Development of New Synthetic Methodologies: Section A ... · of different chlorinating agents such...

Chapter 3

Chapter 3 Development of New Synthetic

Methodologies:

Section A: Reaction of Carbohydrates with

Vilsmeier reagent: A tandem selective chloro

O-formylation of sugars

Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3

Page 123

Reaction of Carbohydrates with Vilsmeier reagent: A tandem selective

chloro O-formylation of sugars:

1. Introduction:

Naturally occurring carbohydrates and their derivatives have been useful during

the last few decades as chiral pool constituents in the enantioselective synthesis of

biologically active natural and non-natural products. The ready availability of a wide

range of carbohydrates in nature and their multi chiral architecture, coupled with their

well-defined stereochemistry, make them attractive starting materials in organic

synthesis. The synthesis of key intermediates by incorporation of suitable functional

groups onto carbohydrates, which can then be further exploited, can be achieved by an

efficient protecting group strategy.1

Development of such protecting group strategy wherein more than one useful

transformation can be carried out under the same reaction conditions without adding

additional reagents and catalysts makes the process more advantageous and

environmentally benign. In this respect, synthesis of the terminal chlorodeoxy sugars via

direct substitution of hydroxyl groups by chlorine is of particular interest as they are in

demand as precursors2,

for the synthesis of deoxy, amino-deoxy and unsaturated sugars

and also as sweetening, anticarcinogenic, and potential male contraceptive agents.

Similarly, O-formylation could be the method of choice for protecting sugar hydroxyl

groups in a complex synthetic sequence because de-esterification can be effected

selectively in the presence of other ester protecting groups e.g. a formate ester can be

cleaved selectively in the presence of acetate and/or benzoate even in neutral alcoholic

conditions.3 Further, if the alcohol group is planned to be oxidized later in a multistep

synthetic scheme, the formylated alcohol can be directly oxidised under Oppenauer

1 Liptak, A.; Borbas, A.; Bajza, I. Protecting Group Manipulation in Carbohydrate Synthesis,

Comprehensive

Glycoscience, Elsevier B. V., 2007, 203. 2 (a)Akhrem, A. A.; Zaitseva, G. V.; Mikhailopulo, I. A. Carbohydrate Research, 1973, 30, 223. (b)

Akhrem, A. A.; Zaitseva, G. V.; Mikhailopulo, I. A. Carbohydrate Research, 1976, 50, 143. (c) Hansessian,

S.; Plessas, N. R. J. Org. Chem., 1969, 34, 2163. (d) Kikugawa, K.; Ichino, M. J. J. Org. Chem., 1972, 37,

284. 3 Reese, C. B.; Stewart, J. C. M. Tetrahedron. Lett., 1968, 9, 4273.


Page 124

conditions.4 Moreover formate esters can also serve as intermediates for the preparation

of glycopolymers.5

Presently several methods are available for selective halogenation and O-

formylation using different sets of reaction conditions. Garegg and Samuelsson6

converted 3-hydroxy sugar derivatives to 3-deoxy-3-iodo sugars using

triphenylphosphine, iodine and imidazole in toluene under reflux conditions, whereas

Hanessian and Plessas7 converted 1,2:5,6-di-O-isopropylidene D-glucofuranoside to the

6-bromo-6-deoxy derivative by treatment with N-bromosuccinimide and

triphenylphosphine in N,N-dimethylformamide. Numerous other reagents have been

developed for the O-formylation of sugar hydroxyl groups,

A brief account on the reported methods for halogenations and O-formylation of sugar

derivatives is described below.

2. Reported methods for halogenations and O-formylation of sugar

derivatives:

2.1. Marta approach:8 Conversion of O-silyl protected sugars into their

corresponding O- formates:

Marta et al. reported direct conversion of O-TBDMS and O-TBDPS protected

primary alcohol of mono and disaccharides into their corresponding O-formates in good

to excellent yields under mild reaction conditions (Scheme-1) using V-H complex

without formation of intermediate alcohol. However, this method is limited to primary

hydroxyl group of sugar derivates into their formates.

OAcO

AcO

OMeOAc

OR

R = TBDMS/TBDPS

OAcO

AcO

OMeOAc

OCHO1) POCl3/DMF

2) NaHCO3

Scheme-1

4 Ringold, H. J.; Loken, B.; Rosenkranz, G.; Sondheimer, F. J. Am. Chem. Soc., 1956, 78, 816

5 (a) David, R.; B. F. Martin, B. F.; Jay, T. G.; Carolyn, R. B. J. Am. Chem. Soc., 2008, 130, 5947. (b)

Rawle, I. H.; Guijun, W. Chem. Rev., 2000, 100, 4267. 6 Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. I, 1980, 2866.

7 Hansessian, S.; Plessas, N. R. Chem. Commun., 1967, 1152.

8 Mart, M. A.; Barros, M. T. Tetrahedron, 2004, 60, 9235.


Page 125

2.2. Jialong approach:9 Conversion of Glycosyl Bromide and Ethyl thio glycosides in

to O-formates:

Jialong et al. prepared 1-O-formyl glycosides, as intermediates in glycopolymers

synthesis from different glycosyl donors (Scheme-2). The synthesized formyl derivatives

appeared to be air and moisture stable.

OAcO

AcOOAc

OAc

SEt HCOOH, NIS, TfOH

4A0 MS, 0 0C

OAcO

AcOOAc

OAc

Br

HCOOH/AgNO3OAcO

AcOOAc

OAc

OCHO

Scheme-2

2.3. Gyorgy approach:10

Halogen exchange in carbohydrates using new Vilsmeier-

type reagent:

Gyorgy et al. achieved O-formylation and halogenation at primary hydroxy group

of sugars derivatives under different set of reaction conditions. In the presence of

triphenylphosphine and N-bromosuccinimide initially formed alkoxy phosphonium salt of

diisopropylidene galactose intermediate had been converted into their corresponding

bromo and O-formate derivatives depending on different reaction condition (Scheme-3).

O

O

OO

OH

O

O

O

OO

O

O

O

O

OO

O

O

PPh3

Br

NMe2 Br

O

O

OO

Br

O

O

O

OO

OCHO

O

H2O

t1/2 40 min

70 0C

70 0C

t1/2 120 min

NO O

Br

PPh3/DMF

Scheme-3

9 Jialong, Y.; Kristof, L.; Holger, L. J. Org. Chem., 2006, 71, 5457.

10 Gyorgy, H.; Benjamin, P.; Janos, K. Carbohydrate Research, 1990, 206, 65.


Page 126

2.4. Ram N. Ram approach:11

Selective formylation of sugar hydroxyl groups:

Ram et al. attempted the selective O-formylation of alcohols in the presence of

chloral. Chloral reacts with alcohol easily to form stable hemiacetals.12

It is also known to

formylate the primary hydroxyl group of methyl manopyranoside when 2 heated in

dichloromethane at reflux in the presence of DCC.13

However the reaction was not found

to be selective on primary sugars hydroxy groups and other hydroxy groups reacted

differently as shown above Scheme-4.

OHO

HO

OHOH

OMe

OO

O

OCONHC6H11OCHO

OMeCl3C

CCl3CHO/DCC

1 2

Scheme-4

2.5. Hanessian approach:4 Migration followed by chlorination:

Hanessian reported the anomalous behavior of Vilsmeier reaction for which they

have chosen 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (3) containing an isolated

secondary hydroxyl group. Compound 3 was allowed to react with Vilsmeier reagent at

room temperature in 1,1,2,2-tetrachloroethane. The major product obtained was its

corresponding 3-O-formate ester (4). Refluxing the same reaction mixture afforded a

syrupy product characterized as 5 (Scheme-5) instead of 3-chlorodeoxy derivative. Here

migration of the 5,6-O-isopropylidene group is noteworthy.14

OO

OHOO

O

OO

OOCl O

(Me2N:CHCl)Cl

OO

OO Oreflux

34 5

OHCO

Scheme-5

11

Ram R. N.; Meher, N. K. Tetrahedron, 2002, 58, 2997. 12

Luknitskii, F. I.; Chem. Rev., 1975, 75, 259-289. 13

Miethchen, R.; Rentsch, D. Synthesis, 1994, 827 14

Baddiley, J.; Buchanan, J. B.; Hardy, F. E. J. Chem. Soc., 1961, 2180.


Page 127

2.6. Akhrem approach:2,3

Tandem chloro acetylation of sugars:

Akhrem and his co-workers were first to report the preparation of chloro

acetylated sugar derivatives for which they choose 3-O-acetyl-1,2-O-isopropylidene-α-D-

ghrcofuranose (6) containing primary and secondary hydroxyl groups, compound 6 was

allowed to react with acetyl salicyloyl chloride (7) in anhydrous p-dioxane at room

temperature to gave 3,5-di-O-actyl-6-chloro-1,2-O-isopropylidine-α-D-glucofuranose (8)

in good yields (Scheme-6). Till date this is only one report of tandem chlorination

acetylation of sugar hydroxy compounds.

OO

OAcO

HO

HO

OO

OAcO

Cl

AcOCOCl

OAcO

O

6 87

+

Scheme-6

Some applications that are pertinent to synthetic carbohydrate chemistry include one step

and selective conversion of silyl ethers of sugar derivatives into their corresponding

formates using either PPh3/CBr4 in HCOOEt/H2O15

or Vilsmeier reagent,16

and reaction

of halomethyleniminium salts with various sugar alcohols to afford formate esters and

chlorodeoxy sugars under different sets of experimental conditions.

All these halo and formylating reagents described above have their limitations. As a result

of the harsh experimental conditions such as medium acidity and high temperature and/or

accompanying side reactions such as migration of isopropylidene rings,4,17

none of them

has given halo-deoxy O-formylated sugars exclusively.

15

Hagiwara, H.; Morohashi, K.; Sakai, H.; Suzuki, T.; Ando, M. Tetrahedron, 1998, 54, 5845. 16

Vilsmeier, A.; Haack, A. Chem. Ber., 1927, 60, 119. 17

(a) Hardegger, E.; Zanetti G.; Steiner, K. Helv. Chim. Acta., 1963, 46, 282. (b) Baddiley, J.; Buchanan J.

B.; Hardy, F. F. J. Chem. Soc., 1961, 2180.


Page 128

3. Present work:

There are several examples of polymers with sugar residues attached to the

backbone via either their anomeric oxygen2, or 3/6-oxygen

3 without a spacer. The

selective derivation of sugars with unsaturated moieties is one of the easiest routes to

prepare such polymers, which in turn require synthesis of O-formyl esters at the

respective position. O-Formylation of alcohols is one of the most useful and versatile

reactions in protective organic chemistry as formate esters can be removed easily and

selectively. The Vilsmeier–Haack (V–H) reaction (discovered in 1927)16

is recognized as

one of the best methods for the direct formylation of electron-rich aromatic nuclei,

enolizable ketones, enol ethers and other active hydrogen compounds. This reaction

continues to receive wide attention in organic chemistry because of its simplicity and

convenience. However according to our knowledge there is no report till date of one pot

chloro-esterification under Vilsmeier conditions. The present work therefore envisaged to

attempt Vilsmeier reaction foe the preparation chloro esters with replacement of OH

group by chlorine atom or exclusively O-formylation.

4. Result and Discussion:

In the present study Vilsmeier reaction has been utilized as a simple, efficient

method initially for O-formylation and thereafter synthetically more useful tandem

selective chloro O-formyaltion under mild reaction conditions. These chloro O-

formylated sugar derivatives can be utilized further for selective amination and/or

reduction to afford 6-amino-6-deoxy sugar derivatives, which are biologically important

precursors.

We initially took protected sugars having one hydroxy group free to investigate the effect

of different chlorinating agents such as thionyl chloride, oxaloyl chloride and benzoyl

chloride along with DMF at room temperature. Thus from 1,2:5,6-di-O-isopropylidene-α-

D-glucofuranose (9) we got O-formylated sugars as a sole products without migration or

cleavage of sensitive isopropylidene group as we anticipated in good yields with POCl3

(Scheme-7) (Entrys 9-11 Table-1). The presence of singlet at δ 8 in the 1H NMR confirms

the formylation of OH group. No chlorinated product was observed during this reaction.


Page 129

DMF/PhCOCl

DMF/POCl3

DMF/SOCl2

DMF/(COCl)2

or

or

0-60 0C 1 h

OOO

O

O

HO

OOO

O

O

OHCO

9 9a

Scheme-7

Further to check the behavior of our reagent system towards anomeric free hydroxy

group; 2,3,4,6-tetra-O-acetylated sugar derivatives were taken into consideration

(Scheme-8). While they turned out to be easily anomerized or hydrolyzed during column

chromatography with both silica gel and aluminum oxide as the column materials but

they can be easily converted into O-vinyl derivatives using Tebbe condensation9 without

further purification. All synthesized O-formates were typically obtained in anomerically

pure form by recrystallization.

V-H reagent

0-60 0C

12-14 12a-14a

O

OAc

AcO

OH

O

OAc

AcO

OCHO

Scheme-8


Page 130

Table 1: Reaction of different sugar derivatives with V-H reagent

S. No Substrate Producta Time (h)

b Yield %

c

1 OOO

O

O

HO

9

OOO

O

O

OHCO

9a

1 87

2

OO

O

O

O

HO

10

OOO

O

O

OHCO

10a

1 83

3

O

O

OO

OH

O

11

O

O

OO

OCHO

O

11a

1 82

4

OAcO

AcOOAc

OH

OAc

12

OAcO

AcOOAc

OCHO

OAc

12a

1 82

5

OAcO

AcO

AcO

OH

OAc

13

OAcO

AcO

AcO

OCHO

OAc

13a

1.5 87

6

O

AcO

AcO

OAcOH

OAc

14

O

AcO

AcO

OAcOCHO

OAc

14a

1.5 87

aCharacterised by

1H NMR and

13C NMR:

bTotal reaction time (sugar: V–H complex, 1:10):

cYield of the

formylated product obtained after column chromatography.

