Pyrrolidine-oxadiazolone Conjugates as Organocatalysts in

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Pyrrolidine-oxadiazolone Conjugates as Organocatalysts in Asymmetric Michael Reaction Chandan Kumar Mahato, Sayan Mukherjee, Mrinalkanti Kundu, and Animesh Pramanik J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02393 • Publication Date (Web): 21 Dec 2018 Downloaded from http://pubs.acs.org on December 22, 2018

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The Journal of Organic Chemistry

Pyrrolidine-oxadiazolone

Conjugates

as

Organocatalysts

in

Asymmetric Michael Reaction Chandan K. Mahato,†,‡ Sayan Mukherjee,‡ Mrinalkanti Kundu,*,† and Animesh Pramanik*,‡ †TCG

Lifesciences Pvt. Ltd., BN-7, Salt Lake City, Kolkata-700091, India. ‡Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700009, India.

R3

N

O

O

NH

R

NO2

+

R1 X

O

N n H .HCl (10 mol%)

O R2

NO2

R1

TEA (10 mol%) Absolute EtOH or Water, RT 1.5-24 h

O

R

X

R2

Yield upto 97% ee upto 99% syn/anti upto >97:3

CF3 N H

H

Octahydroindole derivative

ABSTRACT: Pyrrolidine-oxadiazolone based organocatalysts are envisaged, synthesized and utilized for asymmetric Michael reactions. Results of the investigations suggest that some of the catalysts are indeed efficient for stereoselective 1,4-conjugated Michael additions (dr: >97:3, ee up to 99%) in high chemical yields (up to 97%) often in short reaction time. As an extension, one enantiopure Michael adduct has been utilized to synthesize optically active octahydroindole.

Molecular chirality shows immense importance in modern pharmaceutical industry. It is widely known in the literature that biological activity, pharmacokinetics, and toxicity of enantiomers differ significantly.1 As an example, the case of thalidomide2 whose enantiomers differ dangerously in pharmacological effect, emphasizes the importance of addressing stereochemistry in drug development. Usually, one particular optically active form of enantiomer is predominant in nature. Similarly, for synthetic chiral drug substances, since one of the enantiomers demonstrates the desired physiological effect, it is desirable to identify new synthetic 1 ACS Paragon Plus Environment

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methodology for specific enantiomers. In asymmetric synthesis however, the formation of the multiple stereocenters in one reaction has been a challenging task.3 The asymmetric Michael reactions are universally acknowledged as one of the most important C-C bond-forming reactions in organic synthesis.4 Stereoselective Michael addition is thus considered for the assessment of the performance of newly designed catalysts5 as various biologically active substances contain these types of 1,4-conjugated adducts with multiple stereogenic centers as their core scaffolds.6 To date, various reagent systems mostly based on metal catalysts7 are used for these types of transformation. On the other hand, for environment-benign nonmetal-catalyzed asymmetric synthesis, substantial attention has also been paid to develop efficient small-molecule chiral organocatalysts.8-10 This field of research has thus seen remarkable progress in the last few years through large number of contributions including the development of new organocatalyst designs. In this context the proline based molecules have been exploited extensively as asymmetric organocatalyst and they accelerate the range of transformations such as Michael addition, aldol or Mannich reaction. Both the enantiomeric forms of proline are inexpensive, have an amine and a carboxylic acid as functional groups. In effect, proline can function as bi-functional asymmetric catalyst and thereby became successful for facilitating stereoselective chemical transformations similar to enzymatic catalysis. Thus, the use of proline and the small molecules derived from it, has been a major breakthrough in the field of organocatalysis to synthesize compounds with improved stereoselectivities.11-21 Typically, the 1,4-Michael additions with proline as organocatalyst afford modest enantioselectivity surprisingly though, homoproline is found to be ineffective.11a, 14c Both proline and homoproline are bipolar molecules; the reactions usually require polar solvents like DMSO or alcohol because of insoluble nature. The 2 ACS Paragon Plus Environment

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oxadiazolone ring is frequently employed as a bioisostere for a carboxylic acid for having similar pKa. Considering this group is non-ionic and thus might improve the solubility in different organic solvents in general, we envisaged to synthesize proline-oxadiazolone conjugates and examined their effect as new organocatalysts in asymmetric Michael addition reactions.

(a) N N N H HN .HCl 1

O O

O NH

N H .HCl

(b) O

O N N O R1

H N R2

N O O

2

Figure 1. (a) Pyrrolidine-oxadiazolone catalysts 1 and 2. (b) Proposed transition state.

To test our hypothesis, compound 1 (Figure 1) was synthesized starting from corresponding cyanopyrrolidine following literature procedure.22 The synthesis of new chiral catalyst 2 (Scheme 1) and its opposite isomer 8 were done using L- and D-prolines Ia and Ib respectively. Accordingly, Ia and Ib were converted to N-Bocprolinols IIIa and IIIb via prolinol intermediates IIa and IIb. O-tosyl intermediates IVa and IVb were synthesized using ptoluenesulfonyl chloride in dichloromethane in the presence of triethyl amine.16,

23

The tosyl

derivatives IVa and IVb were then converted to cyano derivatives Va and Vb using NaCN in DMSO, which were then transformed into VIIa and VIIb respectively.22 Finally, BOC-group was removed by 4.0 M HCl in 1,4-dioxane and the crude compounds were triturated with diethyl ether and dried to give pure 2 and 8.

