Variation in the site of lithiation of 2-(2-methylphenyl)ethanamine derivatives

Article abstract of DOI:10.1021/jo3023445

Unexpectedly, lithiation of N′-(2-(2-methylphenyl)ethyl)-N,N- dimethylurea with 3 equiv of n-butyllithium in anhydrous THF at 0 C takes place on the nitrogen and on the CH₂ next to the 2-methylphenyl ring (α-lithiation). The lithium reagent thus obtained reacts with various electrophiles to give the corresponding substituted derivatives in excellent yields. Similarly, lithiation of N-(2-(2-methylphenyl)ethyl)pivalamide under similar reaction conditions followed by reaction with benzophenone as a representative electrophile gave the corresponding α-substituted product in high yield. Surprisingly, no products resulting from lateral lithiation were observed under the conditions tried, which sharply contrasts with the reported results for lateral lithiation of tert-butyl (2-(2-methylphenyl)ethyl)carbamate.

Full text of DOI:10.1021/jo3023445

Article
pubs.acs.org/joc
Variation in the Site of Lithiation of 2‑(2-Methylphenyl)ethanamine
Derivatives
Keith Smith,* Gamal A. El-Hiti,*,‡ and Mohammed B. Alshammari
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, U.K.
S
* Supporting Information
ABSTRACT: Unexpectedly, lithiation of N′-(2-(2-methyl-
phenyl)ethyl)-N,N-dimethylurea with 3 equiv of n-butyllithium
in anhydrous THF at 0 °C takes place on the nitrogen and on the
CH2 next to the 2-methylphenyl ring (α-lithiation). The lithium
reagent thus obtained reacts with various electrophiles to give the
corresponding substituted derivatives in excellent yields. Similarly,
lithiation of N-(2-(2-methylphenyl)ethyl)pivalamide under similar
reaction conditions followed by reaction with benzophenone as a
representative electrophile gave the corresponding α-substituted
product in high yield. Surprisingly, no products resulting from
lateral lithiation were observed under the conditions tried, which sharply contrasts with the reported results for lateral lithiation
of tert-butyl (2-(2-methylphenyl)ethyl)carbamate.
We wished to see whether there were similar effects of chain
length on lateral lithiation of ω-(2-methylphenyl)alkyl deriva-
tives. Recently, we have shown that lateral lithiation of
2‑methylbenzyl derivatives 1 with t-BuLi at −78 °C followed
by reactions with various electrophiles was successful in
producing the corresponding substituted derivatives 2 in high
yields (Scheme 1).9 We have now turned our attention to
investigation of lithiation of 2-(2-methylphenyl)ethyl deriva-
tives.
INTRODUCTION
■
Phenylethylamines represent an important class of chemicals
encompassing a whole range of biologically active compounds.
They are therefore significant for both industry and academia,
and methods for their synthesis are of considerable interest.
Organolithium reagents produced in situ in lithiation reactions
play a reliable and efficient role in functionalizing a broad-range
of aromatic and/or heterocyclic systems regioselectively.1−4
Lateral (benzylic) lithiation of alkyl groups that are ortho- to a
directing metalating group (DMG) is a well-known example of
such methodology in organic synthesis.1a,5 Such lateral
lithiation of benzenoid systems is encouraged by a stabilizing
group capable of delocalizing a negative charge, stabilizing the
organolithium by coordination, or acidifying the benzylic
proton by an electron-withdrawing inductive effect.1a,5
Scheme 1. Lateral Lithiation and Substitution of
2‑Methylbenzylamines (1)
In the course of our own studies of lithiation reactions, we
have developed several simple and efficient lithiation
procedures for preparation of various substituted aromatics
and heteroaromatics.6 For example, we have successfully
lithiated and substituted various N′-phenyl-N,N-dimethylureas,
N-(substituted benzyl)pivalamides, and N′-(substituted ben-
zyl)-N,N-dimethylureas regioselectively using n-butyllithium or
tert-butyllithium in anhydrous tetrahydrofuran.7−9 Such pro-
cesses have been applied for the production of various
