Structural optimization of thiourea-based bifunctional organocatalysts for the highly enantioselective dynamic kinetic resolution of azlactones

Article abstract of DOI:10.1039/b607574f

This article describes the synthesis of a library of structurally diverse bifunctional organocatalysts bearing both a quasi-Lewis acidic (thio)urea moiety and a Bronsted basic tertiary amine group. Sequential modification of the modular catalyst structure and subsequent screening of the compounds in the alcoholytic dynamic kinetic resolution (DKR) of azlactones revealed valuable structure-activity relationships. In particular, a "hit-structure" was identified which provides e.g. N-benzoyl-tert-leucine allyl ester in an excellent enantiomeric excess of 95%. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b607574f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Structural optimization of thiourea-based bifunctional organocatalysts for the
highly enantioselective dynamic kinetic resolution of azlactones†
Albrecht Berkessel,* Santanu Mukherjee, Thomas N. Mu¨ller, Felix Cleemann, Katrin Roland,
Marc Brandenburg, Jo¨rg-M. Neudo¨rfl and Johann Lex
Received 30th May 2006, Accepted 29th September 2006
First published as an Advance Article on the web 1st November 2006
DOI: 10.1039/b607574f
This article describes the synthesis of a library of structurally diverse bifunctional organocatalysts
bearing both a quasi-Lewis acidic (thio)urea moiety and a Brønsted basic tertiary amine group.
Sequential modification of the modular catalyst structure and subsequent screening of the compounds
in the alcoholytic dynamic kinetic resolution (DKR) of azlactones revealed valuable structure–activity
relationships. In particular, a “hit-structure” was identified which provides e.g. N-benzoyl-tert-leucine
allyl ester in an excellent enantiomeric excess of 95%.
We reasoned that compounds of this general structure could also
be efficient catalysts for the asymmetric alcoholytic ring opening
Introduction
of azlactones and oxazinones.8,9 The azlactone carbonyl can be
activated by double hydrogen bonding from the quasi-Lewis acidic
(thio)urea while the Brønsted basic tertiary amine can increase
the nucleophilicity of the alcohol (Scheme 1). Because of the
configurational lability of azlactones, asymmetric alcoholytic ring
opening of these species leads to highly valuable protected a-amino
acid derivatives via dynamic kinetic resolution (DKR) (Scheme 2).
The simultaneous activation of both nucleophilic and electrophilic
substrates is a general concept of enzyme catalysis.1 The synergistic
cooperation of two functional groups in the active site helps
to improve the reactivity as well as the stereodiscrimination. To
achieve efficient double catalytic activation of the reaction part-
ners, the two complementary functionalities have to be suitably
positioned in a chiral environment.2 This powerful concept has
been successfully implemented by synthetic organic chemists for
a variety of asymmetric transformations.3 The Lewis basic part of
the catalysts is often taken over by “organic” bases such as amines
and phosphine oxides. On the other hand, transition metals were
usually applied as Lewis acids for the activation of electrophilic
substrates. One of the rare examples of purely organic quasi-Lewis
acids is the (thio)urea moiety which is able to activate by forming
hydrogen bonds with appropriate acceptors.4 This property was
utilized to develop efficient organocatalysts5 which can activate
carbonyl groups and related functionalities6 for the attack of
nucleophiles. Takemoto et al. combined a thiourea moiety with
a tertiary amine in an effective bifunctional organocatalyst (1a
in Scheme 1) for enantioselective Michael additions and the aza-
Henry reaction.7
Scheme 2 Basic principle of the DKR of azlactones.
In this article, we describe the synthesis of a library of
bifunctional (thio)urea based organocatalysts and their screening
in the DKR of azlactones.
Results and discussion
The goal of our initial experiments was to examine the catalytic
activities of both Brønsted basic tertiary amine and quasi-
Lewis acidic (thio)urea functionalities individually, as well as in
combination. It is particularly noteworthy that the X-ray crystal
structure of the urea catalyst 26b revealed bifurcate intermolecular
hydrogen bonding between the urea N–H groups and the urea
oxygen atom of a neighbouring molecule of 26b (Fig. 1). The
urea moiety of 26b is planar and there is no intramolecular
H bond to the N atom of the tertiary amine. Thus, the H-bonding
behaviour of 26b, as revealed by its crystal structure, corresponds
Scheme 1 Takemoto’s catalyst 1a and the bifunctional mode of activation
for the DKR of azlactones (X = S, O).
Institut fu¨r Organische Chemie der Universita¨t zu Ko¨ln, Greinstrasse 4, D-
50939 Ko¨ln, Germany. E-mail: berkessel@uni-koeln.de; Fax: +49-221-470-
5102; Tel: +49-221-470-3283
† Electronic supplementary information (ESI) available: General exper-
imental details, syntheses of 1a–g and 16–29, ORTEP structures and
crystallographic data of selected catalysts. See DOI: 10.1039/b607574f
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During the process of structure optimization, we first screened
the 3,5-bis(trifluoromethyl)phenyl ureas or thioureas derived from
twelve structurally distinct diamines. In this sense, we synthe-
sized ten compounds derived from 1,2-diamines 6–12 and three
from 1,4-diamines 13–15 (Table 2). As shown in Table 2, all
bifunctional (thio)ureas derived from 1,4-diamines were found
to be completely inactive for the alcoholytic ring opening of the
tert-butyl substituted azlactone 2b (entries 12–14). In contrast,
all the compounds containing 1,2-functionalities showed variable
activities and enantioselectivities (entries 1–11). The catalysts with
a quinuclidine backbone 6, 7, 11, 12, a proline derivative 8 and the
ephedrine derived catalyst 10 afforded enantioselectivities below
60%. Significantly higher enantioselectivities were obtained using
catalysts derived from pseudoephedrine 9 and trans-1,2-diamino
cyclohexane 1 (entries 5–7). In the case of thiourea 1a and urea
1b, similar conversions and comparable enantioselectivities were
Fig. 1 Packing of 26b in the crystal, intermolecular H bonding between
neighbouring molecules of 26b.
to the design features summarized in Scheme 1 for a bifunctional
organocatalyst.
Table 2 Optimization of the diamine backbone
We first investigated the catalytic activity of NEt3 for the
ring opening of the benzyl substituted azlactone 2a with allyl
alcohol (Table 1, entry 1). Using 5 mol% of NEt3 after a reaction
time of 24 h, only 14% conversion was observed. Similarly,
when the symmetric urea 4 was used as the catalyst, even lower
conversion (4%) was achieved after 24 h (entry 2). However, when
a combination of 4 and NEt3 (5 mol% each) was applied, a
significantly higher conversion of 50% was obtained after 24 h
(entry 3). In the hope to achieve asymmetric induction, we tested
the chiral (thio)ureas 5a,b in combination with NEt3. In these
cases, similar levels of conversion were obtained as in the above
case (entries 4 and 5). Although the achieved enantioselectivities
were low, these experiments clearly proved the synergistic action
of the achiral amine and the chiral (thio)ureas.
As the next step, we synthezised a library of bifunctional
(thio)urea based organocatalysts. These compounds bearing both
a (thio)urea and a tertiary amine moiety within the same molecule
can be easily prepared by condensation of a chiral diamine and an
iso(thio)cyanate.
