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CHAPTER-II
53
1. INTRODUCTION
Tartaric acid (“acid of grapes”) is a chiral dicarboxylic acid found in wine must. It is used
in the food industry to give an acid taste, and as an antioxidant. The chirality of tartaric acid was
discovered in 1832 by Jean-Baptiste Biot, who observed its ability to rotate polarized light.1
When Louis Pasteur repeated the work of Biot in 1847 as research practice,2 he found that one of
the isomers of tartaric acid consists of equal quantities of the Levo- and Dextro- forms. This
optically inactive form is called Racemic Acid (Greek; racemus, which means bunch of grapes).
The term ‘racemic’ originally referred to the origin of the acid (grapes), but nowadays in
chemistry it refers to an equal mixture of opposite enantiomers.
By slow crystallization of a solution of the sodium ammonium salt of tartaric acid Pasteur
obtained two types of colorless mirror image crystals (Fig. 1). By using a magnifying glass and a
pair of tweezers, he separated the crystals by hand. Equimolar solutions of these separated
crystals showed equal but opposite optical activity. Even though this is the first reported
resolution in the literature.
Fig. 1: French stamp of Louis Pasteur (left). Actual crystals of the ‘right-handed’ and ‘left-
handed’ enantiomorphic forms of sodium ammonium tartrate (right).
A more practical and the most frequently applied method is the ‘classical’ resolution of
racemates through formation and separation of diastereomeric salts. In this strategy, an acid-base
reaction is involved between a racemate and a resolving agent, which is in practice an
CHAPTER-II
54
enantiopure (single) enantiomer. If the two diastereomeric salts formed differ in their solubility,
filtration can be used to separate diastereomeric pair. This process is known as “classical method
of resolution”. After Pasteur a number of trial and error methods have been reported to explain
resolution techniques like computer assisted modeling,3 examination of crystal structure data of
diastereomeric salts4 and study of the energy differences of diasteromeric salts.
5
The raising demand for optically pure compounds was focused increasing attention on
asymmetric synthesis. In spite of success achieved in this field, the classical resolution remains
the main stay for the production of pure enantiomers; especially for their production on a multi
gram scale.
N
HO
O
N
HO
O
(R)-(+)-Propoxyphene (Darvon)
(S)-(-)-Propoxyphene (Novrad)
1b1a
O
O
S (+)-Carvone
R (-)-Carvone
2b
2a
NH
HN
OH
EtOH
Et
NH
HN
OH
OH
HEt
Et
(S,S)-Ethambutol (R,R)-Ethambutol
3a 3b
Fig 2
H
NN O
COOH
Cl
(R)-Cetirizine
4a
COO-Na+
CH3
H
H3CO
5a
(S)-Naproxen sodium
CHAPTER-II
55
The desirable reasons for producing optically pure compounds are 1) enantiomers may
exhibit different types of activity (Fig. 2). For example: (R)-propoxyphene (Darvon) 1a is
marketed as a painkiller, whereas the antipode (S)-propoxyphene (Novrad) 1b is a cough
suppressant.6 (S)-Carvone 2a is a naturally occurring ketone that can be found in caraway seeds,
and is used in the perfume industry and as a flavouring spice. (R)-Carvone 2b is found in mint
leaves.7 (S,S) isomer of ethambutol 3a is used for treatment of tuberculosis where as (R,R)
isomer 3b causes blindness. The (R)-enantiomer of cetirizine 4a acts as a antihistamine and
antipode (S) is inactive and S- (+)-Naproxen Sodium 5a active as an analgesic, antipyretic and
anti-inflammatory and antipode (R)- is inactive. Eantiopure trans-2-aminocyclohexanol (R,R)-6
is a useful intermediate for various drugs, such as RSD 1235(anti-arrhythmic) 8 and OPC-33509
(anti-thrombotic) 7. However the basic skeleton of trans-2-aminocyclohexanol is also found in
many promising medicines with various indications currently being developed, such as protease
inhibitors and anti-obesity drug.8a
(S)-3-(methylamino)-1-(2-thienyl)propan-1-ol 9 is a key
