Synthesis of novel chiral (thio)ureas and their application as organocatalysts and ligands in asymmetric synthesis

Article abstract of DOI:10.1071/CH08116

The synthesis of novel chiral (thio)ureas 1 - 10 and 14 - 26 is described. These (thio)ureas incorporate chiral auxiliaries derived from (R)- or (S)-α-phenylethylamine, (R)-phenylglycine, or (1R,2S)-ephedrine. The phenylethyl group in compounds 1 - 10 and

Full text of DOI:10.1071/CH08116

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 364–375
www.publish.csiro.au/journals/ajc
Synthesis of Novel Chiral (Thio)ureas and Their Application
as Organocatalysts and Ligands in Asymmetric Synthesis
Marcos Hernández-Rodríguez,A Claudia Gabriela Avila-Ortiz,A
Jorge M. del Campo,A Delia Hernández-Romero,A
María J. Rosales-Hoz,A and Eusebio JuaristiA,B
ADepartamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto
Politécnico Nacional, Apartado Postal 14-740, 07000, México, DF, Mexico.
BCorresponding author. Email: juaristi@relaq.mx
The synthesis of novel chiral (thio)ureas 1–10 and 14–26 is described. These (thio)ureas incorporate chiral auxiliaries
derived from (R)- or (S)-α-phenylethylamine, (R)-phenylglycine, or (1R,2S)-ephedrine. The phenylethyl group in com-
pounds 1–10 and 21–24 adopts a particular orientation in the molecular structure as a consequence of 1,3-allylic strain
with the (thio)carbonyl group. Ureas 1–10 were tested as Lewis basic organocatalysts in epoxide ring opening and in
aldolic condensation, and it was found that the tetrasubstituted urea (R,R)-2 afforded the best results in terms of reaction
yields. (Thio)ureas 20–26 were examined as ligands in the enantioselective diethylzinc addition to benzaldehyde, observ-
ing that C2-symmetric chiral urea (R,S,R,S)-20 provides the expected carbinol in nearly quantitative yield and in up to
62% enantiomeric excess.
Manuscript received: 20 March 2008.
Final version: 18 April 2008.
Introduction
In this context, Denmark’s work with chiral phosphoramides
(chiral HMPA analogues) provided a novel kind of organocat-
alytic activity, i.e. by means of Lewis basic activation, in the
following reactions: aldol condensation,[11] epoxide ring open-
ing by weak nucleophiles,[12] and allylation.[13] In principle,
ureas can also be employed as Lewis bases for this kind of
nucleophilic reactions,[14] as well as in organolithium chem-
istry. In particular, related Lewis bases that have been used as
chiral organocatalysts in enantioselective allylation reactions are
N-oxides,[15] and sulfoxides.[16]
In addition, thioureas have been shown to be efficient and
air-stable ligands that enhance reaction rates in a large variety
of systems.[17] Furthermore, the capability to act as hydrogen-
bond donors enables (thio)ureas to function as anion recognizing
and sensing agents.[18] Indeed, when a chiral carboxylate is per-
ceived with a chiral thiourea, enantiodiscrimination becomes
feasible.[19]
The search for new synthetic methodologies by means of novel
reagents or catalysts is a never-ending task in organic chemistry.
In the past few years, organocatalysis has become a powerful
tool in synthetic chemistry as a consequence of several major
advantages; in particular, (1) it employs relatively simple and
inexpensive reagents; (2) it proceeds under mild reaction condi-
tions; and (3) it does not require of the use of potentially toxic
or sensitive metals.[1] Salient developments in organocatalysis
recently reported are based in the (thio)urea moiety, which can
act as a Brønsted acid by forming hydrogen bonds to activate
the substrate.[2] Here it is worth mentioning relevant applica-
tions such as the enantioselective 1,4-additions achieved with
bifunctional organocatalysts,[3] enantioselective Mannich reac-
tions in the generation of β-amino acids,[4] asymmetric Strecker
reactions in the preparation of natural and unnatural α-amino
acids,[5] Baylis–Hillman reactions,[6] and others.[7] These appli-
cations demonstrate the usefulness of hydrogen bonding with
chiral Brønsted acids in the activation of prochiral substrates for
the preparation of enantioenriched derivatives.
Results and Discussion
Synthesis of Chiral Ureas 1–9, 14–18, and 20
The urea functionality is also present in the structure of N,Nꢀ-
dimethylpropyleneurea(DMPU), whichisapolaraproticsolvent
that is used as a non-toxic substitute to the even more polar but
known carcinogen hexamethylphosphoric triamide (HMPA).[8]
An interesting effect of HMPA and DMPU as solvents or addi-
tives in organolithium chemistry is that both of them have a
determinant effect on the aggregation state of alkyllithiums and
thus on their reactivity.[9] With these precedents, a few years ago
we synthesized several chiral analogues of DMPU and explored
their potential use in regio- and enantioselective addition of
2-(1,3-dithianyl)lithium to 2-cyclohexenone.[10]
The α-phenylethylamine group was selected as chiral adju-
vant as it has showed extended applicability in asymmetric
synthesis.[20] In a previous article,[21] we showed that ureas 1–4
(Scheme 1) incorporating the α-phenylethylamine group exhibit
O
O
O
O
Ph
N
N
Ph
Ph
N
NH
N
N
Ph
N
H
N
H
Ph
Ph
Ph
(R,R)-1
(R,R)-2
(S,S)-3
(R)-4
Scheme 1.
© CSIRO 2008
10.1071/CH08116
0004-9425/08/050364

Synthesis of Novel Chiral (Thio)ureas
365
a substantial preference (6.3–10.9 kJ mol−1) in favour of those
conformations with a syn-periplanar arrangement of the C–H
bond and the N–C(O) segment (Fig. 1). This substantial con-
formational bias is a consequence of allylic A[1,3] strain[22] and
could lead, in principle, to good enantioinduction in reactions
catalyzed by them.
Additional ureas incorporating the α-phenylethylamine
group ((R)-5–7) were obtained via the deprotonation of (R)-4
with sodium hydride and subsequent alkylation with the corre-
sponding alkyl halide (Scheme 2). Repeated attempts to synthe-
size bis-ureas with 1,3-diiodopropane as the electrophile were
unsuccessful because of a competitive elimination–substitution
reaction to give (R)-7 (Scheme 2).
Nevertheless, chiral bis-ureas (R,R)-8 and (R,R)-9 were suc-
cessfully prepared when 1,2-di(bromomethyl)benzene and 1,8-
di(bromomethyl)naphthalene, which lack labile α-hydrogens,
were employed as the electrophiles (Scheme 3).
Interestingly, when (S,S)-bis-α-phenylethylamine was treated
with triphosgene, air-stable chloroformamide (S,S)-10 was
formed instead of the expected linear urea (Scheme 4). Recrys-
tallization of (S,S)-10 gave suitable crystals for X-ray analysis
(Fig. 2).
Scheme 5 shows the synthetic procedure used in the prepa-
ration of ureas (R)-14–16. The synthesis started with (R)-
phenylglycine, which was protected at the amino function with
a benzyloxycarbonyl group (Cbz) and converted to the corre-
sponding amides incorporating bulky groups such as diphenyl-
methyl (Dpm), tert-butyl (t-Bu), and triphenylmethyl (trityl,
Tr), obtaining in this form (R)-11–13. The next step consisted
in the removal of the protecting group, and reduction of the
amide function afforded the expected diamines, which on reac-
tion with triphosgene afforded the desired ureas (R)-14–16 in
good yields (Scheme 5). Recrystallization of (R)-14 provided
suitable crystals for X-ray crystallographic analysis (Fig. 3).
A third family of compounds incorporating an additional
coordination site was synthesized with (1R,2S)-ephedrine as chi-
ral auxiliary, where the β-hydroxy group was anticipated to act
as an additional coordinating site. The straightforward reaction
of the aminoalcohol present in ephedrine with the correspond-
ing isocyanate gave the desired ureas, compounds (1S,2R)-17
and (1S,2R)-18 (Scheme 6). Finally, for the synthesis of the
C2-symmetric urea 20, protection of the hydroxy group with
trimethylsilane (TMS) provided a suitable precursor (Scheme 6).
