Directed lithiation of N′-[2-(4-methoxyphenyl)ethyl]-N, N-dimethylurea and tert-butyl [2-(4-methoxyphenyl)ethyl]carbamate

Article abstract of DOI:10.1055/s-0033-1338570

N′-[2-(4-Methoxyphenyl)ethyl]-N,N-dimethylurea and tert-butyl [2-(4-methoxyphenyl)ethyl]carbamate are doubly lithiated on the nitrogen and ortho to the directing metalating group at -20 to 0 °C with three mole equivalents of n-BuLi in anhydrous THF. Reactions of the dilithium reagents produced in situ with various electrophiles give high yields of the corresponding substituted products. In the case of the urea, side-products due to lithiation and substitution on one of the methyl groups of the urea unit are obtained in low yields (0-17%). Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338570

394▌
PAPER
paper
Directed Lithiation of N′-[2-(4-Methoxyphenyl)ethyl]-N,N-dimethylurea and
tert-Butyl [2-(4-Methoxyphenyl)ethyl]carbamate
Lithiation of Methoxyphenethylamine Urea and Carbamate Compounds
Keith Smith,*a Gamal A. El-Hiti,*b Mohammed B. Alshammaria,1
a
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20870600; E-mail: smithk13@cardiff.ac.uk
b
Department of Optometry, College of Applied Medical Sciences, King Saud University, P. O. Box 10219, Riyadh 11433, Saudi Arabia
Fax +966(11)4693536; E-mail: gelhiti@ksu.edu.sa
Received: 31.10.2013; Accepted: 11.11.2013
Simig and Schlosser.12 They found that lithiation of 1 us-
Abstract: N′-[2-(4-Methoxyphenyl)ethyl]-N,N-dimethylurea and
ing t-BuLi at –75 to –50 °C, followed by treatment with
tert-butyl [2-(4-methoxyphenyl)ethyl]carbamate are doubly lithiat-
carbon dioxide, resulted in carboxylation at the CH2 next
to the 4-methoxyphenyl ring (α-lithiation) to give 2 in
ed on the nitrogen and ortho to the directing metalating group at
–20 to 0 °C with three mole equivalents of n-BuLi in anhydrous
THF. Reactions of the dilithium reagents produced in situ with var- 79% yield (Scheme 1).
ious electrophiles give high yields of the corresponding substituted
products. In the case of the urea, side-products due to lithiation and
substitution on one of the methyl groups of the urea unit are ob-
tained in low yields (0–17%).
CO2H
H
H
1) t-BuLi (3.0 equiv), THF
–75 to –50 °C, 3 h
2) CO2
N
t-Bu
N
t-Bu
O
O
MeO
MeO
Key words: directed lithiation, side-chain lithiation, N′-[2-(4-me-
thoxyphenyl)ethyl]-N,N-dimethylurea, tert-butyl [2-(4-methoxy-
phenyl)ethyl]carbamate, electrophile
3) dilute HCl
1
2 (79%)
Scheme 1 Lithiation of 1 followed by reaction with CO2 as reported
by Simig and Schlosser12
Many biologically active compounds, such as dopamine,
adrenaline, and mescaline, possess a phenylethylamine
unit bearing an oxygen substituent on the phenyl ring, and
selective methods for synthesis of such derivatives are of
considerable interest. Lithiation reactions2,3 can be impor-
tant in the development of clean and environmentally
friendly processes for the regioselective substitution of
aromatic compounds. In particular, lithiation often takes
place proximal to a directing metalating group (DMG),
which typically possess an oxygen or nitrogen atom.4 Use
of such DMGs to facilitate lithiation, followed by reac-
tions of the organolithium intermediates obtained in situ
with electrophiles, has therefore found wide application in
a variety of synthetic transformations to produce substi-
tuted aromatics or heterocycles.5,6
We wished to investigate the possibility of ring lithiation
of N′-[2-(4-methoxyphenyl)ethyl]-N,N-dimethylurea and
tert-butyl [2-(4-methoxyphenyl)ethyl]carbamate under
similar reaction conditions to those used with the pival-
amide, since such derivatives do not necessarily behave in
a similar manner. We now report that we have been able
to establish conditions for a high-yielding and general
ring-substitution process.
2-(4-Methoxyphenyl)ethanamine (4) was synthesized
from the corresponding nitrile 3 based on a literature pro-
cedure.13 Reduction of 3 with lithium aluminum hydride
(2.2 equiv) in the presence of aluminum chloride (0.75
equiv) in diethyl ether at room temperature overnight pro-
vided 4 in 96% yield without the need of further purifica-
tion (Scheme 2).
In connection with other work on the use of lithium re-
agents in organic synthesis,7,8 we have reported a detailed
study of the regioselective lithiation and substitution of
various substituted phenylamines and benzylamines,9,10 in
which different products were sometimes formed, de-
pending on the nature of the lithium reagent used, the na-
ture of the directing group, and/or the reaction conditions.
NH2
CN
LiAlH4, AlCl3, Et2O
r.t, overnight
MeO
MeO
4 (96%)
3
Scheme 2 Synthesis of 2-(4-methoxyphenyl)ethanamine (4)
Recently, we have been interested in regioselective lithia-
tion and substitution of phenethylamine derivatives and
found that directed lithiation of N-[2-(4-methoxyphe-
nyl)ethyl]pivalamide (1) with n-BuLi at –20 to 0 °C in
THF occurred smoothly and cleanly on the ring next to the
DMG.11 This is in sharp contrast with results reported by
N′-[2-(4-Methoxyphenyl)ethyl]-N,N-dimethylurea
(5)
and tert-butyl [2-(4-methoxyphenyl)ethyl]carbamate (6)
were synthesized, in 97 and 92% yield, respectively,
based on a literature procedure for analogous compounds7
involving the reaction of 4 with dimethylcarbamoyl chlo-
ride or di-tert-butyl dicarbonate in dichloromethane in the
presence of triethylamine for one hour under reflux
(Scheme 3).
SYNTHESIS 2014, 46, 0394–0402
Advanced online publication: 04.12.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338570; Art ID: SS-2013-Z0717-OP
© Georg Thieme Verlag Stuttgart · New York

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Lithiation of Methoxyphenethylamine Urea and Carbamate Compounds
395
Me
N
Me
N
OH
Ph
Me
N
H
N
Li
Ph
N
N
Me
OLi
O
OLi
MeO
MeO
MeO
7
8
9
Figure 1 Structures of compound 7 and lithium intermediates 8 and 9
H
NH2
N
R
RCOCl or (RCO)2O
CH2Cl2, Et3N, 1 h
O
MeO
MeO
4
5 R = NMe2 (97%)
6 R = t-BuO (92%)
Scheme 3 Synthesis of substituted 2-(4-methoxyphenyl)ethan-
amines 5 and 6
Initially, 5 was lithiated with n-BuLi (3 molar equiv) in
anhydrous THF under a nitrogen atmosphere at –78 °C for
two hours, then benzophenone (1.4 mol equiv) was added.
Following workup, the starting material was recovered
quantitatively, indicating that no C-lithiation had taken
place under such conditions. The reaction was repeated
with t-BuLi under identical conditions. The crude product
was separated by column chromatography to give a new
product, N-(2-hydroxy-2,2-diphenylethyl)-N′-[2-(4-meth-
oxyphenyl)ethyl]-N-methylurea (7, Figure 1), obtained in
5% yield along with recovered 5 (89%). Compound 7 was
clearly obtained via the intermediacy of dilithium species
9, produced in situ from lithium reagent 8 (Figure 1).
