Lithiation and substitution of N′ -(ω-phenylalkyl)-N,N- dimethylureas

Article abstract of DOI:10.1055/s-0031-1291008

Lithiation of N-phenethyl-N,N-dimethylurea with three equivalents of tert-butyllithium in anhydrous tetrahydrofuran at -78°C takes place on the nitrogen and on the side-chain of the CHnext to the phenyl ring (α-lithiation). The 2-lithio isomer can be obta

Full text of DOI:10.1055/s-0031-1291008

PAPER
▌2013
paper
Lithiation and Substitution of N′-(ω-Phenylalkyl)-N,N-dimethylureas
Keith Smith,* Gamal A. El-Hiti,*1 Mohammed B. Alshammari
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20870600; E-mail: smithk13@cardiff.ac.uk; E-mail: el-hitiga@cardiff.ac.uk
Received: 12.02.2012; Accepted after revision: 11.04.2012
identical manner towards lithiation9 and the urea deriva-
tives are more generally useful for synthesis.
Abstract: Lithiation of N′-phenethyl-N,N-dimethylurea with three
equivalents of tert-butyllithium in anhydrous tetrahydrofuran at
–78 °C takes place on the nitrogen and on the side-chain of the CH2
next to the phenyl ring (α-lithiation). The 2-lithio isomer can be ob-
tained via bromine–lithium exchange of N′-2-(2-bromophenyl)eth-
yl-N,N-dimethylurea using methyllithium followed by tert-
butyllithium in tetrahydrofuran at –78 °C. The lithium reagents thus
obtained react with various electrophiles to give the corresponding
substituted derivatives in excellent yields. Lithiation of N′-(3-phen-
ylpropyl)-N,N-dimethylurea takes place on the α-CH2 with tert-bu-
tyllithium at 0 °C. On the other hand, lithiation of N′-(4-
phenylbutyl)-N,N-dimethylurea with tert-butyllithium at 0 °C takes
place on one of the methyl groups of the urea unit.
We now report the successful lithiation and substitution of
N′-phenethyl-N,N-dimethylureas using a simple, general
and efficient α-lithiation procedure using tert-butyllithi-
um. We also report a procedure for ring-substitution by
Br–Li exchange with methyllithium followed by tert-bu-
tyllithium in tetrahydrofuran at –78 °C.
The first tasks were to synthesise N′-phenethyl-N,N-di-
methylurea (2)16 and to try to find conditions under which
its lithiation could be effected. Reaction of phenethyl-
amine (1) with dimethylcarbamoyl chloride (DMCC) in
dichloromethane and in the presence of triethylamine un-
der reflux for one hour gave 2 in 99% yield (Scheme 1) af-
ter crystallisation.
Key words: N′-phenethyl-N,N-dimethylurea, side-chain lithiation,
bromine–lithium exchange, electrophile, synthesis
Many aromatic compounds undergo lithiation ortho to a
functional group,2–4 and the organolithium reagents in
such reactions are useful intermediates for the synthesis of
ortho-disubstituted aromatics.5 Moreover, ortho-lithiation
has been applied to various heterocycles to produce the
corresponding substituted derivatives.6
Me
H
NH2
N
N
DMCC, Et3N
Me
O
CH2Cl2, refux, 1 h
2 99%
1
Scheme 1 Synthesis of N′-phenethyl-N,N-dimethylurea (2)
For example, we have developed several efficient lithia-
tion procedures for preparation of various substituted aro-
matics and heteroaromatics that might be difficult to
prepare by other means.7 As part of such studies we have
successfully lithiated and substituted various N-(substitut-
ed benzyl)pivalamides and N′-(substituted benzyl)-N,N-
dimethylureas selectively using n-butyllithium or tert-bu-
tyllithium in tetrahydrofuran.8–10 Such processes have
been applied for the production of substituted isoindoline
and isoquinoline derivatives.11–13
Initially the reaction of 2 with n-butyllithium (2.2 equiv)
was carried out in anhydrous tetrahydrofuran under a ni-
trogen atmosphere at –78 °C. Initial addition of n-butyl-
lithium provided a pale yellow solution, presumably
because of formation of the monolithium reagent 3, until
approximately one equivalent had been added, then gave
a deep yellow solution as the remaining n-butyllithium
was added, presumably because of formation of the dilith-
ium reagent 4. The mixture was stirred for two hours at
–78 °C. Benzaldehyde (1.1 equiv) was added and the mix-
ture was stirred for another two hours (Scheme 2) at –78
°C and then quenched by the addition of aqueous ammo-
nium chloride solution. The starting material 2 was recov-
ered in 95% yield, but a new compound, shown by its 1H
NMR spectrum to be 5, was produced in very low yield
(Table 1, entry 1).
As part of such studies we became interested in directed
lithiation of N′-phenethyl-N,N-dimethylureas. Lithiation
of N-phenethylpivalamide derivatives have been reported
by Schlosser.14,15 For example, lithiation of N-phenethyl-
pivalamide itself took place on the side chain (α-lithia-
tion) with three equivalents of tert-butyllithium in
tetrahydrofuran at –75 °C. Reaction of the dilithium re-
agent thus obtained with carbon dioxide, the only electro-
phile tried, gave the corresponding acid in 72% yield.14
However, there are no reports of lithiation and substitu-
tion of N′-phenethyl-N,N-dimethylureas, and pivalamide
and dimethylurea derivatives do not always behave in an
Several experiments were conducted to try to improve the
yield of 5 or to find conditions under which ortho-lithia-
tion could be achieved instead. Double lithiations of 2
with various lithiating agents (n-BuLi, t-BuLi, LDA) at
various reaction temperatures (–78 and 0 °C) followed by
reaction with benzaldehyde were attempted. The crude
products were analysed by 1H NMR spectroscopy and the
approximate yields of 5 obtained are summarised in Table
1.
SYNTHESIS 2012, 44, 2013–2022
Advanced online publication: 05.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291008; Art ID: SS-2012-Z0143-OP
© Georg Thieme Verlag Stuttgart · New York

2014
K. Smith et al.
PAPER
Me
H
Me
N
Clearly, lithiation and substitution of 2 took place on the
side chain. In the 13C NMR spectrum of compound 7 the
carbons of the two phenyl groups appeared as separated
signals, verifying that they are diastereotopic. Similarly,
the carbons of the two methyl groups originating from
acetone in compound 8 and the two sides of the cyclohex-
ane ring in compound 9 appeared as separated signals in
their 13C NMR spectra. Also, the NMR spectra of all com-
pounds showed that the signals of the two hydrogens of
the CH2 group are diastereotopic.
N
N
N
RLi, THF
Me
Me
O
OLi
2
3
RLi, THF
OH
Me
N
Li
Me
N
H
N
1) PhCHO
2) aq NH4Cl
N
Me
Me
O
OLi
5
4
Table 2 Synthesis of Substituted N′-Phenethyl-N,N-dimethylureas
5–11
Scheme 2 Lithiation of 2 followed by reaction with benzaldehyde
Product
Electrophile
E
Yield (%)a
Table 1 Synthesis of 5 under Various Reaction Conditions
5
6
PhCHO
PhCOMe
Ph2CO
Me2CO
(CH2)5CO
EtI
PhCH(OH)
PhC(OH)Me
Ph2C(OH)
Me2C(OH)
(CH2)5C(OH)
Et
97b
96b
98
98
98
86
99
Entry
Lithium reagent (equiv)
Temp (°C)
Yield (%)
2a,b
1
2
3
4
5
6
7
8
n-BuLi (2.2)
n-BuLi (2.2)
t-BuLi (2.2)
t-BuLi (3.3)
t-BuLi (4.4)
t-BuLi (2.2)
t-BuLi (3.3)
LDA (2.2)
–78
0
7
c
–
8
c
0
–
9
c
0
–
10
11
c
0
–
D2O
D
–78
–78
0
62d
97d
a Yield of pure product after isolation.
b The 1H NMR showed the presence of two diastereoisomers in ap-
proximately equal proportions.
c
–
a Yield by 1H NMR analysis.
Clearly, directed lithiation of N′-phenethyl-N,N-dimethyl-
urea (2) did not take place on the ring. However, ring sub-
stitution could in principle be achieved via bromine–
lithium exchange of the corresponding bromo substrate.
Therefore, we decided to synthesise N′-2-(2-bromophe-
nyl)ethyl-N,N-dimethylurea (13) and attempt its bro-
mine–lithium exchange and substitution.
b Starting material 2 was recovered in significant quantities.
c A complex mixture of unidentified products was formed.
d Yield of 5 after purification.
