USEFUL SYNTHESIS OF HYDROXY AMIDES: VALUABLE INTERMEDIATES...

CHAPTER - 6

USEFUL SYNTHESIS OF HYDROXY

AMIDES: VALUABLE INTERMEDIATES

FOR 8-BENZYL BERBINES

R2

R3

NHO

HO

OCH3

OCH3

OCH3

OCH3

R1

R1, R2, R3 = H, OCH3, OC2H5

Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines

School of Chemical Sciences, NMU, Jalgaon. Page 218

CHAPTER 6

USEFUL SYNTHESIS OF HYDROXY AMIDES: VALUABLE

INTERMEDIATES FOR 8-BENZYL BERBINES.

6.1 INTRODUCTION

There are some tetrahydroprotoberbines bearing a benzyl group attached to

C-8 which are uncommon protoberberine isolated from natural sources such as

Aristolochia gigantea, Talinum paniculatum.1,4

These compounds are interesting from

both the chemical and pharmacological points of view because they incorporate the

phenylethylamine moiety in their structure, which is an important biological

pharmacophore.1

The natural 8-benzyl berbines (8-arylmethylberbines) contain oxygen

functions on both A and D rings and exists in two diastereomeric forms, cis (1a) and

trans (1b) distereomers, 3, 4

due to the presence of two asymmetric carbons. Although

both cis (1a) and trans (1b) diastereomers have been isolated from natural sources,

the cis isomer is major2. Some of the recently isolated 8-benzyl berbine alkaloids from

natural sources3, 4

are depicted below.

N

R1

R2

R4

R5

R6

R7

HR3

HN

R1

R2

R4

R5

R6

R7

HR3

1a 1b

H

A B

C

D

A B

C

D



Table 1. 8-arylmethyl berbine alkaloids from natural sources.

1

1a &1b

R1

R2

R3

R4

R5

R6

R7

a OH OH OH OH H OH OH

Javaberine- A

b

c

d

e

f

g

h

i

j

k

l

m

n

OCH3

OCH3

OH

H

H

H

OAc

OAc

OAc

OH

OH

OH

OAc

OH

OH

OCH3

OCH3

OCH3

OCH3

OCH3

OCH3

OCH3

OCH3

OCH3

OCH3

OCH3

H

OH

OH

H

H

H

α-Glc-Ac4

H

H

H

OH

OH

OAc

OGlc

OGlc

OGlc

Oβ-Glc

Oβ-Xyl

H

OAc

OAc

Oβ- Glc-Ac4

OH

Oβ-Xyl

Oβ-Glc

OAc

OH

H

H

OH

OH

OH

H

OAc

OAc

OH

H

H

H

OH

OH

OH

OH

OH

OH

OAc

OAc

OAc

OCH3

OH

OH

Oβ-Glc-Ac4

H

H

H

H

H

H

H

H

H

H

H

H

H

(−) Theoneberine (2) a brominated berbine isolated from a marine organism is

the only known example of a halogen containing 8-arylmethylberbine5.

N

H3CO

HO

OCH3

Br

OCH3

Br

HOH

H

Br

Br

HO

2



Latifolines-A (3a) and Latifolines-B (3b) are 8-(aryl methyl) berbinium salts

isolated from Gnetum Latifolium in which the isoquinolinic nitrogen is additionally

linked to C-6 of the benzyl substituent6.

N

HO

HO

OH

HOH

OH

OH

3a

N

HO

HO

OH

HOH

OH

OCH3

3b

Recently 8-(4’-methoxybenzyl)-xylopinine (4) was isolated from stephania

glabra Tubers.7 This compound showed a good antibacterial activity against S.aureus

and S.typhi.

N

H3CO

H3CO

OCH3

OCH3

OCH3

4

The natural 8-aryl methyl berbines possess good biological activities.

Javaberine-A shows strong inhibitory activity on the lipopolysaccharide-induced

tumor necrosis factor.2 Theoneberine exhibits antimicrobial and cytotoxic activities.

5

Some of the 8-substituted berbines are found to possess anti-arrhythmic and

antifungal properties.8



6.2 LITERATURE SURVEY

Various methods reported for the synthesis of 8-substituted berbines using

intramolecular Mannich reaction9,

Bischler-Napiralaski10

and Picted-Spengler

cyclisation11

. The C-8 substituent may also be incorporated once the berbines skeleton

has been formed. 8-oxoprotoberberine12

or Protoberberinium salts13

are treated with

organometallic reagents to obtain the corresponding 8-substituted berbines. Another

method is also reported for the synthesis of 8-substituted berbines14

. Some of the

methods reported for the synthesis of 8-benzyl berbines are presented below.

