Organocatalytic Enantioselective Henry Reactions

Abstract

A large number of interesting organocatalytic enantioselective protocols have been explored and successfully applied in the last decade. Among them, the Henry (nitroaldol) reaction represents a powerful carbon-carbon bond-forming procedure for the preparation of valuable synthetic intermediates, such as enantioenriched nitro alcohols, which can be further transformed in a number of important nitrogen and oxygen-containing compounds. This area of research is still in expansion and a more complex version of this useful process has recently emerged, the domino Michael/Henry protocol, affording highly functionalized cycles with multiple stereogenic centers.

1. Introduction

The reaction between an in situ generated nitronate species and a carbonyl compound, known as Henry (nitroaldol) reaction, is an important carbon-carbon bond-forming method in organic synthesis [1]. This process represents a powerful and useful tool for the synthesis of valuable β-nitroalcohols [2], providing, after further transformation of the β-nitroalcohols, efficient access to interesting and highly functionalized intermediates like nitroalkenes, 1,2-amino alcohols and α-hydroxy carboxylic acids [3,4].

In the last decade a new discipline: asymmetric organocatalysis, has attracted much attention by many research groups [5,6,7]. Very interesting progresses have been achieved in this intriguing area, with the development of an incredible number of new processes, such as epoxidations [8], reductions [9], aza-Henry [10], Morita-Baylis-Hillman [11], aldol reaction [12], Pudovick [13], Strecker [14], Friedel-Crafts [15,16], Michael addition [17,18,19,20,21], Diels-Alder [22], and Mannich reactions [23]. In the context of this novel field, appealing advances have been also accomplished in the enantioselective synthesis of very complex molecules [24,25].

The Henry reaction may be promoted under many different conditions and using diverse catalytic systems providing from moderate-to-good enantioselectivities. This review will focus on the current progress of the Henry reaction in the field of asymmetric organocatalysis. The most significant contributions since 2007 will be discussed and illustrated, since earlier examples have been extensively reported in other main works dedicated to this process [26,27], although in some cases references to the pioneering models will be necessary.

2. Enantioselective Henry Reaction with Aldehydes

In spite of the significant importance of controlling the absolute stereochemistry in the final Henry adducts, limited organocatalytic methods have been reported so far in the literature for this purpose, and the reaction still presents some limitations. Among the key catalysts used with this aim we can find Cinchona alkaloids, phase transfer catalysts, thioureas and guanidines.

The first organocatalytic enantioselective example of this reaction was published in 1994 by Nájera et al. [28]. They used enantiomerically pure guanidines 1 and 2 as catalysts, affording enantiomeric excess up to 54%. Following this report, many efforts have been initiated and different kinds of organocatalysts have been designed in order to improve those pioneering results (Figure 1). In this context, further chiral guanidines were developed, such as guanidinium salt 3 synthesized by Murphy et al. [29], however lower enantiomeric excesses were obtained in comparison with those previously reported and catalyst 4 used in a diastereoselective Henry reaction [30]. Moreover, in 2005, Nawasaga et al. [31,32,33,34] developed the novel bifunctional catalyst 5 bearing guanidine and thiourea moieties in the same skeleton. Compound 5 catalyzed the reaction of nitromethane with α-branched aldehydes reaching enantioselectivities up to 88%, although the induction was lower in the case of unbranched aldehydes (55% ee) [31]. The use of KI in the reaction seemed to be crucial for the inhibition of the retro-nitroaldol reaction observed by the authors, and the achievement of better values of enantioselectivity.

In addition, the same authors extended the application of guanidine 5 as catalyst to a variety of nitroalkanes with different aldehydes, obtaining high syn diastereoselectivities and enantioselectivities (

Table 1. Enantio- and syn-selective Henry reaction of aldehydes with nitroalkanes in presence of catalyst 5.

