Letter pubs.acs.org/OrgLett

Catalytic Enantioselective Mannich-Type Reaction via a Chiral Silver Enolate Akira Yanagisawa,* Yuqin Lin, Ryoji Miyake, and Kazuhiro Yoshida Department of Chemistry, Graduate School of Science, Chiba University, Chiba 263-8522, Japan S Supporting Information *

ABSTRACT: A catalytic asymmetric Mannich-type reaction of alkenyl trichloroacetates with aldimines was achieved using SEGPHOS·AgOTf as the chiral precatalyst and N,Ndiisopropylethylamine as the base precatalyst in the presence of 2,2,2-trifluoroethanol. Optically active β-amino ketones with up to >99% ee were syn-selectively obtained in moderate to high yields via the in situ generated chiral silver enolates.

T

chiral cocatalyst because the BINAP·AgOTf complex has turned out to be an efficient chiral catalyst for the asymmetric aldol reaction of aldehydes or ketones with alkenyl trichloroacetates in the presence of a catalytic amount of dibutyltin dimethoxide.6 When a 2:1 mixture of 1-trichloroacetoxycyclohexene (1a)7 and 4-(trifluoromethoxy)aniline-derived benzaldimine 2a was treated with (R)-SEGPHOS (10 mol %), AgOTf (20 mol %), and Bu2Sn(OMe)2 (10 mol %) in the presence of MeOH (5 equiv) and MS 3 Å in THF at −20 °C for 48 h, 2((4-(trifluoromethoxy)phenylamino)(phenyl)methyl)cyclohexanone (3aa) was obtained in 27% yield with a syn/anti ratio of 87/13. The syn isomer had 84% ee (Table 1, entry 1). Then, we examined the effectiveness of a tertiary amine as an additive in an effort to avoid the aforementioned product inhibition and increase product yield. As a result, we found that the isolated yield of 3aa improved to 55% in the presence of 20 mol % of N,N-diisopropylethylamine (entry 2). Triethylamine was also effective in raising the catalytic activity of the catalysts (entry 4). What was even more significant is that these amines afforded the syn product in higher diastereoselectivity (syn/anti = 97/3−99/1) with remarkable enantioselectivity (98% ee). In marked contrast, the use of pyridine resulted in a totally unacceptable chemical yield, a very low syn/anti ratio, and low enantioselectivity (entry 3). In order to obtain better results, we further attempted to optimize the reaction conditions. An increase in the amount of N,N-diisopropylethylamine to 40 mol % realized perfect syn/anti selectivity (>99/1) and enantiomeric ratio (>99% ee) as well as a practically meaningful isolated yield that exceeded 80% (entry 5). Lowering the reaction temperature to −30 °C improved the chemical yield to 90% (entry 6). To our great surprise, however, it proved that Bu2Sn(OMe)2 was not necessary for the present asymmetric Mannich-type reaction. In fact, the reaction in the absence of the tin catalyst at −30 °C for 25 h provided the target Mannich adduct in 63% yield without reducing its syn/anti ratio and ee (entry 7).

he asymmetric Mannich-type reaction of enolates with imines is a convenient way to produce nonracemic βamino carbonyl compounds, which are versatile synthetic intermediates of natural products or other useful organic molecules.1 To acquire such chiral Mannich products in satisfactory isolated yields and high optical purity, a variety of methods employing asymmetric catalysts have been developed.2,3 Among the methods reported so far, the chiral Lewis acid catalyzed Mannich-type reaction of silyl enolates is one of the most well accepted; however, it has an intrinsic disadvantage in that an imine is readily hydrolyzed into an aldehyde and an amine when a strong chiral Lewis acid catalyst is used. In addition, the catalyst is deactivated by the Mannich product that is a better ligand for the Lewis acid (i.e., product inhibition).1a,4 We report here a novel example of the enantioselective Mannich-type reaction of alkenyl trichloroacetates with aldimines using the SEGPHOS·AgOTf complex as the asymmetric precatalyst and N,N-diisopropylethylamine as the base precatalyst in the presence of 2,2,2-trifluoroethanol (Scheme 1). Scheme 1. Enantioselective Mannich-Type Reaction of Alkenyl Trichloroacetates with Aldimines Catalyzed by SEGPHOS·AgOTf Complex

We have previously reported that dibutyltin dimethoxide behaves as a catalyst in the Mannich-type reaction of alkenyl trichloroacetates with imines.5 The reaction occurs through a tin enolate, and the tin methoxide is regenerated with the assistance of MeOH. We envisioned that if a suitable chiral cocatalyst could selectively interact with an imine without interrupting the tin catalysis, the asymmetric version of the Mannich-type reaction would be possible. Thus, we tested the possibility of using a chiral phosphine·silver(I) complex as the © 2013 American Chemical Society

