of the transition states for the Michael addition of dimethylmalonate to β-nitrostyrene.

R

R

O

O–

N

O

–O

PhR R

O O–

NMe2N

N

XH

H

H

+

N

Me2N

N

X

HH

NOO

N

O

O–

PhR R

O O–

NMe2N N

X

HH

H

+

H

R R

O– O

NNMe2

N

X

H H

NO

Ph

O–H

+

+

TSa-R -aST)N=X( S (X = N)R = OMe; 0R = Me; 0

R = OMe; 2.6R = Me; 2.8

R = OMe; 1.9R = Me; 2.6

R = OMe; 2.4R = Me; 4.4

Ph

R = OMe; 3.9R = Me; 5.1

R = OMe; 2.3R = Me; 5.2

TSa-H+-R (X = + H-aST)HN +-S (X = +NH)R = OMe; 0R = Me; 0

R = OMe; 1.9R = Me; 6.6

TSb-R -bST)N=X( S (X = N)TSb-H+-R (X = +NH) TSb-H+-S (X = +NH)

++

+ +

–

Fig. 4: Values correspond to Gibss free energies (G, kcal/mol) relative to TSa-R (G = 0) computed at B3LYP/G-311++G∗∗ level for the conjugate addition of dimethyl malonate and acetylacetone to β-nitrostyrene.




of catalyst loading in dichloromethane (DCM) as solvent at –20 °C during 40–96 good yields (67–99 %) and ee (91–99 %) were obtained. Further contribution from this group with 10 mol % of trans-cyclohexane-1,2-diamine organocatalyst 5e (R = Me, X = 5,7-(CF3)2) revealed that under neutral conditions, the addition of dimethyl malonate in DCM at 0 °C gave 90–96 % ee [52]. They proposed that the nitro group is activated by double HB with the 2-aminobenzimidazole unit and confirmed that in the absence of CF3 groups in the benzimidazole 5b needs the presence of TFA and proposed the same interaction mode in agreement with our results. When organocatalyst 5b was employed in enantioselective intramolecular oxa-Michael addition, the reaction failed. However, organocatalyst 4 gave high yields and enantioselectivities [38]. In the case of the α-amination of 1,3-dicarbonyl compounds with diazodicarboxylates only ethyl cyclopentanecarboxylate gave, in the presence of 10 mol % of 5b, a 92 % ee [53].

For the conjugate addition of isobutyraldehyde to nitroalkenes the presence of a primary amine in the 2-amin-obenzimidazole (S,S)-5a (20 mol %) in DCM at 25 °C during 3 days allowed the synthesis of γ-nitroaldehydes in moderate to high yields and enantioselectivities (Scheme 2) [54]. DFT calculations [M06-2X/6-31+G(d,p) level] support the approaching of nitrostyrene behind the enamine and the two NH of the 2-aminobenzimidazole unit are forming two HB with one oxygen atom of the nitro group with 1.9 Å and 2.3 Å distances (Scheme 2). In addition, the sp2 nitrogen of the benzimidazole acts as hydrogen acceptor of the enamine hydrogen being the distance 2.1 Å. These calculations corroborate the bifunctional character of this organocatalyst.

Enantioenriched succinimides can be prepared by asymmetric conjugate addition to maleimides [55]. The succinimide unit is present in natural products such as moramide B and andrimid and in some drugs

N

OMe

NH

N

HN N

CF3

F3C

14

F3C

CF3

N

NH

NH

N

N

OMe

15

Fig. 6: Cinchona alkaloids derived 2-aminobenzimidazole organocatalysts.

(S,S)-5a

+(S,S)-5a (20 mol %)

CH2Cl2, 25 °C, 3 days

NH2

NH

Me CHO

Me

yields: 52–99 %ee: 76–92 %

RNO2 NO2OHC

Me Me

R

NH

N

NN H H

N

N

H

2.1 Å

2.3 Å

1.9 ÅN+

-O O

TS2-S

Scheme 2: Michael addition of isobutyraldehyde to nitroalkenes catalyzed by the primary amine-2-aminobenzimidazole (S,S)-5a.




such as phensuximide, ethosuximide and palasimide [56–61]. In addition, succinimides can be transformed into γ-lactams or pyrrolidines by partial or total reduction, and in succinic acid derivatives by acid or basic hydrolysis [62, 63]. Initial studies on the conjugate addition of acetylacetone to maleimide were assayed with different organocatalysts of the type 5 (10 mol %) and TFA (10 mol %) in toluene at rt afforded low ee (13–41 %) [64, 65]. However, when the C2 symmetric bis(2-aminobenzimidazole) 6 (10 mol %) and TFA (10 mol %) as cocatalyst were used the addition took place quantitatively in 97 % ee. The scope of the reaction was studied with different maleimides giving the corresponding adducts in general high yields (65–99 %) and enantioselectivities (74–97 % ee) (Scheme 3) [64, 65]. This catalytic behavior can be explained accepting that one 2-aminobenzimidazole unit is acting as a Brønsted base and the other, which is protonated by TFA, is acting as a Brønsted acid.