Recrystallization of (1S,2R)-17 provided suitable crystals for
X-ray crystallographic analysis (Fig. 4).
H
O
Me
N
O
Ph
H
Me
Ph
Synthesis of Chiral Thioureas 21–26
N
N
N
The C2-symmetric thiourea (S,S)-21 was prepared by reaction
of thiophosgene and two equivalents of (S)-α-phenylethylamine
(Scheme 7). For the preparation of tetrasubstituted thiourea
(R,R)-22, a similar procedure was followed with N,Nꢀ-bis-((S)-α-
phenylethylamine)-propane-1,3-diamine and half an equivalent
Fig. 1. Conformational preference of the α-phenylethylamine in chiral
ureas 1–4.
O
O
R
(1) NaH
(2) RX
Ph
N
N
Ph
N
NH
(R)-4
(R)-5 R ꢀ Me 62%
(R)-6 R ꢀ Bn 47%
C11
C10
C12
O
(1) NaH
Ph
N
N
O3
C9
(2) I-(CH2)3-I
C6
(R)-7
C7
Scheme 2.
C1
C8
Ph
O
N
O
N
Ph
C5
O
Br
Br
N
N
NaH
67%
N2
ꢁ
Cl4
Ph
N
NH
C13
C20
C16
(R)-4
C19
C17
(R,R)-8
C18
Ph
Ph
C15
C14
Br
Br
N
O
O
N
O
NaH
70%
ꢁ
N
N
Ph
N
NH
(R)-4
Fig. 2. X-Ray crystallographic structure and solid-state conformation of
chloroformamide (S,S)-10.[23]
(R,R)-9
Scheme 3.
O
Cbz
Ph
Cbz
Ph
NH
O
NH
O
H
N
(1) H , Pd/C
2
(1) ClCO Me, NMM
2
R
N
HN
Ph
OH
R
(2) LiAlH , AlCl
4
3
O
(2) RNH , NMM
2
O
Et3N
(3) (Cl CO) CO
3
2
ꢁ (Cl3CO)2CO
Ph
Ph
(S,S)-10
N
Cl
Ph NH
Ph
Ph
N
N
Ph
Ph
no
(R)-14 R ꢀ Dpm 67%
(R)-15 R ꢀ Tr 52%
(R)-16 R ꢀ t-Bu 55%
CH2Cl2
72%
(R)-11 R ꢀ Dpm 79%
(R)-12 R ꢀ Tr 77%
(R)-13 R ꢀ t-Bu 82%
Ph
(S,S)
Scheme 4.
Scheme 5.

366
M. Hernández-Rodríguez et al.
S
S
of thiophosgene (Scheme 7). Recrystallization of (R,R)-22 gave
suitable crystals for X-ray diffraction analysis, showing the syn-
periplanar orientation of the C–H bond at the phenylethyl group
and the thiocarbonyl group, again as a consequence of allylic
1,3-strain (Fig. 5).[22]
TEA
ꢁ
Ph
N
H
N
H
Ph
Ph NH2
CH2Cl2
77%
Cl
Cl
S
(S,S)-21
S
TEA
H
H
N
Ph
N
Ph
ꢁ
Ph
N
N
Ph
CH2Cl2
40%
Cl
Cl
(R,R)-22
Scheme 7.
C12
C11
C13
C14
C5
C4
C17
C16
C18
C19
C6
C15
C10
N3
C23
C8
C2
N7
S1
C22
C21
C9
C20
Fig. 3. X-Ray crystallographic structure and solid-state conformation of
cyclic urea (R)-14.[23]
Fig. 5. X-Ray crystallographic structure and solid-state conformation of
thiourea (R,R)-22.[23]
Ph OH
Ph OH
O
R
ꢁ RNCO
NH
N
N
H
(1S,2R)-17 R ꢀ Ph 90%
(1S,2R)-18 R ꢀ Dpm 93%
Ph OH
NH
Ph OTMS
Ph OHHO Ph
(1) (Cl3CO)2CO, Et3N
Et3N
O
ꢁ HMDS
NH
N
N
Cl(CH2)2Cl
84%
(2) Hꢁ
60%
(1S,2R)-19
(1S,2R,1ꢂS,2ꢂR)-20
Scheme 6.
C8
C7
C6
O21
C5
C4
C9
C17
C11
C20
C10
C16
C12
C13
N1
N3
C19
C2
C15
C14
O18
Fig. 4. X-Ray crystallographic structure and solid-state conformation of hydroxylated urea (1S,2R)-17.[23]

Synthesis of Novel Chiral (Thio)ureas
367
S
The replacement of oxygen by sulfur in the urea fragment
does not affect significantly the angles around the carbon atom
of the carbonyl (or thiocarbonyl) group, suggesting little change
on the hybridization of the carbon atom.
Ph
ꢁ PhNCS
R
N
H
N
H
R
NH2
CH2Cl2
(S)-23 R ꢀ Ph
98%
(S)-24 R ꢀ 1-Naphth 95%
As anticipated, the presence of a ring around the urea frag-
ment has a much larger effect on the N–C–O angles. The effect
is more pronounced in (R)-14 where the small size of the ring
leads to a smaller N–C–N angle (107.29(18)◦) and simultane-
ously to wider N–C–O angles (1278(16) and 124.92(18)◦). The
angle about the nitrogen atoms inside the ring show values closer
to an ideal of 109◦ (110.17(16)◦ and 113.56(16)◦), in sharp con-
trast with the angles around the carbon atoms that complete the
ring, which show angles N(3)–C(4)–C(5) and N(1)–C(5)–C(4)
of 100.91(17) and 101.90(15)◦, respectively.
Ph OH
NH
Ph OH
S
ꢁ PhNCS
ꢁ PhNCS
Ph
N
N
H
88%
(1S,2R)-25
Ph OH
Ph OH
NH2
S
Ph
N
H
N
H
94%
(1R,2S)-26
The chloro–carbonyl–nitrogen fragment in compound (S,S)-
10 shows a nearly planar conformation with torsion angles for
O(3)–C(1)–N(2)–C(5) and O(3)–C(1)–N(2)–C(13) of −5.4(3)
and −176(2)◦, respectively, whereas the Cl(4)–C(1)–N(2)–C(5)
and Cl(4)–C(1)–N(2)–C(13) show values of 174.03(14) and
4.6(3)◦, respectively.
Thiourea (R,R)-22 also shows nearly planar conformations
in the Y–C–N–C fragments, with torsion angle values between
174.1(8) and 178.2(6)◦. Larger deviations are observed in com-
pound (R)-14 with absolute values of 163.34(16), 168.3(2),
17.8(3)◦, owing to the conformation imposed by the five-
membered ring. Interestingly, related five-membered ring urea
derivatives[25] do not show substantial differences from 0 or 180◦
angles; these last compounds have SiMe3 groups substituted on
the nitrogen atoms and these bulky groups probably affect the
overall conformation or the urea fragment.
Scheme 8.
By the same token, thioureas (S)-23, (S)-24, (1S,2R)-25, and
(1R,2S)-26 were prepared in almost quantitative yield by treat-
ment of the corresponding chiral amine or aminoalcohol with
phenylisothiocyanate (Scheme 8).
Analysis of the X-Ray Crystallographic Structures
Obtained in the Present Work
Molecular structures for compounds (S,S)-10, (R)-14, (1S,2R)-
17, and (R,R)-22 are shown in Figs 2–5. Selected bond lengths
and angles are given in Table 1.
