View
4
Download
0
Category
Preview:
Citation preview
�
Chapter – 3
Section-A Synthesis of Cyclobutane and Quinoline Derivatives
63
Introduction
A series of N-substituted-quinolinone-3-aminocycloamides derivatives were
synthesized and evaluated for antiviral, antifungal and antibacterial activities. In general,
the derivatives were found to be potent Antifungal agents and Antibacterial agents the
results are discussed in terms of structure-activity relationships and an attempt is made to
define the structural features required for activity.
AIDS is essentially a viral disease and should be treated by antiretroviral agents.1
Although a combination of antiretroviral therapy has made it possible to suppress the
replication of HIV-1 in infected individuals to such an extent that it becomes
undetectable in the plasma, the virus persists in reservoirs such as peripheral blood
mononuclear cells or resting T lymphocytes which went back to a latent state after an
early replicative stage.2-4
Thus, after more than 3 years of multidrug therapy, it turned out
that the HIV-1 infection can be controlled but not eradicated with current treatments.
Besides, the emergence of resistance against both reverse transcriptase and protease
inhibitors, which was a frequent issue of the single-agent regimen, was not completely
suppressed by the use of combination therapy. It is therefore important to identify new
agents that could block the virus at a step of its replicative cycle which is not yet affected
by current treatments. For these reasons, the integrase (IN), the third viral enzyme which
is strictly required for the establishment of a stable infection, 5
is an attractive target for
new antiviral agents and potential synergy with currently available HIV reverse
transcriptase and protease inhibitors.6
Recently the fragment-based approach (F-BA) to drug discovery has gained
stronger attention than ever before. During the last 10 years of this methodology has been
intensively developing and now it can be successfully used as an alternative for poorly
effective.7-8
However , it should be remembered that the molecules used as fragments do
not possess high activity, but they are much more druggable than huge, sophisticated
structures usually pointed out in HTS. Thus in F-BA we are looking rather for possibility
of creating a new drug than for activity. Successful molecular scaffold should be easily
accessible and transferable into real drug. Probably the best way to achieve this aim is to
64
explore the so called privileged structures as a scaffold.9 unfortunately there are no single
rule that specify which structure is really privileged.
On the other hand quinoline and its derivatives such as quinoline antibiotic can be
the most spectacular example of the potential efficiency of this system.10
Quinine
molecule, which also contain quinoline moiety, proves the nature preference for the
system. Quinoline scaffold can be also found in many classes of other biologically active
compounds used as antifungal, antibacterial and antiprotozoic drug 11-14
as well as
antituberculotic agents.15
some quinoline analogues shows antineoplastic activity.
Through knowledge of all interaction which occur in solutions or crystals of
molecules proposed as scaffolds is very important for better understanding its fate in
biological system and for SAR studies Certain specific interactions are able to change
crucial parameters of molecules or even to change the structure via shift of tautomeric
equilibrium.16
Quinoline-5, 8-dione is substantial molecular fragment of lavndomycin
and related compounds. Lavendomycin was originally isolated from the fermented broth
of Streptomyces, lavenduale and the compounds of this class were identified in the 1970s
as anti-tumour agents. Although the toxicity of Lavendomycin makes it unsuitable for
clinical use, its activity has inspired several investigations.17-20
Quinolinone- based antibiotics
N
O
O
N
N
H2NCOOH
CH3
N
O
O
N
H2N
H2NCOOH
CH3
MeO
OH
OMe
OMe
Lavendamycin Streptonigrin
N
O
O
HN
H2N
H2N
CH3
MeO
OH
OMe
OMe
O
Streptonigrone
Styrylquinoline as HIV Integrase inhibitor
65
Styrylquinoline have been recognized as potent HIV-1 IN inhibitors that block
HIV-1 replication in cell based assays.21
with the aim to explore their mechanism of
action, various novel Styrylquinoline derivatives were synthesized and their biological
properties were evaluated. Since Styrylquinoline fall within the general category of
inhibitors characterized by two aryl groups linked through a central spacer, we have
examined the molecular determinants of each of these subunits, through a progressive
series of analogues. These results clearly demonstrate that the presence of a free carboxyl
group at C-7 and a hydroxyl at C-8 in the quinoline half is required for the biological
activity of the drug. The other prerequisite for in vitro potency was the presence of an
ancillary aromatic ring.
However the in vitro inhibitory profile tolerates the introduction of various
substituent’s in this ring or its replacement by heteroatomic nuclei. The structural
requirements for ex vivo activity are more stringent than for in vitro IN inhibition. In
addition to the presence of an o-hydroxyl acid group in the quinoline, the anti-HIV
activity indeed requires the presence of one ortho pair of substituent’s in the ancillary
phenyl ring: a free hydroxyl group at C-4 and a hydroxyl or methoxy group at C-3.
Examination of SARs developed for our compounds, interpreted in the light of literature
data, led to a putative binding mode of Styrylquinoline to HIV-1 IN. Since the Mg2+
ion
is a cofactor required for the enzymatic activity of HIV-1 IN, we hypothesized that the o-
hydroxyl acid group lies in a possible coordination to this metal cation. The additional
binding force which plays a significant role in the recognition of the drug by the protein
apparently involves the ancillary aromatic ring.
However, since the exact mechanism by which Styrylquinoline inhibited
productive infection is unknown, the definitive mapping of the binding sites of these
inhibitors awaits further investigation. In summarizing the above findings, it can be
concluded that the insights so gained are likely to aid the design and development of new
useful HIV-1 IN inhibitors. HIV-1 IN has indeed become an attractive target for
intervention by chemotherapeutics, because of the rapid emergence of resistance against
66
both reverse transcriptase and protease inhibitors, currently used in combination regimens
for the treatment of AIDS.22
Binding mechanism of Styrylquinoline related compound to active site of HIV
integrase inhibitor
Most of HIV integrase inhibitors are be lived to interact with divalent metal
cations such as magnesium or manganese, located at the protein active site.23
Crystal
structures of the core domain of HIV-1 IN mutants complexes with Mg2+
have been
reported.24
The magnesium is coordinated in the active site by Asp- 64 and Asp-116, whereas
the third residue of the catalytic amino acid triad, Glu-152, does not directly participate in
metal binding. Such a binding site was unequivocally identified by X-ray structure
determination of a complex between a naphthalene disulfonic inhibitor (Y-3) and ASV
IN, a protein which exhibits great similarity with HIV-1 IN.25
The Y-3 molecule in the
crystal is located in close proximity to the enzyme active site. Recently, the X-ray
structure of the HIV-1 IN catalytic domain complexes with an inhibitor (5CITEP) has
been determined. The inhibitor binds centrally in the active site of the IN and makes a
number of close contacts with the protein. Only minor changes in the protein accompany
inhibitor binding.26
Since it was recognized that HIV-1 IN requires a divalent cation as cofactor for its
enzymatic activity (presumably Mg2+
), and assuming that an o-hydroxyl acid group in the
quinoline subunit is crucially involved in both in vitro and ex vivo inhibitory activities,
they hypothesized that this group lies in a possible coordination to the metal cation. Such
an assumption has been recently reinforced by computational studies. Indeed,
minimization of the energy of interaction between Styrylquinoline drugs on the whole
surface of the catalytic core domain of RSV IN revealed that the best fits were found for
binding of the drugs on Mg2+
in the vicinity of the active site.27
Recently retroviral has been elucidated by mean crystal structure of IN from PFV
virus.28-29
Designing drugs is a complex issue that still lacks general approach. Although
we usually do not realize that, the lack of the appropriate wide spectrum biological data is
one of the important problems. In fact, this contributes to the low efficiency of the current
67
molecular design. Thus, molecular modeling provides us with molecular data describing
small molecule effectors. However, we cannot model so efficiently biological records. On
the other side, only very few experimental information are available on such compounds
with the exception of the certain activities under investigations. It has been suggested that
QSAR efficiency could be significantly improved by the incorporation into the respective
models of not only structural, physical or chemical parameters but also a spectrum of
biological activities. From the medicinal chemist point of view this strategy suggests that
we should investigate and report the data for a variety of biological effects. Quinoline
moiety is present in many classes of biologically active compounds.
A number of them have been clinically used as antifungal, antibacterial, and
antiprotozoic drugs as well as antineoplastics.30
Styrylquinoline derivatives have gained
strong attention recently due to their activity as perspective HIV integrase inhibitors.31–34
Quinoline Salicylic Acids derivatives and SAR as P-selectin activity
Letter on Neelu Kaila and coworkers defined SAR of Quinoline Salicylic Acids
and show that both hydroxyl and carboxylic acid must require for P-selectin activity.
N
O OH
OH
Boths groups are required for Activity.