intermediate for duloxetin 10, is expected to be not only a new potent antidepressant but also a
nore-pinephrine (NE) reuptake inhibitor and a new drug for stress urinary incontinenece.8b
S
NH
OH
(S)-9
S
NH
O
OH
NH2
O
O
OOH
NNH
O
O
HN
O
N
OH
and
OPC-33509RSD-1235
Fig 3
(S)-Duloxetine-10
(R,R)-6
78
CHAPTER-II
56
2. Resolution:
Resolution is the separation of a racemate into two enantiomeric constituents. It may be
broadly classified into two types which is described below.9
2.1.0 Physical Process2.1.1 Crystal Picking Triage2.1.2 Conglomerates2.1.3 Preferential Crystallization2.1.4 Preferential Crystallization in presence of Additives2.1.5 Asymmetric Transformation
2.2.0. Chemical Reactions
2.2.a Diastereomer formation.2.2.1 Separation of diastereomers. Resolving agents.2.2.2 Separation via complexes and inclusion compounds2.2.3 Chromatographic Resolution
2.2.b Kinetic Resolution
Resolution
2.1.0. Physical process
2.1.1 Crystal picking. Triage: During the crystallization of a racemate both enantiomers of the
substance deposit in equal quantities as enantiomorphous crystals. The manual sorting of
conglomerate crystals into fractions whose solutions are dextrorotatory and levorotatory is called
triage. Pasteur separated aspargine based on different shapes of crystals.
2.1.2 Conglomerates: The racemate should form conglomerate under conditions of
crystallization. Even if a racemate does not crystallize as a conglomerate, it may be possible to
convert into a derivative. For example alanine, leucine, and tryphtophan crystallize as racemic
compounds, but their benzene sulfonate salts are conglomerates.
CHAPTER-II
57
2.1.3 Preferential crystallization: When the resolution of a racemate is initiated by inoculation
of a saturated or supersaturated solution of the racemate with crystals of one enantiomer, it is
preferential crystallization since only enantiomer is seeded. It works only for substances that are
conglomerates. Histidine.HCl (11) is resolved by preferential crystallization above 45 oC. Other
examples are given below (Fig. 4)
11- Histidine Hydrochloride >45 oC
NaO2CHC CHCO2NH4
OH
-
12- Pasteurs salt > 27 oC
C
H
OH
CH2CO2NH4HO2C
13- Ammonium malate > 73oC 14- Phenylglycine sulfate, <5 oC
15- 1,1'-binaphthyl > 76 oC
-+ +
- +
OH
CH CO2H
NH32
SO42
-
+
HN
N
CH2CHCOOH
NH3Cl+
-
Fig 4
Compounds resolvable by preferential crystallization as a function of temperature.
2.1.4 Preferential Crystallization in Presence of Additives: (R,R)-(+)-Sodium ammonium
tartarate preferentially crystallizes from an aqueous solution of racemate containing either
dissolved (S)-(-)sodium ammonium malate, Na(NH4)[O2C-CH(OH)CH2CO2] or S-(-) aspargine,
H2NCOCH2CH(NH2)CO2H.
2.1.5 Asymmetric Transformation of Racemates-Total Spontaneous Resolution:
When configurationally labile racemates are crystallized rapidly, the enantiomeric composition
of the liquid phase equilibrium is reproduced in the solid state, the crystalline mass is racemic.
The solid racemate may exist either as racemic compound or conglomerate. With conglomerate
CHAPTER-II
58
systems, slow crystallization occurring spontaneously, or induced by means of enantiopure seeds
may result exclusive deposition of only one enantiomer called total spontaneous resolution.
2.2.0. Chemical Separation of enantiomers via diasereomers:
2.2.1 Separation of diastereomers: Resolving agents: The substrate to be resolved is treated
with one enantiomer of a chiral substance (the resolving agent). The first such resolution,
described by Pasteur in 1853 is shown below (scheme 1).
COOH
H OH
COOH
HO H
(+) Cinchotoxine
(+) quinotoxine
17
18
less soluble more soluble
less soluble more solublerac-Tartaric acid
16
Scheme 1
Diastereomeric pairs prepared in connection with resolution may be ionic (diastereomeric
salts), covalent, charge transfer compounds or inclusion compounds. Majority of resolutions
mediated by diasteromers are based on solubility differences of solids, and some covalent
diastereomer separations are based on chromatography.
