Chapter 2
Part B
A review of the synthetic approaches to urea and related
derivatives
The classical approach related to Wohler’s original synthesis of urea
still continues to influence the research efforts of synthesizing ureas with
organic isocyanates being the preferred precursors. Other earlier methods
have taken advantage of the amidation of phosgene and carbamates. In
recent years, however, increasing attention has been devoted to
mediation of metallic and organometallic catalysts to synthesise them.
Some of them exploit reactions of amines with carbon monoxide or carbon
dioxide which provide for industrial synthesis of some of these ureas. In
more recent times, efforts are also focused on the ‘greenness’ of the
chemistry involved, applying the tenets of green chemistry. In the
following narration, a select review of these methods is presented.
[However, the rich synthetic chemistry of thioureas and guanidines are
excluded from this report.] A summary of synthetic routes to ureas is
shown in Chart 1.
23
Chart 1 : Summary of Synthetic routes to ureas
Ref [37]
Ref [34,35]
COCl 2
(7)
RCON 3
(15)
RNCO
(8)
RNH 2
(6)
a
RNH 2
(6)
i
Ref [7-28,36]
b
RNH 2
(6)
Ref [59]
O
R
O
X
NH
OH
h
R1
(14)
M.W.
Ref [46]
R4
N
N
R2 (16)
R3
CO
(9)
RNH 2
(6)
d
g
RNH 2
(6)
ArNH 2
(13)
Ref [32,33,38-42]
c
RNH 2
(6)
Ref [43-45]
CO 2
f
Pb(OAc) 4 e
(10)
Ref [51]
RHNCON
(12) NO
R
Ref [29,30]
RCONH 2
(11)
Reaction conditions: a, (i) Et3N, DMAP (cat), CH2Cl2, (ii) Pyridine, THF. b, CH2Cl2, 0oC, rt. c, Cu/Pd/Se/Et3NH2Se/Rh on act.carbon/PdI2 and
excess KI. d, Diphenyl phosphate, pyridine/ RuCl3.3H2O/PdCl2(MeCN)2, PPh3,/MeCN,CCl4. e, RCOOH . f, Et3N, DMF. g, CH3COCH2COOC2H5,
450 W, 15 min h, TFA, 25oC. i, (i) toluene, reflux, 30 min (ii) DIEA/ NMM, DCM, rt.
24
The available methods for the synthesis of ureas and its
precursors may be grouped as below:
1.
Isocyanate based reactions.
2.
In situ generation of isocyanate and conversion to ureas.
3.
Carbonylation = based reactions.
4.
Miscellaneous reactions.
While we confine outlining the synthetic approaches to urea
incorporated molecules in this section, studies of their utility as potential
drug application is taken up in Part C.
1. Isocyanate based reactions (Table 1 shown below):
As early as 1943, Hoover and Rothrock reported a route to ureas by
the little studied reaction of α- alkoxy isocyanates 8 obtained by the
addition of isocyanic acid 7 to α,β-unsaturated ethers 6. The reaction of
an α,β-unstaurated ethers and isocyanic acid is strongly exothermic and
proceeds rapidly especially in presence of acids Scheme 1.[7] A facile
preparation of (Hydroxyethyl) tolylurea 12 is also possible by reacting the
primary amine 10 with p-tolylisocyanate 11 Scheme 2[8] The synthesis of
N-Benzyl-N’- isopropylurea 14 is effected by reaction of benzylamine 13
with isopropy iso cyanate Scheme 3[9]. Aminocyclopentanetetral 15 was
treated with chloroethylisocyanate 16 to give the ureido derivative 17
Scheme 4 [10].
25
A BOC- protected secondary amine 18 was allowed to react with
phenylisocyanate 19 to get the BOC-containing urea 20 Scheme 5[11].
Kim et al[12] reported synthesis of several 1,3- Disubstituted ureas as
potent inhibitors of sEH (soluble epoxide hydrolase) that are active both
in vitro and in vivo. However, their poor solubility in either water or lipid
reduces their in vivo efficacy and makes them difficult to formulate.
Reaction of 4- amino butyric acid 21 with aryl or cycloalkyl isocyanate
gave the corresponding urea acid 22 Scheme 6[12]. Kim et al[13] further
reported regarding 1,3- disubstituted ureas functionalized with an ether
group as potent soluble epoxide hydrolase (sEH) inhibitor, a therapeutic
target for treating hypertension and inflammation. In the process of the
above synthesis adamantyl isocyanate 23 was reacted with hydroxyl alkyl
amine to give adamantyl hydroxyalkyl urea 24 Scheme 7 [13].
A primary amine 25 was reacted with sodium cyanate for the
synthesis of photo labile derivatives of urea 26 in which α- substituted 2nitrobenzyl groups are covalently attached to the urea nitrogen Scheme 8
[14]
.
Imidazolyl alkyl aryl ureas 28 have also been obtained from the
reaction of imidazolyl alkyl amines 27 and isocyanates Scheme 9.[15]The
isocyanate protocol is also used for the preparation of heteroarotinoids
30 Scheme 10[16].
26
Reaction of bis(isocyanato)ferrocene 31 with the appropriate primary
amine allowed isolation of the bis(ureido)ferrocene 32 Scheme 11[17].
Urea is an attractive building block for anion receptors because it
contributes two relatively strong hydrogen-bonding sites, the amide
carbonyl and the amide nitrogen. Simple and easy to make chemosensors
for anions incorporating urea units were studied by combining the redox
activity of the ferrrocene moiety with the strong hydrogen- bonding
ability of the urea group.