R1
R8
R7
R6
small groups are prefferdeg.R= Cl,Br, I-Pr, N-(Et)2, CF2,OCF3Polar groups are inactiveAryl groups are not activeAmide functionality is not tolerated.
R8= hydrophobic groups areprefferdsmall steric bulk is toleratedhydrophelic groups have generally negative impact on activityAryl substitution result in increase in activity.
R7 = Substitution at seven position does not lead to potent compound.
R6 = Substitution at six position does not lead to potent compound
Figure 3.132
68
4-Hydroxy 3-quinolinecarboxamide derivatives
Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and
evaluated for treatment of autoimmune disorders.36
For a long time Katarzyna and
coworkers had been interested in quinoline chemistry 7 and this situation prompted us to
study 4-hydroxy-3-quinolinecarboxamides, which could actually be regarded as possible
bioisosteres of oxicams I.37
Katarzyna and coworkers selected three basic quinoline
scaffolds as a fragment of HIV integrase inhibitors. Their crystal structures and in vitro
activities were collected and molecular docking were performed.38
O
O
NH
O
1
N
OH
O
OH
2
N
OHO
HO
3
Figure 3.2
Some differences in the molecular interaction between inhibitors and enzyme
seem to elucidate the activity pattern. Most active scaffold of 5-hydroxy-quinaldine -6-
carboxylic acids (Scaffold2) acids was found to be more efficient in hydrogen bonding
interaction with enzyme active site other than two compounds.
69
Present work
Our conclusion from literature survey
1) Quinoline pharmacocore is important for biological activity.
2) Both acid and hydroxyl groups must be ortho required for HIV Integrase activity.
3) In case of aryl substituent on basic quinoline pharmacocore has less impact on Anti
HIV activity.
4) Aryl substituent at 8 position of quinoline salicylic acid must be tolerated.
5) Substituent on any other does not give potent compound.
6) According to literature survey and best of our knowledge nobody had tried. Synthesis
of compound having hydroxyl and amide groups ortho to each other and does not test
against Anti HIV activity.
7) We had changed position of hydroxyl and carboxylic acid group.
Keeping these things in mind we have designed novel series of compounds with
different variations. In summery we have done
1) Basic quinoline Scaffold was kept constant.
2) Put cycloamide and hydroxyl groups are put on quinoline ring at 3&4 position
hypothetical mechanism of these groups with magnesium cation has derived using
literature.
3) Aromatic substitution on 8 positions may lead to increase in activity.
General Structure of Proposed compound
N
NH
OOH
Basic quinoline pharmacocore
Both groups required for activity
newly praposed novel amide group.
novel substitutent at 8 position.
R
Figure 3.3 General Structure of Proposed compound
70
Hypothetical mechanism of designed quinoline cyclobutyl carboxyamide
OH
O
HN
Mg2+
O
O
N
OH
OH
O
N
H
OASP64ASP116
Ar
Figure 3.4 Hypothetical mechanism of designed quinoline cyclobutyl carboxyamide derivative –
magnesium cation interaction at the active sites of HIV integrase.
Retro synthetic approach for synthesis of proposed compound
N
NH
OOH
R
N
NH
OOH
BrN
Br
OH
OOH
NH2
Br
DEMM
Figure 3.5 Retro synthetic approaches for synthesis of designed compound
71
GENERAL APPROACHES TO 4-HYDROXY QUINOLINE
OH
OH
O
NH
H
O
COOR
NH
COOR
COOR
X
O
COOR
NR2
NH2
O
COOR
R2
R1
O
R1 = OCH3; R2 = NHCOArR1= NEt2; R2 -N=NR2
Based- catalysedcyclisation
Cyclization usingsubstituted o-N-vinylamino derivaties
FriedelCraft enaminoester cyclization.
Intramolecular SNAr using halogenated aminovinyl phenyl ketones.
Closure by an intramolecular michel reaction
Figure 3.6 Current approaches to the synthesis of 4-hydroxy quinoline.
72
Results and Discussion
The 4-hydroxyl-3-carboxy cyclobutyl amide analogues were synthesized 14 as
shown in Scheme 2. 1. Starting from ortho bromo aniline. O-Bromo Aniline was reacted
with diethoxyethylmethlene malonate to give Michel type of adduct (Compound14). This
on refluxing in biphenyl ether gives compound 15. Further compound 15 was reacted
with different boronic acid under Suzuki reaction conditions gives compound (15A-15G).
Br
NH2
Br
NH
COOEt
COOEt
N
Br
OH
O
O
N
Br
OH
OOH
N
O
N
OH
Br
N
O
N
OH
a b c
d
e
13 1415 16
1718A-18GR
N
O
OEt
OH
R
N
O
OH
OH
R
15A-15G 16A-16G
b1 c1
Scheme 3.1 Synthesis of 8-bromo- N-cyclobutyl-4-hydroxyquinoline-3- carboxamide
Reactions and conditions: a) Diethoxy methyl ethylene malonate, o-bromo aniline heat
at 90 0C, 2 h, 92%; (b) Biphenyl ether, 270
0C, 3 h, 88%; Toluene, (b1) Phenyl Boronic
Acid, Tetrakis, CS2CO3, 111 0C, 2 h, 78%; (c) 10%Aq. NaOH, THF, 70
0C, 2.5 h, 74.5%;
(c1)Toluene, Phenyl Boronic Acid, Tetrakis, CS2CO3, 111 0C, 2 h, 65%; (d) DMF, EDCI,
HOBT, NMM, rt, 4 h, 90%; (e) Toluene, Phenyl Boronic Acid, Tetrakis, CS2CO3, 111
0C, 2 h, 60%.
73
Compound 15A-15G may acts as prodrugs in biological system. Compound 15
was hydrolyzed to give 4-hydroxy 3- carboxylic acid quinoline derivatives (compound
16). Compound 16 was reacted with different boronic acid to give Compound (16A-
16G). Compound 16 was converted in to cyclobutyl amide derivatives compound (17)
using EDCI, HOBT, NMM, in DMF. Compound 17 was reacted with different boronic
acid under Suzuki reaction condition gives Compound (18A-18G).
All synthesized compounds (15A-15G, 16A-16G, 18A-18G) were characterized
by NMR, ms and HPLC. Few of selected compounds were submitted for Anti HIV
activity. Biological activity result and SAR of compounds were discussed in chapter 5.
74
Synthesis of diethyl 2-((2-bromophenylamino)methylene)malonate (14)
Br
NH
COOEt
COOEt
A suspension of 2-bromo aniline (1)5gm (31mmol) diethyl ethoxymethylene malonate
(8g, 37.2mol) was heated to 110 0C for 4h. The reaction mixture was cooled to rt. The
solid thus formed was taken in pet ether and stir for 15 min and filtered to get Compound
2 as a white crystalline solid 9.7g (95% yield.
Spectral data
IR (KBr, Cm-1) v: 3467(NH), 1709(C=O), 1765(C=C); 1H NMR (300MHz,CDCL3)
δppm: 8.45 (d, J = 9.6Hz, 1H),7.62 (m, 2H), 7.36 (d, J = 6.1Hz, 1H), 7.25 (m, 1H), 4.34
(q, 2H), 1.38 (t, J = 5.3Hz, 3H), 1.35 (t, J = 5.3Hz, 3H); MS (ESI+) (342.3) Calcd for
C14H16BrNO4 : 341.03.
Synthesis of ethyl 4-hydroxy-8-phenylquinoline-3-carboxylate (15)
N
OH
OEt
O
Br
Compound 2 (9g, 27mmol) was heated at 250 0C for 4hr in dry medium, the reaction
mixture was cooled to rt and added hexane (200ml) and stired for 15 min, the precipited
solid was filtered and dried to get compound 3 as white solid. 8.8gm (88% yield.
Spectral data
IR (KBr, Cm-1) v: 3519(OH), 1709(C=O), 1H NMR (300MHz ,CDCL3) δppm: 11.68
(br s, 1H), 9.68 (s, 1H), 8.47 (m, 2H), 7.59 (t, J = 7.8Hz, 1H), 4.24 (q, 2H), 1.29 (t, J =
7.2Hz, 3H); MS(ESI+) Calcd. For C10H12BrNO3; 294.98.
75
General process for synthesis of compound (15A-15G)
To a solution of 3 (2.99 g, 9.83 mmol), CS2CO3 (4.076 g, 29.49 mmol), and
Tetrakis (0.80 g, 0.98 mmol) in dry Toluene (15 mL) was added phenyl boronic acid
(1.2334 gm, 20994 mmol).
The reaction mixture was heated to reflux at 111 0C for 6 h, then cooled to
ambient temperature, poured into a water (50 mL), and extracted with EtOAc (3 _ 40
mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4,
and evaporated. The crude solid was purified over silica gel-60 via MPLC (EtOAc/pet
ether) to afford 2.64 g (91% yields) of a solid.