The desirable characteristics of a good resolving agents are:
a) ready availability, b) stability of supply, c) stability in use and storage, d) low price or
ease of preparation, e) ease of recovery and reuse, f) low molecular weight, g) availability in
high enantiomeric purity, h) availability of both enantiomers, i) low toxicity and j) reasonable
solubility.
Resolving agents for acids:
For the separation of racemic acids naturally occurring alkaloids have been used like
cinchotoxine 17, quinotoxine 18, ephedrine 21 and menthol 25 (Fig. 5). Also synthetic bases like
20, 23 24, 1-phenylethylamine 19 and amphetamine 22 have been employed in resolution
experiments. The advantage of synthetic resolving agents like 19 and 22 is the (commercially)
availability of both enantiomers.
CHAPTER-II
59
N
NH
H
H
O
R
NH2
OH
NH NH2
NH2
CH3
NH2
CH3
CH3
OH
H3C CH3
H2N
17 R=H, cincotoxine 18 R=Bz, quinotoxine
19 20
21 22 23
24
25
Fig 5
Basic resolving agents are generally used to transform racemic covalent substrates like
carboxylic, sulfonic and variety of phosphorus acids into diastereomeric salts that are separated
by crystallization.
Resolving agents for bases:
Among the preparative methods used for obtaining enantio-enriched amines by
resolution, there are procedures involving the use of acidic resolving agents like N-acetylleucine
26, phenoxypropionic acid 27, mandelic acid 28, tartaric acid 16 and its dibenzoyl derivative 29,
and pyroglutamic acid 30 and Moshers acid 32 (Fig. 6). Also synthetic acids like L-
phenylcarbamoyllactic acid 31 can be versatile resolving agents. For instance, 31 is used for the
resolution of 1-(p-chlorophenyl)ethylamine, a key intermediate in the synthesis of a chiral
fungicide.
CHAPTER-II
60
OH
NHAc
O
OOH
CH3 OH
OH
O
HOOH
O
ONH
COOHO
HN O
OH
O
O
OR
OR
O
CO2H
OCH3
CF3
Fig 6
26 2728
16 R=H29 R=Bz
30 31 32
2.2.2 Separation via complexes and inclusion compounds: Chiral alkenes, arens, sulfoxides
and phosphines for which alternative resolution routes are limited may be resolved by
incorporation into diastereomeric metal complexes or by reaction with chiral n-acids, 2-vinyl
tetrahydropyran was resolved by formation of cis platinum complex. Displacement of pyran
from complex with excess ethylene gave S-185 (92% ee) (Scheme 2).
O
Cl
Cl
H2NPt
CH3
H
CH2=CH2+
Scheme-2
33 34
Cl
Cl
H2N CH3
HCH3
O+
35
Pt
CH3
2.2.3 Chromatographic resolution: Ion-pair chromatographic resolutions have involved
addition of nonracemic counter ions to mobile phase. (+)-10-Camphorsulfonic acid served as a
mobile phase additive in resolution of chiral amino alcohols and (-) quinine HCl was used as
additive in resolution of (+)-10-Camphorsulfonic acid.
2.2.b. Kinetic resolution: It is a chemical reaction of a racemate in which one of the
enantiomers forms a product more rapidly than the other. The rate difference is due to difference
in activation energy required to reach the transition states for respective enantiomers of substrate
CHAPTER-II
61
of reaction. Recovery of unreacted enantiomer, (S)-A in nonracemic form constitutes a
resolution. The other enantiomer (R)-A was recovered from product B.
The Sharpless epoxidation of allylic alcohols with TBHP/Ti(O-iPr)4/diisopropyl- tartarate
is a highly enantioface-selective reaction10
(Scheme 3).
R2 R1
R3OH
O
O
TBHP/Ti-(O-iPr)4
DIPT
O
R2 R1
R3
OH
36 37 38
O
R3
R2 R1
OH
Scheme 3
For chiral alcohols 39, 40, this enantioface selectivity is modified by diastereofacial
influence of carbinol centre which leads to formation of erythro epoxy alcohols. Thus for each
DIPT enantiomer one matched (kinetically fast) 42, 43 mismatched (kinetically slow) 41, 44
diastereomers are formed (Scheme 4).