substituted heterocycles.10−12 As part of such studies, we
have recently shown that lithiation of N′-phenethyl-N,N-
dimethylurea and N′-(3-phenylpropyl)-N,N-dimethylurea, at
−78 and 0 °C, respectively, with 3 equiv of t-BuLi in anhydrous
THF takes place on the nitrogen and on the CH2 next to the
phenyl ring (α-lithiation).13 On the other hand, lithiation of
N′‑(4-phenylbutyl)-N,N-dimethylurea, where the coordinating
group is further away from the α-CH2 position, takes place on
one of the methyl groups of the urea unit with t-BuLi at 0 °C.13
Lateral lithiation of tert-butyl 2-(2-methylphenyl)ethyl-
carbamate with t-BuLi (2.4 equiv) at −60 °C has been
reported by Clark.14 The lithium reagent obtained was allowed
to react with iodomethane and carbon dioxide (in the presence
of CH2N2) as electrophiles at ca. −25 to −30 °C to give the
corresponding substituted products in 80 and 67% yields,
respectively.14 However, there are no reports of lithiation and
substitution of N′-(2-(2-methylphenyl)ethyl)-N,N-dimethylur-
ea and N-(2-(2-methylphenyl)ethyl)pivalamide. We now report
Received: October 24, 2012
Published: November 28, 2012
© 2012 American Chemical Society
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Article
that lithiation of these derivatives unexpectedly take place at the
α-CH2 position, rather than laterally on the methyl group.
Table 1. Synthesis of 7 under Various Reaction Conditions
According to Scheme 3
n-BuLi
RESULTS AND DISCUSSION
■
a
molar
equiv
time
(h)
temp
(°C)
Ph2CO (molar
equiv)
yield of 7
The first task was to synthesize N′-(2-(2-methylphenyl)ethyl)-
N,N-dimethylurea (4). Compound 4 was synthesized in 95%
yield after crystallization, based on a literature procedure for
analogous compounds,9,13 from reaction of 2-(2-methyl-
phenyl)ethanamine (3) with dimethylcarbamoyl chloride
(DMCC) in dichloromethane in the presence of triethylamine
under reflux for 1 h (Scheme 2).
entry
(%)
b
1
2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
3.0
3.0
3.0
2
−78
0
1.2
1.2
2.2
2.2
1.2
2.2
3.3
1.2
1.2
1.2
12
b
b
b
b
,
,
,
,
c
c
c
c
0.5
0.5
1
65
69
78
76
83
83
80
83
93
3
0
4
0
5
2
0
6
2
0
7
2
0
Scheme 2. Synthesis of N′-(2-(2-Methylphenyl)ethyl)-N,N-
8
0.5
1
0
dimethylurea (4)
9
0
10
2
0
a
Yield of 7 after purification by column chromatography unless
b
otherwise indicated. Starting material 4 was recovered in significant
quantities. Yield by H NMR.
c
1
Initially, the reaction of 4 with n-BuLi (2.2 equiv) was carried
out in anhydrous THF under a nitrogen atmosphere at −78 °C.
Initial addition of n-BuLi provided a pale yellow solution,
presumably because of formation of the monolithium reagent 5
(Scheme 3), until approximately 1 equiv had been added, and
obtained when LDA was used as the lithium reagent. In none of
the reactions was any product of lateral lithiation isolated.
Therefore, use of n-BuLi at 0 °C was selected for further study,
and several experiments were conducted to try to improve the
yield of 7 or to find conditions under which lateral lithiation
could be achieved instead. The crude products were analyzed
Scheme 3. Lithiation of 4 Followed by Reaction with
Benzophenone
1
by H NMR spectroscopy, and the approximate yields of 7
obtained are summarized in Table 1.
The results indicated that the highest yield of 7 was obtained
by use of 3 equiv of n-BuLi as the lithium reagent at 0 °C for 2
h (Table 1, entry 10), giving 7 in 93% yield after purification by
column chromatography, although a good yield (up to 83%)
could be achieved with just a small excess over the theoretical 2
equiv of n-BuLi. Use of a larger quantity of n-BuLi probably
simply increased the rate of lithiation, particularly in the later
stages of the reaction, but clearly had practical advantage in
terms of yield of desirable product. It was obvious that no
lateral lithiation had taken place under the conditions tried and
in all cases 7 was the only new product isolated. Clearly,
α‑lithiation had taken place on the CH2 group rather than
lateral lithiation on the methyl group at the 2-position, which
was unexpected.