Table 1 Screening of amine bases and bis-ureas
Entry
Catalyst
Time/h
Conversion (%)a
ee (%)a
1
2
3
4
5
6a
6b
7
72
72
72
48
48
48
48
48
72
24
48
24
24
24
78
68
71
5
69
67
16
6
9
8
27
<2
<2
<2
38b
45b
33b
21b
83
8
1a
1b
1a
9
10
11
12
13
14
15
6
87
7c
8
91
78b
<2
7
9
Entry
Catalyst
Conversion (%)a
ee (%)a
10
11
12
13
14
55
1
2
3
4
5
NEt3
4
4 + NEt3
5a + NEt3
5b + NEt3
14
4
50
50
33
—
—
—
<2
5
<2
<2
<2
a Conversion and ee were determined by chiral HPLC analysis.
b (S)-Enantiomer was formed in excess. c Reaction was carried out at
−20 ◦C.
a Conversion and ee were determined by chiral HPLC analysis.
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Table 3 Variation of the tertiary amine part
Table 4 Optimization of the (thio)urea N-substituents
Entry Catalyst R2
R3
Conversion (%)a ee (%)a
1
2
3
4
5
6
1b
1c
1d
1e
1f
Me
Me
67
75
16
<2
<2
87
75
73
n.d.
n.d.
n.d.
−(CH2)4–
Et
Et
Bn
Bn
Bn
Me
Allyl
1g
Allyl <2
Entry
Catalyst
Time/h
Conversion (%)a
ee (%)a
a Conversion and ee were determined by chiral HPLC analysis.
1b
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
16
24
48
48
48
66
48
48
48
48
48
72
24
24
48
48
48
48
24
48
7
66
9
58
86
84
82
78
81
87
88
87
80
85
88
91
90
95
92
86
77
92
17
18
19
12
35
13
47
33
32
30
28
18
23
26
28
38
15
3
achieved at room temperature (entries 5 and 6). However, in the
case of catalyst 1a, by lowering the temperature to −20 ◦C, the
enantioselectivity could be increased to 91% albeit at the expense
of reaction rate (entry 7). For further optimization of the catalyst
structure, trans-1,2-diamino cyclohexane was exclusively used as
the diamine backbone.
20
21
22
23
24
25
26a
26b
27a
27b
27c
27d
27e
28
We next turned our attention to the substitution pattern on the
Brønsted basic tertiary amine part of the catalyst (Table 3). The
exchange of the dimethylamino group for a pyrrolidine unit (1c)
resulted in slightly higher conversion (75% compared to 67%)
and a lower enantioselectivity of 75% compared to 87% with
catalyst 1b (entries 1 and 2). Increasing the steric demand of the
N-substituents from methyl to ethyl resulted in drastically
diminished conversion (67 to 16% after 48 h, entries 1 and 3). A
similar but less pronounced trend was observed for the enantio-
selectivities, with a drop of ee from 87 to 73%. Further increase in
steric bulk of the substituents completely eliminates the catalytic
activity (entries 4–6). It is interesting to note that even the
replacement of one methyl group on the tertiary amine by a benzyl
group (1f) is sufficient to inactivate the catalyst (entry 5). These
examples demonstrate that the catalytic activity is quite sensitive
to the substituents on the tertiary amine nitrogen atom whereas
the selectivity is almost unaffected by these substituents.
Having optimized the diamine part of the catalyst to N,N-
dimethyl-1,2-diaminocyclohexane, we went on for further screen-
ing to find out the optimum substituent on the other (thio)urea
nitrogen atom. At this stage of optimization, the best catalysts
we found in terms of both activity and enantioselectivity were
the bifunctional thiourea 1a and urea 1b containing the 3,5-
bis(trifluoromethyl)phenyl moiety (see Table 2, entries 5–7). We
reasoned that changing the steric and electronic properties of
the substituent at this part of the molecule would substantially
influence both the catalytic activity as well as the enantioselectivity.
For this purpose, we synthesized several ureas and thioureas
containing substituents with varying steric and electronic demand
(Table 4). First, we replaced the 3,5-bis(trifluoromethyl)phenyl
moiety of compound 1b with only a hydrogen atom. To our
29
23
a Conversion and ee were determined by chiral HPLC analysis.
b Phenylalanine-derived azlactone rac-2a was used as substrate.
surprise, even this simplest bifunctional urea derivative 16 proved
to be moderately enantioselective in the ring opening of the
phenylalanine-derived azlactone 2a although the activity was low
(entry 1). Because of its higher reactivity towards alcoholytic
ring opening, the phenylalanine-derived azlactone was chosen in
this particular case instead of azlactone 2b. The exchange of the
trifluoromethyl groups of catalyst 1b with nitro groups gave the
urea 17 which showed similar activity and enantioselectivity as
1b (entry 2). In contrast, the urea 18 containing the electron rich
and bulky mesityl substituent on the urea nitrogen atom showed
considerably lower conversion (9%), whereas the enantioselectivity
remained almost the same (entry 3). In line with this observation,
the pyridine substituted thiourea 19 was found to have similar
catalytic behaviour as the mesityl urea 18 with 12% conversion and
82% ee after 48 h (entries 3 and 4). In the next stage of the optimiza-
tion, we examined a series of bifunctional organocatalysts bearing
simple aliphatic substituents with increasing sterical demand
(20–22, 24). Methyl and benzyl substituted catalysts 20 and 21
provided similar enantioselectivities of 78 and 81% respectively but
with lower conversions (entries 5 and 6). Cyclohexyl substitution
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(thiourea 22), on the other hand, increased both reactivity and
enantoselectivity. After 48 h, the product 3b was obtained in
87% ee and with a conversion of 47% (entry 7). Please note
that the C2-symmetric bifunctional thiourea 23 showed selectivity
comparable to 22 (entry 8). Further enhancement of steric bulk
by exchanging the cyclohexyl for a 1-adamantyl group (catalyst
24) did not improve the selectivity but the conversion dropped
from 47 to 32% (entries 7 and 9). The idea to enhance reactivity
by incorporating two active centers in a single molecule yielded
compound 25 (Table 4). Unfortunately, the reaction rate was not
improved significantly when 5 mol% 25 was used as the catalyst in
our test reaction (entry 10). However, the selectivity obtained was
on the same level as with catalysts 20 and 21 (vide supra).
Experimental
General
All reactions were carried out in oven-dried or flame-dried round
bottomed flasks, and the reactions were conducted under a
positive pressure of argon, unless otherwise stated. Stainless steel
syringes or cannulae were used to transfer air- and/or moisture-
sensitive liquids. Chromatographic separations were performed
using silica gel 60 (230–400 mesh) from MN GmbH & Co.
Commercial reagents were purchased from standard suppliers,
and used as received. Solvents were distilled and dried prior to
use following standard procedures.10 Nuclear magnetic resonance
(1H and 13C) spectra were recorded on Bruker AC250 (250 MHz),
Bruker AC300 (300 MHz), Bruker DPX300 (300 MHz) or Bruker
DRX500 (500 MHz) NMR spectrometers. Chemical shifts for
protons and carbon atoms are reported in parts per million
(ppm) downfield from tetramethylsilane and are referenced to
residual protons in the NMR solvent (CHCl3: d 7.24) and carbon
resonances of the solvent (CDCl3: d 77.0) respectively. Infrared
(IR) spectra were recorded on a Perkin-Elmer 1600 Series FTIR
or Perkin-Elmer Paragon 1000 FT-IR spectrometer with ATR
technique. Data are reported as: wave number of absorption
band (cm−1), intensity of absorption band (vs = very strong, s =
strong, m = medium, w = weak, br = broad, sh = sharp).
