Organocatalytic Conjugate Hydroazidation and Hydrocyanation: A Metal-Free Approach to Synthetically Versatile Chiral Building Blocks

Abstract

Chiral β-azido- and β-cyanocarbonyl compounds are extremely useful building blocks in asymmetric synthesis, thanks to the manyfold reactivity of their functional groups. The enantioselective synthesis of such compounds, until the beginning of the 21st century, has been mostly achieved using transition-metal chiral catalysts. The explosion of enantioselective organocatalysis, however, has enabled the development of efficient metal-free methodologies with significant benefits in terms of costs and environmental safety. An overview of the advances made in recent years in this field is herein presented.

1. Introduction

Asymmetric synthesis is an indispensable and fascinating tool for generating chiral molecules useful in many sectors of organic chemistry, especially in the context of medicinal chemistry and the pharmaceutical industry for the preparation of chiral drug candidates.

At the beginning of the current century, enantioselective synthesis heavily started to rely on organocatalysis, which is based on reactions mediated by small organic molecules [1,2,3,4].

The landscape of catalysis has significantly changed over the last decades, and an increasing number of organic transformations are now carried out using organocatalysts, which have superior air and moisture tolerance and excellent compatibility with a wide range of functional groups in comparison with transition-metal catalysts [5]. In addition, most organocatalysts are inexpensive, non-toxic, and safe for the environment.

Chiral azides and nitriles are interesting building blocks and key intermediates for the synthesis of several enantioenriched compounds. One of the most useful means to prepare such molecules is the enantioselective conjugate azidation or cyanation of electron-poor alkenes, which has long been confined to transition-metal catalyzed processes. The potential advantages of metal-free synthesis have inspired this review, which describes the advances for asymmetric organocatalytic conjugated hydroazidation and hydrocyanation reactions.

2. Enantioselective Conjugate Azidation

In recent decades, azides have received a lot of interest as useful and versatile intermediates in synthetic organic chemistry, serving as precursors among others of amines, amides, or heterocycles like pyrroles, pyridines, and 1,2,3-triazoles [6,7,8,9]. Additionally, they are commonly employed in chemical biology and pharmaceutical chemistry [10].

In spite of their toxicity and explosiveness, numerous synthetic techniques have been developed to install the azide moiety in an enantioselective fashion, via both nucleophilic and electrophilic azidations [11].

In 1999, Jacobsen and coworkers described the asymmetric synthesis of β-amino acid derivatives via conjugate addition of hydrazoic acid to unsaturated imides (Scheme 1A) in the presence of a chiral (salen)Al(III) complex [12]. Subsequently, the same research group reported the asymmetric hydroazidation of α,β-unsaturated ketones (Scheme 1B) using a similar catalytic system [13]. The major drawback of this highly enantioselective methodology is the high toxicity and explosivity of hydrazoic acid.

2.1. Organocatalyzed Enantioselective Hydroazidation

Various research groups, with the purpose of meeting green chemistry principles, explored enantioselective metal-free catalyzed azidation reactions under mild conditions, avoiding the direct use of hydrazoic acid as a nucleophilic azide source.

The first organocatalytic hydroazidation was reported by Miller and collaborators in 1999 [14]. Tertiary amines were employed as catalysts for the β-azidation of α,β-unsaturated carbonyl compounds. The azide source was generated by mixing TMSN₃ and AcOH (Scheme 2).

In 2000, the same research group reported the asymmetric organocatalytic hydroazidation promoted by the small β-turn peptide derivative 7, armed with a τ-(benzyl)-His residue (

Table 1. β-Azidation of α,β-unsaturated carbonyl compounds catalyzed by the small peptide derivative 7.

) [15].

Based on these results, Miller and coworkers in 2002 elaborated an enantioselective azidation/cycloaddition sequence achieving optically enriched triazoles and triazolines [16].

Various organocatalytic systems have been developed to carry out the enantioselective conjugate addition of the azide group to unsaturated nitroalkenes.