It was therefore interesting to see if reactions of the lithium
intermediate 6 with other electrophiles would be useful, making
the reaction more general. Consequently, reactions of 6,
prepared in situ from compound 4, with other electrophiles
(4′‑methoxyacetophenone, cyclohexanone, dimethyl forma-
mide, benzaldehyde, and 4-anisaldehyde) were carried out.
Each reaction was conducted under identical conditions and
then quenched by the addition of aq NH4Cl. Afterward, the
crude products were purified by column chromatography (silica
gel; Et2O) to give the corresponding substituted derivatives 8−
12 (Scheme 4) in high yields (Table 2).
then gave a deep yellow solution as the remaining n-BuLi was
added, presumably because of formation of a dilithium reagent.
The mixture was stirred for 2 h at −78 °C. Benzophenone (1.2
equiv) was added, and the mixture was stirred for another 1 h at
−78 °C and then quenched by the addition of aqueous
ammonium chloride solution. The starting material 4 was
recovered in 80% yield, but a new compound, shown by its 1H
NMR spectrum (which exhibited diastereotopicity for the CH2
protons) to be 7 (Scheme 3), was produced in 12% yield after
purification by column chromatography (Table 1, entry 1).
This implied that the intermediate dilithium reagent was 6
(Scheme 3) and not the expected laterally lithiated one.
Use of MeLi (1.1 equiv) to remove the NH proton, followed
by n-BuLi (1.1 equiv) at −78 °C under similar reaction
conditions, provided only a trace of 7. The yield of 7 was
improved but to only 30% when MeLi (1.1 equiv) followed by
n-BuLi (2.2 equiv) were used at −78 °C under similar reaction
conditions. Raising the temperature of lithiation to 0 °C had a
much greater effect on the yield of product, giving 7 in 65%
yield after a lithiation period of just 30 min (Table 1, entry 2).
On the other hand, use of t-BuLi or s-BuLi at 0 °C gave 7 in
lower yields, 55 and 2%, respectively, and no product was
Scheme 4. Lithiation and Substitution of
N′‑(2‑(2‑Methylphenyl)ethyl)-N,N-dimethylurea (4)
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with the lateral lithiation of tert-butyl 2-(2-methylphenyl)-
ethylcarbamate (15) reported by Clark,14 although Clark’s
conditions were somewhat different (lithiation with t-BuLi at
−60 °C, 1.5 h).
Table 2. Synthesis of Substituted
N′‑(2‑(2‑Methylphenyl)ethyl)-N,N-dimethylureas 7−12
According to Scheme 4
a
products
electrophile
Ph2CO
E
yield (%)
Lithiations of 4 and 13 were therefore attempted under
Clark’s conditions,14 followed by reactions with benzophenone
in each case. The corresponding α-substituted products 7 and
14 were still obtained, in 63 and 52% yields, respectively, along
with significant quantities of starting materials. No products
due to lateral lithiation and substitution were isolated.
In view of this significant difference, we decided to
reinvestigate lithiation of 15, and this compound was therefore
synthesized by the literature procedure.15 It was obtained in
90% yield. Lithiation of 15 under the standard conditions that
were used for 4 using 3 equiv of n-BuLi, followed by reaction
with benzophenone (1.2 equiv) as a representative electrophile
at 0 °C, gave the corresponding lateral-substituted product 16
(Figure 1) as the only observable product, but in low yield
b
7
Ph2C(OH)
93
c
8
4-MeOC6H4COMe
(CH2)5CO
4-MeOC6H4C(OH)Me
(CH2)5C(OH)
CHO
82
d
9
90
10
11
12
Me2NCHO
PhCHO
84
c
PhCH(OH)
82
c
4-MeOC6H4CHO
4-MeOC6H4CH(OH)
78
a
b
Yield of the pure product. The 13C NMR spectrum showed that the
carbons of the two phenyl groups appeared as separated signals,
c
verifying that they are diastereotopic. The NMR spectra showed a
mixture of two racemic diastereoisomers in approximately equal
d
proportions. The 13C NMR spectrum showed that the two sides of
the cyclohexane ring appeared as separated signals, verifying that they
are diastereotopic.
