urea eros.ru002, biotransformation, Dokumenty [ Pobierz całość w formacie PDF ]
1
UREA
Urea
1
Urea reacts with orthoesters and related compounds to
form alkylideneurea derivatives. The reaction with
N,N-
Dimethylformamide Diethyl Acetal
gives
N
-carbamoyl-
N
′
,
N
′
-
dimethylamidine (eq 5).
8
Active methylene compounds may
further participate in the condensation reaction of
Triethyl Ortho-
formate
and urea to form ureidomethylene derivatives (eq 6).
9
Treatment of urea with
Chlorine
in the presence of
Calcium
Carbonate
provides monochlorourea, which may be utilized as
a source of
Hypochlorous Acid
(eq 7).
10
,
11
O
H
2
N
NH
2
[57-13-6]
CH
4
N
2
O
(MW 60.07)
InChI = 1/CH4N2O/c2-1(3)4/h(H4,2,3,4)/f/h2-3H2
InChIKey = XSQUKJJJFZCRTK-UBUOBULFCP
NH
2
(nitrogen nucleophile; carbonyl cation equivalent; formation of
inclusion complexes is used to purify long, slender compounds)
Physical Data:
mp 132.7–132.9
◦
C;
d
1.335 g cm
−
3
.
Solubility:
sol H
2
O (108 g/100 mL at 20
◦
C), EtOH (5.4 g/100
mL at 20
◦
C), MeOH (22 g/100 mL at 20
◦
C).
Form Supplied in:
colorless solid.
Purification:
reagent graded commercial products are sufficiently
pure for most purposes. For further purification, see Perrin and
Armarego.
2
85 °C
41%
O
(
1
)
+
(EtO)
2
CHNMe
2
(5)
N
NMe
2
OH
i
-PrOH
+
HC(OEt)
3
+
(
1
)
reflux
90%
O
O
O
NHCONH
2
(6)
Original Commentary
O
O
Yoshinao Tamaru
Nagasaki University, Nagasaki, Japan
H
2
O
H
2
O
(1)
+
Cl
2
+
CaCO
3
H
2
NCON•HCl
AcOH
0–15 °C
Nitrogen Nucleophile.
The three heteroatoms of urea, i.e.
two nitrogens and an oxygen, are moderately nucleophilic. A
number of highly regioselective alkylation reactions of urea have
been developed. In most cases, the nitrogen atom is alkylated to
afford the corresponding ureides or amino compounds. On heating
a mixture of a carboxylic acid and urea (
1
) at around 160
◦
C,
the corresponding amide is obtained (eq 1).
3
,
4
In the presence
of
Triphenyl Phosphite
and
Pyridine
, aromatic carboxylic acids
react with urea at lower temperatures to give the corresponding
arylcarbonylureas in good yields (eq 2).
5
(7)
[HOCl]
Cl
OH
52–56%
Under mild conditions, urea undergoes nucleophilic addition to
carbon–carbon triple bonds (eq 8)
12
and double bonds (eq 9)
13
ac-
tivated by the coordination of Pd
II
species. Under 1 atm of
Carbon
Monoxide
, intramolecular aminocarbonylation proceeds at 0
◦
C
to room temperature to provide protected -amino acids (eq 9).
13
O
O
O
160 °C
HO
2
C
2
H
+
(1)
( )
8
S
( )
8
S
H
2
N
NH
2
H
2
N
NH
2
10 mol % PdCl
2
(PhCN)
2
MeCN, reflux
78%
(1)
N
(8)
N
O
O
O
N
H
O
N
DMF
(2)
ArCO
2
H
+
(1)
+
P(OPh)
3
+
pyridine
Ar
N
H
NH
2
100 °C
88%
1 mol % PdCl
2
3 mol equiv CuCl
2
CO
2
Me
(9)
N
NHMe
NN
Urea serves as a nitrogen nucleophile toward tertiary carbo-
cationic species to give
N
-
t
-alkylureas;
6
,
7
for example, the
t
-butyl cation, generated by treatment of
t
-BuOH with H
2
SO
4
,
is trapped with urea to give
t
-BuNHCONH
2
, a useful precursor of
tert-Butylamine
(eqs 3 and 4).