In 2007, Jørgensen and coworkers described the first asymmetric conjugate addition of azide to α,β-unsaturated nitroalkenes catalyzed by Cinchona alkaloids derivatives [17]. In this methodology, the simultaneous presence of TMSN₃ and a carboxylic acid provided hydrazoic acid in situ. The best Cinchona alkaloid-derived catalyst 9 led to adducts in high conversions but moderate enantioselectivities (27–62% ee) (Scheme 3).

This process turned out to be strongly dependent on the steric and electronic nature of the acid additive. As a matter of example, the reaction of 1-nitro-hept-1-ene performed in the presence of benzoic acid led to 50% ee, whereas AcOH and 2,4,6-trimethoxy benzoic acid furnished 57% ee and 62% ee, respectively.

In 2015, Della Sala and collaborators reported the asymmetric hydroazidation of nitroalkenes promoted by the secondary amine-thiourea catalyst (11) [18]. After a thorough screening of bifunctional catalysts, the asymmetric hydroazidation of various nitroalkenes in the presence of TMSN₃ and AcOH was achieved with a good level of enantioselectivity (71–82% ee), as reported in

Table 2. Asymmetric hydroazidation of nitroalkenes catalyzed by tertiary amine-thiourea (14).

Entry	R	t (h)	Yield (%)	ee (%)
1	PhCH2CH2 (8a)	17	95 (10a)	79
2	(CH3)2CH (8b)	18	63 (10b)	71
3	(CH3)2CHCH2 (8c)	19	78 (10c)	71
4	CH3(CH2)4 (8d)	18	92 (10d)	71
5	(CH3)3C (8e)	15	86 (10e)	82
6	Cyclohexyl (8f)	15	76 (10f)	75
7	Ph (8g)	24	81 (10g)	39

. The only exception, in terms of enantioselectivity (39% ee), is represented by nitrostyrene (Table 2, entry 7). However, it would be stressed that this is the first example of asymmetric hydroazidation of nitrostyrenes.

A tandem hydroazidation–hydroxylation reaction of α,β-unsaturated aldehydes was realized by Jang in 2014 by using TMSN₃, TEMPO, FeCl₃·6H₂O, and the Jørgensen–Hayashi catalyst 13 [19]. This methodology afforded optically active α,β-disubstituted aldehydes, which are key intermediates of biologically interesting β-amino α-hydroxy esters [20,21,22]. Under the optimized reaction conditions, diverse α,β-unsaturated aldehydes were used for the tandem azido/TEMPO addition, achieving moderate yields (42–71%) and good enantioselectivities (71–90% ee) (

Table 3. Tandem hydroazidation–hydroxylation reaction of α,β-unsaturated aldehydes.

).

Luo and coworkers reported, in 2017, the first example of asymmetric hydroazidation of α-substituted vinyl ketones carried out with TMSN₃ and a chiral primary tertiary diamine catalyst (17) [23]. This transformation was performed under mild reaction conditions, achieving good yields (56–91%) and enantioselectivities, as reported in

Table 4. Substrate scope of asymmetric hydroazidation of α-substituted vinyl ketones.

Entry	R’	R	Product	Time (h)	Yield (%)	ee (%)
1	H	Me	18a	16	72	69
2	4-F	Me	18b	16	76	70
3	4-Cl	Me	18c	16	78	70
4	4-Br	Me	18d	16	91	75
5	4-OMe	Me	18e	18	78	69
6	4-CF3	Me	18f	24	67	59
7	4-Et	Me	18g	16	90	45
8	3-F	Me	18h	18	72	44
9	3-Cl	Me	18i	18	74	55
10	3-Br	Me	18j	18	76	54
11	3-OMe	Me	18k	24	79	38
12	3-Br,4-F	Me	18l	24	69	56
13	H	Et	18m	18	68	43
14	H	n-Pr	18n	24	68	11
15	H	Br	18o	32	56	16

.

With the aim of exploring the ability of hydrogen bonding amine bifunctional organocatalysts to activate TMSN₃ and direct the enantioselective addition to Michael acceptors, Aleman and coworkers, in 2019, reported the asymmetric hydroazidation of α,β-unsaturated ketones using the bifunctional squaramide 19. This catalyst proved capable of simultaneously activating the enone and the TMSN₃ without using any carboxylic acid additive [24]. The presence of trace amounts of water was found to be essential to activate TMSN₃ and promote the conjugate addition without generating free hydrazoic acid. DFT calculations demonstrated that the desilylation of TMSN₃ and generation of azide anion is carried out by an H₂O molecule pre-coordinated to the tertiary nitrogen atom of the catalyst (Figure 1).