Methods for preparation of nucleotides 34 , 36 & 38 with urea moiety
have also been described Scheme 12 &13 [18]. Reaction of a primary amine
boronate 39 with isocyanate gave the corresponding urea boronate 40
Scheme 14 [19]. In a similar method, aminoindazole 41 was reacted with
tolyliso cyanate affording aminoimidazole ureas 42 Scheme 15 [19].
Diamino maleonitrile 43 with phenyl isocyanate gives a monourea 44
at room temperature Scheme 16[20]. The classic method of converting the
primary amine hydrochloride 45 to ureas 47 by reacting with KNCO 46
was studied Scheme 17[21].
Reaction of aryl isocyanate 48 with a secondary amine 49 afforded
the formation of trisubstituted ureas 50 Scheme 18[22]. Aminoalcohol 51
was reacted with the appropriate isocyanate to complete the synthesis of
the urea isostere 52 Scheme 19 [23]. Reaction of 3-chlrophenyl isocyanate
27
with the secondary amine 53 in presence of TEA provided 1,3disubstituted urea 54 Scheme 20 [12].
Preparation of tri-substituted phenyl biaryl urea derivative 56, also
tagged with a piperidyl residue has been reported Scheme 21[24]. While
the final step leading to urea is a simple reaction, the precursor amine 55
is obtained employing a sophisticated protocol. The target molecule 56,
though successful in initial trials for activity has to be abandoned due to
the presence of diaryl nitrogen, a suspected carcinogen. Another related
urea formation 58 with Suzuki coupling is also reported Scheme 22[24].
Fotsch et ali[25] reported the synthesis of trisubstituted phenylurea
derivative 60 Scheme 23[25]. The synthesis of bicycloalkylureas 62,64 was
reported by McBriar et al Scheme 24 & 25[26]. In further applications, the
synthesis of cyclopentyl ureas 66 and bicyclo[3.1.0] hexylureas 68, 70
Scheme 26& 27[27] are also reported .
In order to facilitate the appreciation of the diverse synthetic
approaches, the reaction schemes are all assembled together with the
essential details (Table 1). An impressive amount of synthetic effort
devoted to these investigations is also a pointer to the emerging
importance of these molecules in designing useful pharmacological
products.
28
Table 1: Isocyanate Based reactions:
SN
Reaction
Scheme 1[7]
1
n-H9C4OHC
CH2
+
Acid
n-H9C4OHC(CH3)NCO
HNCO
6
8
7
C6H5NH 2
n-H9C4OHC(CH3)NHCONHC6H5
(64%)
9
Scheme 2[8]
2
Toluene
HOCH 2CH 2NH 2
+
H3C
NCO
10
H3C
rt, stir, 4h
NHCONHCH 2CH 2OH
12
11
(80 -94%)
Scheme 3[9]
3
(CH3)2CHNCO
C6H5CH2NH 2
C6H5CH2NHCONHCH(CH 3)2
13
14 (91%)
[10]
4
Scheme 4
OH
OH
NH2
o
HO
+
OH OH
15
5 - 10 C
Cl
NHCONHCH 2CH 2Cl
HO
CH 2CH 2NCO
16
OH OH
17 ( 28 - 60%)
29
Scheme 5[11]
5
BOCHNH 2C
NH2
+
C6H5NCO
i) cat. Et 3N, THF, 8h
ii) excess MeOH, 5h
BOCHNH 2C
NHCONHC 6H5
19
18
20
[12]
6
Scheme 6
H2NCH 2CH 2CH 2COOH
aryl or cycloalkyl
isocyanate
RNHCONHCH 2CH 2CH 2COOH
DMF, rt
22
21
Scheme 7[13]
7
HO(CH 2)2 - 6NH 2
NCO
NHCONH
DMF, rt
23
(CH 2)2
- 6OH
(95 -100%)
24
[14]
8
Scheme 8
NO 2
NO 2
R
CHNH 2
25
R
NaOCN
CHNHCONH 2
HOAc/ H2O
rt, 6 h
26
(48 - 60%)
30
Scheme 9[15]
9
OCH 3
3,4 - (OCH 3)C 6H3NCO
N
CH 2CH 2CH 2NH 2
N
CH 3CN, 8 h, rt
CH 2CH 2CH 2NHCONH
OCH 3
N
N
28
27
(48%)
Scheme 10[16]
10
CH3
H3C
H3C
H3C
NH2
H3C
THF
O
CH3
4-OCNC 6H4COOC 2H5
NH CO
H3C
H3C
29
NH
O
COOC 2H5
30
(69%)
Scheme 11[17]
11
NHCONH C6H5
NCO
C6H5NH 2
Fe
Fe
THF, rt
NHCONHC6H5
NCO
31
32
(60 - 80%)
31
Scheme 12[18]
12
NH2
N
O
HO
P
O
O
HO
o
O
-
C 6H 5NCO, DMF
N
N
O
NHCONHC6H5
N
45 C, 1h
N
P
O
N
N
O
O
-
OH OH
N
OH OH
33
(17%)
34