6.2.1 Methods for the synthesis of 8-benzyl berbines using protoberberinium

salts.

I) Method due to Shamma et al.15

Quaternary protoberberine salt of berberine (5) was reacted with benzyl

magnesium bromide to obtained 8-benzyl-7, 8-dihydroberbine (6), which on reduction

with sodium borohydride yields 8-benzylcanadine (7) as shown in scheme 1.

N

O

O

OCH3

OCH3

X

5

N

O

O

OCH3

OCH3

Ph

PhCH2-MgBr NaBH4 N

O

O

OCH3

OCH3

Ph

6 7

Scheme 1. Synthesis of 8-benzylcanadine (7) from Quaternary protoberberine salt (5).

II) Method due to Valpusta et al.1, 2

Recently Valpusta and coworkers have developed a new approach for the

synthesis of 8-benzyl berbines, which involves insertion of a substituent at C-8

position based on Steven’s rearrangement. In this method the cis/trans N-(aryl



methyl) berbinium salt (8) undergo Stevens’ rearrangement using NaH & DMSO to

obtaine cis/trans 8-(aryl methyl) berbines (9). The required cis/trans N-(aryl methyl)

berbinium salt (8) was prepared from 2-(3, 4-substituted phenyl) ethylamine and

substituted phenyl acetic acids in six steps as shown in scheme 2.

N

R1

R2

R3

R4

I

NH2

R1

R2

COOH

R4215 C

R1

R2

NHO

R4

R1

R2

NH

R4

ClPOCl3CH3CN

R1

R2

N

R4

CHO

CHCl3 ,RT

R3

R3R3

R3

Dioxane:t BuOH RT

RT

Br

R5

K2CO3/CHCl3 RT

N

R1

R2

R3

R4

R5N

R1

R2

R3

R4

R4

Br

NaH/DMSO

RTH H

Diethoxymethyl acetate

Reflux

hv /HINaBH4

MeOHN

R1

R2

R3

R4

R1, R2, R3, R4, R5 = H/ -OCH3 /-O-CH2-O-/ -OH / -OBn / -OTf

8 9

Scheme 2. Steven’s rearrangement approach for the synthesis of 8-arylmethyl

berbines (9).

6.2.2 Method for the synthesis of 8-substituted berbine alkaloids using hydroxy

amide derivative as a key intermediate.

As discussed in chapter 5, we synthesized various berbine alkaloids using

hydroxy amides as key intermediate. A method involving the utilization of hydroxy

amide intermediates for the synthesis of 2, 3 9, 10-tetra oxygenated 8-substituted

berbines alkaloids was first reported by Mali and Sharadbala Patil.16

In their approach



condensation of 1-substituted 7,8-dimethoxy isochroman-3-ones (11) with substituted

β-phenylethylamines (10) provides hydroxy amide intermediate (12) which on

Bischler Napieralski cyclization, followed by sodium borohydride reduction gives

distereomers of 8-substituted berbines (13) as shown in scheme 3.

MeO

MeONH2 MeO

OMe

O

R

OEtOH

MeO

MeONH

OMe

OMe

RO

OH

10 11 12

1. PCl5/CHCl3

2. NaBH4/MeOH

MeO

MeON

OMe

OMe

R

13

R = Me / Ph

Scheme 3. Utilization of hydroxy amide intermediate (12) for the synthesis of

8-substituted berbines (13).

6.3 PRESENT WORK

Considering the importance of 8-substituted berbines, in this chapter we are

describing the synthesis of new hydroxy amides derivatives (17a-d), which could be

used for the synthesis of 8-benzyl berbine alkaloids using the same strategy depicted

in Scheme 3. The reaction of 1-arylmethyl isocromanone (16) with substituted

phenethylamines (10a-d) provides hydroxy amides intermediates (17a-d) as shown in

Scheme 4.