The results clearly indicated that the optimum conditions
involved use of three equivalents of tert-butyllithium as
the lithium reagent at –78 °C (Table 1, entry 7) to give 5
in 97% yield after purification by column chromatogra-
phy. The 1H NMR spectrum of 5 showed diastereotopicity
for the CH2 protons in both diastereoisomers.
N′-2-(2-Bromophenyl)ethyl-N,N-dimethylurea (13) was
synthesised in 98% yield as described in Scheme 4, based
on a literature procedure for analogous compounds.16
It was of interest to see if the reaction of the lithium inter-
mediate 4 with other electrophiles would be useful and
general. Consequently, reactions of 4, prepared in situ
from 2 under the conditions described above, with various
electrophiles were carried out. Each reaction was conduct-
ed under identical conditions. The crude products were
purified by column chromatography (silica gel; Et2O–
hexane, 1:3), to give the corresponding substituted deriv-
atives 6–11 (Scheme 3) in high yields (Table 2).
Me
H
NH2
N
N
Me
DMCC, Et3N
O
CH2Cl2, refux, 1 h
Br
Br
13 98%
12
Scheme 4 Synthesis of N′-2-(2-bromophenyl)ethyl-N,N-dimethyl-
urea (13)
Successful bromine–lithium exchange of 13, which pos-
sesses a proton-donating group (PDG), followed by trap-
ping of the organolithium reagent with an electrophile,
relies on clean initial deprotonation of the urea group
(Scheme 5). If bromine–lithium exchange should precede
deprotonation, then the incipient organolithium reagent
could self-quench to give species 3 (Scheme 2). However,
there are also other potential complications. For example,
the initially formed intermediate 14 could complex further
1) t-BuLi (3.3 equiv), THF
–78 °C, 2 h
2) electrophile (E+)
–78 °C, 2 h
Me
N
E
Me
N
H
H
N
N
Me
Me
3) aq NH4Cl
O
O
2
5–11
Scheme 3 Lithiation and substitution of N′-phenethyl-N,N-dimethyl-
urea (2)
Synthesis 2012, 44, 2013–2022
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lithiation of N′-(ω-Phenylalkyl)-N,N-dimethylureas
2015
organolithium reagent RLi and provide intramolecular as- produces a by-product that is less volatile and more diffi-
sistance for bromine–lithium exchange. If this process be- cult to remove. We have previously found that methyllith-
comes faster than the initial deprotonation, the new ium can be used for selective deprotonation of N-(2-
organolithium intermediate can then compete with the bromobenzyl)pivalamide, followed by two equivalents of
added organolithium for deprotonation of further 13, tert-butyllithium to effect bromine–lithium exchange.9
which would ultimately lead to recovery of 2.
This method is more attractive to us and therefore we pro-
posed to investigate this method in the first instance if
simple use of tert-butyllithium alone should prove unsat-
isfactory for Br–Li exchange of 13.
Me
N
Me
H
RLi, THF
N
N
N
–78 °C
Me
Me
Against this background, Br–Li exchange of 13 was at-
tempted under various reaction conditions, followed by
reaction with benzophenone as an electrophile. The re-
sults obtained are recorded in Table 3.
OLi
O
Br
Br
13
14
RLi, THF
–78 °C
Me
N
Me
The results reported in Table 3 showed that treatment of
13 with tert-butyllithium alone (2.2 or 3.3 equiv, at –78 °C
or 0 °C, for short or long periods) did not provide more
than traces of the desired product 16. However, use of 1.2
equivalents of methyllithium (to deprotonate the nitrogen)
to give the monolithium reagent 14 and then 2.5 equiva-
lents of tert-butyllithium to bring about bromine–lithium
exchange led smoothly at –78 °C in tetrahydrofuran for 15
minutes to the dilithium reagent 15 (Scheme 5), which
could be trapped with excess benzophenone at room tem-
perature in tetrahydrofuran. After workup, the crude prod-
uct was purified by column chromatography (silica gel;
Et2O–hexane, 1:3) to give 16 in 95% yield (Table 3, entry
9). Other conditions were successful to produce 16 but in
lower yields.
H
N
1) Ph2CO, 2 h
2) aq NH4Cl
N
N
Me
Me
OH
O
OLi
Li
Ph
16
15
Ph
Scheme 5 Bromine–lithium exchange of 13 followed by reaction
with benzophenone
Some of these issues were investigated by Beak et al. for
2-bromo-N-ethylbenzamide and other substrates possess-
ing PDGs, but primarily from a mechanistic rather than
synthetic perspective.17 For other PDG-containing sub-
strates a Japanese group has used the less reactive dibutyl-
magnesium to effect the initial deprotonation, prior to
bromine–lithium exchange,18 but this suffers from the
complication that the waste products of the reaction will
contain two different metals, making recovery of the met-
als more difficult. The same group has also used mesityl-
lithium for initial deprotonation of substrates containing
active methylene groups,19 but mesityllithium is more ex-
pensive and less widely available than common organo-
lithium reagents, is more wasteful of organic material, and
Reactions of 15, prepared in situ from 13 under the opti-
mum conditions, with representative electrophiles (4
equiv) were carried out at room temperature for two
hours. Purification of the crude products by column chro-
matography (silica gel; Et2O–hexane, 1:3) gave the corre-
sponding substituted derivatives 17–19 (Scheme 6) in
high yields (Table 4).
Table 3 Synthesis of 16 under Various Reaction Conditions
Entry
Lithiation step (–78 °C), RLi (equiv)
Reaction with Ph2CO
Yield (%)a
MeLi
t-BuLi
Time (min)
Temp (°C)
Equiv
1
0
2.5
2.5
3.3
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
120
120
60
–78
–78
–78
0
1.2
1.2
1.2
1.2
2.0
1.2
2.0
3.0
4.0
2.0
19 (8)b
23
2
0
3
0
30
4
0
9
5
1.2
1.2
1.2
1.2
1.2
1.2
15
–78
20
46
6
15
72
7
15
20
82
8
15
20
86
9
15
20
95
10
60
20
90
a Yield of pure 16.
b The figure in parentheses is for a similar reaction in anhyd Et2O.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2013–2022

2016
K. Smith et al.
PAPER
1) MeLi (1.2 equiv),
yl-N,N-dimethylurea (22; Figure 1) was synthesised from
21 in 98% yield by the method16 shown in Scheme 4 for
synthesis of 13.
THF
–78 °C, 10 min
2) t-BuLi (2.5 equiv),
THF
Me
N
Me
N
H
N
H
N
–78 °C, 15 min
The Br–Li exchange of 22 under conditions identical to
those used in Scheme 6, followed by reaction with benzo-
phenone (4 equiv), gave a mixture of 7 and 23 (Scheme 8)
in 85 and 13% yield, respectively. Product 23 would be
produced as a result of Br–Li exchange followed by reac-
tion with benzophenone at the 3-position. We assume that
product 7 arose as a result of isomerisation of the 3-lithio
derivative formed by the initial Br–Li exchange reaction
into the α-lithio derivative, probably because the 3-lithio
reagent acted as a base to remove a proton from the side
chain of another molecule. In an attempt to improve the
yield of 23 we shortened the reaction time with tert-butyl-
lithium so as to reduce the opportunity for such isomerisa-
tion. Indeed, the yield of 23 was improved to 58% when
the reaction time with tert-butyllithium was only 5 min-
utes, while the yield of 7 decreased to 13%. A significant
quantity (22%) of unbrominated starting material 2 was
also recovered, which supports the assumption that the
initial Br–Li exchange product acts as a base.
Me
Me
O
O
3) electrophile
(4 equiv)
THF, r.t., 2 h
4) aq NH4Cl
E
Br
13
16–19
Scheme 6 Lithiation and substitution of N′-2-(2-bromophenyl)ethyl-
N,N-dimethylurea (13)
Table 4 Synthesis of N′-2-(2-Substituted phenyl)ethyl-N,N-dimeth-
ylureas 16–19
Product Electrophile
E
Yield (%)a
16
17
18
19
Ph2CO
Ph2C(OH)
PhCH(OH)
95
90
87
98
PhCHO
4-MeOC6H4CHO 4-MeOC6H4CH(OH)
D2O
D
a Yield of pure product after isolation.
1
OH
The H NMR spectra of compounds 17 and 18 showed
that the signals for the two hydrogens of the two CH2
groups are diastereotopic.
Ph
Ph
Me
N
H
N
Me
Me
1) MeLi
(1.2 equiv)
2) t-BuLi
(2.4 equiv)
Me
N
Reaction of the dilithium reagent 15, obtained from 13,
with excess of iodoethane (4.0 equiv) gave rise to the di-
ethyl derivative 20 in 86% isolated yield (Scheme 7). Al-
though we did not attempt to prepare the monoethyl
derivative in this case, there is ample precedent to show
that C-ethylation occurs much more readily than N-ethyl-
ation (see formation of 10, Table 2, for example), so that
simple C-ethylated products are easily obtained when the
amount of iodoethane is restricted to one equivalent.
