Synthesis and conformational analysis of chiral ureas incorporating N-1-phenylethyl groups. Manifestation ofallylic 1,3-strain

Article abstract of DOI:10.1002/poc.939

The synthesis of novel chiral ureas (R,R)-2, (S,S)-3 and (R)-6 incorporating the α-phenylethyl group is described. Conformational analysis of these ureas, and of previously reported (R,R)-1, was carried out computationally, both at semiempirical (AMI and

Full text of DOI:10.1002/poc.939

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2005; 18: 792–799
Published online 5 May 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.939
Synthesis and conformational analysis of chiral ureas
incorporating N-1-phenylethyl groups. Manifestation
y
of allylic 1,3-strain
´
´
´
Marcos Hernandez-Rodrıguez, Roberto Melgar-Fernandez and Eusebio Juaristi*
´
´
´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apdo. Postal 14-740,
´
´
07000 Mexico, D. F., Mexico
Received 1 February 2005; revised 20 February 2005; accepted 25 February 2005
ABSTRACT: The synthesis of novel chiral ureas (R,R)-2, (S,S)-3 and (R)-6 incorporating the ꢀ-phenylethyl group is
described. Conformational analysis of these ureas, and of previously reported (R,R)-1, was carried out computation-
ally, both at semiempirical (AM1 and PM3) and ab initio (HF and B3LYP) levels, and experimentally from x-ray
crystallographic analysis of (R,R)-2 and (S,S)-3, and in the case of (R)-6 by means of NOE NMR spectroscopy.
A substantial preference of 1.5–2.6 kcal molꢀ1 in favor of conformations with syn-periplanar arrangements between
the C—H bond at the ꢀ-phenylethyl N-substituent and the N—C(O) segment was found, and this observation
confirms the relevance of allylic A1,3 strain in this system. The possibility of hydrogen bonding in the syn-periplanar
—
C—Hꢁ ꢁ ꢁO C—N arrangement was discarded in the light of topological analysis of (R,R)-1, within the frame of
—
Bader’s atoms in molecules theory. Copyright # 2005 John Wiley & Sons, Ltd.
KEYWORDS: chiral ureas; conformational analysis; allylic 1,3-strain; theoretical chemistry; density functional theory;
ab initio calculations
INTRODUCTION
potential of these chiral Lewis bases as promoters of
stereoselective reactions will depend on the possibility
that the N-1-phenylethyl chiral adjuvant (for recent
reviews on applications of 1-phenylethylamine in the
preparation of enantiomerically pure compounds, see
Ref. 13) adopts a single or predominant conformation
in the molecule. In particular, conformations presenting
coplanar orientation between the C—H bond and the
N—C(O) segment should be preferred in order to prevent
allylic A1,3 strain,14 which would be present in the other
Urea and its derivatives constitute an important class of
organic compounds with a great variety of applications in
fundamental and applied science. They find extensive
application as antioxidants in gasoline,1 dyes for cellulose
fibers,1 non-linear optical devices,2 resin precursors3 and
synthetic intermediates.4 Moreover, the presence of the
urea moiety in many biologically important natural com-
pounds, such as nucleotides, vitamin B13 and enzymes,5
renders it a subject of great interest in biochemistry and
related areas. Furthermore, urea-based drugs have been
developed that are effective antitumor agents6 and HIV
protease inhibitors.7 Finally, the anion binding properties
of urea, owing to its ability to form two hydrogen bonds,8
have been exploited in several relevant areas such as anion
recognition and sensing,9 enantioselective asymmetric
synthesis10 and kinetic resolution of chiral compounds.11
In this context, the synthesis of new chiral ureas (R,R)-
1 and (S,S)-1, incorporating the 1-phenylethyl group at
the N-atoms was recently reported12 [Scheme 1(a)]. The
possible conformations around the N—CHMePh bond.
—
Indeed, N ! C O conjugation in the urea segment
—
effectively places the phenethyl group in an allylic-like
position, so that the C—H bond, being the smallest
substituent at the stereogenic carbon, should adopt a
syn-periplanar arrangement in relation to the N—C(O)
segment [Scheme 1(b)].