Chiral HPLC analyses were performed using Agilent 1100 Series
or Merck-Hitachi Lachrom HPLC instruments. Melting points
were measured on a Bu¨chi 535 Melting Point apparatus and are
uncorrected. HRMS data were recorded on a Finnigan MAT 900S
instrument (Dmu = 5). Optical rotations were measured using a
1 mL cell with a 1 dm path length on a Perkin-Elmer 343plus
polarimeter at 20 ◦C.
After studying the effect of various achiral substituents at the
(thio)urea nitrogen atom, we set out to investigate the influence of
an additional chiral centre at this part of the molecule. Incorpora-
tion of a 1-phenylethyl group furnished the two diastereomeric
catalysts 26a–b, neither of them showing enhanced selectivity
(entries 11–12). We reasoned that inclusion of a bulkier group
at the additional chiral centre might have a beneficial effect on the
selectivity of the DKR. To prove this, we synthesized the L-tert-
leucine amide-derived catalysts 27a–e with different substituents at
the amide nitrogen atom (Table 4). To our delight, enhancement in
enantioselectivity, with a “jump” of ee values to the range >90%
resulted with catalysts 27a–d (entries 13–16). It was found that
the substitution pattern of the amide controls both reactivity and
enantioselectivity. Whereas N,N-dimethyl and N,N-diethyl amide
catalysts 27a and 27b showed comparable selectivities of 90% and
91% ee, respectively, changing to N-methyl-N-benzyl substituents
in 27c significantly improved the selectivity (entries 13–15). After
48 h, the product ester 3b was formed with 28% conversion and
an excellent ee of 95% (entry 15). At this point, it is interesting
to note that the “mismatched” diastereomeric catalyst 28, derived
from D-tert-leucine, provided significantly lower conversion and
enantioselectivity (77% vs. 95%; entry 18). Replacement of the
methyl group of the “matched” catalyst 27c with a hydrogen atom
(27d) increased the reaction rate (from 28 to 38% after 48 h) at
the expense of enantioselectivity (95 vs. 92% ee; entries 15 and
16). That the optimum steric bulk of these substituents is essential
for providing efficient catalytic performance is supported by the
behaviour of the N,N-diisobutyl amide catalyst 27e: both lower
conversion (15%) and selectivity (86% ee) were obtained after 48 h
(entry 17). In line with this argumentation, increasing the steric
demand of the substituent at the additional chiral centre from tert-
butyl to neopentyl in 29 did not provide any further enhancement
(entry 19).
Synthesis of azlactones
The azlactones were prepared by cyclodehydration of the corre-
sponding racemic N-benzoyl amino acids with acetic anhydride
according to the procedure by Goodman and Glaser.11
2-Phenyl-4-benzyloxazolone rac-2a. Compound rac-2a was
prepared from rac-N-benzoylphenylalanine (1.00 g, 3.71 mmol)
and isolated as a crystalline solid (730 mg, 78%). Mp 69–70 ◦C
[lit.12 70–71 ◦C]. 1H-NMR (300 MHz, CDCl3): d = 3.19 (dd, J =
6.7, 14.0 Hz; 1H), 3.38 (dd, J = 4.9, 13.9 Hz; 1H), 4.70 (dd, J =
4.9, 6.7 Hz; 1H), 7.18–7.28 (m; 5H), 7.42–7.48 (m; 2H), 7.52–7.58
(m; 1H), 7.90–7.94 (m; 2H). 13C-NMR (75 MHz, CDCl3): d =
37.3, 66.5, 125.7, 127.2, 127.8, 128.4, 128.7, 129.5, 132.7, 135.2,
161.7, 177.6. FT-IR (ATR):m[cm−1] = 1827 (s), 1814 (s), 1651 (s),
1450 (w), 1323 (w), 1296 (m), 1079 (m), 1048 (m), 943 (w), 902
(m), 756 (w), 659 (s).
Conclusions
In summary, we have described the synthesis and screening of a
library of (thio)urea-based bifunctional organocatalysts for the
alcoholytic DKR of azlactones. Due to the modular structure
of the compounds, it was possible to vary different parts of the
catalyst structure independently. This allowed us to identify and
optimize the parts of the catalyst structure which are crucial for
both high reactivity and enantioselectivity. By this approach, the
catalyst 27c was found to be optimally selective in the DKR of
tert-leucine derived azlactone 2b with allyl alcohol.
2-Phenyl-4-tert-butyloxazolone rac-2b. Compound rac-2b was
prepared from (S)-N-benzoyl-tert-leucine (1.00 g, 4.25 mmol) and
isolated as a crystalline white solid (580 mg, 63%). Mp 69 ◦C [lit.13
73–74 ◦C]. 1H-NMR (300 MHz, CDCl3): d = 1.14 (s; 9H), 4.08 (s;
1H), 7.46–7.60 (m; 3H), 8.00–8.04 (m; 2H). 13C-NMR (75 MHz,
CDCl3): d = 26.2, 35.9, 74.1, 125.9, 127.9, 128.7, 132.6, 161.2,
177.0. FT-IR (ATR): m[cm−1] = 1814 (m), 1652 (s), 1603 (s), 1346
(m), 1143 (w), 1066 (w), 1019 (m), 923 (w), 888 (m), 782 (w), 702
(m), 586 (w).
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Synthesis of allyl esters
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(dimethyl-
amino)cyclohexyl}thiourea 1a. Compound 1a was prepared from
the corresponding amine (526 mg, 3.69 mmol, 1.00 eq.) and 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (670 lL, 3.69 mmol,
1.00 eq.), and isolated as a yellowish foam (1.28 g, 84%). Mp
The allyl esters 3a–b were prepared by reaction of the correspond-
ing racemic N-benzoyl amino acids with thionyl chloride (1.15 eq.)
in allyl alcohol as solvent.
◦
111–113 C. [a]589 = −30.9, [a]546 = −39.5, [a]405 = −166.2 (c =
2-Benzoylamino-3-phenylpropionic acid allyl ester 3a. Com-
pound rac-3a was prepared from rac-N-benzoylphenylalanine
(500 mg, 1.86 mmol, 1.00 eq.) and thionyl chloride (150 lL,
2.14 mmol, 1.15 eq.) in allyl alcohol (3.5 mL), and isolated as
a white solid (482 mg, 84%). Mp 70 C. H-NMR (300 MHz,
CDCl3): d = 3.19–3.34 (m; 2H), 4.63–4.66 (m; 2H), 5.07–5.15 (m;
1H), 5.25–5.38 (m; 2H), 5.82–5.98 (m; 1H), 6.60 (d, J = 7.62 Hz;
1H), 7.12–7.52 (m; 8H), 7.70–7.75 (m; 2H). 13C-NMR (75 MHz,
CDCl3): d = 37.9, 55.5, 66.2, 119.2, 127.0, 127.2, 128.6, 129.4,
131.3, 131.7, 133.9, 135.8, 166.8, 171.3. FT-IR (ATR): m[cm−1] =
3313 (w), 2926 (m), 1741 (s), 1642 (s), 1601 (m), 1579 (m), 1530 (s),
1487 (m), 1453 (w), 1180 (m), 1099 (m), 987 (w), 933 (w), 700 (m).