O
O
H
N
7
+
Me
O
3) Ph2CO
(4 equiv)
4) aq NH4Cl
Me
N
H
N
Br
22
Ph
Ph
OH
23
Scheme 8 Bromine–lithium exchange of 21 followed by reaction
with benzophenone
1) MeLi (1.2 equiv),
THF
–78 °C, 10 min
Me
N
Et
N
Me
N
2) t-BuLi (2.4 equiv),
THF
–78 °C, 15 min
H
It was also of interest to know whether lithiation of other
N′-(ω-phenylalkyl)-N,N-dimethylureas would behave in
the same way towards lithiation as the phenethyl deriva-
tive. Therefore, N′-(3-phenylpropyl)-N,N-dimethylurea
(26) and N′-(4-phenylbutyl)-N,N-dimethylurea (27) were
synthesised (in 94 and 90% yields, respectively) from the
corresponding amino derivatives 24 and 25. Lithiation of
26 under the standard conditions that were used for 2
(Scheme 2) followed by reaction with benzophenone as a
representative electrophile at –78 °C gave the correspond-
ing α-substituted product 28 in 44% yield. The yield of 28
N
Me
Me
O
O
3) EtI (4 equiv),
THF, r.t.,
2 h
4) aq NH4Cl
Br
Et
13
20 (86%)
Scheme 7 Lithiation of 13 followed by reaction with iodoethane
It was of interest to see whether the conditions that were
successful for Br–Li exchange of 13 would also apply for
Br–Li exchange of a compound with the Br at a different
location on the ring. Therefore, N′-2-(3-bromophenyl)eth-
O
Me
H
NH2
Me
N
N
(
)
n
(
)
n
NH2
N
N
Me
H
Me
O
24 n = 1
25 n = 2
26 n = 1
27 n = 2
Br
Br
21
22
Figure 1 Structures of compounds 21, 22, and 24–27
Synthesis 2012, 44, 2013–2022
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lithiation of N′-(ω-Phenylalkyl)-N,N-dimethylureas
2017
OH
Ph
O
O
1) t-BuLi (3.3 equiv), THF, 0 °C, 2 h
2) Ph2CO, 20 °C, 2 h
3) aq NH4Cl
Ph
Me
Me
N
N
N
N
H
H
Me
Me
28 (89%)
26
Scheme 9 Lithiation of 26 followed by reaction with benzophenone
Me
N
Me
Ph
1) t-BuLi (3.3 equiv), THF, 0 °C, 2 h
2) Ph2CO, 0 °C, 2 h
3) aq NH4Cl
Ph
OH
H
H
N
N
N
Me
O
O
27
29 (89%)
Scheme 10 Lithiation of 27 followed by reaction with benzophenone
was improved to 85% when the whole reaction was car- place on the α-CH2, although a higher temperature was re-
ried out at 0 °C and to 89% when the lithiation was con- quired for a good yield. By contrast, lithiation of N′-(4-
ducted at 0 °C and reaction with benzophenone was phenyl)butyl-N,N-dimethylurea took place on one of the
carried at room temperature (Scheme 9).
methyl groups of the urea unit.
By contrast, lithiation of 27 followed by reaction with
benzophenone at 0 °C gave product 29, in which lithiation
and substitution had taken place on a methyl group of the
urea (Scheme 10), in 89% yield. No product was obtained
when the reaction was carried out at –78 °C.
Melting point determinations were performed by the open capillary
method using a Gallenkamp melting point apparatus and are report-
ed uncorrected. 1H and 13C NMR spectra were recorded on a Bruker
AV500 spectrometer operating at 500 MHz for 1H and 125 MHz for
13C measurements. Chemical shifts δ are reported in parts per mil-
lion (ppm) relative to TMS and coupling constants J are in Hz and
have been rounded to the nearest whole number. 13C multiplicities
were revealed by DEPT signals. Assignments of signals are based
on integration values, coupling patterns, and expected chemical
shift values, and have not been rigorously confirmed. Signals with
similar characteristics might be interchanged. Low-resolution mass
spectra were recorded on a Waters GCT Premier spectrometer and
high-resolution mass spectra were recorded on a Waters LCT Pre-
mier XE instrument. IR spectra were recorded on a Jasco FT/IR-660
plus instrument by dissolving the product in CHCl3, applying drop-
lets on a NaCl plate and allowing evaporation of the solvent. Col-
umn chromatography was carried out using Fischer Scientific silica
60A (35–70 micron). Alkyllithiums were obtained from Aldrich
These results illustrate how sensitive reactions of this na-
ture are to subtle variations in structure, method of gener-
ation of lithium compound and reaction conditions. For
the series of compounds Ph(CH2)nNHCONMe2, with n =
0–4, direct lithiation at –20 °C gives side-chain substitu-
tion on a methyl group of the urea unit for n = 0,7e ortho-
substitution at –78 °C for n = 1,9 and α-substitution for
n = 2 (this work) at –78 °C. Although α-substitution also
prevails for n = 3, a higher temperature during the lithia-
tion step is needed for a good yield, while no lithiation oc-
curs at –78 °C for n = 4 and at 0 °C lithiation occurs on an
N-methyl group. Similarly, conditions optimised for Br– Chemical Company and were estimated prior to use by the method
of Watson and Eastham.20 Other chemicals were obtained from Al-
Li exchange of 2-bromophenethyl derivative 13 produced
only a low yield of the corresponding product from 3-bro-
mophenethyl derivative 21, although the yield could be
drich Chemical Company and used without further purification.
Solvents were purified by standard procedures.21,22
improved substantially by varying the reaction conditions.
Optimisation of each of these cases is beyond the scope of
this work, but it is clear that it is important for researchers
to be aware of the need for such optimisation for any spe-
cific case of interest.
N′-Phenethyl-N,N-dimethylurea (2)
A stirred mixture of 1 (10.39 g, 85.8 mmol), dimethylcarbamoyl
chloride (DMCC, 10.37 g, 96.5 mmol) and Et3N (11.97 g, 118.3
mmol) in CH2Cl2 (100 mL) was heated under reflux for 1 h. The
mixture was allowed to cool and the solid formed was collected by
filtration and then washed with H2O (2 × 25 mL). The solid was pu-
rified by crystallisation from a mixture of EtOAc and Et2O (1:3 by
volume) to give pure 2; yield: 16.30 g (99%); colourless crystalline
solid; mp 88–90 °C (Lit.16a mp 81–82 °C, Lit.16b mp 98 °C).
In conclusion, simple and efficient procedures that allow
side-chain lithiation of N′-(phenylalkyl)-N,N-dimethyl-
ureas have been developed. Lithiation of N′-phenethyl-
N,N-dimethylurea took place at the CH2 group next to the
phenyl ring (α-lithiation) with three equivalents of tert-
butyllithium in tetrahydrofuran at –78 °C. Ring substitu-
tion could be achieved via bromine–lithium exchange of
N′-2-(2-bromophenyl)ethyl-N,N-dimethylurea using methyl-
lithium followed by tert-butyllithium in tetrahydrofuran
at –78 °C. Reactions of the dilithium reagents obtained
with a variety of electrophiles gave the corresponding α-
or 2-substituted derivatives in high yields. Similarly, lithi-
ation of N′-(3-phenylpropyl)-N,N-dimethylurea took
IR (FT): 3341, 2933, 1634, 1539, 1332, 1203 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.32–7.19 (m, 5 H, C6H5), 4.38 (br
s, 1 H, NH, exch.), 3.48 (app q, J = 7 Hz, 2 H, CH2 NH), 2.85 [s, 6
H, N(CH3)2], 2.82 (t, J = 7 Hz, 2 H, CH2Ph).
13C NMR (125 MHz, CDCl3): δ = 158.3 (s, C=O), 139.5 (s, C-1 of
C6H5), 128.8 (d, C-3/C-5 of C6H5), 128.5 (d, C-2/C-6 of C6H5),
126.3 (d, C-4 of C6H5), 42.1 (t, CH2NH), 36.5 (t, CH2Ph), 36.1 [q,
N(CH3)2].
MS (EI): m/z (%) = 192 (29, [M]+), 147 (8), 101 (42), 72 (100).
HRMS (EI): m/z [M]+ calcd for C11H16N2O: 192.1263; found:
192.1260.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2013–2022

2018
K. Smith et al.
PAPER
Substituted N′-Phenethyl-N,N-dimethylureas 5–11; General
Procedure
1H NMR (500 MHz, CDCl3): δ = 7.77–6.80 (m, 15 H, 3 C6H5), 6.38
(br s, 1 H, OH, exch.), 5.96 (t, J = 6 Hz, 1 H, NH, exch.), 4.28 (app
t, J = 7 Hz, 1 H, CH), 3.62 (m, 1 H, CHaHb), 3.26 (m, 1 H, CHaHb),
2.43 [s, 6 H, N(CH3)2].