Scheme 13[18]
13
NHCONHC6H5
NH2
O
HO
O
P
O
N
O
P
-
O
O
N
N
O
O
-
35
C6H5NCO, DMF
o
HO
O
P
45 C, 1h
N
O
N
O
-
P
O
O
-
OH OH
36
NH2
NHCONH
(48%)
F
N
O
P
OH OH
N
N
O
HO
N
N
O
N
O
O
O
p-F- C 6H 4NCO,DMF
o
HO
P
60 C
OH
O
N
O
O
O
-
OH OH
OH OH
37
(83%)
38
32
Scheme 14[19]
14
H3C
H3C
O
H3C
H3C
H3C
B
NH2
RNCO, CH 2Cl 2
o
O
0 C
O
H3C
rt
B
O
H3C
H3C
39
NHCONHR
40
(70 -95%)
Scheme 15[19]
15
CH 3
O
NH2
NH
NH
CH 3
OCN
H2N
o
H2N
CH 2Cl 2 0 C rt,
N
N
N
H
N
H
R
41
42
35 - 70%
R
Scheme 16[20]
16
NC
NH2
NC
NHCONHC 6H5
C6H5NCO
NC
NH2
CH 3CN, rt
43
DAMN
NC
NH2
(93%)
44
DAMN = Diaminomaleonitrile
33
Scheme 17[21]
17
reflux 1 h
RNH 2.HCl
+
45
KNCO
46
RNHCONH 2
( 50 -81 %) 47
Scheme 18[22]
18
NCO
X
+
NHR 1R2
hexane, rt,2h
NHCONR 1R2
X
49
48
50
86%
Scheme 19[23]
19
R2NCO, CH 2Cl 2
CH 2C6H5
BocHN
CHCH(OH) CH 2NHR 1
51
rt
CH 2C6H5
BocHN
CHCH(OH) CH 2N(R 1)CONHR 2
52
Scheme 20[12]
20
(H 3C) 3CO
CO
NHCH 2CH 2CH 2CONHC 5H11
53
4M HCl, dioxane
NH CO
m-ClC 6H4NCO
TEA, DMF,rt
NHCH 2CH 2CH 2CONHC 5H11
54
Cl
100%
34
Scheme 21[24]
21
NHC 6H5
O
NH
N
C6H5NCO, Et 3N
N
R
2
CH 2Cl 2
N
55
R
R
56
1
R
2
(75 -100%)
1
Scheme 22[24]
22
NHCH 2CH2R
CONHC6H5
C6H5NCO, Et3N
NCH2CH2R
CH2Cl2
57
NC
58
75- 100%
NC
Scheme 23[25]
23
R'RNCONH
OCN
R'RNH
CH2Cl2
O
O
59
60
Scheme 24[26]
24
NH
61
CH 2CH 2CH 2 N
N
NHCONHC 6H5
CH 3
C6H5NCO
i-Pr 2NEt, CH 2Cl 2
(79%)
62
CH 2CH 2CH 2 N
N
CH 3
35
Scheme 25[26]
25
CF 3
NHCH 2CH 2R2
CF 3
OCN
CONH
F
NCH 2CH 2R2
F
i-Pr 2NEt, CH 2Cl 2
63
64
R1
R1
(48%)
Scheme 26[27]
26
CONHC 6H5
O
NCH 2CH 2CH 2 N
i)
H 2 NH 2CH 2 CH 2C
N
N
N
CH3
CH3
Ti(O-i-Pr) 4 ,18h, NaBH4, MeOH
ii) C 6H5NCO, i-Pr 2NEt, CH 2Cl2
65
NHBOC
NHBOC
66
(68%)
36
Scheme 27[27]
27
NC
O
(i) 1-(2- aminoethyl) pyrrolidine,
NaB(OAc)3H
NC
NCONHC 6H5
CH2CH2 N
(ii) C6H5NCO, i-Pr2NEt,
67
68
10%
CH2Cl2
CONHC6H5
NHCH 2CH 2CH 2
NC
N
N
CH3
NC
NCH 2CH 2CH 2
N
N
CH3
C6H5NCO
69
i - Pr2NEt, CH 2Cl2
70
(61%)
37
2. In situ generation of isocyante and conversion to ureas
(Table 2 shown below):
The reaction of hydroxamic acids 71 with sulfur trioxide - tertiary
amine Complex 72 gives crystalline water soluble tetra - ammonium Nacyl hdroxylamine -O- sulfonates 73[28]. The isocyante formed insitu was
intercepted by the secondary amine yielding a urea 74. Scheme 28[28].
In a different approach to ureas, oxidative rearrangement of simple
amides 75 using lead tetra acetate 76 has been exploited Scheme 29 [29].
This method is useful to obtain unsymmetrical ureas 78. Beckwith further
investigated the lead-mediated conversion of amides to ureas 84 Scheme
30[30]. The reaction was postulated to go through incipient formation of
alkyl isocyanates 80 which in presence of another carboxylic acid
(R’COOH) rearranged to give small yields of 1,3- dialkylureas 84 along with
other contaminants.
The preparation of isocyanate 90 from corresponding amine 85,
carbonyl sulphide 86 and S-ethylchlorothioformate was reported
sometime ago. These reactions are summerised in Scheme 31[31].
Pd- catalysed oxidative carboylation of primary amines 91 to the
corresponding symmetrically disubstituted ureas 96 with oxygen as
oxidizing agent has been reported Scheme 32[32].
A general method for making isocyanates 98 from readily
38
available azides 97 was reported Scheme 33[33]. Peptide acid azide 99
was
converted
into
corresponding
isocyanate
100
via
Curtius
rearrangement followed by reaction with a mixture of pentafluorophenol
and NMM resulting in pentafluoropeptidyl carbamate Scheme 34[34].
