Guanidine catalyzed enantioselective desymmetrization of meso aziridines 3

General methods for the synthesis of dithiocarbamate derivatives involved the reactions of amines with costly and toxic reagents, such as thiophosgene and isothiocyanate.7 Recently, the

Chapter 3

Guanidine Catalyzed Enantioselective Desymmetrization

of meso-Aziridines with Carbamodithioic Acids

3.1 Introduction

Dithiocarbamates (Figure 3.1) have received considerable biological and medical interest in recent time because they are ubiquitously found in a variety of biologically active compounds.1 They have also been used as agrochemicals,2 linkers in solid-phase organic synthesis,3 radical precursors,4 and recently in the synthesis of ionic liquids.5 Furthermore, dithiocarbamates are versatile classes of ligands with the ability to stabilize transition metals in a wide range of oxidation states.6 Therefore, the synthesis

of dithiocarbamate derivatives with varied substitution patterns at the thiol chain has become a field of increasing interest in synthetic organic chemistry during the past few years

Figure 3.1 General structure of dithiocarbamate

General methods for the synthesis of dithiocarbamate derivatives involved the reactions of amines with costly and toxic reagents, such as thiophosgene and isothiocyanate.7 Recently, the preparation of dithiocarbamate derivatives by an one-pot reaction of an amine, inexpensive and readily available carbon disulfide, and

a nucleophile acceptor was developed.8-15 Various amines reacted smoothly with

carbon disulfide to in situ generate incipient carbamodithioic acids, which could

subsequently undergo Michael additions to conjugated alkenes, condensations with alkyl halides, or ring opening reactions of epoxides to produce a variety of functionalized dithiocarbamates (Scheme 3.1)

Scheme 3.1 Synthesis of dithiocarbamates

The addition of carbamodithioic acids to epoxides provided a simple approach towards β-hydroxy dithiocarbamate derivatives In 1993, Toda and co-workers12 reported the synthesis of a five-membered heterocyclic compound 2-thiazolidine-

thione from the reaction of N-substituded-2-aminomethyloxiane with CS2 as a hetero-

cumulene (Scheme 3.2) The in situ generated carbamodithioic acid could undergo an

intramolecular ring opening of epoxide to afford the corresponding β-hydroxy dithiocarbamate in a stereospecific manner

Scheme 3.2 Reaction of 2-aminomethyloxiranes with carbon disulfide

Scheme 3.3 One-pot reaction of epoxides with amine/CS2

Saidi and co-workers13 reported the one-pot ring opening of epoxides with a

variety of carbamodithioic acids generated in situ from structurally diverse amines

and CS2 in water (Scheme 3.3, A) The reactions were catalyst- and organic-solvent-

free and complete within 1.5 hours This was a clean, mild, efficient and neutral method for the preparation of β-hydroxy dithiocarbamate derivatives Recently, Banerjee and co-workers14 observed a significant rate acceleration for the ring opening reaction by employing a simple and inexpensive ionic liquid 1-methyl-

3-pentylimidazolium bromide {[pmIm]Br} to in situ generate dithiocarbamate anions

(Scheme 3.3, B) The reactions of different cyclic and open-chain amines proceeded

smoothly at room temperature, affording β-hydroxy dithiocarbamate derivatives in high regio- and stereoselectivities

One-pot ring opening of epoxides with dithiocarbamate anions using inexpensive and readily available starting materials has been utilized to introduce carbodithioic

acid moiety into fluoxetine (Figure 3.2) As shown in Scheme 3.4, S-[3-dialkylamino

propan-2-ol] esters of fluoxetine carbodithioic acid were synthesized from the sodium salt of carbamodithioic acid derived from fluoxetine In another modification,

fluoxetine was introduced as dialkylamine in propanolamino group, which was a side chain in carbamodithioic acid esters of different dialkylamines These modifications

at 3-amino terminus of fluoxetine led to compounds with better antifungal and

anti-Trichomonas activities

Figure 3.2 Structure of fluoxetine

Scheme 3.4 Synthesis of carbodithioic acid esters of fluoxetine.

