UREA 1
Urea reacts with orthoesters and related compounds to
Urea1
form alkylideneurea derivatives. The reaction with N,N-
Dimethylformamide Diethyl Acetal gives N-carbamoyl-N ,N -
O
dimethylamidine (eq 5).8 Active methylene compounds may
further participate in the condensation reaction of Triethyl Ortho-
H2N NH2
formate and urea to form ureidomethylene derivatives (eq 6).9
Treatment of urea with Chlorine in the presence of Calcium
[57-13-6] CH4N2O (MW 60.07)
Carbonate provides monochlorourea, which may be utilized as
InChI = 1/CH4N2O/c2-1(3)4/h(H4,2,3,4)/f/h2-3H2
a source of Hypochlorous Acid (eq 7).10,11
InChIKey = XSQUKJJJFZCRTK-UBUOBULFCP
NH2
(nitrogen nucleophile; carbonyl cation equivalent; formation of
85 °C
O
(1) + (EtO)2CHNMe2 (5)
inclusion complexes is used to purify long, slender compounds)
N
41%
ć% NMe2
Physical Data: mp 132.7 132.9 C; d 1.335 g cm-3.
ć%
Solubility: sol H2O (108 g/100 mL at 20 C), EtOH (5.4 g/100
OH
ć% ć%
mL at 20 C), MeOH (22 g/100 mL at 20 C).
i-PrOH
Form Supplied in: colorless solid.
+ HC(OEt)3 + (1)
reflux
Purification: reagent graded commercial products are sufficiently
90%
O O
pure for most purposes. For further purification, see Perrin and
Armarego.2
O NHCONH2
(6)
Original Commentary O O
Yoshinao Tamaru
H2O H2O
(1) + Cl2 + CaCO3 H2NCON" HCl
Nagasaki University, Nagasaki, Japan
AcOH
0 15 °C
Nitrogen Nucleophile. The three heteroatoms of urea, i.e.
two nitrogens and an oxygen, are moderately nucleophilic. A
(7)
[HOCl]
number of highly regioselective alkylation reactions of urea have
Cl OH
been developed. In most cases, the nitrogen atom is alkylated to
52 56%
afford the corresponding ureides or amino compounds. On heating
ć%
a mixture of a carboxylic acid and urea (1) at around 160 C,
Under mild conditions, urea undergoes nucleophilic addition to
the corresponding amide is obtained (eq 1).3,4 In the presence
carbon carbon triple bonds (eq 8)12 and double bonds (eq 9)13 ac-
of Triphenyl Phosphite and Pyridine, aromatic carboxylic acids
tivated by the coordination of PdII species. Under 1 atm of Carbon
react with urea at lower temperatures to give the corresponding
ć%
Monoxide, intramolecular aminocarbonylation proceeds at 0 C
arylcarbonylureas in good yields (eq 2).5
to room temperature to provide protected ²-amino acids (eq 9).13
O O O
160 °C
HO2C
+ (1)
( )8CO2H
S
( )8 S
H2N NH2 H2N NH2
10 mol % PdCl2(PhCN)2
(1)
N (8)
N
MeCN, reflux
78%
O O
O N
O N
DMF
(2)
H
ArCO2H + (1) + P(OPh)3 + pyridine
Ar N NH2
100 °C
H
88%
1 mol % PdCl2
CO2Me
3 mol equiv CuCl2
N NHMe N N (9)
Urea serves as a nitrogen nucleophile toward tertiary carbo-
Bn Bn Me
1 atm CO, MeOH
cationic species to give N-t-alkylureas;6,7 for example, the
0 °C to rt
O O
78%
t-butyl cation, generated by treatment of t-BuOH with H2SO4,
is trapped with urea to give t-BuNHCONH2, a useful precursor of
Two of the three heteronucleophilic centers of urea react with di-
tert-Butylamine (eqs 3 and 4).6
functionalized carbonyl compounds (e.g. dicarbonyl compounds,
1. H2SO4
t-BuNH NH2 Ä…-halo- or Ä…-hydroxy carbonyl compounds, and Ä…,²-unsaturated
(1) (3)
2. t-BuOH carbonyl compounds) to furnish a wide range of nitrogen hetero-
O
20 25 °C
cycles. The dicarbonyl compounds include Glyoxal, Ä…-diketones
31 33%
(eqs 10 and 11),14-16 Ä…-keto esters (eq 12),17 oxalic and mal-
ethylene glycol onic esters (eq 13),18,19 ²-diketones (eq 14),20 and ²-keto esters
t-BuNH NH2
+ 40% aq NaOH
t-BuNH2 (4)
(eq 15).21 A three component connection reaction of urea, alde-
reflux
O
hydes, and ²-keto esters provides dihydropyrimidines (Biginelli
71 78%
reaction) (eq 16).22
Avoid Skin Contact with All Reagents
2 UREA
H
H H
R
O R
Br N
N N
acid
N
+ (1) (10)
O O DMF
"
EtO O + (1)
N N
O R
reflux
R
H H
24%
O
R = H, alkyl, aryl
Br
H
Br N
Ph
O
N
Ph
O Ph (18)
KOH, EtOH
EtO
N
(1)
+ (11)
HN NH
NH2
reflux
O Ph
O
66%
O
O
Ä…,²-Unsaturated ketones and acids react with urea to give
Ph dihydropyrimidine derivatives (eq 19)25 and dihydrouracils
O
COPh
(eq 20),26 respectively. Ä…,²-Unsaturated aldehydes and ketones
100 110 °C
O + (1) (12)
HN NH
with ²-substituents, such as alkoxy,27 amino,28 halogeno,29
97%
trichloromethyl,30 etc.,31 provide substituted pyrimidines (eq 21).