Reaction of this compound with aminoacid ester yielded the peptidyl
ureas 102. It is found that the direct exposure of powdered solid acid
azides 103 to microwaves for 60 s resulted in complete rearrangement to
isocyantes 104 Scheme 35 [35]. The reaction was found to be clean and
complete, affording a ‘greener’ method to obtain isocyanates, which, in
turn, can be reacted with amines 105 to form ureas 106.
In an one -pot process, the oxidation of the β- isocyanides 107 to
isocyanates 108 was accomplished using pyridine N-oxide and a catalytic
amount of iodine in acetonitrile as the oxidizing agent Scheme 36[36].
The aniline 110 was converted to the isocyanate using triphosgene
and base followed by reaction with 3-aminobenzyl alchohol to get the
urea 112 Scheme 37 [37].
39
Table 2: Insitu generation of isocyante and conversion to ureas
SN
1
Reaction
Scheme 28[28]
C6H5CONHOH
71
+
(CH 3)3N:SO3
72
acetone
-
[C6H5CONHO] [SO3HN(CH 3)3]
rt
+
C6H5NCO ]
[C6H5CON :
73
R'R"NH
C6H5NHCONR'R"
(80%) 74
Scheme 29[29]
2
RCONH2
+
Pb(OAc)4
75
DMF
76
1
[RNCO]
R NH 2
RHNCONHR
77
1
78 (74 -97%)
Scheme 30[30]
3
RCONH2
79
Pb(OAc)4
C6H6, 3h, reflux
R'COOH
[RNCO]
80
RNHCO 2COR'
81
82 (40-46%)
(RNHCO)2O
RNHCONHR
83
RNHCOR'
84 (5%)
40
Scheme 31[31]
4
Scheme 32[32]
5
O
-HI
RNH 2
91
+ CO +
92
- [Pd(0)+ HI]
PdI 2
93
R
N
NHR
IPd
C
O
95
RNH2
94
RNHCONHR
96
Scheme 33[33]
6
o
160 -180 C, 15 mins
N3
R
97
+ CO
NCO
200 -300 atm
+ N2
R
98 (47%)
41
Scheme 34[34]
7
R
R
O
m.w in toluene
1 min or
NH
N3
FmocHN
O
99
NH
refux 1 h
R1
NCO
FmocHN
O
R1
100
Pentafluorophenol
NMM
F
R
COOR 3
H2N
NH
NH
NH
COOR 3
FmocHN
NH
R2
O
102
R1
O
R2
NH
F
O
FmocHN
DMF: THF [1:1]
NMM
(70 - 94%)
F
R
O
101
R1
O
F
F
Scheme 35[35]
8
R
H
N3
FmocHN
R
R1
H
NCO
104
OR 2
-
104
(85- 91%)
DIEA / NMM
DCM
r.t, 10 -12 min
O
O
H
R1
H
OR 2
FmocHN
+
Cl H3 N
105
NCO
FmocHN
R
H
+
FmocHN
H
reflux, 30 min
or
toluene, M..W. 35 -45 sec
or
M..W. 45 - 60 sec
O
103
R
toluene
NH
NH
106
(89-97%)
O
42
Scheme 36[36]
9
CH 2OAc
O
AcO
NC
AcO
AcO
CH 2OAc
Pyridine N - oxide
cat. I2,
3A molecular sieves
NCO
AcO
AcO
CH 3CN
107
O
AcO
108
NH2
CH 2OAc
O
AcO
NHCONH
AcO
AcO
109 77%
Scheme 37[37]
10
H29C14O
NH2
i) triphosgene, Et 3N
DMAP cat, CH 2Cl 2
H29C14O
NCO
111
110
H2N
CH2OH
pyridine, THF
H29C14O
NHCONH
(74%)
112
CH 2OH
43
3. Carbonylation of amines (Table 3 shown below):
As stated earlier, arising out of the recent interest in the
substituted ureas as a pharmcophore functionality in drug candidates
such as HIV protease inhibitors, many efforts have been made to find new
efficient synthesis of ureas to replace the classical reactions of amines
with
phosgene
or
related
compounds
such
as
isocyanates,
carbonyliimidazole, or disuccinimide carbonate.
The synthesis of symmetrical ureas 115,116,119 & 120 from amines
113 can be accomplished by oxidative carbonylation of amines by means
of carbon monoxide and a transition-metal catalyst (W, Ni, Mn, Co, Rh, Ru
and Pd) Scheme 38 [38]. Among these the most commonly used is Pd.
The remarkable effect of various phosphines on selectivity in the
carbonylation of amines catalysed by Rhodium complexes is reported
Scheme 38[39]. The primary aliphatic amines are converted into
substituted formamides 117 and disubstituted ureas 116 as minor
product. The selectivity depends largely on the metal used. Copper gives
rise to substituted formamide 118 alone, manganese to disubstituted
urea 119, palladium to both of these compounds 116 & 117 Scheme
38[39].
Electrochemistry has also been used as a reoxidising system.
Recently Deng and co-workers have applied electrochemistry to the
44
synthesis of symmetrical dialky ureas 120 using Pd(PPh)3Cl2 as catalyst
and Cu(OAc)2 as co-catalyst, instead of high pressure of CO/O2 (Scheme
38)[38]. In this case, Cu(OAc)2 acted as not only an electron transfer agent
but also a catalyst. In the carbonylation route to synthesis of ureas, a side
reaction of double carbonylation to oxamides 121 also takes place. It is
therefore important to ensure high selectivity to minimize the side
reactions by proper choice of catalyst and reaction conditions.