Bond distances and angles in the C(X)–NR segment show
some differences in the four compounds depending on the sub-
stituents at the urea fragment. An analysis of data obtained from
the Cambridge Crystallographic database some years ago[24]
reports that C–N distances in substituted ureas present average
values of 1.347 and 1.363 Å for N-monosubstituted and N,N-
disubstituted derivatives respectively. The values observed in
compounds(R)-14and(R,S)-17, whichincorporateanNH–C(O)
fragment, show C–N distances of 1.352(1) and 1.366(1) Å –
larger than the values given above but similar to those described
in other cases.[25,26]
A larger value of C–N bond length appears to correlate with
the steric demand of the substituent. Thus, the largest C–N
distance, 1.382(2) Å, is observed in cyclic urea (R)-14, where
a diphenylmethyl –C(H)Ph2 group is bonded to the nitrogen
atom. The shortest C–N bond length among the four compounds
described here is 1.336(3) Å, observed in (S,S)-10; neverthe-
less, this value is probably influenced by the presence of the
electronegative chlorine atom bonded to the carbonyl group.
Compound (1S,2R)-17 shows slightly different values for the
two C–N bonds; in this case, not only are the N-substituents dif-
ferent, but the nitrogen atom bound to ephedrine is also involved
in an intramolecular hydrogen bridge with the proton on the –OH
group. The oxygen–nitrogen distance is 2.854 Å.
Compound (1R,2S)-17 presents torsion angles that indicate a
substantial deviation from planarity, and this could be due to the
presence of the hydrogen bridge already mentioned that affects
the conformation adopted by the urea group.
Ureas in Organocatalysts (Lewis Bases)
As demonstrated by Denmark,[12] Lewis bases such as phosphor-
amide or N-oxide derivatives are able to coordinate to weak
Lewis acids such as SiCl4, allyltrichlorosilane, and trichloro-
silylenolethers and are efficient promoters of epoxide ring
opening, allylation, and aldol condensation reactions. In the
present paper, we show that ureas are also capable of promoting
those reactions.
Indeed, the opening of cyclohexene oxide with silicon tetra-
chloride does not proceed in the absence of a promoter. However,
in the presence of 0.1 equiv. of the urea as Lewis base, the desired
reaction took place and afforded good yields of the expected
chlorohydrin 27, especially under activation by tetrasubstituted
ureas (R,R)-2 and (S,S)-3 (entries 3 and 4 in Table 2).
By the same token, several (thio)ureas prepared in the current
work were tested as potential activators in the aldol condensation
reaction of acetophenone trimethylsilyl ether enolate via in situ
transilylation to the corresponding trichlorosilylenol derivative.
As shown in Table 3, essentially no reaction takes place in the
absence of (thio)urea (entry 1 inTable 3); however, aldol product
28 is obtained in moderate to good yields with urea activation.
Two salient observations from Table 3 are: (1) relative to car-
bonyl, thiocarbonyl results in a dramatic decrease of the reaction
rate (entries 2 and 3 in Table 3), which can be explained in terms
of the softer nature of the thioureas (weaker coordination to the
benzaldehyde carbonyl). (2) Trisubstituted ureas are less effec-
tive than tetrasubstitued ureas (cf. entries 4 and 8–12 v. entries 2
CarbonylC=Odistancesshowasmallincreaseongoingfrom
(R)-14, 1.228(2) Å, to (1R,2S)-17, 1.243(2) Å, but both values
are within the range observed for this type of bond. The cor-
responding bond in (S,S)-10 is much shorter, 1.191(3) Å, again
probably as a consequence of the electronegative chlorine atom.
The thiocarbonyl C=S bond in (R,R)-22 shows a value
of 1.703(8) Å, which is significantly shorter than the values
reported by Flippen and Karle (1.73 Å)[27] but that determination
was not very precise.

368
M. Hernández-Rodríguez et al.
Table 1. Some selected bond lengths [Å] and angles [◦] of compounds (S,S)-10, (R)-14, (1S,2R)-17, and
(R,R)-22
E, heteroatom
Compound bond
(S,S)-10
(R)-14
(1S,2R)-17
(R,R)-22
C=Y(E=O, S)A
1.191(3)
1.336(3)
1.228(2)
1.352(2) (N3)
1.382(2) (N1)
1.243(2)
1.357(3) (N3)
1.366(3) (N1)
1.703(8)
1.359(8) (N3)
1.360(7) (N7)
N–C(Y)A
Cl–C(O)
N–C–YA
1.803(2)
128.4(2)
127.78(16) (N3)
124.92(18) (N1)
121.45(18)
122.77(19)
121.5(5) (N3)
120.7(5) (N7)
Cl–C–O
N–C–XB
C–N–C(E)
116.20(16)
115.44(17)
124.31(17)
107.29(18)
110.17(17) (C5)
113.46(16) (C4)
115.78(17)
115.78(17)
117.8(6)
122.0(5) (C2)
123.1(5) (C7)
AY = O in compounds (S,S)-10, (R)-14, and (S,R)-17; Y = S in (R,R)-22. BX = Cl in compound (S,S)-10, and
X = N in compounds (R)-14, (1S,2R)-17, and (R,R)-22.
Table 4. Aldol condensation reaction between the
Table 2. Opening of cyclohexene oxide with silicon tetrachloride
trichlorosilyloxicyclohexene and benzaldehyde
OH
All products were nearly racemic
OSiCl3
O
O
OH
Ph
OH
Cl
10% cat.
(1) 10% cat., ꢃ78°C
ꢁ
ꢁ
O
SiCl4
Ph
ꢃ78°C
40min
(2) PhCHO
27
syn-29
anti-29
Entry
Catalyst
Yield [%]
Entry
Catalyst
Yield [%]
syn/anti
1
2
3
4
–
<5
46
83A
82
1
2
3
(R,R)-2
(R)-14
(R,S,R,S)-20
83
44
43B
95:5A
59:41
74:26B
(R,R)-1
(R,R)-2
(S,S)-3
A8% ee was determined for the syn isomer.
B10% ee was determined for the syn isomer.
A95% yield with 1 equiv. catalyst.
evaluated. The results are collected in Table 4 and show again
moderate to good chemical yields of syn-29 and anti-29. Tetra-
substituted urea (R,R)-2 proved to be the best organocatalyst
for this conversion (83% yield, 95% diastereoselectivity, 8%
enantiomeric excess (ee)).
Table 3. Aldol condensation reaction between acetophenone
trimethylsilyl ether enolate and benzaldehyde
All products were nearly racemic
(1) SiCl4, Hg(OAc)2, rt 1.5h
OTMS
O
OH
(2) 10% cat., ꢃ78°C
(3) PhCHO
Ph
Ph
Ph
*
28 ee Ca.O
(Thio)ureas as Ligands in the Addition of Diethylzinc
to Benzaldehyde
Entry
Catalyst
Yield [%]
The enantioselective reaction between organometallic reagents
and carbonyl compounds is one of the most useful methods for
the synthesis of carbinols. Among organometallic compounds,
dialkylzincs have the limitation that no addition reaction takes
place without the activation of the metal by a ligand (usually
aminoalcohols). It was deemed of interest to verify whether the
addition of diethylzinc to benzaldehyde could be promoted by
the (thio)ureas prepared in the present work.
The reaction was carried out with 5 mol-% of the ligand
in a mixture of solvents, toluene/hexane (1:1). As it can be
observed in Table 5, monodentade ligands were not efficient
ligands for this reaction because they led to product formation
in only poor yield (entries 1–3). Bis-ureas gave better yields of
the addition product 30, although this product was obtained in
racemic form (entries 4 and 5 in Table 5). Most interestingly,
among those ureas containing a hydroxy group, the one with
two ephedrine segments (entry 8 in Table 5) afforded a 46% ee
of the (R)-enantiomer. Also remarkably, disubstituted thioureas
provided carbinol 30 in a quantitative yield (entries 9–11 and 13
in Table 5).
1
2
3
4
5
6
7
8
–
<5
90
42
42
79
77
79
57
42
46
20
33
(R,R)-2
(R,R)-22
(R)-4
(R)-5
(R,R)-8
(R,R)-9
(R)-14
(R)-15
(R)-16
(R,S)-17
9
10
11
12
(R,S,R,S)-20
and 5–7 in Table 3). Unexpectedly, all aldol products in Table 3
were nearly racemic.