R1	R2	KOH (mol%)	Time (h)	Yield (%)	syn:anti	ee (syn) (%)
CH3(CH2)2	CH3(CH2)2NO2	5	48	63	90:10	85
CH3(CH2)2	TBSO(CH2)2NO2	3	48	51	97:3	87
CH3(CH2)2	TIPSO(CH2)2NO2	3	24	58	92:8	87
CH3(CH2)2	PhCH2NO2	10	24	70	91:9	87
c-C6H11	CH3(CH2)2NO2	5	40	61	99:1	95
c-C6H11	TBSO(CH2)2NO2	7	48	63	99:1	90
c-C6H11	TIPSO(CH2)2NO2	6	48	60	99:1	90
c-C6H11	PhCH2NO2	7	48	67	99:1	95

) [33,34].

In order to explain the major syn selectivity obtained in the final products of this reaction, the authors suggested three plausible transition states (TSI-TSIII) (Figure 2). Among them, the anti, anti-conformational transition state TSI (nitro group and R₁ are in an anti relationship, carbonyl group and R₂ are anti), is considered to be more favorable since it avoids steric repulsion [33,34].

The synthetic utility of this methodology was demonstrated by the straightforward synthesis of (4S,5R)-epi-cytoxazone (Scheme 1) and cytoxazone [33,34].

More recently, Terada et al. [35] designed novel axially chiral guanidine bases and applied them as efficient chiral Brønsted base catalysts in the Henry reaction between nitroalkanes and aldehydes (Scheme 2 and

Table 2. Henry reaction of nitroethane with aldehydes catalyzed by guanidine 6.

R	Yield (%)	anti:syn	ee (anti) (%)	ee (syn) (%)
	72	79:21	78	87
	56	76:24	81	89
	75	94:6	69	74
	81	80:20	58	57
	66	87:13	56	10

). After an extensive screening of promising catalyst structures, catalyst 6, having 3,5-bis(trifluoromethyl)phenyl groups introduced in the 3,3′-positions of the binaphthyl backbone, was found to be the best in terms of both enantioselectivity and catalytic activity.

On the basis of these experimental results, the activation was envisioned to occur between the nitronate specie and the chiral guanidinium ion through the two hydrogen bonds as shown in Figure 3.

In agreement with the anti selectivity observed by the authors in the final adducts, the transition state is assumed to proceed through an acyclic extended transition state, where the substituents in the nitronate ion and in the aldehyde would be orientated in order to avoid unfavorable steric interactions. The substituents in the 3,3′-positions would drive the appropriate attack of the aldehyde by its si-face affording the established (S)-configuration.

Furthermore, the N-spiro C₂-symmetric chiral quaternary ammonium bifluoride 7 was successfully applied by Maruoka et al. as efficient phase transfer catalyst in the reaction of silyl nitronates with aldehydes (Figure 4) [36].

In addition, cinchona alkaloid derivatives have been also used as suitable asymmetric catalysts in the Henry reaction (Figure 4). Hiemstra et al. reported moderate results with the bifunctional estructure 8a [37]. Later, they found that the replacement of the phenol moiety on compound 8a with a better hydrogen bond donor, such as a thiourea moiety, resulted in a more powerful catalyst 9 [38]. In fact, this organocatalyst promoted the direct enantioselective nitroaldol reaction of aromatic and heteroaromatic aldehydes with nitromethane with very good yields and enantioselectivities, improving the results obtained previously with catalyst 8a.

The thiourea moiety is also present in the catalyst (10) designed by Shi et al. in 2007 (Scheme 3) [39]. The used of this axially chiral bis(arylthiourea)-based organocatalyst in the enantioselective Henry reaction of aromatic aldehydes with nitromethane provided the corresponding adducts with good yields and moderate enantioselectivities.

3. Enantioselective Henry Reaction with Ketones

The use of ketones as suitable substrates for this reaction has been less well explored compared to the use of aldehydes, perhaps due to the lesser reactivity shown by ketones. However, the obtainment of tetrasubstituted chiral carbons is, in general, a demanding task in organic chemistry [40]. Additionally, the preparation of chiral tertiary alcohols is potentially attractive for the synthesis of medicinal targets [41]. For these reasons, it remains a challenge in synthetic chemistry, and a few examples concerning this interesting area will be detailed below.

3.1. Henry Reaction with α-Ketoesters

In 2007, Deng et al. [42] described the first efficient organocatalytic enantioselective nitroaldol reaction with α-ketoesters (Scheme 4). In this case, C6′-OH cinchona alkaloids 11a and 11b were used as catalysts, obtaining very good results at low temperature.