76
Spectral data
Ethyl 4-hydroxy-8-(4-methoxyphenyl) quinoline-3-carboxylate (15A)
N
OH
OEt
O
OMe
Nature: Solid; MP: 172-174 oC; Yield: 75%;
1H NMR (300MHz, DMSO-d6) δppm;
9.68 (s, 1H), 8.01- 7.90(m, 2H), 7.74 (d, J = 7.5Hz, 2H) 7.59 (t, J = 7.8Hz, 1H), 7.42 (d, J
= 7.5Hz, 2H), 4.24 (q, 2H), 3.95 (s, 3H), δ1.29 (t, J = 7.2Hz, 3H); MS (ESI+) m/z: 324.3
(M+1) Calcd. For C19H17NO4: 323.3.
Ethyl-8-(4-fluorophenyl)-4-hydroxyquinoline-3-carboxylate (15C)
N
OH
OEt
O
F
Nature: Solid; MP: 170-171 oC; Yield: 77%;
1H NMR (300MHz, DMSO-d6) δppm;
9.68 ( s, 1H), 8.01-7.91 (m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H), 7.36 (d,
J = 7.5Hz, 2H), 4.24 (q, 2H), δ1.29 (t, J = 7.2Hz, 3H); MS(ESI+)m/z: 312.3 (M+1) Calcd.
For C18H14FNO3 : 311.3.
Ethyl 4-hydroxy-8-(4-(methyl sulfonyl) phenyl) quinoline-3-carboxylate (15D)
N
OH
OEt
O
SO
O
77
Nature: Solid; MP: 178-179 oC; Yield: 80%;
1H NMR (300MHz, DMSO-d6) δppm;
9.68 ( s, 1H), 8.01- 7.88(m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H), 7.58 (d,
J = 7.5Hz, 2H), 2.68 ( s, 3H), 4.24 (q, 2H), δ1.29 (t, J = 7.2Hz, 3H); MS(ESI+) m/z: 372.3
(M+1) Calcd. For C19H17NO5S: 371.4.
Ethyl 4-hydroxy-8-phenylquinoline-3-carboxylate (15E)
N
OH
OEt
O
Nature: Solid; MP: 176-178 oC; Yield: 82%;
1H NMR (300MHz, DMSO-d6) δppm;
9.68 ( s, 1H), 8.01(d, J = 7.5Hz, 1H), 7.70 – 7.68 (m, 2H), 7.54 – 7.48 (m, 3H), 7.40 (d, J
= 7.5Hz, 2H), 4.24 (q, 2H), δ1.29 (t, J = 7.2Hz, 3H); MS(ESI+) m/z: 294.3 (M+1); Calcd.
For C18H15NO3: 293.2.
Ethyl 4-hydroxy-8-P-tolylquinoline-3-carboxylate (15F)
N
OH
OEt
O
Me
Nature: Solid; MP: 178-179 oC; Yield: 78%;
1H NMR (300MHz, DMSO-d6) δppm;
9.68 ( s, 1H),7.98-7.88(m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H), 7.37 (d, J
= 7.5Hz, 2H), 2.31 ( s, 3H), 4.24 (q, 2H), δ1.29 (t, J = 7.2Hz, 3H); MS(ESI+) m/z: 308.3
(M+1) Calcd. For C19H17NO3: 307.3.
Ethyl 8-(4-cyanophenyl)-4-hydroxyquinoline-3-carboxylate (15G)
78
N
OH
OEt
O
CN
Nature: Solid; MP: 189-190 oC; Yield: 70%;
1H NMR (300MHz, DMSO-d6) δppm;
9.68 ( s, 1H),7.98-7.88(m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H), 7.48 (d, J
= 7.5Hz, 2H), 4.24 (q, 2H), δ1.29 (t, J = 7.2Hz, 3H); MS(ESI+) m/z: 319.3 (M+1) Calcd.
For C19H17NO3: 318.3.
79
Synthesis of 8 – bromo-4-hydroxyquinoline-3-carboxylic acid (16)
N
Br
OH
OH
O
To A solution of 3 (4gm, 1.222mmol) in THF (50ml) 10 % Aq. NaOH (20mL)
was added. The reaction mixture was stirred at rt for 4 hr and reaction was monitored by
TLC.
After complete disappearance of starting material from TLC RM was concentrate
to remove THF on rotavapour. Residue was diluted with water and neutral ph was
maintained by using dil. HCl solution and compound was extracted in DCM (2 × 25 mL).
Combined DCM layer was dried over anhydrous sodium sulphate and concentrate on
rotaevapo. To get compound (4)
white solid. 1H NMR (300MHz, CDCl3) δppm: 11.68 (br s, 1H, OH), 10.02 (s, 1H), 8.47
(m, 2H), 7.59 (t, J = 7.8Hz, 1H), MS(ESI+) m/z: 269.1 (M+1) Calcd. For C10H6BrNO3;
268.1
General Procedure for synthesis of compound (16A-16G)
To a solution of 16 (2.99 g, 9.83 mmol), CS2CO3 (4.076 g, 29.49 mmol), and
Tetrakis (0.80 g, 0.98 mmol) in dry Toluene (15 ml) was added phenyl boronic acid
(1.2334gm, 20994mmol).
The reaction mixture was heated to reflux at 111 0C for 6 h, then cooled to
ambient temperature, poured into water (50 mL), and extracted with EtOAc (3x40 mL).
The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and
evaporated. The crude solid was purified over silica gel-60 via MPLC (EtOAc/hexane) to
afford 2.64 g (91% yield) of a solid.
80
Ethyl 4-hydroxy-8-(4-methoxyphenyl) quinoline-3-carboxylic Acid (16A)
N
OH
OH
O
OMe
Nature: Solid; MP: 272-274 oC; Yield: 82%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 8.01- 7.90(m, 2H), 7.74 (d, J = 7.5Hz, 2H) 7.59 (t, J = 7.8Hz, 1H), 7.42 (d,
J = 7.5Hz, 2H), 4.10 (t, 3H); MS(ESI+) m/z: 296.3 (M+1) Calcd. For C17H13NO4: 295.3.
Ethyl-8-(4-fluorophenyl)-4-hydroxyquinoline-3-carboxylic Acid (16C)
N
OH
OH
O
F
Nature: Solid; MP: 260-262 oC; Yield: 80%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 8.01- 7.90(m, 2H), 7.74 (d, J = 7.5Hz, 2H) 7.59 (t, J = 7.8Hz, 1H), 7.38 (d,
J = 7.5Hz, 2H); MS (ESI+) m/z: 284.3 (M+1) Calcd. For C16H10FNO3 : 283.3.
Ethyl 4-hydroxy-8-(4-(methyl sulfonyl) phenyl) quinoline-3-carboxylic acid(16D)
N
OH
OH
O
SO
O
81
Nature: Solid; MP: 273-275 oC; Yield: 82%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 8.01- 7.90(m, 2H), 7.74 (d, J = 7.5Hz, 2H) 7.59 (t, J = 7.8Hz, 1H), 7.44 (d,
J = 7.5Hz, 2H); 2.68 (s, 3H); MS (ESI+) m/z: 344.4 (M+1) Calcd. For C19H17NO5S:
343.1.
Ethyl 4-hydroxy-8-phenylquinoline-3-carboxylic Acid (16E)
N
OH
OH
O
Nature: Solid; MP: 272-274 oC; Yield: 82%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 8.22 (s, 1H) 8.01(d, J = 7.5Hz, 1H), 7.70 – 7.68 (m, 2H), 7.54 – 7.48 (m,
3H), 7.42 (d, J = 7.5Hz, 2H); MS(ESI+) m/z: 266.3 (M+1); Calcd. For C18H15NO3: 265.1.
Ethyl 4-hydroxy-8-P-tolylquinoline-3-carboxylic Acid (16F)
N
OH
OH
O
Me
Nature: Solid; MP: 271-272 oC; Yield: 82%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 8.01- 7.90(m, 2H), 7.74 (d, J = 7.5Hz, 2H) 7.59 (t, J = 7.8Hz, 1H), 7.40 (d,
J = 7.5Hz, 2H), 2.31 (s, 3H), 4.24 (q, 2H), δ1.29 (t, J = 7.2Hz, 3H); MS(ESI+) m/z: 280.3
(M+1) Calcd. For C17H13NO3: 279.3.
Ethyl 8-(4-cyanophenyl)-4-hydroxyquinoline-3-carboxylic Acid (16G)
82
N
OH
OH
O
CN
Nature: Solid; MP: 275-276 oC; Yield: 82%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 8.01- 7.90(m, 2H), 7.74 (d, J = 7.5Hz, 2H) 7.59 (t, J = 7.8Hz, 1H), 7.48 (d,
J = 7.5Hz, 2H); MS (ESI+) m/z: 319.3 (M+1) Calcd. For C19H17NO3: 318.3.