After accomplishing monoformylation successfully, our next goal was to see how

anomeric protected poly hydroxy sugar derivatives behave towards modified Vilsmeier-

Haack complex. So, we took methyl glucoside 15 as a model compound. Treatment of 15

with DMF–POCl3 complex (6 eq.) at 0 0C to rt indeed proceeded to completion in 1 h, but


Page 131

afforded a mixture of two products 15a and 15b in almost equal amounts (Scheme-9)18

.

Gratifyingly compound 15a was identified as methyl-2,3,4-tri-O-formyl-6-chloro-6-

deoxy-α-D-glucopyranoside instead of expected performylated derivatives on the basis of

NMR and mass-spectral data. The signals for H-6,6’ and C-6 in the 1HNMR and

13C

NMR spectra of 15a were shifted upfield compared to those of the corresponding nuclei

in the performylated product 15b thereby indicating the introduction of the chlorine

substituent at position 6 (Scheme-9) (Table-3).

OOHCO

OHCO

OMeOHCO

Cl

OOHCO

OHCO

OMeOHCO

OCHO

+

15a 15b

OHO

HO

OMeOH

OH

15

DMF/PhCOCl

DMF/POCl3

DMF/SOCl2

DMF/(COCl)2

or

or

0-60 0C 1 h

Scheme-9

In a bid to obtain 15a as a sole product, modifications in experimental conditions were

effected such as raising the temperature to 60 0C and also allowing more time (6 h) and

this afforded 15a in 85% yield along with only a trace amount of 15b. In a separate

control experiment treatment of 15b with DMF–POCl3 complex (6 eq.) at room

temperature indeed afforded 15a almost exclusively suggesting that the latter could be the

thermodynamically controlled product.

In addition to POCl3 we have also used different chlorinating agents such thionyl chloride

(SOCl2), benzoyl chloride (PhCOCl), and oxaloyl chloride (COCl)2 along with DMF at

room temperature to 60 0C failed to improve the yields as shown in Table-2.

18

Thota, N.; Debaraj. M.; Reddy, M. V.; Syed. K. Y.; Koul. S.; Taneja. S. C. Organic & Biomolecular

Chem., 2009, 7, 1280.


Page 132

Table 2: Optimization of reaction conditions for methyl glucoside 15.

Entry Chlorinating agent Ratioa

Temp (0C) Time (h) Yield

b (9a:9b)

1 DMF+POCl3 1:6 0 to rt 0.5 50:50

2 DMF+POCl3 1:6 0 to rt 1 70:30

3 DMF+POCl3 1:10 0 to rt 1 55:45

4 DMF+POCl3 1:6 0 to 60 1 55:45

5 DMF+POCl3 1:10 rt to 60 6 85:trace

6 DMF+SOCl2 1:10 0 to rt 6 45:trace

7 DMF+SOCl2 1:10 rt to 60 6 45:trace

8 DMF+PhCOCl 1:10 rt to 60 6 30:45

9 DMF+(COCl)2 1:10 rt to 60 6 50:50

a Ratio between methyl glucoside and V-H- complex:

b Yield obtained after column chromatography.

Encouraged by this observation, this method was extended to check the reactivity

of various protected sugar derivatives with Vilsmeier reagent for the synthesis of formate

esters and chloroformate esters. Allyl glucoside 16 was subjected to Vilsmeier reagent,

the product 16a was obtained in good yields (83%) and 16b was obtained in traces, after

purification of the crude reside on silica gel column chromatography (Scheme-10). The

products 16a and 16b confirmed by 1H/

13C NMR spectra.

OHO

HO

OHO

OH

OOHCOOHCO

OHCOO

Cl

DMF/POCl3

16

OOHCOOHCO

OHCOO

OCHO

+

16b16a

Scheme-10


3

The phenyl-β-D-thio-glucoside 17 also proved to be efficient by reacting with Vilsmeier

reagent to afford the corresponding chloroformylated product 17a was obtained in good

yields (82%) and per formylated product 17b in traces amount (Scheme-11).

DMF/POCl3

17 17a

OHO

HO

OH

S

OH

OOHCO

OHCO

OCHO

S

Cl

OOHCO

OHCO

OCHO

S

OCHO

+

17b

Scheme-11

In addition, several other chloro formylated and performylated derivatives have been

prepared (Table-3 18-22) from different derivatives of sugars using similar reaction

conditions. In all the cases the chloro-formylated products were obtained in good yields

except with galactopyranoside 13 (Scheme-12) (Table -3 entry no 11) where the O-

formylated product 19b was isolated with traces of the chloro-formylated product 19a.

+DMF/POCl3

19 19a

O

HO

HO

OHOMe

OH

O

OHCO

OHCO

OHCOOMe

Cl

O

OHCO

OHCO

OHCOOMe

OCHO

19b

Scheme-12


Page 134

5. Mechanism of Vilsmeier-Haack reaction:

The sequence of reactions leading to tandem chlorination and O-formylation is

depicted in Scheme 13. It is well known that during Vilsmeier-Haack reaction DMF

combines with inorganic acid chloride to form active reagent halomethyleniminium salt

which is an equilibrium mixture of the two salts A and B (Vilsmeier-Haack reagent).19

This is useful as formylating, halogenating, and dehydroxylating agents.20

We envisioned

that equilibrium mixture of A to B can effective both O-formylation and chlorination

simultaneously in polyhydroxy sugar derivatives. This sequence of reactions leading to

formylation and chlorination of alcohols is illustrated in Scheme-13.

NMe Me

Cl2P(O)O

ClN

Me Me

Cl

Cl2P(O)ODMF-POCl3

A B

RCHOH

R'

+ Me2N CHO(O)PCl2 Cl R CHOHCH

R'

NMe2

Cl

+ HCl

RHC

R'

O CH NMe2

Cl

RCHOCHO + Me2NH + HCl

R'

H2O

RCHCl +Me2NCHO

R'

A B C

D

+ HOPOCl2

RHC

R'

O CH NHMe2

OH

Scheme-13

19

(a) Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, H. Helv. Chim. Acta, 1959, 42, 1653. (b) Bosshard,

H. H.; Zollinger, H.; ibid., 1959, 42, 1859. 20

Fieser, L. F.; Fieser, M. “Reagents for Organic Synthesis,” Wiley, New York, New. York., 1967, 284.


Page 135

6. Anomalous behavior of galactose has fallows:

It is noteworthy that the reaction proceeded smoothly without affecting other

protecting groups. In all the cases chlorination took place selectively at the sterically less

crowded primary hydroxy group of the sugar moiety leaving the secondary hydroxy

groups, perhaps due to easy access of the bulky chloride ion. The anomalous behaviour of

the galactose derivative can be rationalized as follows. The C6–O bond needs to be

oriented anti to the C5–H for smooth attack by the chloride ion (Scheme 14). However

this conformation is less favoured in the galactose series (Newman projection-A) than in

the glucose series (Newman projection-B) due to torsional strain involving the axial C4–

OR group and oxoforminium group in the case of the former. Therefore the galactose

substrate furnishes the performate as the major product. With the exception of

galactosides our results clearly show that compounds having primary hydroxyl groups

afforded the chloro-formylated product.

O

H

O

HH

CHNMe2

O

O

H

O

HH

CHNMe2

H

O

R

R

H

A B

Scheme-14


Page 136

Table 3: Reaction of different sugar derivatives with V-H reagent:

S. No Substrate Chloro formylated

Producta

Performylated

producta

Time

(h)b

Yield

(a:b)%c

7 O

HOHO

OHOMe

OH

15

OOHCO

OHCO

OHCOOMe

Cl

15a

OOHCO

OHCO

OHCOOMe

OCHO

15b

6 85:10

8 O

HOHO

OHO

OH

16

OOHCOOHCO

OHCOO

Cl

16a

OOHCOOHCO

OHCOO

OCHO

16b

5 83:10

9 O

HOHO

OH

SPh

OH

17

OOHCOOHCO

OCHO

SPh

Cl

17a

OOHCOOHCO

OCHO

SPh

OCHO

17b

4 82:17

10 O

HOHO

HO

OMe

OH

18

OOHCOOHCO

OCHO

OMe

Cl

18a

OOHCOOHCO

OCHO

OMe

OCHO

18b

7 77:15

11 O

HO

HO

OHOMe

OH

19

O

OHCO

OHCO

OHCOOMe

Cl

19a

O

OHCO

OHCO

OHCOOMe

OCHO

19b

5 25:65d

12 O

HOHO

OH

OPMP

OH

20

OOHCOOHCO

OCHO

OPMP

Cl

20a

-

7 85:ND

13

OHO

HO

O

O

HO

21

OClOHCO

O

O

OHCO

21a

-

2

79d

14

OHO

HO

O

O

HO

22

OClOHCO

O

O

OHCO

22a

- 2

81d

a Characterised by

1H NMR and

13C NMR:,

b Total reaction time (sugar:V–H complex, 1:10):

c Yield of the

a and b products obtained after column chromatography. d Performylated product obtained in major amount

(65-81%). ePMP=p-methoxyphenol and SPh=thiophenol.


Page 137

7. Conclusion:

In conclusion, the Vilsmeier reaction proved to be a versatile method for the

preparation of various unsubstituted 1-O-formyl as well as tandem one pot selective

chloro-O-formylation of sugars, the 1-O-alkyl glycosides used as the substrates. The

application of the 1-O-formyl glycosides as chiral auxiliaries for the preparation of

glycopolymers and glycoconjugates. And also this method offers operational simplicity

and proceeds with moderate to high yields. This together with the enormous importance

of the downstream products in the synthesis of glycopolymers and glycoconjugates

establishes the utility of the method.

8. Experimental:

8.1. General methods:

All reagents for chemical synthesis were purchased from Sigma–Aldrich and used

as received. And some of the substrates like 12-14,21

16, 1722

, 20, 21, and 2223

were

prepared according to the literature methods. All the solvents used in reactions were

distilled and dried before use. All reactions were monitored by TLC on 0.25 mm silica gel

60 F254 plates coated on aluminum sheet (E. Merck). 1H NMR and

13C NMR spectra

were recorded on Brucker Avance DPX-200 instrument at 200 MHz and 50 MHz,

respectively, using CDCl3 as solvent with TMS as internal standard. Chemical shifts are

expressed in parts per million (δ ppm); and coupling constant values are given in Hertz.

Mass spectra were recorded on ESI-esquire 3000 Bruker Daltonics instrument.

8.2. Typical procedure for chloro-O-formylation:

A stirred, cooled DMF solution of the complex POCI3/DMF (prepared from 1.52

g POCl3, in 5 mL anhydrous DMF, 0 0C) was added dropwise to a cold solution of α-D-

methyl-glucopyranoside 15 (0.2 g, 1.0 mmol in 10 mL DMF) under an inert atmosphere.

The mixture was then agitated at 60 0C and the reaction monitored by TLC. After

completion of the reaction (reaction time given in table-3) the contents were treated with

21

(a) Wolfrom, M. L.; Thompson, A. Methods in Carbohydr. Chem., 1963, 2, 211 (b) Steglich, W.; Hofle,

G. Angew. Chem., Int. Ed. Engl., 1969, 8, 981. 22

Fernandez-Bolanos, J. G.; Al-Masoudi, N. A. L.; Maya, I. Adv. Carbohydr. Chem. Biochem., 2001, 57,

21. 23

(a) Manna, S.; Jacques, Y. P.; Falck, J. R. Tetrahedron Lett., 1986, 27, 2679. (b)Hanessian, S, Ed.;

Marcel, D. Synthesis of Isopropylidene Benzylidene and Related Acetals, New York, 1997, 3.


Page 138

saturated NaHCO3 solution (30 mL), then extracted with solvent ether (4 x 30 mL), the

organic solvent was evaporated, and the crude product was purified by column

chromatography over silica gel to afford a syrupy mass methyl 6-chloro-2,3,4-tri-O-

formyl-α-D-glucopyranoside (15a) and methyl-2,3,4,6-tetra-O-formyl-α-D-

glucopyranoside (15b) in 85:10% with overall yields.

9. Spectral data:

9.1. 3-O-Formyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (9a):

1H NMR (200 MHz, CDCl3): δ 1.25, 1.29, 1.35, 1.47 (3H each, s,

4xC-CH3), 4.01-4.07 (3H, m, H-5, H-6a, H-6

b), 4.12 (1H, br s, H-4),

4.53 (1H, d, J = 3.6 Hz, H-2), 5.35 (1H, br s, H-3), 5.89 (1H, d, J =

3.6 Hz, H-1), 8.08 (1H, s, -OCHO). 13

C NMR (50 MHz, CDCl3): δ

24.0, 24.2, 25.2, 25.6, 66.1, 69.0, 71.1, 77.8, 82.0, 103.9, 107.3, 109.9, 158.2. MS (%) M

at m/z 289. Anal. Calcd. For C13H20O7: C, 54.16, H, 6.99. Found: C, 54.86, H, 7.16.