In the case of unsymmetrical 1,3-diketones and β-keto esters, modest to high diastereomeric ratios (58/42–97/3) and modest to high enantioselections (24–99 % ee) were obtained (Fig. 7). When these processes were scaled up to gram scale in 5–20 mmol, excellent results were achieved (Fig. 7). For the recovery of the organocatalysts 6 the reaction of acetylacetone and 4-(bromophenyl)maleimide was chosen. After the reac-tion was complete, isopropanol was added and the corresponding succinimide precipitated and was filtered off. From the solution 6, as trifluoroacetate salt, was isolated after evaporation of the solvents in 99 % yield and was used in a second run without further purification giving the succinimide in 99 % yield and 93 % ee [65]. The presence of one equivalent of TFA was crucial to obtain good yields and enantioselectivities. Notably, a complete deactivation of the catalyst was observed when using a twofold excess (20 mol %) of cocatalyst. Also, dependence of the enantioselectivity of the process on catalyst loading was observed. However, at high concentrations, product racemization due to thermodynamic control of the process was discharged, as the enantioselectivity of the reaction was kept constant within the course of the experiment when a 0.1 M catalyst concentration was used in the conjugate addition. The ee values obtained at different catalyst concentrations were fairly consistent with the diffusion coefficients of 6·TFA, strongly indicating that the degree of hydro-gen-bonded self-association of bifunctional organocatalyst in solution plays a crucial role in determining the enantioselectivity of the process.

The excellent catalytic activity of 6 was unexpected because this compound failed in the previously described Michael addition of dimethyl malonate to nitrostyrenes [52, 66]. However, the addition of dimetyl malonate to maleimides took place under neutral conditions (Scheme 4). This was probably due to the lower acidity of the nucleophile compared to 1,3-diketones and β-keto esters, thus requiring a catalyst with an stronger basic character.

N

N

NH H

R*

acid

N

N

NH H

R*

base

H+

Brønsted Brønsted

+ NR

O

O

O O NO

O

COMe

COMe

6 (10 mol %)TFA (10 mol %)

Toluene, 30 °C, 24 h

R

65–99 %74–97 % ee

NHNH N

H

N

N

NH

6

R = H, Me, Et, Bn, Ph,4-BrC6H4, 4-AcC6H4

Scheme 3: Conjugate addition of acetylacetone to maleimides organocatalyzed by 6.




DFT computational studies carried out in a solvent model (IEFPCM, toluene) at B3LYP/6-311++G∗∗ level, were conducted aimed at detailing the H-bond network between catalyst, nucleophile and maleimide respon-sible for the observed reactivity/enantioselectivity. It was assumed that the reaction is initiated with the deprotonation of the pronucleophile (2,5-pentadione) by one of the 2-aminobenzimidazole units to form an enolate/protonated catalyst binary complex. Further hydrogen bonding with the maleimide renders a ternary complex that evolves to the final products through the corresponding transition state [65].

Three possible mechanistic scenarios were considered: a) in the absence of acid, the basic catalyst depro-tonates and binds the nucleophile (A, Fig. 8). Four NH groups are available for Nu/maleimide activation, arranged in a flexible and open reactive site; b) if partial protonation (1 equiv of acid) of the catalyst is consid-ered, the neutral portion of the catalyst deprotonates the nucleophile leading to structure B, which possesses a tighter reactive space decorated with three or four NH groups for reagent activation; c) further protonation of the catalyst with a second molecule of acid would cancel the basicity of the catalyst, and only the enol form of the nucleophile could act as a nucleophile, like in structure C, lowering its reactivity [65].

After an extensive conformational search, the calculated energies for the optimal transition states in model A predict a high reactivity and a moderate selectivity [1.7 kcal/mol energy difference between TSA2(S) and TSA2(R), Fig. 9], which is in fair agreement with the experimental results in the absence of acid ( > 99 % conversion, 51 % ee). The privileged transition structures for each enantiomer [TSA2(S) and TSA2(R)] bear an intramolecular H bond between the protonated and the neutral benzimidazole portions of the catalyst. As a consequence, a very open reaction space is formed, in which the remaining four NH bonds are involved

NH

O

O

MeOC

O

93 %, dr: 58/4295 % ee/98 % ee

NPh

O

O

COMe

MeOCMe

NH

O

O

COMe

PhOC

97 %, dr: 58/4297 % ee/94 % ee

56 %, 86 % ee

NH

O

O

NH

O

O

COPh

EtO2CEtO2C

O

99 %, dr: 67/3389 % ee/95 % ee

99 %, dr: 87/1398 % ee/98 % ee

NH

O

O

O

MeOC

O

93 %, dr: 58/4295 % ee/98 % ee

O CO2Me

NH

O

O

98 %, dr: 76/2499 % ee/99 % ee

NH

O

O

COMe

MeOC

scale: 5 mmol6 (10 mol %)

81 % yield, >99 % ee

N

O

O

COMe

MeOC


83 % yield, >99 % ee

Ph N

O

O

COMe

MeOC


87 % yield, >99 % ee

C6H4-4-Ac


89 % yield, 100/0 dr, >99 % ee

NPh

O

O

O

MeOC

O

Fig. 7: Selected examples on the Michael addition of 1,3-dicarbonyl compounds to maleimides.

74–90 %78–99 % eeR = H, Me, Ph

+ NR

O

O

MeO OMe

O O NO

O

CO2Me

CO2Me6 (10 mol %)

Toluene, 30 °C, 24 h

R

Scheme 4: Conjugate addition of dimethyl malonate to maleimides catalyzed by 6.




in a low-selective binding of the nucleophile and electrophile. In contrast, the inclusion of one molecule of trifluoroacetic acid might produce a fast protonation of the catalyst (model B). The CF3COO− anion is able to bind the two imidazole units, eliminating the possibility of an intramolecular H-bonding between them. The optimal transition structures were found, in which three of the NH groups are exposed to the trifluoroacetate anion and solvent. In this structure, the activation of the maleimide is achieved by a single NH bond, and

NN

H

N

N

HN

N HH

HH

NO O

O

O

-

++

H

NN

H

N

NH

N

N HH

HH

NOO

O

O

+

+

H

OO

CF3

- OO

CF3

-

NN

H

NN

H

N

N

H

H

H

NO O

O

O-

+

H

Widereactive space

H

O

O

F3C-

Tight

A BC

reactive space

Enol form

Fig. 8: Computed mechanistic alternatives A–C.

