A convenient, one-step synthesis of benzyl (Ar) ureas of the type ArCH 2NHCONHR from Ar and R1OCH2NHCONHR via ureidoalkylation

Article abstract of DOI:10.1021/jo900002n

A method for the one-step C-ureidoalkylation of phenol, anisole, or aniline rings furnishing ArCH₂NHCONHR (Ar ) benzyl) products in moderate to good yields is described. With phenol ring systems, higher yields were attained when the reaction was worked up with an acidic ethanethiol addition to cleave any O-ureidoalkylation products that formed during the reaction.

Full text of DOI:10.1021/jo900002n

SCHEME 1. Examples of Amidoalkylation and
Ureidoalkylation
A Convenient, One-Step Synthesis of Benzyl (Ar)
Ureas of the Type ArCH2NHCONHR from Ar
and R1OCH2NHCONHR via Ureidoalkylation
F. Alex Meece, Champika Jayasinghe, Gary Histand,† and
Dennis H. Burns*
Department of Chemistry, Wichita State UniVersity,
Wichita, Kansas 67260
dennis.burns@wichita.edu
ReceiVed January 1, 2009
naphthalene was reacted with the similar diurea reagent 2, only
low yields of cyclic urea products were observed (Scheme 1).9
Additionally, a more recent article reports the reaction of
1-hydroxymethyl-3-phenylurea with a calix[4]arene.10 The
monoaddition of a 1-methylene-3-phenylurea group to the upper
rim of the macrocycle (whose phenolic ethers were linked with
diethylene glycol bridges) occurred in low yield.
A method for the one-step C-ureidoalkylation of phenol,
anisole, or aniline rings furnishing ArCH2NHCONHR (Ar
) benzyl) products in moderate to good yields is described.
With phenol ring systems, higher yields were attained when
the reaction was worked up with an acidic ethanethiol
addition to cleave any O-ureidoalkylation products that
formed during the reaction.
The driving force behind our interest in this type of
methodology was to determine if bis-anisole 3 or bis-phenol 4
would undergo efficient bis-ureidoalkylation (Scheme 2), as they
were intermediates in target anion receptors.11 A model study
was undertaken to determine whether the two types of ring
systems would differ in their reactivity with the alkoxyurea
reagent 5. Cresol and 4-methylanisole were used as model
compounds because only the ortho position was available to
undergo ureidoalkylation to produce either 8 or 9, respectively
(Scheme 3). Various reaction conditions were studied, utilizing
different acids (TFA, TsOH, BF3, or SnCl4), temperatures,
solvents, equivalencies, and reaction times. With both ring
systems, very little difference in product yields was found
whether the reagents were all mixed together at the same time
or if the alkoxyurea reagent was added to the mix over the
course of 10-15 min. The reaction conditions that furnished
the best yields of product 9 utilized 1:2 equiv of 4-methylanisole
to alkoxyurea 5, respectively, in conjunction with 1-2 equiv
of BF3 or SnCl4 in CH2Cl2 held at reaction temperatures between
-25 and -32 °C for usually not more than 30 min. In contrast,
when more than 1.0 equiv of alkoxyurea was used in the reaction
with cresol, the yields of the monourea product 8 did not
Urea functional groups have been used by our group and
many others as neutral and highly directionally binding units
in anion receptors.1-5 Our interest in the preparation of urea
groups led us to examine whether a nonprefunctionalized Ar
ring could be efficiently transformed into ArCH2NHCONH in
one step. While amidoalkylation has been extensively used to
add alkylamide groups to aromatic rings via one-step electro-
philic aromatic substitution reactions, the analogous ureidoalky-
lation method to place an alkylurea group directly on an aromatic
ring has seen few applications (Scheme 1).6,7 It has been
reported that the reaction of bis-urea 1 with ArR (R ) alkyl,
CH3O, amide) resulted in moderate yields of ortho and para
urea addition product mixtures.8 Interestingly, when 2-amino-
† Present address: Department of Chemistry, Bethel College, North Newton,
Kansas 67117.
(1) Sessler, J.; Gale, P.; Cho, W.-S. Anion Receptor Chemistry; RSC
Publishing: Cambridge, UK, 2006.