This paper concerns the preparation and conforma-
tional analysis of several chiral ureas structurally related
to 1.
RESULTS AND DISCUSSION
´
*Correspondence to: E. Juaristi, Departamento de Quımica, Centro de
Investigacion y de Estudios Avanzados del Instituto Politecnico
´
´
´
´
Nacional, Apdo. Postal 14-740, 07000 Mexico, D. F., Mexico.
E-mail: ejuaristi@cinvestav.mx
Preparation of chiral ureas 2–5
Contract/grant sponsor: Conacyt; Contract grant number: 45157.
ySeleted paper presented for a special issue dedicated to Professor Otto
Exner on the occasion of his 80th birthday.
Acyclic chiral urea (R,R)-2 was obtained by reaction of
(R)-1-phenylethylamine with triphosgene in the presence
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 792–799

SYNTHESIS AND CONFORMATIONAL ANALYSIS OF CHIRAL UREAS
793
Scheme 1
of triethylamine and methylene chloride as solvent,
according to the procedure described in the literature15
[Scheme 2(a)]. Similarly, N,N0-bis[(S)-1-phenylethy-
l]ethane-1,2-diamine16 was the starting material for the
preparation of five-membered urea (S,S)-3 [Scheme 2(b)].
Non-C2-symmetric chiral urea (R)-6 was synthesized
from acrylonitrile via conjugate addition of (R)-1-pheny-
lethylamine followed by catalytic hydrogenation and
condensation with triphosgene [Scheme 2(c)].
syn-periplanar to the N—C(O) segment.12 This solid-
state conformation is also predicted to be the most stable
in the gas phase, at various levels of theory (Table 1).
All ab initio methods predict conformation A to
be significantly more stable than conformation B, by
2.2–2.6 kcal molꢀ1 (1 kcal ¼ 4.184 kJ). For comparison,
Broeker et al.17 calculated (4S)-phenyl-(2Z)-pentene to
—
prefer the a syn-periplanar (C C/C—H) arrangement C
—
by 1.5 kcal molꢀ1 over arrangement D [Eqn (1)]:
Conformational analysis
ð1Þ
N,N0-Bis[(R)-1-phenylethyl]propyleneurea, (R,R)-1
As expected from allylic A1,3 strain, x-ray analysis of
single crystals of (R,R)-1 showed an orientation of the 1-
phenylethyl groups in which the C—H bonds are nearly
whereas Tietze and Schulz18 found from ab initio calcu-
lations on 3-methyl-1-butene rotamer E (syn-periplanar
Scheme 2
Copyright # 2005 John Wiley & Sons, Ltd.
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M. HERNANDEZ-RODRIGUEZ, R. MELGAR-FERNANDEZ AND E. JUARISTI
794
Table 1. Calculated (gas-phase) conformational preference of the N-(1-phenylethyl) N-substituents in (R,R)-1
ÁE
Dihedral [H—C*—N—C(O)] angles ( ꢂ)
Method
(kcal molꢀ1
)
A
B
AM1
PM3
HF/3–21G
HF/6–31G**
B3LYP/6–31G*
B3LYP/6–31G**
B3LYP/6–311þG**//B3LYP/6–31G*
1.69
1.27
2.19
2.54
2.35
2.33
2.59
28.9 and 26.5
27.1 and 32.4
14.7 and 14.9
2.9 and ꢀ14.5
3.0 and 7.9
28.6 and ꢀ163.7
34.0 and ꢀ176.7
5.9 and ꢀ165.1
ꢀ3.6 and 170.4
2.8 and ꢀ169.4
2.8 and ꢀ170.1
2.8 and ꢀ169.4
3.0 and 7.6
3.0 and 7.9
—
orientation between the C C double bond and the
—
Two of the most important contributions of the AIM
theory are the precise definition of an atom in a molecule
and the definition of the chemical bond. These concepts
correspond to the topological properties of the electron
density.21 The chemical structure of a molecule is un-
ambiguously described determining the critical points
through the electron density (ꢁ) and corresponds to the
gradient zero density points. These points, and also
the first and second derivatives, can be determined with
the use of the AIM200022 program. From the second
derivative, it is possible to determine the three principal
curvatures associated with a critical point due to its index
(the algebraic addition of the curvature sign). In addition
to density, ellipticity is an important property of a critical
point. This is defined as the coefficient of the negative
curves along the perpendicular axis to the bonding path,
" ¼ ꢂð1Þ=ꢂð2Þ ꢀ 1, and should be considered as an index
methine C—H bond) to be 2.48 kcal molꢀ1 more stable
than rotamer F (anti-periplanar orientation) [Eqn (2)]:
ð2Þ
The experimentally obtained [x-ray diffraction analysis
of crystalline (R,R)-1; see Ref. 12] interatomic distance
between the carbonyl oxygen and the methine C—H
˚
hydrogen on the 1-phenylethyl group is 2.27 A, which is
less than the sum of the atomic van der Waals radii for
19
˚
oxygen and hydrogen, 1.50 and 1.20 A, respectively.