13C NMR (125 MHz, CDCl3): δ = 158.6 (s, C=O), 148.2, 149.0,
141.6 (3 s, C-1 of 3 C6H5), 127.6, 127.9, 127.5 (3 d, C-3/C-5 of 3
C6H5), 126.2, 126.3, 126.0 (3 d, C-2/C-6 of 3 C6H5), 125.95, 125.92,
125.3 (3 d, C-4 of 3 C6H5), 79.0 (s, COH), 52.6 (d, CH), 43.6 (t,
CH2), 35.9 [q, N(CH3)2].
MS (EI): m/z (%) = 356 (40, [M – H2O]+), 311 (15), 256 (100), 192
(97).
HRMS (EI): m/z [M – H2O]+ calcd for C19H22N2O: 356.1889;
found: 356.1883.
A solution of t-BuLi in pentane (4.51 mL, 1.9 M, 8.60 mmol) was
added to a stirred solution of 2 (0.50 g, 2.60 mmol) at –78 °C in an-
hyd THF (20 mL) under a N2 atmosphere. The mixture was stirred
at –78 °C for 2 h and a solution of the electrophile (2.60 mmol), in
anhyd THF (8 mL) if solid, neat otherwise, was added. The reaction
mixture was stirred for 2 h at –78 °C, and then allowed to warm to
r.t. The mixture was quenched with a sat. aq NH4Cl (20 mL) and di-
luted with Et2O (20 mL). The organic layer was separated, washed
with H2O (2 × 20 mL), dried (MgSO4), and evaporated under re-
duced pressure. The crude product was purified by column chroma-
tography (silica gel; Et2O–hexane, 1:3) to give the pure products 5–
11. The yields obtained were in the range of 86–99% (Table 2).
N′-(3-Hydroxy-2,3-diphenylpropyl)-N,N-dimethylurea (5)
Product 5 was a mixture of two racemic diastereoisomers in approx-
imately equal proportions; yield: 0.75 g (97%); white solid; mp
180–184 °C.
N′-(3-Hydroxy-3-methyl-2-phenylbutyl)-N,N-dimethylurea (8)
Yield: 0.74 g (98%); white solid; mp 148–151 °C.
IR (FT): 3321, 2968, 1617, 1547, 1351, 1221 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.32–7.22 (m, 5 H, C6H5), 4.41 (br
s, 1 H, NH, exch.), 3.85 (dd, J = 6, 14 Hz, 1 H, CHaHb), 3.37 (dd,
J = 9, 14 Hz, 1 H, CHaHb), 2.73 (dd, J = 6, 9 Hz, 1 H, CH), 2.72 [s,
6 H, N(CH3)2], 1.23 (s, 3 H, CH3), 1.16 (s, 3 H, CH3).
13C NMR (125 MHz, CDCl3): δ = 158.6 (s, C=O), 140.4 (s, C-1 of
C6H5), 129.4 (d, C-3/C-5 of C6H5), 128.3 (d, C-2/C-6 of C6H5),
126.9 (d, C-4 of C6H5), 72.5 (s, COH), 56.5 (d, CH), 41.7 (t, CH2),
35.9 [q, N(CH3)2], 29.1, 27.6 (2 q, 2 CH3).
IR (FT): 3352, 2929, 1633, 1537, 1332, 1230 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.23–7.11 (m, 20 H, 4 C6H5), 6.25
(t, J = 7 Hz, 1 H, NH, exch.), 6.00 (t, J = 7 Hz, 1 H, NH, exch.), 5.72
(d, J = 4 Hz, 1 H, OH, exch.), 5.53 (d, J = 4 Hz, 1 H, OH, exch.),
4.94 (app t, J = 4 Hz, 1 H, CHOH), 4.81 (dd, J = 4, 7 Hz, 1 H,
CHOH), 3.58–3.49 (m, 2 H, 2 CHPh), 3.44 (dd, J = 7, 14 Hz, 1 H,
CHaHb), 3.28 (m, 1 H, CHaHb), 3.18 (dd, J = 7, 14 Hz, 1 H, CHaHb),
3.13–3.09 (m, 1 H, CHaHb), 2.77 [s, 6 H, N(CH3)2], 2.71 [s, 6 H,
N(CH3)2].
MS (EI): m/z (%) = 232 (25, [M – H2O]+), 217 (10), 192 (100).
13C NMR (125 MHz, CDCl3): δ = 159.1, 158.8 (2 s, 2 C=O), 144.7,
144.6, 142.0, 140.7 (4 s, C-1 of 4 C6H5), 129.8, 129.3, 128.1, 127.9
(4 d, C-3/C-5 of 4 C6H5), 127.9, 127.8, 127.1, 126.7 (4 d, C-2/C-6
of 4 C6H5), 126.9, 126.6 (2 d, C-4 of 4 C6H5), 75.8, 73.0 (2 d, 2
CHOH), 53.34, 53.32 (2 d, 2 CHPh), 43.5, 42.7 (2 t, 2 CH2), 36.3,
36.2 [2 q, 2 N(CH3)2].
HRMS (EI): m/z [M – H2O]+ calcd for C14H20N2O: 232.1576;
found: 232.1570.
N′-[2-(1-Hydroxycyclohexyl)-2-phenylethyl]-N,N-dimethyl-
urea (9)
Yield: 0.74 g (98%); white solid; mp 149–151 °C
IR (FT): 3358, 2931, 1634, 1538, 1380, 1228 cm–1.
MS (EI): m/z (%) = 298 (2, [M]+), 280 (20), 208 (32), 180 (100).
1H NMR (500 MHz, CDCl3): δ = 7.33–7.18 (m, 5 H, C6H5), 3.88
(dd, J = 5, 14 Hz, 1 H, CHaHb), 3.42 (dd, J = 9, 14 Hz, 1 H, CHaHb),
2.78 (dd, J = 5, 9 Hz, 1 H, CH), 2.64 [s, 6 H, N(CH3)2], 1.07–1.57
(m, 10 H, c-Hex).
13C NMR (125 MHz, CDCl3): δ = 158.6 (s, C=O), 140.1 (s, C-1 of
C6H5), 129.7 (d, C-3/C-5 of C6H5), 128.3 (d, C-2/C-6 of C6H5),
126.8 (d, C-4 of C6H5), 72.9 (s, C-1 of c-Hex), 55.5 (d, CH), 40.9 (t,
CH2), 36.2, 36.0 (2 t, C-3/C-5 of c-Hex), 35.9 [q, N(CH3)2], 25.6 (t,
C-4 of c-Hex), 21.9, 21.7 (2 t, C-2/C-6 of c-Hex).
HRMS (EI): m/z [M]+ calcd for C18H22N2O2: 298.1681; found:
298.1677.
N′-(3-Hydroxy-2,3-diphenylbutyl)-N,N-dimethylurea (6)
Product 6 was a mixture of two racemic diastereoisomers in approx-
imately equal proportions; yield: 0.78 g (96%); white solid; mp
131–135 °C.
IR (FT): 3365, 2928, 1615, 1537, 1367, 1222 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.44–7.13 (m, 20 H, 4 C6H5), 3.94
(br s, 1 H, NH, exch.), 4.82 (br s, 1 H, NH, exch.), 4.77 (dd, J = 4,
7 Hz, 1 H, CH), 3.78 (m, 1 H, CH), 3.52 (m, 1 H, CHaHb), 3.40 (m,
1 H, CHaHb), 3.31 (dd, J = 7, 14 Hz, 1 H, CHaHb), 3.18 (dd, J = 7,
14 Hz, 1 H, CHaHb), 2.83 [s, 6 H, N(CH3)2], 2.42 [s, 6 H, N(CH3)2],
1.10 (s, 3 H, CH3), 0.85 (s, 3 H, CH3).
MS (ES+): m/z (%) = 581 (48, [M + MH]+), 354 (55, [M +
MeCNNa]+), 313 (47, [M + Na]+), 291 (100, [MH]+), 272 (30).
HRMS (ES+): m/z [MH]+ calcd for C17H27N2O2: 291.2073; found:
291.2080.