After this pioneering example, Nagasawa’s group [43] explored the same asymmetric nitroaldol reaction of α-ketoesters using guanidine−thiourea bifunctional organocatalyst 5 at temperatures below the freezing point of water. Various cyclic, branched-type and linear α-ketoesters, afforded chiral tert-nitroaldols with very good enantioselectivities and moderate yields (Scheme 5).

The authors invoked a transition state based on a bifunctional mode of action of the catalyst to explain the absolute stereochemistry observed in the final products (Figure 5). In this plausible transition state, the larger substituents belonging to the nitronate ion and the α-ketoester are preferentially placed in an anti-relationship in order to minimize steric repulsion.

3.2. Henry Reaction with α-Ketophosphonates

Zhao et al. [44] carried out the first organocatalytic highly enantioselective nitroaldol reaction of α-ketophosphonates and nitromethane using cupreine (12) or 9-O-benzylcupreine (8b) as catalysts at a low catalyst loading (5 mol%) (Scheme 6). The resulting α-hydroxy-β-nitrophosphonates, obtained with good yields and excellent enantioselectivities, were transformed in β-amino-α-hydroxyphosphonates without loss of the enantioselectivity.

Later, Hu et al. [45] reported the secondary amine amide 13 as efficient catalyst in the asymmetric Henry reaction of α-ketophosphonates (Scheme 7). Excellent enantioselectivities and moderate-to-high yields were achieved for a variety of α-ketophosphonates using a low catalyst loading (5 mol%). Preliminary theoretical calculations supported hydrogen-bond interactions between catalyst 13 and the substrates, which could be crucial for the reactivity and enantioselectivity of this process.

3.3. Henry Reaction with Fluoromethylketones

The first organocatalytic enantioselective nitroaldol reaction of fluoromethylketones was described in 2008 by Umani-Rochi et al. (Scheme 8) [46]. They used as catalyst the novel cupreine derivative 14 bearing electron-withdrawing groups in the benzoyl moiety. The corresponding fluorinated β-nitroalcohol adducts were isolated with high yield and excellent enantiomeric excesses, using aromatic and aliphatic substrates and being tolerant to different electronic groups.

4. Enantioselective Domino Michael/Henry Reactions

During the last decade, the design of more complex processes and structures has become a significant synthetic challenge in organic chemistry. In this sense, great efforts have been motivated in the discovery of new multicomponent [47,48], and domino reactions [49,50,51], which lead to highly functionalized molecules with multiple stereogenic centers. The importance of this protocol relies on the synthesis of valuable chiral building blocks, which are motifs present in biologically active compounds.

4.1. Aminocatalysis

The first example of this combined process was reported in 2007 by Hayashi et al. They developed a highly diastereo- and enantioselective tandem Michael/Henry reaction catalyzed by diphenylprolinol silyl ether 15 (Scheme 9) [52]. They obtained very good results in terms of both enantio- and diastereoselectivity and moderate yields in a single step involving several 2-substituted nitroalkenes and pentane-1,5-dial. This procedure renders substituted chiral nitrocyclohexanecarbaldehydes derivatives with control of four stereogenic centers with the formation of two carbon-carbon bonds.

The formation of the final adducts can be explained by the mechanistic hypothesis proposed in Scheme 10, where, after the first Michael addition reaction via enamine activation, an intramolecular Henry reaction occurs affording final cyclic products with four stereogenic centers.

Concurrently, Jørgensen et al. [53] developed the Michael addition of dinitroalkanes to α,β-unsaturated aldehydes followed by an intramolecular Henry reaction using catalyst 16 (

Table 3. Scope of the organocatalytic nitro-Michael/Henry reaction catalyzed by chiral secondary amine 16.