O O
O
O
NaH
cat MeOH
O O
1. NaOR, ROH
+ (1)
n
O O
(R = Me, Et)
benzene
n
+ (1) HN NH (13)
75%
OMe
2. HCl O
OEt OEt
O
NH
HN
n = 0 parabanic acid 71.5 76%
n = 1 barbituric acid 72 78% (19)
O O OH
OMe
ethylene glycol
reflux
O
+ (1)
ethylene glycol
O
60 80%
+ (1) (20)
OBu HN NH
190 °C
OH 2.5 mol equiv
45%
O
OH
R
N N OH
conc HCl
X R
(14)
+ (1) (21)
N N
22 °C
O
OH
OBu
X = OEt, NMe2, Cl, CCl3, etc
R = H, alkyl, aryl
1. cat HCl, EtOH, rt O
O 2. aq NaOH, 65 °C
+ (1) (15)
HN NH
3. HCl
Carbonyl Cation Equivalent. In the reaction with heteronu-
EtO O
71 77%
O
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-
Br
CO2Et
pared by transamination of the urea nitrogen atoms with primary
Br O OEt
cat HCl, EtOH
amines (eqs 22 and 23).32 Reaction of urea with vic-diamines
++ (1)
O
reflux
(eq 24)33 and 2-aminophenols (eq 25)34 gives imidazolidin-2-ones
HO HN NH
86%
and oxazolidin-2-ones, respectively. The reaction with aliphatic
(16)
OH O
O
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,
The reaction of urea and carbonyl compounds with Ä…-substi-
obtained by fusing (-)- or (+)-ephedrine hydrochloride and urea,
tuents, such as Ä…-hydroxy ketones23 and Ä…-halo ketones,11 may
are useful chiral auxiliaries for asymmetric syntheses.36
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
120 °C
NH2 (1) NHCONH2 (22)
+
of urea.
O O
1 equiv quantitative
Ph Ph
Ph Ph
"
H
+ (1) (17) 180 °C
HN NH
NH2 (1) N
85% (23)
+
X O O O
CO
89% 2
O
X = OH, Br 2 equiv
A list of General Abbreviations appears on the front Endpapers
UREA 3
Ph Ph
an aldehyde, and urea, is used to prepare dihydropyrimidinones
Ph Ph
200 °C
(eq 16).22 There has been a remarkable amount of attention given
+ (1) + H2O (24)
HN NH
87% to this transformation due to the interesting pharmacological
H2N NH2
O properties associated with dihydropyrimidinones.42 Many
biologically active molecules including calcium channel modu-
lators, anticancer compounds, and Ä…1a adrenoreceptor-selective
H
EtOC NH2 conc HCl EtOC antagonists contain the dihydropyrimidinone scaffold. Some
N
+ (1) (25)
O examples are illustrated below.