13C NMR (125 MHz, CDCl3): δ = 159.9, 158.3 (2 s, 2 C=O), 149.0,
148.9, 140.5, 140.4 (4 s, C-1 of 4 C6H5), 129.7, 128.4, 128.35,
128.31 (4 d, C-3/C-5 of 4 C6H5), 127.89, 127.86, 127.5, 127.0 (4 d,
C-2/C-6 of 4 C6H5), 126.2, 125.9, 124.67, 124.62 (4 d, C-4 of 4
C6H5), 75.3, 75.0 (2 s, 2 COH), 56.3, 49.2 (2 d, 2 CH), 42.1, 42.0 (2
t, 2 CH2), 35.7, 36.3 [2 q, 2 N(CH3)2], 31.3, 31.1 (2 q, 2 CH3).
MS (EI): m/z (%) = 294 (40, [M – H2O]+), 279 (3), 208 (32), 192
(100).
HRMS (EI): m/z [M – H2O]+ calcd for C19H22N2O: 294.1732;
found: 294.1737.
N′-(2-Phenylbutyl)-N,N-dimethylurea (10)
Yield: 0.50 g (88%); yellow oil.
IR (FT): 3346, 2928, 1635, 1540, 1377, 1230 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.25–7.08 (m, 5 H, C6H5), 4.11 (br
s, 1 H, NH, exch.), 3.62 (m, 1 H, CHaHbNH), 3.06 (m, 1 H, CHaH-
bNH), 2.67 [s, 6 H, N(CH3)2], 2.60 (m, 1 H, CH), 1.65 (m, 1 H,
CHaHbCH3), 1.50 (m, 1 H, CHaHbCH3), 0.74 (t, J = 7 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): δ = 159.3 (s, C=O), 143.1 (s, C-1 of
C6H5), 128.6 (d, C-3/C-5 of C6H5), 127.8 (d, C-2/C-6 of C6H5),
126.5 (d, C-4 of C6H5), 48.0 (t, CH2), 46.3 (d, CH), 35.9 [q,
N(CH3)2], 26.5 (t, CH2CH3), 11.9 (q, CH3).
N′-(3-Hydroxy-2,3,3-triphenylpropyl)-N,N-dimethylurea (7)
Yield: 0.95 g (98%); white solid; mp 202–205 °C.
IR (FT): 3239, 2920, 1609, 1531, 1360, 1211 cm–1.
MS (ES+): m/z (%) = 463 (20, [2 M + Na]+), 243 (100, [M + Na]+),
221 (30, [MH]+).
HRMS (ES+): m/z [MH]+ calcd for C13H21N2O: 221.1646; found:
221.1654.
Synthesis 2012, 44, 2013–2022
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lithiation of N′-(ω-Phenylalkyl)-N,N-dimethylureas
2019
N′-(2-Deuterio-2-phenylethyl)-N,N-dimethylurea (11)
Yield: 0.50 g (99%); white solid; mp 89–90 °C (Lit.16a, undeuterated
analogue mp 81–82 °C; Lit.16b mp 98 °C).
IR (FT): 3342, 2932, 1634, 1538, 1382, 1231 cm–1.
127.6 (d, C-5), 127.0 (d, C-4 of 2 C6H5), 125.2 (d, C-3), 82.9 (s,
COH), 42.5 (t, CH2NH2), 36.0 [q, N(CH3)2], 34.3 (t, CH2Ar).
MS (EI): m/z (%) = 356 (90, [M – H2O]+), 312 (20), 279 (97), 255
(65), 191 (40), 178 (100), 165 (68), 105 (90).
1H NMR (500 MHz, CDCl3): δ = 7.24–7.11 (m, 5 H, C6H5), 4.38 (br
s, 1 H, NH, exch.), 3.40–3.38 (m, 2 H, CH2), 2.76 [s, 6 H, N(CH3)2],
2.72 (m, 1 H, CH).
13C NMR (125 MHz, CDCl3): δ = 158.4 (s, C=O), 139.4 (s, C-1 of
C6H5), 128.8 (d, C-3/C-5 of C6H5), 128.5 (d, C-2/C-6 of C6H5),
126.3 (d, C-4 of C6H5), 42.1 (t, CH2), 36.1 [q, N(CH3)2], 36.2 (seen
as three lines, 1:1:1, because of coupling to D, CH).
MS (EI): m/z (%) = 193 (48, [M]+), 180 (8), 101 (55), 83 (89), 72
(100).
HRMS (EI): m/z [M]+ calcd for C11H15DN2O: 193.1325; found:
193.1328.
HRMS (EI): m/z [M – H2O]+ calcd for C24H24N2O: 356.1889;
found: 356.1892.
N′-2-{2-[Hydroxy(phenyl)methyl]phenyl}ethyl-N,N-dimethyl-
urea (17)
Yield: 0.49 g (90%); white solid; mp 145–148 °C.
IR (FT): 3325, 2932, 1626, 1537, 1358, 1218 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.40–7.17 (m, 10 H, H-3, H-4, H-
5, H-6, C6H5, and OH), 6.17 (s, 1 H, CHOH), 4.66 (br s, 1 H, NH,
exch.), 3.52–3.39 (m, 2 H, CH2NH), 3.04 (m, 1 H, CHaHbAr), 2.83
[s, 6 H, N(CH3)2], 2.79 (m, 1 H, CHaHbAr).
13C NMR (125 MHz, CDCl3): δ = 158.6 (s, C=O), 143.7 (s, C-1 of
C6H5), 142.2 (s, C-1), 137.1 (s, C-2), 130.2 (d, C-6), 128.3 (d, C-3),
128.2 (d, C-3/C-5 of C6H5), 127.6 (d, C-4), 127.2 (d, C-4 of C6H5),
126.74 (d, C-5), 126.73 (d, C-2/C-6 of C6H5), 72.6 (d, CHOH), 42.0
(t, CH2NH2), 36.1 [q, N(CH3)2], 33.5 (t, CH2Ar).
N′-(2-Bromophenethyl)-N,N-dimethylurea (13)
The procedure was identical with that described for the synthesis of
2 in which a stirred mixture of 12 (8.00 g, 40.0 mmol), DMCC (5.37
g, 49.9 mmol), and Et3N (5.57 g, 55.0 mmol) in CH2Cl2 (60 mL)
was heated under reflux for 1 h. Following workup, the crude prod-
uct was purified by column chromatography (silica gel; Et2O) to
give pure 13; yield: 10.73 g (99%); yellow oil.
MS (ES–): m/z (%) = 335 (40), 333 (100, [M + Cl]–), 319 (1).
HRMS (ES–): m/z [M + Cl]– calcd for C18H2235ClN2O2: 333.1370;
found: 333.1384.
IR (FT): 3333, 2931, 1633, 1537, 1356, 1230 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.46 (d, J = 8 Hz, 1 H, H-3), 7.16–
7.19 (m 2 H, H-4, H-6), 7.01 (m, 1 H, H-5), 4.43 (br s, 1 H, NH,
exch.), 3.41 (app q, J = 7 Hz, 2 H, CH2 NH), 2.90 (t, J = 7 Hz, 2 H,
CH2Ar), 2.80 [s, 6 H, N(CH3)2].
N′-2-{2-[Hydroxy(4-methoxyphenyl)methyl]phenyl}ethyl-N,N-
dimethylurea (18)
Yield: 0.52 g (87%); white solid; mp 149–151 °C.
IR (FT): 3437, 2930, 1640, 1509, 1390, 1173 cm–1.
13C NMR (125 MHz, CDCl3): δ = 158.4 (s, C=O), 138.9 (s, C-1),
132.7 (d, C-3), 131.0 (d, C-6), 128.0 (d, C-4), 127.5 (d, C-5), 124.5
(s, C-2), 40.7 (t, CH2NH2), 36.5 (t, CH2Ar), 36.1 [q, N(CH3)2].
1H NMR (500 MHz, CDCl3): δ = 7.34–7.16 (m, 7 H, H-3, H-4, H-
5, H-6, H-2/H-6 of 4-MeOC6H4, and OH), 6.87 (d, J = 9 Hz, 2 H, H-
3/H-5 of 4-MeOC6H4), 6.11 (s, 1 H, CHOH), 4.63 (br s, 1 H, NH,
exch.), 3.81 (s, 3 H, OCH3), 3.48–3.40 (m, 2 H, CH2NH), 3.01 (m,
1 H, CHaHbAr), 2.83 [s, 6 H, N(CH3)2], 2.79 (m, 1 H, CHaHbAr).
MS (EI): m/z (%) = 273 (4, [M81Br + H]+), 271 (4, [M79Br + H]+),
192 (100, [M – 79Br]+), 171 (98), 146 (10), 101 (97).
13C NMR (125 MHz, CDCl3): δ = 158.8 (s, C-4 of 4-MeOC6H4),
158.6 (s, C=O), 142.3 (s, C-1), 137.0 (s, C-1 of 4-MeOC6H4), 135.9
(s, C-2), 130.2 (d, C-6), 128.0 (d, C-2/C-6 of 4-MeOC6H4), 127.9
(d, C-3), 127.5 (d, C-4), 126.6 (d, C-5), 113.7 (d, C-3/C-5 of 4-
MeOC6H4), 72.3 (d, CHOH), 55.2 (q, OCH3), 41.9 (t, CH2NH2),
36.1 [q, N(CH3)2], 33.3 (t, CH2Ar).