Using the optimized reaction condition, various differently substituted α,β-unsaturated ketones were tested, resulting in good yields and enantioselectivities as described in

Table 5. Substrate scope of asymmetric conjugate azidation to enones catalyzed by 19.

.

2.2. Organocatalyzed Enantioselective Hydrocyanation

The asymmetric conjugate addition of cyanide to α,β-unsaturated carbonyl derivatives was first accomplished by Jacobsen [25,26,27] using chiral aluminum salen complexes and by Shibasaki [28] using chiral gadolinium catalyst, producing highly valuable chiral building blocks for pharmaceuticals.

Bifunctional compounds, such as β-amino acids, can be synthesized from β-nitro nitriles. The simple pathway to such molecules, according to an intuitive retrosynthesis study, involves a direct conjugate cyanide addition to nitroalkenes. The great tendency of nitroalkenes to polymerize under basic conditions, however, limits the development of this reaction.

In 2010, Lassaletta and coworkers decided to explore the asymmetric unprecedented cyanosilylation of nitroalkenes [29]. The employment of hydrogen bonding bifunctional tertiary amine organocatalysts resulted in disappointing conversions, whereas much better performances were achieved by using bifunctional Cinchona alkaloids derived from halide or cyanide ammonium salts. After an in-depth screening of Cinchona alkaloid derivatives, the model reaction was efficiently catalyzed by 21 in TBME. The products 22 were always produced with excellent yields and good enantioselectivities when with a variety of aliphatic substrates (

Table 6. Substrate scope of asymmetric cyanosilylation of nitroalkenes.

). The authors proposed a mechanism involving the activation of TMSCN triggered by the nucleophilic attack of the halide or cyanide anion (Figure 2).

In the key stereoselective cyanation step, the CN^– counterion attacks the substrate bound to the thiourea moiety.

Both methods of Jacobsen and Lassaletta use trimethylsilyl cyanide (TMSCN), an expensive source of cyanide ions. In 2010, Ricci and collaborators [30] started their investigation using acetone cyanohydrin as a cyanide donor under phase-transfer conditions for the addition to β,β-disubstituted nitroolefins promoted by Cinchona alkaloids derived catalysts (

Table 7. Substrate scope of addition of acetone cyanohydrin to β,β-disubstituted nitroolefins.

Entry	R	R’	Product	Yield (%)	ee (%)
1	Ph	Me	25a	72	67
2	Ph	Pr	25b	60	33
3	2-naphtyl	Me	25c	68	72
4	4-ClC6H4	Me	25d	75	64
5	4-MeC6H4	Me	25e	62	58
6	4-MeOC6H4	Me	25f	64	56
7	2-furyl	Me	25g	52	65

).

The organocatalytic ion pair is generated by the base-promoted decomposition of cyanohydrin liberating cyanide ion. The transfer of the C-nucleophile to the electrophilic nitroolefin’s conjugated site then occurs.

Some years later, Deng and coworkers [31] employed cupreidinium salts for the asymmetric 1,4-addition of cyanide to enones with acetone cyanohydrin and Cs₂CO₃ in toluene/CHCl₃ (Scheme 4).

Using the best PTC catalysts (27 and 28) (Figure 3), a wide range of acyclic enones bearing linear and branched alkyl groups as the β substituents performed satisfactorily (

Table 8. Substrate scope for the asymmetric 1,4 addition of cyanide.