9.2. 3-O-Formyl-1,2:5,6-di-O-isopropylidene-β-D-glucofuranose (10a):


4xC-CH3), 4.04-4.17 (3H, m, H-5, H-6a, H-6

b), 4.19 (1H, br s, H-

4), 4.54 (1H, d, J = 3.6 Hz, H-2), 5.35 (1H, br s, H-3), 5.89 (1H, d,

J = 7.6 Hz, H-1), 8.10 (1H, s, -OCHO). 13

C NMR (50 MHz,

CDCl3): δ 24.1, 24.2, 25.1, 25.6, 66.3, 69.0, 71.1, 77.8, 82.0, 103.9, 107.3, 109.9, 158.2.

MS (%) M at m/z 289. Anal. Calcd. For C13H20O7: C, 54.16, H, 6.99. Found: C, 54.86,

H, 7.16.

9.3. 6-O-Formyl-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (11a):

1H NMR (500 MHz, CDCl3): δ 1.33, 1.34, 1.45, 152 (3H each, s, 4xC-

CH3), 4.08 (1H, br s, H-5), 4.24-4.37 (4H, m, H-2, H-4, H-6a, H-6

b),

4.64 (1H, d, J = 7.8 Hz, H-3), 5.56 (1H, d, J = 4.7 Hz, H-1), 8.09 (1H,

s, -OCHO). 13C NMR (125 MHz, CDCl3): δ 24.3, 24.5, 25.9, 26.0,

60.4, 63.0, 70.4, 70.6, 70.7, 96.3, 108.8, 109.7, 160.9. MS (%) M at

m/z 288. Anal. Calcd. For C13H20O7: C, 54.16, H, 6.97. Found: C, 54.89, H, 7.06.

OO

OO O

OHCO

OO

OO O

OHCO

O

O

OO

OCHO

O


Page 139

9.4. Formyl-2,3,4,6-Tetra-O-acetyl-α-D-glucopyranoside (12a):


4xCH3), 4.05 (1H, dd, J = 12.4, 4.6 Hz, H-6a), 4.08-4.12 (1H, m,

H-5), 4.19-4.29 (1H, dd, J = 12.5, 2.5 Hz, H-6b), 5.05 (1H, dd, J =

10.1, 3.7 Hz, H-2), 5.10 (1H, t, J = 10.1 Hz, H-4), 5.46 (1H, t, J =

10.2 Hz, H-3), 6.38 (1H, d, J = 3.7 Hz, H-1), 8.10 (1H, s, -OCHO). 13

C NMR (125 MHz,

CDCl3): δ 20.2, 20.4, 20.7, 20.9, 61.2, 67.5, 69.0, 69.4, 70.0, 88.8, 158.4, 169.2, 170.3.

MS (%) (M + Na)

+ at m/z 399. Anal. Calcd. For C15H20O11: C, 47.88, H, 5.43. Found: C,

48.06, H, 5.49.

9.5. Formyl-2,3,4,6-Tetra-O-acetyl-α-D-galactopyranoside (13a):


4xCH3), 4.00 (1H, m, H-5), 4.07-4.12 (1H, dd, J = 12.4, 4.6 Hz, H-

6a), 4.19-4.29 (1H, dd, J = 12.5, 2.5 Hz, H-6

b), 4.44 (1H, d, J = 3.7

Hz, H-2), 5.24-5.31 (2H, m, H-3, H-4), 5.66 (1H, d, J = 3.7 Hz, H-

1), 8.08 (1H, s, -OCHO). 13

C NMR (125 MHz, CDCl3): δ 20.3, 20.4, 20.6, 20.9, 61.4,

67.5, 69.1, 69.5, 70.2, 88.9, 158.4, 169.6, 170.5. MS (%) (M + Na)

+ at m/z 399. Anal.

Calcd. For C15H20O11: C, 47.88, H, 5.43. Found: C, 48.06, H, 5.49.

9.6. Formyl 2,3,4,6-Tetra-O-acetyl-α-D-manopyranoside (14a):


4xCH3), 4.05 (1H, dd, J = 12.4, 4.6 Hz, H-6a), 4.08-4.12 (1H, m,

H-5), 4.17-4.27 (1H, dd, J = 12.5, 2.5 Hz, H-6b), 5.10 (1H, dd, J =

10.3, 3.9 Hz, H-2), 5.16 (1H, t, J = 10.6 Hz, H-4), 5.49 (1H, t, J =

9.7 Hz, H-3), 6.38 (1H, d, J = 3.9 Hz, H-1), 8.10 (1H, s, -OCHO). 13

C NMR (125 MHz,

CDCl3): δ 20.3, 20.5, 20.7, 20.9, 61.4, 67.7, 69.1, 69.6, 70.4, 88.9, 158.4, 169.6, 170.7.

MS (%) (M + Na)

+ at m/z 399. Anal. Calcd. For C15H20O11: C, 47.88, H, 5.43. Found: C,

48.06, H, 5.49.

9.7. Methyl 6-chloro-2,3,4-tri-O-formyl-α-D-glucopyranoside (15a):

1H NMR (500 MHz, CDCl3): δ 3.47 (3H, s, -OCH3), 3.59 (1H, dd,

J = 12.2, 6.1 Hz, H-6a), 3.69 (1H, dd, J = 12.2, 2.4 Hz, H-6

b), 4.10

(1H, ddd, J = 9.6, 6.1, 2.4 Hz, H-5), 5.03-5.05 (1H, m, H-2), 5.08

OOHCO

OHCO

OHCOOMe

Cl

OAcO

AcO

OCHOAcO

OAc

O

AcO

AcO

OCHOAcO

OAc

OAcO

AcO

OCHO

OAcOAc


Page 140

(1H, d, J = 3.4 Hz, H-1), 5.23 (1H, t, J = 9.6 Hz, H-3/H-4), 5.69 (1H, t, J = 9.5 Hz, H-

3/H-4), 8.05 (2H, s, 2x-OCHO), 8.08 (1H, s, -OCHO). 13

C NMR ( 125 MHz, CDCl3): δ

43.6, 56.1, 68.9, 69.2, 69.6, 71.5, 96.7, 159.9, 160.7, 160.9. MS (%) M at m/z 297. Anal.

Calcd. For C10H13ClO8: C, 40.49; H, 4.42; Cl, 11.95. Found: C, 40.52; H, 4.49; Cl, 11.99.

9.8. 2,3,4,6-tetra-O-formyl-α-D-methyl-glucopyranoside (15b):

1H NMR (500 MHz, CDCl3): δ 3.47 (3H, s, -OCH3), 4.12-4.18

(1H, m, H-5), 4.19-4.24 (1H, dd, J = 11.3, 6.3 Hz, H-6a), 4.35-4.38

(1H, dd, J = 11.3, 2.4 Hz, H-6b), 4.44 (1H, d, J = 3.8 Hz, H-2),

5.25-5.38 (2H, m, H-3, H-4), 5.63 (1H, br s, H-1), 8.05 (2H, s, 2x-

OCHO), 8.08 (2H, s, 2x-OCHO). 13

C NMR (125 MHz, CDCl3): δ 55.2, 61.4, 66.5, 68.9,

70.3, 70.9, 101.6, 159.9, 160.7, 160.9. MS (%) M at m/z 307. Anal. Calcd. For

C11H14O10: C 43.14, H 4.61. Found: C, 43.24; H, 4.69.

9.9. Allyl 6-chloro-2,3,4-tri-O-formyl-α-D-glucopyranoside (16a):

1H NMR (500 MHz, CDCl3): δ 3.56 (1H, dd, J =12.2, 6.1 Hz, H-

6a), 3.63 (1H, dd, J = 12.2, 2.5 Hz, H-6

b), 4.04 (1H, dd, J = 12.8,

6.3 Hz, -OCH2), 4.11 (1H, ddd, J = 9.3, 6.3, 2.5 Hz, H-5), 4.22

(1H, dd, J = 12.8, 5.3 Hz, -OCH2), 5.00-5.03 (1H, m, H-2), 5.18-

5.24 (3H, m, =CH2 & H-1), 5.32 (1H, t, J = 9.6 Hz, H-3/H-4), 5.68 (1H, t, J = 10.0 Hz, H-

3/H-4), 5.82-5.90 (1H, m, =CH), 8.02, 8.03, 8.04 (1H each, s, 3x-OCHO). 13

C NMR (125

MHz, CDCl3): δ 43.6, 56.1, 68.9, 69.2, 69.6, 71.5, 96.7, 159.9, 160.7, 160.9. MS (%) M

at m/z 297. Anal. Calcd. For C10H13ClO8: C, 40.49; H, 4.42; Cl, 11.95. Found: C, 40.52;

H, 4.49; Cl, 11.99.

9.10. Allyl-2,3,4,6-tetra-O-formyl-α-D-glucopyranoside (16b):

1H NMR (500 MHz, CDCl3): δ 3.32-3.43 (1H, m, H-5), 3.56 (1H,

dd, J = 12.2, 6.1 Hz, H-6a), 3.63 (1H, dd, J = 12.2, 2.5 Hz, H-6

b),

4.04 (2H, dd, J = 12.8, 6.3 Hz, -OCH2), 5.00-5.03 (1H, m, H-2),

5.18-5.24 (3H, m, =CH2 & H-1), 5.32-5.57 (2H, m, H-3, H-4),

5.82-5.90 (1H, m, =CH), 8.02, 8.03, 8.04, 8.06 (1H each, s, 4x-OCHO). 13

C NMR (125

MHz, CDCl3): δ 43.9, 56.5, 67.8, 69.6, 70.6, 71.3, 96.6, 159.7, 160.9. MS (%) M

at m/z

332. Anal. Calcd. For C13H16O10: C, 46.99; H, 4.85. Found: C, 47.52; H, 4.99.

OOHCOOHCO

OHCOO

Cl

OOHCO

OHCO

OMeOHCO

OCHO

OOHCOOHCO

OHCOO

OCHO


Page 141

9.11. Phenyl 6-chloro-2,3,4-tri-O-formyl-β-D-thio-glucopyranoside (17a):

1H NMR (500 MHz, CDCl3): δ 3.55-3.57 (1H, dd, J = 12.3,

6.1 Hz, H-6a), 3.60-3.65 (1H, dd, J = 12.3, 2.4 Hz, H-6

b),

3.74-3.78 (1H, ddd, J = 9.3, 6.1, 2.4 Hz, H-5), 4.71 (1H, d,

J = 10.1 Hz, H-1), 5.02 (1H, t, J = 9.6 Hz, H-2), 5.12 (1H, t, J = 10.7 Hz, H-3/H-4), 5.39

(1H, t, J = 9.3 Hz, H-3/H-4), 7.24-7.28 (3H, m, 3xAr-H), 7.48 (2H, d, J = 5.4 Hz, 2xAr-

H), 7.93, 7.96, 7.99 (1H each, s, 3xOCHO). 13

C NMR (125 MHz, CDCl3): δ 41.8, 67.6,

68.0, 71.4, 84.3, 127.7, 128.0, 129.7, 132.5, 157.8, 157.9, 158.4. MS (%) M+

at m/z 475.

Anal. Calcd. For C15H15ClO7S: C, 48.07; H, 4.03; Cl, 9.46; S, 8.56. Found: C, 48.04; H,

4.09; Cl, 9.53; S, 8.62.

9.12. Phenyl-2,3,4,6-tetra-O-formyl-β-D-thio-glucopyranoside (17b):

1H NMR (500 MHz, CDCl3): δ 3.77-3.83 (1H, m, H-5),

4.25-4.29 (1H, dd, J = 12.3, 5.1 Hz, H-6a), 4.35-4.38 (1H,

dd, J = 12.3, 1.9 Hz, H-6b), 4.76 (1H, d, J = 10.0 Hz, H-1),

5.13 (1H, t, J = 9.6 Hz, H-3/H-4), 5.25 (1H, t, J = 9.8 Hz, H-3/H-4), 5.49 (1H, t, J = 9.4

Hz, H-2), 7.26-7.39 (3H, br s, 3xAr-H), 7.50 (2H, d, J = 6.2 Hz, 2xAr-H), 8.01 (2H, br s,

2x-OCHO), 8.07 (2H, br s, 2x-OCHO). 13

C NMR (125 MHz, CDCl3): δ 60.9, 68.1, 69.8,

73.2, 76.0, 129.6, 129.7, 129.9, 134.0, 159.6, 160.1, 160.4, 160.9. MS (%) M+

at m/z 475.

Anal. Calc. For C16H16ClO9S: C, 50.00; H, 4.20; S, 8.34. Found: C, 51.00; H, 4.29; S,

8.39.

9.13. Methyl 6-chloro-2,3,4-tri-O-formyl-α-D-manopyranoside (18a):


J = 12.2, 6.2 Hz, H-6a), 3.69 (1H, dd, J = 12,2, 2.6 Hz, H-6

b), 4.06

(1H, ddd, J = 9.3, 6.2, 2.6 Hz, H-5), 4.79 (1H, d, J = 1.4 Hz, H-1),

5.43-5.57 (3H, m, H-2, H-3, H-4), 7.96, 8.08, 8.12 (1H each, s, 3x-

OCHO). 13

C NMR (125 MHz, CDCl3): δ 43.2, 55.7, 66.7, 68.3, 68.8, 69.7, 98.2, 159.4,

159.5, 160.9. MS (%) M at m/z 296. Anal. Calcd. For C10H13ClO8: C, 40.55; H, 4.42; Cl,

11.95. Found: C, 40.59; H, 4.46; Cl, 12.02.

OOHCOOHCO

OCHO

OMe

Cl

OOHCOOHCO

OCHO

S

Cl

OOHCOOHCO

OCHO

S

OCHO


Page 142

9.14. Methyl-2,3,4,6-tetra-O-formyl-α-D-methyl-mano pyranoside (18b):

1H NMR (500 MHz, CDCl3): δ 3.54 (3H, s, -OCH3), 3.79-3.85 (1H,

m, H-5), 4.33-4.38 (1H, dd, J = 12.2, 5.2 Hz, H-6a), 4.51-4.60 (1H,

dd, J = 12.1, 2.5 Hz, H-6b), 4.72 (1H, d, J = 2.5 Hz, H-1), 5.22-5.29

(2H, m, H-2, H-3), 5.45 (1H, d, J = 9.7 Hz, H-4), 7.95, 8.06, 8.10,

8.15, (1H each, s, 4x-OCHO). 13

C NMR (125 MHz, CDCl3): δ 55.4, 61.2, 66.2, 68.1,

70.3, 70.7, 101.3, 115.8, 159.3, 159.5, 159.7, 160.2. MS (%) M at m/z 307. Anal. Calcd.