MS (ES–): m/z (%) = 365 (38), 363 (100, [M + Cl]–), 349 (1).
HRMS (ES–): m/z [M + Cl]– calcd for C19H2435ClN2O3: 363.1475;
HRMS (EI): m/z [M + H]+ calcd for C11H1679BrN2O: 271.0446;
found: 271.0441.
N′-2-(2-Substituted Phenyl)ethyl-N,N-dimethylureas 16–20;
General Procedure
A solution of MeLi in Et2O (1.38 mL, 1.6 M, 2.2 mmol) was added
to a stirred solution of 13 (0.50 g, 1.84 mmol) at –78 °C in anhyd
THF (20 mL) under a N2 atmosphere. The mixture was stirred for
10 min after which a solution of t-BuLi in pentane (2.42 mL, 1.9 M,
4.6 mmol) was added. The mixture was stirred at –78 °C for 15 min
and a solution of the electrophile (7.36 mmol), in anhyd THF (8 mL)
if solid, neat otherwise, was added. The cooling bath was removed
and the reaction mixture was stirred for 2 h at r.t. The mixture was
quenched with a sat. aq NH4Cl (20 mL) and diluted with Et2O (20
mL). The organic layer was separated, washed with H2O (2 × 20
mL), dried (MgSO4), and evaporated under reduced pressure. The
crude product was purified by column chromatography (silica gel;
Et2O–hexane, 1:3) to give the pure products 16–20. The yields ob-
tained were in the range of 86–98% (Table 4).
found: 363.1480.
N′-2-(2-Deuteriophenyl)ethyl-N,N-dimethylurea (19)
Yield: 0.34 g (98%); white solid; mp 89–91 °C (Lit.16a, undeuterated
analogue mp 81–82 °C; Lit.16b mp 98 °C).
IR (FT): 3337, 2929, 1634, 1539, 1357, 1231 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.33–7.20 (m, 4 H, H-3, H-4, H-
5, H-6), 4.46 (br s, 1 H, NH, exch.), 3.49 (t, J = 7 Hz, 2 H, CH2NH),
2.85 [s, 6 H, N(CH3)2], 2.83 (t, J = 7 Hz, 2 H, CH2Ar).
13C NMR (125 MHz, CDCl3): δ = 158.3 (s, C=O), 139.4 (s, C-1),
128.8 (d, C-5), 128.54 (d, C-3), 128.52 (seen as three lines, 1:1:1,
because of coupling to D, C-2), 128.4 (d, C-6), 126.3 (d, C-4), 42.1
(t, CH2NH), 36.4 (t, CH2Ar), 36.0 [q, N(CH3)2].
N′-[2-(Hydroxydiphenylmethyl)-2-phenyl]ethyl-N,N-dimethyl-
urea (16)
Yield: 0.65 g (95%); white solid; mp 186–188 °C.
IR (FT): 3348, 2925, 1624, 1541, 1334, 1191 cm–1.
MS (EI): m/z (%) = 193 (90, [M]+), 148 (28), 101 (93), 72 (100).
1H NMR (500 MHz, CDCl3): δ = 7.33–7.22 (m, 13 H, 2 C6H5, H-4,
H-5, and OH), 7.02 (m, 1 H, H-6), 6.63 (d, J = 8 Hz, 1 H, H-3), 4.93
(br s, 1 H, NH, exch.), 3.37 (app q, J = 7 Hz, 2 H, CH2NH), 2.81 [s,
6 H, N(CH3)2], 2.68 (t, J = 7 Hz, 2 H, CH2Ar).
13C NMR (125 MHz, CDCl3): δ = 158.7 (s, C=O), 147.6 (s, C-1 of
2 C6H5), 145.4 (s, C-2), 139.2 (s, C-1), 131.8 (d, C-6), 130.0 (d, C-
4), 127.81 (d, C-2/C-6 of 2 C6H5), 127.83 (d, C-3/C-5 of 2 C6H5),
HRMS (EI): m/z [M]+ calcd for C11H15DN2O: 193.1325; found:
193.1329.
N′-Ethyl-N′-2-(2-ethylphenyl)ethyl-N,N-dimethylurea (20)
Yield: 0.39 g (86%); yellow oil.
IR (FT): 2965, 1646, 1489, 1354, 1230 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.12–7.02 (m, 4 H, H-3, H-4, H-
5, H-6), 3.20 (t, J = 7 Hz, 2 H, ArCH2CH2N), 3.13 (q, J = 7 Hz, 2 H,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2013–2022

2020
K. Smith et al.
PAPER
CH3CH2N), 2.77 (t, J = 8 Hz, 2 H, ArCH2CH2N), 2.73 [s, 6 H,
N(CH3)2], 2.62 (q, J = 7 Hz, 2 H, ArCH2CH3), 1.16 (t, J = 7 Hz, 3
H, CH3CH2N), 1.04 (t, J = 7 Hz, 3 H, ArCH2CH3).
13C NMR (125 MHz, CDCl3): δ = 165.2 (s, C=O), 142.2 (s, C-1),
137.1 (s, C-2), 129.7 (d, C-6), 128.4 (d, C-3), 126.5 (d, C-4), 125.8
(d, C-5), 48.9 (t, ArCH2CH2N), 43.5 (t, CH3CH2N), 38.6 [q,
N(CH3)2], 31.2 (t, ArCH2CH2N), 25.4 (t, ArCH2CH3), 15.5 (q,
ArCH2CH3), 13.3 (q, CH3CH2N).
MS (ES): m/z (%) = 519 (100, [2 M + Na]+), 312 (50, [M +
MeCNNa]+), 287 (5, [M + K]+), 271 (23, [M + Na]+), 249 (15,
[MH]+).
HRMS (ES): m/z [MH]+ calcd for C15H25N2O: 249.1967; found:
249.1959.
N′-(Substituted Phenyl)-N,N-dimethylureas 26 and 27
The procedure was identical with that described for the synthesis of
2 except that a stirred mixture of 24 or 25 (63.75 mmol), DMCC
(8.75 g, 81.36 mmol), Et3N (9.05 g, 89.44 mmol) in CH2Cl2 (50 mL)
was heated under reflux for 1 h. Following workup the crude prod-
uct was purified by column chromatography (silica gel; Et2O) to
give pure products.
N′-(3-Phenylpropyl)-N,N-dimethylurea (26)
Yield: 12.36 g (94%); white crystals; mp 72–74 °C.
IR (FT): 3374, 2934, 1630, 1496, 1379, 1245 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.17–7.14 (m, 2 H, H-3, H-5), 7.0–
7.05 (m, 3 H, H-2, H-4, H-6), 4.61 (br s, 1 H, NH, exch.), 3.15 (t,
J = 7.4 Hz, 2 H, CH2NH), 2.71 [s, 6 H, N(CH3)2], 2.54 (t, J = 7.4 Hz,
2 H, CH2Ph), 1.74 (pent, J = 7.4 Hz, 2 H, CH2CH2CH2).
13C NMR (125 MHz, CDCl3): δ = 158.5 (s, C=O), 141.9 (s, C-1),
128.38 (d, C-3/C-5), 128.36 (d, C-2/C-6), 125.8 (d, C-4), 40.7 (t,
CH2NH2), 36.0 [q, N(CH3)2], 33.5 (t, CH2Ph), 31.9 (t,
CH2CH2CH2).
MS (EI): m/z (%) = 206 ([M]+, 47), 162 (49), 117 (49), 102 (47), 91
(69), 72 (100).
HRMS (EI): m/z [M]+ calcd for C12H18N2O: 206.1419; found:
206.1418.
N′-2-(3-Bromophenyl)ethyl-N,N-dimethylurea (22)
The procedure was identical to that described for the synthesis of 2
except that it involved stirring a mixture of 21 (5.00 g, 25.1 mmol),
DMCC (3.44 g, 32.1 mmol), and Et3N (3.56 g, 35.3 mmol) in
CH2Cl2 (30 mL) under reflux for 1 h. Following workup, the crude
product was purified by crystallisation from a mixture of hexane
and Et2O (3:1 by volume) to give pure 22; yield: 6.65 g (98%);
white crystalline solid; mp 62–64 °C.