1
1.035, CHCl3). H-NMR (300 MHz, CDCl3): d = 1.07–1.36 (m;
4H, H-3), 1.69–1.91 (m; 3H), 2.26 (s; 6H), 2.41–2.55 (m; 2H, H-
1), 3.88 (m; 1H), 7.58 (s; 1H), 7.83 (s; 2H). 13C-NMR (75 MHz,
CDCl3): d = 21.9, 24.5, 24.8, 32.8, 40.1, 56.6, 67.4, 118.3, 123.0
(q, J = 271.05 Hz), 123.3, 132.5 (q, J = 33.15 Hz), 140.4, 178.7.
FT-IR (CsI): m[cm−1] = 3225 (br w), 2944 (m), 2867 (w), 1544
(s), 1474 (m), 1386 (s), 1280 (s), 1181 (s), 1132 (s), 885 (m), 683
(m). HRMS (EI): calcd for [C17H21F6N3S] ([M]+): 413.136, found:
413.138. Elemental analysis: anal. calcd. for C17H21F6N3S: C 49.39,
H 5.12, N 10.16, found: C 49.19, H 5.15, N 10.12%.
◦
1
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(dimethyl-
amino)cyclohexyl}urea 1b. Compound 1b was prepared from
the corresponding amine (735 mg, 5.17 mmol, 1.00 eq.) and
3,5-bis(trifluoromethyl)phenyl isocyanate (939 lL, 5.17 mmol,
1.00 eq.), and isolated as an off-white crystalline solid (1.79 g,
87%). Mp 163–165 ◦C. [a]589 = −35.1, [a]546 = −41.5, [a]405 = −83.1,
[a]365 = −106.8 (c = 1.00, CHCl3). 1H-NMR (300 MHz, CDCl3):
d = 1.09–1.35 (m; 4H), 1.67–1.89 (m; 3H), 2.20–2.25 (m; 1H), 2.26
(s; 6H), 2.34–2.38 (m; 1H), 3.47–3.55 (m; 1H), 5.76 (br s; 2H), 7.36
(s; 1H), 7.76 (s; 2H), 8.06 (br s; 1H). 13C-NMR (75 MHz, CDCl3):
d = 21.4, 24.7, 25.0, 33.8, 40.1, 51.6, 67.4, 115.3, 118.5, 123.2 (q,
J = 271.0 Hz), 131.9 (q, J = 32.97 Hz), 140.9, 155.6. FT-IR (CsI):
m[cm−1] = 3320 (br), 2941 (m), 2866 (w), 2787 (w), 1853 (s), 1604
(s), 1574 (s), 1516 (m), 1474 (m), 1388 (s), 1342 (m), 1279 (s), 1235
(w), 1175 (s), 1132 (s), 1067 (w), 1045 (w), 942 (w), 884 (m), 849 (w),
704 (m), 685 (m), 664 (w). HRMS (EI): calcd for [C17H21F6N3O]
([M]+): 397.159, found: 397.159. Elemental analysis: anal. calcd
for C17H21F6N3O: C 51.38, H 5.33, N 10.57, found: C 51.29, H
5.40, N 10.41%.
2-Benzoylamino-3,3-dimethylbutyric acid allyl ester 3b. Com-
pound rac-3b was prepared from rac-N-benzoyl-tert-leucine
(500 mg, 2.13 mmol, 1.00 eq.) and thionyl chloride (172 lL,
2.45 mmol, 1.15 eq.) in allyl alcohol (3.5 mL), and isolated as
a colourless oil (270 mg, 46%). 1H-NMR (300 MHz, CDCl3): d =
1.05 (s; 9H), 4.62–4.66 (m; 2H), 4.72 (d, J = 9.4 Hz; 1H), 5.22–5.39
(m; 2H), 5.84–6.00 (m; 1H), 6.68 (d, J = 9.1 Hz; 1H), 7.39–7.54 (m;
3H), 7.77–7.81 (m; 2H). 13C-NMR (75 MHz, CDCl3): d = 26.7,
35.3, 60.2, 65.8, 119.2, 127.0, 128.6, 131.4, 131.7, 134.2, 167.1,
171.4. FT-IR (ATR): m[cm−1] = 3340 (w), 2962 (m), 1734 (s), 1647
(s), 1601 (w), 1579 (w), 1517 (s), 1485 (s), 1445 (w), 1400 (w), 1368
(m), 1335 (m), 1268 (w), 1211 (m), 1166 (m), 1091 (w), 1029 (w),
987 (m), 933 (w), 854 (w), 800 (w), 750 (w).
Typical procedure for the DKR of azlactones
To a solution of 8.33 lmol of the catalysts 6–30 (0.05 eq.) in
667 ll abs. toluene, 1.5 eq. of allyl alcohol were added. In the
case of the monofunctional catalysts 4 and 5, 8.33 lmol NEt3
(0.05 eq.) were added. After addition of a solution containing
167 lmol of the azlactone rac-2a–b (1.00 eq.) in 1.00 ml abs.
toluene, the homogeneous reaction mixture was stirred at ambient
temperature. For analysis, 100 ll samples were withdrawn, diluted
with 900 ll dichloromethane, and conversion and enantiomeric
excess were determined immediately by HPLC (Daicel Chiralpak
AD, n-hexane–2-propanol). Quantification was based on UV
detection at k = 230 nm and 210 nm, respectively. Conversion was
determined by comparison with the peak areas of stock solutions
of the azlactones and the corresponding N-benzoyl amino acid
esters in dichloromethane. The absolute configurations of the
product esters 3a–b were determined by comparison with the esters
synthesized from enantiomerically pure a-amino acids.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(pyrrolidin-1-
yl)cyclohexyl}urea 1c. Compound 1c was prepared from the
corresponding amine (325 mg, 1.93 mmol, 1.00 eq.) and
3,5-bis(trifluoromethyl)phenyl isocyanate (350 lL, 1.93 mmol,
1.00 eq.), and isolated as a yellowish foam (578 mg, 71%). Mp
98–100 ◦C. [a]589 = −18.7, [a]546 = −21.9, [a]405 = −37.7 (c =
1
1.00, CHCl3). H-NMR (300 MHz, CDCl3): d = 1.07–1.36 (m;
4H), 1.62–1.86 (m; 7H), 2.25–2.29 (m; 1H), 2.44–2.48 (m; 1H),
2.62–2.71 (m; 4H), 3.50 (m; 1H), 5.87 (br s; 1H), 7.36 (s; 1H),
7.80 (s; 2H), 8.56 (br s; 1H). 13C-NMR (75 MHz, CDCl3): d =
23.1, 23.6, 24.3, 24.6, 33.1, 48.0, 53.3, 63.4, 115.2, 118.2, 123.0
(q, J = 271.1 Hz), 132.0 (q, J = 32.97 Hz), 141.1, 155.9. FT-IR
(CsI): m[cm−1] = 3320 (br), 3112 (w), 2940 (m), 1863 (w), 1813 (w),
1663 (s), 1575 (s), 1508 (w), 1475 (m), 1390 (s), 1340 (w), 1278 (s),
1235 (w), 1182 (s), 1133 (s), 1040 (w), 941 (w), 881 (m), 848 (w),
704 (m), 682 (m). HRMS (ESI): calcd for [C19H24F6N3O] ([M +
H]+): 424.182, found: 424.183. Elemental analysis: anal. calcd for
C19H23F6N3O: C 53.90, H 5.48, N 9.92, found: C 53.58, H 5.47, N
9.81%.