Hence the possibility of the existence of a hydrogen
bonding interaction that could contribute to the stabiliza-
tion of conformer A in the equilibrium depicted in
Table 1 was considered. Nevertheless, it must be pointed
out that two recent, high-level theoretical studies20 of the
N-methyl rotational barriers in amide and urea derivatives
concluded that staggered conformers G are 0.3–
0.8 kcal molꢀ1 more stable than conformers H [Eqn (3)],
in which one could expect that hydrogen bonding stabi-
lization would be more efficient.
of a bond’s anisotropy.
—
Figure 1 shows the calculated C—Hꢁ ꢁ ꢁO C bond
—
trajectories and critical points between atoms in the
electron density analysis of (R,R)-1. Most relevant, the
—
C—Hꢁ ꢁ ꢁO C bond trajectories present low electronic
—
ð3Þ
To obtain information regarding the nature of the C—
—
Hꢁ ꢁ ꢁO C interaction in A (Table 1), theoretical analy-
—
sis within the frame of the topological theory of atoms in
molecules21 was carried out. The AIM200022 set of
programs was used, obtaining the properties of atoms
and critical points (cps) in the charge density: electron
Figure 1. Critical points and bonding trajectories in the
electron density of (R,R)-1 calculated at the HF/6–
311þG**//HF/6–31G** level of theory (for clarity, Ph
groups have been deleted)
2
density (ꢁ), Laplacians (r ꢁ) and ellipticities (").
Copyright # 2005 John Wiley & Sons, Ltd.
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SYNTHESIS AND CONFORMATIONAL ANALYSIS OF CHIRAL UREAS
795
Table 2. Properties of critical points associated with weak
interactions in (R,R)-1 (see Fig. 1)
respectively) (Table 2) are indicative of a minor
interaction.23
ꢀ3
˚
Point ꢁ (e A
)
ꢃ
xa
ya
za
N,N0-Bis[(R)-1-phenylethyl]urea, (R,R)-2. Relative to
cyclic urea (R,R)-1 (see above), the conformational
behavior of the acyclic urea (R)-2 is much more complex
since rotation around the amidic segments leads to
various possible arrangements of the 1-phenylethyl group
in combination with E and Z conformations (see, for
example, Ref. 24). An ab initio DFT (B3LYP/6–31G*
level) evaluation of all rotamers originating from rotation
around the N—C(O) and N—C(H) bonds afforded the
seven energy minima (E < 5.0 kcal molꢀ1), which are
given in Table 3. This table does not include conformer
EEa, whose energy was estimated to be
ab
bb
cc
dc
ec
0.022
1.865 ꢀ0.0230
3.752 ꢀ0.0221
ꢀ0.022
ꢀ0.0080
ꢀ0.0046
0.0097
0.0052
0.0769
0.1326
0.1301
0.1272
0.1275
0.0825
0.0213
0.0215
0.0213
0.0197
ꢀ0.0215
ꢀ0.0148
a Eigenvalues of the Hessian at critical point.
b Critical bond point (3, ꢀ1).
c Critical ring point (3, þ1).
density at the critical points a and b (ꢁ ¼ 0.022 and
0.021 e Aꢀ3, respectively) which is indicative of a very
˚
weak bonding interaction. In contrast, bonding interac-
tions are usually associated with much larger electronic
densities; for example, a typical A—Hꢁ ꢁ ꢁB hydrogen
>12.0 kcal molꢀ1
.