H3CO

H3COO

H3CO

OCH3

O

16

R2

R3

10a-d

NH2

Ethanol

R2

R3

NHO

HO

OCH3

OCH3

OCH3

OCH317a-d

R1

R1

10 & 17 R1 R2 R3

a H -OCH3 -OCH3

b H -OCH3 -OC2H5

c H -OC2H5 -OCH3

d -OCH3 -OCH3 -OCH3

Scheme 4. Synthesis of new hydroxy amides derivatives (17a-d).

6.3.1 Synthesis of 1-(3, 4-dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen-3(4H)-

one (16).18

The common starting material for hydroxy amides derivatives (17a-d),

1-arylmethyl isocromanone (16) was prepared from 3, 4-dimethoxy phenylacetic acid

in two steps using the reported procedure.18

3, 4 Dimethoxy phenylacetic acid (14)

on heating with PPA at 80ºC for one hr gave the keto acid17

(15) which on reduction

with sodium borohydride, followed by acidic workup provided 1-(3,4-

dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen-3(4H)-one (16) in 78 % yield18

(Scheme 5).

H3CO

H3CO

COOH

H3CO

H3CO

COOH

O

H3CO

OCH3

H3CO

H3COO

H3CO

OCH3

O

14 15 16

NaBH4PPA

MeOHH /

Scheme 5. Synthesis of 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen-

3(4H)-one (16).



6.3.2 Synthesis of substituted β-phenylethylamines (10a-d).19

The well known nitrostyrenes (19a-d) and β-phenylethylamines (10a-d)

required for the synthesis of 17a-d were prepared using literature methods from easily

available aldehydes.19

The substituted aldehydes (18a-d) on Henry condensation using

nitromethane and ammonium acetate in gl.acetic acid give substituted nitrostyrenes

(19a-d), which on reduction with Lithium aluminium hydride in THF provide

substituted β-phenylethylamines (10a-d) as shown in Scheme 6.

R2

R3

CHO

R1

R2

R3

R1

NO2 R2

R3

10a-d

NH2

R1

19a-d

Nitromethane

NH4OAC

Gl. Acetic acid

LAH

THF

/

18a-d

10, 18 & 19 R1 R2 R3

a H -OCH3 -OCH3

b H -OCH3 -OC2H5

c H -OC2H5 -OCH3

d -OCH3 -OCH3 -OCH3

Scheme 6. Synthesis of substituted β-phenylethylamines (10a-d).

6.3.3 Synthesis of hydroxy amide derivatives.

N-(3,4-dimethoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4-dimethoxyphenyl)ethyl)-4,5-

dimethoxyphenyl) acetamide (17a).

The condensation of 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen-

3(4H)-one (16) with substituted β-phenylethylamines (10a-d) in ethanol was planned

to obtain hydroxy amides derivatives (17a-d) as shown in Scheme 4. To check the

feasibility of this reaction it was planned to synthesize N-(3,4-dimethoxyphenethyl)-2-

(2-(1-hydroxy-2-(3,4-dimethoxyphenyl)ethyl)-4,5-dimethoxyphenyl)acetamide (17a).

Thus, when 1-(3,4-dimethoxy benzyl)-6,7-dimethoxy-1H-isochromen-3(4H)-one (16)



was reacted with 2-(3,4-dimethoxy phenyl)ethanamine (10a) in ethanol the desired

hydroxy amide 17a was obtained in 81% yield, mp.98-100°C. IR spectrum (KBr,

Fig.1) of 17a it showed absence of lactone carbonyl (no band at ~ 1732 cm-1

) It

exhibited a broad bond at 3277-3350 cm-1

which could be attributed to OH/NH group.

In carbonyl region it showed a band at 1628 cm-1

which could be due to the amide

carbonyl. The band at 1248, 1158 cm-1

and 1034 cm-1

indicates presence of -C-O

stretching of methoxy group. The 1H NMR spectrum (300MHz, CDCl3, Fig.2) of

17a showed a triplet at 4.88 δ (J = 5.5 Hz) for one proton of Ar-CH-(OH)-CH2. The

two protons of -CH-(OH)-CH2-Ar were merged in a multiplet with two protons of

Ar-CH2-C=O at 3.38-3.43 δ. A triplet was seen at 2.65 δ (J = 6.9 Hz) which could be

assigned to Ar-CH2-CH2-N group. Another multiplet found at 2.88 δ was assigned for

two protons of Ar-CH2-CH2-N group. The five singlets which appeared at δ 3.79

(3H), 3.82 (3H), 3.83 (6H), 3.85 (3H) and 3.91 (3H) could be assigned to six -OCH3

groups. A singlet at 2.51 δ and broad singlet at 5.63 δ, disappeared on addition of D2O

could be due to OH/NH protons. The eight aromatic protons appeared in the region of

6.49 – 7.03 δ. LC-MS spectrum (Fig.3) shows base peak of 562 (M+Na).