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OH LAH, THF N H

O

(BOC)2O

OH N H

70 °C, 3 h

Ia S Ib R

NaHCO3

IIa S IIb R

80 °C, 8 h

N O

RT, 48 h

O Va S Vb R

4 (M) HCl in Dioxane RT, 4 h

N N H .HCl

O

O

O

O

CDI, THF O

O

O

NH

N

70 °C, 16 h

VIa S VIb R

O

IVa S IVb R N

NH2

N

O

IIIa S IIIb R

N

N 50% aq.NH OH 2 EtOH

OTs N

RT, 16 h

O

OH NaCN DMSO

PTSCl, Et3N, OH DMAP, DCM

N

THF: water (1:1) RT, 16 h

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O VIIa S VIIb R

O

NH

2S 8R

Scheme 1. Synthesis of Organocatalyst 2 and 8 Initial investigations were performed on two model reactions in parallel using nitrostyrene 3a and cyclohexanone 4 as Michael acceptor and donor respectively (Scheme 2). The reactions were done using 10 mol% catalyst under neat condition at room temperature which resulted in the desired 1,4-addition product 5a in excellent yields in short reaction time (Table 1). Catalyst 1 gave low stereoselectivity whereas catalyst 2, to our delight, was extremely efficient in achieving high diastereo and enantioselectivity probably suggesting the introduction of a flexible methylene linker is crucial for attaining ideal transition state geometry (Figure 1b) where an electrostatic interaction between the nitrogen of the pyrrolidine ring and the nitro group including an extended hydrogen-bonding can be proposed in line with literature precedence.14c, 24

O NO2

+ 3a

O NO2

Catalyst (10 mol%)

4

TEA (10 mol%) Neat, RT

5a

Scheme 2. Asymmetric Organocatalysis in Michael Reaction


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Table1. Effect of the Two Catalysts in Michael Addition Reactiona entry 1 2

catalyst 1 2

% yieldb 84 72

time [h] 8 6

syn/antic [dr] 93:7

eed [%] 29 98

aReactions

were carried out using nitrostyrene 3a (1 eqv.), cyclohexanone 4 (5 mol eqv.), catalyst 1/2 (10 mol%), TEA (10 mol%) in neat condition at room temp. bIsolated yields, GCMS of reaction mixture indicated full conversion of reactants. cDiastereomeric ratio (dr) was calculated from the 1H NMR of the crude product. dEnantiomeric excess (ee, corresponds to syn-isomer) was determined by chiral HPLC.

In going forward, we then picked catalyst 2 and various solvents were screened to optimize the reaction condition (Table 2). Table 2. Role of Different Solvents in Michael Addition Using Catalyst 2a entry

solvent

time [h]

% yieldb

1 2 3 4 5 6 7 8

DMSO Neat THF DCE CHCl3 Absolute EtOH 2-Propanol Water

24 6 24 16 16 4 6 28

61 72 68 78 72 82 65 20

syn/antic [dr] >97:3 93:7 95:5 93:7 92:8 >97:3 92:8 -

eed [%] 75 98 89 97 94 98 93 -

aReactions

were carried out using nitrostyrene 3a (1 eqv.), cyclohexanone 4 (5 mol eqv.), catalyst 2 (10 mol%), TEA (10 mol%) in neat or solvent at RT. bIsolated yields. cDiastereomeric ratio (dr) was calculated from the 1H NMR of the crude product, dr >97:3, syn-isomer is major. dChiral HPLC was used to determine enantiomeric excess (ee), corresponds to syn-isomer.

Results in Table 2 show that the catalyst 2 was found to be efficient indeed in a wide range of solvents such as DMSO, THF, DCE, CHCl3, 2-propanol though the yields and enantioselectivities differ in compare to the reaction conducted under neat condition (entries 1-5, 7). Amongst these, except 2-propanol, reactions in other solvents (entries 1, 3-5) were relatively sluggish. It is worth noting that the reaction in absolute ethanol gave us the best result w. r. to yield as well as both diastereo and enantioselectivity. Moreover, the duration of the reaction was reasonably short (entry 6). Pleasingly, our results demonstrate significant improvement over the 5 ACS Paragon Plus Environment


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data reported for both proline11a, 14c and homoproline14c.The use of more polar solvent water was detrimental (entry 8; due to meagre chemical yield % ee and syn/anti ratio were not determined). Having optimized the solvent as absolute EtOH for our reaction, the Michael addition of 4 to 3a was planned using different catalyst loading. Table 3 shows that the reaction with 5 mol% catalyst loading was low yielding and less enantioselective, that led us to employ 10 mol% of catalyst in our subsequent experiments. Table 3. Effect of Catalyst 2 Concentrationa entry

catalyst (mol%)

TEA (mol%)

time [h]

1 2

10 5

10 5

4 24

% syn/antic yieldb [dr] 82 >97:3 30 >97:3

eed [%] 98 87

aReactions

were carried out using nitrostyrene 3a (1 eqv.), cyclohexanone 4 (5 mol eqv.) in absolute EtOH at room temp. bIsolated yields. cDiastereomeric ratio (dr) was calculated from the 1H NMR of the crude product, dr >97:3, syn-isomer is major. dChiral HPLC was used to determine enantiomeric excess (ee), corresponds to syn-isomer.

