Accepted Manuscript

Novel approach towards one pot stereospecific synthesis of carbohydrate de-rived substituted imidazolines

Vibha Gautam, Veera Babu Kagita, Sudhir Nambiar, Gutala Phaneendra, SulurG Manjunatha, Sridharan Ramasubramanian, M Suresh Babu, JaikumarKeshwan, Sagar Bhagat, Ravindran Prakash, Ramachandra Puranik

PII: S0040-4039(14)01183-6DOI: http://dx.doi.org/10.1016/j.tetlet.2014.07.030Reference: TETL 44873

To appear in: Tetrahedron Letters

Received Date: 28 May 2014Revised Date: 7 July 2014Accepted Date: 8 July 2014

Please cite this article as: Gautam, V., Kagita, V.B., Nambiar, S., Phaneendra, G., Manjunatha, S.G.,Ramasubramanian, S., Suresh Babu, M., Keshwan, J., Bhagat, S., Prakash, R., Puranik, R., Novel approach towardsone pot stereospecific synthesis of carbohydrate derived substituted imidazolines, Tetrahedron Letters (2014), doi:http://dx.doi.org/10.1016/j.tetlet.2014.07.030

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Novel approach towards one pot

stereospecific synthesis of carbohydrate

derived substituted imidazolines

Vibha Gautam, Veera Babu Kagita, Sudhir Nambiar, Phaneendra Gutala, Sulur G Manjunatha, Sridharan

Ramasubramanian, Suresh Babu M, Jaikumar Keshwan, Sagar Bhagat, Prakash Ravindran, Ramachandra Puranik*

Leave this area blank for abstract info.

Tetrahedron Letters journal homepage: www.e lsevier .com

Novel approach towards one pot stereospecific synthesis of carbohydrate derived

substituted imidazolines

Vibha Gautam, Veera Babu Kagita, Sudhir Nambiar, Gutala Phaneendra, Sulur G Manjunatha, Sridharan

Ramasubramanian, Suresh Babu M, Jaikumar Keshwan, Sagar Bhagat, Ravindran Prakash, Ramachandra

Puranik*

Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Bellary Road, Bangalore, Karnataka, India-560024

2-Imidazolines are an important class of small molecules with

diverse pharmacological properties.1 The importance of

imidazoline units arises, as they are found in a wide range of

biologically relevant compounds.2 Imidazoline containing natural

products, e.g. spongotine, topsentin and nortopsentin, are shown

to be important for their antiviral and antitumor properties.3

Furthermore, imidazolines with binding sites are involved in the

regulation of the cardiovascular system, hypertension, regulation

of blood pressure, insulin secretion control and brain disorders

and 2-imidazoline units are reported to show affinity for these

binding sites.4 Recently, Nutlins-chiral nonracemic cis-

imidazolines were shown to be potent and selective antagonists

of MDM2.5

In addition to their biological relevance, 2-imidazoline units

are used as chiral ligands in asymmetric catalysis6

and also

precursors for N-heterocyclic carbine.7

With wide range of applications it is clear that 2-imidazolines

have attracted substantial attention in medicinal and synthetic

organic chemistry. Though several methods have been reported

in literature8 there still exists a great need to explore the simple

and efficient methods for the synthesis of imidazolines. Synthetic

approaches facilitating the development of libraries of 2-

imidazolines with the control of its stereochemistry are more

beneficial as illustrated by NF-kB inhibitory scaffold and p53

activator scaffold. 9

To the best of our knowledge, the stereospecific synthesis of

2- imidazolines employing aminosugars has not been reported.

Using this approach we believe, we have been able to generate a

new class of imidazolines. The sugar scaffold can be manipulated

further to generate new derivatives whose biological activity can

be investigated further.

Herein, we report a conceptually simple and direct method for

the synthesis of carbohydrate derived 1,2,4- trisubstituted 2-

imidazolines with chirality introduced at 4th position employing

N-acetyl 2-aminosugars (Figure 1). This has been accomplished

by reductive amination10

followed by in-situ dehydrative

cyclization in mild acidic condition. N-Acetyl glucosamine11

(1a)

was chosen initially due to its commercial availability. It was

observed that acetyl group at C-2 position in N-acetyl

glucosamine (1a) was an important factor to carry out

intramolecular dehydrative cyclization which has resulted in

stereospecific synthesis of substituted 2-methyl 2- imidazolines.12

Figure 1. R = alkyl, aryl groups.

