USEFUL SYNTHESIS OF HYDROXY AMIDES: VALUABLE INTERMEDIATES...
Transcript of 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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 219
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 220
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 221
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 222
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 223
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.
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 224
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).
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 225
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)
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 226
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.
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 227
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 228
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 229
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 230
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.
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 231
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 232
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 233
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 234
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
Molecular weight : 539.62
Appearance : Off white amorphous
powder
MP : 98-100°C
IR
(KBr, cm-1
)
: 3375-3313 (brs), 2341,
2360, 1635, 1516, 1458,
1259 and 1029.
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 235
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).
Molecular Formula : C31H39NO8
Molecular weight : 553.64
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.
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 236
N-(3-ethoxy-4-methoxyphenethyl)-2-(2-(1-hydroxy-2-(3,4dimethoxyphenyl)
ethyl)-4,5-dimethoxyphenyl) acetamide (17c).
Molecular Formula : C31H39NO8
Molecular weight : 553.64
C2H5O
H3CONHO
HO
OCH3
OCH3
OCH3
OCH3
Appearance :White amorphous
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).
Molecular Formula : C31H39NO9
H3CO
H3CONHO
HO
OCH3
OCH3
OCH3
OCH3
OCH3
Molecular weight : 569.64
Appearance :White amorphous
powder
MP :146-148°C
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 237
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).
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 238
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 /
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 239
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 240
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 241
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
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 242
REFERENCES
1. M. Valpusta, M. Ariza, A. Diaz, R. Suau, G. Torres, Eur. J. Org. Chem.
2010, 638.
2. M. Valpusta, A. Diaz, R. Suau, G. Torres, Eur. J. Org. Chem, 2004, 4313.
3. H. Shimoda, N. Nishida, K. Ninomiya, H. Matsuda, M.Yoshikawa,
Heterocycles, 2001, 55, 2043.
4. a) L. M. X. Lopes, Phytochemistry, 1992, 31, 4005. b) L. M. X. Lopes, E.
Humpfer, Phytochemistry, 1997, 45, 431.
5. J. Kobayashi, K. Kondo, H. Shigemori, M. Ishibashi, T. Sasaki, Y. Mikami,
J. Org. Chem., 1992, 57, 6680.
6. S. J. Richfort, L. Towerzey, A. Carroll, G.King, J. Whitemore. R. J. Quinn,
J. Nat. Product, 2005, 68, 1080.
7. D. K. Semwal, R. B. Semwal, R. Semwal, Pharmacologia, 2012, 3, 539.
8. G.R.Lenz, US. 4,013,666; Chem. Abstract, 1977, 87, 23587g.
9. a) R. Suau, M. V. Silva, M. Valpusta, Tetrahedron, 1990, 46, 4421, b) T.
Kametani, A. Ujiie, M. Ihara, K. Fukumoto, S. T. Lu, J Chem. Soc. Perkin
Trans 1, 1976, 1 1218.
10. R. S. Mali, S. D. Patil, S. L. Patil, Tetrahedron, 1986, 42, 2075.
11. R. T. Dean, H. Rapoport, J. Org. Chem. 1978, 44, 4183.
12. a) Jahangir, D. B. Maclean, H. L. Holland, Can. J. Chem. 1987, 65, 727. b)
E. Reimann, H. Benend, Monatsh. Chem. 1992, 123, 939. c) K. Orito, M.
Miyazawa, R. Kanbayashi, T. Tatsuzawa, M. Tokuda, H. Suginome, J. Org.
Chem. 2000, 65, 7495.
13. a) P.C. Shrivastava, M. L. Tedjamulia, F. F. Knapp Jr, J. Heterocycl.chem.
Chapter 6 Synthesis of hydroxy amides: valuable intermediates for 8-benzyl berbines
School of Chemical Sciences, NMU, Jalgaon. Page 243
1986, 1, 1167. b) P. D. Baird, J. Blagg, S. G. Davies. K. H. Sutton,
Tetrahedron 1988, 44, 171. c) J. L. Moniot, T. M. Kravtz, A. H. Abd el
Rahman, M. Shamma, J. Pharm. Sci, 1979, 68, 705, d) M. Shamma, A. S.
Rothenbeng. G. S. Jayatilake. S. F. Hussain, Tetrahedron, 1978, 34, 635.
14. a) Jahangir and D. B. Maclean, Can. J. Chem, 1987, 727. b) R. Suau, F.
Najera and R. Rico, Tetrahedron 2000, 56, 9713. c) K. Iwasa, D. U. Lee, S.
I. Kang, W. Wiegrebe, J. Nat. Prod. 1998, 61, 1150. d) N. Sotomayor, E.
Dominguez, E. Lete, J. Org. Chem. 1996, 61, 4062.
15. M. Shamma, The protoberberines and retroprotoberberines .In; M. Shamma
(Ed). The Isoquinoline Alkaloids, Academic Press, New York, London,
pp-268-314, (1972).
16. a) R. S. Mali, S. D. Patil, S. L. Patil, Tetrahedron, 1986, 42, 2075. b) Thesis
by S. D. Patil and R. S. Mali “Synthesis of Protoberberine alkaloids”1988.
17. a) T. Yamato, H. Inoue, M. Fukumoto and M. Tashiro, Org. Prep. Proced.
Int. 1995, 27, 495. b) S. Nizamuddin and M. Ghosal, Indian J. Chem. 1981,
20B, 431.
18. I. W. Elliott, J. Org. Chem., 1977, 42, 1090.
19. S. H. Yang, C. H. Song, H. T. M. Van, E. Park, D. B. Khadka, E. Y. Gong,
K. Lee, and W. J. Cho, J. Med. Chem. 2013, 56, 3414.
20. K. A. Walker, M. R. Boots, J. F. Stubbins, M. E. Rogers, C. W. Davis,
J. Med. Chem. 1983, 26, 174.
21. a) Indian J. Chem. 1989, 28B, 431. b) US 6191138 B1, 2000
22. B. Gutterer, US 6,127,378 A1, 2000.
23. Y. Yoshida, K. Mohri, K. Isobe, T. Itoh, and K. Yamamoto, J. Org. Chem.
2009, 74, 6010.