R1	R2	Yield (%)	dr	ee (%)
Et		45	4:2:1	90
Me		43	4:1:1	75
n-Pr		44	4:2:1	86
i-Pr		38	3:1:1	90
n-Bu		43	4:2:1	87
CH2OTIPS		56	3:1:0	94
cis-C6H11		52	4:2:1	86
C7H16		50	4:2:1	87
Et		48	4:2:1	92
i-Pr		53	5:1:1	89
i-Pr		65	12:2:3	90
i-Pr		48	5:2:1	90
i-Pr		40	5:1:1.2	84
i-Pr		47	5:1:1	88
i-Pr		61	5:0:1	88
Et		60	4:2:1	86
i-Pr		43	6:1:0	88
Et		42	4:0:1	80
i-Pr		43	5:1:1	90

). This was the first example of one-pot asymmetric formation of five contiguous streocenters by an intermolecular two-component reaction. The final pentasubstituted cyclohexanols were furnished with moderate-to-good yields and high diastereo- and enantioselectivities.

In this case, the first step would be the Michael addition reaction of the deprotonated nitroalkane over an iminium ion resulted from the initial activation of the α,β-unsaturated aldehyde with the catalyst, followed by an intramolecular Henry reaction to render the final nitroalcohol derivatives with very good enantioselectivity (Scheme 11).

More recently, Ruano, Alemán et al. [54] have shown that the appropriate combination of two catalysts, diarylprolinol silyl ether 16 and TBAF, in a one-pot process resulted in an effective synthesis of cyclohexanes with five chiral centers starting from α,β-unsaturated aldehydes, β-dicarbonyl compounds and nitromethane (Scheme 12).

The authors invoked a complex mechanism formed by three cycles in order to explain the formation of the highly functionalized cyclohexane adducts (Scheme 13). The first cycle would be a Michael addition reaction over the activated α,β-unsaturated aldehydes. The second one would be an intermolecular Henry reaction, and the third one an intramolecular Henry reaction, closing the cycle and furnishing the final product with excellent enantioselectivity.

In order to synthesize interesting chromene derivatives, Xu et al. applied this tandem methodology using the chiral secondary amine organocatalyst 17 with salicylaldehydes and β-nitrostyrenes via a domino oxa-Michael/Henry reaction (Scheme 14) [55]. The mechanism proposed by the authors explains the isolated final adducts. It involves a first oxa-Michael reaction followed by an intramolecular Henry attack to the activated iminium ion, thus, the elimination of the catalyst closes the catalytic cycle (Scheme 15). This work represents the first example of the activation of aromatic aldehydes involving an iminium ion.

Very recently, Hong et al. discovered an unprecedented asymmetric domino Michael/acetalization/Henry reaction that allows the synthesis of tetrahydro-6H-benzo[c]chromen-6-ones with excellent enantioselectivity (

Table 4. Synthesis of tetrahydro-6H-benzo[c]chromen-6-ones via an asymmetric domino Michael/acetalization/Henry reaction.

R	in EtOH (95%)		in H2O		Yield (%) b	ee (%) c
	t (h)	cis:trans a	t2 (h)	cis:trans a
	42	88:12	24	81:19	50 (76)	>99
	45	86:14	24	88:12	63 (77)	>99
	46	87:13	30	80:20	65 (81)	>99

^a Determined by ¹H NMR after oxidation. ^b Isolated yield (Tandem Michael/acetalization/Henry reaction (oxidation)). ^c The ee of the major oxidation product (i.e., cis-isomer).

) [56]. The formation of four contiguous chiral centers in a three-bond-forming cascade is especially remarkable, although the methodology is only applied to a small number of examples.

In order to explain the high enantioselectivity obtained, a plausible mechanism was suggested by the authors (Scheme 16). After the formation of the enamine from the glutaraldehyde and the catalyst, a Michael addition with nitrostyrene occurs through the transition state (TS), depicted in the scheme. Then, the formed cis iminium intermediate is further subject to the intramolecular Henry reaction and acetalization to produce the corresponding chromanol.

4.2. Cinchona Alkaloids

Zhao et al. [57] reported another example of tandem Michael/Henry reaction for the interesting preparation of thiochromanes, like suitable important targets with possible biological activities, using cupreine 12 as catalyst and starting from 2-mercaptobenzaldehydes and β-nitrostyrenes (Scheme 17). In this protocol, the authors synthesized chiral 2-aryl-3-nitrothiochroman-4-ols with good diastereomeric ratios and enantioselectivities after recrystallization, using a very low catalyst loading (2 mol%).