Entry	R	R’	PTC	Product	Time (h)	Yield (%)	ee (%)
1	Ph	Et	28	30a	24	77	95 (S)
2	Ph	Et	29	30a	24	97	90 (R)
3	Ph	Me	28	30b	24	78	97(S)
4	Ph	Me	29	30b	24	92	91(R)
5	Ph	n-C5H11	28	30c	96	89	96(S)
6	Ph	n-C5H11	29	30c	24	73	92(R)
7	Ph	iPr	28	30d	72	69	94(S)
8	Ph	iPr	29	30d	24	80	93(R)
9	Ph	CH2iPr	28	30e	72	80	97(S)
10	Ph	CH2iPr	29	30e	24	91	93(R)
11	Ph	CH2OSiEt3	28	30f	48	75	93(S)
12	Ph	CH2OSiEt3	29	30f	24	77	87(R)
13	4-Me-C6H4	Me	28	30g	48	78	95(S)
14	4-Me-C6H4	Me	29	30g	24	99	92(R)
15	4-OMe-C6H4	Me	28	30h	48	88	97(S)
16	4-OMe-C6H4	Me	29	30h	24	98	94(R)
17	4-Cl-C6H4	Me	28	30i	6	82	96(S)
18	4-Cl-C6H4	Me	29	30i	4	77	90(R)

).

In 2010, Chen and coworkers described an enantioselective 1,4-addition of TMSCN to aromatic chalcones catalyzed by a chiral sodium phosphate [32]. The catalytic sodium salt was generated in situ from the corresponding phosphoric acid and sodium hydroxide. After a screening of BINOL-derived phosphoric acid salts, the best catalysts was found to be a derivative bearing bulky adamantyl groups at 3,3′ positions with excellent yields (86–99%) and moderate enantioselectivities (53–72% ee).

Later, in 2013, the same research group reported the asymmetric conjugate hydrocyanation of enones with benzophenone cyanohydrin catalyzed by an anionic chiral phosphate catalyst [33]. The best catalyst was 31, bearing adamantyl substituents at 6,6′ positions. In the scope of reaction (

Table 9. Asymmetric conjugate hydrocyanation of enones.

Entry	R	R’	Product	Yield (%)	ee (%)
1	Ph	Ph	30j	91	95
2	Ph	Ph	30j	91	94
3	Ph	4-FC6H4	30k	95	96
4	Ph	4-ClC6H4	30l	93	96
5	Ph	4-BrC6H4	30m	93	94
6	4-MeC6H4	3-BrC6H4	30n	96	95
7	Ph	4-MeOC6H4	30o	94	97
8	Ph	4-MeC6H4	30p	93	94
9	4-MeC6H4	Ph	30q	94	97
10	2-MeOC6H4	Ph	30r	72	96
11	3-MeOC6H4	Ph	30s	90	92
12	4-FC6H4	Ph	30t	90	98
13	4-FC6H4	Ph	30u	91	93
14	3-FC6H4	Ph	30v	95	96
15	2-ClC6H4	Ph	30n	93	93
16	4-ClC6H4	Ph	30w	93	95
17	2,4-Cl2C6H3	Ph	30x	96	92
18	4-BrC6H4	Ph	30y	93	94
19	tBu	Ph	30z	91	94
18	cHex	Ph	30z’	91	95

), all the chalcone analogs exhibited excellent enantioselectivities (92–98% ee) with the exclusive formation of 1,4-adducts up to 96% yields.

A possible mechanism is described in Figure 4: firstly, the cyanohydrin decomposes into HCN, reacting with the in situ generated sodium phosphate A, the real catalyst, to form the negative-charged intermediate B. After being altered by the chiral anion via hydrogen bonding, the HCN nucleophile gave an asymmetric conjugate addition to the enone to produce a cyano-enolate C. This is then acidified by the phenol additive to produce sodium phenolate D and the hydrocyanation product. Finally, the phenolate D deprotonates the chiral phosphoric acid, regenerating A.

3. Conclusions

Over the past few years, chemical synthesis has undergone a revolution via enantioselective organocatalysis. More efficient chiral organocatalysts have emerged as interesting and useful alternatives to metal catalysts for conjugate hydroazidation and hydrocyanation reactions, avoiding the high toxicity and explosivity of reagents.

This review highlighted in the first section how it is possible to introduce the azide moiety in an enantioselective fashion, via both nucleophilic and electrophilic azidations. The second part analyzed the asymmetric conjugate addition of cyanide to α,β-unsaturated carbonyl derivatives. These asymmetric metal-free transformations produced important chiral building blocks for pharmaceutical industries. The main future goal will surely be the design of even more efficient systems with optimal catalytic properties, leading to greener and more sustainable processes.