For C11H14O10: C 43.14, H 4.61. Found C 44.01, H 4.67.

9.15. Methyl 6-chloro-2,3,4-tri-O-formyl-α-D-galactopyranoside (19a):


J = 12.3, 6.1 Hz, H-6a), 3.68 (1H, dd, J = 12.2, 2.4 Hz, H-6

b), 4.10

(1H, ddd, J = 9.7, 6.1, 2.4 Hz, H-5), 5.04-5.07 (1H, m, H-2), 5.08

(1H, d, J = 3.5 Hz, H-1), 5.23 (1H, t, J = 9.6 Hz, H-3/H-4), 5.69

(1H, t, J = 9.5 Hz, H-3/H-4), 8.06 (2H, s, 2x-OCHO), 8.10 (1H, s, -OCHO). 13

C NMR (

125 MHz, CDCl3): δ 43.7, 56.4, 69.1, 69.4, 69.8, 72.0, 97.0, 160.2, 160.7, 161.0. MS (%)

M at m/z 297. Anal. Calcd. For C10H13ClO8: C, 40.48; H, 4.43; Cl, 11.95. Found: C,

40.54; H, 4.49; Cl, 11.99.

9.16. Methyl-2,3,4,6-tetra-O-formyl-α-D-methyl-galactopyranoside (19b):

1H NMR (500 MHz, CDCl3): δ 3.49 (3H, s, -OCH3), 4.03 (1H, t, J

= 6.3 Hz, H-5), 4.19-4.23 (1H, dd, J = 11.3, 6.5 Hz, H-6a), 4.35-

4.38 (1H, dd, J = 11.3, 6.6 Hz, H-6b), 4.40 (1H, d, J = 3.6 Hz, H-

2), 5.22-5.29 (2H, m, H-3, H-4), 5.62 (1H, br s, H-1), 7.95, 8.06,

8.10, 8.15, (1H each, s, 4x-OCHO). 13

C NMR (125 MHz, CDCl3): δ 55.4, 61.2, 66.2,

68.1, 70.3, 70.7, 101.3, 159.3, 159.5, 159.7, 160.2. MS (%) M at m/z 308. Anal. Calcd.

For C11H14O10: C 43.14, H 4.61. Found: C, 44.86, H, 4.66.

9.17. p-methoxy phenol-6-chloro-2,3,4-tri-O-formyl-β-D-glucopyranoside (20a):

1H NMR (500 MHz, CDCl3): δ 3.53-3.59 (1H, dd, J

= 12.1, 6.1 Hz, H-6a), 3.62-3.66 (1H, dd, J = 12.2,

2.4 Hz, H-6b), 3.73 (3H, s, -OCH3), 3.77-3.84 (1H,

m, H-5), 4.89 (1H, d, J = 9.7 Hz, H-1), 5.03 (1H, t, J = 9.6 Hz, H-2), 5.11 (1H, t, J = 10.7

O

OHCO

OHCO

OHCOOMe

Cl

OOHCOOHCO

OCHO

O

Cl

OMe

OOHCO

OHCO

OMe

OCHOOCHO

O

OHCO

OHCO

OMeOHCO

OCHO


Page 143

Hz, H-3/H-4), 5.42 (1H, t, J = 9.3 Hz, H-3/H-4), 6.87 (2H, d, J = 8.3 Hz, 2xAr-H), 6.99

(2H, d, J = 8.4 Hz, 2xAr-H), 7.93, 7.96, 7.99 (1H each, s, 3x-OCHO). 13

C NMR (125

MHz, CDCl3): δ 42.1, 56.3, 67.4, 68.2, 71.8, 83.8, 126.9, 128.1, 129.6, 132.5, 157.4,

157.9, 158.4. MS (%) M+

at m/z 362. Anal. Calcd. For C15H15ClO8: C, 50.22; H, 4.21; Cl,

9.88. Found: C, 50.31; H, 4.29; Cl, 9.93.

9.18. 6-Chloro-3,5-di-O-formyl-1,2-O-isopropylidene-β-D-glucofuranose (21a):

1H NMR (500 MHz, CDCl3): δ 1.34 & 1.53 (3H each, s, 2xCH3),

3.77-3.99 (2H, m, CH2Cl), 4.52 (1H, d, J = 3.6 Hz, H-2), 4.59

(1H, d, J = 2.9 Hz, H-4) 5.35-5.41 (1H, m, H-5), 5.46 (1H, d, J =

5.9 Hz, H-3), 5.93 (1H, d, J = 3.5 Hz, H-1), 8.1 (2H, s, 2x-OCHO). 13

C NMR (125 MHz,

CDCl3): δ 26.6, 27.0, 44.3, 66.6, 68.6, 74.7, 83.6, 105.5, 113.3, 159.6, 159.6. MS (%) M

at m/z 295. Anal. Calcd. For C11H15ClO7: C 44.83, H 5.13, Cl 12.03: found C 44.86, H

5.17, Cl 12.08.

9.19. 6-Chloro-3,5-di-O-formyl-1,2-O-isopropylidene-α-D-glucofuranose (22a):

1H NMR (500 MHz, CDCl3): δ 1.33 & 1.54 (3H each, s, 2xCH3),

3.77-3.99 (2H, m, CH2Cl), 4.53 (1H, d, J = 3.5 Hz, H-2), 4.59

(1H, d, J = 2.7 Hz, H-4) 5.31-5.38 (1H, m, H-5), 5.42 (1H, d, J =

2.7 Hz, H-3), 5.93 (1H, d, J = 3.5 Hz, H-1), 8.0 (2H, s, 2x-

OCHO). 13

C NMR (125 MHz, CDCl3): δ 26.7, 27.1, 44.4, 66.6, 68.6, 74.8, 83.4, 105.4,

113.4, 159.6, 159.6. MS (%) M at m/z 295. Anal. Calcd. For C11H15ClO7: C 44.83, H

5.13, Cl 12.03. Found C 44.86, H 5.17, Cl 12.08.

OClOHCO

O

O

OHCO

OClOHCO

O

O

OHCO

Chapter 3

Chapter 3

Some of selected compounds 1H & 13C

Spectra:


Page 144

1H NMR spectram of compound 10a in CDCl3 (500 MHz)

13

C NMR spectram of compound 10a in CDCl3 (500 MHz)

OO

OO O

OHCO

OO

OO O

OHCO


Page 145


13


O

O

OO

OCHO

O

O

O

OO

OCHO

O


Page 146


13C NMR spectram of compound 15a in CDCl3 (200 MHz)

OOHCO

OHCO

OHCOOMe

Cl

OOHCO

OHCO

OHCOOMe

Cl


Page 147


13C NMR spectram of compound 16a in CDCl3 (500 MHz)

OOHCOOHCO

OHCOO

Cl

OOHCOOHCO

OHCOO

Cl


Page 148


13


OOHCOOHCO

OCHO

S

Cl

OOHCOOHCO

OCHO

S

Cl


Page 149

1H NMR spectram of compound 17b in CDCl3 (500 MHz)

13

C NMR spectram of compound 17b in CDCl3 (500 MHz)

OOHCOOHCO

OCHO

S

OCHO

OOHCOOHCO

OCHO

S

OCHO


Page 150


13


OOHCOOHCO

OCHO

OMe

Cl

OOHCOOHCO

OCHO

OMe

Cl


Page 151


13

C NMR spectram of compound 19b in CDCl3 (500 MHz)

O

OHCO

OHCO

OMeOHCO

OCHO

O

OHCO

OHCO

OMeOHCO

OCHO


Page 152


13C NMR spectram of compound 21b in CDCl3 (200 MHz)

OClOHCO

O

O

OHCO

OClOHCO

O

O

OHCO

Chapter 3:

Chapter 3:

Section B: Chemo-enzymatic Approach

for the Synthesis chiral Pyridyl

alcohols:

Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3

Page 153

Chemo-enzymatic Approach for the Synthesis of chiral Pyridyl alcohols:

1. Introduction:

Over the past decade, a great deal of progress has been made in the area of

enantioselective reactions1 and molecular recognition chemistry,

2 in which chiral ligands

play a critical role in stereoselective reactions and recognition processes. Therefore, the

synthesis of novel chiral ligands has become increasingly valuable for organic chemist. In

particular, the three-dimensional design of ligand molecules is important to achieve high

stereoselective face and site recognition. In this context chiral pyridyl ethanols are

important intermediates in the synthesis of a variety of pharmaceuticals as well as

alkaloids such as akuamidine, heteroyohimidine,3 having therapeutic values and have also

been used as common donor ligands.4 These chiral alcohols are useful as dopants, which

give spiral structures for liquid crystal molecules in liquid crystal compositions. Apart

from this, chiral pyridyl ethanols are useful chiral auxiliaries as they serve as an efficient

catalyst in a number of asymmetric addition reactions.5 The asymmetric reduction of

heteroaryl ketones is a straightforward approach to prepare these classes of compounds.

Although many chiral pyridyl ligands have been reported6 so far, most of these have been

constituted involving a non-chiral unit connected by a carbon-heteroatom bond with a

chiral unit. The chiral part is generally obtained from commercial sources. On the other

hand, those with a chiral center on the pyridine side have rarely been adopted as chiral

ligands.7 The limited use of chiral pyridyl and 2,2'-bipyridyl ligands may be due to the

limited availability of chiral pyridines and 2,2'-bipyridines. The introduction of a chiral

center directly attached to pyridyl or 2,2'-bipyridyl rings poses a difficult problem.

1 Stereoselective synthesis, Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.; Eds.; Georg

Thieme Verlag: Stuttgart, 1996. 2 Comprehensive Supramolecular Chemistry; Lehn, J.-M., Ed. In chief; Elsevier Science Ltd.: New York,

1996. 3 Uskokovic, M. R.; Lewis, R. L.; Partridge, J. J.; Despreaux, C. W. J. Am. Chem. Soc., 1979, 101, 6742.

4 Reedijk, J. In Comprehensive Coordination Chemistry; Wilikinson, Sir G., Ed.; Pergamon Press: London,

1987, Vol. 2; p 73. Constable, E. C. Metals and Ligand Reactivity; VCH: Weinheim, 1995. 5 (a) Quallich, G. J.; Woodall, T. M. Tetrahedron Lett., 1993, 34, 4145. (b) Collomb, P.; Zelewsky, A.

Tetrahedron Asymmetry, 1998, 9, 3911. 6 (a) Brunner, H.; Reiter, B.; Riepl, G. Chem. Ber. 1984, 117, 1330. (b) Nishiyama, H.; Sakaguchi, H.;

Nakamura, T.; Horihata, M.; Kondo, M.; Itoh, K. Organometallics, 1989, 8, 846. (c) Chelucci, G.; Falorni,

M.; Giacomelli, G. Tetrahedron Asymmetry, 1990, 1, 843. (d) Brunner, H.; Brandl, P. Tetrahedron

Asymmetry, 1991, 2, 919. (e) Chelucci, G.; Soccolini, F. Tetrahedron Asymmetry, 1992, 3, 1235. (f)

Kandzia, C.; Steckhan, E.; Knoch, F. Tetrahedron Asymmetry, 1993, 4, 39. (g) Scrimin, P.; Tecilla, P.;

Tonellato, U. J. Org. Chem., 1994, 59, 4194. 7 (a) Botteghi, C.; Caccia, G.; Chelucci, G.; Soccolini, F. J. Org. Chem., 1984, 49, 4290. (b) Chelucci, G.

Tetrahedron Asymmetry, 1995, 6, 811. (c) Bolm, C.; Ewald, M. Tetrahedron Lett., 1990, 31, 5011. (d)

Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber., 1992, 125, 1191.


Page 154

2. Brief review on Reported methods:

Presently several methods are available for the synthesis of chiral pyridines. A

brief review on the reported methods for the preparation of chiral pyridine compounds are

described here.

2.1. Junichi Approach:8 Optical resolution of 1-(2-pyridyl) and 1-[6-(2,2'-bipyridyl)]

ethanols by lipase-catalyzed enantioselective acetylation:

Recently Junichi et al.8 developed a method for the resolution of racemic 1-(2-

pyridyl) ethanols, by lipase-catalyzed asymmetric acetylation with vinyl acetate.