After successful synthesis of the desired hydroxy amide 17a and its

characterization using IR, 1H NMR and LCMS, we decided to synthesize other

hydroxy amides 17b-d using this approach.



F

ig.1

- IR

spec

tru

m o

f N

-(3,4

-dim

ethoxyphen

ethyl)

-2-(

2-(

1-h

ydro

xy

-2-(

3,4

-dim

ethoxy p

hen

yl)

eth

yl)

-4,5

-

d

imet

hoxyphen

yl)

ace

tam

ide

(17a).

H3C

O

H3C

ON

HO

HO

OC

H3

OC

H3

OC

H3

OC

H3

17a

IR i

n K

Br



Fig

.2-

1H

NM

R s

pec

trum

of

N-(

3,4

-dim

ethoxyphen

ethyl)

-2-(

2-(

1-h

ydro

xy

-2-(

3,4

-dim

ethoxy p

hen

yl)

eth

yl)

-4,5

-

d

imet

hoxyphen

yl)

ace

tam

ide

(17a).

H3C

O

H3C

ON

HO

HO

OC

H3

OC

H3

OC

H3

OC

H3

17a

1H

NM

R (

CD

Cl 3

)

300M

Hz



Fig.3- LCMS spectrum of N-(3,4-dimethoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4-

dimethoxy phenyl) ethyl)-4,5-dimethoxyphenyl) acetamide (17a).

H3CO

H3CONHO

HO

OCH3

OCH3

OCH3

OCH3

17a

Mol. Wt.: 539.62



N-(2,3,4-trimethoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4-dimethoxyphenyl)ethyl)-

4,5-dimethoxyphenyl) acetamide (17d).

H3CO

H3CONHO

HO

OCH3

OCH3

OCH3

OCH3

OCH3

17d

IR (KBr, cm-1

, Fig.4): 3248(broad), 3385, 3369, 2931, 2831, 1631, 1514, 1257, 1236,

1103, 1029.

1H NMR (300 MHz, CDCl3, Fig.5):

2.13 δ brs 1H OH/NH (Exchanged with D2O)

2.66 δ brs 2H Ar-CH2-CH2-N

2.89 δ m 2H Ar-CH2-CH2-N

3.30-3.45 m 4H Ar-CH-(OH)-CH2-Ar &

Ar-CH2-C=O.

3.75 s 3H OCH3

3.82 s 3H OCH3

3.83 s 6H 2 X OCH3

3.85 s 6H 2 X OCH3

3.91 s 3H OCH3

4.92 brs 1H Ar-CH-(OH)-CH2.

6.04 brs 1H OH/NH (Exchanged with D2O)

6.50 d (J = 6.7 Hz) 1H Ar-H

6.60-6.80 m 5H Ar-H

7.07 s 1H Ar-H

LCMS (Fig.6) = 592 (M+Na) and 552.



F

ig.4

- I

R s

pec

trum

of

N-(

2,3

,4-t

rim

ethoxyphen

ethyl)

-2-(

2-(

1-h

ydro

xy

-2-(

3,4

-dim

ethoxyphen

yl)

ethyl)

- 4,5

-

dim

ethoxy

phen

yl)

acet

amid

e (1

7d

).

H3C

O

H3C

ON

HO

HO

OC

H3

OC

H3

OC

H3

OC

H3

H3C

O

20d

IR i

n K

Br



F

ig.5

1H

NM

R s

pec

trum

of

N-(

2,3

,4-t

rim

ethox

yphen

ethyl)

-2-(

2-(

1-h

ydro

xy

-2-(

3,4

-dim

ethoxyphen

yl)

ethyl)

- 4,5

-

dim

ethoxy

ph

enyl)

ace

tam

ide

(17d

).

H3C

O

H3C

ON

HO

HO

OC

H3

OC

H3

OC

H3

OC

H3

17d

1H

NM

R (

CD

Cl 3

)

30

0M

Hz

H3C

O



Fig.6- LCMS spectrum of N-(2,3,4-trimethoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4-

dimethoxyphenyl)ethyl)-4,5-dimethoxyphenyl) acetamide (17d).