6
Bn
Bn
Me
1 atm CO, MeOH
0 °C to rt
78%
O
O
Two of the three heteronucleophilic centers of urea react with di-
functionalized carbonyl compounds (e.g. dicarbonyl compounds,
-halo- or
-hydroxy carbonyl compounds, and
,
-unsaturated
carbonyl compounds) to furnish a wide range of nitrogen hetero-
cycles. The dicarbonyl compounds include
Glyoxal
,
-diketones
(eqs 10 and 11),
14
−
16
-keto esters (eq 12),
17
oxalic and mal-
onic esters (eq 13),
18
,
19
-diketones (eq 14),
20
and
-keto esters
(eq 15).
21
A three component connection reaction of urea, alde-
hydes, and
-keto esters provides dihydropyrimidines (Biginelli
reaction) (eq 16).
22
1. H
2
SO
4
t
-BuNH
NH
2
(
1
)
(3)
2.
t
-BuOH
20–25 °C
O
31–33%
ethylene glycol
t
-BuNH
NH
2
+
40% aq NaOH
(4)
t
-BuNH
2
reflux
71–78%
O
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2
UREA
H
N
H
N
H
N
R
O
R
Br
acid
N
+
(
1
)
(10)
O
O
DMF
∆
+
(
1
)
EtO
O
N
H
N
H
O
R
reflux
24%
R
O
R = H, alkyl, aryl
Br
H
N
Ph
Br
O
N
Ph
Ph
O
(18)
KOH, EtOH
EtO
(
1
)
N
+
(11)
HN
NH
NH
2
reflux
66%
O
Ph
O
O
O
,-Unsaturated ketones and acids react with urea to give
dihydropyrimidine derivatives (eq 19)
25
and dihydrouracils
(eq 20),
26
respectively. ,-Unsaturated aldehydes and ketones
with
-substituents, such as alkoxy,
27
amino,
28
halogeno,
29
trichloromethyl,
30
etc.,
31
provide substituted pyrimidines (eq 21).
Ph
O
COPh
100–110 °C
+
O
(
1
)
(12)
HN
NH
97%
O
O
O
O
NaH
cat MeOH
O
O
1. NaOR, ROH
(R = Me, Et)
+
(
1
)
n
O
O
benzene
75%
n
+
(
1
)
HN
NH
(13)
OMe
O
2. HCl
OEt
OEt
O
NH
HN
n
= 0
n
= 1
parabanic acid
barbituric acid
71.5–76%
72–78%
(19)
O
O
OH
OMe
ethylene glycol
reflux
O
+
(
1
)
ethylene glycol
O
60–80%
+
(
1
)
(20)
OBu
HN
NH
190 °C
45%
OH
2.5 mol equiv
O
OH
R
NN
OH
X
R
conc HCl
(14)
+
(
1
)
(21)
NN
22 °C
O
OH
OBu
X = OEt, NMe
2
, Cl, CCl
3
, etc
R = H, alkyl, aryl
O
1. cat HCl, EtOH, rt
2. aq NaOH, 65 °C
O
+
(
1
)
(15)
HN
NH
3. HCl
Carbonyl Cation Equivalent.
In the reaction with heteronu-
cleophiles, urea acts as a carbonyl cation or dication equiva-
lent, like phosgene and carbonates, though requiring more drastic
conditions.
N
-Substituted or
N,N
′
-disubstituted ureas can be pre-
pared by transamination of the urea nitrogen atoms with primary
amines (eqs 22 and 23).
32
Reaction of urea with
vic
-diamines
(eq 24)
33
and 2-aminophenols (eq 25)
34
gives imidazolidin-2-ones
and oxazolidin-2-ones, respectively. The reaction with aliphatic
2-amino alcohols, on the other hand, gives imidazolidin-2-ones
via substitution by the hydroxyl group for a nitrogen of urea
(eq 26).