NR Br

NR CHO

NRR'

OH

R'MgBr

Et2O

1) BuLi, -78 0C

Hexane: Et2O: THF (1:2:1), DMA

2) NaBH4/MeOH, rt

Lipase

Vinyl acetate, iso-Pr2O

Molecular sieves 4A0

NRR'

OAc

NRR'

OH

2a-k (racemic)

R (2a-k) S (2a-k)

1a R = H, R' = Me: 1b R = Br, R' = Me: 1c R = TBDMSOCH2, R' = Me: 1d

R = TrOCH2, R' = Me: 1e R = Ph, R' = Me: 1f R = 2-Ph, R' = Me1f:

1g R = , R' = Me: 1h R = , R' = Me:

1i R = H, R' = Et: 1j R = H, R' = Vinyl: 1k R = H, R' = allyl

NBr NTBDMSO

1a-h

1i-k

+

Scheme-1

The reactions were carried out in diisopropyl ether at either room temperature or

60 0C using Candida Antarctica lipase (CAL) to give (R)-acetate and unreacted (S)-

alcohol with excellent enantiomeric purities in good yields.

Junichi and his co-workers have further shown that for substrates bearing a sp3-type

carbon at the 6-position on the pyridine ring, for example methyl substitution, and for

those bearing 1-hydroxypropyl and allyl groups at the 2-position on the pyridine ring the

8 (a) Junichi, U.; Takao, H.; Shinichiro, H.; Kenji, N.; Osamu, Y. J. Org. Chem., 1998, 63, 2481. (b)

Junichi, U.; Nishiwaki, K.; Hata, S.; Nakamura, K. Tetrahedron Lett., 1994, 35, 616.


Page 155

reaction rate was relatively slow at room temperature in such cases, running the reaction

at higher temperature at 60 0C, resulted in the acceleration 3- to 7-fold without losing the

high enantiospecificity (Scheme-1).

2.2. Yves approach:9 First one-pot chemo-, regio and enantioselective

functionalisation of pyridine compounds:

Yves et al. have developed a novel method for the preparation of optically active

pyridine compounds. They aimed to develop a new and useful super base formed by

association of BuLi with chiral vicinal aminoalkoxides.10

NX

1) BuLi-R*OLi (3 eq)

Hexane, -78 0C

NXR'

OH

2) R1CHO in THF

-78 0C

R*OLi = LiOMe

NMe2

LiO

NMe2

Me

OLi

NMe2

OLi

N

(3) X = Cl, R' = (4) X = Cl, R' = (5) X = Cl, R' =

OMe Cl

Scheme-2

The obtained BuLi–R*OLi reagent should allow direct and regioselective metallation of

the pyridinic ring while controlling unprecedented asymmetric addition of the formed

pyridyl lithium to aldehydes. But the developed method affords products bearing

moderate enantiomeric excess (Scheme-2).

9 Yves, F.; Philippe, G.; Alain, L. R. Tetrahedron Asymmetry, 2001, 12, 2631.

10 Pu, L.; Yu, H.-B. Chem. Rev., 2001, 101, 757.


Page 156

2.3. Soni approach:11

Biocatalytic reduction of hetero aryl methyl ketones:

Soni and co-workers have accomplished the enantioselective reduction of various

heteroaryl methyl ketones, such as 2-, 3-, and 4-acetyl pyridines, 2-acetyl thiophene, 2-

acetyl furan, and 2-acetyl pyrrole, with the resting cells of a novel yeast strain Candida

viswanathii. Excellent results were obtained with acetyl pyridines. Moderate conversion

took place with 2-acetyl thiophene, but no significant reduction was observed with 2-

acetyl furan and 2-acetyl pyrrole. In the case of acetyl pyridines, the bioreduction was

found to be sensitive toward the nature of substitution on the pyridine nucleus and the

conversion followed the order 4-acetyl pyridine > 3-acetyl pyridine > 2-acetyl pyridine.

Reduction of 3-acetyl pyridine with a high conversion (>98%) and excellent

enantioselectivity (ee >99%) provided the biocatalytic preparation of (S)-(3-pyridyl)

ethanol. Finally, preparative scale reduction of 3-acetyl pyridine has been carried out with

excellent yield (>85%) and almost absolute enantioselectivity (ee >99.9%).

R CH3

O

R CH3

OHCandida viswanathii

0.2 M, pH 7.0 buffer

(6) R = 2-pyridyl (7) R = 3-pyridyl (8) R = 4-pyridyl(9) R = 2-thienyl (10) R = 2-furyl (11) R = 2-pyrrolyl

S-(2a) R = 2-pyridyl S-(12) R = 3-pyridyl S-(13) R = 4-pyridylS-(14) R = 2-thienyl S-(15) R = 2-furyl S-(16) R = 2-pyrrolyl

Scheme-3

The reduction of 2-acetyl pyridine 6 took place with 81–85% conversion. Although 2-

acetyl thiophene 9 was reduced to some extent (9–12% conversion), negligible reduction

of 2-acetyl furan 10, and 2-acetyl pyrrole 11 was observed.

To obtain the best biocatalyst, about 50 oxidoreductase producing soil isolates were tried

for the reduction of ketones (6, 9-11) (Scheme-3). Three yeast species Candida

viswanathii, Candida parapsilopsis, and Candida melibiosa were found to possess

appreciable reductive properties (Table 1).

11

(a) Soni, P.; Kaur, G.; Chakraborti, S. K.; Banerjee, U. C. Tetrahedron Asymmetry, 2005, 16, 2425. (b)

Soni, P.; Kamble, A. L.; Banerjee U. C. Indian Patent Appl, No. 440/DEL/2005. (c) Kamble, A. L.; Soni,

P.; Banerjee, U. C. J. Mol. Catal. B: Enzym., 2005, 35, 1.


Page 157

Table 1: Screening results of heteroaryl methyl ketone reduction:

Microorganisms 2-acetyl

pyridine 6

2-acetyl

thiophene 9

2-acetylfuran

10

2-acetyl pyrrole

11

C. viswanathii 85.39 12.08 3.07 2.13

C. parapsilopsis 81.05 8.95 - -

C. melibiosa 83.38 10.98 - - Reaction conditions: Resting cells (166 g/L) in phosphate buffer (pH 7.0, 0.2 M) and ketone concn. in

reaction (2 g/L); reaction for 12 h at 30 0C (200 rpm).

2.4. Stepanenko approach:12

Synthesis of pyridyl and related heterocyclic alcohols

using spiroborate esters in the borane-mediated asymmetric reduction:

Stepanenko et al. have shown the effectiveness of several spiroborate ester

catalysts in the asymmetric borane reduction of 2-, 3-, and 4-acetylpyridines (6-8) under

different reaction conditions. Highly enantiomerically enriched 1-(2-, 3-, and 4-pyridyl)

ethanols (2a, 12 and 13) and 1-(heterocyclic)ethanols have been obtained using 1–10%

catalytic loads of the spiroborate derived from diphenylprolinol and ethylene glycol

(Scheme-4).

Cat. (0.1-10%)

BH3-DMS

Cat:

BO O

ONH

R CH3

O

R CH3

OH

(R)- 2a, 12, 13

BO O

ONH

(6) R = 2-pyridyl (7) R = 3-pyridyl (8) R = 4-pyridyl

Scheme-4

2.5. Szatzker approach:13

Chemo enzymatic preparation of all the stereoisomers of

2-(1 hydroxyethyl)-pyridines and their acetates:

Recently Szatzker et al. have screened various lipases for the enantio selective

acetylation of racemic 1-[6-(1-hydroxyethyl)-pyridin-2-yl]ethanone racemic and the

12

Stepanenko, V.; De Jesús, M.; Correa, W.; Guzmán, I.; Vázquez, C.; Ortiz, L.; Ortiz-Marciales, M.

Tetrahedron Asymmetry, 2007, 18, 2738. 13

Szatzker, G.; Moczar, I.; Kolonits, P.; Novak, L.; Huszthy, H.; Poppe, L. Tetrahedron asymmetry, 2004,

15, 2483.


Page 158

reaction of 18 has furnished alcohol (S)-18 and acetate (R)-19 using most selective

Novozym 435 lipase in vinyl acetate. Furthermore, hydrolysis of acetyl derivatives of

racemic 18 also afforded optically active acetylated product (S)-19 and hydrolyzed

product (R)-18 (Scheme-5).

NH

O

0.25 eq/NaBH4

N

OH

N

OAc

N

OH

Ac2O, Et3N

Novozyme 435

lipase

Vinyl acetate

N

OAc

+

N

OH

N

OAc

+

rac-19

17 rac-18

(R)-18 (S)-19

(S)-18 (R)-19O

H

O

H

O

H

O

H

O

H

O

H

O

H

Scheme-5

2.6. Orrenius approach:14

Preparation of 1-(2-, 3-, and 4-pyridinyl) ethanols of high

enantiomeric purity by lipase catalysed transesterification:

Orrenius et al. reported high enantioselectivity of 1-pyridylethanols in catalyzing

transesterification reaction in non-aqueous media using lipase of the candida Antarctica

yeast.

NOH N

OLipaseS C7H15

O

+ C7H15

O N

OHSH+ +

Racemic 2a, 12, 13 (R = H)Racemic 20 (R = Br)

R R

(S)21-24

25

R

(R)-2a, 12, 13 (R = H)(R)-20 (R = Br)

Scheme-6

This methodology has been exploited by the another to resolve racemates of 1-(2-, 3-, and

4-pyridyl) ethanols (2a, 12 and 13) and 1-(6-bromopyridine-2-yl) ethanol (20). The lipase

esterified the (R)-alcohols (2a, 12 and 13) of the 1-(pyridyl) ethanols in ≥99%

enantiomeric excess in less than three hours with 30-40 isolated yields. Remaining (S)-

14

Orrenius, C.; Mattson, A.; Norin, T. Tetrahedron Asymmetry, 1994, 5, 1363.


Page 159

enantiomers (21-24) were isolated in similar yields and in 97-98% ee (Scheme-6) (Table-

2).

Table 2: enantiomeric purities and yields of resolved secondary alcohol and their acyl

derivatives: Substrate Convn. (%)

Products

Remaining alcohol Reacted alcohol (Acyl

derivatives)

ee Rot. Conf. Yield ee Rot. Conf. Yield

2a 49 (50) 97 (-) S 45 >99 (+) R 39

12 50 (50) 98 (-) S 44 99 (+) R 35

13 49 (50) 97 (-) S 38 >99 (+) R 33

20 49 (40) 98 (-) S 46 >99 (+) R 31

2.7. Nakamura Approach:15

Asymmetric synthesis of both enantiomers of secondary

alcohols by reduction with a single Microbe:

Recently Nakamura et al. have prepared both enantiomers of secondary alcohols

by reduction of the corresponding ketones with a single microbe. Thus, reduction of

aromatic ketones (6-8) with Geotrichum candidum IFO 5767 afforded the corresponding

(S)-alcohols (2a, 12 and 13) in an excellent ee when amberlite™ XAD-7, a hydrophobic

polymer, was added to the reaction system and the same microbe afforded (R)-alcohols

(2a, 12 and 13) also in an excellent ee when the reaction was conducted under aerobic

conditions (Scheme-7).

(R)-2a-, 12, 13(S)- 2a, 12, 13

92->99%ee96->99%yield

85->99%ee61->99%yield

XAD-7aerobic conditionsN

G. candidum IFO5767a

6-8

G. candidum IFO5767a

OH

N

OH

N

O

Scheme-7

15

Nakamura, K.; Takenaka, K.; Fujiib, M.; Idb, Y. Tetrahedron. Lett., 2002, 43, 3629.


Page 160

2.8. Carsten Bolm approach:16

Optically active bipyridines in asymmetric catalysis:

Bolm et al. have reported the enantioselective synthesis of homochiral C2-

symmetric bipyridines 31and 32, the X-ray structure analysis of a complex of (R,R)-32

and cobalt (II) chloride, and the first investigations of the use of these optically active

bipyridines as enantioselective catalysis. For the synthesis of the enantiomerically pure

bipyridine (-)-(R,R)-31 they have used the optically active alcohol (R)-27, which is

accessible in a two-step reaction from 2,6-dibromopyridine (26) (Scheme-8).

NBr Br NBr

OH

BuLi, tBuCHO, THF

NBr

O

N

OH

NBr

OH

NBr

OCH3

BuLi,tBuCOOCH3, THF

PCC/CH2Cl2

1) (-)-B-chlorodiisopinocam phenyl borane2) iminodiethanol/ether

NaH, CH3I/THF

Bu3SnH, AIBN/Toluene

NiCl2 . 6H2O, Zn, PPh3, DMF

NiCl2. 6H2O, Zn, PPh3, DMF

26 rac-27

28 (R)-29

(R)-27

(R)-30

31 (-)-(R,R) (R = H) 32 (+)- (R,R) (R = CH3)

N N

OR RO

Scheme-8

16

Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., 1990, 29, 205.


Page 161

2.9. Garrett Approach:17

Enantio-complementary preparation of (S)- and (R)-1-

Pyridyl alkanols via ketone reduction and alkane hydroxylation using whole cells of

Pseudomonas putida UV4:

In 2002 Garrett et al. reported the combination of oxidative and reductive

biotransformations that provides a method for the preparation of both enantiomers of

chiral 1-pyridyl alkanols using one biocatalyst (Scheme-9).

N

RPseudomonas putida UV4

N

R

OH

+minor productsincluding

N

R

O

N

R

N

R OH

N

R

OH

NO N

R

OH

N

OO

ADHN

OHOH

33-35 (R)-2a, 12, 13 6-8

35(R)-13

36

6-8

(S)-2a, 12, 13

17 (S,S)-37

alcohol dehydrogenases (ADH)

toluene dioxygenase (TDO)

Scheme-9

For that they have used a previously unreported alcohol dehydrogenase enzyme in

the mutant soil bacterium Pseudomonas putida UV4 catalyses, the reduction of 2-, 3- and

4-acylpyridines (6-8) afforded the corresponding (S)-1-pyridyl alkanols with moderate to

high ee, whilst under the same conditions 2,6-diacetylpyridine (17) is readily converted to

the corresponding enantiopure C2-symmetric (S,S)-diol (37) in one step. In contrast the

17

Garrett, M. D.; Scott, R.; Sheldrake, G. N.; Tetrahedron Asymmetry, 2002, 13, 2201.