H3CO

H3CONHO

HO

OCH3

OCH3

OCH3

OCH3

OCH3

17d

Mol. Wt.: 569.64



6.4 CHARACTERIZATION DETAILS OF SYNTHESIZED

COMPOUNDS

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen-3(4H)-one (16).

Molecular Formula : C20H22O6

Molecular weight : 358.39

H3CO

H3CO

OCH3

OCH3

O

O

Appearance : White amorphous

powder

MP : 174°C

IR

(Nujol, cm-1

)

: 2933, 1732, 1612, 1516,

1346, 1259, 1234, 1175,

1120.

1H NMR

(300MHz,CDCl3)

: δ 6.72 ( d, 1H, J = 8.2 Hz, ArH), 6.55 ( t, 2H, J = 8.2 Hz, &

J = 4.1 Hz, ArH), 6.46 ( s, 1H, ArH), 6.32 ( s, 1H, ArH),

5.64 (t, J = 4.8 Hz, 1H, Ar-CH-O) 3.83 (s, 9H, 3 X OCH3),

3.66 δ (s, 3H, OCH3) 3.33-3.24 (m, 2H, Ar-CH2-CO), 3.08

and 2.56 (AB, 2H, J = 19.2 Hz, Ar- CH2-C-O).

LC-MS (m/z)

: 359 (M+H).

N-(3,4-dimethoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4-dimethoxyphenyl)ethyl)-4,5-

dimethoxyphenyl) acetamide (17a).

Molecular Formula : C30H37NO8

H3CO

H3CONHO

HO

OCH3

OCH3

OCH3

OCH3


Appearance : Off white amorphous

powder

MP : 98-100°C

IR

(KBr, cm-1

)

: 3375-3313 (brs), 2341,

2360, 1635, 1516, 1458,

1259 and 1029.



1H NMR

(300MHz,CDCl3)

: δ 7.03(s, 1H, ArH), 6.66-6.80 (m, 4H, ArH), 6.49-6.60 (m,

3H, ArH), 5.63 (brs, 1H, NH), 4.88 (t, J = 5.5 Hz, 1H, Ar-

CH-(OH)-CH2), 3.91 (s, 3H, OCH3), 3.85 (s, 3H, OCH3) 3.83

(s, 6H, 2 X OCH3), 3.82 (s, 3H, OCH3), 3.79 (s, 3H, OCH3),

3.38-3.43 (m, 4H, Ar-CH-(OH)-CH2-Ar and Ar-CH2-CO),

2.88 (m, 2H, Ar-CH2-CH2-N), 2.65 (t, J = 6.9 Hz, 2H, Ar-

CH2-CH2-N), 2.51 (s, 1H,-OH).

LC-MS (m/z)

: 562 (M+Na).

N-(4-ethoxy-3-methoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4dimethoxyphenyl)

ethyl)-4,5-dimethoxyphenyl) acetamide (17b).



H3CO

C2H5ONHO

HO

OCH3

OCH3

OCH3

OCH3

Appearance :White amorphous

powder

MP :108-110°C

IR

(KBr, cm-1

)

: 3369-3354 (broad),

2985, 1629, 1589,

1512, 1257, 1236,

1138, 1103 and 1031.

1H NMR

(300MHz,CDCl3)

:7.02 (s, 1H, ArH), 6.67-6.81 (m, 4H, ArH), 6.59 (m, 2H,

ArH), 6.48 (dd, 1H, J = 8 Hz, ArH), 5.63 (brs, 1H, NH), 4.88

(bs, 1H, Ar-CH-(OH)-CH2), 4.04 (q, J = 6.9 Hz, 2H, -OCH2-

CH3), 3.92 (s, 3H, OCH3), 3.86 (s, 3H, OCH3) 3.84 (s, 6H, 2

X OCH3), 3.79 (s, 3H, OCH3), 3.38-3.43 (m, 4H, Ar-CH-

(OH)-CH2-Ar and Ar-CH2-CO), 2.88 (m, 2H, Ar-CH2-CH2-

N), 2.65 (t, J = 6.8 Hz, 2H, Ar-CH2-CH2-N), 2.44 (s, 1H,-

OH), 1.44 (t, J = 7 Hz, 3H, -OCH2-CH3).