(2) Supramolecular Chemistry of Anions; Bianchi, A., Bowman-James, K.,
Garcia-Espana, E., Eds.; VCH: Weinheim, Germany, 1997.
(3) Filby, M. H.; Steed, J. W. Coord. Chem. ReV. 2006, 250, 3200–3218.
(4) Jagessar, R. C.; Shang, M.; Scheidt, W. R.; Burns, D. H. J. Am. Chem.
Soc. 1998, 120, 11684–11692.
(5) Burns, D. H.; Calderon-Kawasaki, K.; Kularatne, S. J. Org. Chem. 2005,
70, 2803–2807.
1
appreciably increase. Instead, H NMR and MS spectra from
crude product mixtures suggested that both monoaddition and
(9) Lofthouse, G.; Suschitzky, H.; Wakefield, B.; Whittalker, J. J. Chem.
Soc., Perkin Trans. 1 1979, 1634–1639.
(10) Arduini, A.; Secchi, A.; Pochini, A. J. Org. Chem. 2000, 65, 9085–
9091.
(11) The synthesis of compounds 3 and 4 will be reported elsewhere. Both
compounds gave satisfactory spectroscopic and elemental analysis. For the
synthesis of similar compounds, see: Burns, D. H.; Chan, H.-K.; Miller, J. D.;
Jayne, C. L.; Eichhorn, D. M. J. Org. Chem. 2000, 65, 5185–5196.
(6) Zaugg, H. Synthesis 1984, 85–110.
(7) Zaugg, H.; Martin, W. Org. React. 1965, 14, 52–269.
(8) Ben-Ishai, D.; Bernstein, Z. Tetrahedron 1997, 33, 3261–3264.
3156 J. Org. Chem. 2009, 74, 3156–3159
10.1021/jo900002n CCC: $40.75 2009 American Chemical Society
Published on Web 03/13/2009

SCHEME 2. Ureidoalkylation of Bis-phenol
SCHEME 3. Ureidoalkylation of Model Systems
byproduct formed from the breakdown of the urea reagent. If
<2 equiv of urea reagents was used, little product was produced
(only small amounts of monourea adducts were found). When
>2 equiv of urea reagent was used, MS showed that tri- and
tetra-addition adducts brought clutter to the already large number
of addition products in the crude reaction material.
It became clear that this method would be viable only if (1)
enough excess equivalents of reagent were used such that urea
functional groups were added to both ortho ring positions in
high yield and (2) a method could be found to remove from
the phenolic oxygens any urea functional groups unavoidably
added during an O-ureidoalkylation reaction. Therefore, ure-
idoalkylation on the bis-phenol 4 was attempted with excess
urea reagent, but then after it was quenched and worked up,
the crude reaction material was subjected to a methanol solution
containing either TsOH or concentrated sulfuric acid and
ethanethiol (sulfuric acid was used in cases where there was a
need to extract semiwater soluble organics). The removal of
the O-urea group by ethanethiol was usually complete after
10-15 min at 0 °C. The addition of the acidic ethanethiol
solution resulted in an impressive reduction of the number of
compounds in the crude reaction material as evidenced from
the before and after 1H NMR spectra (Supporting Information).
Because a large percentage of the acetyl groups underwent
transesterification with TFA during the course of the ureidoalky-
lation reaction, hydrolysis of the esters with a methanol-carbonate
solution was done without prior purification of the reaction
mixture following the acidic ethanethiol reaction to produce 13
rather than 12. However, the acetate groups could also be
removed if the acidic ethanthiol solution was allowed to warm
to room temperature and left for a 1-2 h time period. Typical
reaction yields for bis-urea 13 ranged between 65% and 72%,
and were 55-60% for bis-urea 14 and 30-35% for bis-urea
15 from the reaction of 4 with ureidoalkylation reagents 6 or 7,
respectively. Interestingly, if ethanethiol were added to the
reaction mixture at the beginning of the ureidoalkylation
reaction, rather than used in a follow-up reaction, yields of bis-
ureas 13-15 were essentially unchanged after the acetates were
cleaved with a methanol-carbonate solution.
bis-addition included a urea adduct that was bound to the
phenolic oxygen (O-ureidoalkylation, 10) as well as bound to
the aromatic ring (C-ureidoalkylation). Urea addition to the
phenolic oxygen made purification of the crude reaction material
more problematic, and yields of the phenol ring adduct were
generally 10-20% lower than those with the anisole adduct,
where yields were as high as 72%.