Page 162

toluene dioxygenase enzyme in the same organism catalyses the hydroxylation of 2-, 3-

and 4-alkylpyridines (33-35) to (R)-1-(2-pyridyl) and (R)-1-(3-pyridyl) alkanols. This

process failed to produce (R)-1-(3-pyridyl) alkanols but produced the ring-hydroxylated

product 36 (Scheme-9).

2.10. Busto Approach18

: Kinetic resolution of 4-chloro-2-(1-hydroxyalkyl)-pyridines

using Pseudomonas cepacia lipase:

Busto et al. reported a detailed protocol for the lipase-mediated kinetic resolution

of various 4-chloro-2-(1-hydroxyalkyl) pyridines (38–41) (Scheme-10), as those

compounds are useful intermediates for the production of chemical catalysts derived from

DMAP. Those catalysts can be used in a wide range of asymmetric processes. In addition,

kinetic resolution permits researchers to obtain derivatives of the opposite

stereochemistry, which allows the possibility of stereoselective complementary processes.

The authors have done an exhaustive study to optimize the reaction conditions for the

stereoselective enzymatic transesterification of racemic alcohols (38-41), finding

Pseudomonas cepacia lipase (PSL) as the optimal biocatalyst; the results obtained using

these enzymes are summarized in Table 3.

NR

OH

PSLO

O

+ +

38 = R = Me39 = R = Et40 = R = Pr41 = R = Bu

Cl

THF 30 0C

250 r.p.m

NR

O

Cl

O

CH3

NR

OH

Cl

(R) 42 = R = Me(R) 43 = R = Et(R) 44 = R = Pr(R) 45 = R = Bu

(S) 38 = R = Me(S) 39 = R = Et(S) 40 = R = Pr(S) 41 = R = Bu

Scheme-10

18

Busto, E.; Gotor-Fernandez, V.; Gotor, V. Nature protocols, 2006, 4, 2061.


Page 163

Table 3: Results of kinetic resolution of alcohols 38–41.

Substrate Time (h) eePa

Yield eeSa

Yield Conversionb Enantioselectivity

c

38 14.5 >99 85% >99 88% 50% >200

39 14.5 99 82% >99 88% 50% >200

40 38 >99 97% >99 89% 50% >200

41 60 >99 88% >99 89% 50% >200

Alcohols were resolved at 30 0C and 250 r.p.m. with vinyl acetate (2) as the acyl donor, P. cepacia lipase as

the biocatalyst and tetrahydrofuran as the solvent. aEnantiomeric excess of the (R)-ester product (eeP) and

the (S)-alcohol remaining substrate (eeS), calculated by HPLC analysis. bConversion ¼ eeS / (eeS + eep).

cEnantioselectivity= ln [(1 – c) x (1 + eeP)] / ln [(1 – c) x (1 – eeP)].

3. Objective of the present work:

Chiral ligands are widely used for asymmetric reactions in organic synthesis. Till

date, a large number of chiral ligands have been prepared (fig-2),19

and their usefulness

for asymmetric reactions also been investigated. Since there is a high demand for new and

efficient chiral ligands for application in asymmetric synthesis, the search for new chiral

ligands and catalysts is continuously increasing. A considerable number of ligands having

phosphine and nitrogen functional moieties have been reported in the past few years.20

In

connection with this, phosphine ligands bearing a pyridine ring are of particular interest to

us. We may said that chiral pyridyl alcohols are of particular interest to us all these can be

an important components of chiral phosphine ligands which have been in use for their

excellent application in chiral asymmetric synthesis.

In addition, Pyridyl alcohols are excellent candidates as chiral substructures of several

ligands for asymmetric synthesis and kinetic resolution. Chiral pyridyl alcohols have

proven to be versatile ligands in a variety of catalytic applications and in many cases

including high stereoselectivity.21

For example chiral pyridines catalyze the

enantioselective addition of diethyl zinc to aldehydes,19f

the nickel catalyzed conjugate

19

(a) Collomb, P.; Von Zelewsky, A. Tetrahedron Asymmetry, 1995, 6, 2903. (b) Macedo, E.; Moberg, C.

Tetrahedron Asymmetry, 1995, 6, 549. (c) Vedejs, E.; Chen, X. J. Am. Chem. Soc., 1996, 118, 1809.(d)

Uenishi, J.; Hamada, M. Tetrahedron Asymmetry, 2001, 12, 2999. (e) Nordstrom, K.; Macedo, E.; Moberg,

C. J. Org. Chem., 1997, 62, 1604. (f) Bolm, C.; Schlingloff, G; Harms, K. Chem, Ber., 1992, 125, 1191. 20

(a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev., 2000, 100, 2159 and references

cited therein. (b) Mino, T.; Tanaka, Y.; Sakamoto, M.; Fujita, T. Heterocycles, 2000, 53, 1485. (c) Suzuki,

Y.; Abe, I; Hiroi, K. Heterocycles, 1999, 50, 89. (d) Zhu, G.; Terry, M.; Zhang, X. Tetrahedron Lett., 1996,

37, 4475. (e) Dai, X.; Virgil, S. Tetrahedron Lett., 1999, 40, 1245. 21

Noyori, G. Gazz, Chim, Ital., 1992, 122, 89.


Page 164

addition to enones,22

and asymmetric epoxidation.23

These compounds also serve as

useful starting materials for the preparation of pyridineoxazoline alcohols,24

which

catalyzes other type of processes. Therefore it would be very important to synthesis and

biocatalytic resolution of these pyridyl alcohols and their acyl derivative are the prime

objective of the present work.

NPhN N

OHHO

42

OH

43

N

OH

O

N

44

N

OH

N

45

N

N

X

Y

N

N

Ph2P

N

N

Ph2P

N

N

Ph2P

46 x = H, Y = PPh2

47 x = Ph, Y = PPh2

48 x = 3,5-dimethylphenyl, Y = PPh2

49 x = 2,6-dimethylphenyl, Y = PPh2

50 x = H, Y = OCH3

51 52 53

Fig-2

4. Result and Discussion:

Pyridyl alcohols which serve as chiral auxiliaries in organic synthesis particularly

asymmetric synthesis can be prepared via Grignard reaction or reduction of

corresponding aldehydes. There are a number of reports describing the preparation of

these chiral intermediates by chemical or chemoenzymatic methods all these methods

described above have their limitations.

As a part of the present study, we envisaged the preparation of chiral Pyridyl alcohols and

their acyl derivatives as these compounds can easily be converted to their corresponding

chiral pyridine-phosphine ligands (Fig-2). In this direction pyridyl alcohols (2a, 2i, 2k,

12, 12a, 13, 13a & 56) were prepared by two different methods: (A) 2-, 3- and 4-formyl

22

Bolm, C. Tetrahedron Asymmetry, 1991, 2, 701. 23

Hawkins, J. M.; Sharpless, K, B. Tetrahedron Lett., 1987, 28, 2825. 24

Macedo, E.; Moberg.; C.; Tetrahedron Asymmetry, 1995, 6, 549.


Page 165

pyridines (1i, 54, 55) were first converted into corresponding alcohols using Grignard

reagent prepared from appropriate alkyl halides and magnesium. (B) By the NaBH4

reduction of 2-, 3- and 4-acetyl pyridines (6-8) (Scheme-11).

Et2O

RMgX

1i R = CH3 (2a)R = C2H5 (2i)R = C2H5 (2k)R = CH2Ph (56)

54 R = CH3 (12)R = C2H5 (12a)

Et2O

C2H5MgI

Et2O

C2H5MgI

55 R = CH3 (13)R = C2H5 (13a )

6

NaBH4/MeOH

NaBH4/MeOH

7

NaBH4/MeOH

8

Method A Method B

H

O

N H3C

O

NR

HO

N

R

HO

NH

O

N H3C

O

N

R

HO

N

H

O

N

H3C

O

N

Scheme-11

Alcohols thus obtained were converted to their acyl derivatives (57-69) (Scheme-12) the

racemic acyl derivatives were directly subjected to kinetic resolution using native as well

as commercial hydrolases for the preparation of corresponding optically enriched alcohols

and their esters.


Page 166

2a R = CH3

2i R = C2H5

2k R = C3H5

56 R = CH2Ph

12 R = CH3

12a R = C2H5

13 R = CH3

13a R = C2H5

Pyridine

57 R = R1 CH3

58 R = C2H5, R1 = CH3

59 R = R1 C2H5

60 R = C3H5, R1 = CH3

61 R = CH2Ph, R1 = CH3

Pyridine

62 R = CH3, R1 = CH3

63 R = CH3, R1 = C2H5

64 R = CH3, R1 = C3H7

65 R = C2H5, R1 = CH3

(R1CO)2O

(R1CO)2O

Pyridine

(R1CO)2O

66 R = R1 = CH3 67 R = C2H5, R1 = CH3

68 R = CH3, R1 = C2H5

69 R = CH3, R1 = C3H7

R

HO

N

R

HO

N

R

HO

N

R

R1

O

ON

R

R1

O

ON

R

R1

O

O

N

Scheme-12

After the preparation of racemic acyl derivatives (57-69), our initial experiments were

designed to find the suitable lipase for the enantioselective hydrolysis of esters. For this

purpose several native as well as commercial enzymes were screened to effect hydrolysis

of the ester group in 57-69 (Scheme-13). The results of primary screening experiments

are summarized in Table-4.

Lipase+

57a-67a 2a, 2i, 2k, 56, 12, 12a, 13, 13a

N

O

R

R1

ON

O

R

R1

O

57-67

N

OH

RpH 7

Scheme-13


Page 167

Table 4: Screening of enzymes for the hydrolysis of 1-(2-, 3- and 4-Pyridyl) alcohol

esters:

Enzyme Substrate

57 58 59 60 61 62 63 64 65 66 67 68 69

CAL + + + + Nd + + + Nd + + + +

CCL + + + + + + + Nd + Nd + + Nd

CRL + + + + + + + + + Nd + + Nd

PLAP + + + + + + + Nd + Nd + Nd Nd

Y-15 + + + + Nd + + Nd + Nd + + Nd

ABL + + + + + + + + + + + + +

BB-1 - - - - - - - - - - - - -

RSP-1 - - - - - - - - - - - - -

RSP-2 - - - - - - - - - - - - -

RSP-3 - - - - - - - - - - - - -

RSP-4 - - - - - - - - - - - - -

RSP-5 - - - - - - - - - - - - -

RSP-6 - - - - - - - - - - - - -

RSP-7 - - - - - - - - - - - - -

RSP-8 - - - - - - - - - - - - -

(+) = hydrolysis; (-) = no reaction; Nd = not determined.

As evident from the above data, out of fourteen enzymes only six lipases i.e. Candida

Antarctica lipase (CAL), Candida cylindracea lipase (CCL), Candida rugosa lipase

(CRL), Pig liver acetone (PLA), Y-15 and ABL were able to hydrolyze the substrate

(shown in positive sign).

The literature study revealed that enzymes such as CAL, CCL, CRL and PLA have been

successfully used in the resolution of pyridyl alcohols using trans-esterification method

and only a few publications have appeared showing hydrolysis of acetates at high

temperatures and high reaction timings. Also after the results of initial screening,

preparation of optically enriched 1-(2, 3- and 4-Pyridyl) acyl derivatives and their

alcohols was achieved (Scheme-14) of the corresponding racemic 1-(2-, 3- and 4-Pyridyl)

alkanoats 57-69 using our native enzymes.


Page 168

R (57a-67a)S (2a, 2i, 2k, 56, 12, 12a, 13, 13a)

lipase (ABL) +

lipase (Y-15)

pH 7

N

O

R

R1

O

57-67

pH 7

N

R

O

O

R1

N

R

OH

S (57a-67a) R (2a, 2i, 2k, 56, 12, 12a, 13, 13a)

+N

R

O

O

R1N

R

OH

Scheme-14

Table 5: ABL catalyzed kinetic resolution of 1-(2-, 3- and 4-Pyridyl) alkanoates 57-69 in

aqueous buffer phase.

Entry Conv. Time (h) Alcohol Ester E

ee% 25

D

Conf. ee% 25

D

Conf.

57 46 3 98 +16.8 R 93 -41.2 S 39

58 53 3 77 +40.6 R 94 -60.0 S 67

59 26 4 94 +42.3 R 66 -39.0 S 176

60 26 4 92 +36.5 R 78 -33.4 S 58

61 22 10 15 +3.5 R 29 -11.3 S 95

62 49 3 97 +26.8 R 71 -40.3 S 278

63 48 3 92 +22.3 R 87 -41.3 S 171

64 39 4 74 +23.6 R 77 -40.6 S 84

65 26 4 34 +44.0 R 64 -33.6 S 184

66 37 3 77 +33.4 R 56 -24.9 S 95

67 37 3 77 +33.4 R 56 -24.9 S 95

68 33 4 66 +23.6 R 85 -23.7 S 32

69 26 6 59 +31.4 R 48 -23.1 S 44

The optical rotations were measured with c 1 CHCl3.