"
O
OH
73%
O2N
O2N
Ph
O
HO
1. 170 175 °C
" HCl + (1) (26)
HN N
Me
i-PrO2C CONH2 MeO2C
2. 200 210 °C
Ph NHMe
N
NH
55 65%
O
N O
N O
H
H
Catalyst. The conversion of Tetracyanoethylene into
SQ 32926
Nitractin
dicyanoketene acetals is catalyzed by urea (eq 27).37
NC CN NC OEt
(1), reflux
A wide variety of modifications to this reaction include the
+ EtOH (27)
72%
use of many different Lewis acids,43 microwave conditions,44
NC CN NC OEt
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
Inclusion Compounds (Differentiation of Linear Comp-
is beyond the scope of this article. There are a number of excel-
ounds from Branched Ones).1,38 Urea forms inclusion com-
lent reviews detailing the scope of the Biginelli reaction.47 In a
plexes, taking normal alkanes having six or more carbon atoms
related application of this reaction, the tethered Biginelli conden-
as guests.39 In the complexes, hydrogen bonded urea molecules
sation is used in the preparation of biologically active guanidine
are oriented in a helical lattice, constructing a cylinder-shaped
alkaloids.48
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-
BocN
plex require a channel diameter of about 5.5 Å. This seems O
H
the upper limit of thickness. Not only hydrocarbons but many
kinds of functionalized alkanes can be included if they are Yb(OTf)3, 4 Å MS
O
EtO2C
long and slender enough. Compounds that form inclusion com-
THF, 70 °C, 14 h
NH2
+
plexes include 1-bromohexane, 1- and 2-octanol, 2-heptanone, 60%
O
1-cyclopentylnonane, and 2-, 3-, and 4- methyltridecane. On the
H2N O
other hand, the following compounds do not form the complex:
3-ethyldodecane, 2-bromooctane, 1-cyclohexyloctane, and 2,4-
O
dimethyldodecane.40 Thus linear compounds, as in the former
BocN
group, can be separated from a mixture with small or branched
ones such as in the latter. syn-9,10-Dihydroxystearic acid has been
EtO2C
ć% (28)
separated from its anti counterpart.41 The syn-diol (mp 95 C),
* NH
which is estimated to require a channel diameter of 5.4 Å, readily
N O
forms a urea complex. On the other hand, the anti-diol
H
ć%
(mp 131 C), which requires a channel diameter of 6 Å, does
4R/4S = 5:1
not form a complex.38
O O O
PhCHO
+ +
OEt H2N NH2
First Update
O Ph
Paul J. Nichols
Array BioPharma, Boulder, CO, USA
cat NBS
EtO NH
(29)
DMA
microwave
Nitrogen Nucleophile. The Biginelli reaction, an acid-
N O
3 min, 92%
H
catalyzed cyclocondensation reaction between a ²-keto ester,
Avoid Skin Contact with All Reagents
4 UREA
O O O
The direct condensation of carboxylic acids with urea can be
+ R3 CHO +
accomplished catalytically in the presence of arylboronic acids
R1 R2 H2N NH2
to generate N-acylurea.53 Condensation of the arylboronic acid
with carboxylic acids generates an (acyloxy)boron complex. Sub-
O R3
sequent nucleophilic attack by the urea nitrogen provides the
100 105 °C
R2 NH N-acylurea (eq 35).
(30)
neat, 1 h
R1 N O
H
R1 = Me, Et
R2 = OMe, OEt
CO2H
R3 = aryl, alkyl, alkenyl
5% catalyst
O
+
toluene azeotropic
H2N NH2
reflux, 26 h
The preparation of tertiary amines can be accomplished in a
Ph
single step by combining urea with alkyl halides in the pres-
O O
ence of sodium hydroxide under pressure at elevated temperatures
N NH2 (35)
(eq 31).49
H
O
aq NaOH, RCl
Ph
92% yield
H2N NH2 60 psi, 80 200 °C
F3C
40 h
2 R3N + salts + alcohols/ether (31) B(OH)2
catalyst =
yields 58 82%
F3C
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
A very interesting rearrangement product is observed when
imine, which is then reduced with NaBH4 to provide alkylated
reacting 3-chloro-1H,3H-quinoline-2,4-diones with urea in
ureas (eq 32). To obtain the mono-substituted alkylation product
AcOH heated at reflux.54 Instead of making the expected imidazo
a large excess of urea (20 equiv) must be used. The excess is easily
[4,5-c]-quinolone, 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-
removed during work up.
diones are produced consistently in high yields (eq 36). The
rearrangement is believed to proceed through an isocyanate
O mechanism.