Bis-anisole 3 was thought to be a better starting material than
the bis-phenol 4 based on the above model studies, since
O-ureidoalkylation byproducts were likely because the latter’s
phenolic oxygens provided two additional sites for urea addition.
Unfortunately, no matter which alkoxyurea reagent was used
(5-7), and no matter the multitude of different conditions
employed, no reaction yielded product 11. To test whether steric
issues were the cause, the methyl groups were removed from
the phenolic oxygens and instead the two oxygens were linked
with a methylene group; however, ureidoalkylation still failed.
The total lack of success with the bis-anisole ring system
forced us to turn to the bis-phenol ring system in the hope that
it would undergo a well-behaved ureidoalkylation. As urea
addition to the phenolic oxygen was shown to occur in the model
studies, it was deemed prudent to use little excess urea reagent
in an attempt to optimize product yield. Unlike the bis-anisole
ring system, the bis-phenol system proved to be reactive to
ureidoalkylation when using TFA as acid with reagents 5-7
(ureidoalkylation reactions with Lewis acids were not well
behaved). However, purification of the product mixture proved
intractable, presumably due to the production of several types
of mono- and bis-phenol addition products (i.e., different
combinations of O-ureidoalkylation and C-ureidoalkylation) and
Due to the success of the bis-ureidoalkylation reaction, we
thought it would prove profitable to examine the scope of the
ureidoalkylation reaction when using reagents 5-7 with several
types of aromatic ring systems. The reaction worked well with
substituted phenols, substituted anisoles, and acetylated aniline,
but just trace ureidoalkylation took place with the less reactive
ring systems p-nitrophenol, p-xylene, or pyrrole. The data in
Table 1 demonstrate that reaction yields depended greatly on
the electrophilic substitution reactivity of the aromatic ring,
which in turn determined the reaction temperature and the acid
J. Org. Chem. Vol. 74, No. 8, 2009 3157

TABLE 1. Ureidoalkylation of Phenols, Anisoles, and Acetanalinea
a Methods A-G are variations on the method illustrated in the Experimental Section. All method variations are presented in detail in the
experimentals of compounds found in the Supporting Information section. Below only major differences that vary from the paper’s experimental will be
presented. Method A: BF3-Et2O used in place of TFA; 1:0.9 equiv of 21:6, respectively; reaction temperature of 0 °C. Method B: 1-2 equiv of 6-8
were used instead of the 6 equiv employed with the bisphenol 10. Method C: Reaction run in 1,2-dichloroethane at 80 °C. Method D1: Reaction run in
dichloromethane at reflux; 2 equiv of 7 added every 10 min, for a total of 6 equiv. Method D2: Reaction run in dichloromethane at room temperature; 2
equiv of 7 added every 10 min, for a total of 6 equiv. Methods E1, E2, E3: Use 1, 1.5, and 2 equiv, respectively, of 6. Method F: Sn4Cl used in place
of TFA; 1:2 equiv of 32:6, respectively; reaction temperature of 0 °C, no acid thiol quench. Method G: H2SO4 added to TFA, reaction run at room
temperature, no acid thiol quench. Paper: Effectively the same as the method in the Experimental Section.
to be used. Ureidoalkylation of phenol ring systems produced
similar product yields to that of anisole ring systems when the
acidic ethanediol step was added. 4-Methoxyphenol was so
reactive to ureidoalkylation, even at -32 °C, that bis-urea 20
was the major product formed even when <1 equiv of urea
reagent was used in the reaction. Monoureidoalkylation product
19 was only obtained when the reaction was done at 80 °C,
presumably a consequence of the reactive urea reagent not being
as stable at the higher temperature, thus making bis-urea addition
less probable. On the other hand, the less reactive 4-bromophe-
nol required reaction temperatures of 80 °C (1,2-dichloroethane
was use in place of dichloromethane) to produce the monourea
adduct 22 in only moderate yield. It should be noted that when
reactions were done at 80 °C, byproducts of some phenols were
formed in trace amounts (<5%) containing a 6-membered ring
composed of a methylene attached to a phenolic oxygen and
urea nitrogen. Presumably the ring was made from the ure-
idoalkylation product and formaldehyde, the latter coming from
a breakdown of the urea reagents 5-7.