O
R4
R1
R2 OH
R3O
R4
R1
R2 OH
R3
O
R1
R2R4
OH
O
R1
R2R4
OH
39 40
41 42
43 44
TBHP/Ti-(O-iPr)4
/DIPT
R3
R2
R1R4
OH
R3
R2
R1R4
OHR3 R3
Scheme 4
CHAPTER-II
62
3. Resolution of 1-arylalkylamines:
The importance of optically pure compounds has increased dramatically in the
chemical, pharmaceutical and agrochemical industries.11
Of particular interest, amines bearing an
adjacent enantiomerically pure chiral carbon center are in important class of compounds. These
molecules are highly valuable building blocks in organic chemistry due to their extensive use as
chiral ligands,12
catalysts,13
resolving agents,14
and intermediates,15
in the synthesis of
biologically important molecules. These optically active amines are valuable synthons in the
synthesis of biologically active natural products and compounds of pharmalogical properties.16
For instance; chiral amines have been used as building blocks in the synthesis of neurological,
cardiovascular, immunological, anti-hypertensive, anti-infective and anti-emetic drugs. In most
cases, the pharmacological activities of these amines are related to the configuration of the
stereogenic center. For example, (S)-amphetamine has higher pharmacologically activity as
stimulant,17
and hyperthermic agent,18
than its (R)-enantiomer. (R)-4-phenylbutan-2-amine 45 is
a precursor of the anti-hypertensive delevalol,19
and (R)-p-methoxyamphetamine 46 is a
constituent of (R,R)-formoterol, a potent bronchodilator.20
Furthermore 1-phenyl-1-propylamine
47 is a precursor of the corticotrophin-releasing factor type-1 receptor antagonist, a potent anti-
depressive agent.21
consequently, there is a need for efficient methods to obtain the desired (R)-
or (S)-enantiomer in optically pure form.
NH2
H3CONH2
NH2
Fig 7
45 46 47
Dibenzofuran 48, is a basic framework in several natural products namely, , Lucidafuran
49 , Eriobofuran 50, Cannabifuran 51 (Fig. 8), Fulicineroside, Ruscodibenzofuran and
Karnatakafurans with pronounced biological properties.22
CHAPTER-II
63
O
48
O
O
OH
OH
OMe
O
OMe
OH
OMe
49
5051
Fig. 8
Simple dibenzofurans are also occurring in higher plants, where they often act as
anitungal, phytoalexins. Synthetic heterocycles derived from dibenzofuran manifests (52, 53, 54)
a number of important and therapeutically useful biological activities (Fig. 9) such as
antibacterial, antidepressant, and antituberculasis.23
In view of the importance of Dibenzofuran as core unit in the above bioactive
molecules, we visined the α-ethyl amines developed on dibenzofuran platform could be useful
synthons in the preparation of new compounds for biological screening, then undertook the work
to prepare and resolve α-dibenzofuranyl ethyl amines.
O
NH
COOMePHO
OH
OO
NH
PHO
OH
O
N N
N
N
O
O
52 53 54
Fig. 9
CGS-35066 CGS-34043
Antitubercularactivity compound
CHAPTER-II
64
4. PRESENT WORK:
Treatment of Dibenzofuran 48, with AlCl3, Acetyl chloride in dichloromethane at 10 oC
for 45 min. gave the 2-Dibenzofuranyl methyl ketone 55 in 93.7% yield (Scheme 5) after
purification over silica gel (ethyl acetate/hexane 2:98). The formation of acetyl group was
confirmed by its spectroscopic data. The 1H NMR spectrum of compound 55 showed a
resonance at 2.69 (3H) as a singlet, IR spectrum showed absorption band at 1672 cm-1
. The
Mass spectrum showed a peak at 211 (M++H) confirms the formation of acetyl group.
Scheme 5
O O
CH2Cl2, AlCl3
CH3COCl, 10 oC
45 min., 93.7%
O
5548
Dibenzofuranyl acetyl compound 55 which on further treatment with Ammonium
formate at 185 oC about 6 h gave the N-(1-(dibenzo[b,d]furan-2-yl)ethyl)formamide 56 in 95.2%
as a white solid (Scheme 6). The 1H NMR spectrum showed signals at 5.39-5.29 (1H) as a
multiplet and 1.60 (3H) as a quartet. An absorption band at 1648 cm-1
in the IR spectrum
indicates the formation of N-formyl group. The Mass spectrum revealed the presence of
molecular ion peak at
m/z 240 (M++H), confirms product N-(1-(dibenzo[b,d]furan-2-
yl)ethyl)formamide 56.