Figure 3 X-ray crystal structure of compound 10
Some general trends can be deduced from the results in
Table 1. At low temperature (–78 °C), no lithiation takes
place with n-BuLi and only a low yield of lithiation–
substitution product (specifically 7) is obtained after two
hours with the more reactive t-BuLi. At –30 to –20 °C,
both reagents bring about lithiation, but the reaction ap-
pears to be slow, yielding about 35% of products after a
two-hour lithiation period with just a small excess of lithi-
ating agent (2.4 equiv instead of the theoretical 2.0). Both
reagents show a small preference for lithiation on the ring
(ratio 10/7 = 1.7 with n-BuLi and 1.3 with t-BuLi). Use of
a larger excess of lithiating agent (3.3 equiv) understand-
ably results in higher levels of lithiation (around 70% after
2 h), but also in greater selectivity for ring-lithiation (ratio
10/7 = 3.2 with n-BuLi and 2.1 with t-BuLi), which is less
easy to understand. Perhaps use of the larger quantity of
reagent resulted in a quicker temperature rise, so that more
of the reaction occurred at the higher end of the tempera-
ture range, at which the selectivity for 10 appears to be
greater. Alternatively, perhaps the rate equation for ring
lithiation involves a higher order in lithiating agent than
the rate equation for N-methyl lithiation, so that it would
be favored to a greater extent at higher concentration of
organolithium. At –20 to 0 °C, the yields were better still
In an attempt to improve the yield of 7 the reaction was
repeated with n-BuLi (2.4 equiv) at a higher temperature
(–30 to –20 °C). The crude product was purified by col-
umn chromatography (silica gel; hexane–Et2O, 1:1 by
volume) to give the starting material 5 (61%), the methyl-
substituted product 7 (13%), and N′-{2-[2-(hydroxy-
diphenylmethyl)-4-methoxyphenyl]ethyl}-N,N-dimeth-
ylurea (10, Figure 2) in 22% yield. Product 10 would have
arisen from reaction of benzophenone with the dilithium
reagent 11 (Figure 2), produced in situ from 8. The iden-
tity of product 10 was confirmed by its X-ray crystal
structure (Figure 3).
Me
N
Me
N
H
N
N
Me
Me
OH
Ph
O
OLi
MeO
MeO
Li
11
Ph
10
Figure 2 The structures of product 10 and its dilithium intermediate
11
Several experiments were conducted in an attempt to find and the selectivity was greater too with n-BuLi (ratio
conditions under which 10 could be produced as the only 10/7 = 12.1). The best yields were achieved at 0 °C, and at
product by varying the molar equivalents and type of lith- that temperature higher selectivity was also recognizable
ium reagent, reaction time, and reaction temperature (Ta- with t-BuLi. Thus, it is clear that the general trend is that
ble 1). Excellent overall yields of up to 98% could be the yields and selectivity for formation of 10 increase as
produced at 0 °C, but mixtures of 7 and 10 were always the temperature increases and with larger quantities of al-
produced.
kyllithium. In terms of selectivity for formation of 10, n-
BuLi is better than t-BuLi. From experiments conducted
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 394–402

396
K. Smith et al.
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Table 1 Lithiation of 5 Followed by Reaction with Benzophenone under Various Reaction Conditions
Entry
RLi (mol equiv)
Time (h)
Temp (°C)
Yield (%)a of 7
Yield (%)a of 10
b
1
2
n-BuLi (3.3)
t-BuLi (3.3)
n-BuLi (2.4)
t-BuLi (2.4)
n-BuLi (3.3)
t-BuLi (3.3)
n-BuLi (3.3)
t-BuLi (3.3)
n-BuLi (2.4)
t-BuLi (2.4)
t-BuLi (3.3)
n-BuLi (3.3)
n-BuLi (3.3)
n-BuLi (3.3)
t-BuLi (3.3)
2
−78
–
5
–
b
2
−78
–
3
2
−30 to −20c
13
16
18
22
7
22
20
57
46
85
55
38
28
62
40
69
83
75
4
2
−30 to −20c
5
2
−30 to −20c
6
2
−30 to −20c
7
2
−20 to 0
8
2
−20 to 0
27
9
9
2
0
0
0
0
0
0
0
10
11
13
14
15
16
2
16
21
10
12
15
23
1
0.25
1
2
2
a Isolated yield after separation by column chromatography.
b Starting material 5 was recovered (90–96%).
c Initial addition of BuLi was at –60 °C.
under similar conditions for different periods of time the Et2O–hexane 1:1 by volume), to give the corresponding
evidence for equilibration of the intermediate organolith- substituted derivatives 12–21 in high overall yields (Table
ium species is not strong, but if it is occurring it appears 2). The 1H NMR spectra of compounds 12, 13 and 16–19
that 10 is the more favored species at 0 °C.
showed diastereotopicity for the CH2 protons.
No conditions were found under which only one product As can be seen from Table 2, lithiation and substitution of
could be obtained in good yield. However, product 10 5 gave mixtures of two products in which ring substitution
could be produced as the major product under conditions products were the major ones. The combined yields were
where the yield of 7 was low. The best conditions found typically around 95%. It appears that directed lithiation
involved use of n-BuLi (3.3 equiv) as the lithium reagent and substitution of 5 were achieved in high yields (77–
at –20 to 0 °C for at least two hours (Table 1, Entry 7).
90%) under the conditions tried, along with side-products
due to methyl substitution in lower yields (0 to 17%).
When iodoethane and dimethylformamide were used as
electrophiles no N-methyl-substitution products were iso-
lated, while in the case of iodoethane as an electrophile a
side-product involving N-alkylation was obtained.
It was of interest to see if the reaction with other electro-
philes would be useful and general. Consequently, reac-
tions of 5 under the conditions described above (Table 1,
entry 7) were carried out with various other electrophiles
[4′-methoxyacetophenone, cyclohexanone, benzalde-
hyde, 4-(dimethylamino)benzaldehyde, dimethylform- When DMF was used as electrophile the isolated yield of
amide, and iodoethane] (Scheme 4). Each reaction was ring-substitution product was 90% and in the case of iodo-
conducted under identical conditions. The crude products ethane the combined yields of products involving ring
were separated by column chromatography (silica gel; substitution including the side-product 22 (Figure 4)
Me
N
Me
N
Me
N
H
H
H
N
E
1) n-BuLi (3.3 equiv), THF
2 h, –20 to 0 °C
2) electrophile (E+)
N
N
Me
Me
+
O
O
O
MeO
MeO
E
MeO
3) aq NH4Cl
5
7, 12, 14, 16, 18 (6–17%)
10, 13, 15, 17, 19–21 (77–90%)
Scheme 4 Lithiation and substitution of N′-[2-(4-methoxyphenyl)ethyl]-N,N-dimethylurea (5)
Synthesis 2014, 46, 394–402
© Georg Thieme Verlag Stuttgart · New York

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Lithiation of Methoxyphenethylamine Urea and Carbamate Compounds
397
Table 2 Lithiation and Substitution of 5 under Various Reaction Conditions (Scheme 4)
Electrophile
E
Product (%)a
Side-chain
ortho
Ph2CO
Ph2C(OH)
7 (7)
12 (12)
14 (17)
16 (6)
18 (10)
–
10 (85)
13 (82)
15 (77)
17 (82)
19 (80)
20 (90)
4-MeOC6H4COMe
(CH2)5CO
PhCHO
4-MeOC6H4C(OH)(Me)
(CH2)5C(OH)
PhCH(OH)
4-Me2NC6H4CHO
Me2NCHO
EtI
4-Me2NC6H4CH(OH)
CHO
Et
–
21 (86)b
a Yield of the isolated pure product after column chromatography.
b Diethyl derivative 22 was produced as a side-product in 9% yield.