Synthesis of catalysts†
General procedure for the preparation of (thio)ureas: the
iso(thio)cyanate (1.00 eq.) was added to a solution of the amine
(1.00 eq.) in abs. THF, and the resulting mixture was stirred at
room temperature under argon for 16 h. The reaction mixture was
then concentrated in vacuo and the residue was purified by silica
gel chromatography using CH2Cl2–CH3OH–NEt3 mixtures as the
eluent.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(diethylamino)-
cyclohexyl}urea 1d. Compound 1d was prepared from the
corresponding amine (325 mmol, 1.91 mmol, 1.00 eq.) and
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1
3,5-bis(trifluoromethyl)phenyl isocyanate (349 lL, 1.91 mmol,
1.00 eq.), isolated as a colourless crystalline solid (580 mg, 71%).
Mp 195–197 ◦C. [a]589 = −58.1, [a]546 = −68.7, [a]405 = −134.5,
(c = 1.01, CHCl3). H-NMR (300 MHz, CDCl3): d = 1.02–1.31
(m; 4H), 1.67 (br d, J = 11.1 Hz; 1H), 1.79–1.90 (m; 2H),
2.43–2.53 (m; 2H), 2.88 (dd, J = 8.0, 14.1 Hz; 2H), 3.27 (ddd, J =
3.8, 6.0, 10.6 Hz; 2H), 3.42 (tt, J = 3.4, 10.5 Hz; 1H), 5.11 (dd,
J = 13.6, 14.5 Hz; 4H), 5.64 (br s; 1H), 5.66–5.78 (m; 2H), 7.25
(br s; 1H), 7.47 (s; 1H), 7.87 (s; 2H). 13C-NMR (75 MHz, CDCl3):
d = 23.3, 24.5, 25.4, 33.3, 52.2, 52.3, 62.1, 115.8, 117.4, 118.8,
123.2 (q, J = 273 Hz), 132.2 (q, J = 33.1 Hz), 136.5, 140.7, 155.4.
FT-IR (ATR): m[cm−1] = 3378 (w, br), 3083 (w), 2933 (m), 2859
(w), 2812 (w), 1653 (s), 1622 (m), 1569 (s), 1500 (s), 1472 (s), 1338
(m), 1275 (s), 1234 (s), 1172 (s), 1130 (s), 1037 (m), 998 (m), 945
(m), 920 (m), 881 (s), 847 (m), 732 (m), 702 (s), 681 (s). Elemental
analysis: anal. calcd for C21H25F6N3O: C 56.12, H 5.61, N 9.35,
found: C 55.71, H 5.50, N 9.16%.
1
[a]365 = −174.0, [a]334 = −226.1 (c = 1.01, CHCl3). H-NMR
(300 MHz, CDCl3): d = 0.98 (t, J = 7.13 Hz; 6H), 1.04–1.31 (m;
4H), 1.63–1.81 (m; 3H), 2.28–2.73 (m; 6H), 3.35–3.41 (m; 1H),
5.92 (br s; 1H), 7.42 (s; 1H), 7.86 (s; 2H). 13C-NMR (75 MHz,
CDCl3): d = 14.2, 23.5, 24.5, 25.5, 33.4, 43.2, 51.9, 63.0, 115.5,
118.6, 123.2 (q, J = 271.1 Hz), 132.1 (q, J = 32.97 Hz), 141.0,
155.8. FT-IR (CsI): m[cm−1] = 3286 (s), 3099 (m), 2974 (m), 2937
(m), 2867 (w), 1667 (s), 1623 (w), 1581 (s), 1493 (s), 1476 (s),
1389 (s), 1338 (m), 1279 (s), 1238 (m), 1169 (s), 1140 (s), 1073
(w), 1000 (w), 957 (m), 882 (m), 734 (m). HRMS (ESI): calcd. for
[C19H26F6N3O] ([M + H]+): 426.198, found: 426.199. Elemental
analysis: anal. calcd for C19H25F6N3O: C 53.64, H 5.92, N 9.88,
found: C 53.56, H 5.93, N 9.85.
N -[3,5-Bis(trifluoromethyl)phenyl]-Nꢀ -[(1R,3S)-3-{[({[3,5-bis-
(trifluoromethyl)phenyl]amino}oxomethyl)amino]methyl}-3,5,5-
trimethylcyclohexyl]urea 5a. Compound 5a was prepared from
the corresponding diamine (272 lL, 1.47 mmol, 1.00 eq.) and
3,5-bis(trifluoromethyl)phenyl isocyanate (534 lL, 3.09 mmol,
2.00 eq.), and isolated as col◦ourless crystals from CHCl3–methanol
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(dibenzylamino)-
cyclohexyl}urea 1e. Compound 1e was prepared from the
corresponding amine (160 mg, 632 lmol, 1.00 eq.) and 3,5-
bis(trifluoromethyl)phenyl isocyanate (109 lL, 632 lmol,
1.00 eq.), and isolated as an off-white solid (270 mg, 83%). Mp
94 ◦C. 1H-NMR (300 MHz, CDCl3): d = 0.85–0.96 (m; 1H),
1.13–1.28 (m; 2H), 1.35–1.48 (m; 1H), 1.62 (br d, J = 11.8 Hz;
1H), 1.85 (br d, J = 10.4 Hz; 1H), 2.12 (br d, J = 11.1 Hz;
1H), 2.30–2.38 (m; 2H), 3.41 (d, J = 13.1 Hz; 2H), 3.51–3.61
(m; 1H), 3.82 (d, J = 13.3 Hz; 2H), 5.08 (br s; 1H), 6.61 (br s;
1H), 7.22–7.27 (m; 10H), 7.51 (s; 1H), 7.81 (s; 2H). 13C-NMR
(75 MHz, CDCl3): d = 23.4, 24.4, 25.4, 33.4, 51.4, 53.6, 61.6,
116.0, 118.8, 123.2 (q, J = 273 Hz), 127.4, 128.5, 129.0, 132.4 (q,
J = 33.6 Hz), 139.8, 140.5, 154.9. FT-IR (ATR): m[cm−1] = 3329
(br, m), 3086 (w), 3026 (w), 2933 (m), 2859 (w), 1651 (s), 1565 (s),
1493 (m), 1470 (s), 1451 (m), 1378 (vs), 1274 (vs), 1173 (vs), 1129
(vs), 1036 (m), 1027 (m), 940 (m), 928 (m), 882 (s), 845 (m), 747
(m), 732 (m), 699 (s), 681 (vs).