3.2 Guanidine catalyzed enantioselective desymmetrization of

meso-aziridines with in situ generated carbamodithioic acids

As shown above, many examples of ring opening reactions of epoxides with in

situ generated carbamodithioic acids have been realized However, no variant with

aziridines was reported Herein we studied the ring opening reactions of meso-

aziridines with various carbamodithioic acids, which were generated in situ from

amines and CS2 As a starting point, several structurally diverse amines were

subjected to the one-pot three-component ring opening reaction with N-tosyl azirdine

4a and CS2 in THF under catalyst-free condition (Scheme 3.5) The reactions for most

of the primary and secondary amines proceeded smoothly to provide the trans β-

tosyl-amino dithiocarbamates as the sole products It was observed that there was no

reaction when aniline 94a was used Secondary amines like N-methylaniline 94d and

the more hindered dicyclohexylamine 94e also failed to produce the desired products

Scheme 3.5 Ring opening reaction of meso N-tosyl aziridine 4a with amines and CS2

3.2.1 Optimization studies on the enantioselective desymmetrization of

meso-aziridines with in situ generated carbamodithioic acids

Table 3.1 Chiral guanidine 79b catalyzed desymmetrization of meso N-tosyl aziridine

4a with various amines and CS2. a

entry amine time /h conversion /%b ee /%c

8 48 90 67

a

All reactions were performed with 0.02 mmol of aziridine, 0.04 mmol of amine and 0.04 mmol of CS2 in 0.4 mL of solvent b Determined by TLC c Determined by chiral HPLC

With the racemic reactions in hand, we embarked on the study of the chiral

guanidine 79b catalyzed asymmetric desymmetrization of meso-aziridines with an

amine and CS2 To reduce the effect of background reaction, which occurred at room temperature without any catalyst, the guanidine catalyzed reaction was studied at 0 °C

With 10 mol% of 79b, this three component reaction was investigated with several

primary and secondary amines (Table 3.1) Benzylamine and tert-butylamine

provided the desired dithiocarbamates in 55% and 50% ee, respectively (entries 1-2) The cyclic secondary amine like piperidine gave 50% ee (entry 3), while pyrrolidine gave only 36% ee (entry 4) Increasing the size of cyclic amine slowed down the reaction rate without an improvement in enantioselectivity (entries 5-6) It was found that the open-chain secondary dibenzylamine provided the product with much higher

ee value than that of dipropylamine (entries 7-8) With electron-donating methoxy

substituents at either para- or meta- positions of dibenzylamine, slightly higher

enantioselectivity was obtained with obvious reaction rate acceleration (entries 9-10)

Table 3.2 Chiral guanidine 79b catalyzed desymmetrization of meso N-acyl aziridine

12a with amines and CS2. a

entry amine 12a:94:CS2 temp /°C time /h yield /%b ee /%c

a

All reactions were performed with 0.02 mmol of aziridine in 1.0 mL of ether

b

Isolated yield c Determined by chiral HPLC d Conversion, determined by TLC

e

Reaction was performed with 2.0 mL of ether

meso N-3,5-dinitrobenzoyl aziridine 12a was also examined in the one-pot three

component ring opening reaction with bis(3-methoxybenzyl)amine and CS2 (Table 3.2, entries 1-5) It was found that the mole ratio of aziridine, amine and CS2 had a significant influence on the reaction rate When the equivalence ratios of amine and

CS2 were increased from 1.1 to 2 (entries 1-2), the reaction conversion was increased

to 80% after 48 hours With this mole ratio (1:2:2), lowering the temperature to -20 °C led to the decrease in both reaction rate and enantioselectivity (entry 3) Increasing the amount of CS2 was shown to be beneficial to the product output, albeit slightly lower

ee value (80%) was obtained (entry 4) Higher enantioselectivity (84% ee) was observed when the reaction concentration was diluted from 0.02 M to 0.01 M (entry