O ONH

O

O

NN

H N

N

HN

N HH

H

+

TSA2(S), G‡toluene = 23.6 kcal/mol TSA2(R), G‡

toluene = 25.3 kcal/mol

NN

H N

N

HN

N HH

H

+

NH

O

O

O O-

Intramolecular H-bond Intramolecular H-bond

Hydrogenbonding

area

TSB2(S)TSA2(S)

NH

O

O

O ONH

O

O

NN

H

N

N

HN

NHH

H

+

TSB2(S), G‡toluene = 24.7 kcal/mol TSB2(R), G‡

toluene = 29.3 kcal/mol

H

-O O

F3C

NN

H

N

N

HN

NHH

H

+

H

-O O

F3C

O O-

+ +

--

∆ ∆

∆ ∆

Fig. 9: Main transition structures computed in models A and B.




two other NH groups bind the nucleophile, in a tight, concave reaction site. This effect increases the energy difference between the diastereomeric forms TSB(S) and TSB(R) (24.7 and 29.3 kcal/mol, respectively), predicting a high reactivity and very good enantioselectivity, as experimentally found ( > 99 % conversion, 94 % ee). As previously mentioned these calculations confirm the bifunctional nature of this organocatalyst 6 [65].

Finally, the distinct outcome shown by the malonates as nucleophiles might be related to the lower basicity of dimethyl malonate versus acetylacetone (pKas in DMSO are 15.7 and 13.3, respectively). In fact, the deprotonation of dimethyl malonate by the TFA-protonated catalyst (mechanism B) is computed to be a disfavored process (Fig. 10). Thus, both reactions of malonate in the presence or absence of TFA proceed through mechanism A, with a computed 86 % ee, in fair agreement with the experimental 78–81 % ee, and at different rates, since the acid exerts the negative effect of lowering the available amount of the necessary free benzimidazole [65].

The conjugate addition of aldehydes to maleimides were performed in the presence of the primary amine-benzimidazole catalyst (S,S)-5a (15 mol %) in toluene at 15 °C during 4 days under neutral conditions (Scheme 5) [54]. The corresponding succinimides were isolated in 47–99 % yield and 55–89 % ee. DFT calcula-tions were performed at M06-2X/6-31+G(d,p) level for the addition of isobutyraldehyde to N-phenylmaleimide (Scheme 5). They showed the bifunctional properties of this organocatalysts confirming that the approach of maleimide takes place by the opposite side than the enamine by formation of two hydrogen bonds of the 2-aminobenzimidazole unit with the carbonyl group (2.0 Å and 2.1 Å). An extra hydrogen bond is formed between the enamine and the sp2 N of the benzimidazole unit as occurred in the addition of isobutyraldehyde to nitrostyrene (Scheme 2). The difference in energy between TS(S) and TS(R) being 1.8 kcal/mol.

The ability of organocatalysts 6·TFA to act as chiral Brønsted acid prompted us to study the enantioselec-tive alkylation of carbon nucleophiles with benzylic alcohols. This asymmetric SN1 reaction [67–70] was previ-ously performed with benzylic alcohols and β-keto phosphonates [71] and 1,3-dicarbonyl compounds [72] by using copper(II) triflate–Box complexes as catalysts. Initial organocatalyst screening [73] was performed with hydrogen donors such as thioureas 12 and 16, 2-aminobenzimidazoles 5a, 5b, 6 and 17 in the presence of TFA for the alkylation of ethyl 2-oxocyclopentanecarboxylate with bis[4-(dimethylamino)phenyl]methanol, which is a precursor of a very stable carbenium ion (E = –7.02) [74] called Michler’s blue [75]. Only in the case of using 6·TFA as organocatalysts a moderate 33 % ee was observed (Scheme 6). Lowering the temperature to –20 °C either with TFA or TfOH the corresponding alkylated β-keto ester was obtained in 85 % and 88 % yield and in 64 % and 67 % ee, respectively.

NN

H

N

N

HN

NH

H G‡toluene = +3.6 kcal/mol

G‡toluene = –5.1 kcal/mol

H

–O O

F3C

NN

H

N

N

HN

NHH

H

+

H

–O O

F3C

O

O

+

+

NN

H

N

N

HN

NHH

H

+

H

–O O

F3C

MeO

OMeOO–

+

Malonate

Acetylacetone

∆

∆

–

Fig. 10: Different binding energies of the computed nucleophiles for mechanism B.




When other carbon nucleophiles were assayed with Mischler’s blue and 6 as organocatalyst in the pres-ence of 1 equiv. of TFA or TfOH, variable results were obtained (26–90 % ee) (Scheme 7) [73].

With respect to other benzylic alcohols only thioxanthydrol gave moderate to high enantioselectivities (18–97 % ee) (Scheme 8) [73].

In this case, the proposed mechanism is based on previous calculations performed with organocatalyst 6·TFA for the Michael addition of 1,3-dicarbonyl compounds to maleimides (Fig. 9). The bifunctional feature of 6·TFA could be explained by the formation of a intermediate B by formation of two hydrogen bonds with the β-keto ester of one of the 2-aminobenzimidazole unit and one hydrogen bond of the protonated 2-amin-obenzimidazole unit with the benzylic alcohol. After formation of the carbenium ion and therefore the cor-responding ion pair, takes place the enantioselective SN1 reaction (Fig. 11) [73].

Recently, a prolinamide 18 and a pyrrolidine 19 bearing a 2-aminobenzimidazole unit were employed as chiral organocatalysts for the conjugate addition of cyclohexanone to β-nitrostyrene affording the cor-responding adduct in 20 % and 98 % ee, respectively [75]. However, 18 has shown excellent catalytic

Me2N NMe2

OH O

CO2Et+

Catalyst (10 mol %)TFA (10 mol %)

PhMe, rt, 1 day Me2N NMe2

OCO2Et

NHNH

NNR2 NH

NR

NHN

NR

N

NHNH

SNMe2

F3C

F3C

NH HNHN

S S

NH

CF3

CF3F3C

F3C

12: 95 %, rac. 16: 90 %, 5 % ee

5a: R = H, 95 %, 2 % ee5b: R = Me, 95 %, rac.