In this context, the diastereo- and enantioselectivity of
the aldol condensation reaction between the corresponding
trichlorosilyl enolate of cyclohexanone with benzaldehyde were

Synthesis of Novel Chiral (Thio)ureas
369
Table 5. Additon of diethylzinc to benzaldehyde in the
presence of (thio)ureas
Experimental
General
OH
O
5% cat.
ꢁ Et2Zn
THF and toluene were distilled from sodium, CH2Cl2 was dis-
tilled from P2O5, and silicon tetrachloride was heated to reflux
for 2 h and distilled before use. High resolution mass spectra
were registered on an Agilent Technology Model LS/MSD Ion
TOF mass spectrometer coupled to a HPLC Model 1100. TLC
was carried out on silica gel F254 plates, with detection using UV
radiation or 10% aqueous H2SO4. Flash column chromatogra-
phy (FC)[28] was carried out with silica gel (230–400 mesh).
Melting points were not corrected. 1H NMR spectra were
recorded using JEOL Eclipse-400 (400 MHz), Bruker Avance
(300 MHz), and Jeol GSX-270 (270 MHz) spectrometers. 13C
NMR spectra were recorded with JEOL Eclipse-400 (100 MHz),
Bruker Avance (75 MHz), and Jeol GSX-270 (68 MHz) spec-
trometers. Chemical shifts (δ) are in ppm downfield from the
internal TMS reference; the coupling constants (J) are given
in Hz. Optical rotations were measured in a Perkin–Elmer 240
polarimeter, using the sodium D-line (589 nm) unless indicated
otherwise.
Ph
Toluene:hexane
(1:1)
Ph
H
30
0–5°C, 20h
Entry
Ligand
Yield [%]
Enantiomeric
ratio (R)/(S)
1
2
3
4
5
6
7
8
(R,R)-2
(R,R)-22
(R)-14
(R,R)-8
(R,R)-9
(1R,2S)-17
(R,S)-18
(R,S,R,S)-20
(S,S)-21
(S)-23
(S)-24
(R,S)-25
(S,R)-26
16
19
15
63
70
37
36
50
99
99
94
82
99
49:51
47:53
55:45
50:50
51:49
49:51
48:52
73:27
56:44
40:60
52:48
63:37
40:60
9
10
11
12
13
General Procedure for the N-Alkylation of (R)-4
A solution of 0.55 g (2.7 mmol) of (R)-4[21] in 25 mL of anhy-
drousTHF under a N2 atmosphere was cooled to 0◦C and treated
with 0.178 g (2.9 mmol) of 40% NaH.The resulting solution was
stirred for 30 min before the addition of the alkylating agent
(2.97 mmol). The resulting mixture was stirred for 20 h at room
temperature and then quenched with the slow addition of 20 mL
of water. The product was extracted with EtOAc (2 × 30 mL),
the combined organic extracts were dried (Na2SO4), filtered,
and concentrated. The purification was accomplished by FC
(hexane/EtOAc, 1:1).
Table 6. Addition of diethylzinc to benzaldehyde with
(R,S,R,S)-20 as ligand
OH HO
O
Ph
5%
Ph
OH
N
N
O
+ Et2Zn
Ph
Ph
H
5°C, 20h
30
Entry Temp. [◦C] Additive
Yield [%]
Enantiomeric
N-Methyl-Nꢀ-(( R)-α-phenylethyl)propyleneurea ( R)-5. The
general procedure for N-alk◦ylation was followed. Yield 62%
(0.37 g). Colourless oil, [α]2D5 +86.5◦ (c 0.86, CHCl3). (Found:
[M + 1]+ 219.1506. Calc. for C13H18N2O: [M + 1]+ 219.1497).
δH (CDCl3, 270 MHz) 7.32–7.12 (5H, m), 5.86 (1H, q, J 7.1),
3.20–2.98 (3H, m), 2.93 (3H, s), 2.78–2.68 (1H, m), 1.82–1.70
(2H, m), 1.43 (3H, d, J 7.1). δC (CDCl3, 68 MHz) 156.4, 141.8,
128.3, 127.3, 126.9, 51.0, 47.8, 39.5, 35.9, 22.3, 15.9.
ratio (R)/(S)
1
2
3
4
5
6
−20
5
25
5
–
–
–
–
10
50
55
54A
51
35
68:32
73:27
68:32
76:24
81:19
76:24
5
5
5% BuLi
10% BuLi
A10% of the urea was employed.
N-Benzyl-Nꢀ-(( R)-α-phenylethyl)propyleneurea ( R)-6. The
general procedure for N-alk◦ylation was followed. Yield 47%
(0.37 g). Colourless oil, [α]2D5 +68.1◦ (c 1.32, CHCl3). (Found:
[M + 1]+ 295.1810. Calc. for C19H22N2O: [M + 1]+ 295.1810).
δH (CDCl3, 270 MHz) 7.41–7.18 (10H, m), 6.00 (1H, q, J 7.1),
4.62 (2H, s), 3.31–3.0 (3H, m), 2.83–2.75 (1H, m), 1.77–1.70
(2H, m), 1.51 (3H, d, J 7.1). δC (CDCl3, 68 MHz) 156.3, 141.8,
138.7, 128.6, 128.3, 127.8, 127.3, 127.1, 127.0, 51.7, 51.2, 45.2,
39.6, 22.4, 15.9.
Additional experiments were carried out to optimize the
results obtained with chiral C2-symmetric (R,S,R,S)-20 as lig-
and (Table 6). When the reaction was carried out at different
temperatures, highest ee was obtained at 5◦C (entries 1–3 in
Table 6). Most relevantly, when 10% of the ligand was used, a
52% ee was obtained (entry 4); furthermore, by adding 5 mol-%
of BuLi, carbinol 30 was formed with a higher 62% ee (entry 5
in Table 6).
1,2-Bis-(3-(R)-α-phenylethyl-2-oxotetrahydropyrimidyl)meth-
ylbenzene (R,R)-8. The general procedure for N-alkylation was
followed with 0.75 g (3.7 mmol) of (R)-4 and 0.44 g (1.66 mmol)
of 1,2-di(bromomethyl)benzene. 67% yield (0.57 g). White
◦
Conclusions
semisolid, mp 45–47◦C. [α]D25 +89.7◦ (c 0.97, CHCl3).
(Found: [M + 1]+ 511.3064. Calc. for C32H39N4O2: [M + 1]+
511.3073). δH (CDCl3, 400 MHz) 7.42–7.23 (14H, m), 6.01 (2H,
q, J 7.0), 4.76 (2H, d, J 15.76), 4.71 (2H, d, J 15.76), 3.17–3.05
(6H, m), 2.87–2.80 (2H, m), 1.80–1.76 (4H, m), 1.54 (6H, d,
J 7.0). δC (CDCl3, 100 MHz) 156.2, 141.8, 136.6, 128.4, 128.3,
127.4, 127.0, 51.3, 48.7, 45.1, 39.7, 22.4, 16.1.
In conclusion, several novel chiral (thio)ureas were prepared,
which showed potential as efficient Lewis basic organocatalysts
in aldol reactions and epoxide ring-opening reactions, although
no significant enantioinduction was observed. The present work
also shows that ureas are good catalysts for the addition of
diethylzinc to benzaldehyde. In particular, C2-symmetric urea
(R,S,R,S)-20 promoted the high-yield formation of carbinol 30
in up to 62% ee.