It can be appreciated from Table 3 that the two
conformers of lowest energy, i.e. EZa and ZZa (Erel ¼ 0.0
0.0 and 0.2 kcal molꢀ1, respectively), fulfil expectations
in terms of the concept of allylic A1,3 strain. Indeed,
the C—H bonds in these conformers are oriented in a
ꢀ3
˚
bond presents ꢁ ꢃ 0.36 e A
(Ref. 21) (Fig. 1 and
Table 2). Furthermore, the large ellipticity parameters
for critical points a and b in (R,R)-1 (1.865 and 3.752,
Table 3. Relative energies for the conformers of lowest energy of (R,R)-2, according to ab initio DFT B3LYP/6–31G*
calculations
Conformer
Total energy (hartree)
Erel. (kcal molꢀ1
)
Dihedral H—C*—N—C(O) angles ( ꢂ)
ZZa
ZZb
ZZc
EZa
EZb
EZc
EZd
ꢀ844.272822
ꢀ844.268623
ꢀ844.266308
ꢀ844.273178
ꢀ844.268699
ꢀ844.26946
ꢀ844.265698
0.22
2.86
4.31
0.00
2.81
2.33
4.69
ꢀ24.6 and ꢀ24.6
ꢀ13.4 and ꢀ167.5
166.7 and ꢀ166.7
ꢀ26.4 and ꢀ38.4
39.8 and 173.4
164.0 and ꢀ39.5
167.7 and 171.6
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 792–799

´
M. HERNANDEZ-RODRIGUEZ, R. MELGAR-FERNANDEZ AND E. JUARISTI
´
´
796
Table 4. Optimized geometry of lowest energy in (R,R)-1,
(R,R)-2, (S,S)-3 and (R)-6 at the B3LYP/6–31G* level (dis-
˚
tances in A, angles in degrees; the phenyl ring is not
included).
Figure 2. X-ray crystallographic structure and solid-state
conformation of N,N0-bis[(R)-1-phenylethyl]urea, (R,R)-2
(R,R)-1
(R,R)-2 (S,S)-3 (R)-6
N1—C2
C2—N3
N1—C4
C4—H5
C2—O6
N1—C2—N3
N1—C4—H5
N1—C2—O6
N3—C2—O6
H5—C4—N1—C2
C4—N1—C2—O6
C4—N1—C2—N3
1.385
1.385
1.478
1.091
1.238
117.3
104.0
121.3
121.4
7.6
1.378
1.391
1.472
1.092
1.230
115.3
104.4
123.8
120.9
ꢀ26.4
8.7
1.387 1.387
1.387 1.381
1.470 1.478
1.094 1.092
1.228 1.232
108.0 116.5
103.5 103.6
126.0 123.2
126.0 120.3
ꢀ26.6 ꢀ12.7
syn-periplanar manner to the N—C(O) segment. In the
rest of the isomers, allylic A1,3 strain induced by the
methyl and phenyl substituents results in higher energy
content (lower stability).