6: R = H, 95 %, 33 % ee17: R = Me, 95 %, 8 % ee

*

Scheme 6: Organocatalyst screening for the alkylation of ethyl 2-oxocyclopentanecarboxylate with a benzylic alcohol.

R1 = Me, (CH2)4, (CH2)5

R2 = H, aryl, alkyl

NR2

O

O

(S,S)-5a

+(S,S)-5a (15 mol %)

CH2Cl2, 15 °C, 4 days

NH2

NH

R1 CHO

R1

47–99%55–89% ee

NH

N

NR2

O

OR1 R1H

O

N OOPh

NH

N N

N

HH

2.0 Å

2.1 Å2.0 Å

2.0 Å

2.1 Å

TS1-S

TS1-R

1.8 Å

2.0 Å

N OOPh

NH N N

N

H

1.8 ÅH

G‡ = +4.1 (Gas phase)+2.3 (Toluene)+0.7 (CH2Cl2)

G‡ = 0

∆∆

∆∆

Scheme 5: Conjugate addition of aldehydes to maleimides catalyzed by the primary amine-2-aminobenzimidazole (S,S)-5a.




6 (10 mol %)TFA or TfOH (10 mol %)

Me2N NMe2

OH

+

PhMe, –20 °C, 20 h Me2N NMe2

R1O

CO2R3

CO2R3

R2R1

O R2

Me2N NMe2

CO2Et

TFA: 70 % yield; 90 % ee (0 °C)

Me2N NMe2

TFA: 70 % yield; 38 % ee

CO2EtPh

O O

Me2N NMe2

Ph

O O

TfOH: 95 % yield, 87 % ee (–50 °C) TfOH: 51 % yield, 48 % ee (23 °C)

Me2N NMe2

SMe

O

Ph

O O

Scheme 7: Enantioselective alkylation of carbon nucleophiles with bis[4-(dimethylamino)-phenyl]methanol.

S

OH

S

6 (10 mol %)Acid (10 mol%)

PhMe, rt, 20 h+

TFA: 70 % yield, 18 % eeTfOH: 30 % yield, 30 % ee

O

CO2Et

O

CO2Et

S

S

O

Ph

O O

TFA: 55 % yield, 83 % eeTfOH: 69 % yield, 97 % ee

Scheme 8: Enantioselective alkylation of carbon nucleophiles with thioxanthydrol.

N

N NHN

N

N

H

O X

CF3

O

HHH

N

NN N

N

N

H

O XCF3

O

HH

H

H

R1

O

EWG

HN

NN N

N

NH

HH

H

R1

O

EWG

H

Ar Ar

O H

Ar Ar

CF3XO2

R1

O

EWG

Ar Ar

OH

Ar Ar

EWGR1

O

H2O

–

A

BC

Fig. 11: Proposed mechanism for the enantioselective SN1 reaction with benzylic alcohols.




activity in the aldol reaction much better than other related prolinamide-guanidine type derivatives 20–22 (Fig. 12) [76].

Chiral 2-aminopyrimidinesThe development of rigid guanidine-type hydrogen bonding bifunctional organocatalysts move us to design 2-aminopyrimidines bonded to trans-cyclohexane-1,2-diamines as a chiral scaffold. We have synthesized two type of 2-aminopyrimidine organocatalysts 7 [77] and 8 [78] in order to study their catalytic activity in aldol reactions and in conjugate additions, respectively (Fig. 1). Diastereomeric prolinamides 7a and 7b were prepared by reaction of N-Boc protected (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine with 2-chloropyrimi-dine followed by Boc-deprotection. Subsequent amidation with N-Boc-(S)-proline in the presence of ethyl chloroformate and final N-Boc deprotection provide these prolinamide-pyrimidines in 40 % overall yield (Scheme 9) [77].

As a benchmark reaction cyclohexanone was allowed to react with 4-nitrobenzaldehyde. This direct aldol reaction was performed under solvent-free conditions [79] in the presence of hexanedioic acid (HDA, 10 mol %) as cocatalyst. 12 equiv. of H2O at 10 °C during 1 day. Both organocatalysts 7a and 7b (10 mol %) gave the corresponding aldol in similar yields and diastereomeric ratios, being 7b (97 % ee) slightly better than 7a (90 % ee) (Scheme 10). Therefore, the absolute configuration of the aldol was determined mainly by the prolinamide unit. For the recovery of catalyst 7b the reaction was scaled up to 1 g scale giving, after extractive work-up with 2 M NaOH, the aldol in 51/1 anti/syn ratio and the anti isomer in 95 % ee and the organocatalysts in 87 % yield were isolated [77].

NH

O

HN

HN

N

18

NH HN

HN

N

19

NH

O

HN

NH2

NH

20

NH

O

HN

HN

N

21

Fig. 12: Proline-guanidine type organocatalysts.

NH2BocHN

(R,R)

NH2BocHN

(S,S)

1. 2-chloropyrimidine2. TFA3.4. TFA

Boc-L-Pro, ClCO2Et

HNHN

(R,R)-Pyr-L-Pro

N

N

ONH

40 %

HNHNN

N

ONH

(S,S)-Pyr-L-Pro

b7a7

Scheme 9: Synthesis of prolinamide-pyrimidine organocatalysts 7.