83
Synthesis of 8-bromo-N-cyclobutyl-4-hydroxyquinoline-3-carboxamide (17)
N
O
N
OH
Br
N-methylmorpholine (12ml,4.43mmol),cyclobutyl amine(13 mg,0.18mmol), 1-
hydroxybenzotriazole(30mg, 0.22mmol), 1-3(3-dimethylamino-propyl)-3-
ethylcarbodiimide hydrochloride(32mg,0.17mmol)were added to a solution of compound
4 in DMF(Dimethyl Formamide). After stirring at room temperature for 6h reaction was
monitored by TLC. The rm was evaporated under reduced pressure to remove DMF and
DCM was added. The DCM layer was washed with an aqueous solution of sodium
bicarbonate solution, with brine (2x3mL) and dried over sodium sulphate and evaporated
under reduced pressure. The crude residue was purified by column chromatography,
Ethyl Acetate: Pet ether as a solvent on combi flash to get compound 5 (46mg,
81%Yield).
1H NMR (300MHz, DMSO-d6)
δppm; 11.68 (br s, 1H,OH), 10.47(s,1H), 8.47 (m, 2H)
7.59 (t, J = 7.8Hz, 1H), 3.73(m, 1H), 2.32- 2.28 (m 4H) 2.1(m, 2H); MS(ESI+) m/z:
222.2 (M+1) Calcd. For C14H13BrN2O3; 221.3.
84
General procedure for Synthesis of Compound (18A-18G)
To a solution of 17 (2.99 g, 9.83 mmol), CS2CO3 (4.076 g, 29.49 mmol), and Tetrakis
(0.80 g, 0.98 mmol) in dry Toluene (15 mL) was added phenyl boronic acid (1.2334gm,
20994mmol). The reaction mixture was heated to reflux at 111 0C for 6 h, then cooled to
ambient temperature, poured into a water (50 mL), and extracted with EtOAc (3 x 40
mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4,
and evaporated. The crude solid was purified over silica gel-60 (EtOAc/hexane) to afford
2.64 g (91% yield) of a solid.
85
Spectral data
N-cyclobutyl-4-hydroxy-8-(4-methoxyphenyl) quinoline-3-carboxamide (18A)
N
O
NH
OH
OMe
Nature: Solid; MP: 162-164 oC; Yield: 77%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 7.98-7.88(m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H), 7.42 (d,
J = 7.5Hz, 2H), 3.95(s, 3H),3.73(m, 1H), 2.32- 2.28 (m, 4H), and 1.9(m, 2H).
N- cyclobutly-4-hydroxy-8-p-tolylquinoline-3-carboxamide (18B)
N
O
NH
OH
Me
Nature: Solid; MP: 168-170 oC; Yield: 70%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 7.98-7.88(m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H), 7.42 (d,
J = 7.5Hz, 2H), 3.95(s, 3H),3.73(m, 1H), 2.32- 2.28 (m, 4H), 1.9(m, 2H); MS(ESI+) m/z:
333.4 (M+1) Calcd. For C21H20N2O2: 332.4
N- cyclobutyl -8-(4-fluorophenyl)-4hydroxyquinoline-3-carboxamide (18D)
N
O
NH
OH
F
86
Nature: Solid; MP: 172-174 oC; Yield: 73%;
1H NMR (300MHz, DMSO-d6)
δppm;10.47 (s, 1H), 7.98-7.88(m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H),
7.37 (d, J = 7.5Hz, 2H), 3.95(s, 3H),3.73(m, 1H), 2.32- 2.28 (m, 4H), 1.9(m, 2H);
MS(ESI+) m/z: 337.3 (M+1) Calcd. For C20H17FN2O2: 336.4
8-(4-cyanophenyl)-N-cyclobutyl-4-hydroxyquinoline-3-carboxamide (18F)
N
O
NH
OH
CN
Nature: Solid; MP: 172-174 oC; Yield: 82%;
1H NMR (300MHz, DMSO-d6) δppm;
10.47 (s, 1H), 7.98-7.88(m, 2H), 7.70 (d, J = 7.5Hz, 2H) 7.54 (t, J = 7.8Hz, 1H), 7.48 (d,
J = 7.5Hz, 2H), 3.95(s, 3H),3.73(m, 1H), 2.32- 2.28 (m, 4H), 1.9(m, 2H); MS(ESI+) m/z:
344.4 (M+1) Calcd. For C21H17N3O2: 343.3.
87
Representative Spectra
1H NMR OF COMPOUND 16A
MS OF COMPOUND 16A
88
HPLC OF COMPOUND16A
1H NMR OF COMPOUND 18A
89
HPLC OF COMPOUND 18A
90
References
1. Ho, D. D.; Neumann, A. U.; Perelson, A. S.; Chen, W.; Leonard,J. M.;
Markowitz, M.; Nature 1995, 373, 123.
2. Zhang, L.; Ramratnam, B.; Tenner-Racz, K.; He Y.; Vesanen, M.; Lewin, S.;
Talal, A.; Racz, P.; Perelson, A.; Korber, B.; Markowitw, M.; Ho, D.; N. Engl. J.
Med. 1999, 340, 1605.
3. Furtado, M.; Callaway, D.; Phair, J.; Kunstman, K.; Stanton, J.; Macken, C.;
Perelson, A.; Wolinsky, S.; N.; Engl. J. Med. 1999,340, 1614.
4. Finzi, D.; Silliciano, R. F.; Cell 1998, 93, 665.
5. Lafemina, R. L.; Schneider, C. L.; Robbins, H. L.; Callahan, P. L.; Legrow, K.;
Roth, E.; Schleif, W. A.; Emini, E. A.; J. Virol.1992, 66, 7414.
6. De Clerq, E.; J. Med.Chem. 1995, 38, 2491.
7. Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R.; Nat. Rev. Drug Disc. 2004,
3, 660.
8. Hajduk, P. J.; Greer, J.; Nat. Rev. Drug Disc. 2007, 6, 211.
9. Kubinyi, H. Fischer, J., Ganellin, C. R., Eds.; Wiley- VCH: Weinheim, 2006, 53.
10. Petersen, U. Quinolone Antibiotics: The Development of Moxifloxacin.
InAnalogue Based Drug Discovery; Fischer, J., Ganellin, C. R., Eds.; VCH-Wiley
Verlag GmbH & Co., 2006; pp 315–370.
11. Fostel, J. M.; Lartey, P. A.; Drug Discovery Today, 2000, 5, 25.
12. Zainaba, D.; Meryem, L.; Abdelmejid, B.; Abdelfatah, A.; Mohammed, H.; Said,
K.; Mohammed, B.; Mohammed, B.; Farmaco, 2004, 59, 195.
13. Musiol, R.; Serda, M.; Hensel-Bielowka, S.; Polanski, J.; Curr. Med. Chem.,
2010, 17, 1960.
14. Majerz-Maniecka, K.; Oleksyn, B.; Musiol, R.; Podeszwa, B.; Polanski, J.; In
Sci. Pharm. 2005; 73, 194.
15. Urbina, J.; Cortes, J.; Palma, A.; Lopez, S.; Kouznetsov, V. V.; Zacchino, S.
A.;Enriz, R. D.; Ribas, J. C.; Bioorg. Med. Chem. 2000, 8, 691.
16. Majerz-Maniecka, K.; Musiol, R.; Nitek, W.; Oleksyn, B. J.; Mouscadet, J.; Le
Bret,M.; Polanski, J.; Bioorg. Med. Chem. Lett, 2006, 16, 1005.
91
17. Doyle, T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.; Gould, S. J.; Tann,
C.-H.; Meows, A. E.; Tetrahedron Lett, 1981, 22, 4595.
18. Hackethal, C. A.; Golbey, R. B.; Tan, C. T. C.; Karnofsky, D. A.; Burchenal, J.
H.; Antibiot. Chemother, 1961, 11, 178.
19. Boger, D. L.; Mitscher, Y. M.; Drake, S. D.; Kitos, P. A.; Thompson, S. C.; J.
Med.Chem., 1987, 30, 1918.
20. Wilson, W. L.; Labra, C.; Barrist, E.; Antibiot. Chemother. 1961, 11, 147.
21. Mekouar, K.; Mouscadet, J.-F.; Desmae¨le, D.; Subra, F.; Savoure´, D.; Auclair,
C.; d'Angelo, J.; J. Med. Chem. 1998, 41, 2846.
22. Mekouar, K.; Mouscadet, J.-F.; Desmae¨le, D.; J. Med. Chem. 2000, 43, 1533.
23. Lubrowski, J.; Yang, F.; Alexandratos, J.; Wlodawer, A.; Zhao, H.; Burke, Jr., T.
R.; Neamati, N.; Pommier, Y.; Merkel, G.; Skalka, A. M.; Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 4831.