Figure 2 presents the x-ray crystallographic struc-
ture and the solid-state conformation of (R,R)-2. The
structure was solved and refined using SHELX-97,25a
within WinGX program version 1.64.05.28.25b Crystal
data: C17H20N2O1, molecular weight ¼ 268.35, ortho-
1.3
ꢀ179.6
1.3
5.6
ꢀ168.9
162.2 ꢀ177.3
˚
˚
rhombic P2 21 21, a ¼ 4.6697(2) A, b ¼ 9.8125(4) A,
ꢂ
ꢂ
ꢂ
˚
c ¼ 16.3979(7) A, ꢀ ¼ 90.0 , ꢄ ¼ 90.0 , ꢅ ¼ 90.0 , V ¼
751.38(5) A , crystal size 0.17 ꢄ 0.30 ꢄ 0.48 mm3,
3
˚
R1 ¼ 0.0401 (wR2 ¼ 0.0982). [Atomic coordinates for
the structures reported in this paper have been deposited
at the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request from the Direc-
tor, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 IEZ, UK (Fax þ44 1223 336036;
E-mail: deposit@ccdc.cam.ac.uk; deposition number
CCDC 263119.] The C—H bonds at the N-1-phenylethyl
groups orient themselves in a syn-periplanar manner
of theory. This difference in conformational bias can
easily be accounted for in terms of the structural differ-
ences in the five- and six-membered rings. In particular,
the interatomic distance between the carbonyl oxygen
and the C—H hydrogen of interest are estimated as
˚
˚
2.15 A in (R,R)-1 and 2.39 A in (S,S)-3. Hence, manifes-
tation of the allylic A1,3 strain effect is more evident in
the former system.
Recrystallization of (S,S)-3 afforded single crystals
suitable for x-ray analysis (Fig. 3). The structure was
solved and refined using SHELX-97,25a within WinGX
— —
O segment. Therefore, as a
--- ---
relative to the N
C
consequence of allylic A1,3 strain, the molecule adopts
a quasi-C2 arrangement in the crystal.
program
version
1.64.05.28.25b
Crystal
data:
C19H22N201, molecular weight ¼ 294.39, orthorhombic
N,N0-Bis[(S)-1-phenylethyl]propyleneurea, (S,S-3.
This chiral urea was modeled at the B3LYP/6–31G*
level. The optimized structure (Table 4) presents a half-
chair ring conformation with the carbonyl group oriented
along the C2 symmetry axis. The calculated energy
difference between conformers I and J [Eqn (4)] is
1.27 kcal molꢀ1, the former being more stable.
P212121, a ¼ 8.6014(3) A, b ¼ 12.1590(4) A, c ¼
˚
˚
ꢂ
ꢂ
ꢂ
˚
15.8840(6) A, ꢀ ¼ 90.0 , ꢄ ¼ 90.0 , ꢅ ¼ 90.0 , V ¼
3
3
˚
1661.22(10) A , crystal size 0.30 ꢄ 0.37 ꢄ 0.40 mm ,
R1 ¼ 0.0394 (wR2 ¼ 0.0846) (deposition number CCDC
263120). Most interesting is the propeller-like orientation
ð4Þ
Again, in conformer I [syn-periplanar arrangement
between the C—H bond and the N—C(O) segment]
allylic A1,3 strain is minimized. Nevertheless, it can be
appreciated that ÁE(IÐJ) ¼ 1.27 kcal molꢀ1 in (S,S)-3 is
significantly lower than ÁE(AÐB) ¼ 2.35 kcal molꢀ1
calculated for six-membered (R,R)-1 at the same level
Figure 3. X-ray crystallographic structure and solid-state
conformation of N,N0-bis[(S)-1-phenylethyl]ethyleneurea,
(S,S)-3
Copyright # 2005 John Wiley & Sons, Ltd.
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SYNTHESIS AND CONFORMATIONAL ANALYSIS OF CHIRAL UREAS
797
Figure 4. Rotation around the N—C* bond in (R)-6, according to HF/3–21G* calculations (fully optimized geometries)
of the 1-phenylethyl groups, which are expected to lead to
high enantioselectivities in reactions taking place with a
Summary
—
suitable substrate coordinated to the C O oxygen atom.
—
Again, the solid-state structure of (S,S)-3 fulfils expecta-
tion based on the concept of allylic A1,3 strain.