The scope of the intermolecular aldol reaction was studied with organocatalyst 7b using different ketones as donors and aldehydes as acceptors obtaining the aldols in 56–99 % regioselectivity range, 72–96 % anti/syn-diastereoselectivity and 86–99 % enantioselectivity (Scheme 11). The selected example is, the protected D-erythro-pentos-4-ulose (68 % yield, 90 % de, 89 % eeanti) obtained from protected 1,3-dihydroxyacetone and 2,2-dimethoxyacetaldehyde in better yield and enantioselectivity than with L-Pro under the same reaction conditions (47 %, 90 % de, 83 % ee) [77].

From DFT calculations the distances between the two hydrogens in the 2-aminopyrimidine unit are variable in the range of 2.1–3.0 Å. Calculations for the reaction of cyclohexanone with 4-nitrobenzaldehyde, in order to obtain insight about the mechanism and the origin of the enantioselectivity with both catalysts, were designed. Geometry optimization was performed at the B3LYP/6-31+G∗∗ level of theory [80–82] in a solvent model system (CPCM, water as solvent) [83, 84]. Single point energies were obtained for the opti-mized structures at the M06-2X/6-311+G∗∗ level [85]. The computed Ha–O and Hc–O bond distances (1.8 Å and 1.6 Å, respectively) are very similar in both structures TSA-anti and TSA-syn for enamine A formed with organocatalysts 7a (Fig. 13). The difference in energy is 0.7 or 2.7 kcal/mol depending on the compu-tational model, M06-2X/6-311+G∗∗ M06-2X/6-311+G∗∗ or B3LYP, respectively. In the case of enamine B formed with organocatalyst 7b a different orientation of the NH groups was observed, being Ha and Hb better suited for carbonyl activation by hydrogen bonding than Ha and Hc. In this case, the energy difference is significantly increased to 4.4 and 7.7 kcal/mol. In the late case the 2-aminopyrimidine unit forms only one hydrogen bond [77].

For the intramolecular aldol Hajos–Parrish–Eder–Sauer–Weichert (HPESW) reaction, the Wieland–Mischer ketone, a valuable intermediate for steroid synthesis, was prepared using both diastereomeric organocatalysts 7 under solvent-free conditions (Scheme 12) [77]. The enantioselectivity was slightly better with 7a (89 %) than with 7b (86 %) and shorter reaction time was observed (10 h towards 20 h). In this case, 7a was recovered in 79 % yield after extractive work-up. Another examples of this HPESW reaction by using organocatalyst 7a are shown in Scheme 12.

7a7b

7 (10 mol %)HDA (10 mol %)

H2O (12 eq)10 °C, 1 day

O

+O2N

CHOO OH

NO2

HNHNN

N

ONH

HNHNN

N

ONH

yield: 89 %dr: 96:4eeanti: 97 %

yield: 88 %dr: 95:5eeanti: 90 %

Scheme 10: Intermolecular direct aldol reaction organocatalyzed by 7a and 7b.

+O

R

O

H

7b (10 mol %)

X′

+O

R

OH

X

anti iso

Regioselectivity: 56–99 %

Diastereoselectivityanti/syn: 72–96 %

Enantioselectivity: 86–99 %

O

R

OH

X′

+

syn

O

R

OH

X′

HDA (10 mol %)

X X X (X′ = H)H2O (12 eq)

10 °C, 3–48 h

HNHN

7b

N

N

ONH

Scheme 11: Intermolecular aldol reaction with organocatalyst 7b.




The primary amine-2-aminopyrimidine organocatalysts 8, prepared according to the procedure described in Scheme 9 in 65 % yield, were assayed in the conjugate addition of aldehydes to maleimides. For the optimi-zation of the reaction conditions the addition of isobutyraldehyde to N-phenylmaleimide was chosen as the benchmark reaction. It was found that aqueous DMF at 0 °C gave the corresponding enantiomeric adducts in 83 % yield and 88 % ee by using the (R,R)-8 or the (S,S)-8 (10 mol %) and HDA (10 mol %) as a co-catalyst.

NN

N

NN

HH

H

O

+

Enamine Acycloxenanone + 7a

N N

O

H

N

O

N

NHa Hc

Hb

O2N

N N

O

N

O

N

NHa Hc

H

Hb

NO2

+ +O

C6H4-NO2

OH O

C6H4-NO2

OH

TSA-antiG = 0

TSA-synG = +0.7 (+2.7)

NN

N

NN

HH

H

O

+

Enamine Bcyclohexanone + 7b

O

H

N

O

N NN

N

HaHb

Hc

N

O

N NN

N

HaHb

Hc

O

H

NO2O2N

++

O

C6H4-NO2

OH O

C6H4-NO2

OH

TSB-antiG = 0

TSB-synG = +4.4

∆∆

∆∆

Fig. 13: Transition states for the aldol reaction of cyclohexanone with 4-nitrobenzaldehyde organocatalyzed by 7a and 7b.

Me

O O

Wieland-Miescher ketone

O

O

MeO

7 (10 % mol)

HDA (10 % mol)

25 °C

HNHN

7a

N

N

ONH

HNHNN

N

ONH

7b

10 hyield: 92 %ee: 89 %

20 hyield: 90 %ee: 86 %

O

yield: 77 %ee: 84 %

O

OPh

O

O

yield: 53 %ee: 77 %

yield: 80 %ee: 79 %

O

Scheme 12: Intramolecular aldol reactions with organocatalysts 7.




The scope of the reaction was studied with different aldehydes and maleimides affording the resulting suc-cinimides in 70–92 % yield and 78–93 % ee (Scheme 13) [78]. These results were better than those results with (S,S)-5a (Scheme 5).