Synthesis was carried out by treating N-acetyl glucosamine

(1a) with benzyl amine (RNH2 = BnNH2) (2) in DMSO as a

solvent followed by addition of sodium cyanoborohydride and

ART ICLE INFO AB ST R ACT

Article history:

Received

Received in revised form

Accepted

Available online

A simple synthetic approach has been developed towards one pot synthesis of 2- imidazolines

under the mild acidic conditions from N-acetyl glucosamine via reductive amination followed by

dehydrative cyclization. Synthetic studies were explored in detail with different amines and

sugar derivatives. While the conversion were good, the corresponding substituted imidazolines

were obtained in moderate yields.

2009 Elsevier Ltd. All rights reserved.

sKeywords:

2-Aminosugars

2-Imidazolines

Dehydrative cyclization

Stereospecific

acetic acid at room temperature. The reaction mixture was made

completely soluble in DMSO by heating to 60-65 o

C which on

completion of reaction yielded 1,2,4 - trisubstituted imidazoline

(2a) as major and 1a’’ as minor product. (Scheme 1). The

reaction conditions were optimized from rt to 60-65 o

C to

maximize the yield of 2-imidazolines.

Scheme 1. Synthesis of tri-substituted imidazoline (2a)13

Different solvents were screened to optimize the reaction

conditions for formation of 2a. It was observed that reductive

amination of 1a was feasible in all solvents attempted as

compared to dehydrative cyclization of 1a’’.

Table 1. Solvent effect on synthesis of 2-imidazoline (2a)

Refluxing 1a in methanol for 48 h yielded the desired product

2-imidazoline (2a) in traces and the reductive aminated

intermediate (1a’’) as a major product. Similarly, reaction in

other solvents such as DMF, THF, ACN and DCM / methanol

mixture also proved to be futile as it ended up with the major

amount of reductive aminated intermediate (1a").

Therefore after screening various solvents we concluded

DMSO to be the best medium for our reaction (Table 1). It was

observed that the reaction mixture was homogeneous in DMSO

whereas it was heterogeneous in DMF and other screened

solvents, even on heating at higher temperature. We inferred that

solubility could be a significant criterion for the successful

dehydrative cyclization of 1a”.

The synthetic protocol was also extended to N-acetyl

mannosamine (1b) being C-2 epimer of N-acetyl glucosamine

(1a) in order to further study the feasibility of reaction as well as

the impact of the C-2 configuration of N-acetyl mannosamine on

the configuration at 4th position of the expected imidazoline (2b).

N-acetylated mannosamine (1b) when subjected to the reaction

gave 2b as a major diastereomer with > 95% purity and it was

presumed that the reaction might have progressed with retention

of configuration at C-4 position in substituted imidazoline (2b)

(Scheme 2). Given the difficulties around unambiguous

stereospecific assignment at C-4 of 2a and 2b by NMR we

decided to develop an analytical HPLC method to resolve 2a and

2b. The diastereomers were isolated by semi-prep HPLC and

characterized by NMR experimentation. (Chromatograms

attached in Supplementary info). At this point it was clear that 2a

was formed in less than < 5% in the reaction mixture along with

2b when 1b was subjected to the reaction thereby indicating

either lack of complete stereospecificity or racemization of 2b

under reaction conditions. This was also observed in a similar way with 1a reaction with benzylamine.

Scheme 2: Synthesis of tri-substituted imidazoline (2b)

To explore the versatility of our methodology, synthesis of

substituted imidazolines was also attempted with various

derivatives of N-acetylated 2-aminosugars and also with selected

aliphatic and aromatic amines. It was inferred that benzylated

protected sugar derived imidazoline (2c) could be obtained in

higher yield and by simple flash chromatography due to less

polar nature as compared to other highly polar unprotected

sugar based imidazolines which were resolved by preparative

HPLC techniques employing reverse phase conditions thereby

resulting in moderate yields. The reaction conversions were ≥

90% (2a-d, 3a, 11a, 12a) with benzyl and substituted benzyl

amines with moderate isolated yields (2a-d, 3a).

Table 2. Preparation of 2-imadozolines from various amines

with different sugar derivatives.

Entry Solvent Product ratio 2a :1a”

Conversion Yield % (2a)

1 DCM + MeOH

10:90 10

2 MeOH 15:85 15

3 DMSO 95:5 95

4 DMF 5:95 5

5 THF 5:95 5

6 ACN 20:80 20

Entry Sugar Amines Product Isolated yield%

1

(1a)

Bn-NH2

(2)

(2a)

55

2

(1b)

Bn-NH2

(2)

(2b)

50

3

(1c)

Bn-NH2

(2)

(2c)

68

4

(1d)

Bn-NH2

(2)

(2d)

62

5.

(1a)

4-OCH3- Bn-

NH2 (3)

(3a)

65

6.