Theoretical analysis by means of semiempirical (AM1
and PM3) and ab initio (HF and DFT) methods confirm
the predominance of those conformations that minimize
allylic A1,3 strain in N-(1-phenylethyl)-containing ureas
1–3 and 6. This conformational bias suggests that chiral
ureas such as 1–3 and 6 or their derivatives should be
effective promoters of stereoselective reactions,27 owing
to the substantial steric and electronic differences pre-
sented by the hydrogen, methyl and phenyl groups in the
1-phenylethyl chiral auxiliary.
N-[(R)-1-Phenylethyl]propyleneurea, (R)-6. The po-
tential energy surface (PES) presented in Fig. 4 was
obtained by constraining the H—C—N—C(O) dihedral
angle for rotation about the C—N bond and fully
optimizing (B3LYP/6–31G* level) the remaining internal
coordinates. Intervals of 10 ꢂ were used.
As seen in Fig. 2, the two lowest energy rotamers
present H—C—N—C(O) dihedral angles of 0 ꢂ and
195 ꢂ, the former being 2.04 kcal molꢀ1 more stable.
Once again, this observation is in agreement with ex-
pectation in terms of minimization of allylic A1,3 strain.
Support for this conclusion was acquired experimen-
tally by means of 1H NMR spectroscopy, and in particular
from observation of a significant nuclear Overhauser
effect (NOE) on one of the diastereotopic26 hydrogens
adjacent to the N-1-phenylethyl group. As illustrated in
Eqn (5), a 2.4% enhancement at HA upon irradiation of
the methyl group is congruent with a predominance of
conformer K and a dihedral angle ꢆ ¼ 0 ꢂ.
EXPERIMENTAL
General methods
TLC: silica gel F254 plates; detection with UV radiation
or iodine vapor. Flash column chromatography:28 silica
gel (230–400 mesh). Melting-points: not corrected.
1H NMR spectra: 60, 270 and 400 MHz spectrometers.
13C NMR spectra: 22.5, 67.8, and 100 MHz spectro-
meters. Chemical shifts (ꢇ) in ppm downfield from
internal TMS reference; the coupling constants (J) are
given in Hz. Optical rotations were measured in a
polarimeter, using the sodium D-line (589 nm). Mass
spectra: 20 eV.
Computational methods
ð5Þ
Geometry optimizations (with no symmetry constraints)
of all conformers were performed using semiempirical
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 792–799

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M. HERNANDEZ-RODRIGUEZ, R. MELGAR-FERNANDEZ AND E. JUARISTI
798
(PM3 and AM1) and ab initio (HF and B3LYP) methods,
using the Gaussian 98, Revision A.7,29 series of pro-
grams. Thermodynamic corrections of energy in ab initio
calculations were carried out by zero-point energy (ZPE)
correction. The consideration of electronic correlation is
very important in conformational studies;30 thus, hybrid
functionals B3LYP at the 6–31G(d,p) or 6–31G(d) level
and also ab initio level were examined.
3-[(R)-1-Phenylethylamino]propionitrile, (R)-4. In
a
125 ml round-bottomed flask provided with a magnetic
stirrer was placed 11.0 g (90.9 mmol) of (R)-1-pheny-
lethylamine dissolved in 60 ml of methanol. To this
solution was added 6.95 ml (100 mmol) of acrylonitrile
and the resulting mixture was heated at reflux for 18 h.
Concentration in a rotary evaporator afforded the crude
product that was distilled in a Kugelrohr at 110–113 ꢂC/
0.1 mmHg to give 14.9 g (95% yield) of (R)-4,
Topological analysis of (R,R)-1 was possible by means
of AIM200022 (atoms in molecules package), a set of
programs that defines the properties of atoms and bond-
25 ꢂC
1
[ꢀ]D
¼ þ69.9 (c ¼ 1.55, CHCl3). H NMR (CDCl3,
400 MHz): ꢇ 1.37 (d, J ¼ 6.6 Hz, 3H), 1.55 (bs, 1H),
2.31–2.49 (m, 2H), 2.69–2.84 (m, 2H), 3.81 (q, J ¼ 6.6,
1H), 7.24–7.37 (m, 5H). 13C NMR (CDCl3, 100 MHz): ꢇ
18.9, 24.5, 42.9, 57.8, 118.8, 126.5, 127.3, 128.6, 144.8.