O
HCOONH4
180 oc, 6 h
95.2%O
CH3
HN H
O
O
55 56
Scheme 6
Compound 56 was subjected to acid hydrolysis using Concentrated HCl at reflux
temperature for 1.5 h. The crude amine formed was purified by acid-base treatment using
CHAPTER-II
65
ethanolic.HCl and aq.NaOH to give (R/S)–1-(dibenzo[b,d]furan-2-yl)ethanamine 57 in 84%
yield as a white color solid. Disappreance of signals, multiplet at 5.39-5.29 (1H) and at 1.60
(3H) as a quartet and appearance of signals at 4.19 (1H) as a quartet and 1.38 (3H) as a
doublet in the 1H NMR. A peak at m/z 212 (M
++H) in the Mass spectrum and absorption band at
3419 cm-1
in the IR spectrum confirmed the formation of amine 57.
5. Resolution of (R/S)–1-(dibenzo[b,d]furan-2-yl)ethanamine 57.
In general a resolving agent for the resolution of 1-(dibenzo[b,d]furan-2-yl)ethanamine
57 is choosen by trial and error method, because there is no criterion for the selecting a suitable
resolving agent.
Various chiral acidic resolving agents such as (L)-tartaric acid-16, dibenzoyl (L) - tartaric
acid-29 , (S)-Naproxen-5a, (R)-Malic acid-58, (R)-Mandelic acid-28, (S)-Mandelic acid-59 and
(S)-phencyphos-60, (R)-phencyphos-61 are used in our study.
HOOCCOOH
OR
OR
COOH
OH
COOH
OH OP
O
O OH
OP
O
O OH
O
HO
O
OH
OH
(R)-58
(R)-28 (S)-59 (S)-60 (R)-61
COOH
O
(S)-5a16 R= H 29 R= Bz
Fig 10: Resolving agaents
O
H2N
O
CH3
HN
Conc.HCl,
reflux, 1.5 h
84%
H
O
Scheme 7
5657
CHAPTER-II
66
Initially the use of (L)-tartaric acid-16, dibenzoyl (L) - tartaric acid-29, (S)-Naproxen-5a
and (R)-Malic acid-58 in various solvents such as MeOH, IPA and EtOH did not give any
resolution of racemic amine 57. Further when subjected to the resolution of racemic amine 57
with (R)-Mandelic acid-28 and (S)-Mandelic acid-59 in IPA as a solvent resulted negligible
eantiomeric excess (3-4% ee) was observed (followed by HPLC and [α] D25
= + 3.68 o
(c 1.0,
CHCl3), [α] D25
= - 6.24 o
(c 1.0, CHCl3) (these values are observed liberated amine after
decomposition of their respective diastereomeric salts).
5.1. Chiral Cyclic Phosphoric acids used as resolving agents:
In 1985 Wynberg et al,24
have synthesized new class of highly acidic resolving agents,
chiral cyclic phosphoric acids (Scheme 8). These cyclic phosphoric acids are fairly strong acids
(PKA 2-3), 25
they might be expected to form salts with amines and amino acids. Indeed, several
of these acids appear to be excellent resolving agents for recimic amines and amino acids
through diastereomeric salt formation. These cyclic phosphoric acids were also the first “family”
to be investigated in the new resolution technique now known as Dutch Resolution.26
R.M.
Kellogg et al, 27
resolved butyl(meta-nitro-phenyl)amine using (S)-phencyphos.