IR (FT): 3337 2928, 1635, 1538, 1356, 1230, 1071 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.36 (m, 2 H, H-2, H-4),
7.20–7.13 (m, 2 H, H-5, H-6), 4.42 (br s, 1 H, NH, exch.), 3.47 (app
q, J = 7.0 Hz, 2 H, CH2NH), 2.88 [s, 6 H, N(CH3)2], 2.80 (t, J = 7.0
Hz, 2 H, CH2Ar).
N′-(4-Phenylbutyl)-N,N-dimethylurea (27)
Yield: 12.63 g (90%); yellow oil.
IR (FT): 3340, 2931, 1617, 1453, 1377, 1234 cm–1.
13C NMR (125 MHz, CDCl3): δ = 158.2 (s, C=O), 141.9 (s, C-1),
131.9 (d, C-2), 130.1 (d, C-4), 129.4 (d, C-6), 127.5 (d, C-5), 122.5
(s, C-3), 41.9 (t, CH2NH), 36.2 [q, N(CH3)2], 36.1 (t, CH2Ar).
MS (ES+): m/z (%) = 272 ([M81Br]+, 100), 270 ([M79Br]+, 98), 227
(12), 225 (14).
HRMS (ES+): m/z [M]+ calcd for C11H1579BrN2O: 270.0368; found:
270.0359.
1H NMR (500 MHz, CDCl3): δ = 7.17–7.13 (m, 2 H, H-3, H-5),
7.06–7.03 (m, 3 H, H-2, H-4, H-6), 4.72 (br s, 1 H, NH, exch.), 3.10
(app q, J = 7.6 Hz, 2 H, CH2NH), 2.74 [s, 6 H, N(CH3)2], 2.51 (t, J =
7.6 Hz, 2 H, CH2Ph), 1.53 (m, 2 H, CH2CH2Ph), 1.42 (m, 2 H,
CH2CH2NH2).
13C NMR (125 MHz, CDCl3): δ = 158.7 (s, C=O), 142.3 (s, C-1),
128.3 (d, C-3/C-5), 128.2 (d, C-2/C-6), 125.7 (d, C-4), 40.7 (t,
CH2NH2), 36.1 [q, N(CH3)2], 35.6 (t, CH2Ph), 33.0 (t,
CH2CH2NH2), 28.7 (t, CH2CH2Ph).
MS (EI): m/z (%) = 220 ([M]+, 54), 175 (54), 146 (15), 130 (35), 116
(94), 104 (90), 91 (100), 72 (97).
HRMS (EI): m/z [M]+ calcd for C13H20N2O: 220.1576; found:
220.1580.
Lithiation and Substitution of N′-2-(3-Bromophenyl)ethyl-N,N-
dimethylurea (22)
The procedure was identical with that described for the bromine–
lithium exchange of 13 except that it involved 22 (0.36 g, 1.33
mmol) and the reaction time was varied. Following workup the
crude product was purified by column chromatography (silica gel;
Et2O) to give the pure products 7 (13–85%) and 23 (13–58%). Prod-
uct 7 was consistent in all respect with the one produced by direct
lithiation of 2 followed by reaction with benzophenone.
Lithiation and Substitution of N′-(w-Phenylalkyl)-N,N-dimeth-
ylureas 26 and 27
The procedure was identical with that described for lithiation and
substitution of 2 except involving 26 or 27 (2.60 mmol), with ben-
zophenone (0.47 g, 2.60 mmol) as the electrophile and carried out
at 0 or 20 °C. Following workup, the crude product was purified by
column chromatography (silica gel; Et2O) to give the pure products
28 or 29.
N′-2-[3-(Hydroxydiphenylmethyl)phenyl]ethyl-N,N-dimethyl-
urea (23)
Yield: 0.065–0.29 g (13–58%); white solid; mp 174–176 °C.
IR (FT): 3348, 2930, 1634, 1532, 1357, 1219, 1032 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.25–7.13 (m, 12 H, 2 C6H5, H-5,
and OH), 7.12 (s, 1 H, H-2), 7.01–6.99 (m, 2 H, H-4, H-6), 4.20 (br
s, 1 H, NH, exch.), 3.35 (app q, J = 7 Hz, 2 H, CH2NH), 2.69 [s, 6
H, N(CH3)2], 2.68 (t, J = 7 Hz, 2 H, CH2Ar).
N′-(4-Hydroxy-3,4,4-triphenylbutyl)-N,N-dimethylurea (28)
Yield: 0.86–0.89 g (85–89%); white solid; mp 229–231 °C.
IR (FT): 3349, 2928, 1636, 1492, 1360, 1221 cm–1.
13C NMR (125 MHz, CDCl3): δ = 158.3 (s, C=O), 147.2 (s, C-3),
146.9 (s, C-1 of 2 C6H5), 139.2 (s, C-1), 128.2 (d, C-5), 128.0 (d, C-
2), 127.95 (d, C-3/C-5 of 2 C6H5), 127.90 (d, C-2/C-6 of 2 C6H5),
127.4 (d, C-4), 127.3 (d, C-4 of 2 C6H5), 126.2 (d, C-6), 81.9 (s,
COH), 42.0 (t, CH2NH), 36.5 (t, CH2Ar), 36.0 [q, N(CH3)2].
MS (ES+): m/z (%) = 375 ([M + H] +, 4), 357 ([M – OH] +, 80), 193
(100), 142 (10), 104 (18).
1H NMR (500 MHz, CDCl3): δ = 7.53–6.91 (m, 16 H, 3 C6H5 and
OH), 4.00 (br s, 1 H, NH, exch.), 3.73 (dd, J = 2.7, 11 Hz, 1 H, CH),
3.14 (m, 1 H, CHaHbNH), 3.03 (m, 1 H, CHaHbNH), 2.61 [s, 6 H,
N(CH3)2], 2.06–1.92 (m, 2 H, CH2CH).
13C NMR (125 MHz, CDCl3): δ = 158.1 (s, C=O), 145.9, 145.8 (2
s, C-1 of 2 C6H5), 140.0 (s, C-1), 130.5, 128.4 (2 d, C-3/C-5 of 2
C6H5), 128.0, 127.7 (2 d, C-2/C-6 of 2 C6H5), 126.9 (d, C-3/C-5),
126.7 (d, C-2/C-6), 126.2 (d, C-4 and C-4 of one C6H5), 125.7 (d,
C-4 of other C6H5), 81.0 (s, C–OH), 52.6 (d, CH), 40.2 (t, CH2NH),
36.0 [q, N(CH3)2], 31.1 (t, CH2CH).
HRMS (ES+): m/z calcd for C24H25N2O ([M – OH]+), 357.1967;
found, 357.1978.
MS (EI): m/z (%) = 370 (5, [M – H2O]+), 325 (28), 269 (30), 207
(53), 194 (90), 182 (93), 152 (46), 105 (100), 77 (97).
Synthesis 2012, 44, 2013–2022
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lithiation of N′-(ω-Phenylalkyl)-N,N-dimethylureas
2021
HRMS (EI): m/z [M – H2O]+ calcd for C25H26N2O: 370.2045;
found: 370.2034.
(5) See, for example: (a) Clayden, J.; Turner, H.; Pickworth, M.;
Adler, T. Org. Lett. 2005, 7, 3147. (b) Clayden, J.; Dufour,
J. Tetrahedron Lett. 2006, 47, 6945. (c) Burgos, P. O.;
Fernández, I.; Iglesias, M. J.; García-Granda, S.; Ortiz, F. L.
Org. Lett. 2008, 10, 537. (d) Porcs-Makkay, M.; Komáromi,
A.; Lukács, G.; Simig, G. Tetrahedron 2008, 64, 1029.
(e) Michon, C.; Murai, M.; Nakatsu, M.; Uenishi, J.;
Uemura, M. Tetrahedron 2009, 65, 752. (f) Tilly, D.; Fu, J.-
M.; Zhao, B.-P.; Alessi, M.; Castanet, A.-S.; Snieckus, V.;
Mortier, J. Org. Lett. 2010, 12, 68. (g) Slocum, D. W.;
Wang, S.; White, C. B.; Whitley, P. E. Tetrahedron 2010,
66, 4939. (h) Cho, I.; Meimetis, L.; Belding, L.; Katz, M. J.;
Dudding, T.; Britton, R. Beilstein J. Org. Chem. 2011, 7,
1315. (i) Schmid, M.; Waldner, B.; Schnürch, M.;
Mihovilovic, M. D.; Stanetty, P. Tetrahedron 2011, 67,
2895.
(6) See, for example: (a) Robert, N.; Bonneau, A.-L.; Hoarau,
C.; Marsais, F. Org. Lett. 2006, 8, 6071. (b) Comoy, C.;
Banaszak, E.; Fort, Y. Tetrahedron 2006, 62, 6036.
(c) Luisi, R.; Capriati, V.; Florio, S.; Musio, B. Org. Lett.