Phenol 25 underwent ureidoalkylation, furnishing not only
the expected monourea adduct 26, but also a diadduct whereby
a second urea was coupled to the phenol’s primary amide,
furnishing amide-urea 27. The reaction of phenol 25 with
reagent 6 provides a good example of how product yields can
vary dramatically with relatively small changes in the reaction
conditions employed. When the ureidoalkylation reaction was
run at 0 °C, neither 26 nor 27 was produced. With the
ureidoalkylation reaction run at room temperature, the monourea
adduct 26 was produced with only a trace of 27, but when the
reaction was done at reflux in CH2Cl2, 27 was furnished in
quantities of 2:1 over that of 26. The results were similar no
matter the number of equivalents of 6 (1.5-6) used, or if 6
were added all at once or over time to the reaction mixture.
From a study of the reaction of phenol 28 with varying
equivalents of urea reagent 5, it was determined that increasing
the number of equivalents does not appreciably increase the
amount of monourea adduct 29, but does increase the amount
of diurea adduct 30.
Ureidoalkylation of acetylated aniline 33 and anisole (35)
essentially furnished only the para-substituted urea adducts,
while ureidoalkylation of phenol (37) afforded a 2:1 ratio of
para:ortho adducts, respectively. Ureidoalkylation of 33 would
take place only when H2SO4 was used in addition to TFA, and
the reaction temperature had to be kept no higher than room
temperature when using the stronger acid or charred products
would result. We hypothesized that H2SO4 was able to keep
the charged urea species (Scheme 2), necessary for ureidoalky-
lation to take place, around in solution for a longer period of
time than could TFA. With a shift of the equilibrium to the
protonated urea, the stronger acid created a greater probability
for product formation. To examine this idea, we placed D2SO4
or deuterated TFA with reagent 5 in an NMR tube containing
CD2Cl2 and ran 1H NMR experiments at different time intervals
at either -20 or 25 °C. At the lower temperature reagent 5 was
transformed into an intermediate that stayed stable for 0.5 h
with either acid (i.e., the proton resonances remained the same
after the addition of acid to the NMR tube). However, at 25
°C, reagent 5 was transformed into a stable intermediate with
only the sulfuric acid during this same time period, whereas in
TFA the intermediate’s proton resonances were observed to
change over a 30 min time span (Supporting Information). This
does not prove, but certainly suggests, that our hypothesis has
3158 J. Org. Chem. Vol. 74, No. 8, 2009

syringed into the chilled solution, and then a solution of 1-ethoxy-
methyl-3-phenylurea (6) (0.884 g, 4.56 mmol) in CH2Cl2 (4 mL)
was added dropwise to the reaction mixture over 15 min. The
mixture was allowed to stir for an additional 30 min, at which time
the reaction was quenched with a saturated NaHCO3 solution. The
reaction mixture was extracted with ethyl acetate (4 × 50 mL),
and the combined organic layers were washed with brine and dried
over sodium sulfate, and the solvent was removed under reduced
pressure furnishing 1.15 g of crude product. This material was
dissolved in methanol (8 mL), then ethanethiol (1 mL, 13.5 mmol)
and p-toluenesulfonic acid monohydrate (1.5 g, 8 mmol) were added
and the reaction mixture was allowed to stir at room temperature
for 1.5 h at which time the reaction was quenched with a saturated
NaHCO3 solution. The mixture was extracted with ethyl acetate (4
× 50 mL), and the combined organics were washed with brine
and dried over sodium sulfate, then the solvent was removed under