35
,
36
The
cis
-1,5-dimethyl-4-phenylimidazolidin-2-ones,
obtained by fusing (
−
)- or (+)-ephedrine hydrochloride and urea,
are useful chiral auxiliaries for asymmetric syntheses.
36
EtO
O
71–77%
O
Br
CO
2
Et
Br
O
OEt
cat HCl, EtOH
+
+
(
1
)
O
reflux
86%
HO
HN
NH
(16)
OH
O
O
The reaction of urea and carbonyl compounds with -substi-
tuents, such as
-hydroxy ketones
23
and
-halo ketones,
11
may
afford either imidazol-2-one derivatives (eq 17) or oxazole deriva-
tives (eq 18).
24
The latter is a rare example of the
N,O
-dialkylation
of urea.
120 °C
NH
2
NHCONH
2
+
(1)
(22)
O
O
1 equiv
quantitative
Ph
Ph
Ph
Ph
∆
H
N
+
(
1
)
(17)
180 °C
HN
NH
NH
2
+
(1)
(23)
85%
O
O
X
O
CO
89%
2
O
X = OH, Br
2 equiv
A list of General Abbreviations appears on the front Endpapers
3
UREA
Ph
Ph
an aldehyde, and urea, is used to prepare dihydropyrimidinones
(eq 16).
22
There has been a remarkable amount of attention given
to this transformation due to the interesting pharmacological
properties associated with dihydropyrimidinones.
42
Many
biologically active molecules including calcium channel modu-
lators, anticancer compounds, and
1a
adrenoreceptor-selective
antagonists
Ph
Ph
200 °C
+
(1)
+
H
2
O
(24)
HN
NH
87%
H
2
N
NH
2
O
H
N
contain
the
dihydropyrimidinone
scaffold.
Some
EtOC
NH
2
EtOC
conc HCl
+
(1)
examples are illustrated below.
O
(25)
∆
73%
O
OH
O
2
N
O
2
N
Ph
O
HO
1. 170–175 °C
+
(1)
(26)
•HCl
HN
N
Me
i-
PrO
2
C
CONH
2
MeO
2
C
2. 200–210 °C
55–65%
Ph
NHMe
N
NH
O
N
H
O
N
H
O
Catalyst.
The
conversion
of
Tetracyanoethylene
into
SQ 32926
Nitractin
dicyanoketene acetals is catalyzed by urea (eq 27).
37
NC
CN
NC
OEt
(
1
), reflux
72%
A wide variety of modifications to this reaction include the
use of many different Lewis acids,
43
microwave conditions,
44
solvent-free green conditions,
45
and reactions performed using
solid support for parallel synthesis (eqs 28–30).
46
The cited refer-
ences are a few examples; a comprehensive list of these reactions
is beyond the scope of this article. There are a number of excel-
lent reviews detailing the scope of the Biginelli reaction.
47
In a
related application of this reaction, the tethered Biginelli conden-
sation is used in the preparation of biologically active guanidine
alkaloids.
48
+
EtOH
(27)
NC
CN
NC
OEt
Inclusion Compounds (Differentiation of Linear Comp-
ounds from Branched Ones).
1
,
38
Urea forms inclusion com-
plexes, taking normal alkanes having six or more carbon atoms
as guests.
39
In the complexes, hydrogen bonded urea molecules
are oriented in a helical lattice, constructing a cylinder-shaped
channel. The guest molecule is not bonded to the host but
merely trapped in the cylinder. The diameter of the channel
is usually about 5.25 Å. Aliphatic hydrocarbons with a single
methyl branch, such as 3-methylhexadecane, that form the com-
plex require a channel diameter of about 5.5 Å. This seems
the upper limit of thickness. Not only hydrocarbons but many
kinds of functionalized alkanes can be included if they are
long and slender enough. Compounds that form inclusion com-
plexes include 1-bromohexane, 1- and 2-octanol, 2-heptanone,
1-cyclopentylnonane, and 2-, 3-, and 4- methyltridecane. On the
other hand, the following compounds do not form the complex:
3-ethyldodecane, 2-bromooctane, 1-cyclohexyloctane, and 2,4-
dimethyldodecane.