Et
N
Me
N
of ring-substitution product. This would explain the 95%
production of ring-substitution products in the case of io-
doethane as electrophile. The result is in sharp contrast
with the early results reported by Simig and Schlosser12
for the α-lithiation of N-[2-(4-methoxyphenyl)ethyl]pival-
amide (1; Scheme 1), since in this case no α-substitution
was observed at all.
Me
O
MeO
Et
22 (9%)
Figure 4 The structure of compound 22
Lithiation of 6 was carried out with n-BuLi under the stan-
dard conditions that were used for 5, followed by reaction
with various electrophiles (benzophenone, 4′-methoxy-
acetophenone, dimethylformamide, and iodoethane)
(Scheme 5). Each reaction was conducted under identical
conditions and then quenched by the addition of aqueous
NH4Cl. Afterwards, the crude products were separated by
column chromatography (silica gel; Et2O–hexane, 1:1) to
give the corresponding substituted derivatives 23–26
(Scheme 5) in high yields (Table 3). Clearly there was no
N-methyl group to be lithiated in this instance, but it is
noteworthy that again no α-substitution was detected.
amounted to 95%. On the other hand, 17% of N-methyl-
substitution product was isolated from the reaction with
cyclohexanone, so that the maximum quantity of ring-
substitution product formed in that case, even allowing for
any losses, could have been not higher than 83%. These
differences appear to be too great to be explained by acci-
dental differences in experimental conditions and cannot
be explained simply by failure to isolate all of one or other
of the products, so the most likely explanation is that there
is equilibration between the two intermediate organolithi-
um species 8 and 11. The equilibrium position would fa-
vor 11 and a highly reactive electrophile such as
cyclohexanone might trap the equilibrium mixture suffi-
ciently rapidly to produce more-or-less the proportions of
products that reflect the two lithium species in the equilib-
rium mixture. However, a relatively unreactive electro-
phile that reacted more rapidly with 11 than with 8 would
remove 11 from the mixture, thereby allowing the equilib-
rium to shift by conversion of 8 into more 11, resulting ul-
timately in the production of a significantly higher yield
In conclusion, N′-[2-(4-methoxyphenyl)ethyl]-N,N-di-
methylurea (5) and tert-butyl (2-(4-methoxyphenyl)eth-
yl)carbamate (6) undergo lithiation with n-BuLi at –20 to
0 °C, followed by treatment with various electrophiles, to
give high yields of the corresponding substituted products
having the substituent ortho to the directing group. Side-
products were obtained in low yields from the urea deriv-
ative as a result of substitution at one of the methyl
groups.
Table 3 Synthesis of Substituted Derivatives 23–26 from Lithiation and Substitution of 6 (Scheme 5)
Product
Electrophile
E
Yield (%)a
23
24
25
26
Ph2CO
Ph2C(OH)
89
93
87
90
4-Me2NC6H4CHO
Me2NCHO
EtI
4-Me2NC6H4CH(OH)
CHO
Et
a Yield of isolated product after purification by flash column chromatography.
© Georg Thieme Verlag Stuttgart · New York
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398
K. Smith et al.
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H
H
1) n-BuLi (3.0 equiv), THF
–20 to 0 °C, 2 h
N
Ot-Bu
N
Ot-Bu
O
2) electrophile, THF
0 °C to r.t., 2 h
O
MeO
MeO
E
23–26 (87–93%)
6
3) aq NH4Cl
Scheme 5 Lithiation and substitution of tert-butyl [2-(4-methoxyphenyl)ethyl]carbamate (6)
Melting point determinations were performed by the open capillary
method using a Gallenkamp melting point apparatus and are uncor-
rected. 1H and 13C NMR spectra were recorded on a Bruker AV500
allowed to cool and the solid formed was collected by filtration and
then washed with H2O (2 × 25 mL). The solid was purified by crys-
tallization from hexane to give pure 5 (14.04 g, 63.3 mmol, 97%) as
a white crystalline solid; mp 80–82 °C.
1
spectrometer operating at 500 MHz for H and 125 MHz for 13C
measurements. Chemical shifts δ are reported in parts per million
(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 in-
tegration values, coupling patterns, and expected chemical shift val-
ues, 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-res-
olution mass spectra were recorded on a Waters LCT Premier XE
instrument. IR spectra were recorded on a Jasco FT/IR-660 plus in-
strument by dissolving the product in CHCl3, applying droplets on
a NaCl plate and allowing the solvent to evaporate. The structure of
10 was solved by direct methods using SHELXS-9614 and refined
with all data on F2 full-matrix least squares using SHELXL-97.15
Non-hydrogen atoms were generally refined anisotropically. Hy-
drogen atom positions were located from difference Fourier maps
and a riding model with atomic displacement parameters 1.2 times
(1.5 times for methyl groups) those of the atom to which they are
bonded was used for subsequent refinements.16 Column chromatog-
raphy was carried out using Fischer Scientific silica 60A (35–70 mi-
cron). Alkyllithiums were obtained from Aldrich Chemical
Company and were estimated prior to use by the method of Watson
and Eastham.17
IR (FT): 3341, 2933, 1634, 1538, 1357 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.12 (d, J = 8 Hz, 2 H, H-2/H-6),
6.85 (d, J = 8 Hz, 2 H, H-3/H-5), 4.42 (br, D2O exch, 1 H, NH), 3.80
(s, 3 H, OCH3), 3.45 (t, J = 7 Hz, 2 H, CH2NH), 2.86 [s, 6 H,
N(CH3)2], 2.76 (t, J = 7 Hz, 2 H, CH2Ar).
13C NMR (125 MHz, CDCl3): δ = 158.3 (s, C-4), 158.2 (s, C=O),
131.5 (s, C-1), 129.7 (d, C-2/C-6), 114.0 (d, C-3/C-5), 55.2 (q,
OCH3), 42.3 (t, CH2NH), 36.1 [q, N(CH3)2], 35.5 (t, CH2Ar).
MS (EI): m/z (%) = 222 (80, [M]+), 190 (25), 177 (40), 134 (100),
72 ([Me2NCO+], 98).
HRMS (EI): m/z [M]+ calcd for C12H18N2O2: 222.1368; found:
222.1374.
tert-Butyl [2-(4-Methoxyphenyl)ethyl]carbamate (6)
To a cooled (0 °C) solution of 4 (5.00 g, 33.1 mmol) and Et3N (5.02
g, 49.7 mmol) in CH2Cl2 (50 mL) was slowly added di-tert-butyl di-
carbonate (8.67 g, 39.7 mmol) in a dropwise manner. The cooling
bath was removed and the reaction mixture was stirred for 1 h at r.t.
The mixture was poured onto H2O (50 mL). The organic layer was
separated, washed with H2O (2 × 50 mL), dried (MgSO4), and the
solvent was removed under reduced pressure. The solid obtained
was purified by crystallization from hexane to give pure 6 (7.98 g,
31.8 mmol, 96%) as a white solid; mp 68–70 °C.