1
(900 mg, 90%). Mp >230 C. H-NMR (300 MHz, DMSO-d6):
d = 0.86–1.12 (m; 12H), 1.13–1.26 (m; 1H), 1.53–1.67 (m; 2H),
2.80–3.00 (m; 2H), 3.74–3.91 (m; 1H), 6.33 (d; J = 7.60 Hz, 1H),
6.50–6.60 (m; 1H), 7.51 (s; 2H), 8.04 (s; 4H), 9.02 (s; 1H), 9.13 (s;
1H). 13C-NMR (75 MHz, DMSO-d6): d = 23.1, 27.4, 31.5, 34.9,
36.2, 41.4, 42.7, 45.7, 46.8, 52.7, 113.3, 113.4, 117.0, 117.1, 121.5,
125.1, 130.5 (q), 130.6 (q), 142.5, 154.0, 155.0. FT-IR (ATR, neat):
m[cm−1] = 3339 (br w), 2955 (br w), 1652 (m), 1558 (m), 1427 (m),
1438 (w), 1385 (m), 1274 (s), 1230 (m), 1172 (m), 1127 (s), 1037 (w),
940 (w), 880 (m), 847 (w), 701, 681 (both m). HRMS (ESI): calcd
for [C28H28F12N4O2Na] ([M + Na]+): 703.192, found: 703.192.
N -[3,5-Bis(trifluoromethyl)phenyl]-Nꢀ -[(1R,3S)-3-{[({[3,5-bis-
(trifluoromethyl)phenyl]amino}thioxomethyl)amino]-methyl}-3,5,5-
trimethylcyclohexyl]thiourea 5b. Compound 5b was prepared
from the corresponding diamine (500 lL, 2.70 mmol, 1.00 eq.)
and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (991 lL,
5.43 mmol, 2.00 eq.), and isolated as colourless crystals from
n-hexane–ethylacetate (1.73 g, 90%). Mp = 153 ◦C. [a]589 = +17.2
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(N-benzyl-N-
methylamino)cyclohexyl}urea 1f. Compound 1f was prepared
from the corresponding amine (421 mg, 1.93 mmol, 1.00 eq.)
and 3,5-bis(trifluoromethyl)phenyl isocyanate (350 lL, 1.93 mmol,
1.00 eq.), and isolated as a colourless crystalline solid (980 mg,
87%). 1H-NMR (300 MHz, CDCl3): d = 0.99–1.25 (m; 4H), 1.57–
1.89 (m; 3H), 2.09 (s; 3H), 2.26–2.37 (m; 2H), 3.34 (d, J = 13.1 Hz;
1H), 3.40–3.47 (m; 1H), 3.61 (d, J = 13.1 Hz; 1H), 5.71 (br s; 1H),
7.15 (s; 5H), 7.38 (s; 1H), 7.68 (s; 2H), 8.18 (br s; 1H). 13C-NMR
(75 MHz, CDCl3): d = 22.7, 24.5, 25.2, 33.4, 36.3, 52.0, 57.9, 66.4,
115.5, 118.8, 123.2 (q, J = 271.4 Hz), 127.1, 128.3, 128.7, 132.1
(q, J = 32.97 Hz), 139.0, 140.9, 156.0. FT-IR (KBr): m[cm−1] =
3346 (br s), 3091 (w), 2939 (s), 2861 (m), 2800 (w), 1659 (s), 1624
(m), 1571 (s), 1497 (m), 1474 (s), 1454 (m), 1388 (s), 1278 (s), 1235
(m), 1182 (s), 1132 (s), 1063 (w), 1042 (w), 1026 (m), 958 (w),
940 (m), 882 (s), 849 (m), 734 (m), 701 (s). HRMS (EI): calcd for
[C23H25F6N3O] ([M]+): 473.190, found: 473.190.
1
(c = 1.00, CHCl3). H-NMR (300 MHz, DMSO-d6): d = 0.96
(s; 3H), 1.02–1.21 (m; 9H), 1.24–1.36 (m; 1H), 1.65–1.85 (m;
2H), 3.28–3.51 (m; 2H), 4.47–4.67 (m; 1H), 7.66–7.75 (m; 2H),
8.09–8.19 (m; 2H), 8.21 (s; 2H), 8.29 (s; 2H), 9.85 (s; 1H), 10.07 (s;
1H). 13C-NMR (75 MHz, DMSO-d6): d = 23.2, 27.4, 31.6, 34.0,
34.7, 36.4, 40.6, 40.8, 44.3, 47.3, 57.3, 115.9, 121.4, 121.5, 121.9,
125.0, 130.2, 141.8, 179.3, 181.2. FT-IR (ATR, neat): m[cm−1] =
3240 (br w), 3049 (br w), 2957 (br w), 1621 (w), 1530 (s), 1469
(m), 1380 (s), 1274 (s), 1170 (s), 1130 (s), 1106 (s), 950 (m), 906
(m), 886 (m), 847 (w), 729 (s), 700 (s), 680 (s). HRMS (ESI): calcd
for [C28H28F12N4S2Na] ([M + Na]+): 735.146, found: 735.147.
Elemental analysis: anal. calcd for C28H28F12N4S2: C 47.19, H
3.96, N 7.86, found: C 47.15, H 4.19, N 7.81%.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(diallylamino)-
cyclohexyl}urea 1g. Compound 1g was prepared from the
corresponding amine (170 mg, 875 lmol, 1.00 eq.) and 3,5-
bis(trifluoromethyl)phenyl isocyanate (152 lL, 875 lmol,
1.00 eq.), and isolated as a colourless crystalline solid (200 mg,
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(2S,5R)-5-vinyl-1-azabi-
cyclo[2.2.2]oct-2-ylmethyl}urea 6a. Compound 6a was prepared
from the corresponding amine (166 mg, 1.00 mmol, 1.00 eq.)
and 3,5-bis(trifluoromethyl)phenyl isocyanate (174 lL, 1.00 mmol,
1.00 eq.), and isolated as a colourless solid (237 mg, 60%). Mp =
78–81 ◦C. [a]589 = −1.4, [a]546 = −2.2, [a]405 = −2.8 (c = 1.03,
◦
51%). Mp 119 C. [a]589 = −13.4, [a]546 = −14.3, [a]405 = −16.1,
4324 | Org. Biomol. Chem., 2006, 4, 4319–4330
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CHCl3). 1H-NMR (500 MHz, DMSO-d6): d = 0.72–0.76 (m; 1H),
1.33, 1.51 (m; 2H), 1.65–1.69 (m; 1H), 2.13 (br s; 1H), 2.39 (br s;
1H), 2.43–2.82 (m; 2H), 2.79 (m; 1H), 2.88–3.13 (m; 2H), 2.98–
3.20 (m; 2H), 4.85–4.93 (m; 2H), 5.75–5.82 (m; 1H), 6.17 (s; 1H),
7.37 (s; 1H), 7.90 (s; 2H), 9.35 (br s; 1H). 13C-NMR (125 MHz,
DMSO-d6): d = 25.7, 27.1, 27.3, 40.4, 42.1, 45.7, 54.9, 55.1, 113.2,
114.2, 116.8, 120.1, 122.2, 124.4, 126.6, 130.3, 130.5, 130.8, 131.0,
142.1, 142.6, 154.6. FT-IR (ATR, neat): m[cm−1] = 3328 (br w),
3084 (w), 2937 (w), 2866 (w), 1664 (m), 1570 (m), 1472 (m), 1386
(m), 1275 (s), 1176 (m), 1127 (m), 989 (w), 942 (w), 913 (w), 879
(w), 702 (w), 681 (m). HRMS (ESI): calcd for [C19H22F6N3O] ([M +
H]+): 422.167, found: 422.167. Elemental analysis: anal. calcd for
C19H21F6N3O: C 54.16, H 5.02, N 9.97, found: C 54.42, H 5.22, N
9.81%.