Clearly, substitution of 4 on the α-position of the side chain
was quite general. The NMR spectra of all compounds showed
that the signals of the two hydrogens of the CH2 group were
diastereotopic.
It was of interest to know whether lithiation of N-(2-(2-
methylphenyl)ethyl)pivalamide would behave in the same way
toward lithiation as the urea derivative. Therefore, N-(2-
methylphenethyl)pivalamide (13) was synthesized (in 93%
yield) on the basis of a literature procedure for analogous
compounds (Scheme 5).9
Scheme 5. Synthesis of
N‑(2‑(2‑Methylphenyl)ethyl)pivalamide (13)
Figure 1. Structures of 15−18.
(13%). The yield of 16 was slightly higher (16%) when t-BuLi
(3 equiv) was used instead of n-BuLi, and slightly higher again
(20%) when 3 equiv of benzophenone was used with t-BuLi.
Significant quantities of 15 (ca. 70−80%) were recovered under
all of the above conditions. There was no evidence for the
formation of α-substitution product in any of the reactions.
When the reaction was carried out under Clark’s conditions
with 1.5 equiv of benzophenone the yield of 16 was good
(80%), and this was improved further to 88% when excess
benzophenone (2.4 equiv) was used.
Lithiation of 13 under the standard conditions that were
used for 4 (Scheme 4), followed by reaction with
benzophenone as a representative electrophile at 0 °C, gave
the corresponding α-substituted product 14 in 86% yield
(Scheme 6). Again, no product due to lateral lithiation and
substitution was isolated.
There are several possible explanations for the low yields of
16 (13−20%) obtained at higher temperature (0 °C). It is
unlikely that lateral lithiation is slow at 0 °C, since lithiation
occurs readily enough at −60 to −25 °C. It was thought to be
possible that the dilithium intermediate 17 (Figure 1),
produced in situ from reaction of 18 and benzophenone, may
be unstable, dissociating back to benzophenone and lateral-
lithiated species 18 and that the proportion of 17 in the
equilibrium mixture would be lower at higher temperature. This
possibility was tested by treating 16 with t-BuLi (2.4 equiv) in
dry THF at 0 °C for 2 h. However, following workup, 16 was
recovered quantitatively (98%). Another possible explanation
would be that at 0 °C the lateral-lithiated species 18 might be
reactive enough to deprotonate THF, leading to the
monolithiated derivative of the starting material 15, which
does not react with benzophenone. A higher yield of 16 (32%
rather than 20%) was obtained when the reaction was
conducted at 0 °C in diethyl ether, providing some support
for this possibility, but it is likely that there are also other
factors in operation.
Scheme 6. Lithiation of 13 Followed by Reaction with
Benzophenone
1
The H NMR spectrum of compound 14 showed that the
signals of the two hydrogens of the CH2 group are
diastereotopic. Also, its 13C NMR spectrum showed that the
carbons of the two phenyl groups appeared as separated signals,
verifying that they are diastereotopic.
The high selectivity for α-lithiation, with no evidence for
lateral lithiation on the methyl group, shown by both N′-(2-(2-
methylphenyl)ethyl)-N,N-dimethylurea (4) and N-(2-(2-
methylphenyl)ethyl)pivalamide (13) was completely at odds
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Article
then washed with H2O (2 × 25 mL). The solid was purified by
crystallization from a mixture of EtOAc and Et2O (1:3 by volume) to
give pure 4 (14.00 g, 95%): white solid; mp 74−76 °C; 1H NMR (500
MHz, CDCl3) δ 7.19−7.14 (m, 4H), 4.48 (br, exch, 1H), 3.46 (t, J = 7
Hz, 2H), 2.88 (s, 6H), 2.86 (t, J = 7 Hz, 2 H), 2.37 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 158.4, 137.5, 136.5, 130.4, 129.4, 126.5, 125.9,
41.0, 36.1, 33.9, 19.3; HRMS calcd for C12H18N2O (M+) 206.1419,
found 206.1414.