LC-MS (m/z)

: 576 (M+Na) & 536.



N-(3-ethoxy-4-methoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4dimethoxyphenyl)

ethyl)-4,5-dimethoxyphenyl) acetamide (17c).



C2H5O

H3CONHO

HO

OCH3

OCH3

OCH3

OCH3


powder

MP :120-122°C

IR

(KBr, cm-1

)

: 3369, 3350, 3284,

2993, 2931, 1633,

1514, 1236, 1139,

1103, 1031.

1H NMR

(300MHz,CDCl3)

: 7.03 (s, 1H, ArH), 6.58-6.81 (m, 6H, ArH), 6.48 (m, 1H,

ArH), 5.64 (bs, 1H, NH), 4.89 (brs, 1H, Ar-CH-(OH)-CH2),

3.96 (q, J = 7.0 Hz, 2H, -OCH2-CH3), 3.83-3.92 (m, 15H, 5 X

OCH3), 3.41-3.59 (m, 4H, -CH-(OH)-CH2-Ar and Ar-CH2-

CO), 2.89 (t, J = 6.6 Hz 2H, Ar-CH2-CH2-N), 2.65 (t, J = 6.7

Hz, 2H, Ar-CH2-CH2-N), 1.80 (brs, 1H,-OH), 1.43 (t, J = 6.6

Hz, 3H, -OCH2-CH3).

LC-MS (m/z)

: 576 (M+Na) & 536.

N-(2,3,4-trimethoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4-dimethoxyphenyl)ethyl)-

4,5-dimethoxyphenyl) acetamide (17d).


H3CO

H3CONHO

HO

OCH3

OCH3

OCH3

OCH3

OCH3



powder

MP :146-148°C



IR

(KBr, cm-1

)

: 3385, 3348(broad), 2997, 2931, 1631, 1514, 1462, 1236,

1103, 1029.

1H NMR

(300MHz,CDCl3)

: 7.07 (s, 1H, ArH), 6.60-6.80 (m, 5H, ArH), 6.50 (d, 1H, J =

6.7 Hz, ArH), 6.04 (bs, 1H, NH), 4.92 (bs, 1H, Ar-CH-(OH)-

CH2), 3.91 (s, 3H, OCH3), 3.85 (s, 6H, 2 X OCH3) 3.83 (s,

6H, 2 X OCH3), 3.82 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),

3.30-3.45 (m, 4H, -CH-(OH)-CH2-Ar and Ar-CH2-CO), 2.89

(m, 2H, Ar-CH2-CH2-N), 2.66 (brs, J = 6.8 Hz, 2H, Ar-CH2-

CH2-N), 2.13 (brs, 1H,-OH).

LC-MS (m/z)

: 592 (M+Na) & 552.

6.5 CONCLUSION:

In this chapter a convenient method is described for the synthesis of hydroxy amides

which could be used for the synthesis of 8-benzyl berbines including the naturally

occurring berbines.

6.6 EXPERIMENTAL

All Melting points were recorded in open capillaries and are uncorrected.

Distilled solvents were used in all cases. Hexane and pet ether refers to the petroleum

ether fraction boiling between 60-65°C. The purity of compounds was checked by

TLC on silica gel G (Merck 60F254). 1HNMR spectra were scanned in CDCl3 on

Varian mercury plus (300MHz) spectrometer using TMS as an internal standard. IR

spectra were recorded on Shimadzu FT-IR Affinity-1 spectrometer using KBr. LC-

MS spectra were recorded on Thermo Finnigan (Model-LCQ Advantage MAX) mass

spectrometer. The products were purified by column chromatography technique using

neutral silica gel (100-200 mesh).



6.6.1 General procedure for the synthesis of substituted nitrostyrenes (19a-d).

R2

R3

CHO

R1

R2

R3

R1

NO2

19a-d

Nitromethane

NH4OAC

Acetic acid

18a-d

6.6.2 General procedure for the synthesis of substituted β-phenylethylamines

(10a-d).

R2

R3

R1

NO2 R2

R3

10a-d

NH2

R1

19a-d

LAH

THF

/

6.6.3 Synthesis of 2-(4,5-dimethoxy-2-(2-(3,4-dimethoxyphenyl) acetyl) phenyl)

acetic acid (15).

H3CO

H3CO

COOH

H3CO

H3CO

COOH

O

H3CO

OCH314 15

PPA

6.6.4 Synthesis of 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen-

3(4H)-one (16).