2-(4-Methoxyphenyl)ethanamine (4)
A solution of AlCl3 (6.70 g, 50 mmol) in anhydrous Et2O (50 mL)
was added to LiAlH4 (5.70 g, 150.0 mmol) at 0 °C. The resulting
mixture was stirred at 0 °C for 10 min. A solution of 2-(4-methoxy-
phenyl)acetonitrile (3; 10.00 g, 68.0 mmol) in anhydrous Et2O (15
mL) was added to the mixture at 0 °C. The reaction mixture was
stirred overnight at r.t. The mixture was diluted with Et2O (25 mL)
and quenched with H2O (100 mL). After acidifying the solution
with concd H2SO4, it was basified with aq 6 M NaOH. The layers
were separated and the aqueous layer was extracted with Et2O
(3 × 25 mL). The combined organic layers were washed with brine
(2 × 25 mL), dried (MgSO4), filtered, and concentrated under re-
duced pressure to afford 4 (9.86 g, 65.3 mmol, 96%) as a white crys-
talline solid; mp 113–115 °C.
IR (FT): 3360, 2932, 1682, 1540, 1365 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.13 (d, J = 9 Hz, 2 H, H-2/H-6),
6.87 (d, J = 9 Hz, 2 H, H-3/H-5), 4.54 (br, D2O exch, 1 H, NH), 3.81
(s, 3 H, OCH3), 3.36 (app q, J = 7 Hz, 2 H, CH2NH), 2.76 (t, J = 7
Hz, 2 H, CH2Ar), 1.46 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 158.3 (s, C-4), 155.9 (s, C=O),
131.0 (s, C-1), 129.7 (d, C-2/C-6), 114.0 (d, C-3/C-5), 79.2 [s,
C(CH3)3], 55.3 (q, OCH3), 42.0 (t, CH2NH), 35.3 (t, CH2Ar), 28.4
[q, C(CH3)3].
MS (EI): m/z (%) = 251 (3, [M]+), 218 (22), 195 (58), 177 (90), 151
(78), 122 (100), 85 (98), 65 (88).
HRMS (EI): m/z [M+] calcd for C14H21NO3: 251.1521; found:
251.1519.
IR (FT): 3319–3201, 2959, 1512 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.02 (d, J = 8 Hz, 2 H, H-2/H-6),
6.75 (d, J = 8 Hz, 2 H, H-3/H-5), 3.69 (s, 3 H, OCH3), 2.83 (t, J = 7
Hz, 2 H, CH2NH2), 2.59 (t, J = 7 Hz, 2 H, CH2Ar), 1.22 (br, D2O
exch, 2 H, NH2).
Lithiation and Substitution of N′-[2-(4-methoxyphenyl)ethyl]-
N,N-dimethylurea (5) and tert-Butyl [2-(4-methoxyphenyl)eth-
yl]carbamate (6); General Procedure
A solution of n-BuLi in hexane (1.85 mL, 1.6 M, 2.97 mmol) was
added to a stirred solution of 5 (0.20 g) or a solution of n-BuLi in
hexane (1.62 mL, 1.6 M, 2.60 mmol) was added to a stirred solution
of 6 (0.20 g) at –20 °C in anhydrous THF (15 mL) under a N2 atmo-
sphere in each case. The mixture was stirred at 0 °C for 2 h. The
mixture was re-cooled to –60 °C and the electrophile (1.26 mmol),
in anhydrous THF (5 mL) if solid, neat otherwise, was added. The
reaction mixture was stirred for 2 h at r.t. The mixture was quenched
with sat. aq NH4Cl (20 mL) and diluted with Et2O (20 mL). The or-
ganic layer was separated, washed with H2O (2 × 20 mL), dried
(MgSO4), and evaporated under reduced pressure. The residue ob-
tained was purified by column chromatography (silica gel; hexane–
Et2O, 1:1 by volume) to give pure products.
13C NMR (125 MHz, CDCl3): δ = 158.1 (s, C-4), 139.9 (s, C-1),
129.7 (d, C-2/C-6), 113.9 (d, C-3/C-5), 55.2 (q, OCH3), 43.7 (t,
CH2NH2), 39.2 (t, CH2Ar).
MS (ES+): m/z (%) = 151 (50, [M]+), 134 (20), 122 (100), 107 (62),
91 (90), 77 (91).
HRMS (ES+): m/z [M+] calcd for C9H13NO: 151.0997; found:
151.1000.
N′-[2-(4-Methoxyphenyl)ethyl]-N,N-dimethylurea (5)
A stirred mixture of 4 (9.86 g, 65.2 mmol), dimethylcarbamoyl
chloride (8.41 g, 78.3 mmol), and Et3N (9.89 g, 97.8 mmol) in
CH2Cl2 (100 mL) was heated under reflux for 1 h. The mixture was
Synthesis 2014, 46, 394–402
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lithiation of Methoxyphenethylamine Urea and Carbamate Compounds
399
N-(2-Hydroxy-2,2-diphenylethyl)-N′-[2-(4-methoxyphenyl)eth-
yl]-N-methylurea (7)
Yield: 0.025 g (0.060 mmol, 7%); colorless oil.
N′-(2-{2-[1-Hydroxy-1-(4-methoxyphenyl)ethyl]-4-methoxy-
phenyl}ethyl)-N,N-dimethylurea (13)
Yield: 0.27 g (0.73 mmol, 82%); white solid; mp 137–140 °C.
IR (FT): 3336, 2952, 1611, 1511, 1301, 1246 cm–1.
IR (FT): 3342, 2933, 1633, 1537, 1299, 1246 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 7 Hz, 4 H, H-2/H-6 of
2 C6H5), 7.24 (app t, J = 7 Hz, 4 H, H-3/H-5 of 2 C6H5), 7.18–7.13
(m, 2 H, H-4 of 2 C6H5), 7.00 (d, J = 8 Hz, 2 H, H-2/H-6), 6.75 (d,
J = 8 Hz, 2 H, H-3/H-5), 6.52 (br, D2O exch, 1 H, OH), 4.38 (t, D2O
exch, J = 7 Hz, 1 H, NH), 4.05 (s, 2 H, CH2COH), 3.70 (s, 3 H,
OCH3), 3.36 (app q, J = 7 Hz, 2 H, CH2NH), 2.67 (t, J = 7 Hz, 2 H,
CH2Ar), 2.16 (s, 3 H, NCH3).
1H NMR (500 MHz, CDCl3): δ = 7.28 (s, D2O exch, 1 H, OH), 7.25
(d, J = 8 Hz, 2 H, H-2/H-6 of 4-MeOC6H4), 7.19 (d, J = 3 Hz, 1 H,
H-3), 7.12 (d, J = 8 Hz, 1 H, H-6), 6.82–6.80 (m, 3 H, H-5 and H-
3/H-5 of 4-MeOC6H4), 4.58 (br, D2O exch, 1 H, NH), 3.84 (s, 3 H,
OCH3), 3.79 (s, 3 H, OCH3), 3.25 (m, 1 H, CHaHbNH), 3.04 (m, 1
H, CHaHbNH), 2.82 [s, 6 H, N(CH3)2], 2.64 (m, 1 H, CHaHbAr),
2.45 (m, 1 H, CHaHbAr), 1.90 (s, 3 H, CH3).
13C NMR (125 MHz, CDCl3): δ = 160.6 (s, C-4), 158.2 (s, C=O),
145.8 (s, C-1 of 2 C6H5), 131.1 (s, C-1), 129.8 (d, C-2/C-6), 128.0
(d, C-2/C-6 of 2 C6H5), 126.9 (d, C-4 of 2 C6H5), 126.5 (d, C-3/C-5
of 2 C6H5), 114.0 (d, C-3/C-5), 78.6 (s, C-OH), 61.0 (t, CH2COH),
55.2 (q, OCH3), 42.4 (t, CH2NH), 36.8 (q, NCH3), 35.1 (t, CH2Ar).