1,8-Bis(3-(R)-α-phenylethyl-2-oxotetrahydropyrimidyl)meth-
ylnaphthalene ( R,R)-9. The general procedure for N-alkylation

370
M. Hernández-Rodríguez et al.
was followed with 0.18 g (0.9 mmol) of (R)-4 and 0.13 g
(0.4 mmol) of 1,8-di(bromomethyl)naphtha◦lene. 70% yield
(0.16 g). White crystals, mp 178–179◦C. [α]D25 +112.8◦ (c 0.91,
CHCl3). (Found: C 76.9, H 7.3, N 10.2. Calc. for C36H40N4O2:
C 77.1, H 7.2, N 10.0%). δH (CDCl3, 400 MHz) 7.76 (2H, d, J
7.0), 7.45–7.34 (12H, m), 7.28 (2H, dd, J 6.6 and 6.2), 6.04 (2H,
q, J 7.0), 5.35 (2H, d, J 16.1), 5.24 (2H, d, J 16.1), 3.30–3.23 (6H,
m), 2.89 (2H, ddd, J 11.4, 5.8 and 5.1), 1.90–1.78 (4H, m), 1.50
(6H, d, J 7.0). δC (CDCl3, 100 MHz) 156.6, 141.8, 136.0, 134.4,
132.0, 128.9, 128.5, 127.4, 127.6, 125.3, 125.1, 53.0, 51.3, 45.6,
39.7, 22.5, 16.0.
5.08 (1H, d, J 12.4), 4.10 (1H, d, J 12.4). δC (CDCl3, 100 MHz)
168.4, 155.7, 144.1, 138.0, 136.3, 129.2, 128.7, 128.5, 128.48,
128.14, 128.04, 127.37, 127.18, 70.72, 66.96, 59.57.
(R)-N-tert-Butylbenzyloxycarbonylaminophenylacetamide
(R)-13.The general procedure was followed. 82% yield (1.48 g).
◦
White solid, mp 136–137◦C. [α]D25 −0.5◦ (c 3.4, CHCl3).
(Found: [M + Na]+ 363.1681. Calc. for C20H24N2O3: [M +
Na]+ 363.1679). δH (CDCl3, 400 MHz) 7.41–7.26 (10H, m),
6.17(1H, br), 5.47(1H, br), 5.63(1H, d, J12), 5.12–5.09(2H, m),
1.27 (9H, s). δC (CDCl3, 100 MHz) 168.8, 155.7, 138.8, 136.4,
129.1, 128.6, 128.4, 128.2, 128.1, 127.3, 67.0, 59.1, 51.9, 28.6.
N,N-Bis(( S)-α-phenylethyl)chloroformamide( S,S)-10. (S,S)-
Bis-α-phenylethylamine4.67 g(20.7 mmol), 5.8 mL(41.4 mmol)
ofEt3N, and40 mLofdryCH2Cl2 wereplacedinaround-bottom
flask, and the resulting mixture was cooled to 0◦C before the
dropwise addition of a solution containing 3.2 g (10.9 mmol) of
triphosgene in 15 mL of CH2Cl2. Stirring was continued at 0◦C
for 2 h and for 18 h at room temperature, and then 30 mL of
1 M HCl were added. The aqueous phase was separated and the
organic layer washed with 40 mL of brine, dried (Na2SO4), and
concentrated. The product was purified by FC (hexane/EtOAc,
General Procedure for the Synthesis of Ureas (R)-14–16
In a flask provided with magnetic stirring was placed 1.7 mmol
of the chiral amide ((R)-11, (R)-12, or (R)-13), Pd/C (10% w/w
relative to amide), and 15 mL of MeOH. The resulting mixture
was exposed to a hydrogen atmosphere (14.6 psi) for 18 h. Filtra-
tion and concentration afforded the unprotected desired product
in quantitative yield, according to 1H NMR analysis. This prod-
uct was redissolved in 40 mL of anhydrous THF and cooled to
0◦C before the addition of 343 mg (2.6 mmol) ofAlCl3 followed
by 325 mg (8.6 mmol) of LiAlH4 (slow addition). The reaction
mixture was stirred at 0◦C for 2 h, the ice-bath was removed
and the reaction continued for 22 h at room temperature. The
reaction mixture was cooled again to 0◦C before the slow addi-
tion of 30 mL of a 1 M aqueous solution of NaOH. Stirring was
continued until the suspension turned white (15 min to 1 h), and
the resulting diamine was extracted with EtOAc (3 × 40 mL).
The organic extracts were combined, dried (Na2SO4), and con-
centrated to afford the pure diamine, according to 13C NMR
spectroscopy. This product was treated with 0.47 mL (3.4 mmol)
of Et3N dissolved in 50 mL of CH2Cl2, and the resulting mix-
ture was cooled to 0◦C before the dropwise addition of a solution
of triphosgene (169 mg (0.57 mmol)) in 10 mL of CH2Cl2. Once
the addition was complete, the ice bath was removed and the stir-
ring was continued for 24 h at room temperature. Then, 50 mL
of HCl (1 M) were added, the aqueous phase was separated
and the organic layer was washed with 30 mL of brine, dried
(Na2SO4), and concentrated. The product was purified by FC
(hexane/EtOAc, 1:1) producing a white solid in all cases.
85:15) yielding 4.65 g (78% yield) of (S,S)-10 as white crystals,
◦
mp 95–97◦C. [α]D25 −191.5◦ (c 2.14, CHCl3). (Found: C 71.1, H
6.6. Calc. for C17H18ClNO: C 71.0, H 6.3%). νmax (KBr)/cm−1
3434, 3066, 3032, 3001, 2977, 2935, 1956, 1888, 1727 (C=O),
1495, 1453, 1414, 1245, 1144, 1097, 1069, 960, 839, 698. δH
(CDCl3, 400 MHz) 7.50–7.05 (8H, m), 6.74 (2H, br), 5.82 (1H,
br), 4.60 (1H, br), 1.80 (6H, d, J 7.1). δC (CDCl3, 100 MHz)
146.9, 139.1, 138.8, 128.7, 128.4, 128.1, 127.9, 127.7, 127.3,
59.1, 56.1, 18.1, 17.3.
General Procedure for the Synthesis of Amides Derived
from Phenylglycine
In a round bottom flask were placed 1.5 g (5.3 mmol) of (R)-
benzyloxycarbonylaminophenylacetic acid[29] in 60 mL of THF.
The solution was cooled to 0◦C before the addition of 0.63 mL
(5.8 mmol) of N-methylmorpholine. The resulting mixture was
stirred for 5 min and then 0.5 mL (5.9 mmol) of methyl chloro-
formate was added slowly. The resulting mixture was stirred
for 1 h and then a solution containing 5.8 mmol of the amine
and 0.75 mL (6.9 mmol) of N-methylmorpholine was added.The
reaction mixture was stirred for 2 h at 0◦C and for 16 h at room
temperature. The reaction was quenched with 50 mL of 0.1 M
HCl and extracted with EtOAc (2 × 30 mL).The organic extracts
were dried and concentrated, and the product purified by FC
using hexane/EtOAc (1:1).
(R)-N-Diphenylmethylbenzyloxycarbonylaminophenylaceta-
mide ( R)-11. This was prepared according to the general
procedure. 78% yield (1.86 g). White solid, mp 187–188◦C.
−98.7◦ (c 1.1, CHCl3). (Found: [M + 1]+ 451.2028. Calc. for
C29H26N2O3: [M + 1]+ 451.2022). δH ([D6]DMSO, 400 MHz)
9.11 (1H, d, J 8.0), 8.0 (1H, d, J 8.4), 7.47 (2H, d, J 7.0), 7.45–
7.15 (16H, m), 7.07 (2H, d, J 6.6), 6.07 (1H, d, J 8.0), 5.46 (1H,
d, J 8.4), 5.04 (2H, s). δC ([D6]DMSO, 100 MHz) 169.7, 156.2,
142.6, 142.5, 138.9, 137.4, 128.9, 128.8, 128.7, 128.7, 128.3,
128.2, 128.1, 128.0, 127.7, 127.6, 127.4, 66.1, 58.6, 56.5.
(R)-N-Triphenylmethylbenzyloxycarbonylaminophenylaceta-
(R)-1-Diphenylmethyl-4-phenylimidazolidin-2-one ( R)-14.