40
Thus linear compounds, as in the former
group, can be separated from a mixture with small or branched
ones such as in the latter.
syn
-9,10-Dihydroxystearic acid has been
separated from its
anti
counterpart.
41
The
syn
-diol (mp 95
◦
C),
which is estimated to require a channel diameter of 5.4 Å, readily
forms a urea complex. On the other hand, the
anti
-diol
(mp 131
◦
C), which requires a channel diameter of 6 Å, does
not form a complex.
38
BocN
O
H
O
Yb(OTf)
3
, 4 Å MS
EtO
2
C
THF, 70
°C, 14 h
60%
NH
2
+
O
H
2
NO
O
BocN
EtO
2
C
(28)
*
NH
N
H
O
4
R/
4
S
= 5:1
OO
O
PhCHO
+
+
OEt
H
2
N
NH
2
First Update
O
Ph
Paul J. Nichols
Array BioPharma, Boulder, CO, USA
cat NBS
EtO
NH
(29)
DMA
microwave
3 min, 92%
Nitrogen Nucleophile.
The Biginelli reaction, an acid-
catalyzed cyclocondensation reaction between a
-keto ester,
N
H
O
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4
UREA
OO
O
The direct condensation of carboxylic acids with urea can be
accomplished catalytically in the presence of arylboronic acids
to generate
N
-acylurea.
53
Condensation of the arylboronic acid
with carboxylic acids generates an (acyloxy)boron complex. Sub-
sequent nucleophilic attack by the urea nitrogen provides the
N
-acylurea (eq 35).
+
R
3
CHO
+
R
1
R
2
H
2
N
NH
2
O
R
3
100–105
°C
neat, 1 h
R
2
NH
(30)
R
1
N
H
O
R
1
= Me, Et
R
2
= OMe, OEt
R
3
= aryl, alkyl, alkenyl
CO
2
H
O
5% catalyst
toluene azeotropic
reflux, 26 h
+
H
2
N
NH
2
The preparation of tertiary amines can be accomplished in a
single step by combining urea with alkyl halides in the pres-
ence of sodium hydroxide under pressure at elevated temperatures
(eq 31).
49
Ph
O
O
N
H
NH
2
(35)
O
aq NaOH, RCl
Ph
92% yield
60 psi, 80–200
°C
40 h
H
2
N
NH
2
F
3
C
2 R
3
N + salts + alcohols/ether
(
31)
B(OH)
2
catalyst =
yields 58–82%
F
3
C
R = allyl, crotyl, butyl, methallyl, octyl, benzyl
The reductive alkylation of urea to provide aryl substituted
ureas has been disclosed.
50
Aryl aldehydes react with urea in
the presence of TMSCl and AcOH to provide the intermediate
imine, which is then reduced with NaBH
4
to provide alkylated
ureas (eq 32). To obtain the mono-substituted alkylation product
a large excess of urea (20 equiv) must be used. The excess is easily
removed during work up.
A very interesting rearrangement product is observed when
reacting 3-chloro-1
H
,3
H
-quinoline-2,4-diones with urea in
AcOH heated at reflux.
54
Instead of making the expected imidazo
[4,5-c]-quinolone, 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-
diones are produced consistently in high yields (eq 36). The
rearrangement is believed to proceed through an isocyanate
mechanism.
O
AcOH
rt
+
ArCHO
+
TMSCl
H
2
N
NH
2
O
O
O
Ar
Cl
Bn
NaBH
4
rt
(32)
urea
AcOH, reflux, 2 h
H
2
N
N
H
H
2
N
N
Ar
N
H
O
Bn
The hindered alcohols 4,4
′
-dimethoxybenzhydrol
51
and 1-
adamantanol
52
undergo a hydroxyl substitution reaction with urea
in acidic media to provide the corresponding
N
-substituted ureas
(eqs 33 and 34). The substitution reaction is likely to occur through
the generation of a carbenium ion.