24. Goldgur, Y.; Dyda, F.; Hickman, A. B.; Jenkins, T. M.; Craigie, R.; Davies, D.
R.; Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 9150.
25. Lubrowski, J.; Yang, F.; Alexandratos, J.; Wlodawer, A.; Zhao,H.; Burke, Jr., T.
R.; Neamati, N.; Pommier, Y.; Merkel, G.; Skalka, A. M.; Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 4831.
26. Goldgur, Y.; Craigie, R.; Cohen, G. H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.;
Sugimoto, H.; Endo, T.; Murai, H.; Davies, D. R.; Proc.Natl. Acad. Sci. U.S.A.
1999, 96, 13040.
27. Ouali, M.; Laboulais, C.; Leh, H.; Gill, D.; Desmae¨le, D.; Mekouar, K.; Zouhiri,
F.; d'Angelo, J.; Auclair, C.; Mouscadet, J.-F.; Le Bret, M. J. Med. Chem. 2000,
43, 1789.
28. Hare, S.; Gupta, S. S.; Valkov, E.; Engelman, A.; Cherepanov, P.; Nature, 2010,
464, 232.
29. Maertens, G. N.; Hare, S.; Cherepanov, P. Nature 2010, 468, 326.
30. Neamati, N.; Sunder, S.; Pommier, Y. Drug Discov. Today 1997, 2, 487.
92
31. Artico, M.; Di Santo, R.; Costi, R.; Novellino, E.; Greco, G.; Massa, S.;
Tramontano, E.; Marongiu, M. E.; De Montis, A.; La Colla,P. J. Med. Chem.
1998, 41, 3948.
32. Weinberg, B.; Shugars, D. C.; Sherman, P. A.; Sauls, D. L.; Fyfe, J. A.; Biochem.
Biophys. Res.Commun. 1998, 246, 393.
33. Jing, N.; Hogan, M. E. J. Biol. Chem. 1998, 273, 34992.
34. Hong, H.; Neamati, N.; Wang, S.; Nicklaus, M. C.; Mazumder, A.; Zhao, H.;
Burke, Jr., T. R.; Pommier, Y.; Milne, G. W. A.; J. Med. Chem. 1997, 40, 930.
35. Journal of Medicinal Chemistry, 2007, Vol. 50, No. 1
36. Weinberg, B.; Shugars, D. C.; Sherman, P. A.; J. Med. Chem. 2004, 47, 2075.
37. Artico, M.; Di Santo, R.; Costi, R.; Novellino, E.; Greco, G.; Journal of
Medicinal Chemistry, 1988, Vol. 31, No. 7)
38. K. Majerz-Maniecka et al. / Bioorg. Med. Chem. 2011, 19, 1606–1612
�
Section-B
Greener Methodology for Synthesis of Urea Derivatives
�
93
Introduction
A simple and efficient route for the synthesis of unsymmetrical N,N`-Diphenyl
urea have been developed in aqueous medium under base and catalyst free condition
from corresponding substituted isocynate and amines. The remarkable key feature of the
reaction include the use of water as an inexpensive and environmentally benign reaction
medium, absence of base and any additional catalyst, and easy isolation of the product.
We report a simple, economical, efficient, high yielding, one-pot synthesis of
unsymmetrical disubstituted ureas, from the corresponding isocynates under aqueous
medium. The remarkable key feature of the reaction include the use of water as an
inexpensive and environmentally benign reaction medium ,absence of base and any
additional catalyst, and easy isolation of the product. We believed that this synthesis
protocol offer a more general method for the formation of C–N, C-O & C-S bonds
essential to numerous organic syntheses. Various unsymmetrical disubstituted urea’s,
thiourea derivatives were prepared in high yields and their spectroscopic confirmation
was achieved.
Recent focus on urea’s stems from their wide range of application in
petrochemicals, agrochemicals, and pharmaceuticals' used as dyes for cellulose fibres,
antioxidants in gasoline or as plant growth regulators, pesticides and herbicides. The
unsymmetrical urea functional group is also encountered in several biologically active
synthetic targets. In particular, potent urea containing HIV-1 protease inhibitors2 and p38
kinase inhibitors3 have recently been disclosed. Substituted urea’s are very important
class of compounds that display a wide range of interesting applications6. They have
extensively been used as agrochemicals7, pharmaceuticals
8, intermediates in organic
synthesis9, for protection of amino groups
10, and as linkers in combinatorial chemistry
11.
These require their preparation by convenient and safe methodology. Traditionally, their
synthesis involves a reaction of amines with phosgene12
, its derivatives13
, carbonyl-
imidazoles14
, or carbon monoxide15
using various kinds of metal and non-metal catalysts.
Despite the growing number of synthetic methodologies, ureas are most
commonly synthesized by reaction of an amine with phosgene or carbamates. This
approach is particularly efficient for symmetrical urea’s. In the case of unsymmetrical
94
urea’s, the synthetic efficiency is limited by the formation of symmetrical urea side
products. In the last few years, toxic and unstable reagents such as phosgene and isolated
isocyanides have been increasingly substituted for cleaner and inherently safer
alternatives4.
These include use of carbonates or carbonyl imidazole or taking advantage of the
reactivity of carbonates’ with amines to produce urea. Unfortunately, production and use
of phosgene opens many worrying toxicological and environmental problems.
Nevertheless, about 2 million tons per year of phosgene are produced and utilised
worldwide.5 Under the new environmental legalization of the developed countries,
industrial and academic research groups have performed methodologies for preparation
of urea based on the use of reagents which are less toxic and less hazardous than
phosgene5.
Method for preparing 1, 3-disubstituted urea through catalytic process by reacting
a cyclic carbonic acid ester with an amine was disclosed16
. This method is too expensive
to use on a large scale. The transformation of amines to disubstituted urea through
catalytic carbonylation provides an alternative environmental benign method and has
been investigated over many years using various kinds of metallic catalysts17
. However,
these methods failed due to the problems of regenerating the catalysts from the products.
Moreover, their formation using CO2 employed harsh reaction conditions, such as long
reaction times, use of expensive strongly basic reagents, tedious work-up, and low
yields18
. Consequently, there is continued interest in developing new and convenient
methods for the synthesis of substituted urea using mild reaction conditions.
95
Results and Discussion
Most of the synthetic approaches to produce urea utilize phosgene or its tamed
analogs. Commercially available reagents such as Benzyl Isocynate & Phenyl Isocynate
also effectively convert into corresponding disubstituted urea under dry reaction
condition. Reaction of Phenyl Isocynate in 1, 4-dioxane/water or pyridine/water unable to
gives desired 1, 3-diphenylurea in required yield. 19
Reaction was very slow and takes
about 12 to 16 h to complete reaction. Reagents like Isocynate might not withstand in
aqueous condition or react efficiently with complex starting materials. According to our
knowledge there was no method for synthesis of urea in water from isocynate and amine.
We have therefore soughed to develop a methodology which should be Simple, scalable
& ecofriendly method to produced disubstituted urea, Use of reagent that electrophonic
enough and effectively react with amines of various structures, yet reasonably stable in
aqueous environments.
Reaction of 1-fluoro-4-isocyanatobenzene with anisole in aq. Medium gives
desired urea in very low yield (10%) and it takes 10-15 hr to complete the reaction. This
could be due to instability of isocynate in water. When we repeated same reaction in
water at 4-50C, excellent yield of desired urea was observed in 30min.From above
observation we conclude that reagent like isocynate may be stable in aq. Medium at
lower temperature. Although this was our observation in this particular case, however we
do not have any proof for the stability of such reagent in water at lower temperature. To
test the feasibility and practical applicability, a reaction on large scale was conducted in
water at 4-50C; 85% of conversion was observed after 30 min. The mixture was just filter
out to get pure biphenyl urea.
Anisole dissolved in water (complete or partial) and the mixture was cooled to
50C. After 5 min 1mol. eq. of 1-fluoro-4-isocyanatobenzene was slowly added in above
reaction mixture in such way that temperature of reaction mixture doesn’t rise above
100C. As reaction proceeds solid falls out. RM was stirred for 30 min at 5
0C & reaction
monitor by TLC. Solid was filter out & residue washed with water. Obtained product
does not required further purification. Solid was collected to report yield and analysis.
96
NCO
F
O
H2N
H2O, 4-5 0C
30 min
HN
HN
F OO
Scheme3.2
Under optimized reaction condition, the scope of reaction was explored with
structurally and electronically diverse amine, thiols, alcohol and isocynate to get
respective urea, thiourea & carbamate. Mosubstituted aryl amine such as n methyl phenyl
amine treated with 1-fluoro-4-isocyanatobenzene under similar condition gives 80%
yield. Also good yield was obtained in case of amine which was partially soluble in aq.