MS: m/z 174 (Mþ, 1), 160 (12), 159 (100), 105 (41),
91 (10).
2
ing patterns [charge density (ꢁ), Laplacians (r ꢁ) and
ellipticities (") of critical points between atoms] in a
molecule.
Syntheses
N-[(R)-1-Phenylethyl]propylene-1,3-diamine, (R)-5. In a
hydrogenation flask were placed 3.33 g (19.1 mmol) of
(R)-4 and 0.33 g of 5% rhodium on alumina before the
addition of 60 ml of methanol saturated with ammonia.
The flask was pressurized to 500 psi of hydrogen and
shaken at ambient temperature for 18 h. The reaction
mixture was filtered over Celite, concentrated and the
crude product was purified by distillation in a Kugelrohr,
N,N0-Bis[(R)-1-phenylethyl]propyleneurea, (R,R)-1. This
compound was prepared according to the procedure
developed in our laboratory.12
N,N0-Bis[(R)-1-phenylethyl]urea, (R,R)-2. The procedure
described in the literature15 was followed. The crude
product was purified by silica gel flash chromatography28
(CH2Cl2–AcOEt, 8:2) to give a white solid (79% yield),
¼ þ
b.p. 100–105 ꢂC/1.0 mmHg, to afford 3.06 g (90% yield)
25 ꢂC
25 ꢂC
m.p. 209–210 ꢂC (lit.31 m.p. 207–209 ꢂC). [ꢀ]D
of (R)-5 as a colorless liquid, [ꢀ]D
¼ þ53.0 ꢂ
25 ꢂC
1
55.6 (c ¼ 0.85, EtOH) {lit.31 [ꢀ]D
¼ þ 51.7 (EtOH,
(c ¼ 1.86, CHCl3). H NMR (CDCl3, 300 MHz): ꢇ 1.34
(d, J ¼ 6.6 Hz, 3H), 1.59 (ꢅq, J ¼ 6.8 Hz, 2H), 2.06 (br,
3H), 2.40–2.59 (m, 2H), 2.72 (ꢅt, J ¼ 6.8, 2H); 3.73 (q,
J ¼ 6.6, 1H), 7.21–7.32 (m, 5H). 13C NMR (CDCl3,
75 MHz): ꢇ 24.5, 34.0, 40.6, 45.7, 58.5, 126.9, 127.2,
128.8, 145.8. MS: m/z 179 (Mþ þ 1, 5), 120 (100), 105
(94), 91 (34), 73 (60). HRMS (FAB): calcd for C11H19N2
(Mþ þ H): 179.1548. Found: 179.1541.
1
concentration not given)}. H NMR (400 MHz, DMSO-
d6): ꢇ 1.26 (d, J ¼ 7.0 Hz, 6H), 4.69 (dq, J1 ¼ 8.0 Hz,
J2 ¼ 7.0 Hz, 2H), 6.25 (d, J ¼ 8.0 Hz, 2H), 7.16–7.32 (m,
10H). 13C NMR (100 MHz, DMSO-d6): ꢇ 23.9, 40.6,
126.2, 126.9, 128.7, 146.2, 157.0.
N,N0-Bis[(S)-1-phenylethyl]ethyleneurea, (S,S)-3. In a
250 ml round-bottomed flask provided with a magnetic
stirrer was placed 5.37 g (20.0 mmol) of N,N0-bis[(S)-1-
phenylethyl]ethane-1,2-diamine16 dissolved in 100 ml of
dichloromethane. The solution was cooled to 0 ꢂC before
the dropwise addition of 2.11 g (7.1 mmol) of triphosgene
dissolved in 50 ml of dichloromethane. The ice–water
bath was removed and stirring was continued for 24 h.