2.84 (m; 3H), 2.60 (s; 3H), 2.90–3.34 (m; 2H), 3.52–3.73 (m; 1H),
7.56 (s; 1H), 7.98 (s; 2H). The signals of the NH-protons could not
be detected. 13C-NMR (75 MHz, DMSO-d6): d = 21.8, 24.2, 26.6,
30.1, 40.1, 40.8, 47.2, 55.9, 56.9, 64.7, 66.0, 116.8, 120.9, 121.9,
124.5, 130.9, 131.5, 141.7, 182.9. FT-IR (ATR, neat): m[cm−1] =
3239 (w), 2945 (w), 2872 (w), 2790 (w), 1609 (w), 1508 (w), 1471
(m), 1383 (s), 1274 (s), 1171 (s), 1128 (s), 1107 (m), 1056 (w),
1006 (w), 952 (w), 882 (m), 847 (w), 719 (w), 699 (m), 681 (m).
HRMS (ESI): calcd for [C15H17F6N3S] ([M + H]+): 389.113, found:
389.113.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(2S)-dimethylamino-(1S)-
phenylpropyl}urea 9. Compound 9 was prepared from the
corresponding amine (190 mg, 1.07 mmol, 1.00 eq.) and
3,5-bis(trifluoromethyl)phenyl isocyanate (186 lL, 1.07 mmol,
100 eq.), and isolated as a colourless solid (280 mg, 62%). Mp
214 ◦C. [a]589 = +15.4, [a]546 = +18.8, [a]405 = +48.1, [a]365 = +74.6
(c = 0.83, CHCl3). 1H-NMR (500 MHz, CD2Cl2): d = 0.80 (d, J =
6.5 Hz; 3H), 2.31 (s; 6H), 2.77–2.81 (m; 1H), 4.29 (d, J = 10.3 Hz;
1H), 6.91 (br s; 1H), 7.30 (t, J = 6.8 Hz; 1H), 7.36–7.41 (m; 4H),
7.46 (s; 1H), 7.59 (s; 1H), 7.82 (s; 2H). 13C-NMR (125 MHz,
CD2Cl2): d = 7.1, 39.7, 59.0, 63.8, 115.4, 118.2, 123.6 (q, J =
271 Hz), 127.7, 127.8, 128.8, 131.9 (q, J = 32.7 Hz), 141.4, 142.1,
155.2. FT-IR (ATR): m[cm−1] = 3307 (m, br), 3110 (w, br), 2934
(m), 2863 (w), 2828 (w), 2786 (w), 1660 (s), 1620 (w), 1570 (s),
1504 (m), 1472 (s), 1386 (s), 1274 (vs), 1233 (m), 1176 (s), 1128
(vs), 1067 (m), 1042 (m), 1028 (m), 939 (w), 878 (m), 848 (w), 702
(m), 681 (s). Elemental analysis: anal. calcd for C20H21F6N3O: C
55.43, H 4.88, N 9.70, found: C 55.02, H 4.81, N 9.68%.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(2S,5R)-5-vinyl-1-azabi-
cyclo[2.2.2]oct-2-ylmethyl}thiourea 6b. Compound 6b was pre-
pared from the corresponding amine (948 mg, 2.25 mmol, 1.00 eq.)
and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (610 mg,
2.25 mmol, 1.00 eq.), and isolated as a colourless crystalline solid
(912 mg, 93%). Mp 54–59 ◦C. [a]589 = −52.6, [a]546 = −61.0, [a]405
=
1
−62.4, [a]365 = +117.6 (c = 1.00, CHCl3). H-NMR (300 MHz,
CDCl3): d = 0.97–1.03 (m; 1H), 1.13–1.31 (m; 1H), 1.53–1.70 (m;
2H), 1.78–2.00 (m; 2H), 2.51–2.75 (m; 2H), 2.83–3.21 (m; 4H),
3.39–3.89 (m; 1H), 5.01–5.14 (m; 2H), 5.77–5.92 (m; 1H), 7.69
(s; 1H), 7.85–7.90 (m; 2H), 7.91 (s; 1H), 13.9 (s; 1H). 13C-NMR
(75 MHz, CDCl3): d = 26.1, 27.3, 27.5, 30.1, 40.4, 42.1, 47.7, 54.8,
115.1, 118.0, 122.6, 123.1 (J = 272.9 Hz), 132.3 (m, br), 140.8,
141.2, 179.8. FT-IR (ATR): m[cm−1] = 2941 (br), 1542 (w), 1472
(w), 1384 (m), 1276 (s), 1177 (m), 1132 (m), 883 (w), 700 (w), 682
(w). HRMS (EI): calcd for [C19H21F6N3S] ([M]+): 437.136, found:
437.136. Elemental analysis: anal. calcd for C19H22F6N3S: C 52.17,
H 4.84, N 9.61, found: C 52.35, H 4.67, N 9.61%.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(2S)-dimethylamino-(1R)-
phenylpropyl}urea 10. Compound 10 was prepared from
the corresponding amine (140 mg, 785 lmol, 1.00 eq.) and
3,5-bis(trifluoromethyl)phenyl isocyanate (136 lL, 785 lmol,
1.00◦eq.), and isolated as a colourless solid (90 mg, 26%). Mp
186 C. 1H-NMR (300 MHz, acetone-d6): d = 1.99 (d, J = 6.4 Hz;
3H), 2.22 (s; 6H), 2.82–2.91 (m; 1H), 5.02–5.07 (m; 1H), 6.67
(br s; 1H), 7.18–7.24 (m; 1H), 7.28–7.38 (m; 4H), 7.50 (s; 1H),
8.12 (s; 2H), 8.88 (s; 1H). 13C-NMR (75 MHz, acetone-d6): d =
11.3, 43.3, 57.5, 65.2, 115.7, 119.2, 125.5 (q, J = 271 Hz), 127.3,
128.5, 129.8, 133.3 (q, J = 32.7 Hz), 144.2, 144.6, 156.1. FT-IR
(ATR): m[cm−1] = 3327 (w, br), 3101 (w), 2831 (w), 2782 (w), 1654
(m), 1576 (m), 1499 (w), 1473 (w), 1386 (s), 1276 (s), 1170 (m),
1137 (s), 950 (w), 880 (w), 705 (m), 681 (m). Elemental analysis:
anal. calcd for C20H21F6N3O: C 55.43, H 4.88, N 9.70, found: C
55.30, H 4.84, N 9.50%.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(2R,5R)-5-vinyl-1-azabi-
cyclo[2.2.2]oct-2-ylmethyl}urea 7. Compound 7 was prepared
from the corresponding amine (166 mg, 1.00 mmol, 1.00 eq.)