Medium at lower temperature. Reaction of p-nitro aniline with 1-fluoro-4-
isocyanatobenzene failed to give desired product under similar reaction condition. This
may be decrease in Nucleophilicity of amine due to p-nitro group.
When Thiol treated with 1-fluoro-4-isocyanatobenzene gives corresponding
thiourea. Similarly when phenol treated with 1-fluoro-4-isocyanatobenzene gives
corresponding carbamate. We found slight lower yields of Thiourea & Carbamate as
compare to urea. We also observed low yields when n methyl phenyl amine was treated
with 1-fluoro-4-isocyanatobenzene. From above observation we conclude that low yield
was due to decrease in nucleophilicity of Phenol, thiols & mosubstituted aryl amine in aq.
Medium.
97
Table 2.B.1 Synthesis of N-N` Biphenyl urea
Sr.No. Product Time (h) Yielda (%) M.P. (°C)
3.B.1
0.5 85 233-237
3.B.2
1 80 120-125
3.B.3
0.5 91 145-150
3.B.4
2 82 135-140
3.B.5
3 73 ---
3.B.6
2 77 155-157
3.B.7
2 80 157-160
3.B.8
2 75 125-127
3.B.9
1.5 80 77-80
3.B.10
0.5 87 132-134
3.B.11
1 75 140-142
3.B.12
1.5 80 130-132
3.B.13
0.5 94 196-198
3.B.14
3 72 120
aIsolated yield
98
Experimental
General procedure: Anisole (Amine) (10mmol) was dissolved in water and the mixture
cooled to 50C. After 5 min 1-fluoro-4-isocyanatobenzene (10mmol) was slowly added in
above reaction mixture in such way that temperature of reaction mixture doesn’t increase
above 50C. As reaction proceeds solid falls out. RM was stirred for 30 min at 5
0C &
reaction was monitor by TLC. After completion of reaction Solid was filter out & residue
washed with water. Solid was collected to report yield & analysis of respective urea. The
product was confirmed by Melting points and spectral analysis such as MS, NMR (Table
1, entry 1)
1H NMR (300MHz ,DMSO-d6) δppm; 8.60 (s, 1 H),8.45 (s, 1 H), 7.45 (dd, J = 9.1, 4.9
Hz, 2H), 7.35 (d, J = 9.1 Hz, 2 H), δ7.10 (t, J = 8.9 Hz, 2 H),δ6.87 (d, J = 8.7Hz, 2 H),
δ3.71 (s, 3 H); MS (ESI+) Calcd for C14H13FN2O2 : 260.26, Found: 261.11 [M+1]. White
solid.
99
General Methods
All Reagents were commercially purchased from Aldrich and used without further
purification. Commercial reagents were used as received. Reaction were monitored by
thin-layer chromatography (TLC) on 0.25mm precoated Merck Silica Gel 60 F254,
visualizing with ultraviolet light or Ninhydrine. 1H NMR spectra were recorded on a
Bruker DPX-400 with standard pulse sequences, operating at 300 MHz. Chemical shifts
were reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which
was used as internal standard. HPLC-MS analyses were performed with an Agilent
Technologies 1100 series consisted of a quaternary pump with degasser, auto sampler,
column oven and DAD detector.
1-(4- fluorophenyl)-3-(4- methoxyphenyl) urea (3.B.1)
HN
HN
OF O
1H NMR (300MHz ,DMSO-d6) δppm: 8.60 (s, 1 H),8.45 (s, 1H), 7.45 (dd, J = 9.1, 4.9
Hz, 2 H), 7.35 (d, J = 9.1 Hz, 2H), 7.10 (t, J = 8.9 Hz, 2H), 6.87 (d, J = 8.7Hz, 2 H), 3.91
(s, 3 H); MS(ESI+) Calcd for C14H13FN2O2 : 260.26, Found: 261.11 [M+1].
3-(4- fluorophenyl)-1methyl-1-phenyl urea (3.B.2)
HN N
OF
1H NMR ( 300MHz, DMSO-d6) δppm; 8.21 (s, 1 H), 7.38 - 7.46 (m, 4H), 7.30 - 7.35 (m,
2H), 7.21 - δ7.28 (m, 1H), 7.02 - 7.10 (m, 2H), 3.26 (s,3H); MS(ESI+) Calcd for
C14H13FN2O :224.12, Found:225.21 [M+1].
N-(4 – fluorophenyl)-3, 4-dihydroisoquinoline-2(1H)-carboxamide (3.B.3)
100
HN N
OF
1H NMR (300MHz, DMSO-d6)δppm; 8.61 (s, 1 H), 7.45 - δ7.55 (m, 2H), 7.19 (s, 4H),
7.08 (t, 2H), 4.63 (s, 2H), 3.69 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 6.0Hz, 2H); MS (ESI+)
Calcd for C16H15FN2O :270.12 ,Found: 271.11 [M+1].
1-(4-fluorophenyl)-3-(2-methoxyethyl) urea (3.B.4)
HN
HN
OF
O
1H NMR (300MHz ,DMSO-d6)δppm; 8.54 (s, 1H), 7.37 (dd, J = 9.3, 5.1 Hz, 2H), 7.05
(t, J = 9.1 Hz, 2H), 6.16 (t, J = 5.5 Hz, 1H), 3.32 - 3.40 (m, 5H), 3.21 -δ 3.25 (m, 2H);
MS (ESI+) Calcd For C10H13FN2O2: 212.22; Found:213.23 [M+1].
S-phenyl N-4- fluorophenylcarbamothioate (3.B.5)
HN S
OF
1H NMR (300MHz ,DMSO-d6) δppm; 10.57 ( s,1H),7.48 - 7.56 (m, 4H), 7.44 - 7.48 (m,
3H), 7.12 - 7.19 (m, 2H); MS (ESI+) Calcd for C13H10FNOS : 247.29 ,Found:248.29
[M+1].
4-fluorophenyl 4- fluorophenyl carbamate (3.B.6)
OHN
OFF
1H NMR (300MHz ,DMSO-d6) δppm; 10.29 (br. s, 1H), 7.51 (dd, J = 9.1, 4.9 Hz, 2H),
7.24 - 7.29\(m, 4H),7.18 (t, J = 8.9 Hz, 2H); MS (ESI+) Calcd for C13H9F2NO2 :
249.21,Found: 250.01 [M+1].
4-methoxyphenyl 4- fluorophenyl carbamate (3.B.7)
101
OHN
OOF
1H NMR (300MHz ,DMSO-d6) δppm; 10.20 (br. s., 1H), 7.51 (dd, J = 9.1, 4.9 Hz,
2H),7.22 – 7.09 (m, 3H), 6.95 (d, J = 9.1Hz, 2H), 3.76 (s, 3H); MS (ESI+) Calcd for
C14H12FNO3 : 261.25; Found:262.15[M+1].
Phenyl 4- fluorophenyl carbamate (3.B.8)
OHN
OF
1H NMR (300MHz ,DMSO-d6) δppm; 10.27 (br. s, 1H), 7.52 (dd, J = 9.1, 4.9Hz, 2H),
7.39 - 7.47(m, 2H), 7.13 - 7.30(m, 5H); MS (ESI+) Calcd for C13H10FNO2 : 231.22;
Found:232.54[M+1].
102
Representative Spectra
1HNMR of Compound 3.B.1
MS of Compound 3.B.1
103
HPLC of Compound 3.B.1
104
References
1. Sartori, G. Green Chemistry, 2000,2, 140.
2. L. Cassar, Chem. Ind. (Milan), 1990, 72, 18.
3. Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.;
Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; Chang, C. N.; Weber, P. C.;
Jackson, D. A.; Sharp, T. R.; Erickson- Viitanen, S. Science1994, 263, 380;
4. Chauhan, Y. S; Apphun, A.; Singh, V. K.; Dwivedi, B. S. Field Crops Res, 2004, 89,
17.
5. Frezza, M.; Castang, S.; Estephanem, J.; Soule`re, L.; Deshayes, C.; Chantegrel, B.;
Nasser, W.; Queneau, Y.; Reverchon, S.; Doutheau, A. Bioorg Med Chem, 2006, 14,
4781.
6. Li, G.; Hasvold, L. A.; Tao, Z. F.; Wang, G. T.; Waltney, S. L.; Patel, J.; Kovar, P.;
Credo, R. B.; Chen, Z.; Zhang, H. Bioorg Med Chem Lett, 2006, 16, 2293.
7. Hegarty, A. F.; Drennan, L. J. In: Katrizky AR, Methocohn, O, Rees CW (eds)
Comprehensive Organic Functional Group Transformations. Pergamon, Oxford,
1995, 6, 499.
8. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd edn. John
Wiley and Sons T. P. 1999. Vishnyakova, 1. A. Golubeva and E. V. Glebova, Russ.