Next, we focused our attention on chiral cyclic phosphoric acids like (S)-
phencyphos 60 and (R)-phencyphos 61 as a resolving agents, which are very often used in
industrial scale productions now a days. To a solution of R/S-amine 57 (8.53 mmol) in IPA was
added (S)-phencyphos 60 (8.53 mmol) in IPA as a solvent and briefly boiled for 4 min. (1 g per
nearly 200 mL, see in experimental part). The mixture was allowed to cool to room temperature
gradually. The precipitate formed was filtered and washed with cold IPA (5 mL) to obtain 85.2%
of the less soluble diastereomeric salt 65 (scheme 9). This salt had M.P.250-252 oC and [α] D
25 =
(+)-29.5 o
(c 1.0, MeOH). The salt was characterized from 1H NMR spectrum the characteristic
O
RO
OH
R
OH
R
OP
O
OHO
KOH
EtOH
1) POCl3
2) NaOH
3) HCl62 63 64
60-61
+
Scheme 8. General synthesis of cyclic phosphoric acids
CHAPTER-II
67
benzylic CH proton shifted from 4.19 (1H) quartet to 4.55 (1H) as quartet, cyclic phosphoric
protons at 4.98 (1H), two methyl protons at 0.79 (3H) and 0.58 (3H) as singlets respectively.
O
H2N
OP
O
O OH
H
O
+H3NO
PO
O
O-
H
O
+H3NO
PO
O
O-
H
O
H2N
O
H2N
+
--------------------------------------------------------------------------------------------------
(+ ) -Less soluble, 65(+)- More soluble, 66
( - )-DBF-ethyl amine, 67( + )-DBF-ethyl amine, 68
R/S-amine, 57 (S)-Phencyphos. 60
Scheme 9: Resolution of racimic amine 57, with (S)-Phencyphos. 60 The salt was treated with 10% aq.HCl (8 mL), dichloromethane (10 mL) was added to
recover the acid. The aqueous layer was treated with alkali to isolate 92.5% of Less soluble
amine 67, M.P. 103-104 oC, [α] D
25 = (-)-27.5
o (c 1.0, CHCl3) and 67.0% e.e.
CHAPTER-II
68
The mother liquor was concentrated to remove maximum IPA and placed at room
temperature. Some solid was observed. Filtered and washed with chilled IPA 5 mL, to obtain
another diastereomeric salt (More soluble salt) 66 in 74.2% yield as a light orange color solid.
M.p.215-217 oC and [α] D
25 = (+)-20.5
o (c 1.0, MeOH). The Salt was characterized from
1H
NMR spectrum the characteristic benzylic CH proton shifted from 4.19 (1H) quartet to 4.36 as
quartet, cyclic phosphoric protons at 5.0 (1H) two methyl protons at 0.80 (3H) and 0.59 3H) as
singlets respectively.
The salt was treated with 10% aq.HCl (8 mL), dichloromethane (10 mL) was added to recover
the acid. The aqueous layer was treated with alkali to isolate 91.2% of More soluble amine 68,
M.P. 99-102 oC, [α] D
25 = (+)-16.5
o (c 1.0, CHCl3) and 54.1% e.e.
6. CONCLUSION:
(S)-Phencyphos acid 60 has been found to serve a first and efficient resolving agent
for (R/S)-amine 57. We also confirmed that (S)-phencyphos could be recovered with sufficient
quality in good recovery.
CHAPTER-II
69
7. EXPERIMENTAL SECTION:
1-(dibenzo[b,d]furan-2-yl)ethanone 55:
To a stirred solution of AlCl3 (7.51 g, 56.33 mmol) and Acetyl chloride (4.42 g, 56.30
mmol) in 45 mL of dichloromethane was added dropwise dibenzofuran 48 (10.08 g, 60.66
mmol) in 120 mL of dichloromethane at 10 oC. After 45 min. it was quenched with the addition
of 1M HCl (120 mL). Organic layer separated was washed with H2O (2x50 mL) and brine (2x25
mL) dried over anhydrous Na2SO4 and concentrated in vacuum. Crude residue was
chromatographed over silica gel (ethyl acetate/hexane 2:98) to afforded 1-(dibenzo[b,d]furan-2-
yl)ethanone 55 (11.81 g, 93.7%) as a white solid.
M. P : 68-70 oC.
IR (neat) : max 2990, 1672, 1584, 1452, 1421, 1304, 1252,
1199, 1117, 1021, 953, 820, 749 cm-1
.