Received: October 25, 2013 Published: December 4, 2013 86

dx.doi.org/10.1021/ol403075u | Org. Lett. 2014, 16, 86−89

Organic Letters

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Table 1. Enantioselective Mannich-Type Reaction of Alkenyl Trichloroacetate 1a with Imine 2a Catalyzed by SEGPHOS· AgOTf and Bu2Sn(OMe)2a

entry 1 2 3 4 5 6 7e

amine (mol %) (i-Pr)2NEt (20) pyridine (20) Et3N (20) (i-Pr)2NEt (40) (i-Pr)2NEt (40) (i-Pr)2NEt (40)

temp (°C)

time (h)

yield (%)b

syn/antic

ee (%) (syn)d

−20 −20

48 43

27 55

87/13 97/3

84 98

−20 −20 −20

46 23 20

18 41 82

69/31 99/1 >99/1

40 98 >99

−30

20

90

>99/1

>99

−30

25

63

99/1

99

Table 2. Enantioselective Mannich-Type Reaction of Alkenyl Trichloroacetate 1a with Imine 2a Catalyzed by Chiral Phosphine·AgOTf without Bu2Sn(OMe)2a

entry 1e 2 3 4 5 6 7f 8 9 10

a

Unless otherwise specified, the reaction was carried out using (R)SEGPHOS (10 mol %), silver triflate (20 mol %), dibutyltin dimethoxide (10 mol %), alkenyl trichloroacetate 1a (2 equiv), imine 2a (1 equiv), amine (20−40 mol %), methanol (5 equiv), and MS 3 Å in THF. bIsolated yield of 3aa. cDetermined by 1H NMR analysis. dThe value corresponds to the syn isomer of 3aa. Determined by HPLC analysis. eThe reaction was performed without Bu2Sn(OMe)2.

chiral phosphine (R)-SEGPHOS (R)-SEGPHOS (R)-SEGPHOS (R)-SEGPHOS (R)-SEGPHOS (R)-SEGPHOS (R)-SEGPHOS (R)-BINAP (RR)-t-BuQuinoxP* (R)-TolSEGPHOS

additive

time (h)

yieldb (%)

MS 3 Å MS 3 Å MS 4 Å MS 5 Å Drierite MgSO4 MS 4 Å MS 4 Å MS 4 Å

25 8 16 16 17 16 16 16 17

MS 4 Å

20

syn/antic

ee (%) (syn)d

63 63 81 57 83 65 19 47 99/1 >99/1 75/25 72/28 83/17 34/66

99 99 >99 >99 86 84 81 99−98% ee without significant loss of reactivity (entries 2−6). Subsequently, we executed a screening for the R3 substituent of imines and found that not only electron-deficient aromatic imines but also an electron-rich aromatic imine showed remarkable stereoselectivities although the isolated yields of their products were moderate (entries 7−

11). Benzaldimines possessing a N-protective group other than aromatic groups did not give satisfactory results.8 The aforementioned results further encouraged us to use the alkenyl trichloroacetates of other cyclic ketones in the asymmetric Mannich-type reaction. Both cyclopentanone and cycloheptanone derivatives 1b and 1c furnished the desired products with high optical purities and predominant syn selectivity similar to those of cyclohexanone-derived alkenyl trichloroacetate 1a (entries 12 and 13 vs entry 5). The reaction of acyclic alkenyl trichloroacetate 1d (E/Z = 1/4) with imine 2a also provided a Mannich product in a somewhat low yield with syn selectivity, but the optical purity (96% ee) of the syn isomer was high (entry 14). In addition, we attempted a reaction between propiophenone-derived alkenyl trichloroacetate (E/Z = 1/4) with imine 2a under reaction conditions similar to those in entry 14; however, the desired product was not obtained at all. A plausible catalytic mechanism is indicated in Figure 1. Initially, (R)-SEGPHOS·AgOTf reacts with an alcohol in the presence of N,N-diisopropylethylamine to yield the corresponding (R)-SEGPHOS·AgOR, which is the true catalyst in the present asymmetric Mannich-type reaction. Next, the thus formed chiral silver alkoxide is allowed to attack alkenyl trichloroacetate 1 to generate chiral silver enolate 2. The subsequent addition reaction of chiral silver enolate 2 with aldimine 3 affords chiral silver amide of Mannich adduct 4. Finally, protonation of chiral silver amide 4 with ROH results in the formation of optically active β-amino ketone 5 with regeneration of the chiral silver alkoxide. The rapid alcoholysis of silver amide 4 promotes the catalytic cycle efficiently. 87