The general procedure was followed, affording 0.37 g (67%
◦
yield) of a white solid, mp 184–185◦C. [α]D25 +63.4◦ (c 1,
CHCl3). (Found: C 80.3, H 6.2, N 8.5. Calc. for C22H20N2O:
C 80.5, H 6.1, N 8.5%). δH (CDCl3, 400 MHz) 7.40–7.13 (15H,
m), 6.49 (1H, s), 5.48 (1H, br), 4.79 (1H, dd, J 8.8 and 8.0), 3.62
(1H, dd, J 8.8 and 8.4), 3.05 (1H, dd, J 8.4 and 8.0). δC (CDCl3,
100 MHz) 161.7, 141.5, 139.3, 139.0, 129.0, 128.5, 128.5, 128.4,
128.1, 127.5, 127.4, 126.1, 59.0, 54.0, 50.6.
(R)-1-Trityl-4-phenylimidazolidin-2-one (R)-15.The general
procedure was followed, aff◦ording 0.36 g (52% yield) of a white
solid, mp 156–158◦C. [α]D25 almost null. (Found: C 83.0, H 6.3,
N 7.2. Calc. for C28H24N2O: C 83.1, H 6.0, N 6.9%). δH (CDCl3,
400 MHz) 7.50–7.15 (20H, m), 5.03 (1H, br), 4.74 (1H, dd, J 8.8
and 8.0), 3.86 (1H, dd, J 8.8 and 8.4), 3.26 (1H, dd, J 8.4 and
8.0). δC (CDCl3, 100 MHz) 161.6, 143.1, 141.4, 129.5, 128.9,
128.3, 127.7, 126.7, 126.3, 73.3, 54.9, 53.8.
mide ( R)-12. The general procedure was followed. 77% yield
(R)-1-tert-Butyl-4-phenylimidazolidin-2-one (R)-16. The
◦
(2.15 g). White solid, mp 150–151◦C. [α]D25 −4.3◦ (c 1.12,
CHCl3). (Found: [M + Na]+ 549.2146. Calc. for C35H30N2O3:
[M + Na]+ 549.2149). δH (CDCl3, 400 MHz) 7.38–7.19 (19H,
m), 7.10–7.08 (6H, m), 6.84 (1H, br), 6.17 (1H, br), 5.31 (1H, br),
general procedure was followed, affording 0.20 g (55% yield)
◦
of a white solid, mp 118–120◦C. [α]D25 −0.5◦ (c 2.51, CHCl3).
(Found: C 71.5, H 8.5, N 12.8. Calc. for C13H18N2O: C 71.5, H
8.3, N 12.8%). δH (CDCl3, 400 MHz) 7.40–7.27 (5H, m), 4.63

Synthesis of Novel Chiral (Thio)ureas
371
(1H, dd, J 8.8 and 8.0), 4.58 (1H, br), 3.88 (1H, dd, J 8.8 and 8.4),
3.22 (1H, dd, J 8.4 and 8.0), 1.37 (9H, s). δC (CDCl3, 100 MHz)
162.1, 141.7, 128.9, 128.2, 126.2, 53.6, 53.0, 52.3, 27.6.
by FC (hexane/EtOAc, 8:2 to 1:1) producing 0.6 g (47% yield◦)
of the desired product as a white solid, mp 170–171◦C. [α]D25
+8.4◦ (c 1.11, CHCl3). (Found: C 70.5, H 7.9, N 7.9. Calc. for
C21H28N2O3: C 70.8, H 7.9, N 7.9%). δH (CDCl3, 400 MHz)
7.42–7.23 (10H, m), 5.48 (2H, s), 4.91 (2H, s), 3.56 (2H, dq, J 7.0
and 3.7), 2.61 (6H, s), 1.21 (6H, d, J 7.0). δC (CDCl3, 100 MHz)
165.2, 142.5, 128.3, 127.4, 126.4, 75.4, 62.0, 36.4, 11.9.
N,Nꢀ-Bis(( S)-α-phenylethyl)thiourea ( S,S)-21. See ref.
[19f].
General Procedure for the Reaction of Ephedrine
with Isocyanates
In a 50-mL round-bottom flask provided with a magnetic stir-
rer was placed 0.92 g (5.6 mmol) of (−)-ephedrine dissolved
in 35 mL of CH2Cl2, before the addition of 5.3 mmol of the
corresponding isocyanate and the resulting mixture was stirred
at room temperature for 15 h. The reaction mixture was treated
with 25 mL of 1.0 M HCl and the organic phase was separated,
washed with brine, dried (Na2SO4) and concentrated to give
the crude product, which was purified by flash chromatography
using hexane/EtOAc (8:2 to 1:1).
N,Nꢀ-Bis(( S)-α-phenylethyl)propylenethiourea ( S,S)-22. In
a round-bottom flask were placed 1.5 g (5.3 mmol) of N,Nꢀ-bis-
((S)-α-phenylethyl)propane-1,3-diamine,[31] 1.5 mL(10.6 mmol)
of Et3N, and 40 mL of dry CH2Cl2. The resulting solution was
cooled to 0◦C and then it was treated slowly with a solution
of 0.2 mL (2.65 mmol) of thiophosgene in 10 mL of CH2Cl2.
The reaction mixture was stirred for 2 h at 0◦C and for 18 h at
room temperature, before the addition of 50 mL of 1 M HCl.
The organic layer was washed with 50 mL of brine, dried
(Na2SO4), and concentrated. The product was purified by FC
1-[(2R)-Hydroxy- (1S)-methyl-2-phenylethyl]-1-methyl-3-
phenylurea (1S,2R)-17. This urea was obtained according to the
general procedure, affording 1.43 g (90% yield). White crystals,
◦
mp 134–135◦C. [α]D25 −217.0◦ (c 1.03, CHCl3). (Found: C 71.6,
H 7.2, N 9.9. Calc. for C17H20N2O2: C 71.8, H 7.1, N 9.9%).
δH (CDCl3, 300 MHz) 7.34–7.23 (10H, m), 7.03–6.98 (1H, m),
4.77 (1H, s), 4.34–4.26 (1H, m), 4.18 (1H, br), 2.48 (3H, s),
1.20 (3H, d, J 7.1). δC (CDCl3, 75 MHz) 157.6, 141.1, 139.5,
129.0, 128.5, 128.1, 126.8, 123.0, 120.0, 77.9, 58.3, 31.6, 14.1.
Enantiomeric [(1R,2S)-17] has been reported previously.[29]
1-[(2R)-Hydroxy-(1S)-methyl-2-phenylethyl]-1-methyl-3-
diphenylmethylurea (1S,2R)-18. This urea was obtained accord-
(hexane/EtOAc, 7:3) yielding 0.77 g (45% yield) of a white
◦
solid, mp 205–206◦C. [α]D25 −144 (c 1.04, CHCl3). (Found: C
73.8, H 7.7. Calc. for C20H24N2S: C 74.0, H 7.5%). δH (CDCl3,
400 MHz) 7.40–7.24 (12H, m), 3.05 (2H, dt, J 12.6 and 5.9),
2.80 (2H, dt, J 12.6 and 5.9), 1.66 (2H, quintuplet, J 5.9), 1.61
(6H, d, J 6.9). δC (CDCl3, 100 MHz) 179.8, 140.7, 128.5, 127.3,
58.9, 41.1, 21.4, 15.1.
General Procedure for the Synthesis of Thioureas
Using Phenylisothiocyanate
ing to the general procedure, affording 1.95 g (93% yield). White
◦
crystals, mp 123–125◦C. [α]D25 −121.3◦ (c 0.8, CHCl3). (Found:
C 77.4, H 7.4, N 7.4. Calc. for C24H26N2O2: C 77.0, H 7.0, N
7.5%). δH (CDCl3, 270 MHz) 7.37–7.17 (15H, m), 6.12 (1H,
d, J 7.2), 5.10 (1H, d, J 7.2), 4.76 (1H, dd, J 3.5 and 3.5),
4.38 (1H, dq, J 7.1 and 3.5), 4.10 (1H, br), 2.48 (3H, s), 1.20
(3H, d, J 7.1). δC (CDCl3, 68 MHz) 158.8, 142.6, 141.6, 128.7,
128.6, 128.2, 127.7, 127.5, 127.4, 127.3, 126.6, 77.9, 58.5, 58.1,
31.3, 13.9.