For the DFT calculations, the structures were initially optimized by using density functional theory (DFT) with the B3LYP [80–82] as implemented in Gaussian 09, combined with the 6-31G∗∗ basis set. Further re-optimization at M06-2X/6-311++G∗∗ level of theory [83] were carried out, including polarization functions for a better description of the hydrogen bond activations. It was found that no internal hydrogen bonds are taking place in this conjugate addition due to the use of aqueous solvents. Furthermore, a number of transition states lacking any internal H-bond were located, and the two lowest in energy among them, are shown in Fig. 4. Both structures lead to the formation of the R-enantiomer. Their charge separation (developing negative charge in the carbonyl oxygen and positive in the enamine-nitrogen) is very high, inducing a polar structure, that would be better stabilized in polar solvents. The energy differences between gas phase and water, ca. 2 kcal/mol, are significant and could justify an increase reactivity of around two orders of magnitude. Also, the two values for TS-R1 are lower than the corresponding values for TS-R2, indicating that the former is oper-ative in the mechanism leading to the R-enantiomer. Thus, in this case the 2-aminopyrimidine unit shows only steric hindrance in the transition state (Fig. 14) [78].

R2 CHO

R1

+ N

O

O

R3(S,S)-8 (10 mol %)

HDA (10 mol %)DMF:H2O (2:1), 0 °C

N

O

O

R3

OHC

R1 R2

N

O

O

HOHC

Me Me

72 h, 76 %, 76 % ee

N

O

O

4-BrC6H4OHC

Me Me

72 h, 70 %, 87 % ee

N

O

O

3-ClC6H4OHC

Me Me

60 h, 92 %, 87 % ee

N

O

O

4-ClC6H4OHC

Me Me

70 h, 87 %, 86 % ee

N

O

O

PhOHC

72 h, 84 %, 89 % ee

N

O

O

PhOHC

60 h, 89 %, 93 % ee

N

O

O

BnOHC

Me Me

48 h, 90 %, 82 % ee

N

O

O

MeOHC

Me Me

60 h, 83 %, 76 % ee

N

O

O

PhOHC

Me

72 h, 2:1 dr, 49 %, 72 %:60 % ee

N

O

O

PhOHC

Me Ph

72 h, dr: 6/1, 72 %, 81 % ee

NH2

N

HN

N

(S,S)-8

Scheme 13: Conjugate addition of aldehydes to maleimides organocatalyzed by the primary amine-2-aminopyrimidine (S,S)-8.

NN

PhN

O

O

TS-R2

Maleimide pro-R approachgas phase: 18.3 kcal/mol

water: 16.2 kcal/mol

HR

N

NN

H

NH

TS-R1

Maleimide pro-R face approachgas phase: 17.2 kcal/mol

water: 15.4 kcal/mol

RPhN

O

O

N

N

Polar TSwater solvated

H

δ–

δ+

δ–

Fig. 14: Computed activation energies for the transition states TS-R1 and TS-R2 in the gas phase and water models for the addi-tion of isobutyraldehyde to N-phenylmaleimide organocatalyzed by (S,S)-5a.




ConclusionsThe 2-aminobenzimidazole unit has shown excellent dual hydrogen bonding capability as a Brønsted base. In the case of enantio-catalyzed conjugate additions or SN1 reactions, the 1,3-dicarbonyl compound is depro-tonated by this 2-aminobenzimidazole fragment. With respect to the electrophile, for the conjugate addition to nitroalkenes, the protonated dimethylamino unit forms a hydrogen bond with the nitro group, in the case of maleimides a hydrogen bond is formed with the protonated 2-aminobenzimidazole unit. For the SN1 reac-tion the protonated 2-aminobenzimidazole unit could form the corresponding benzylic carbocation acting as a Brønsted acid. According to the calculations the conjugate addition of aldehydes to nitroalkenes and maleimides takes place by enamine formation and double hydrogen bonding with the Michael acceptor by the 2-aminobenzimidazole unit. However, in the case of the aldol reaction organocatalyzed by 2-aminopy-rimidine prolinamides the activation of the aldehyde acceptor occurs by formation of one hydrogen bond from the protonated prymidine and the other from the prolinamide. However, the 2-aminopyrimidine unit in the enantio-catalyzed conjugate addition of aldehydes to maleimides, no hydrogen bonds were observed acting as a face blocking group in the TS. The presence of the chiral trans-cyclohexane-1,2-diamine scaffold controls the enantioselectivity of all the described processes.

Acknowledgments: The Spanish Ministerio de Ciencia e Innovación (MICINN) (projects CTQ2010-20387, and Consolider Ingenio 2010, CSD2007-00006), the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), FEDER, the Generalitat Valenciana (PROMETEO 2009/039 and PROMETEOII/2014/017), the Basque Government (GV Grant IT-291-07), the FP7 Marie Curie Actions of the European Commission via the ITN ECHONET network (MCITN-2012-316379) and the Universities of Alicante and Basque Country are gratefully acknowledged for financial support. We also thank for techni-cal and human support provided by IZO-SGI SGIker of UPV-EHU and European funding (ERDF and ESF). We thank all the collaborators that have participate in this subject.

References[1] M. S. Taylor, E. N. Jacobsen. Angew. Chem. Int. Ed. 45, 1520 (2006).[2] X. Xu, W. Wang. Chem. Asian J. 3, 516 (2008).[3] M. Petri, M. Pihko (Eds.). Hydrogen Bonding in Organic Synthesis, Wiley-VCH, Weiheim (2009).[4] K. Maruoka (Ed.). Science of Synthesis, Asymmetric Organocatalysis 2, Brønsted Base and Acid Catalysts, and Additional

Topics, Thieme, Stuttgart (2012).[5] L. Albrecht, H. Jiang, K. A. Jørgensen. Chem. Eur. J. 20, 358 (2014).[6] C. L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang. Org. Lett. 8, 2401 (2006).[7] Y.-J. Cao, H.-H. Lu, Y.-Y. Lai, L.-Q. Lu, W.-J. Xiao. Synthesis 3795 (2006).[8] Y.-J. Cao, Y.-Y. Lai, X. Wang, Y.-J. Li. W.-J. Xiao. Tetrahedron Lett. 48, 21 (2007).[9] T. Okino, Y. Hoashi, Y. Takemoto. J. Am. Chem. Soc. 125, 12672 (2003).