The clear distinction between the carbamate 15 on the one
hand and the urea 4 and pivalamide 13 derivatives of 2-(2-
methylphenyl)ethylamine on other hand, with 15 leading to
clean lateral lithiation on the methyl group while the other
derivatives lead to clean α-lithiation on the CH2 group, is
surprising. PM3 calculations suggested that for all three
compound types the dianions (such as 18) resulting from
abstraction of protons from the NH and methyl positions are
intrinsically more stable than the corresponding dianions (such
as 6) resulting from abstraction of protons from the NH and α-
CH2 positions, by 18−43 kJ mol−1 depending on the acyl
substituent. Therefore, the intrinsic pKa values of the
appropriate protons would be expected to lead to lateral
lithiation in all cases. On the basis of the CO stretching
frequencies of the three derivatives, the carbamate would
probably be the poorest at coordinating the organolithium
reagent and therefore least likely to effect proximity-directed
lithiation. This would imply that directed lithiation in the case
of 4 and 13 favors α-lithiation, which would involve a smaller
ring size of interaction between the coordinated organolithium
and the α-protons than between the coordinated organolithium
and the protons of the methyl group. It would further imply
that when coordination is insufficiently strong to effect directed
lithiation, so that the intrinsic reactivity of the relevant protons
becomes the dominant influence over the site of lithiation, a
more acidic methyl proton in monodeprotonated 15 is the one
removed. However, whatever the precise explanation, it is clear
that by varying the acyl substituent on nitrogen, it is possible to
select either α-lithiation or lateral lithiation of a 2-(2-
methylphenyl)ethylamine derivative, which must have signifi-
cant benefit for organic synthesis.
Substituted N′-(2-(2-Methylphenyl)ethyl)-N,N-dimethylur-
eas 7−12: General Procedure. A solution of n-BuLi in hexane
(1.82 mL, 1.60 M, 2.91 mmol) was added to a stirred solution of 2
(0.20 g, 0.97 mmol) at 0 °C in anhydrous THF (15 mL) under a N2
atmosphere. The mixture was stirred at 0 °C for 2 h, and the
electrophile (1.16 mmol), in anhydrous THF (5 mL) if solid, neat
otherwise, was added. The reaction mixture was stirred for 2 h at 0 °C.
The reaction mixture was quenched with a saturated aqueous solution
of 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 residue obtained was purified
by column chromatography (silica gel; Et2O) to give the pure
products. The yields obtained of products 7−12 were in the range of
74−93% based on the starting material 4 (Table 2).
N′-[3-Hydroxy-2-(2-methylphenyl)-3,3-diphenylpropyl]-N,N-
1
dimethylurea (7): 0.35 g (93%); white solid; mp 163−166 °C; H
NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8 Hz, 1H), 7.70 (dd, J = 1, 8
Hz, 2H), 7.24 (apt. t, J = 8 Hz, 2H), 7.17 (dd, J = 1, 8 Hz, 2H), 7.10
(app. t, J = 8 Hz, 1H), 6.95 (app. dt, J = 1, 8 Hz, 1H), 6.90−6.86 (m,
4H), 6.79 (app. t, J = 8 Hz, 1H), 5.53 (br s, exch, 1H), 4.40 (dd, J = 5,
8.5 Hz, 1H), 4.03−3.92 (m, 2H), 3.20 (m, 1H), 2.43 (s, 6H), 2.22 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 158.6, 148.6, 146.7, 138.6, 135.9,
129.7, 129.5, 127.9, 127.2, 126.22, 126.20, 125.8, 125.8, 125.6, 125.5,
79.2, 48.0, 42.6, 35.8, 20.2; HRMS calcd for C25H26N2O (M − H2O+)
370.2045, found 370.2040.