The synthesis of ureas 126 from aliphatic amines 122, carbon
monoxide 124 and oxygen using selenium 123 as catalyst is reported
Scheme 39 [40]. Hydrogen selenide-triethylamine catalysed synthesis from
aromatic amines 127 and carbon monoxide 128 was reported Scheme 40
[41]
. The weak complex from H2Se and Et3N has been also used to promote
this mode of reaction. While use of 1 mole of the amine 133 led to
formation of the formamide 135, use of 2 moles of amine 127 in presence
of Se and Et3N resulted in formation of disubstituted urea 131. It may be
noted that the catalyst could be generated insitu by reaction 2.
Catalytic
synthesis
of
carbamates
140
by
the
oxidative
alkoxycarbonylation of amines 136 was reported Scheme 41[42]. The
catalyst system comprising platinum group metal and alkali metal halide
45
or onium halide was found very effective for the oxidative
alkoxycarbonylation of amines by CO and oxygen for the synthesis of
carbamates. This is an industrially useful reaction since carbamates are
important precursors for preparing organic isocyanates without using
dangerous phosgene. They are thermally dissociated to give isocyanates
and alcohols in good yields in a clean reaction. Another ‘greener’ method.
In a related study, Gabreiele et al, reported a full account on the
Pd-catalysed oxidative carbonylation of primary aliphatic or aromatic
amines 142 to the corresponding symmetrically disubstituted ureas 145
with oxygen as the oxidizing agent Scheme 42 [32].
Reports are also on record reacting CO2 146 with amines 147
Scheme 43[43]. These reactions are achieved using phosphite salts in
presence of tertiary amines Scheme 43[43]. Substitution of CS2 in place of
CO2 in this protocol furnished the corresponding thiourea.
Another approach in using CO2 153 for reacting with amines 152 to
form ureas 154 used alkyl acetylenes in presence of Ru catalyst Scheme
44
[44]
. Among the several Ru derivatives used, the best results were
obtained using RuCl3. 3H2O.
As outlined in the foregoing methods, a range of reactions of CO2
with primary amines give dialkylureas[45]. Unfortunately, the preparation
of tetralkylureas from CO2, and secondary amines has been more difficult.
46
Fischer et al[45] found that the tendency of the carbamates of ammonia
and primary amines to be dehydrated to the corresponding ureas was not
observed with the carbamates of secondary amines. This transformation
has been however, achieved with catalysis and elevated temperatures
(120 -250oC). At moderate temperatures (i.e, below 100oC), the only
published synthesis using CO2 156 and amine 155 required large
concentrations of PdCl2(MeCN)2 cataylst and a stoichiometric amount of
triphenylphosphine in CCl4/ MeCN Scheme 45[45] (eq 1). The yields of urea
157 are variable. (53 – 99%).
47
Table 3: Carbonylation of amines based reactions:
SN
Reaction
Scheme 38[38, 39]
1
RNHCHO
118
Cu
RNHCONHR
+
116
Pd
RNHCHO
117
P(CH 3)3 in benzene
Mn
RNH 2 + CO
113
114
Pd(OAc) 2 or Pd(Ph3)4/CH3CN
+ 0.4 V vs SCE
o
(n-Bu)4NBF4, 50 C, 4 hrs
Rh 2Cl 2(CO) 4
RNHCONHR
(51 -100%)
115
RNHCONHR
119
RNHCONHR
(83%)
120
+
RNHCOCONHR
+
2H
+
+
2e
-
121
Scheme 39[40]
2
2RNH2
122
+ Se + CO
123
124
4 hr
THF
(RNH3)
125
+
-
(RNHCOSe)
O2
(RNH) 2CO
126
(95 -99%)
48
Scheme 40[41]
3
2 C 6H5NH 2
+
CO
127
C6H5NH 2
133
128
+
CO
134
+
Se
+
129
Et 3N
(C 6H5NH) 2CO
130
131
Et 3N.H2Se
C6H5NHCHO
o
100 C, 4.5 h
Scheme 41[42]
5
Scheme 42[32]
142
143
144
Et 3N.H2Se
--- (1)
132
-------(2)
135
4
2 RNH 2 + CO + (1/2) O 2
+
PdI 2 cat/ KI/DME
-H 2O
RNHCONHR
145
(68 - 98%)
49
Scheme 43[43]
6
-
CO 2
146
+
NH2
+
H
148
147
P(OPh) 2
N
Py
NH
o
O
OPh
P
4 h, 40 C
O
OPh
+
O
H
OH
149
C6H5NCO 150
C6H5NH 2
C6H5NH 2
C6H5NHCONHC 6H5
151
(55%)
Scheme 44[44]
7
2 RNH 2
152
+ CO 2
H
C
C
o
153
1
R / RuCl 3. 3H 2O
o
120 C - 140 C
RHNCONHR
39%
154
Scheme 45[45]
8
'
2RR NH
155
+
CO 2
156
PdCl 2(MeCN) 2/ PPh3
CCl 4, MeCN
RR'NCONRR'
157
50
4. Miscellaneous reactions (Table 4 shown below)
A rapid microwave assisted synthesis of N,N’-diarylureas 161 under
solvent-free condition was reported Scheme 46[46]. The conventional
methods reported for the synthesis of arylureas are essentially based on
phosgene
and
isocyanates,
phosgene
substitutes,
carbonates,
carbamates, carboxylic acid derivatives and aniline and urea. Phosgene
and isocyanates are expensive, hazardous and toxic chemicals to handle.