Once we established the optimal reaction condition from all the above experiments, we investigated the substrate scope for the 1,4-Michael addition reactions using various nitroolefins as acceptors and cyclohexanone 4 as donor in the presence of 10 mol% catalyst 2. The results are summarized in Table 4.


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Table 4. Stereoselective 1,4-Conjugated Addition of Cyclohexanone to Nitrostyrenes Using Catalyst 2a, b O NO2

R

O

+

3b-l

O

O

O

CF3

O NO2

NO2

NO2

5b-l

O

O

F

Cl

NO2

TEA (10 mol%) Absolute EtOH, RT

4

5b 15 h, 86%, dr >97:3, 93% ee

R

2 (10 mol%)

5d 16 h, 80%, dr >97:3, 94% ee

5c 10 h, 52%, dr >97:3, 93% ee

O NO2

5e 5 h, 79%, dr >97:3, 99% ee

Cl

O

S O

5f 11 h, 76%, dr >97:3, 96% ee

O

O

NO2

NO2

5g 4 h, 82%, dr >97:3, 92% ee

O

NO2

NO2

5h 4 h, 60%, dr 94:6, 97% ee

5i 7 h, 72%, dr >97:3, 90% ee

N

O

O NO2

5j 8 h, 83%, dr >97:3, 95% ee

O NO2

5k 4 h, 66%, dr >97:3, 93% ee

NO2

5l 24 h, 47%, dr >97:3, 93% ee

aReactions

were carried out using nitrostyrene (1 eqv.), cyclohexanone (5 eqv.), catalyst 2 (10 mol%), TEA (10 mol%), absolute EtOH, RT. bIsolated yields, dr determined by the 1H NMR of the crude product, dr >97:3, syn-isomer is major; chiral HPLC was used to determine enantiomeric excess (ee), corresponds to the syn-isomer.

Table 4 shows that the new organocatalyst 2 is also efficient for other nitrostyrenes bearing both electron donating and withdrawing group/s. The corresponding Michael adducts (5b-g) were obtained in high yields and having very good enantioselectivity where 5e was found to be the best. Nitroolefins containing naphthyl group and heteroaryl groups were equally efficient in terms of both chemical yield and stereoselectivity, providing desired adducts 5h-k. Interestingly, non-aromatic Michael acceptor such as 3l was also consistent with the formation of 5l in high diastereo and enantioselectivity.



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Encouraged by these findings, 1,4-conjugated additions between other easily available ketones and aldehydes as donors and 3a as the Michael acceptor were attempted next (Table 5). Table 5. Asymmetric Michael Addition with Different Ketones and Aldehydes Using Catalyst 2a, b O

O NO2

2 (10 mol%)

R1

+

R2 TEA (10 mol%) Absolute EtOH, RT 6a-g X

3a

O

O NO2

S 7b 1.5 h, 55%, dr >97:3, 85% ee

O

X

R2

7a-g

O

O

NO2 O 7a 4 h, 89%, dr 94:6, 84% ee

NO2

R1

NO2

NO2 7c 24 h, 40%, dr 86:14, 44% ee

7d 24 h, 30%, 77% ee

O NO2

7e 14 h, 97%, 25% ee

NO2 OHC 7f 24 h, 15%, 84% ee

NO2

7g 4 h, 62%, dr 76:24, 46% ee

aReaction

conditions: ketones and aldehydes (5 eqv.), nitrostyrene (1 eqv.), catalyst 2 (10 mol %), TEA (10 mol%), absolute EtOH, RT. bIsolated yields, dr determined by the 1H NMR of the crude product, dr >97:3, syn-isomer is major; chiral HPLC was used to determine enantiomeric excess (ee), corresponds to the syn diastereomer.

From this study we observed that, amongst the different ketones, pyran-4-one and thiopyran-4one were more suitable affording products 7a and 7b in short reaction time with high diastereo and enantioselectivity. As expected, 2-butanone resulted in regioisomeric products 7c and 7d with low to moderate enantioselectivity. Use of acetone was non-beneficial w. r. to reaction time and enantioselectivity albeit high yield of the Michael adduct 7e. 3-pentanone afforded meagre conversion to 7f. When propanaldehyde was used as Michael donor, it rendered moderate yield and diastereoselectivity for 7g; whereas, the enantioselectivity was found to be 46%. It is to note that the reaction was very slow in case of cycloheptanone (

Pyrrolidine-oxadiazolone Conjugates as Organocatalysts in

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