MS (EI): m/z (%) = 386 (40, [M – H2O]+), 298 (80), 182 (83), 121
(97), 83 (100).
13C NMR (125 MHz, CDCl3): δ = 158.6 (s, C-4), 158.2 (s, C-4 of 4-
MeOC6H4), 157.4 (s, C=O), 146.6 (s, C-2), 141.4 (s, C-1 of 4-
MeOC6H4), 132.6 (d, C-6), 130.3 (s, C-1), 126.4 (d, C-2/C-6 of 4-
MeOC6H4), 113.7 (d, C-3), 113.3 (d, C-3/C-5 of 4-MeOC6H4),
111.6 (d, C-5), 76.5 (s, COH), 55.28 (q, OCH3), 55.22 (q, OCH3),
42.5 (t, CH2NH), 36.1 [q, N(CH3)2], 33.1 (q, CH3), 33.0 (t, CH2Ar).
MS (EI): m/z (%) = 354 (60, [M – H2O]+), 312 (45), 266 (100), 253
(93), 222 (50), 163 (90), 134 (98), 83 (99).
HRMS (EI): m/z [M – H2O]+ calcd for C21H26N2O3: 354.1943;
HRMS (EI): m/z [M – H2O]+ calcd for C25H26N2O2: 386.1994;
found: 386.1989.
found: 354.1936.
N′-{2-[2-(Hydroxydiphenylmethyl)-4-methoxyphenyl]ethyl}-
N,N-dimethylurea (10)
N-[(1-Hydroxycyclohexyl)methyl]-N′-[2-(4-methoxyphe-
nyl)ethyl]-N-methylurea (14)
Yield: 0.048 g (0.15 mmol, 17%); colorless oil.
IR (FT): 3348, 2931, 1633, 1539, 1245 cm–1.
Yield: 0.30 g (0.76 mmol, 85%); white solid; mp 157–159 °C.
IR (FT): 3227, 2952, 1620, 1541, 1318, 1242 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.23–7.16 (m, 10 H, 2 C6H5), 7.08
(d, J = 8 Hz, 1 H, H-6), 6.69 (dd, J = 3, 8 Hz, 1 H, H-5), 6.14 (d,
J = 3 Hz, 1 H, H-3), 4.87 (s, D2O exch, 1 H, OH), 4.72 (br, D2O
exch, 1 H, NH), 3.52 (s, 3 H, OCH3), 3.23 (app q, J = 7 Hz, 2 H,
CH2NH), 2.73 [s, 6 H, N(CH3)2], 2.50 (t, J = 7 Hz, 2 H, CH2Ar).
13C NMR (125 MHz, CDCl3): δ = 158.7 (s, C-4), 156.9 (s, C=O),
147.3 (s, C-1 of 2 C6H5), 146.8 (s, C-2), 132.6 (d, C-6), 130.9 (s, C-
1), 127.8 (d, C-3/C-5 of 2 C6H5), 127.7 (d, C-2/C-6 of 2 C6H5),
127.0 (d, C-4 of 2 C6H5), 117.0 (d, C-3), 111.9 (d, C-5), 82.4 (s,
COH), 54.9 (q, OCH3), 42.6 (t, CH2NH), 36.0 [q, N(CH3)2], 33.5 (t,
CH2Ar).
1H NMR (500 MHz, CDCl3): δ = 7.05 (d, J = 9 Hz, 2 H, H-2/H-6),
6.78 (d, J = 9 Hz, 2 H, H-3/H-5), 4.97 (br, D2O exch, 1 H, NH), 3.72
(s, 3 H, OCH3), 3.36 (app q, J = 7 Hz, 2 H, CH2NH), 3.15 (s, 2 H,
CH2COH), 2.82 (s, 3 H, NCH3), 2.69 (t, J = 7 Hz, 2 H, CH2Ar),
1.54–1.18 (m, 10 H, c-Hex).
13C NMR (125 MHz, CDCl3): δ = 160.3 (s, C-4), 158.2 (s, C=O),
131.5 (s, C-1), 129.8 (d, C-2/C-6), 114.0 (d, C-3/C-5), 73.0 (s, C-1
of c-Hex), 60.6 (t, CH2COH), 55.3 (q, OCH3), 42.3 (t, CH2NH),
37.8 (q, NCH3), 35.7 (t, CH2Ar), 35.3 (t, C-2/C-6 of c-Hex), 25.8 (t,
C-4 of c-Hex), 22.0 (t, C-3/C-5 of c-Hex).
MS (EI): m/z (%) = 386 (25, [M – H2O]+), 316 (98), 285 (99), 209
(97), 165 (100), 83 (98).
MS (EI): m/z (%) = 320 (12, [M]+), 222 (98), 177 (89), 150 (11),
134 (100), 121 (97), 99 (83), 77 (81).
HRMS (EI): m/z [M – H2O]+ calcd for C25H26N2O2: 386.1994;
found: 386.1992.
HRMS (EI): m/z [M]+ calcd for C18H28N2O3: 320.2100; found:
320.2100.
N′-[2-Hydroxy-2-(4-methoxyphenyl)propyl]-N-[2-(4-methoxy-
phenyl)ethyl]-N-methylurea (12)
Yield: 0.04 g (0.10 mmol, 12%); colorless oil.
N′-{2-[2-(1-Hydroxycyclohexyl)-4-methoxyphenyl]ethyl}-N,N-
dimethylurea (15)
Yield: 0.22 g (0.69 mmol, 77%); colorless oil.
IR (FT): 3327, 2933, 1611, 1543, 1300, 1247 cm–1.
IR (FT): 3349, 2932, 1634, 1538, 1245 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 9 Hz, 2 H, H-2/H-6 of
4-MeOC6H4), 7.11 (d, J = 8 Hz, 2 H, H-2/H-6), 6.88 (d, J = 9 Hz, 2
H, H-3/H-5 of 4-MeOC6H4), 6.85 (d, J = 8 Hz, 2 H, H-3/H-5), 5.24
(br s, D2O exch, 1 H, OH), 4.78 (br, D2O exch, 1 H, NH), 3.81 (s, 3
H, OCH3), 3.80 (s, 3 H, OCH3), 3.67 (d, J = 15 Hz, 1 H, CHaHb-
COH), 3.51–3.37 (m, 2 H, CH2NH), 3.28 (d, J = 15 Hz, 1 H,
CHaHbCOH), 2.78–2.75 (m, 2 H, CH2Ar), 2.48 (s, 3 H, NCH3),
1.55 (s, 3 H, CH3).
13C NMR (125 MHz, CDCl3): δ = 160.3 (s, C-4), 158.4 (s, C-4 of 4-
MeOC6H4), 158.2 (s, C=O), 138.5 (s, C-1 of 4-MeOC6H4), 131.2 (s,
C-1), 129.8 (d, C-2/C-6), 126.5 (d, C-2/C-6 of 4-MeOC6H4), 114.0
(d, C-3/C-5 of 4-MeOC6H4), 113.4 (d, C-3/C-5), 75.4 (s, COH),
62.8 (t, CH2COH), 55.3 (q, OCH3), 55.2 (q, OCH3), 42.3 (t,
CH2NH), 37.1 (q, NCH3), 35.2 (t, CH2Ar), 27.2 (q, CH3).
1H NMR (500 MHz, CDCl3): δ = 7.09 (d, J = 8 Hz, 1 H, H-6), 6.87
(d, J = 3 Hz, 1 H, H-3), 6.78 (dd, J = 3, 8 Hz, 1 H, H-5), 4.97 (br s,
D2O exch, 1 H, OH), 4.28 (br, D2O exch, 1 H, NH), 3.72 (s, 3 H,
OCH3), 3.37 (app q, J = 7 Hz, 2 H, CH2NH), 3.07 (t, J = 7 Hz, 2 H,
CH2Ar), 2.77 [s, 3 H, N(CH3)2], 1.78–1.18 (m, 10 H, c-Hex).