Page 169

Table 6: Y-15 catalyzed kinetic resolution of 1-(2-, 3- and 4-Pyridyl) alkanoates 57-69 in

aqueous buffer phase.

Entry Conv.

Time (h) Alcohol Ester E

ee% 25

D

Conf. ee% 25

D

Conf.

57 33 5 66 -22.2 S 73 +32.6 R 165

58 23 5 71 -26.0 S 94 +40.4 R 244

59 21 5 36 -37.0 S 61 +42.3 R 56

60 23 5 77 -33.0 S 71 +39.3 R 225

61 20 12 13 -11.3 S 33 +3.9 R 67

62 49 5 91 -36.5 S 90 +24.6 R 278

63 49 5 86 -40.3 S 94 +20.4 R 24

64 39 5 56 -40.8 S 17 +23.1 R 84

65 33 5 77 -40.0 S 54 +24.5 R 88

66 30 5 77 -24.0 S 56 +33.8 R 32

67 33 5 77 -24.0 S 56 +37.4 R 86

68 21 5 66 -33.0 S 85 +31.8 R 225

69 18 8 64 -33.1 S 38 +31.4 R 48

The optical rotations were measured with c 1 CHCl3.

For the detailed investigation, stereoselective hydrolysis was carried out in aqueous 0.1

M-phosphate buffer at pH 7.0 in the temperature range 25-35 0C. It was found that the

reaction time was reduced as well as enantioselectivity was quite high in almost all the

cases (ee 94%). In order to improve the rate of hydrolysis as well as enantioselective

manipulation of the reaction medium was another practical option. Biphasic system using

an organic solvent proved to be advantageous. Both non polar as well as polar solvents 5-

10% v/v were used in the resolution studies and finally acetonitrile was found to be the

co-solvent of choice in terms of conversion rates as well as enantioselectivity as shown in

Table 7 and 8 for the substrate 62. Addition of acetonitrile as co-solvent with (10% v/v)

in buffer reduced the reaction time and also increased the ee. Therefore acetonitrile was

selected as co-solvent for detailed kinetic resolution studies of the other substrates. The

enantiomeric excess of alcohols and their acyl derivatives were determined by chiral

HPLC analysis. The racemic and the resolved byproducts were analyzed using HPLC

with chiral columns like ODH, OJH.


Page 170

Table 7: Effect of co-solvent on ABL catalyzed hydrolysis of (±) 62.

Co-solvent Convn. T (h) ees eep

Acetonitrile 50 3 >99.99 >99.99

Dimethyl formamide 48 4 94 99

Dimethyl sulphoxide 43 3 99 99

Acetone 39 4 94 81

Hexane 61 3 91 86

Toluene 76 3 78 85

Enantiomeric excess of the (R)-ester remaining substrate (ees) and the (S)-alcohol product (eep),

Table 8: Effect of co-solvent on Y-15 catalyzed hydrolysis of (±) 62.

Co-solvent Convn. T (h) ees eep

Acetonitrile 49 3 >99.99 >99.99

Dimethyl formamide 46 3 99 >99

Dimethyl sulphoxide 44 3 88 86

Acetone 44 4 74 97

Hexane 33 3 68 77

Toluene 36 3 46 64

Enantiomeric excess of the (S)-ester remaining substrate (ees) and the (R)-alcohol product (eep),

In general kinetic resolution studies of compounds 57-69 using acetonitrile as the co-

solvent displayed comparatively faster conversion rates as well as improved

enantioselectivity. The results of the experiments are presented in Table -9.


Page 171

Table 9: ABL catalyzed kinetic resolution of 57-69 with acetonitrile as co-solvent.

Sub. Con

v.

Time

(h)

Alcohol Ester E

ee% 26

D Yield Conf. ee% 26

D Yield Conf.

57 47 1.45 >99.99 +17.3 47% R >99.99 -44.2 46% S 225

58 36 1.45 94 +40.8 41% R 99 -66.0 43% S 92

59 49 1.45 94 +42.3 42% R >99 -38.2 43% S 176

60 50 1.45 98 +42.3 42% R 94 -24.6 47 S 177

61 21 6 93 +6.8 12% R 78 -14.6 74% S 92

62 50 0.30 >99.99 +25.8 49% R >99.99 -40.8 48% S 278

63 49 0.30 >99.99 +22.3 48% R >99.99 -41.3 49% S 171

64 49 1 >99 +23.8 31% R >99.99 -40.6 58% S 56

65 49 2 >99 +44.8 47% R >99 -34.0 46% S 184

66 47 1 >99.99 +30.4 43% R >99.99 -24.9 45% S 244

67 33 2 >99 +34.2 43% R >99 -25.6 47% S 95

68 47 1 >99 +23.0 49% R >99.99 -23.7 49% S 500

69 39 1.45 99 +31.4 49% R 94 -23.1 49% S 44

8. ABL catalyzed Transesterification of 1-(2, 3- and 4-Pyridyl) alcohols

(2a, 12 and 13):

In order to further reduce the reaction time as well as to harvest high yield of the

products we used transesterification approach in a bid to obtained enantiomerically pure

1-(2-, 3- and 4-Pyridyl) acyl derivatives from their corresponding alcohols. In this

experiment transesterification of substrates was attempted again with a panel of

biocatalysts encompassing both commercial as well as lyophilized cells preparation of

enzyme from the institute’s repository. The lipase ABL was able to exhibit best results in

less time and with good enantioselectivity as shown in Table 10. Pyridyl ethanols (2a, 12

and 13) were chosen as substrates for the primary examination of lipases. An enzymatic

acetylation was carried out in diisopropyl ether with vinyl acetate in the presence of lipase

(ABL) at room temperature (Scheme-15). Other lipases like CAL (Candida Antarctica

lipase) and Y-15 were also used. Both of these lipases gave (+)-acetates 57a, 62a and 66a

with an (R)-configuration and the recovery of (S)-alcohols respectively with excellent

enantiomeric excess. Among these the lipases used, ABL gave the best enantioselectivity


Page 172

and chemical yields for both the acetate and alcohols, while other lipases were less

effective interims of time of the reaction and enantiomeric excess of the byproduct results

are summarized in Table 10.

lipase+

R (57a, 62a, 66a) S (2a, 12, 13)

N

OH

RVinyl acetate

2a, 12, 13

N

R

O

O

R1N

R

OH

Scheme-15

Table 10: ABL catalyzed transesterification of (2a, 12 and 13).

Sub. Convn. Time

(h)

Alcohol ((2a, 12 and 13) Ester (57a, 62a, 66a) E

ee% 26

D Yield Conf. ee% 26

D Yield Conf.

2a 50 1.45 99.99 +18.3 49% S 99.99 -46.2 46% R 225

12 44 1.45 99.99 +42.0 50% S 99.99 -66.6 43% R 92

13 49 1.45 99.99 +42.3 47% S 99.99 -38.2 43% R 176

5. Conclusion:

The synthesis of important enantiopure pyridyl alcohols has been achieved in high

chemical yield by a rapid and practical procedure for small and potentially large-scale

industrial use. Resolution of a wide range of pyridyl ethanols and their derivatives

catalyzed by ABL and Y-15 was achieved with good yields and in excellent optical

purity. This method offers several advantages: 1) A simple and very convenient recipe, 2)

A clean reaction even at a large scale, 3) Excellent enantioselectivity and a high chemical

yield, 4) Both (R)- and (S)-isomers are available in single reaction. The obtained optically

pure pyridyl ethanols and their derivatives may be important building blocks for the

construction of chiral ligand molecules, which should be useful in asymmetric reactions

and molecular recognition chemistry. Among the several commercial as well as native

lipases tested for the hydrolysis of 1-(2-, 3- and 4-Pyridyl)alcohol esters and their

derivatives and trans-esterification of corresponding 1-(2-, 3- and 4-Pyridyl)alcohols,


Page 173

ABL was found to exhibit excellent lipase giving good selectivity with less time as well

as good yields. Further exploiting the potential of this microorganism for the synthesis of

other optically active alcohols is also in progress.

6. Experimental:

6.1. Typical procedure for the Preparation of Pyridyl Alcohols:

(Method A):

In a typical procedure to an etheral solution (186 mL) of 2-

pyridinecarboxaldehyde (1i) (2 g, 18.7 mmol) was added ethyl magnesium bromide in

diethyl ether or THF (24.27 mmol) at 0 0C. The mixture was stirred for 2 h, quenched

with ice-water (5 mL), and extracted with EtOAc. The extract was washed with water and

brine and dried over Na2SO4. The solvent was removed, and the residue was purified by

column chromatography over silica gel with hexane: ethyl acetate (50:50) as an eluent to

give oily liquid corresponding alcohols 2i in 95% yield. Compounds 2k, 56, 12a, 13a

were prepared using the same method.

Method B:

To a solution of 2-acetylpyridine 6 (4 g, 25 mmol) in anhydrous ethanol (120 mL)

NaBH4 (0.87 g, 3.7 mmol) was added portion wise at rt and the resulting mixture stirred

overnight. After concentration the contents under reduced pressure on a rotavapour, the

residue was dissolved in ethyl acetate (50 mL) and washed with water (10 mL), 5% HCl

solution (10 mL), saturated NaHCO3 solution (10 mL) and brine (10 mL) and dried over

sodium sulfate. From this solution, ethyl acetate was distilled off by rotary evaporator and

the residue purified by column chromatography over silica gel hexane: acetone (50:50) to

give racemic 2a (1.67 g, 41%) as a colourless oil. Compounds 12, 13 were prepared using

the same method.

6.2. Typical procedure for the alkylation of Pyridyl Alcohols:

In a typical procedure a solution of 2a (1.0 g, 8.13 mmol), acetic anhydride (0.830

g, 8.13 mmol) and pyridine (2 ml) in dichloromethane (10 ml) was kept over night at

room temp. After the completion of the reaction, the contents were poured into ice-cold

water and extracted with dichloromethane (3x50 ml). The organic layer was washed with


Page 174

water, dried with sodium sulfate, and concentrated to furnish the crude product which on

purification by column chromatography over silica gel with hexane: ethyl acetate (70:30)

as eluent to give 57. Compounds 58-69 were prepared using same method.

6.3. General procedure of lipase catalyzed kinetic resolution of 43:

In a typical procedure a mixture 57 (100 mg), acetonitrile (0.5 mL) crude enzyme ABL

(100 mg) in phosphate buffer (pH 7.0) was stirred at rt. The course of the reaction was

monitored by chiral HPLC. After the certain degree of conversion the reaction was

terminated, extracted with ethyl acetate (2x20 mL), washed with water, dried over sodium

sulfate and concentrated in vacuo to gave crude product which on column

chromatography on silica gel with ethyl acetate: hexane (30;70) as eluent furnished

corresponding alcohol 2a and recovered compound 57. Using the same procedure all

derivatives (58-69) was resolved.

7. Spectral data:

7.1. 1-(2-pyridyl) ethanol (2a):

1H NMR (200 MHz, CDCl3): δ 1.50 (3H, d, J = 6.5 Hz, CH3), 4.91 (1H, q,

J = 6.6 Hz, CHOH), 7.28 (1H, dd, J = 7.6, 4.3 Hz), 7.34 (1H, d, J = 7.7

Hz), 7.76 (1H, dd, J = 7.6, 1.7 Hz), 8.60 (1H, d, J = 4.8 Hz). 13

C NMR ( 50 MHz, CDCl3):

δ 24.1, 74.1, 120.0, 123.1, 136.4, 148.4, 162.3. MS (%) M at m/z 124. Anal. Calcd. For

C7H9NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.59; N, 11.49.

7.2. 1-(2-pyridyl) propanol (2i):

1H NMR (200 MHz, CDCl3): δ 0.94 (3H, t, J = 7.3 Hz, CH2CH3), 1.64-

1.96 (2H, m, CH2CH3), 4.70 (1H, dd, J = 7.4, 4.7 Hz, CHOH), 7.18 (1H,

dd, J = 7.7, 4.4 Hz), 7.24 (1H, d, J = 7.7 Hz), 7.69 (1H, dd, J = 7.7, 1.7

Hz), 8.55 (1H, d, J = 4.8 Hz). 13

C NMR ( 50 MHz, CDCl3): δ 9.3, 31.1, 73.9, 120.3,

122.1, 136.5, 148.0, 162.2. MS (%) M at m/z 138. Anal. Calcd. For C8H11NO: C, 70.04;

H, 8.08; N, 10.21. Found: C, 70.52; H, 8.49; N, 10.39.

OH

N

HO

N


Page 175

7.3. 1-(2-pyridyl)-3-butene-1-ol (2k):

1H NMR (200 MHz, CDCl3): δ 2.49 & 2.63 (1H each, m,

CHCH2CH=), 4.26 (1H, br s, CHCH2CH), 4.81 (1H, dd, J = 7.1, 4.9

Hz, CHOH), 5.08-5.13 (2H, m, CH=CH2), 7.19 (1H, dd, J = 7.7, 4.7

Hz), 7.31 (1H, d, J = 7.7 Hz), 7.68 (1H, td, J = 7.7, 1.7 Hz), 8.52 (1H, d, J = 4.7 Hz). 13

C

NMR (50 MHz, CDCl3): δ 42.8, 72.3, 117.9, 120.4, 122.3, 134.1, 136.6, 148.2, 161.5. MS

(%) M++Na

at m/z 173. Anal. Calcd. For C9H11NO: C, 72.36; H, 7.43; N, 7.43. Found: C,

72.92; H, 7.92; N, 7.87.