N′-[3-Hydroxy-2-(2-methylphenyl)-3-(4-methoxyphenyl)-
butyl]-N,N-dimethylurea (8). Product 8 (0.28 g, 82%) was a
mixture of two racemic diastereoisomers in approximately equal
proportions: yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.66 (br d, J =
8 Hz, 1H), 7.43 (d, J = 9 Hz, 2H), 7.26−6.97 (m, 11H), 6.89 (d, J = 9
Hz, 2H), 6.78 (d, J = 9 Hz, 2H), 4.34 (br s, exch, 1H), 4.04 (br s, exch,
1H), 3.87 (m, 1H), 3.83 (s, 3H), 3.79 (m, 1H), 3.74 (s, 3H), 3.75 (m,
1H), 3.39−3.29 (m, 2H), 3.20 (m, 1H), 2.79(s, 6H), 2.57 (s, 6H),
2.39 (s, 3H), 2.28 (s, 3H), 1.61 (s, 3H), 1.21 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 158.6, 158.5, 158.3, 158.1, 141.2, 139.0, 138.9, 137.5,
137.0, 136.5, 130.4, 130.3, 129.5, 128.3, 127.1, 126.6, 126.7, 126.2,
126.3, 125.8, 113.2, 113.0, 75.6, 74.6, 55.3, 55.2, 49.8, 46.3, 42.1, 41.0,
36.1, 35.8, 30.4, 29.8, 20.4, 19.3; HRMS calcd for C21H26N2O2 (M −
H2O+) 338.1994, found 338.1997.
CONCLUSIONS
■
Unexpected side-chain lithiation of N′-(2-(2-methylphenyl)-
ethyl)-N,N-dimethylurea took place at the CH2 group next to
the phenyl ring (α-lithiation) with 3 equiv of n-BuLi in THF at
0 °C. Reactions of the dilithium reagent obtained with a variety
of electrophiles gave the corresponding α-substituted deriva-
tives in high yields. The process is simple, general, efficient, and
high yielding to provide a range of substituted urea derivatives
that might be difficult to prepare by other means. Similarly,
lithiation of N-(2-(2-methylphenyl)ethyl)pivalamide followed
by reaction with benzophenone as a representative electrophile
gave the corresponding α-substituted product in high yield. No
products due to lateral lithiation and substitution were obtained
under the conditions tried, which is in sharp contrast with the
results obtained with tert-butyl 2-(2-methylphenyl)ethyl-
carbamate.
N′-[2-(1-Hydroxycyclohexyl)-2-(2-methylphenyl)ethyl]-N,N-
1
dimethylurea (9): 0.26 g (90%); white solid; mp 164−166 °C; H
NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7.5 Hz, 1H), 7.13−7.03 (m,
3H), 4.22 (dd, J = 5, 6 Hz, exch, 1H), 3.87 (m, 1H), 3.35 (m, 1H),
3.15 (m, 1H), 2.63 (s, 6H) 2.23 (s, 3H), 1.57−1.01 (m, 10H); 13C
NMR (125 MHz, CDCl3) δ 158.7, 138.9, 137.9, 130.4, 128.0, 126.3,
126.0, 73.5, 49.7, 41.4, 36.3, 35.5, 35.9, 25.7, 21.8, 21.6), 20.6; HRMS
calcd for C18H28N2O2 (M+) 304.2151, found 304.2145.
EXPERIMENTAL SECTION
General Experimental Details. Melting point determinations
N′-[3-Oxo-2-(2-methylphenyl)propyl]-N,N-dimethylurea
■
1
(10): 0.23 g (84%); yellow oil; H NMR (500 MHz, CDCl3) δ 9.64
(br, 1H), 7.20−7.04 (m, 3H), 6.83 (dd, J = 1, 7 Hz, 1H), 4.91 (app. t, J
= 5 Hz, exch, 1H), 4.15 (dd, J = 5, 9 Hz, 1H), 3.54 (m, 1H), 3.45 (m,
1H), 2.79 (s, 6H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
201.4, 158.2, 137.8, 132.4, 131.3, 128.0, 126.5, 55.7, 41.1, 36.1, 19.6;
HRMS calcd for C13H18N2O2 (M+) 234.1368, found 234.1372.
N′-[3-Hydroxy-3-phenyl-2-(2-methylphenyl)propyl]-N,N-di-
methylurea (11). Product 11 (0.24 g, 82%) was a mixture of two
racemic diastereoisomers in approximately equal proportions: yellow
were performed by the open capillary method using a melting point
apparatus and are reported uncorrected. H and 13C NMR spectra
1
1
were recorded on a 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, reported to the nearest 0.5 Hz. High-resolution mass spectra
were recorded on a time-of-fight mass spectrometer using electron
impact (EI).