5) bis(2-Methoxybenzyl)amine was then employed under the same reaction

conditions, affording the desired product in 98% yield and 79% ee with much faster reaction rate (entry 6) The ee value could be further improved to 89% by lowering the reaction temperature (entries 7-8) It was observed that the same level of enantioselectivity and yield could be obtained when the amounts of amine and CS2 were reduced (entry 9)

3.2.2 Highly enantioselective desymmetrization of meso N-acyl aziridines

with in situ generated carbamodithioic acids

The optimal reaction conditions were then applied to the desymmetrization of

various meso N-3,5-dinitrobenzoyl aziridines (Table 3.3) Good enantioselectivities

and yields of the ring-opened products were obtained for the six- and five-membered ring aziridines (entries 1-3) A bit lower ee and much lower yield were observed when

the bulkier seven-membered ring aziridine 12f was used (entry 4) With 10 mol% of

79b as the catalyst, the acyclic meso-aziridine 12j provided the corresponding

dithiocarbamate in 62% yield with 86% ee (entry 5) The use of 20 mol% catalyst was

required for the reaction to complete, resulting in the formation of 96f in 91% yield with 90% ee All ring-opened products 96b-f were obtained as solids, and their optical

purity could be efficiently enhanced to excellent ee values (>90%) after a single recrystallization from CH2Cl2 and hexane

Table 3.3 Chiral guanidine 79b catalyzed desymmetrization of various meso N-acyl

aziridines 12 with amine and CS2. a

(R=3,5-dinitrobenzoyl) 96 x mol% time /h yield /%

b

ee /%c

a

All reactions were performed with 0.05 mmol of aziridine, 0.06 mmol of amine and 0.12 mmol of CS2 in 5 mL of ether b Isolated yield c Determined by chiral HPLC; ees after recrystallization are reported in parentheses d Reaction was performed at -50 °C

3.3 Synthesis of chiral β-amino sulfonic acid

Taurine analogues (2-amino sulfonic acids) are important naturally occurring amino acids16 that have been found in many mammalian tissues17, marine algae, fish and shellfish.18 They are also involved in various physiological processes.19 The

synthesis of structurally diverse substituted taurines has attracted increasing attention recently due to their high importance in the fields of biological and medicinal chemistry.20 To the best of our knowledge, there has been no efficient synthetic approach towards optically pure substituted taurines We designed herein two

pathways to synthesize chiral β-amino sulfonic acid 99 (Scheme 3.6)

Scheme 3.6 Preparation of chiral β-amino sulfonic acid 99.

In pathway A, the ring-opened product β-acylamino dithiocarbamate 96b was directly oxidized to the substituted taurine 97 with the pre-prepared performic acid,

followed by hydrolysis in 6 M hydrochloric acid under reflux condition The desired

zwitterionic β-amino sulfonic acid 99 was obtained in only 30% yield In pathway B, dithiocarbamate 96b was first transformed into dithiocarbamate 98 in 78% yield

without any loss in optical activity by Boc protection and the removal of the

3,5-dinitrobenzoyl group with 6 M aqueous NaOH The subsequent oxidation of 98 with performic acid provided the desired product 99 in 92% yield Thus pathway B

was developed as a practical and efficient method for the synthesis of chiral β-amino sulfonic acid

3.3 Conclusion

In this chapter, we have discovered a highly enantioselective desymmetrization of

meso-aziridines with carbamodithioic acid, which was generated in situ from an

amine and CS2 This is the first time on the use of carbamodithioic acid as a nucleophile in the asymmetric ring opening of aziridines to form chiral dithiocarbamate derivatives This method also provided a novel protocol for the synthesis of chiral substituted taurines Although this one-pot three component reaction was a quite novel concept, the enantioselcitivity was still not excellent Future efforts are still needed to improve the enantioselectivity and to explore the scope of the desymmetrization

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