The authors proposed two different transition states (TSI-TSII) to justify the formation of the major (2R,3S,4R)-trans,trans-isomer (Figure 6). TSI is the preferred state, since it avoids steric interaction between the aromatic substituent of the nitroalkene and the catalyst.

The same group developed two novel organocatalytic tandem Michael/Henry reactions consecutively, efficiently catalyzed by 9-amino-9-deoxyepiquinine 18 to give highly functionalized chiral cyclohexanes [58] and cyclopentanes [59] in good-to-excellent yields, high diastereoselectivities and excellent enantioselectivities (Scheme 18). The final products have four stereogenic centers containing two quaternary stereocenteres in both cases.

4.3. Thiourea Catalysts

More recently, Xu et al. described an efficient enantioselective domino aza-Michael/Henry reaction of 2-aminobenzaldehydes and aromatic and aliphatic nitroolefins, catalyzed by chiral thiourea 19, to generate synthetically versatile 3-nitro-1,2-dihydroquinoline in moderate yields and from moderate-to-high enantioselectivities (Scheme 19) [60].

The thiourea catalyst 19 is proposed to react as a bifunctional catalyst by generating an iminium ion with the primary amine and the aldehyde, and at the same time, approaching the nitroalkene via hydrogen bonds with the thiourea moiety in order to facilitate the domino aza-Michael/Henry reaction as depicted in Scheme 20.

In 2010, Barbas et al. presented a simple methodology for the asymmetric synthesis of pyranosa derivatives with talo- and manno- configurations from simple achiral precursors through organocatalytic asymmetric intermolecular Michael/Henry reaction sequences [61]. The procedure was applied for a variety of nitroalkenes and catalyzed by the bifunctional thiourea catalyst 20 rendering the final adducts with very high enantioselectivities (

Table 5. Domino Michael/Henry reaction to give 3,4-dideoxy-d-talose derivatives catalized by thiourea 20.

R	t1 (h)	t2 (h)	Yield (%)	dr		ee (%)
				A+B:C	A:B
	4	1	68	>10:1	3:1	98
	4	0.5	62	>10:1	4:1	98
	4	1.5	76	>10:1	3:1	97
	5	0.5	68	>10:1	6:1	97
	16	4	37	1:0	0:1	99
	7	0.5	63	7:1	13:1	97
	6	0.3	43	6:1	1:0	93
C7H15	5	18	44	>10:1	1:0	96

and

Table 6. Domino Michael/Henry reaction to give dideoxy-d-mannopyranose derivatives catalized by thiourea 20.

R	t1 (h)	t2 (h)	Yield (%)	ee (%)
	4	1	51	98
	4	1	65	96
	23	1	48	95
	5	1	57	98
	7	1	59	96
	20	2	66	93
C7H15	5	1	50	96

).

Morover, Zhong et al. developed a highly enantio- and diastereoselective organocatalytic domino Michael/Henry process for the preparation of medicinally important byciclo[3.2.1]octane derivatives with four stereogenic centers, including two quaternary stereocenters (Scheme 21) [62].

In addition, a new catalytic model for this domino reaction was proposed (Figure 7). The thiourea catalyst 21 is invoked to react according to a dual activation model, where the two substrates involved in the reaction are activated simultaneously. However, two different modes of activation were suggested, for which, after a Michael addition over the nitroalkene, a subsequent Henry reaction takes place, resulting in a highly enantioselective product. Between the two different modes of activation depicted in Figure 7, DFT computational calculations supported Mode b as the more suitable transition state for this process.

5. Conclusions

In this work we have compiled significant examples concerning the organocatalytic enantioselective Henry reaction from three different points of view: the addition of nitroalkane to aldehydes, and to ketones, and, in a more complex approach, via domino Michael/Henry reactions. In a variety of protocols, several kinds of organocatalysts have been efficiently employed, such as chiral thioureas, guanidines, cinchona alkaloids derivatives and phase transfer organocatalysts. This is a very interesting and useful reaction in organic synthesis proven by the growing interest and efforts focused in this area. However, in spite of its importance, investigation of this key reaction is still needed, and we expect that, in the near future, new, efficient and more complex examples regarding the nitroaldol reaction will be reported.