Therefore, the reported formation of the ureas by the reaction of amine
with β- keto compounds is a much greener method.
A recent preparation of aromatic carboxylic acids 166 containing a
urea moiety has been reported Scheme 47[47] involving a ring opening
reaction of the versatile isatoic anhydride 163 with amines, or of Nalkylsulphonyl phthalimides 164 with amines. Yet another route takes
recourse to a coupling reaction of anthranalic acids 165 with amines using
N,N’- carbonylimidazole .
A very convenient method for the synthesis of unsymmetrical ureas
171 based on isopropenyl carbamate was described Scheme 48[48]. Upon
reaction with an amine 168, isopropenyl carbamate liberates acetone
enol, which quickely tautomerises to acetone and enables the reaction to
go to completion avoiding reversal of reaction, maximizing the yield with
a clean work –up.
51
Another such formation of urea dipeptides 174,177 using
carbonyldiimidazole (CDI) was reported Scheme 49 [49]. Ureas 179 were
prepared by reacting (+)–ephedrine with amines 178 activated by
triphosgene (Scheme 50)[25]. The succinate salt of the benzylic amine 180
was reacted with phenyl carbamate and N,N’- diisopropyl ethylamine to
get the benzylurea 181 Scheme 51 [50].
52
Table 4: Miscellaneous reactions:
SN
Reaction
Scheme 46[46]
1
C6H5NH 2
158
MW
450 W, 15 min
+ CH 3COCH 2COOC 2H5
C6H5NHCOCH 2COCH 3
159
C6H5NH 2
160
C6H5NHCONHC 6H5
161
+
CH 3COCH 3
162
Scheme 47[47]
2
165
R3
NH2
164
R4
R3
COOH
N
OSO 2Me
R4
i) N,N'- carbonyldiimidazole, CH 2Cl 2, rt
ii) HNR 1R2, rt
163
H2C
i) HNR 1R2, acetone, H 2O, reflux
(54%)
H
N
O
O
H2C
o
ii) HCl, 5 C
(20%)
HNR 1R2, H2O, rt (or)
HNR 1R2, EtOH, H 2O, reflux
R3
NHCONR 1R2
O
R4
COOH
166
53
Scheme 48[48]
3
(H 3C) 3C
NH2
N
N
+
CH3
N
1,4-dioxane, 2d
o
55 C (80%)
NH2
N
N
+
CH3
NHCOO
C(CH 3)
CH3
N-Me-pyrr
168
167
(H 3C) 3C
N
(H 3C) 3C
NHCOOCH 2CF 3
NHCO NH
171
N-Me-pyrr
1-4-dioxane
o
3h, 55 C (97%)
CH2
169
170
Scheme 49[49]
4
C6H5
i) carbonyldiimidazole CH 2Cl 2
CH3
O
CH3
N-methylmorpholine
H2N
COOCH 2C6H5
172
H3C
SO 3H
ii) Phenylalanine Me ester. HCl
iii) H 2, Pd-C
173
COOBn
175
NH
H3C
SO 3H
176
NH
COOH
80%
174
C6H5
CH3
H2N
H3COOC
O
CH3
i), iii) as above
H3COOC
NH
177
NH
COOH
(70%)
54
Scheme 50[25]
5
OH
CH3
NH
CH3
R
NH 2(CH 2)n
OH
triphosgene, i-Pr 2NEt, CH 2Cl 2, rt
N(CH 3)CONH(CH 2)n
179
CH3
178
R
Scheme 51[50]
6
F 3C
CH 2NH 3Succinate
i) NaHCO 3
ii) C 6H5OCONH 2 F3C
iii) Pyridine
CH 2NHCONH 2
CH 2CH 2C(CH 3)3
CH 2CH 2C(CH 3)3
180
181
(98%)
55
Part C
Application of substituted ureas as Pharmacophores:
Urea is a primary pharmacophore. Some of the ureas and related derivatives mentioned in part A of Introduction
act as pharmacologically active molecules. Several of these bioactive molecules are mentioned below.
Table 5: Urea, Bisurea and Thiourea derivatives as bioactive molecules:
O
R1
R2
N
R3
SN
1
R1
R2
R3
CH3
NH
Urea
UreaNPY5RA-972 is a potent antagonist of the neuropeptide Y5 receptor.
Ref
32
ACAT inhibitors are seen as potentially beneficial agents against
22
Comments
H
O
N
i-Pr
2
(CH2)3CH3
CH2
H3C
CH3
hypercholesterolemia and atherosclerosis. (2) showed consistent ACAT
inhibitory activity as a class. Compounds were evaluated in vitro as ACAT
inhibitors and in vivo as inhibitors of dietary -cholesterol absorption.
Structure -activity trends were also defined, with respect to the length of
the N-n-alkyl chain and the nature of the substituent on the aniline ring.
56
CH 3CH(CH 3)2 (or)
CH 2CH 2CH(CH 3)2 (or)
CH 2C6H5 (or)
CH 2(4-pyridyl)
3.
Ph
O
C(CH 3) 3
NH
N
N
O
H2N
H
OH
A novel series of HIV-1 protease inhibitors have been developed 23
which replace the (hydroxyl ethyl) urea isostere. These compounds
are very effective antiviral agents and show a good correlation
between their IC50 and EC50 values suggestive of effective cell
O
penetration and stability to the assay conditions.