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Table 3. Enantioselective Mannich-Type Reaction of Alkenyl Trichloroacetates 1 with Imines 2 Catalyzed by (R)SEGPHOS·AgOTfa

Figure 2. Proposed cyclic transition-state structures.

model B having a boat conformation connects the E-enolate to the anti product.9 Between these two transition-state models, A is evaluated to be more favorable than B because the latter possesses a thermodynamically unfavorable boat form. A hypothesis for the enantiofacial discrimination between an imine and a silver enolate in the present asymmetric Mannichtype reaction catalyzed by (R)-SEGPHOS·AgOTf is exhibited in Figure 3. An aldimine approaches the α-carbon atom of a

a Unless otherwise specified, the reaction was carried out using (R)SEGPHOS (10 mol %), silver triflate (20 mol %), alkenyl trichloroacetate 1 (2 equiv), imine 2 (1 equiv), diisopropylethylamine (40 mol %), 2,2,2-trifluoroethanol (3 equiv), and MS 4 Å in THF at −30 °C. bIsolated yield of 3. cDetermined by 1H NMR analysis. dThe value corresponds to the syn isomer of 3. Determined by HPLC analysis. eThe absolute configuration is shown in parentheses. fMS 3 Å was used. gThe reaction was performed at −20 °C.

Figure 3. Hypothesis for enantioface discrimination between an imine and a silver enolate.

chiral silver enolate while avoiding steric repulsion from a phenyl group of the chiral phosphine ligand. Thus, carbon− carbon bond formation takes place selectively between the Re face of the silver enolate and the Si face of the aldimine to provide the (2S,1′S)-β-amino ketone. In conclusion, we have developed a novel catalytic asymmetric Mannich-type reaction. The use of in situ generated chiral silver alkoxide as the chiral catalyst allows for the synthesis of various nonracemic syn-α-alkyl-β-amino ketones with enantioselectivities of up to >99% ee. The catalytic cycle via a chiral silver enolate affords an alternative asymmetric Mannich process. To the best of our knowledge, this is the first example of the generation of a chiral silver alkoxide and its application as a chiral catalyst to the asymmetric reaction via a chiral silver enolate.10,11 Further studies on the extension of the present silver catalytic system to other asymmetric reactions are underway.

Figure 1. Plausible catalytic cycle for the asymmetric Mannich-type reaction catalyzed by chiral silver alkoxide.



ASSOCIATED CONTENT

S Supporting Information *

From the aforesaid catalytic mechanism and the outcome that cyclic alkenyl trichloroacetates reacted with aldimines synselectively, cyclic transition-state structures A and B described in Figure 2 can be presumed as the plausible models for the Mannich-type reaction of the cyclic substrates. In these assemblies, the imine coordinates to a silver atom of the enolate to furnish a six-membered cyclic structure. Accordingly, from the cyclic enolate (E-enolate), the syn-Mannich adduct is formed through chair-type transition-state structure A, while

Experimental procedures and spectral data for products in Tables 1−3. This material is available free of charge via the Internet at http://pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] 88

dx.doi.org/10.1021/ol403075u | Org. Lett. 2014, 16, 86−89

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Letter

Notes

(5) Yanagisawa, A.; Saito, H.; Harada, M.; Arai, T. Adv. Synth. Catal. 2005, 347, 1517. (6) (a) Yanagisawa, A.; Ichikawa, T.; Arai, T. J. Organomet. Chem. 2007, 692, 550. (b) Yanagisawa, A.; Terajima, Y.; Sugita, K.; Yoshida, K. Adv. Synth. Catal. 2009, 351, 1757. (7) Libman, J.; Sprecher, M.; Mazur, Y. Tetrahedron 1969, 25, 1679. (8) The reaction of 1a with diversely N-protected benzaldimines was performed under the optimized reaction conditions. The results are as follows (imine, additive, time, yield, syn/anti, enantioselectivity of syn isomer): N-tosylbenzaldimine, MS 3A, 8 h, 75% yield, 92/8, 1% ee; Nbenzylbenzaldimine, MS 4A, 16 h,

Catalytic enantioselective Mannich-type reaction via a chiral silver enolate.

A catalytic asymmetric Mannich-type reaction of alkenyl trichloroacetates with aldimines was achieved using SEGPHOS·AgOTf as the chiral precatalyst an...
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