In a 25 mL round-bottom flask provided with a magnetic stirrer
was placed 2.94 mmol of the chiral amine dissolved in 10 mL
of CH2Cl2. To this solution was added 0.6 mL (2.94 mmol) of
phenylisothiocyanate and the resulting mixture was stirred at
room temperature for 15 h.The reaction mixture was treated with
15 mL of 1 M HCl and the organic phase was separated, washed
with brine solution, dried (Na2SO4), and concentrated to give
the crude product, which was purified by flash chromatography
using hexane/EtOAc (9:1 to 7:3).
N-Methyl-[(1S,2R)-(2-phenyl-1-methyl-2-trimethylsilyloxy)]
ethylamine (1R,2S)-19. Following the reported protection for
pseudoephedrine,[30] in a round-bottom flask were placed 1.4 g
(8.9 mmol) of (−)-ephedrine, 2.6 mL (18.9 mmol) of triethyl-
amine and 4.0 mL (18.9 mmol) of hexamethyldisilazane in
10 mL of dichloroethane. The resulting mixture was heated to
reflux for 5 h and then concentrated. The product was distilled
N-(( S)-α-Phenylethyl)-Nꢀ-phenylthiourea ( S)-23. This was
obtained according to the general procedure and afforded 0.74 g
◦
(98% yield) of a white solid, mp 64–65◦C. [α]D25 +87.7◦ (c 1.06,
CHCl3). (Found: [M + 1]+ 257.1111. Calc. for C15H17N2S:
[M + 1]+ 257.1112). δH (CDCl3, 400 MHz) 8.27 (1H, br), 7.55–
7.12 (10H, m), 6.31 (1H, br), 5.68 (1H, br), 1.53 (3H, d, J 7.0).
δC (CDCl3, 100 MHz) 179.7, 142.3, 136.3, 130.2, 128.9, 127.7,
127.2, 126.3, 125.1, 54.7, 21.7.
in a Kugelrohr apparatus, bp 110◦C/0.05 psi, producing 1.77 g
◦
(84% yield) of a colourless oil. [α]2D5 −49.0◦ (c 2.06, CHCl3).
(Found: [M + 1]+ 238.1629. Calc. for C13H24NOSi: [M + 1]+
238.1627). δH (CDCl3, 400 MHz) 7.40–7.26 (5H, m), 4.42 (1H,
d, J 4.8), 4.41 (1H, dq, J 6.6 and 4.8), 2.12 (3H, s), 1.05 (1H,
br), 0.77 (3H, d, J 6.6), 0.21 (9H, s). δC (CDCl3, 100 MHz)
142.8, 127.9, 127.0, 126.5, 77.1, 61.2, 33.8, 14.3, 0 (SiCH3). δSi
(CDCl3, 399.8 MHz) 18.02 (s).
N-(( S)-1-(α-Naphthyl)ethyl)-Nꢀ-phenylthiourea( S)-24.This
was obtained according to the general procedure and afforded
◦
0.86 g (95% yield) of a white solid, mp 97–98◦C. [α]D25 +128.8◦
(c 0.81, CHCl3). (Found: C 74.7, H 6.1, N 9.5. Calc. for
C19H18N2S: C 74.5, H 5.9, N 9.1%). δH (CDCl3, 400 MHz)
8.24 (1H, d, J 8.4), 8.17 (1H, br), 7.87 (1H, d, J 8.0), 7.80 (1H,
dd, J 6.9 and 2.9), 7.60 (1H, ddd, J 7.6, 7.3 and 1.4), 7.55–7.50
(1H, m), 7.46–7.39 (2H, m), 7.27 (2H, dd, J 7.8 and 7.8), 7.21–
7.15 (1H, m), 7.05 (2H, d, J 7.7), 6.39 (1H, br), 6.25 (1H, br),
1.75 (3H, d, J 6.6). δC (CDCl3, 100 MHz) 179.4, 137.4, 136.2,
134.0, 131.3, 130.2, 128.9, 128.8, 127.1, 127.0, 126.1, 125.2,
124.9, 123.9, 123.0, 51.1, 20.2.
Bis-1,3-[( 2R)-Hydroxy-(1S)-methyl -2-phenylethyl]-1,3-
dimethylurea (1S,2R,1ꢀS,2ꢀR)-20. The starting amine (1R,2S)-
19 (0.86 g, 3.6 mmol), Et3N (1.0 mL, 7.8 mmol), and 15 mL of
dry CH2Cl2 were placed in a round-bottom flask and the result-
ing mixture was cooled to 0◦C before the dropwise addition
of a solution of 0.18 g (0.6 mmol) of triphosgene in 10 mL of
CH2Cl2. Stirring was continued at room temperature for 34 h,
and then 30 mL of 1 M HCl were added. The aqueous phase was
separated and extracted with two 30-mL portions of CH2Cl2,
the combined organic phases were washed with brine solution,
dried (Na2SO4), and concentrated. The product was purified
1- ((2R)-Hydroxy-(1S)-methyl-2-phenylethyl)-1-methyl-3-
phenylthiourea (1S,2R)-25. This was obtained according to the
general procedure and afforded 0.77 g (88% yield) of a white
◦
solid, mp 105–107◦C (lit. 97–98◦C[32]). [α]2D5 −281.4◦ (c 0.97,

372
M. Hernández-Rodríguez et al.
Table 7. Summary of crystal data for compounds 10, 14, 17, and 22
Parameter
Coumpound 10
Coumpound 14
Coumpound 17
Coumpound 22
Empirical formula
Molecular weight
Crystal size [mm3]
Temperature [K]
Space group
Crystal system
a [Å]
C17H18ClNO
287.77
C22H20N2O
328.40
C17H20N2O2
284.35
C20H24N2O
308.41
0.30 × 0.25 × 0.20
0.45 × 0.27 × 0.25
0.27 × 0.27 × 0.1
0.64 × 0.5 × 0.42
293(2)
293(2)
293(2)
223(2)
P 21 21 21
Orthorhombic
7.6657(2)
12.4219(3)
16.2106(4)
90
P 21 21 21
Orthorhombic
6.28700(10)
8.70050(10)
32.4210(6)
90
P 21 21 21
Orthorhombic
10.4910(4)
11.3633(5)
13.0381(6)
90
P 43 21 2
Orthorhombic
14.460(5)
14.460(5)
8.385(5)
90
b [Å]
c [Å]
α [◦]
β [◦]
90
90
90
90
90
90
90
90
γ [◦]
U [Å3]
1543.62(7)
0.71069
1.238
1773.43(5)
0.71069
1.230
1554.30(12)
0.71069
1.215
1753.2(14)
0.71069
1.168
µ(MoKα) [Å]
Dcalc [Mg m−3
Z
]
4
4
4
4
F(000)
608
3.51–27.48
3262
1904
0.0174
696
3.44–27.47
3560
3560
0.0000
608
4.08–27.41
3458
3458
0.0000
664
2.81–26.95
4380
1921
0.6237
θ range [◦]
Reflections collected
Unique reflections
Rint
R1, wR2 [I > 2σ(I)]
R1, wR2 (all data)
Goodness-of-fit on F2
0.0357, 0.0826
0.0495, 0.0885
1.055
0.0426, 0.0808
0.0895, 0.0949
1.012
0.0469, 0.0868
0.0845, 0.1002
1.043
0.0530, 0.1343
0.1242, 0.1549
1.137
CHCl3). δH (CDCl3, 400 MHz) 7.45–7.10 (10H, m), 5.27 (1H,
br), 4.95 (1H, br), 3.22 (1H, br), 2.80 (3H, s), 1.70 (1H, s), 1.25
(3H, d, J 7.0). δC (CDCl3, 100 MHz) 183.9, 140.5, 140.1, 128.8,
128.6, 128.3, 126.6, 125.3, 124.8, 77.5, 61.0, 35.2, 13.5.