4
H
(CH 2)nCOZ
(1-7)
1,3,5,7
2,4,6
Comments mentioned below the Table.
n
1,2,3,5
1,2,3
5
12
Z
OH
OCH3
R
O
n
n = 0 R = C7H15 n =1 R = C H
6 13
n = 2 R = C5H11 n =3 R = C4H9
n = 4 R = C3H7
H
The 1,3- Disubstituted ureas functionalized with an ether group as
potent Soluble epoxide hydrolase (sEH) inhibitor was reported as a
therapeutic target for treating hypertension and inflammation. This
was done by analyzing the effects of structural changes of 1,3disubstituted ureas with an ether function present at least three
atoms away from the urea carbonyl on inhibition potency, physical
properties, and metabolic stability. The inhibition studies showed that
a hydrophobic group as a linker between the primary urea and the
ether function is necessary to yield potent inhibitors. Across the three
species studied, it was found the bioavailability is enhanced by the
presence of cyclohexyl as a linker between the urea and the ether and
by a polar group, such as diethylene glycol or morpholine, on the
other side of the ether.
57
13
CF 3
6
Bicycloalkylurea was developed as an orally active series of MCHCH2CH2R
F
R =(R)-3-OHpyrrolydinyl (or)
pyrrolydinyl (or)
CH 2(4-methylpiperazinyl)
CN
R1 anatgonist that exhibit invivo efficacy in rodent obesity
26
models. These compounds are selective for MCH-R1 over MCHR2. Additional studies have shown acceptable in vivo and
pharmacokinetic properties.
7
24
N
Comments mentioned below the Table.
R
NC
R = 3-Cl,4-F (or)
4-F,3-CF3
8
N
HN
19
H
NH2
Comments mentioned below the Table.
H3C
F
9
H
Wissner prepared series of bis-aryl amide and diaryl urea
antagonists of platelet activating factor (PAF) and evaluated in
H29C14O
+
S
vivo. Diarylurea anatagonist of platelet activation factor (PAF) was
N
Br
-
CH3
prepared. Best activity was observed for compounds having
linkages of the type –CH2CONH, –CH2N(COR) and –CH2NHCO in
place of the urea linkage. Many of these compounds inhibit PAFinduced platelet aggregation with IC50’s under 1 μM.
58
37
10
ClCH2CH2
ClCH2CH2
NO
A number of N-nitrosoureas have been synthesized and evaluated
for activity against Leukemia L1210. The most active member of
(or)
the series was 1,3-bis(2-chloroethyl)-1-nitrosourea which was
RH4C6
quite active again a number of mouse, rat, hamster tumors as well
21,
51
as other animal leukemia. Its activity against intra cerebrally
implanted L1210 leukemia was the basis for the initiation of
R = 2,6-CH 3 , m-CH 3O, p-Cl,
p-CON(CH 3)2, p-CH 3O,
clinical trials.
p-COOH, m-COOH , m-Cl
CH3
11
H3C
CH(OH)CH(CH3)
Analogues of trisubstituted phenylurea derivatives were prepared
25
and their activity relationship as Neuropeptide Y5 receptor
O
R
antagonist was studied. The most potent compounds in this class
have IC50s less than 0.1 nM at NPY5 receptor. All the urea
R = 4-F (or) 3,4-CH
3
analogues tested acted as antagonists.
N
12
N
O
O
-
O
O
N
P
CH2CH3
H
A series of highly functionalized nucleotides were prepared
18
resulting in the selection of adenosine monophosphate derivative.
N
On the basis of pharmacological, physicochemical and synthetic
considerations, this compound was nominated as a candidate for
OH
O
O
HC
further development as an inhibitor of platelet aggregation.
CH
59
13
1 N(Et)2
2 N(Me)cyclohexyl
3 N(Me)cyclohexyl
4 N(Et)2
R
R
'
1H
2H
3 (CH3)
4 -CH=CHCH=CH-
HOOC
14
2- ureido benzoic acids were investigated in search of MRP1 inhibitors to
47
identify active representatives. The presence of a diethylureido and a
cyclohexylmethylureido
moiety
provided
active
compounds
(1-
4).
Replacement of cyclohexyl residue by phenyl, benzyl or phenylethyl group
mostly led to a loss of potency. These 2-ureido benzoic acids inhibited MRP1.
CH2CH2Cl
Water soluble (2-chloroethyl)nitrosoureido derivatives of cyclopentanetetrols
NO
OH
were prepared and their antitumor activities were determined against
HO
(or)
HO
10
HO
OH
leukemia L1210 in mice. Compounds 1,2 and 3 were highly effective inhibitors
2
of leukemia L1210; however compounds 1 and 3 appeared to be some what
OH OH
1
(or)
OH
superior to compound 2 in producing long term survival.
OH
HO
3
OH OH
O
O
R
H2N
NH
NH
NH2
Bisurea
SN
15
R
Activity
N,N’-[5-[bis(2-chloroethyl)amino-1,3-phenylene]bisurea
showed
Ref
significant 52
antitumour activity against P388 lymphocytic leukemia in mice.
(ClH 2CH 2C) 2N
60
S
R1
R2
NH
NH
Thioure a
SN
16
R1
R2
Activity
O
H2NO 2S
The on resin screening assay was developed for the
Ref
53
inhibition test of different CA isozymes with the on-resin
O
NH
PEG
O
O
CH3
supported sulfonamides allowing the direct identification
of the biologically active lead compounds. Resin - coupled
sulfonamide (4-sulfamoylphenylthiourea) was developed
possessing interesting antiglucoma properties.