Chem. Rev. (Engl. Transl.), 1985, 54, 249.
9. Han, Q.; Chang, C.-H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y. S. J. Med.
Chem.1998, 41, 2019.
10. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E.; Klaus,
B.; Madwed, J.; Moriak, M.; Moss, N.; Torcellini, C. J. Med. Chem.,2002, 45, 2994.
11. Mensal, M.; Gutschow, M. Tetrahedron Lett 2005, 46, 2231.
12. Smith, M. B.; March, J. Advanced Organic Chemistry. Reactions, Mechanisms, and
Structure, 5th edn. Wiley Interscience, New York, Chichester, Brisbane, Toronto,
Singapore. 2001.
13. Guichard, G.; Semety, V.; Didierjean, C.; Asubry, A.; Briand, J. P.; Rodriguez, M., J
Org Chem.1999, 64, 8702.
105
14. Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Taylor, S. D. Tetrahedron Lett,
1998, 39, 6267.
15. McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.; McElwee-White, L. J
Org Chem. 2000,65, 5216.
16. US Patent. 5902899, May 11, 1999
17. Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. J Mol Catal A Chem. 1997,
122, 103.
18. Tai, C. C.; Huck, M. J.; McKoon, E. P.; Woo, T.; Jessop, P. G. J Org Chem 2002, 67,
9070.
19. Liu, Q.; Luedtke, N. W.; Yitzhak, T. Tetrahedron Lett. 2001, 42, 1445.
�
Section-C
Green Methodology for Synthesis of Carbonyl
Compounds from Alkyl
�
106
3.C.1 Introduction
P-amino benzyl derivatives were found to react with 2, 3-dichloro-5,6-dicyno-1,4-
benzoquinone(DDQ) in 5% aq. HCl to give p-amino benzyl derivatives in good yields.
Thus, p- amino benzaldehyde was easily isolated from the reaction with p-toludine at
ambient temperature. Similarly hindered p-amino benzyl derivatives were
regiospecificaly oxidized to corresponding carbonyl compound in high yield in Aq.
Medium.
The discovery of new environmentally friendly methods for selective catalytic
oxidation of alkyl substrates to aldehyde and ketones in presence of amine is an important
goal in the development of modern methods for chemical synthesis.1
With the
considerable development of selective organic chemistry in the last few decades, specific
reagents have seen their potential increase dramatically. The spectrum of their
applications in modern organic chemistry has been enlarged to offer new challenging
synthesis opportunities.2 Not an exception, DDQ has been investigated as a powerful
oxidizing agent by several research groups, and was proved to be useful for a wide range
of reactions. Although several uses of DDQ have been mentioned in many patents from
the pharmaceutical and chemical specialties industries, we will restrict this article to
regiospecific oxidation by DDQ of an unhindered alkyl groups in sterically hindered
aromatic amine.
Amino benzaldehydes are the important key intermediate for synthesis of many
biologically active compounds. They are use for synthesis of inosine monophosphate
dehydrogenase (IMPDH) inhibitors 3ab
in development of anticancer drugs,4Chk1 kinase
inhibitors5 and also in the preparation of an intermediate of one of the major metabolites
of the antihypertensive Trequisin,6 Novel thyroid hormone receptor antagonists.
7
The oxidation of the sterically hindered aromatic amine has been reported using
enzymatic, 8
electrochemical9 and chemical reactions
10, 11a, b
. In the reaction the nitrogen
of the molecule is envold in the oxidation and not the alkyl group.
107
2, 3- Dichloro- 5,6- dicyno-1,4 benzoquinone (DDQ) and related high potential
oxidant interact with aliphatic amino groups and doubts have been raised about the nature
of reaction with aromatic amines. One of the earlier reports13
was successful to do
regiospecific oxidation of mesidine to 4-amino-3, 5-dimethylaldehyde by using DDQ.
They have isolated above product in solid crystalline from by using 1, 4-dioxane as
solvent. This method has certain drawbacks such as 1) as low yield, long reaction time
and tedious workup, 2)failed to give p-amino benzaldehyde from p- toludine.3) 2,6-
dimethyl-4-propylaniline to corresponding carbonyl compound gives very less yield. An
aerobic oxidations by using molybdovanadophosphate as a catalyst Convert 2,4,6-
trimethylaniline to 4-amino-2,6-dimethylbenzaldehyde in good yield (64%) which is
difficult to prepare by conventional methods however this reaction was catalyzed by
metal and required high temperature with long reaction time.12
This method is also not
suitable for oxidation of p- toludine. To overcome these drawbacks we have decided to
develop methodology which is high yielding, short reaction time, and use of greener
protocol.
There are no previous reports, to the best of our Knowledge, of the use of water as
a solvent and method for the regiospecific oxidation of p-toludine to p-amino
benzaldehyde.
108
3.C.2 Results and Discussion
To continue our interest in conversion of aromatic methyl group into
corresponding carbonyl compound we have selected mesidine as model substrate for
further studies. As mention earlier studies when mesidine treated with 3eq DDQ in 1, 4 -
Dioxane in 6 hr give corresponding aldehyde in 49 % yield.13
When above reaction was
done with 1 eq. and 2 eq. gives only 12% and 20% yield of product respectively. To
improve yield of reaction we have decided to use different solvent keeping rest of thing
constant. Similar reaction was repeated in solvent such as THF, Acetonitrile and DMF
gives almost similar yield. Drastic change in yield was observed when reaction was done
in water, this method gives 70% desired product of aldehyde from mesidine. Although
the amines are partially soluble in water the advantages of the employment of water as a
solvent are numerous: not only is it cheap, nontoxic, and inflammable, but it also has the
feature that the stability of intermediate (A, B, C) in water which leads to high yield of
desired product.
NH2
DDQ
NH2
CHO
DDQH2
23 24
a
Scheme-3.3
When mesidine treated with DDQ in 5% aq. HCl the 4- methyl group was
regiospecificaly oxidized to corresponding aldehyde with 94% yield. It has isolated in
pure state and can be store for longer time. For consistency of result we have repeated
same protocol 3 times for mesidine and we have got similar result as we done previously.
Mesidine (1gm) was taken in 5% aq. HCl (20ml) to which DDQ (3eq) was added in it
and mixture was allow to stir for 4 hr. reaction was monitor by TLC. After complete
disappearance of starting material from TLC, reaction mixture was basified with 10% aq.
NaOH and compound was extracted in Ethyl Acetate. Ethyl Acetate layer was dried over
anhydrous sodium sulphate and concentrated to get white crystalline solid. Under
109
optimized reaction condition, the scope of reaction was explored with structurally and
electronically diverse amine.
Steric hindrance certainly plays role in the success of this reaction. Based on
earlier observation amino group is not a favorable substituent in DDQ oxidation13,15
still
gives good yield, as long as it is crowded by other groups. Less hindered anilines are not
suitable for the DDQ oxidation such as P-Toludine failed to give P-amino
benzaldehyde13
and 2, 4 dimethyl aniline gave only 10% of respective aldehyde.13
Reaction of p-Toludine with DDQ in H2O gives only 35% yield of p- amino
benzaldehyde. Whereas 58% yield was achieved when similar reaction was carried out in
5% Aq HCl with DDQ. We believed that this is novel method for oxidation of P-
toludine to P-aminobenzaldehyde in water at ambient temperature.
A considerable increase in the yield was observed when the substituent in ortho
position to the amine was more bulky. More the steric bulk at ortho position of amine
will give more yield of respective aldehyde. Similarly, 2- chloro-4-methylaniline gives 4-
amino-3-chlorobenzaldehyde in 80%.and 2 bromo-4methyl Aniline were successfully
oxidized to 4-amino-3-bromobenzaldehyde the corresponding aldehyde with very good
yield. While oxidation of 2-methyl-4- methyl aniline to 4-amino-3-methyl benzaldehyde
gives 72% yield. Reactions of 4- benzyl-2-methylbenzenamine (Table3.C.1 entry 9) with
DDQ under optimize condition gives 73% of (4-amino-3-methylphenyl1) (phenyl)
methanone.
DDQ oxidation of 2, 6-dimethyl1-4propaniline in to respective ketone gives only 10 %
yield. The poor yield might be due to a further dehydrogenation of the – CO-CH2CH3
group there by generating very active species – CO-CH=CH2, although this is only our
speculation, since we do not have evidence on this matter.
110
Table- 3.C.1
Sr. No.