1
oil; H NMR (500 MHz, CDCl3) δ 7.28−6.92 (m, 18H), 4.94 (br s,
N′-(2-(2-Methylphenyl)ethyl)-N,N-dimethylurea (4). A stirred
mixture of 3 (9.67 g, 71.6 mmol), dimethylcarbamoyl chloride
(DMCC, 8.68 g, 80.7 mmol), and Et3N (9.97 g, 98.5 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
exch, 2H), 4.90 (d, J = 5.5 Hz, 1H), 4.82 (d, J = 5.5 Hz, 1H), 4.58
(app. t, J = 5.5 Hz, exch, 1H), 4.38 (app. t, J = 5.5 Hz, exch, 1H), 3.93
(m, 1H), 3.57 (m, 1H), 3.37−3.30 (m, 4H), 2.77 (s, 6H), 2.70 (s, 6H),
1.99 (s, 3H). 1.96 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.18,
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159.15, 142.96, 142.94, 139.12, 139.11, 136.31, 136.30, 130.54, 153.53,
127.98, 127.82, 127.35, 127.34, 127.03, 127.00, 126.6, 126.5, 126.35,
126.34, 125.73, 125.72, 75.1, 74.6, 49.4, 48.8, 43.0, 42.3, 36.2, 36.1,
19.72, 19.70; HRMS calcd for C19H23N2O (M − OH+) 295.1810,
found 295.1798.
tert-Butyl 2-(2-(2-Hydroxy-2,2-diphenylethyl)phenyl)ethyl-
carbamate (16). A solution of t-BuLi in hexane (1.07 mL, 1.90 M,
2.04 mmol) was added to a stirred solution of 15 (0.20 g, 0.85 mmol)
at −60 °C in anhydrous THF (15 mL) under a N2 atmosphere. The
mixture was stirred at ca. −30 to −25 °C for 1.5 h. A solution of
benzophenone (0.37 g, 2.04 mmol) in anhydrous THF (5 mL) was
added at −60 °C, and the reaction mixture was allowed to warm to 0
°C and stirred for 2 h. The reaction mixture was quenched with a
saturated aqueous solution of 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;
N′-[3-Hydroxy-3-(4-methoxyphenyl)-2-(2-methylphenyl)-
propyl]-N,N-dimethylurea (12). Product 12 (0.26 g, 78%) was a
mixture of two racemic diastereoisomers in approximately equal
proportions: yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.41 (br d, J =
8 Hz, 2H), 7.32 (d, J = 9 Hz, 2H), 7.13 (br t, J = 8 Hz, 2H), 7.06−6.98
(m, 6H), 6.83 (d, J = 9 Hz, 2H), 6.69 (d, J = 9 Hz, 2H), 4.84 (d, J = 6
Hz, 2H), 4.30 (app. t, J = 5.5 Hz, exch, 2H) 3.68 (s, 6H), 3.32−3.28
(m, 4H), 3.17−3.12 (m, 2H), 2.98 (br s, 2H), 2.70 (s, 12H), 1.98 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 158.98, 158.95, 158.83, 158.81,
137.7, 137.6, 134.5, 134.4), 132.5, 132.4, 130.25, 130.21, 129.12,
129.09, 127.77, 127.74, 126.64, 126.61, 126.12, 126.09, 113.57, 113.51,
74.87, 74.85, 55.3, 55.2, 48.55, 48.52, 43.12, 43.14, 36.12, 36.10, 19.9,
19.8; HRMS calcd for C20H25N2O2 (M − OH+) 325.1916, found
325.1912.