13C NMR (125 MHz, CDCl3): δ = 158.9 (s, C-4), 157.7 (s, C=O),
142.3 (s, C-2), 133.2 (d, C-6), 129.8 (s, C-1), 114.0 (d, C-5), 111.1
(d, C-3), 74.5 (s, C-1 of c-Hex), 55.2 (q, OCH3), 43.9 (t, CH2NH),
38.5 (t, CH2Ar), 36.3 [q, N(CH3)2], 35.3 (t, C-2/C-6 of c-Hex), 25.4
(t, C-4 of c-Hex), 22.1 (t, C-3/C-5 of c-Hex).
MS (ES): m/z (%) = 384 (20, [M + MeCNNa]+), 359 (22, [M + K]+),
343 (100, [M + Na]+).
HRMS (ES): m/z [M + Na]+ calcd for C18H28N2O3 + Na: 343.1998;
found: 343.1995.
MS (EI): m/z (%) = 354 (6, [M – H2O]+), 222 (77), 177 (94), 135
(97), 121 (100), 107 (55), 91 (70), 77 (87).
HRMS (EI): m/z [M – H2O]+ calcd for C21H26N2O3: 354.1943;
found: 354.1951.
N-(2-Hydroxy-2-phenylethyl)-N′-[2-(4-methoxyphenyl)ethyl]-
N-methylurea (16)
Yield: 0.016 g (0.050 mmol, 6%); colorless oil.
IR (FT): 3338, 2932, 1639, 1541, 1246 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 394–402

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K. Smith et al.
PAPER
1H NMR (500 MHz, CDCl3): δ = 7.33 (t, J = 7 Hz, 1 H, H-4 of
C6H5), 7.29–7.25 (m, 4 H, H-2/H-3/H-5/H-6 of C6H5), 7.05 (d, J = 8
Hz, 2 H, H-2/H-6), 6.78 (d, J = 8 Hz, 2 H, H-3/H-5), 4.82 (dd, J = 3,
8 Hz, 1 H, CH), 4.65 (br, D2O exch, 1 H, NH), 4.60 (br, D2O exch,
1 H, OH), 3.72 (s, 3 H, OCH3), 3.47 (dd, J = 7, 15 Hz, 1 H, CHaHb-
CHOH), 3.45–3.33 (m, 3 H, CHaHbCHOH and CH2NH), 2.70 (app
t, J = 7 Hz, 2 H, CH2Ar), 2.58 (s, 3 H, NCH3).
13C NMR (125 MHz, CDCl3): δ = 160.0 (s, C-4), 158.2 (s, C=O),
142.4 (s, C-1 of C6H5), 131.2 (s, C-1), 129.8 (d, C-2/C-6), 128.4 (d,
C-3/C-5 of C6H5), 127.5 (d, C-4 of C6H5), 125.8 (d, C-2/C-6 of
C6H5), 114.0 (d, C-3/C-5), 73.9 (d, CHOH), 58.3 (t, CH2CHOH),
55.2 (q, OCH3), 42.3 (t, CH2NH), 36.0 (q, NCH3), 35.3 (t, CH2Ar).
IR (FT): 3361, 2926, 1612, 1521, 1351, 1245 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.99 (d, J = 8 Hz, 1 H, H-6), 6.95
(d, J = 8 Hz, 2 H, H-2/H-6 of 4-Me2NC6H4), 6.70 (dd, J = 2, 8 Hz,
1 H, H-5), 6.55 (d, J = 8 Hz, 2 H, H-3/H-5 of 4-Me2NC6H4), 6.50
(d, J = 2 Hz, 1 H, H-3), 6.02 (s, D2O exch, 1 H, OH), 5.96 (s, 1 H,
CH), 4.24 (app. t, D2O exch, J = 7 Hz, 1 H, NH), 3.64 (s, 3 H,
OCH3), 3.53 (dddd, J = 1, 2, 7, 14 Hz, 1 H, CHaHbNH), 3.18 (app
ddd, J = 5, 12, 14 Hz, 1 H, CHaHbNH), 2.90–2.82 [m, 7 H, CHaHbAr
and 4-(CH3)2NC6H4], 2.77 [s, 6 H, N(CH3)2], 2.63 (ddd, J = 2, 5, 16
Hz, 1 H, CHaHbAr).
13C NMR (125 MHz, CDCl3): δ = 164.6 (s, C-4), 157.5 (s, C=O),
149.6 (s, C-4 of 4-Me2NC6H4), 137.4 (s, C-2), 132.0 (s, C-1 of 4-
Me2NC6H4), 130.7 (s, C-1), 129.5 (d, C-2/C-6 of 4-Me2NC6H4),
126.8 (d, C-6), 113.3 (d, C-3), 112.7 (d, C-5), 112.0 (d, C-3/C-5 of
4-Me2NC6H4), 77.4 (d, COH), 55.3 (q, OCH3), 40.6 (t, CH2NH),
40.3 [q, 4-(CH3)2NC6H4], 38.8 [q, N(CH3)2], 27.8 (t, CH2Ar).
MS (EI): m/z (%) = 329 (17, [M + H]+), 222 (100), 207 (17), 190
(32), 178 (90), 150 (9), 134 (99), 121 (97), 105 (93), 91 (96).
HRMS (EI): m/z [M + H]+ calcd for C19H25N2O3: 329.1865; found:
329.1875.
MS (EI): m/z (%) = 353 (83, [M – H2O]+), 308 (67), 281 (100), 264
(64), 236 (42), 165 (31), 83 (45), 72 (65).
HRMS (EI): m/z [M – H2O]+ calcd for C21H27N3O2: 353.2103;
found: 353.2114.
N′-(2-{2-[Hydroxy(phenyl)methyl]-4-methoxyphenyl}ethyl)-
N,N-dimethylurea (17)
Yield: 0.24 g (0.73 mmol, 82%); colorless oil.
IR (FT): 3337, 2927, 1630, 1537, 1249 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.32 (d, J = 7 Hz, 2 H, H-2/H-6 of
C6H5), 7.26 (app t, J = 8 Hz, 2 H, H-3/H-5 of C6H5), 7.20–7.17 (m,
2 H, OH and H-4 of C6H5), 7.00 (d, J = 8 Hz, 1 H, H-6), 6.79 (d,
J = 3 Hz, 1 H, H-3), 6.70 (dd, J = 3, 8 Hz, 1 H, H-5), 6.04 (s, 1 H,
CH), 4.48 (br, D2O exch, 1 H, NH), 3.66 (s, 3 H, OCH3), 3.43–3.25
(m, 2 H, CH2NH), 2.87 (ddd, J = 6, 8, 14 Hz, 1 H, CHaHbAr), 2.76
[s, 6 H, N(CH3)2], 2.64 (app dt, J = 8, 14 Hz, 1 H, CHaHbAr).
13C NMR (125 MHz, CDCl3): δ = 158.6 (s, C-4), 158.3 (s, C=O),
143.5 (s, C-1 of C6H5), 135.1 (s, C-2), 131.3 (d, C-6), 129.0 (s, C-
1), 128.3 (d, C-3/C-5 of C6H5), 127.3 (d, C-4 of C6H5), 126.8 (d, C-
2/C-6 of C6H5), 113.7 (d, C-3), 113.0 (d, C-5), 72.7 (d, CH), 55.2 (q,
OCH3), 42.5 (t, CH2NH), 36.2 [q, N(CH3)2], 32.8 (t, CH2Ar).