1-((2S)-Hydroxy-(1R)-methyl-2-phenylethyl)-3-phenylthio-
urea (1R,2S)-26. This was obtained according to the general
3-Hydroxy-1,3-diphenylpropan-1-one 28. In a Schlenk flask
was placed 288 mg (1.5 mmol) of the phenyltrimethylsily-
loxyethene with 4.7 mg (0.015 mmol) of mercury acetate under
a nitrogen atmosphere and dissolved in 3 mL of dry CH2Cl2.
After the addition of 0.34 mL (3 mmol) of silicon tetrachloride,
the mixture was stirred for 1.5 h for complete transilylation.
The mixture was concentrated to dryness under vacuum and the
resulting oil was redissolved with a solution of 0.1 mmol of the
Lewis base in 2.5 mL dry CH2Cl2, and cooled to −78◦C with a
dry ice–acetone bath before 0.1 mL (1 mmol) of benzaldehyde
was slowly added and the mixture stirred for 2.5 h. The dry-
ice bath was removed and 30 mL of a solution of 1:1 1 M NaF
saturated NaH2PO4 was added. After 1.5 h of continuous stir-
ring, the product was extracted with CH2Cl2 (2 × 40 mL), the
organic phases were combined, washed with 40 mL of brine,
dried (Na2SO4), and concentrated. The aldol product was puri-
fied with FC (hexane/EtOAc, 9:1) yielding a semisolid with yield
dependent on the Lewis base employed (Table 2), mp 49–51◦C.
δH (CDCl3, 400 MHz) 8.00–7.25 (10H, m), 5.38–5.33 (1H, m),
3.69 (1H, br), 3.40–3.35 (2H, m). δC (CDCl3, 100 MHz) 200.2,
143.1, 136.7, 133.7, 128.8, 128.7, 128.3, 127.8, 125.9, 70.1,
47.5.
procedure and afforded 0.79 g (94% yield) of a white solid, mp
◦
138–139◦C. [α]D25 +49.1◦ (c 0.55, CHCl3). (Found: C 67.2, H
6.4, N 9.9, S 11.6. Calc. for C16H18N2OS: C 67.1, H 6.3, N 9.8,
S 11.2%). δH (CDCl3, 270 MHz) 7.98 (1H, br), 7.46–7.15 (10H,
m), 6.22 (1H, d, J 8.4), 5.08 (1H, dd, J 3.5 and 3.2), 4.89 (1H,
br), 0.85 (1H, d, J 3.5), 0.97 (3H, d, J 6.9). δC (CDCl3, 68 MHz)
179.8, 140.4, 135.9, 130.2, 128.3, 127.7, 127.3, 126.1, 125.1,
75.8, 56.2, 13.9.
trans-2-Chlorocyclohexanol 27. In a 50-mL round-bottom
flask provided with a magnetic stirrer and under a nitrogen
atmosphere was placed the chiral urea (0.1 mmol) dissolved
in 10 mL of dry CH2Cl2, and this solution was treated with
0.1 mL (1.0 mmol) of cyclohexene oxide. The reaction mixture
was cooled to −78◦C (dry ice/acetone bath) before the addi-
tion of 0.13 mL (1.1 mmol) of silicon tetrachloride. Following
40 min of stirring, the reaction was placed in an ice bath and
quenched with 20 mL of an aqueous saturated NaHCO3 solu-
tion. Then 20 mL of CH2Cl2 were added and the aqueous phase
separated and extracted with CH2Cl2 (2 × 15 mL). The organic
extracts were combined and washed with 30 mL of brine, dried
(Na2SO4), and concentrated. The product was purified with FC
using hexane/EtOAc (95:5), producing a colourless liquid with
the yields summarized in Table 2. δH (CDCl3, 400 MHz) 3.68
(1H, ddd, J 11.5, 9.3 and 4.5), 3.50–3.43 (1H, m), 2.85 (1H,
s), 2.22–2.13 (1H, m), 2.08–2.00 (1H, m), 1.73–1.53 (3H, m),
1.34–1.18 (3H, m). δC (CDCl3, 100 MHz) 75.2, 67.3, 35.1, 33.1,
25.6, 23.9.
1-Cyclohexyl-3-hydroxy-3-phenylpropan-1-one 29. In
a
Schlenk flask under a nitrogen atmosphere was placed 278 mg
(1.2 mmol) of the trichlorosilyloxycyclohexene.[33] The corre-
sponding urea was added (0.1 mmol) dissolved in 10 mL of
dry CH2Cl2 and then the solution was cooled to −78◦C before
the slow addition of 0.1 mL (1.0 mmol) of benzaldehyde. After
2 h with stirring, the dry-ice bath was removed and a 30 mL
solution of 1:1 saturated NaF:NaH2PO4 was added and the
resulting mixture was stirred for 2 h. The product was extracted
with CH2Cl2 (2 × 40 mL), the organic phases were combined,
washed with 40 mL of brine, dried (Na2SO4), and concentrated.

Synthesis of Novel Chiral (Thio)ureas
373
The aldol product was purified with FC (hexane/EtOAc, 9:1)
producing a semisolid with yields that depended on the Lewis
base employed (see Table 4). δH (CDCl3, 270 MHz) 7.37–7.19
(5H, m), 5.38 (1H, br), 3.02 (1H, br), 2.66–2.29 (3H, m), 2.14–
2.00 (1H, m), 1.90–1.40 (5H, m). δC (CDCl3, 68 MHz) 214.9,
141.5, 70.6, 57.3, 42.7, 28.0, 26.1, 24.9. HPLC: Chiracel-OD
(Detector wavelength 220 nm), eluent hexane/PriOH (90:10),
flow 0.5 mL min−1, retention time (tR) 14.67 and 17.57 min.
1-Phenylpropanol 30. In a 50-mL round bottom flask pro-
vided with a magnetic stirrer and nitrogen atmosphere was
placed the urea ligand (0.1 mmol) dissolved in 5 mL of dry
toluene (for some ligands, the use of an ultrasonic bath or heating
was required for complete dissolution). The solution was cooled
with an ice bath and then 5 mL (5 mmol) of a 1 M solution of
diethylzinc in hexane was added slowly. After 45 min stirring,
0.2 mL (2 mmol) of benzaldehyde was added and the reaction
mixture was allowed to react for 20 h at a temperature between
0 and 5◦C. The remaining diethylzinc was destroyed with the
slow addition of 15 mL of 1 M HCl (vigorous evolution of gas).
A white suspension was formed and following the dissolution
of the solid (15 min to 1 h), the product was extracted with ether
(2 × 15 mL). The organic extracts were dried (Na2SO4), con-
centrated, and the product purified by FC (hexane/EtOAc, 9:1),
producing a colourless liquid in the yield and enantiomeric ratios
summarized in Table 6. δH (CDCl3, 400 MHz) 7.38–7.25 (5H,
m), 4.60(1H, t, J6.6), 2.05(1H, br), 1.89–1.70(2H, m), 0.92(3H,
t, J 7.5). δC (CDCl3, 100 MHz) 144.7, 128.5, 127.6, 126.1, 76.1,
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Crystallographic Studies
Datasets were collected in a Nonius Kappa CCD diffractometer
using MoKα radiation. All the structures were solved using
SHELX-97[23] and were refined by full matrix least-squares
methods. All non-hydrogen atoms were refined anisotropically.
Most hydrogen atoms were placed in idealized positions and
included in the refinement. Crystal data, data collection param-
eters, and results of the analyses are listed in Table 7. Full
crystallographic information can be found in the supplementary
data deposited at the Cambridge Crystallographic Data Centre.
(m) Y.-J. Cao, H.-H. Lu, Y.-Y. Lai, L.-Q. Lu, W.-J. Xiao, Synthesis
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Supporting Information Available
The crystallographic data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, UK; fax +44 1223 336033. CCDC nos. 666357–666360.
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Acknowledgements
The authors are grateful to Rodrigo González Olvera andYamir Bandala for
technical assistance.
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