Final
product
Starting
Material
Final Producta Physical constant
(M.P) 0C
Yield (%)b
3.C.1
101-102
94
3.C.2
98-100
82
3.C.3
109-110
80
3.C.4
104-106
75
3.C.5
161-163
80
Me
Me Me
NH2
C
Me Me
NH2
HO
Me
Me
NH2
C
Me
NH2
HO
Me
Br
NH2
C
Br
NH2
HO
Me
Cl
NH2
C
Cl
NH2
HO
C
Br
NH2
HO
Br
Me
Br
NH2
Br
111
3.C.6
42-44
58
3.C.7
169-170
80
3.C.8
81-82
10
3.C.9
121-122
73
3.C.10
169-170
95
aAll the products are characterised by 1H-NMR and purity checked by HPLC and the melting point and
spectroscopic data are in good agreement with those in reported method 13; bIsolated Yield.
Me
NH2
C
NH2
HO
NH2
O
Me
NH2
Me
NH2
MeNH2
Me
O
NH2
Me
Br
Br
Me
NH2
OH
Br
Br
Me
NH2
Br
Br Me
HO
NH2
Me
Br
Br Me
112
Abstraction of a hydride ion at the activated para-benzylic carbon as a possible
first Step could ultimately result in the formation either of an iminoquinone Methide
intermediate (A).12,16
Then 1, 6 addition of Aq. HCl to A gives compound (B) And final
Aminobenzaldehyde may be produced By the hydrolysis of dihydroxy intermediate (C).
C was derived from (B) and Aq. HCl via similar reaction path as the formation of (B).
Above mechanism was proposed on the basis of oxidation of phenolic compound. Use of
more polar protic solvent such as MeOH, Water stabilize intermediate A and B which
will automatically result in high yield of respective amino benzaldehyde.15
Similarly we
are getting high yield of aminobenzaldehyde due to stability of A and B in aq. HCl.
Me Me
CH2
NH
OHH
NH2
Me
OHHO
NH2
Me MeMe
HO
NH2
Me Me
10%Aa NaOH1
(A) (B) (C)
In section we report a simple, economical, efficient, high yielding, method for
regiospecific oxidation of aromatic alkyl group in to corrourpounding carbonyl
compound in presence of amine depending on nature of substrate. Various Amino
Benzaldehyde (Table 2.C.1) were prepared in high yields under optimize reaction
protocol and their spectroscopic confirmation was achieved.
113
3.C.3 Experimental
General procedure
Mesidine (15.0 g; 0.111 moles) was dissolved in 5% Aq. HCl (300 ml) and DDQ
(15.0 g; 0.225 moles) was added. A green colour complex was generated. This changed
its colour to dark brown, within five minutes of stirring. Stirring was further continued
for 4 hrs and the residue was treated with dilute sodium hydroxide and extracted with
ethyl acetate and then worked up in the usual manner. Final purification by column
chromatography on silica gel, Using hexane as eluent, gave, the main fraction 2,6-
dimethyl-4-formylaniline.
114
Spectral data
4- amino-3, 5-dimethylbenzaldehyde
NH2
Me Me
OH
Crystalline solid ; M.p.78 - 800C;
1H NMR (CDCl3, 300 MHz) ppm: 9.71 (s, 1H), 7.47
(s, 2H), 2.23 (s, 6H), 4.22 (br.s, 1H)
p- aminobenzaldehyde.
NH2
OH
p-Aminobenzaldehyde) Crystalline solid; Mp 41-43 o C;
1H NMR (CDCl3, 400 MHz)
ppm; 9.74 (s, 1H), 7.68 (d, J = 8.5Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 4.37 (br.s, 2H) 4-
amino-3-bromobenzaldehyde
NH2
OH
Br
Solid; Mp 109-110 0C;
1H NMR (CDCl3, 300 MHz) ppm; 9.71 (s, 1H), 7.95 (d, J = 8.2
Hz, 2H), 7.64 (d, 1H, J = 8.2 Hz), 6.80 (s, 1H), 4.73 (br.s, 2H, NH2)
115
4-amino-3-Chlorobenzaldehyde
NH2
OH
Cl
Solid; Mp 104-106 0C;
1H NMR (CDCl3, 300 MHz) ppm; 9.71 (s, 1H), 7.95 (d, J = 8.2
Hz, 2H), 7.64 (d, 1H, J = 8.2 Hz) 6.80 (s, 1H), 4.73 (br.s, 2H) and 9.71 (s, 1H)
4-amino-2, 3-dibromo-6- methyl benzaldehyde
NH2
OH
Br
Br Me
Mp 169-170 0C;
1H NMR (CDCl3, 300 MHz) ppm; 10.33 (s, 1H) 6.54 (s, 1H), 4.76 (br.
s, 2H), 2.51 (s, 3H).
4-amino-2, 3-dibromo-5- methyl benzaldehyde
NH2
OH
Br
Br
Me
Mp 169-170 0C;
1H NMR (CDCl3, 300 MHz) ppm; 10.33 (s, 1H) 6.54 (s, 1H), 4.76 (br.
s, 2H), 2.51 (s, 3H)
1-(4amino-3, 5-dimethylphenyl) propan-1-one
116
NH2
Me Me
O
Mp 81-82 oC;
1H NMR (CDCl3, 400 MHz) ppm; 7.47 (s, 2H), 2.23 (s, 6H), 2.122 (q,
2H), 1.21 (t, J = 6.9, 3H).
4-amino-3-methylphenyl1) (phenyl) methanone
NH2
Me
O
Mp 121- 122 oC;
1H NMR (CDCl3, 300 MHz) ppm; 7.47 - 7.71 (m, 4H), 7.57 (m, 1H),
6.86 (d, J = 7.6,1H), 7.51 (d, J = 7.6,1H), 7.41 (s,1H, Ar H)2.21 (s, 3H), 4.22 (br.s, 2H)
4- amino-3, methylbenzaldehyde.
NH2
Me
HO
Mp 98-100 0C; IR (neat) 1677 cm
-1;
1H NMR (CDCl3, 400 MHz) ppm; 9.87 (s, 1H),
6.72 (s, 1H), 7.57 (d, J = 7.6,1H), 7.67 (d, J = 7.6,1H), 2.23(s, 3H), 4.22 (br. s, 2H), and
9.87 (s, 1H).
117
3.C.4 Representative Spectra
1HNMR of Compound 3.C.1
HPLC of Compound 3.C.1
118
References
1. Chiellini, G.; Nguyen, N.-H.; Yoshihara, H. A.; Scanlan, T. S.; Bioorg. Med.
Chem. Lett. 2000, 10, 2607
2. Elke Fritz-Langhals; Johannes Freudenreich; US Patent no. US006023000A.
3. Iwanowicz, E.J.; Watterson, S.H.; Guo, J.; Pitts, W.J.; Muralidhar, T.G.; Shen,
Z.; Chen, P.; Gu, H.H.; Fleener, C.A.; Rouleau, K.A.; Cheney, D.L.; Townsend,
R.M.; Hollenbaugh, D.L;. Bioorganic & Medicinal Chemistry Letters 2003,13,
2059.
4. Rangarajan, M.; Kim, J.S.; Sim, S.P.; Liu, A.; Liu, L.F.; LaVoie, E.J.; Bioorganic
& Medicinal Chemistry 2000,8, 2591.
5. Gaoquan, Li,Lisa.; Hasvold, A.; Bioorganic & Medicinal Chemistry Letters 2006,
16 ,2293.
6. Bansi Lal; Bhattacharya, B. K.; Dadkar, N. K.; Dohadwalla,A. N.; H.; Dornauer,
N. J.; Weithmann, U.; IRCS Med. Sci., 1981,2, 325.
7. Komatsu, T.; Hirano, T.; Songkram, C.; Kawachi, E.; Kagechika, H.; Bioorganic
& Medicinal Chemistry, 2007 15,3115.
8. Bartling, G. J.; and L. J. Forrester, Trans. M. O.; Acad. Sci., 1973 ,78 , 220
9. Tiedemann, W.; and Newmann, J.; Electroanal, J.; Chem. Interfacial
Electrochem., 1975, 63, 187
10. Hedayatullah, M,; Dechatre, J. P.; and Denivelle, E. L.; Tetrahedron Lett.1975,
2039; Konand, E.; and MC Nelis, E, Chem. Comm. 1973, 562.
11. (a) Goldstein, S. L.; and McNelis, E,; J.Org. Chem., 1973, 38, 183; (b) Holmer-
Siedle, A. G.; and Saunders B. C.; Chem. Ind., 1959, 164.
12. Bartling, G. J.; and L. J. Forrester, Trans. M. O.; Journal of Molecular Catalysis
A: Chemical 1996,110, 105.
13. Bansilal, Genial disuza; Tet.Lett., 1984, 29, 2901.
14. LEE-RUFF, E.; and ABLENAS F. J.; Canedian. J. Chem.1989, 67, 699.
15. Becker H. D.; "The Chemistry of Quinonoids compounds". (Ed. S. Patai), Wiley
Interscience, New York (1974). P. 398.
16. Becker H. D.; J. Org. Chem., 1980, 45, 1596.
Recommended