7.4. 2-phenyl-1-(pyridine-2-yl) ethanol (56):

1H NMR (200 MHz, CDCl3): δ 2.92 (2H, m, CHCH2), 4.96 (1H,

dd, J = 7.2, 4.7 Hz, CHOH), 7.10-7.27 (7H, m, 5xAr-H & 2pyridyl

protans), 7.63 (1H, dd, J = 7.7, 1.9 Hz), 8.52 (1H, d, J = 4.7 Hz).

13C NMR (50 MHz, CDCl3): δ 44.5, 46.2, 71.3, 120.7, 120.8, 126.5, 129.5, 129.6, 136.5,

137.8, 148.4, 161.3. MS (%) M at m/z 200. Anal. Calcd. For C13H13NO: C, 78.36; H,

6.58; N, 7.03. Found: C, 78.52; H, 6.79; N, 7.39.

7.5. 1-(3-pyridyl) ethanol (12):

1H NMR (200 MHz, CDCl3): δ 1.50 (3H, d, J = 6.49, CH3), 4.92 (1H, q,

1H, CHOH), 5.28 (1H, s, OH), 7.23 (1H, dd, J = 7.8, 4.6 Hz), 7.74 (1H, d,

J = 7.8 Hz), 8.32 (1H, d, J = 4.7 Hz), 8.41 (1H, d, J = 4.9 Hz). 13

C NMR (50 MHz,

CDCl3): δ 25.0, 68.3, 123.8, 133.4, 142.3, 148.0, 148.8. MS (%) M at m/z 124. Anal.

Calcd. For C7H9NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N, 11.39.

7.6. 1-(3-pyridyl) propanol (12a):



s, 1H, OH), 7.23 (1H, dd, J = 7.8, 4.6 Hz), 7.74 (1H, d, J = 7.8 Hz), 8.32

(1H, d, J = 4.7 Hz), 8.41 (1H, d, J = 1.9 Hz). 13

C NMR (50 MHz, CDCl3): δ 25.0, 68.3,

123.8, 133.4, 142.3, 148.0, 148.8. MS (%) M at m/z 138. Anal. Calcd. For C8H11NO: C,

68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N, 11.39.

OH

N

OH

N

HO

N

OH

N


Page 176

7.7. 1-(4-pyridyl) ethanol (13):

1H NMR (200 MHz, CDCl3): δ 1.50 (3H, d, J = 6.5, CH3), 4.94 (1H, q,

CHOH), 7.32 (2H, d, J = 5.7 Hz), 8.48 (2H, d, J = 5.7 Hz). 13

C NMR (50

MHz, CDCl3): δ 22.8, 73.7, 123.8, 123.9, 149.3, 149.8, 152.7. MS (%) M at m/z 124.

Anal. Calcd. For C7H9NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N,

11.39.

7.8. 1-(4-pyridyl) propanol (13a):



d, J = 5.8 Hz), 8.48 (2H, d, J = 5.8 Hz). 13


22.8, 73.7, 123.8, 123.9, 149.3, 149.8, 152.7. MS (%) M at m/z 138. Anal. Calcd. For

C8H11NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N, 11.39.

7.9. 1-(2-pyridyl) ethanol acetate (57):

1H NMR (200 MHz, CDCl3): δ 1.56 (3H, d, J = 6.5 Hz, CH3), 2.03

(3H, s, COCH3), 5.41 (1H, q, CHCH3), 7.27 (1H, dd, J = 7.4, 4.4 Hz),

7.36 (1H, d, J = 7.7 Hz), 7.66 (1H, dd, J = 7.4, 1.7 Hz), 8.63 (1H, d, J

= 4.9 Hz). 13

C NMR ( 50 MHz, CDCl3): δ 21.3, 23.1, 73.4, 120.3, 123.3, 136.4, 148.4,

162.3. MS (%) M at m/z 166. Anal. Calcd. For C9H11NO2: C, 65.44; H, 6.71; N, 8.48.

Found: C, 65.66; H, 7.01; N, 8.93.

7.10. 1-(2-pyridyl) propanol acetate (58):

1H NMR (200 MHz, CDCl3): δ 0.91 (3H, t, J = 7.4 Hz, CH2CH3), 1.98

(2H, m, CH2CH3), 2.13 (3H, s, 3H, COCH3), 5.72 (1H, t, J = 6.6 Hz,

CHCH2), 7.23 (2H, m), 7.67 (1H, dd, J = 7.7, 1.7 Hz), 8.59 (1H, d, J =

4.6 Hz). 13

C NMR ( 50 MHz, CDCl3): δ 9.5, 20.9, 27.7, 77.6, 120.9, 122.4, 136.6, 149.2,

159.3, 170.2. MS (%) M at m/z 180. Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N,

7.82. Found: C, 67.52; H, 7.89; N, 7.99.

OH

N

OH

N

O

ON

O

ON


Page 177

7.11. 1-(2-pyridyl) propanol propionate (59):

1H NMR (200 MHz, CDCl3): δ 0.96 (3H, t, J = 7.7 Hz, CHCH2CH3),

1.14 (3H, t, J = 7.7 Hz, COCH2CH3), 1.90 (2H, m, CHCH2CH3), 2.28

(2H, q, J = 4.4 Hz, COCH2CH3), 5.82 (1H, t, J = 6.6 Hz, CHCH2), 7.26

(2H, m), 7.69 (1H, dd, J = 7.8, 1.8 Hz), 8.60 (1H, d, J = 4.6 Hz). 13

C NMR ( 50 MHz,

CDCl3): δ 7.9, 9.5, 27.9, 28.7, 77.1, 122.9, 123.4, 136.6, 149.0, 159.9, 171.2. MS (%) M

at m/z 194. Anal. Calcd. For C11H15NO2: C, 68.39; H, 7.82; N, 7.25. Found: C, 68.52; H,

7.96; N, 7.59.

7.12. 1-(2-pyridyl)-3-butene-1-ol acetate (60):

1H NMR (200 MHz, CDCl3): δ 2.08 (3H, s, COCH3), 2.51 & 2.66 (1H

each, m, CHCH2CH=), 4.29 (1H, br s, CHCH2CH=), 4.81 (1H, dd, J =

7.1, 4.9 Hz, CHCH2CH=), 5.08-5.13 (2H, m, CH=CH2), 7.19 (1H, dd, J

= 7.7, 4.7 Hz), 7.31 (1H, d, J = 7.7 Hz), 7.68 (1H, td, J = 7.7, 1.7 Hz), 8.52 (1H, d, J = 4.7

Hz). 13

C NMR (50 MHz, CDCl3): δ 21.0, 39.0, 75.6, 118.1, 121.1, 122.7, 133.0, 136.5,

149.3, 158.7, 170.2. MS (%) M at m/z 193. Anal. Calcd. For C11H13NO2: C, 69.09; H,

6.85; N, 7.32. Found: C, 70.42; H, 6.91; N, 7.87.

7.13. 2-phenyl-1-(pyridine-2-yl) ethanol acetate (61):

1H NMR (200 MHz, CDCl3): δ 2.07 (3H, s, COCH3), 2.92 (2H, m,

CHCH2), 6.04 (1H, dd, J = 6.7, 5.7 Hz, CHCH2), 7.11-7.25 (7H, m, 5xAr-

H & 2pyridyl protans), 7.63 (1H, dd, J = 7.7, 1.9 Hz), 8.63 (1H, d, J = 4.7

Hz). 13

C NMR (50 MHz, CDCl3): δ 20.0, 40.3, 120.9, 122.2, 125.8, 127.4,

128.7, 136.0, 136.2, 136.3, 148.2, 157.7, 169.5, 176.0. MS (%) M +Na at

m/z 265. Anal. Calcd. For C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.82; H,

6.79; N, 5.99.


1H NMR (200 MHz, CDCl3): δ 1.56 (3H, d, J = 6.6 Hz, CHCH3), 2.08

(3H, s, COCH3), 5.90 (1H, q, J = 6.6 Hz, CHCH3), 7.28 (1H, dd, J =

7.9, 7.8 Hz), 7.67 (1H, d, J = 7.8 Hz), 8.54 (1H, d, J = 4.6 Hz), 8.62

O

ON

N

O

O

O

O

N

O

ON


Page 178

(1H, d, J = 1.7 Hz). 13

C NMR (50 MHz, CDCl3): δ 21.4, 25.3, 67.5, 124.8, 132.4, 141.7,

148.0, 148.8, 165.5. MS (%) M at m/z 166. Anal. Calcd. For C9H11NO2: C, 65.44; H,

6.71; N, 8.48. Found: C, 65.62; H, 6.89; N, 8.79.

7.15. 1-(3-pyridyl) ethanol propionate (63):

1H NMR (200 MHz, CDCl3): δ 1.09 (3H, t, J = 7.4 Hz, CH2CH3), 1.53

(3H, d, J = 6.4 Hz, CHCH3), 2.11 (3H, q, J = 4.4 Hz, CH2CH3), 5.81

(1H, m, CHCH3), 7.25 (1H, dd, J = 7.6, 7.1 Hz), 7.64 (1H, d, J = 7.6

Hz), 8.54 (1H, d, J = 4.5 Hz), 8.66 (1H, d, J = 1.91 Hz). 13


9.4, 21.4, 27.3, 67.3, 124.7, 132.3, 140.7, 147.3, 147.8, 166.5. MS (%) M at m/z 180.

Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.62; H, 7.66; N,

8.11.

7.16. 1-(3-pyridyl) ethanol butyrate (64):

1H NMR (200 MHz, CDCl3): δ 0.93 (3H, t, J = 7.4 Hz, CH2CH3),

1.60 (5H, m, CH2CH2CH3 & CHCH3), 2.31 (2H, t, J = 5.7 Hz,

COCH2), 5.89 (1H, q, J = 6.7 Hz, CHCH3), 7.27 (1H, dd, J = 7.4,

7.3 Hz), 7.66 (1H, d, J = 7.6 Hz), 8.52 (1H, d, J = 4.5 Hz), 8.66 (1H, d, J = 2.0 Hz). 13

C

NMR (50 MHz, CDCl3): δ 9.4, 18.7, 27.3, 77.3, 123.4, 133.1, 140.1, 147.0, 147.8, 166.5.

MS (%) M at m/z 194. Anal. Calcd. For C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found:

C, 68.62; H, 7.56; N, 7.61.



2.03-2.14 (5H, m, CH2CH3 & COCH3), 5.45 (1H, m, CHCH2), 7.28

(1H, dd, J = 7.7, 7.4 Hz), 7.67 (1H, d, J = 7.8 Hz), 8.54 (1H, d, J = 4.6

Hz), 8.62 (1H, d, J = 1.7 Hz). 13

C NMR (50 MHz, CDCl3): δ 8.1, 21.3, 28.6, 79.3, 123.7,

135.3, 138.4, 148.1, 148.4, 166.5. MS (%) M at m/z 180. Anal. Calcd. For C10H13NO2:

C, 67.02; H, 7.31; N, 7.82. Found: C, 67.62; H, 7.99; N, 8.11.

O

O

N

O

ON

N

O

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Page 179


1H NMR (200 MHz, CDCl3): δ 1.53 (3H, d, J = 6.5, CHCH3), 2.09

(3H, s, COCH3), 5.74 (1H, m, CHCH3), 7.34 (2H, d, J = 5.7 Hz), 8.60

(2H, d, J = 5.7 Hz). 13

C NMR (50 MHz, CDCl3): δ 22.8, 24.6, 73.9,

123.6, 123.9, 149.7, 149.9, 154.7. MS (%) M at m/z 166. Anal. Calcd. For C9H11NO2: C,

65.44; H, 6.71; N, 8.48. Found: C, 65.82; H, 6.99; N, 8.79.



2.03-2.14 (5H, m, CH2CH3 & COCH3), 5.74 (1H, m, CHCH2), 7.34

(2H, d, J = 5.7 Hz), 8.60 (2H, d, J = 5.7 Hz). 13

C NMR (50 MHz,

CDCl3): δ 22.8, 24.6, 73.9, 123.6, 123.9, 149.7, 149.9, 154.7. MS (%) M at m/z 180.

Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.71; H, 7.55; N,

7.94.

7.20. 1-(4-pyridyl) ethanol propionate (68):


1.71 (3H, d, J = 6.5 Hz, CHCH3), 2.25 (2H, q, J = 4.7 Hz, CH2CH3),

5.71 (1H, m, CHCH3), 7.31 (2H, d, J = 5.7 Hz), 8.65 (2H, d, J = 5.7

Hz). 13

C NMR (50 MHz, CDCl3): δ 9.9, 19.1, 28.3, 74.4, 123.4, 149.1, 152.3, 171.1. MS

(%) M at m/z 180. Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,

67.81; H, 7.67; N, 7.97.

7.21. 1-(4-pyridyl) ethanol butyrate (69):

1H NMR (200 MHz, CDCl3): δ 0.96 (3H, t, J = 7.6 Hz,

CH2CH3), 1.45-1.61 (5H, m, CH2CH2CH3 & CHCH3), 2.33 (2H,

t, J = 5.7 Hz, COCH2), 5.89 (1H, q, J = 6.7 Hz, CHCH3), 7.34

(2H, d, J = 5.7 Hz), 8.60 (2H, d, J = 5.7 Hz). 13

C NMR (50 MHz, CDCl3): δ 13.5, 18.3,

19.3, 34.1, 123.3, 148.4, 149.4, 167.7. MS (%) M at m/z 194. Anal. Calcd. For

C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.82; H, 7.91; N, 7.71.

O

O

N

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O

N

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Development of New Synthetic Methodologies: Section A ... · of different chlorinating agents such...

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