NH
O
N
(36)
N
H
O
71% yield
urea
AcOH, cat H
2
SO
4
20
°C, 15 h
75% yield
(33)
Ar
2
CHNHCONH
2
Ar
2
CHOH
Ar = 4-MeOC
6
H
4
The reaction of bromopyruvic acid with urea in the presence
of BF
3
provides 5-(bromomethylene)hydantoins (eq 37). The
5-(bromomethylene)hydantoins can subsequently react with a
variety of nucleophiles to give 5-(substituted-methylene)hydan-
toins.
55
urea (2 equiv)
TFA (10 equiv)
90
°C, 8 h
94% yield
O
(34)
OH
N
H
NH
2
A list of General Abbreviations appears on the front Endpapers
5
UREA
O
O
BF
3
·
Et
2
O
CH
3
CN
The condensation of isatoic anhydride with primary amines
and urea in the presence of
N
,
N
-dimethyl acetamide (DMA) under
microwave irradiation proceeds rapidly to form the corresponding
quinazolinediones (eq 41).
58
HO
Br
H
2
N
NH
2
O
O
H
HN
O
(37)
DMA
O
+
+
RNH
2
N
H
Br
H
2
N
NH
2
microwave
O
N
H
O
47% yield
R = Me, aryl
O
R
N
(41)
Microwave Assisted Transformations.
A solvent-free
procedure has been developed for the preparation of primary
amides from urea and carboxylic acids using imidazole and
microwave irradiation.
56
The reaction is believed to proceed
through generation of the imidazolium carboxylate salt followed
by displacement with ammonia that is liberated from urea under
the reaction conditions (eq 38).
N
H
O
72–93% yield
Metal-mediated Catalysis.
Alkyl halides can be coupled with
urea in the presence of 1 mol % Pd
2
dba
3
CHCl
3
, Xantphos lig-
and, and Cs
2
CO
3
as a base to give
N
,
N
′
-diarylureas.
59
The re-
action is general for aryl bromides and aryl iodides contain-
ing electron-withdrawing groups at
para
postion (eq 42). The
use of 3,5-(CF
3
)
2
Xantphos as a ligand allows the coupling of
ortho
- and, in limited cases,
meta
-substituted aryl bromides as
well (eq 43).
60
O
O
imidazole
MW (300 W), 90–360 s
+
R
OH
H
2
N
NH
2
R = alkyl, aryl
Pd
2
dba
3
·CHCl
3
Xantphos
O
X
O
(38)
+
R
NH
2
H
2
N
NH
2
CS
2
CO
3
dioxane, 100 °C
R
4788% yield
R = CF
3
, CN, CO
2
Et, NO
2
, PhCO, Cl, H
Another reaction that involves the production of ammonia from
urea is the solvent-free reaction with dicarbonyl compounds in the
presence of montmorillonite K10 clay under microwave condi-
tions.
57
Reactions with
-diketones provide enamino ketones and
reactions with
-diketones give
N
-unsubstituted pyrroles (eqs 39
and 40).
R
R
O
(42)
N
H
N
H
6492% yield
O
OO
K10 Clay
+
Pd
2
dba
3
3,5-(CF3)2 Xantphos
CS
2
CO
3
dioxane, 100 °C
MW (200 W), 4 min
H
2
N
NH
2
R
1
R
2
O
+
Br
R
1
= Me
R
2
= Me, Ph
H
2
N
NH
2
R
O
R
2
R = Cl, Me, OMe
(39)
R
1
NH
2
O
R
R
(43)
5499% yield
N
H
N
H
O
O
K10 Clay
62–91% yield
+
MW (400 W), 5 min
H
2
N
NH
2
PPh
2
PPh
2
PAr
2
PAr
2
O
O
O
H
N
(40)
Ar = 3,5–(CF
3
)
2
C
6
H
3
3,5-(CF
3
)
2
Xantphos
Xantphos
60% yield
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