(1a)

n-Bu-NH2

(4)

(4a)

40

The structure of 2-imidazolines (Table 2) isolated by

preparative HPLC were established with the help of 2D

experiments including COSY, ROESY and 1D NOE

(Supplementary info.).15

NHMBC showed the correlation of the

methyl group to both the nitrogen atoms to propose the formation

of benzyl substituted imidazoline (2c). (Supplementary info.)

In continuation of our study, effect of substitution on aliphatic

and aromatic amines was studied with N-acetyl glucosamine (1a)

to probe the reaction course (Table 3).

Table 3. Reaction of N-acetyl glucosamine with various

substituted amines

Entry Amines

(RNH2) Product

Reaction

conversion(%)

1.

Et-NH2

(5)

(5a)

Trace

2.

HO(CH2)2-

NH2

(6)

(6a)

Trace

3.

Ph-NH2

(7) (7a)

20

4.

4-OMe-

Ph-NH2

(8)

(8a)

25

5.

3,4,5-tri-

OMe-Ph-NH2

(9)

(9a)

47

6.

4-NO2-Ph-

NH2

(10)

(10a)

0

7.

4-NO2-Bn-

NH2

(11)

(11a)

90

8. 3-Cl-4-F-Bn-NH2

(12) (12a)

91

However, reactions with aliphatic amines like ethyl amine (5)

and butyl amine (4) with low boiling point have resulted in poor

conversion. The reaction with ethanolamine resulted in poor

conversion as it reacted with acetic acid to form corresponding

ester (confirmed by mass).14

In another attempt, reaction of N-acetyl glucosamine (1a) was

also examined with aniline. Reductive aminated compound 7a”

was observed as a major product in comparison to its imidazoline

7a counterpart presumably because lone pair of electrons on

nitrogen being in resonance with benzene ring reduces the

nucleophilic character to a greater extent resulting further in low

conversion of its respective imidazoline 7a. (Scheme 3)

Scheme 3: Reductive aminated intermediate (7a”) as a major product.

In case of substituted anilines, nitro aniline with electron

withdrawing nature did not yield any cyclized product whereas

electron donating effect of p-methoxy and 3,4,5- trimethoxy

substitutions gave better conversions, 25% and 47% respectively.

Unlike the substituted anilines, substituted benzyl amines 11 and

12 exhibited excellent conversions (≥ 90%) to 11aand 12a

respectively. (Table 3). In the latter case, effect of substitutions

on the ring was less pronounced. The comparative studies clearly

indicate the greater nucleophilicity of substituted benzyl amines

over substituted anilines probably due to the availability of lone

pair of electrons on the nitrogen atom of the substituted

benzylamines.

The proposed mechanism involves the formation of imidazoline

through reductive amination of the carbonyl group of (1a) with

benzyl amine (2) to form hemiaminal species which loses water

molecule to form imine (1a’). The intermediate imine (Schiff

base) (1a’) is further reduced in-situ to form desired amine (1a")

which undergoes dehydrative cyclization to form tri-substituted

imidazoline (2a) in acidic medium (Scheme 4). The proposed

mechanism was supported with the isolation of 7a” (Scheme 3)

and characterization with the help of NMR studies.

Scheme 4: Plausible mechanism for synthesis of

imidazolines.

In summary, we report a highly stereospecific synthesis of 2-

imidazolines based on N-acetyl-2-aminosugars using one-pot

protocol via reductive amination followed by dehydrative

cyclization. Though, the reaction conversions were good as

monitored by LC, the highly polar nature of the 2-imidazolines

resulted only in moderate isolated yields.

Acknowledgments

The authors acknowledge the support provided by

management of AstraZeneca. They thank Steve Coombes for

helpful discussions during NMR study. We are also grateful to

Suresh Kumar Sythana and analytical staff of their support and

discussions during the course of work. We thank Papu M. for

carrying out purification for all synthesized compounds by

Preparative HPLC method.

Supplementary data

Representative Experimental section and analytical data for all

new synthesized compounds are attached with the article.

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13. General Procedure: To a stirred solution of (1g, 4.52 mmol) N-acetyl glucosamine (1a) in 10 ml of DMSO was added (0.73g,

6.78 mmol) benzylamine (2) followed by subsequent addition of

(1.33g, 21.2 mmol) sodium cyanoborohydride and (3.89 ml, 67.81 mmol) acetic acid dropwise. The above reaction mixture was

heated to 60-65 °C and stirred for 24h. The reaction mixture was

neutralized by sodium carbonate and taken for purification by Preparative HPLC on a reverse phase column.

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