MS (EI): m/z (%) = 328 (40, [M]+), 310 (93), 282 (50), 265 (24),
238 (100), 209 (96), 194 (88), 149 (89), 134 (58), 121 (87), 105
(83), 77 (95).
HRMS (EI): m/z [M]+ calcd for C19H24N2O3: 328.1787; found:
328.1787.
N′-[2-(2-Formyl-4-methoxyphenyl)ethyl]-N,N-dimethylurea
(20)
Yield: 0.20 g (0.81 mmol, 90%); colorless oil.
IR (FT): 3346, 2932, 1700, 1685, 1540, 1362 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.38 (s, 1 H, CHO), 7.58 (d, J = 2
Hz, 1 H, H-3), 7.35 (dd, J = 2, 8 Hz, 1 H, H-5), 6.88 (d, J = 8 Hz, 1
H, H-6), 4.48 (br D2O exch, 1 H, NH), 3.85 (s, 3 H, OCH3), 3.39
(app q, J = 7 Hz, 2 H, CH2NH), 2.80 [s, 6 H, N(CH3)2], 2.73 (t, J = 7
Hz, 2 H, CH2Ar).
13C NMR (125 MHz, CDCl3): δ = 189.9 (d, CHO), 160.63 (s, C=O),
160.61 (s, C-4), 140.7 (s, C-2), 140.5 (s, C-1), 136.5 (d, C-6), 128.4
(d, C-5), 112.0 (d, C-3), 55.8 (q, OCH3), 42.1 (t, CH2NH), 36.3 [q,
N(CH3)2], 35.4 (t, CH2Ar).
MS (AP): m/z (%) = 251 (100, [M + H]+), 224 (9), 206 (10), 135
(22), 124 (13), 84 (6).
HRMS (AP): m/z [M + H]+ calcd for C13H19N2O3: 251.1760; found:
251.1764.
N-{2-[4-(Dimethylamino)phenyl]-2-hydroxyethyl}-N′-[2-(4-
methoxyphenyl)ethyl]-N-methylurea (18)
N′-[2-(2-Ethyl-4-methoxyphenyl)ethyl]-N,N-dimethylurea (21)
Yield: 0.19 g (0.77 mmol, 86%); colorless oil.
Yield: 0.030 g (0.09 mmol, 10%); colorless oil.
IR (FT): 3381, 2932, 1634, 1531, 1246 cm–1.
IR (FT): 3371, 2926, 1611, 1520, 1349, 1245 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.00 (d, J = 8 Hz, 1 H, H-6), 6.69
(d, J = 3 Hz, 1 H, H-3), 6.62 (dd, J = 3, 8 Hz, 1 H, H-5), 4.37 (br,
exchangeable, 1 H, NH), 3.72 (s, 3 H, OCH3), 3.34 (app q, J = 7 Hz,
2 H, CH2NH), 2.80 [s, 6 H, N(CH3)2], 2.72 (t, J = 7 Hz, 2 H,
CH2Ar), 2.60 (q, J = 8 Hz, 2 H, CH2CH3), 1.15 (t, J = 8 Hz, 2 H,
CH2CH3).
13C NMR (125 MHz, CDCl3): δ = 158.34 (s, C-4), 158.27 (s, C=O),
132.7 (s, C-2), 131.1 (s, C-1), 130.6 (d, C-6), 114.4 (d, C-5), 111.0
(d, C-3), 55.2 (q, OCH3), 41.9 (t, CH2NH), 36.2 [q, N(CH3)2], 32.5
(t, CH2Ar), 25.7 (t, CH2CH3), 15.8 (q, CH2CH3).
MS (AP): m/z (%) = 251 (100, [M + H]+), 206 (8), 163 (5), 135 (10),
90 (4).
HRMS (AP): m/z [M + H]+ calcd for C14H23N2O2: 251.1760; found:
251.1771.
1H NMR (500 MHz, CDCl3): δ = 7.14 (d, J = 8 Hz, 2 H, H-2/H-6 of
4-Me2NC6H4), 7.05 (d, J = 8 Hz, 2 H, H-2/H-6), 6.79 (d, J = 8 Hz,
2 H, H-3/H-5), 6.65 (d, J = 8 Hz, 2 H, H-3/H-5 of 4-Me2NC6H4),
6.57 (br, D2O exch, 1 H, OH), 4.73 (br dd, J = 2, 8 Hz, 1 H, CH),
4.70 (br, D2O exch, 1 H, NH), 3.72 (s, 3 H, OCH3), 3.48 (dd, J = 8,
15 Hz, 1 H, CHaHbCHOH), 3.42 (s, 3 H, NCH3) 3.39 (app q, J = 7
Hz, 3 H, CH2NH), 3.27 (dd, J = 3, 15 Hz, 1 H, CHaHbCHOH), 2.87
[s, 6 H, N(CH3)2], 2.70 (app t, J = 7 Hz, 2 H, CH2Ar).
13C NMR (125 MHz, CDCl3): δ = 158.1 (s, C-4), 157.9 (s, C=O),
150.3 (s, C-4 of 4-Me2NC6H4), 131.4 (s, C-1), 130.0 (s, C-1 of 4-
Me2NC6H4), 129.8 (d, C-2/C-6), 126.7 (d, C-2/C-6 of 4-
Me2NC6H4), 114.0 (d, C-3/C-5), 112.5 (d, C-3/C-5 of 4-Me2NC6H4),
73.6 (d, COH), 58.2 (t, CH2CHOH), 55.2 (q, OCH3), 42.4 (t,
CH2NH), 40.6 [q, N(CH3)2], 36.0 (q, NCH3), 35.4 (t, CH2Ar).
MS (EI): m/z (%) = 371 (14, [M]+), 353 (92), 232 (95), 176 (51),
134 (100), 121 (82), 91 (26), 77 (32).
HRMS (EI): m/z [M]+ calcd for C21H29N3O3: 371.2209; found:
371.2209.
N′-Ethyl-N′-[2-(2-ethyl-4-methoxyphenyl)ethyl]-N,N-dimethyl-
urea (22)
Yield: 0.025 g (0.090 mmol, 10%); colorless oil.
IR (FT): 2935, 1652, 1505, 1251 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.98 (d, J = 8 Hz, 1 H, H-6), 6.67
(d, J = 3 Hz, 1 H, H-3), 6.62 (dd, J = 3, 8 Hz, 1 H, H-5), 3.71 (s, 3
H, OCH3), 3.19–3.10 (m, 4 H, ArCH2CH2N and NCH2CH3), 2.73 [s,
N′-(2-{2-[(4-(Dimethylamino)phenyl)(hydroxy)methyl]-4-
methoxyphenyl}ethyl)-N,N-dimethylurea (19)
Yield: 0.26 g (0.72 mmol, 80%); colorless oil.
Synthesis 2014, 46, 394–402
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lithiation of Methoxyphenethylamine Urea and Carbamate Compounds
401
6 H, N(CH3)2], 2.71 (q, J = 7 Hz, 2 H, ArCH2CH3), 2.60 (t, J = 7 Hz,
2 H, ArCH2CH2N), 1.16 (t, J = 7 Hz, 3 H, NCH2CH3), 1.05 (t, J = 7
Hz, 3 H, ArCH2CH3).