2007, 9, 1263. (d) Clayden, J.; Hennecke, U. Org. Lett.
2008, 10, 3567. (e) McLaughlin, M.; Marcantonio, K.;
Chen, C.; Davies, I. W. J. Org. Chem. 2008, 73, 4309.
(f) Capriati, V.; Florio, S.; Luisi, R.; Mazzanti, A.; Musio, B.
J. Org. Chem. 2008, 73, 3197. (g) Affortunato, F.; Florio, S.;
Luisi, R.; Musio, B. J. Org. Chem. 2008, 73, 9214.
(h) Musio, B.; Clarkson, G. J.; Shipman, M.; Florio, S.;
Luisi, R. Org. Lett. 2009, 11, 325. (i) Clayton, J.; Clayden, J.
Tetrahedron Lett. 2011, 52, 2436. (j) Ibrahim, N.; Chevot,
F.; Legraverend, M. Tetrahedron Lett. 2011, 52, 305.
(7) (a) Smith, K.; El-Hiti, G. A.; Abdo, M. A.; Abdel-Megeed,
M. F. J. Chem. Soc., Perkin Trans. 1 1995, 1029. (b) Smith,
K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M. A.
J. Org. Chem. 1996, 61, 647. (c) Smith, K.; El-Hiti, G. A.;
Abdel-Megeed, M. F.; Abdo, M. A. J. Org. Chem. 1996, 61,
656. (d) Smith, K.; El-Hiti, G. A.; Pritchard, G. J.; Hamilton,
A. J. Chem. Soc., Perkin Trans. 1 1999, 2299. (e) Smith, K.;
El-Hiti, G. A.; Shukla, A. P. J. Chem. Soc., Perkin Trans. 1
1999, 2305. (f) Smith, K.; El-Hiti, G. A.; Hawes, A. C.
Synthesis 2003, 2047. (g) Smith, K.; El-Hiti, G. A.;
Mahgoub, S. A. Synthesis 2003, 2345. (h) El-Hiti, G. A.
Synthesis 2003, 2799. (i) Smith, K.; El-Hiti, G. A.; Abdel-
Megeed, M. F. Synthesis 2004, 2121. (j) El-Hiti, G. A.
Synthesis 2004, 363. (k) Smith, K.; El-Hiti, G. A.; Hegazy,
A. S. J. Sulfur Chem. 2005, 26, 121. (l) Smith, K.; El-Hiti,
G. A.; Hegazy, A. S. Synthesis 2005, 2951. (m) Smith, K.;
Barratt, M. L. J. Org. Chem. 2007, 72, 1031.
N′-(2-Hydroxy-2,2-diphenylethyl)-N′-methyl-N-(4-phenylbu-
tyl)urea (29)
Yield: 0.93 g (89%); yellow oil.
IR (FT): 3348, 2934, 1601, 1543, 1318, 1217 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.33 (dd, J = 1, 8 Hz, 4 H, H-2 and
H-6 of 2 C6H5), 7.18–7.03 (m, 11 H, H-2, H-3, H-4, H-5, H-6, and
H-3/H-4/H-5 of 2 C6H5), 6.05 (s, 1 H, OH, exch.), 4.34 (br s, 1 H,
NH, exch.), 3.98 (s, 2 H, CH2COH), 3.11 (app q, J = 7.6 Hz, 2 H,
CH2NH), 2.51 (t, J = 7.6 Hz, 2 H, CH2Ph), 2.17 (s, 3 H, NCH3), 1.51
(m, 2 H, CH2CH2Ph), 1.39 (m, 2 H, CH2CH2NH).
13C NMR (125 MHz, CDCl3): δ = 160.7 (s, C=O), 145.8 (s, C-1 of
2 C6H5), 142.2 (s, C-1), 128.4 (d, C-3/C-5), 128.3 (d, C-2/C-6),
128.0 (d, C-3/C-5 of 2 C6H5), 126.9 (d, C-4 of 2 C6H5), 126.6 (d, C-
2/C-6 of 2 C6H5), 125.8 (d, C-4), 78.6 (s, COH), 61.0 (t, CH2COH),
40.9 (t, CH2NH), 36.9 (t, CH2Ph), 35.5 (q, NCH3), 29.8 (t,
CH2CH2NH2), 28.5 (t, CH2CH2Ph).
MS (EI): m/z (%) = 403 ([M + H]+, 100), 385 (98), 305 (25), 234
(25), 210 (59), 191 (68).
HRMS (EI): m/z [M]+ calcd for C26H31N2O2: 403.2386; found:
403.2402.
Acknowledgment
We thank Cardiff University and the Saudi Government for finan-
cial support.
References
(1) Permanent address: G. A. El-Hiti, Department of Chemistry,
Faculty of Science, Tanta University, Tanta 31527, Egypt.
(2) See, for example: (a) Clayden, J. Organolithiums:
Selectivity for Synthesis; Pergamon: Oxford, 2002.
(b) Schlosser, M. Organometallics in Synthesis, 2nd ed.;
Wiley: Chichester, 2002, 1–352.
(3) See, for example: (a) Gschwend, H. W.; Hamdan, A. J. Org.
Chem. 1975, 40, 2008. (b) Fitt, J. J.; Gschwend, H. W.
J. Org. Chem. 1976, 41, 4029. (c) Fuhrer, W.; Gschwend, H.
W. J. Org. Chem. 1979, 44, 1133. (d) Beak, P.; Snieckus, V.
Acc. Chem. Res. 1982, 15, 306. (e) Nájera, C.; Sansano, J.
M.; Yus, M. Tetrahedron 2003, 59, 9255. (f) Whisler, M. C.;
MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed.
2004, 43, 2206. (g) Chadwick, S. T.; Ramirez, A.; Gupta, L.;
Collum, D. B. J. Am. Chem. Soc. 2007, 129, 2259.
(4) See for example: (a) Beak, P.; Zajdel, W. J.; Reitz, D. B.
Chem. Rev. 1984, 84, 471. (b) Snieckus, V. Chem. Rev.
1990, 90, 879. (c) El-Hiti, G. A. Heterocycles 2000, 53,
1839. (d) Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57,
4059. (e) Turck, A.; Plé, N.; Mongin, F.; Quéguiner, G.
Tetrahedron 2001, 57, 4489. (f) Anctil, E. J.-G.; Snieckus,
V. J. Organomet. Chem. 2002, 653, 150. (g) Smith, K.; El-
Hiti, G. A. Curr. Org. Synth. 2004, 1, 253. (h) Chinchilla, R.;
Nájera, C.; Yus, M. Chem. Rev. 2004, 104, 2667.
(8) Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synlett 2009, 2242.
(9) Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Fekri, A.; Kariuki,
B. M. ARKIVOC 2009, (xiv), 266.
(10) Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synthesis 2010,
1371.
(11) Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Fekri, A.
Heterocycles 2010, 80, 941.
(12) Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Chem. Commun.
2010, 46, 2790.
(13) Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Kariuki, B. M.
Beilstein J. Org. Chem. 2011, 7, 1219.
(i) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376.
(j) Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9, 459.
(k) Rathman, T. L.; Bailey, W. F. Org. Process Res. Dev.
2009, 13, 144. (l) Florio, S.; Aggarwal, V.; Salomone, A.
Org. Lett. 2004, 6, 4191. (m) Capriati, V.; Florio, S.; Luisi,
R. Chem. Rev. 2008, 108, 1918. (n) Capriati, V.; Florio, S.;
Salomone, A. Top. Stereochem. 2010, 26, 135. (o) Houlden,
C. E.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett.
2010, 12, 3090.
(14) Simig, G.; Schlosser, M. Tetrahedron Lett. 1991, 32, 1963.
(15) Schlosser, M.; Simig, G. Tetrahedron Lett. 1991, 32, 1965.
(16) (a) Wilson, A. A.; Garcia, A.; Houle, S.; Sadovski, O.;
Vasdev, N. Chem.–Eur. J. 2011, 17, 259. (b) Borgna, P.;
Vicarini, L.; Calderara, G. Farmaco 1979, 33, 510.
(17) Beak, P.; Musick, T. J.; Liu, C.; Cooper, T.; Gallagher, D. J.
J. Org. Chem. 1993, 58, 7330.
(18) Kato, S.; Nonoyama, N.; Tomimoto, K.; Mase, T.
Tetrahedron Lett. 2002, 43, 7315.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2013–2022

2022
K. Smith et al.
PAPER
(19) Yamamoto, Y.; Maeda, K.; Tomimoto, K.; Mase, T. Synlett
(21) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell,
A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th
ed.; Longman: Harlow, 1989.
2002, 561.
(20) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9,
165.
(22) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
Synthesis 2012, 44, 2013–2022
© Georg Thieme Verlag Stuttgart · New York