H3CO

H3CO

COOH

O

H3CO

OCH3

H3CO

H3COO

H3CO

OCH3

O

15 16

NaBH4

MeOHH /



6.6.5 General procedure for the synthesis of hydroxyl amide derivatives (17a-d).

H3CO

H3COO

H3CO

OCH3

O

16

R2

R3

10a-d

NH2 Ethanol

R2

R3

NHO

HO

OCH3

OCH3

OCH3

OCH317a-d

R1

R1

Reflux

6.6.1 General procedure for the synthesis of substituted nitrostyrenes (19a-d).19

A mixture of appropriate benzaldehyde (18a-d, 12 mmol), nitromethane

(36 mmol) and ammonium acetate (6 mmol) in glacial acetic acid (20 mL) was heated

at 100°C for 12 h. The completion of reaction was checked by TLC. The reaction

mixture was allowed to come to room temperature. The solid obtained was filtered,

washed with water, dried and recrystallized from ethyl acetate-n-hexane to afford

nitrostyrene (19a-d) as light yellow needles. The yield and melting points of

nitrostyrene (19a-d) are given in Table 2.

Table 2: yield and melting points of -nitrostyrene (19a-d).

Product

Yield

(%)

MP

(ºC)

Lit. MP

(ºC)

19a 81 140 140-14120

19b 73 148 147-14821

19c 69 132 132-13322

19d 78 76 75-7619,23



6.6.2 General procedure for the synthesis of substituted β-phenylethylamines

(10a-d).19

To the suspension of LiAlH4 (4.7 mmol) in dry THF (25 mL) in three neck-

flask was injected a solution of nitrostyrene (19a-d, 9.7 mmol) in dry THF (15 mL) at

0°C. The reaction mixture was heated at 80℃ for 12 h. After completion of the

reaction, the mixture was cooled to 0°C, followed by the addition of moisturized THF

(5 mL) and 30% NaOH solution (1 mL). Then the reaction mixture was stirred for 1h,

the resulting heavy suspension was filtered through celite and the filtrate was

concentrated under reduced pressure to afford the crude product as brown oil. This

crude product was immediately used in the next step.

6.6.3 Synthesis of 2-(4,5-dimethoxy-2-(2-(3,4-dimethoxyphenyl) acetyl) phenyl)

acetic acid (15)17

A mixture of homoveratric acid (14, 10 mmol) and polyphosphoric acid (20 g)

was heated at 90-95°C and stirred for 30 min. The reaction mixture was quenched

with cold water (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined

organic layers was washed with water (2 x 50 mL), dried using Na2SO4 and

concentrated at reduced pressure to obtain a pale brown solid, which was

recrystallized using ethanol-water (6:4) to provide 15 (1.3 g, 66.18 %) as off white

powder, mp. 154-156°C, lit. 17b

mp.152-153°C.

6.6.4 Synthesis of 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen- 3(4H)-

one (16).18

To a solution of (4,5-dimethoxy-2-(2-(3,4-dimethoxyphenyl) acetyl) phenyl)

acetic acid (15, 1.l g) in ethanol (20 mL) was added NaBH4 (0.4 g) and the mixture

was heated on a water bath for 10 min. Water (50 mL)was added, cooled and then

added 20% HC1 to achieved pH 3 which gives colorless solid, The crude product was



recrystallized using ethanol water (5:5) to provide pure compound (16), (0.7 g,

66.6 %), mp. 174°C, lit.18

mp.174-175°C.

6.6.5 General procedure for the synthesis of hydroxyl amides (17a-d).

A solution of 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1H-isochromen-

3(4H)-one (16, 0.279 mmol) and substituted β-phenylethylamines (10a-d, 0.558

mmol) in absolute ethanol (10 mL) was refluxed for 14-16 h. Ethanol was removed

under reduced pressure and the residual thick liquid thus obtained was purified by

column chromatography over silica gel (Neutral, 60-120 mesh) using eluent 2-5%

methanol in dichloromethane to obtain hydroxy amide (17a-d). The yield and melting

points of (17a-d) are given in Table 3.

Table 3. The yield and melting points of hydroxyl amides 17a-d.

Product

Yield

(%)

MP

(ºC)

17a 81 98-100

17b 73 108-110

17c 74 120-122

17d 78 146-148



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