13C NMR (125 MHz, CDCl3): δ = 165.3 (s, C=O), 158.3 (s, C-4),
143.7 (s, C-2), 131.5 (s, C-1), 130.7 (d, C-6), 114.3 (d, C-5), 111.0
(d, C-3), 55.2 (q, OCH3), 49.2 (t, ArCH2CH2N), 43.5 (t, NCH2CH3),
38.7 [q, N(CH3)2], 30.6 (t, ArCH2CH2N), 25.7 (t, ArCH2CH3), 15.4
(q, ArCH2CH3), 13.5 (q, NCH2CH3).
13C NMR (125 MHz, CDCl3): δ = 189.7 (d, CHO), 160.6 (s, C-4),
155.8 (s, C=O), 136.3 (s, C-2), 131.3 (s, C-1), 128.4 (d, C-6), 124.8
(d, C-5), 112.0 (d, C-3), 79.3 [s, C(CH3)3], 55.7 (q, OCH3), 41.7 (t,
CH2NH), 35.1 (t, CH2Ar), 28.4 [q, C(CH3)3].
MS (ES+): m/z (%) = 597 (57, [2 M + K]+), 581 (100, [2 M + Na]+),
343 (63, [M + MeCNNa]+), 318 (60, [M + K]+), 302 (23, [M +
Na]+), 287 (18).
HRMS (ES+): m/z [M + Na]+ calcd for C15H21NO4
+
23Na:
MS (EI): m/z (%) = 278 (17, [M]+), 220 (22), 205 (64), 162 (25),
302.1368; found: 302.1375.
129 (60), 85 (100), 72 (80).
HRMS (EI): m/z [M]+ calcd for C16H26N2O2: 278.1994; found:
278.1991.
tert-Butyl [2-(2-Ethyl-4-methoxyphenyl)ethyl]carbamate (26)
Yield: 0.19 g (0.71 mmol, 90%); colorless oil.
IR (FT): 3355, 2932, 1610, 1501, 1365, 1250 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.91–6.89 (m, 2 H, H-3 and H-5),
6.70 (d, J = 8 Hz, 1 H, H-6), 4.46 (br, D2O exch, 1 H, NH), 3.73 (s,
3 H, OCH3), 3.26 (br app q, 2 H, CH2NH), 2.64 (t, J = 7 Hz, 2 H,
CH2Ar), 2.54 (q, J = 7 Hz, 2 H, CH2CH3), 1.37 [s, 9 H, C(CH3)3],
1.11 (t, J = 7 Hz, 3 H, CH2CH3).
13C NMR (125 MHz, CDCl3): δ = 156.0 (s, C-4), 155.9 (s, C=O),
132.8 (s, C-2), 130.7 (s, C-1), 129.5 (d, C-6), 126.8 (d, C-3), 110.3
(d, C-5), 79.1 [s, C(CH3)3], 55.4 (q, OCH3), 42.0 (t, CH2NH), 35.4
(t, CH2Ar), 28.4 [q, C(CH3)3], 23.2 (t, CH2CH3), 14.2 (q, CH2CH3).
tert-Butyl {2-[2-(Hydroxydiphenylmethyl)-4-methoxyphe-
nyl]ethyl}carbamate (23)
Yield: 0.30 g (0.70 mmol, 89%); colorless oil.
IR (FT): 3351, 2977, 1620, 1541, 1318, 1242 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.22–7.14 (m, 10 H, 2 C6H5), 7.02
(dd, J = 2, 8 Hz, 1 H, H-5), 6.80 (d, J = 8 Hz, 1 H, H-6), 6.24 (d,
J = 2 Hz, 1 H, H-3), 5.18 (s, D2O exch, 1 H, OH), 4.37 (br, D2O
exch, 1 H, NH), 3.50 (s, 3 H, OCH3), 3.10 (br app q, 2 H, CH2NH),
2.60 (t, J = 7 Hz, 2 H, CH2Ar), 1.33 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 156.1 (s, C-4), 155.8 (s, C=O),
146.6 (s, C-1 of 2 C6H5), 135.7 (s, C-2), 131.0 (s, C-1), 130.6 (d, C-
6), 127.8 (d, C-3/C-5 of 2 C6H5), 127.7 (d, C-2/C-6 of 2 C6H5),
127.0 (d, C-4 of 2 C6H5), 114.0 (d, C-3), 112.5 (d, C-5), 82.0 (s,
COH), 79.1 [s, C(CH3)3], 55.9 (q, OCH3), 41.8 (t, CH2NH), 35.4 (t,
CH2Ar), 28.5 [q, C(CH3)3].
MS (ES+): m/z (%) = 279 (45, [M]+), 223 (91), 206 (48), 162 (100),
135 (87), 121 (47), 105 (36), 85 (99).
HRMS (ES+): m/z [M]+ calcd for C16H25NO3: 279.1834; found:
279.1835.
MS (ES+): m/z (%) = 456 (100, [M + Na]+), 416 (5), 205 (2).
Acknowledgment
HRMS (ES+): m/z [M + Na]+ calcd for C27H31NO4
+
23Na:
We thank the Saudi Government for financial support. G. A. El-Hiti
would like to extend his appreciation to the Deanship of Scientific
Research at King Saud University for its funding for this research
through the research group project RGP-VPP-239.
456.2151; found: 456.2141.
tert-Butyl (2-{2-[(4-(Dimethylamino)phenyl)(hydroxy)methyl]-
4-methoxyphenyl}ethyl)carbamate (24)
Yield: 0.29 g (0.73 mmol, 93%); white solid; mp 179–181 °C.
IR (FT): 3361, 2974, 1612, 1520, 1364, 1248 cm–1.
Supporting Information for this article is available online at
1H NMR (500 MHz, CDCl3): δ = 7.15 (d, J = 9 Hz, 2 H, H-2/H-6 of
4-Me2NC6H4), 7.07 (br, 1 H, H-3), 6.98 (dd, J = 1, 8 Hz, 1 H, H-5),
6.73 (d, J = 8 Hz, 1 H, H-6), 6.62 (d, J = 9 Hz, 2 H, H-3/H-5 of 4-
Me2NC6H4), 5.88 (br, D2O exch, 1 H, NH), 4.45 (br, D2O exch, 1 H,
OH), 3.70 (s, 3 H, OCH3), 3.25 (app q, J = 7 Hz, 2 H, CH2NH), 2.85
[s, 6 H, N(CH3)2], 2.64 (t, J = 7 Hz, 2 H, CH2Ar), 1.36 [s, 9 H,
C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 155.9 (s, C-4), 155.4 (s, C=O),
149.9 (s, C-4 of 4-Me2NC6H4), 132.6 (s, C-2), 131.4 (s, C-1 of 4-
Me2NC6H4), 131.0 (s, C-1), 128.4 (d, C-6), 127.9 (d, C-3), 127.6 (d,
C-2/C-6 of 4-Me2NC6H4), 112.4 (d, C-3/C-5 of 4-Me2NC6H4),
110.9 (d, C-5), 79.2 [s, C(CH3)3], 72.0 (d, CH), 55.6 (q, OCH3), 41.9
(t, CH2NH), 40.6 [q, N(CH3)2], 35.5 (t, CH2Ar), 28.5 [q, C(CH3)3].
MS (ES+): m/z (%) = 400 (69, [M]+), 384 (88), 310 (99), 296 (37),
284 (70), 267 (28), 255 (96), 240 (100), 224 (31), 148 (48), 134
(98), 120 (44), 104 (16), 83 (93).
HRMS (ES+): m/z [M]+ calcd for C23H32N2O4: 400.2366; found:
400.2362.
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Synthesis 2014, 46, 394–402
© Georg Thieme Verlag Stuttgart · New York