reduced pressure furnishing 1.25 g of crude product. The crude
material was purified by silica gel chromatography (40% acetone
in CH2Cl2) to afford 0.35 g of bis-urea 18 as a white solid (0.547
mmol, 72% yield): mp 157.5-159 °C; 1H NMR (400 MHz, DMSO-
d6) δ 1.62-1.69 (m, 4H), 1.69-1.78 (m, 2H), 2.46-2.49 (m, 4H),
2.51-2.59 (m, 4H), 3.39 (q, 4H, J ) 6.23 Hz), 4.20 (d, 4H, J )
5.68 Hz), 4.36 (t, 2H, J ) 5.13 Hz), 6.73 (t, 2H, J ) 6.23 Hz),
6.84 (d, 4H, J ) 1.74 Hz), 6.92 (t, 2H, J ) 7.32 Hz), 7.23 (t, 4H,
J ) 7.51 Hz), 7.36 (d, 4H, J ) 7.69 Hz), 8.68 (s, 2H), 9.06 (s,
2H); 13C (100 MHz, DMSO-d6) δ 30.1, 30.9, 34.7, 60.2, 118.1,
121.6, 126.1, 127.3, 128.7, 129.4, 132.5, 139.9, 150.7, 156.6; FTIR
(KBr) ν 1556, 1595, 1635, 3388 cm-1; MS (ESI) m/z 647.1 (M +
Li)+, 663.1 (M + Na)+. Anal. Calcd for C37H44N4O6: C, 69.35; H,
6.92; N, 8.74. Found: C, 69.52; H, 6.99; N, 8.66.
merit. Unfortunately, the use of H2SO4 in the ureidoalkylation
of 4-bromophenol, p-xylene, or pyrrole ring systems did not
prove fruitful. Under the above experimental conditions, reagent
7 did not exhibit stable proton resonances even at low
temperatures. Therefore, one probable reason for the consistent
lower yields of 3-methylurea adducts was due to the shortened
time that active charged intermediate was present in solution.
In summary, ureidoalkylation of aromatic ring systems with
reagents of the type R1O-CH2NHCONHR furnish the adduct
benzyl urea in acceptable yield. However, the reaction is limited
in scope, and works best with phenol, anisole, or acetylated
aniline ring systems. A Bronsted or Lewis acid catalyst was
required to activate the reagent by furnishing the protonated
intermediate necessary for the reaction to take place, while
concentrated H2SO4 was able to keep the protonated species in
solution longer than TFA or BF3. With phenol ring systems,
higher yields were attained when the reaction was worked up
with an acidic ethanethiol addition to cleave any O-uriedoalky-
lation products that formed during the reaction. Since the two
phenol ring systems in 4 each had only one open ortho-position
and no open para-position, excess reagent of 5-7 could be used
for the ureidoalkylation reaction. When ring systems were used
with open ortho- and para-positions, the para-adduct was
selectively formed if the ortho-position was hindered with
groups larger than an OH. The choice of temperature and acid
used in ureidoalkylation of a given aromatic ring system was
tailored to each starting material, as product yields were very
dependent on the reactivity of the given ring system toward
electrophilic substitution.
Acknowledgment. We thank the Watkins Foundation for
providing a Summer Watkins Fellowship to G.H.
Experimental Section
Supporting Information Available: Complete synthetic
details and characterizations of compounds 5-7, 8, 9, 14, 15,
17, 19, 20, 22-24, 26, 27, 29-31, 34, 36, 38, and 39, as well
The following is a representative example of the synthetic method
utilized to prepare benzyl urea groups. See the Supporting Informa-
tion for complete details of the variations utilized in the preparation
of all other benzyl urea groups discussed in Table 1.
1
as H NMR and 13C NMR spectra of these compounds and
3,3′-(1,3-Propanediyl)bis[1-(2-hydroxy-5-(3-hydroxypropyl)-
benzyl)-3-phenylurea] (18). Bis-phenol 10 (0.325 g, 0.76 mmol)
was dissolved in CH2Cl2 (2 mL) and the solution brought to -25
°C with a dry ice/acetone/water bath. TFA (2 mL, 26 mmol) was
compound 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO900002N
J. Org. Chem. Vol. 74, No. 8, 2009 3159