[10] T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto. J. Am. Chem. Soc. 127, 119 (2005).[11] For a review, see: O. V. Serdyuk, C. M. Heckel, S. S. Tsogoeva. Org. Biomol. Chem. 11, 7051 (2013).[12] A. G. Doyle, E. N. Jacobsen. Chem. Rev. 107, 5713 (2007).[13] R. Chinchilla, C. Nájera, P. Sánchez-Agulló. Tetrahedron: Asymmetry 5, 1393 (1994).[14] E. J. Corey, H. J. Grogan. Org. Lett. 1, 157 (1999).[15] T. Ishikawa, T. Isobe. Chem. Eur. J. 8, 553 (2002).[16] D. Leow, C.-H. Tan, Synlett 1589 (2010).[17] T. Ishikawa. Chem. Pharm. Bull. 58, 1555 (2010).[18] K. Nagasawa, Y. Sohtome. Science of Synthesis, Asymmetric Organocatalysis 2, Brønsted Base and Acid Catalysts, and

Additional Topics, K. Maruoka (Ed.), Thieme, Stuttgart (2012).[19] P. Selig. Synthesis 45, 703 (2013).[20] A. Ávila, R. Chinchilla, C. Nájera. Tetrahedron: Asymmetry 23, 1625 (2012).[21] A. Ávila, R. Chinchilla, E. Gómez-Bengoa, C. Nájera. Eur. J. Org. Chem. 5085 (2013).[22] A. Ávila, R. Chinchilla, B. Fiser, E. Gómez-Bengoa, C. Nájera. Tetrahedron: Asymmetry 25, 462 (2014).[23] D. Uraguchi, Y. Ueki, T. Ooi. J. Am. Chem. Soc. 130, 14088 (2008).[24] D. Uraguchi, Y. Ueki, T. Ooi. Science 326, 120 (2009).




[25] D. Uraguchi, D. Nakashima, T. Ooi. J. Am. Chem. Soc. 131, 7242 (2009).[26] M. Ganesh, D. Seidel. J. Am. Chem. Soc. 130, 16464 (2008).[27] J. P. Malerich, K. Hagihara, V. H. Rawal. J. Am. Chem. Soc. 130, 14416 (2008).[28] Y. Zhu, J. P. Malerich, V. H. Rawal. Angew. Chem. Int. Ed. 49, 153 (2010).[29] W. Zhuang, T. B. Poulsen, K. A. Jørgensen. Org. Biomol. Chem. 3, 3284 (2005).[30] T. Schuster, M. Kurz, M. W. Göbel. J. Org. Chem. 65, 1697 (2000).[31] B. M. Nugent, R. A. Yoder, J. N. Johnston. J. Am. Chem. Soc. 126, 3418 (2004).[32] Z. Tang, L.-F. Cun, X. Cui, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong. Org. Lett. 8, 1263 (2006).[33] N. Takenaka, R. S. Sarangthem, S. K. Seerla. Org. Lett. 9, 2819 (2007).[34] A. Singh, R. A. Yoder, B. Shen, J. N. Johnston. J. Am. Chem. Soc. 129, 3466 (2007).[35] A. Singh, J. N. Johnston. J. Am. Chem. Soc. 130, 5866 (2008).[36] A. S. Hess, R. A. Yoder, J. N. Johnston. Synlett 147 (2006).[37] T. Inokuma, M. Furukawa, T. Uno, Y. Suzuki, K. Yoshida, Y. Yano, K. Matsuzaki, Y. Takemoto. Chem. Eur. J. 17, 10470 (2011).[38] Y. Kobayashi, Y. Taniguchi, N. Hayama, T. Inokuma, Y. Takemoto. Angew. Chem. Int. Ed. 52, 11114 (2013).[39] U. Scheffer, A. Strick, V. Ludwig, S. Peter, E. Kalden, M. W. Göbel. J. Am. Chem. Soc. 127, 2211 (2005).[40] F. M. Muñiz, V. Alcázar, F. Sanz, L. Simón, A. L. Fuentes de Arriba, C. Raposo, J. R. Morán. Eur. J. Org. Chem. 6179 (2010).[41] F. Janssens, J. Torremans, M. Janssen, R. A. Stok-Broekx, M. Luyckx, P. A. Janssen. J. Med. Chem. 28, 1925 (1985).[42] W. Nawrocka. Bull. Chim. Farm. 135, 18 (1996).[43] P. Winstanley. Lancet 352, 1080 (1998).[44] A. Carpio, J. Neurol., Neurosurg. Psychiatry 66, 411 (1999).[45] R. J. Snow, M. G. Cardozo, T. M. Morwick, C. A. Busacca, Y. Dong, R. J. Eckner, S. Jacober, S. Jakes, S. Kapadia, S. Lukas,

M. Panzenbeck, G. W. Peet, J. D. Peterson, A. S. Prokopowicz, III, R. Sellati, R. M. Tolbert, M. A. Tschantz, N. Moss. J. Med. Chem. 45, 3394 (2002).

[46] A. Kling, G. Backfisch, J. Delzer, H. Geneste, C. Graef, W. Hornberger, U. Lange, A. Lauterbach, W. Seitz, T. Subkowski. Biorg. Med. Chem. 11, 1319 (2003).