17
O
T
O
OH
An unusual dinucleoside that produced significant
T
HO
inhibition of TMPK mt (Ki = 37 μM) was discovered.
CH3
17a
On the basis of the structure of the dinucleoside shown in
O
Cl
F 3C
54
O
N
NH
54
serial (11) as a selective TMPKmt inhibitor, a series of 5’substituted α- Thymidine derivatives were synthesized.
This compound showed good inhibitory activity on the
O
growing M.bovis and M. tuberculosis strain.
OH
61
18
(1)
(1)
H3C
Among a series of heteroarotinoids prepared and evaluated for
CH3
CO2Et
H3C
(2)
CH3
H3C
activity against Mycobacterium bovis BCG, (1) and (2) exhibited
activity at 5 to 10 and 10 to 20 μg/ mL respectively.
O
H3C
H3C
16
(2)
CH3
N
H
N
CH3
H3CO
19
N
OCH 3
NCH 2CH 2CH 2
A library of thiourea derivatives revealed a strong impact on the
15
inhibitory efficacy and resulted in the development of new class of
potent inhibitors for human glutaminyl cyclase (QC).
20
H3C
CH3
H3CO 2SHN
F
Isosteric replacement of the phenolic hydroxyl group in potent
55
vallinoid receptor (VR1) agonist with the alkyl sulphonamido group
(H 3C) 3COCOH 2C
provided this compound which was effective antagonist to the
action of the capsaicin on rat. It exhibited enhanced analgetic
potency with an ED50 of 7.43 ± 6.4 μg/Kg
62
Comments for SN (4) of Table 4:
1,3-disubstituted ureas with various alkyl, cycloalkyl and aryl groups as
potent sEH inhibitors were described. These urea inhibitors efficiently reduced
epoxide hydrolysis in several in vitro and in vivo models.The free carboxylic acids
1,3,5 and 7 failed to show significant inhibition activity for either murine or human
sEHs. However, the conversion of the carboxylic acid function to the methyl ester
2,4,6 increased inhibition potency for both mouse and human sEHs, indicating that
the free acid functionality at the end of short aliphatic chains negatively impacts
inhibitor potency. An innovatively crafted adamantly urea (B) shown below has
revealed interesting factors.
In particular, the methyl ester of butanoic acid 6 showed 8- 100 fold higher
activity for both enzymes than the esters of acetic acid and propanoic acids 2 and 4,
suggesting that a polar functional group located on the fifth atom (approximately
7.50 Å) from the carbonyl group of the primary urea pharmacophore may be
effective for preparing potent sEH inhibitors of improved water solubility. In
particular, the methyl ester of butanoic acid 6 showed 8- 100 fold higher activity for
both enzymes than the esters of acetic acid and propanoic acids 2 and 4, suggesting
that a polar functional group located on the fifth atom (approximately 7.50 Å) from
the carbonyl group of the primary urea pharmacophore may be effective for
preparing potent sEH inhibitors of improved water solubility (Figure 1). The
addition of a polar functional group at the end of a long aliphatic chain of urea
inhibitors made compounds less lipophilic while their inhibitory potencies were
retained. As one adds polar groups to liphophilic inhibitors, the biological activity
is often dramatically reduced, because the water shell around the polar
functionality reduces binding at the active site. However, if the new polar groups
63
can hydrogen bond to the enzyme within the active site, without disturbing the
binding of the primary pharmacophore, this offsets the energy required to strip the
water shell. On the basis of the specificity, the authors designed urea compounds
with a polar carbonyl group on the fifth atom (approximately 7.5 Å) from the
primary urea pharmacophore to improve the water solubility of liphophilic sEH
inhibitors.
Comments for SN (7) of Table 4:
Substituted phenyl biaryl urea derivatives were synthesized and evaluated
as MCH-R1 antagonists for the treatment of obesity. The structure activity
relationship studies in the series resulted in identification of urea as a potent and
selective MCH-R1 antagonist. The 3-chloro-4-fluorophenyl and 3-trifluoro-methyl-4fluoro substitution were some of the best among the several disubstituted ureas
prepared. One possible explanation for this increased affinity could be due to
enhancement of urea N-H hydrogen bonding interaction with the receptor by
electron- withdrawing groups.
This compound showed excellent in vitro and moderate in vivo activity; however,
further studies with this compound were discontinued due to the presence of a
highly mutagenic, Ames positive biarylaniline subunit.
Comments for SN (8) of Table 4:
3- aminoindazole, 4- diarylureas proved to be potent inhibitors against the
members of the VEGFR and PDGFR families. From a study of series of compounds, a
potential clinical candidate (ABT-869) was identified. Incorporation of an N,N’diaryl urea moiety at the 4- position of the indazole ring afforded a series of
compounds that potently inhibited VEGFR and PDGFR kinases. A KDR homology
model suggested that these compounds bind to the ATP- binding site of an inactive
KDR conformation, with the urea portion interacting with the distal hydrophobic
pocket. By optimizing the substituents at both the urea terminal phenyl ring and
the 7- position of the 3 - aminoindazole, a series of compounds with potent
enzymatic and cellular activity were obtained. A number of these compounds
possessed potent oral activity in the mouse. In particular, this compound was
extremely potent, with an ED50 value of 0.5 mg/kg. Further evaluation of this
compound showed that it displayed good PK profiles in different species and
significantly inhibited tumor growth in a number of preclinical animal models.
64