Isolation of the product involved addition of 50 ml of
1.0 M HCl. The aqueous phase was separated and washed
with 50 ml of dichloromethane and the combined organic
layers were dried and concentrated in a rotary evaporator.
The crude product was purified by flash chromatogra-
phy28 (hexane–EtOAc, 9:1) to give 2.36 g (40% yield)
N-[(R)-1-Phenylethyl]propyleneurea, (R)-6. In a 150 ml
round-bottomed flask provided with a magnetic stirrer
were placed 2.3 g (12.8 mmol) of (R)-5, 3.6 ml
(26.1 mmol) of triethylamine and 8.0 ml of dichloro-
methane. The resulting solution was cooled to 0 ꢂC before
the dropwise addition of 1.3 g (4.5 mmol) of triphosgene
dissolved in 30 ml of dichloromethane. Stirring was
continued for 30 min at 0 ꢂC and for 2 days at ambient
temperature. The reaction mixture was treated with 50 ml
of 1.0 M HCl and the organic phase was separated,
washed with brine solution, dried and concentrated to
give the crude product, which was purified by flash
cromatography28 with EtOAc as eluent. (R)-6 was ob-
of (S,S)-3 as white crystals, m.p. 73–74 ꢂC.
25 ꢂC
[ꢀ]D
¼ ꢀ 84.4 (c ¼ 2.2, CHCl3). 1H NMR
tained (2.05 g, 78% yield) as white crystals, m.p. 94–
96 ꢂC [ꢀ]D
25 ꢂC
(300 MHz, CDCl3): ꢇ 1.49 (d, J ¼ 7.1 Hz, 6H), 2.86 (m,
2H), 3.17 (m, 2H), 5.32 (q, J ¼ 7.1 Hz, 2H), 7.24–7.35
(m, 10H). 13C NMR (75 MHz, CDCl3): ꢇ 16.3, 37.7, 50.3,
127.2, 127.3, 128.4, 140.9, 160.1. MS: m/z 294 (Mþ, 53),
280 (14), 189 (42), 175 (45), 105 (100). Anal. calcd for
C19H22N2O: C, 77.51; H, 7.53. Found: C, 77.59; H,
7.75%.
¼ þ99.2 ꢂ (c ¼ 1, CHCl3). 1H NMR
(CDCl3, 400 MHz): ꢇ 1.50 (d, J ¼ 7.0 Hz, 3H), 1.78 (m,
2H), 2.79 (m, 1H), 3.08 (m, 1H), 3.27 (m, 2H), 5.28 (bs,
1H), 5.89 (q, J ¼ 7.0 Hz, 1H), 7.21–7.36 (m, 5H). 13C
NMR (CDCl3, 100 MHz): ꢇ 15.8, 22.3, 39.3, 40.5, 50.6,
127.0, 127.4, 128.4, 141.5, 156.5. MS: m/z 205 (Mþ þ 1,
17), 204 (Mþ, 100), 189 (87), 161 (24), 127 (16), 105
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 792–799

SYNTHESIS AND CONFORMATIONAL ANALYSIS OF CHIRAL UREAS
799
11. Berkessel A, Cleemann F, Mukherjee S, Mueller TN, Lex J.
Angew. Chem. Int. Ed. 2005; 44: 807–811.
(21). Anal. Calcd for C12H16N2O: C, 70.56; H, 7.90; N,
13.70. Found: C, 70.45; H, 8.11; N, 13.78%
´
´
´
12. Juaristi E, Hernandez-Rodrıguez M, Lopez-Ruiz H, Avin˜a J,
Mun˜oz-Mun˜iz O, Hayakawa M, Seebach D. Helv. Chim. Acta
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We are grateful to Professor Maria de Jesus Rosales for
useful discussions, Q. C. Gabriela Avila-Ortiz for tech-
´
nical assistance and Conacyt, Mexico, for generous
financial support via grant 45157.
´
Herradon B, Hidber PC, Irwin JJ, Locher R, Maestro M, Maetzke
T, Mourin˜o A, Pfammatter E, Plattner DA, Schickli C, Schweizer
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Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 792–799