1H NMR (300 MHz, CDCl3)
ESI-MS
:
:
8.55 (d, J=1.51, 1H), 8.09 (dd, J= 9.06, 2.26,
1H), 8.02-7.94 (m, 1H), 7.59 (d, J= 9.06, 2H), 7.48
(dt, J= 7.55, 1.51, 1H), 7.36 (t, J= 7.55, 1H), 2.69
(s, 3H).
m/z 211 (M+ + H).
N-(1-(dibenzo[b,d]furan-2-yl)ethyl)formamide 56:
1-(dibenzo[b,d]furan-2-yl)ethanone 55 (10.0 g, 47.61 mmol) and ammonium
formate (9.60 g, 152.38 mmol) was taken in round bottom flask and heated at 180 oC-185
oC for
6 h. After completion, the reaction mixture was cooled the flask to room temperature, extracted
into benzene (3x100 mL). The organic layer was washed with H2O (3x100 mL), dried over
Na2SO4 and evaporated under vacuum. The crude residue was flash column chromatographed
over silica to yield N-(1-(dibenzo[b,d]furan-2-yl)ethyl)formamide 56 (10.83g, 95.2%) as a white
solid.
M. P : 150-152 oC.
IR (neat) : max 3252, 3037, 2971, 2865, 1648, 1539, 1451,
1380, 1229, 1199, 1091, 813, 747 cm-1
.
1H NMR (300 MHz, CDCl3)
:
8.14 (s, 1H), 7.90 (d, J=9.25, 2H), 7.53-7.35 (m,
4H), 7.29 (t, J=7.74, 1H), 5.91 (brs, 1H), 5.39-5.29
CHAPTER-II
70
13C NMR (75MHZ, CDCl3)
ESI-MS
:
:
(m, 1H), 1.60 (q, J=7.55, 3H).
160.1, 147.7, 137.2, 127.3, 125.3, 122.7, 120.6,
118.2, 117.7, 111.6, 109.1, 47.6, 21.9.
m/z 240 (M+
+ H).
(R/S)- 1-(dibenzo[b,d]furan-2-yl)ethanamine 57:
The formamide compound 56 (10.20 g, 42.67 mmol) in 50 mL RB flask was added
conc.HCl (6.68 mL, 64.0 mmol) and refluxed for 1.5 h. The reaction mixture was cooled to room
temperature and added H2O (100 mL). The aqueous layer was washed with benzene (3x50 mL),
cooled to 5 oC and neutralized with 1M aq.NaOH. Aqueous phase was then extracted with
CH2Cl2 (2x50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to
yield curde amine. It was then purified through Amine. HCl salt formation using ethanolic.HCl.
The salt formed was neutralized with aq.NaOH to yield recemic pure amine 57 (7.56 g, 84%) as
a white color solid.
M.P. : 100- 103 oC
IR (neat) : max 3419, 2962, 1539, 1451, 1334, 1196, 1102,
947, 816, 748 cm-1
.
1H NMR (300 MHz, CDCl3)
13C NMR (75MHZ, CDCl3)
ESI-MS
:
:
:
7.49 (d, J=8.12, 1H), 7.42-7.31 (m, 3H), 7.24
(dt, J=7.55, 0.94, 1H), 4.19 (q, J= 6.61, 1H), 1.38
(d, J= 6.61, 3H).
156.5, 155.2, 142.2, 127.0, 125.1, 124.2, 122.5,
120.5, 117.5, 111.6, 111.3, 51.3, 26.1.
m/z 212 (M+
+ H).
Resolution of (R/S)- 1-(dibenzo[b,d]furan-2-yl)ethanamine 57 with (S)-Phencyphos. 60:
To a solution of R/S- amine 57 (1.80g, 8.53 mmol) in IPA (20 mL) was added
(S)-phencyphos 60 (2.06g, 8.53 mmol) in IPA (380 mL) at reflux temperature for 5 min. The
resulting clear solution was allowed to cool slowly to room temperature. The precipitate obtained
was filtered to give Less soluble salt 65 (1.64 g, 85.2%).
M.P.
[α] D25
:
:
250-252 oC
(+) 29.5 o (c 1.0, MeOH).