AcOH
+ ArCHO
+
TMSCl
rt
H2N NH2
O
O
O
Ar
NaBH4 Cl
(32)
urea
H2N N
H2N N
rt
Bn
H
AcOH, reflux, 2 h
Ar
N O
H
Bn
NH
The hindered alcohols 4,4 -dimethoxybenzhydrol51 and 1-
adamantanol52 undergo a hydroxyl substitution reaction with urea
O
N
(36)
in acidic media to provide the corresponding N-substituted ureas
(eqs 33 and 34). The substitution reaction is likely to occur through
N O
the generation of a carbenium ion. H
71% yield
urea
AcOH, cat H2SO4
Ar2CHNHCONH2 (33)
Ar2CHOH
20 °C, 15 h
75% yield
Ar = 4-MeOC6H4
The reaction of bromopyruvic acid with urea in the presence
of BF3 provides 5-(bromomethylene)hydantoins (eq 37). The
urea (2 equiv)
O
TFA (10 equiv)
5-(bromomethylene)hydantoins can subsequently react with a
(34)
OH N variety of nucleophiles to give 5-(substituted-methylene)hydan-
90 °C, 8 h
NH2
94% yield H
toins.55
A list of General Abbreviations appears on the front Endpapers
UREA 5
O
O BF3 · Et2O
The condensation of isatoic anhydride with primary amines
HO Br
CH3CN
H2N NH2
and urea in the presence of N,N-dimethyl acetamide (DMA) under
microwave irradiation proceeds rapidly to form the corresponding
quinazolinediones (eq 41).58
O
O
H
HN O
DMA
(37)
+
O RNH2
+
N
Br
H2N NH2 microwave
O
H
N O
H
47% yield
R = Me, aryl
O
R
N
(41)
Microwave Assisted Transformations. A solvent-free
N O
procedure has been developed for the preparation of primary
H
amides from urea and carboxylic acids using imidazole and
72 93% yield
microwave irradiation.56 The reaction is believed to proceed
through generation of the imidazolium carboxylate salt followed
Metal-mediated Catalysis. Alkyl halides can be coupled with
by displacement with ammonia that is liberated from urea under
urea in the presence of 1 mol % Pd2dba3·CHCl3, Xantphos lig-
the reaction conditions (eq 38).
and, and Cs2CO3 as a base to give N,N -diarylureas.59 The re-
action is general for aryl bromides and aryl iodides contain-
O O ing electron-withdrawing groups at para postion (eq 42). The
imidazole
+
use of 3,5-(CF3)2Xantphos as a ligand allows the coupling of
R OH H2N NH2 MW (300 W), 90 360 s
ortho- and, in limited cases, meta-substituted aryl bromides as
R = alkyl, aryl well (eq 43).60
Pd2dba3·CHCl3
O X
O
Xantphos
(38)
+
R NH2
CS2CO3
H2N NH2
R
dioxane, 100 °C
47-88% yield
R = CF3, CN, CO2Et, NO2, PhCO, Cl, H
Another reaction that involves the production of ammonia from
urea is the solvent-free reaction with dicarbonyl compounds in the
R R
O
presence of montmorillonite K10 clay under microwave condi-
(42)
tions.57 Reactions with ²-diketones provide enamino ketones and
N N
reactions with Å‚-diketones give N-unsubstituted pyrroles (eqs 39
H H
and 40).
64-92% yield
O
O O K10 Clay
+
Pd2dba3
MW (200 W), 4 min
R1 R2 H2N NH2
O
3,5-(CF3)2 Xantphos
+
Br
CS2CO3
R1 = Me
H2N NH2 dioxane, 100 °C
R
R2 = Me, Ph
O
R2 R = Cl, Me, OMe
(39)
R1 NH2
O
R R
(43)
54-99% yield
N N
H H
O
O
K10 Clay
62 91% yield
+
H2N NH2 MW (400 W), 5 min
PPh2 PPh2 PAr2 PAr2
O
O O
H
N
(40)
Ar = 3,5 (CF3)2C6H3
3,5-(CF3)2Xantphos
Xantphos
60% yield
Avoid Skin Contact with All Reagents
6 UREA
Catalytic amidations of aryl halides can also be performed using 27. (a) Reichardt, C.; Budnik, U., Chem. Ber. 1990, 123, 2023 (Chem. Abstr.
1990, 113, 174 068v). (b) Gerus, I. I.; Vdovenko, S. I.; Gorbunova, M.
substituted ureas.60,61
G.; Kukhar, V. P., Chem. Heterocycl. Compd. (Engl. Transl.) 1991, 398
(translated from Khim. Geterotsikl. Soedin. 1991, 502).
Related Reagents. Hydrogen Peroxide Urea.
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530.
29. Abdel Galil, F. M.; Saleh, S. S., Sulfur Lett. 1989, 9, 9.
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247.
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