1
Et2O) to give pure 16 (0.31 g, 88%): colorless oil; H NMR (500
MHz, CDCl3) δ 7.31 (d, J = 8 Hz, 4H), 7.18 (app. t, J = 8 Hz, 4H),
7.12 (app. t, J = 8 Hz, 2H), 7.03−6.99 (m, 2H), 6.82 (app. dt, J = 2, 8
Hz, 1H), 6.54 (d, J = 8 Hz, 1H), 4.56 (br s, exch, 1H), 4.27 (br, exch,
1H), 3.62 (s, 2H), 3.16 (br, 2H), 2.55 (t, J = 7 Hz, 2H), 1.30 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 156.1, 147.1, 139.1, 134.5, 131.9,
129.5, 128.7, 128.0, 126.9, 126.5), 125.7, 79.3, 77.3, 43.7, 41.4, 33.0,
28.4; HRMS calcd for C27H29NO2 (M − H2O+) 399.2198, found
399.2210.
N-(2-(2-Methylphenyl)ethyl)pivalamide (13). To a cooled
solution (0 °C) of 3 (6.50 g, 48.1 mmol) and Et3N (12.0 mL) in
CH2Cl2 (50 mL) was slowly added pivaloyl chloride (6.42 g, 53.3
mmol) in a dropwise manner over 30 min. The reaction mixture was
stirred at room temperature for 1 h. The mixture was poured onto
H2O (50 mL), the organic layer was separated, washed with H2O (2 ×
50 mL), and dried (MgSO4), and the solvent was then removed under
reduced pressure. The solid obtained was purified by crystallization
from Et2O−hexane (1:1 by volume) to give pure 13 (9.81 g, 93%):
white solid; mp 85−88 °C; 1H NMR (500 MHz, CDCl3) δ 7.20−7.12
(m, 4H), 5.69 (br s, exch, 1H), 3.49 (app. q, J = 7 Hz, 2H), 2.85 (t, J =
7 Hz, 2H), 2.38 (s, 3H), 1.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
178.3, 137.0, 136.4, 130.5, 129.4, 126.6, 126.0, 39.4, 38.7, 33.1, 27.5,
19.3; HRMS calcd for C14H21NO (M+) 219.1623, found 219.1623.
N-[3-Hydroxy-3,3-diphenyl-2-(2-methylphenyl)propyl]-
pivalamide (14). The procedure was identical with that described for
lithiation and substitution of 4 except that it involved 13 (0.20 g, 0.91
mmol), with benzophenone (0.20 g, 1.09 mmol) as the electrophile,
and was carried out at 0 °C. Following workup the crude product was
purified by column chromatography (silica gel; Et2O) to give pure 14
(0.31 g, 86%): white solid; mp 95−98 °C. 1H NMR (500 MHz,
CDCl3) δ 7.63 (dd, J = 1, 7.5 Hz, 2H), 7.58 (d, J = 8 Hz, 1H), 7.26
(app. t, J = 7.5 Hz, 2H), 7.13−7.09 (m, 1H), 6.99 (dd, J = 1, 7.5 Hz,
2H), 6.96 (t, J = 7.5 Hz, 1H), 6.86 (app. t, J = 7.5 Hz, 2H), 6.89−6.80
(m, 3H), 5.32 (t, J = 6 Hz, exch, 1H), 4.37 (app. t, J = 7 Hz, 1H), 3.94
(br s, exch, 1H), 3.83 (m, 1H), 3.26 (m, 1H), 1.97 (s, 3H), 0.78 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 179.4, 146.8, 146.3, 137.6,
137.1, 130.0, 129.1, 128.3, 127.3, 126.9, 126.4, 126.3, 126.0, 125.9,
125.7, 79.8, 46.3, 41.2, 38.4, 27.2, 20.0; HRMS calcd for C27H29NO
(M − H2O+) 383.2253, found 383.2249.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full characterization and NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +44(2920)870600. Fax: +44(2920)870600. E-mail:
(K.S.) smithk13@cardiff.ac.uk, (G.A.E.) el-hitiga@cardiff.ac.uk.
■
Present Address
‡Authors Permanent Address: Department of Chemistry,
Faculty of Science, Tanta University, Tanta 31527, Egypt.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Cardiff University and the Saudi Government for
financial support. We are grateful to Dr. M. C. Elliott and Mr.
B. Saleh for carrying out PM3 calculations.
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1
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1
4H), 4.51 (br s, exch, 1H), 3.26 (t, J = 7 Hz, 2H), 2.73 (t, J = 7 Hz,
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11214
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