[47] C. G. O’Neill, D. Slipetz, J. Wang. Biorg. Med. Chem. Lett. 14, 3195 (2004).[48] For a review on chiral benzimidazoles, see: C. Nájera, M. Yus. Tetrahedron Lett. 56, 2623 (2015).[49] D. Almaşi, D. A. Alonso, E. Gómez-Bengoa, C. Nájera. J. Org. Chem. 74, 6163 (2009).[50] A. Hamza, G. Schubert, I. Pápai. J. Am. Chem. Soc. 128, 13151 (2006).[51] L. Zhang, M.-M. Lee, S.-M. Lie, J. Lee, M. Cheng, B.-S. Jeong, H.-g. Park, S.-s. Jew. Adv. Synth. Catal. 351, 3063 (2009).[52] M. Lee, L. Zhang, Y. Park, H.-g. Park. Tetrahedron 68, 1452 (2012).[53] P. Trillo, M. Gómez-Martínez, D. A. Alonso, A. Baeza. Synlett 26, 95 (2015).[54] T. de A. Fernandes, P. Vizcaíno-Milla, J. M. J. M. Ravasco, A. Ortega-Martínez, J. M. Sansano, C. Nájera, P. R. R. Costa, B.

Fiser, E. Gómez-Bengoa. Tetrahedron: Asymmetry 27, 118 (2016).[55] For a recent review, see: P. Chauhan, J. Kaur, S. S. Chimni. Chem. Asian J. 8, 328 (2013).[56] A. Fredenhagen, S. Y. Tamura, P. T. M. Kenny, H. Komura, Y. Naya, K. Nakanishi, K. Nishiyama, M. Sugiura, H. Kita. J. Am.

Chem. Soc. 109, 4409 (1987).[57] C. Malochet-Grivois, C. Roussakis, N. Robillard, J. F. Biard, D. Riou, C. Debitus, J. F. Verbist. Anti-Cancer Drug Des. 7, 493

(1992).[58] Y. Ando, E. Fuse, W. D. Figg. Clin. Cancer Res. 8, 1964 (2002).[59] C. Freiberg, N. A. Brunner, G. Schiffer, T. Lampe, M. Polmann, D. Habich, K. Ziegelbauer. J. Biol. Chem. 279, 26066 (2004).[60] M. Isaka, N. Rugseree, P. Maithip, P. Kongsaeree, S. Prabpai, Y. Thebtaranonth. Tetrahedron 61, 5547 (2005).[61] J. Uddin, K. Ueda, E. R. O. Siwu, M. Kita, D. Uemura. Biorg. Med. Chem. 14, 6954 (2006).[62] For selected examples, see: E. J. Yoo, M. Wasa, J.-Q. Yu. J. Am. Chem. Soc. 132, 17378 (2010).[63] S. Das, D. Addis, L. R. Knöpke, U. Bentrup, K. Junge, A. Brückner, M. Beller. Angew. Chem. Int. Ed. 50, 9180 (2011).[64] E. Gómez-Torres, D. A. Alonso, E. Gómez-Bengoa, C. Nájera. Org. Lett. 13, 6106 (2011).[65] E. Gómez-Torres, D. A. Alonso, E. Gómez-Bengoa, C. Nájera. Eur. J. Org. Chem. 1434 (2013).[66] D. Almaşi. PhD Thesis, University of Alicante (2009).[67] J. Muzart. Eur. J. Org. Chem. 2007, 3077 (2007).[68] E. Emer, R. Sinisi, M. Guiteras-Capdevilla, D. Petruzzielo, F. DeVicentis, P. G. Cozzi. Eur. J. Org. Chem. 2011, 647 (2011).[69] B. Biannic, A. Aponick. Eur. J. Org. Chem. 3605 (2011).[70] A. Baeza, C. Nájera. Synthesis 46, 25 (2014).[71] M. Shibata, M. Ikeda, K. Muyoyama, Y. Miyake, Y. Nishibayashi. Chem. Commun. 48, 9528 (2012).[72] P. Trillo, A. Baeza, C. Nájera. Adv. Synth. Catal. 355, 2815 (2013).[73] P. Trillo, A. Baeza, C. Nájera. Synthesis 46, 3399 (2014).[74] Electrophilicity parameter in Mayr’s scales: S. Minegishi, H. Mayr. J. Am. Chem. Soc. 125, 286 (2003).[75] J. Lin, H. Tian, Y.-J. Jiang, W.-B. Huang, L.-Y. Zheng, S.-Q. Zhang. Tetrahedron: Asymmetry 22, 1434 (2011).[76] G. Tang, U. Gün, H.-J. Altenbach. Tetrahedron 68, 10230 (2012).[77] P. Vizcaíno-Milla, J. M. Sansano, C. Nájera, B. Fiser, E. Gómez-Bengoa. Eur. J. Org. Chem. 2614 (2015).[78] P. Vizcaíno-Milla, J. M. Sansano, C. Nájera, B. Fiser, E. Gómez-Bengoa. Synthesis 47, 2199 (2015).




[79] A. Bañón-Caballero, G. Guillena, C. Nájera. Mini-Rev. Org. Chem. 11, 118 (2014).[80] C. Lee, W. Yang, R. G. Parr. Phys. Rev. B 37, 785 (1988).[81] A. D. Becke. J. Chem. Phys. 98, 5648 (1993).[82] W. Kohn, A. D. Becke, R. G. Parr. J. Phys. Chem. 100, 12974 (1996).[83] E. Cancés, B. Mennucci, J. Tomasi. J. Chem. Phys. 107, 3032 (1997).[84] J. Tomasi, B. Mennucci, E. Cancés. J. Mol. Struct.: THEOCHEM 464, 211 (1999).[85] Y. Zhao, D. G. Truhlar. Theor. Chem. Acc. 120, 215 (2008).



carmen nájera*, josé miguel sansano and enrique gómez...

Documents