CHAPTER-II
71
1H NMR (DMSO-d6, 300
MHz)
: δ 8.34 (S, 1H), 8.14 (d, J= 7.5Hz, 1H), 7.73 (t, J= 8.3Hz,
2H), 7.67 (d, J=8.6 Hz, 1H), 7.55 (t, J= 7.5Hz, 1H), 7.41
(t, J= 7.5Hz, 1H), 7.31-7.22 (m, 5H), 4.98 (s, 1H), 4.55 (q,
J= 13.4, 6.6 Hz, 1H), 4.02 (d, J=10.19 Hz, 1H), 3.50 (d,
J= 10.5 Hz, 1H), 1.62 (d, J= 6.6Hz, 3H), 0.79 (s, 3H),
0.58 (s, 3H).
The Less soluble salt was decomposed to get the free amine. To the salt 65 (1.0g) was
added 10% aq. HCl (8 mL) and extracted into CH2Cl2 (10 mL) to recover the acid (0.48g, 92%).
To the aqueous layer was added 1N NaOH solution until it is alkaline (8 mL). Then extracted
into dichloromethane (2x10 mL) to get the Amine. The organic phase was separated, washed
with H2O (2x5 mL), dried over Na2SO4 and concentrated to obtain (-)-Less soluble Amine 67
(0.43g, 92.5%) as a white color solid.
M.P. 103-104 oC
[α] D25
: (-) 27.5 o (c 1.0, CHCl3).
1H NMR (CDCl3, 300 MHz) : δ 7.92-7.88 (m, 2H), 7.50 (t, J= 8.30, 1H), 7.44-7.37 (m,
3H), 7.28 (t, J= 7.5Hz, 1H), 4.30 (q, J= 12.8, 6.7 Hz, 1H),
1.47 (d, J= 6.7, 3H).
The mother liquor was concentrated to remove maximum IPA and placed at room
temperature. Some solid was observed. Filtered through a Buchner funnel and washed with
chilled IPA 5 mL, to afford 1.43g more of the another diastereomeric salt (More soluble salt) 66
in 74.2% yield as a light orange color solid.
M.P.
[α] D25
:
:
215- 217 oC
(+)-20.5 o (c 1.0, MeOH).
1H NMR (DMSO-d6, 300
MHz)
: δ 8.24 (s, 2H), 8.14 (d, J= 7.5Hz, 2H), 7.69 (t, J= 7.5Hz,
4H), 7.61 (dd, J= 8.3, 1.5 Hz, 2H), 7.53 (t, J= 8.3Hz, 2H),
7.40 (t, J= 7.5Hz, 2H), 7.32-7.23 (m, 4H), 5.0 (d,
J=3.0Hz, 1H), 4.36 (q, J 13.6, 6.7Hz, 2H), 4.04 (dd, J=
10.5, 1.5Hz, 1H), 1.49 (d, J= 6.7Hz, 3H), 0.8 (s, 3H), 0.59
(s, 3H).
CHAPTER-II
72
13C NMR (DMSO-d6, 75
MHz)
: δ 155.7, 139.3, 127.5, 127.3, 127.2, 127.1, 126.0, 123.4,
123.3, 123.0, 120.9, 118.8, 111.6, 111.3, 83.3, 83.2, 75.3,
75.2, 50.2, 23.8, 20.9, 17.3.
The salt was decomposed to get the free More soluble amine. The salt 66 (1.0g) was
treated with 10% HCl (8 mL) and extracted into CH2Cl2 (10 mL) to recover the acid (0.47g,
88.4%). To the aqueous layer was added 1 N NaOH solution until it is alkaline (8 mL) and
extracted into CH2Cl2 (2x10 mL) to isolate the amine. Removal of the solvent gave (+)-More
soluble amine 68 (0.42g, 91.2%) as a light whitish color solid.
M.P. : 99- 102 oC
[α] D25
: (+)- 16.5 o (c 1.0, CHCl3).
1H NMR (CDCl3, 300
MHz)
: δ 7.91-7.88 (m, 2H), 7.50 (d, J= 8.1Hz, 1H), 7.45 (d,
J= 8.4Hz, 1H), 7.40 (dt, J= 7.1, 1.7Hz, 2H), 7.29 (dt,
J= 8.1, 0.7Hz, 1H), 4.28 (q, J= 13.2, 6.4Hz, 1H), 1.44
(d, J= 6.4Hz, 3H).
MS (ESI) : m/z 212 (M+ + H).
CHAPTER-II
73
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