and 3,5-bis(trifluoromethyl)phenyl isocyanate (174 lL, 1.00 mmol,
1.00 eq.), and isolated as colourless solid (260 mg, 66%). Mp =
65 ◦C. [a]589 = +65.0, [a]546 = +77.2, [a]405 = +156.0 (c = 1.01,
1
CHCl3). H-NMR (300 MHz, CDCl3): d = 1.25–1.34 (m; 1H),
1.55–1.66 (m; 4H), 1.80 (br s; 1H), 2.32 (m; 1H), 2.75–3.05 (m;
6H), 3.27 (br s; 1H), 5.06 (dd, J = 7.3, 13.8 Hz; 2H), 5.76–5.89
(m; 1H), 6.63 (br s; 1H), 7.39 (s; 1H), 7.75 (s; 2H). 13C-NMR
(75 MHz, CDCl3): d = 25.3, 26.1, 27.4, 39.3, 43.9, 46.2, 46.3, 48.6,
115.0, 115.3, 117.8, 118.0, 121.4, 125.0, 128.7, 131.3, 131.7, 132.1,
132.6, 139.2, 141.6, 155.6. FT-IR (ATR, neat): m[cm−1] = 3310 (br
w), 3080 (w), 2940 (w), 2869 (w), 1665 (m), 1572 (m), 1473 (m),
1385 (s), 1275 (s), 1176 (s), 1127 (s), 943 (w), 912 (w), 879 (w),
702 (m), 681 (m). HRMS (ESI): calcd for [C19H22F6N3O] ([M +
H]+): 422.167, found: 422.167. Elemental analysis: anal. calcd for
C19H21F6N3O: C 54.16, H 5.02, N 9.97, found: C 54.07, H 5.34, N
9.87%.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-(quinuclidin-3-yl)urea 11.
Compound 11 was prepared from the corresponding amine
(160 mg, 1.27 mmol, 1.00 eq.) and 3,5-bis(trifluoromethyl)phenyl
isocyanate (220 lL, 1.27 mmol, 1.00 eq.), and isolated as a
colourless, hygroscopic solid (60 mg, 15%). 1H-NMR (300 MHz,
CDCl3): d = 1.45–1.55 (m; 1H), 1.65–1.73 (m; 2H), 2.03 (m; 2H),
2.69–2.88 (m; 4H), 2.95–3.03 (m; 1H), 3.31–3.39 (m; 1H), 3.95
(br s; 1H), 5.90 (br s; 1H), 7.35 (s; 1H), 7.92, (s; 2H), 9.31 (br s;
1H). 13C-NMR (75 MHz, CDCl3): d = 19.3, 24.6, 25.5, 46.2, 47.0,
52.8, 55.6, 114.5, 117.6, 123.3 (q, J = 270 MHz), 131.7 (q, J =
32.5), 141.6, 155.5. HRMS (EI): calcd for [C16H18F6N3O] ([M +
H]+): 382.135, found: 382.135.
(S)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1-methylpyrrolidin-2-
yl)methyl]thiourea 8. Compound 8 was prepared from the
corresponding amine (264 mg, 2.31 mmol, 1.00 eq.) and 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (464 lL, 2.54 mmol,
1.10 eq.), and isolated as a brownish solid (82.0 mg, 12%). Mp =
71 ◦C. 1H-NMR (300 MHz, CDCl3): d = 1.55–2.11 (m; 3H), 2.13–
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1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(R)-(6-methoxyquinolin-4-
yl)-(8-vinylquinuclidin-2-yl)methyl]thiourea 12. Compound 12
was prepared from the corresponding amine (50 mg, 155 lmol,
1.00 eq.) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate
(31 lL, 170 lmol, 1.10◦eq.), and isolated as a pale yellow solid
(56 mg, 61%). Mp = 150 C (decomposition). 1H-NMR (300 MHz,
CDCl3): d = 0.90–1.06 (m; 1H), 1.17–1.35 (m; 1H), 1.43–1.74 (m;
3H), 2.27–2.41 (m; 1H), 2.71–3.32 (m; 5H), 3.96 (s; 3H), 5.11–
5.25 (m; 2H), 5.77–5.99 (m; 2H), 7.08–7.19 (m; 1H), 7.35 (dd;
J = 9.06, 2.49 Hz, 1H), 7.64 (s(br); 1H), 7.67 (s; 1H), 7.85 (s;
2H), 7.95 (d; J = 9.06 Hz, 1H), 8.46–8.58 (m; 1H). The signals
of the NH-protons could not be detected. 13C-NMR (75 MHz,
CDCl3): d = 25.0, 26.0, 27.1, 38.6, 47.1, 48.6, 55.7, 61.4, 101.7,
115.4, 118.7, 118.8, 121.1, 122.4, 123.6, 124.8, 128.4, 131.6, 132.5
(q; CF3), 139.5, 144.7, 145.7, 147.3, 158.2, 181.4. FT-IR (ATR,
neat): m[cm−1] = 3234, 2937, 2872 (all w), 1620, 1507, 1472, 1381
(all m), 1275 (s), 1226 (w), 1175 (s), 1130 (s), 1106 (m), 1029, 957,
908, 883, 849, 824, 728 (all w), 680 (m). HRMS (ESI): calcd for
[C29H29F6N4OS] ([M + H]+): 595.197, found: 595.197.
(s; 6H), 3.00–3.20 (m; 1H), 3.78–3.79 (m; 1H), 5.57 (br s; 1H), 7.60
(br s; 2H). 13C-NMR (75 MHz, CDCl3): d = 23.0, 24.3, 24.4, 33.7,
39.1, 49.4, 66.6, 159.0. HRMS (ESI): calcd for [C9H19N3O] ([M +
H]+): 185.153, found: 185.153.
1-(3,5-Dinitrophenyl)-3-{(1R,2R)-2-(dimethylamino)cyclohexyl}-
urea 17. Compound 17 was prepared from the corresponding
amine (295 mg, 2.07 mmol, 1.00 eq.) and 3,5-dinitrophenyl
isocyanate (433 mg, 2.07 mmol, 1.00 eq.), and isolated as a yellow
foam (584 mg, 80%). Mp 97–99 ◦C. [a]589 = −40.3, [a]546 = −48.4
1
(c = 1.00, CHCl3). H-NMR (300 MHz, CDCl3): d = 1.13–1.28
(m; 4H), 1.66–1.89 (m; 3H), 2.28 (s; 6H), 2.31–2.35 (m; 2H),
3.47–3.50 (m; 1H), 5.87 (br s; 1H), 8.44–8.46 (m; 1H), 8.53–8.54
(m; 2H). 13C-NMR (75 MHz, CDCl3): d = 21.6, 24.6, 24.9, 33.6,
40.1, 51.9, 67.2, 110.9, 117.8, 142.5, 148.6, 155.4. FT-IR (CsI):
m[cm−1] = 3330 (br), 3113 (w), 2940 (m), 2865 (w), 1780 (w), 1677
(s), 1601 (s), 1547 (s), 1475 (m), 1346 (s), 1261 (m), 1225 (m),
1068 (m), 1044 (w), 894 (m), 829 (w), 731 (s). HRMS (ESI): calcd
for [C15H22N5O5] ([M + H]+): 352.162, found: 352.162. Elemental
analysis: anal. calcd for C15H21N5O5: C 51.28, H 6.02, N 19.93,
found: C 51.20, H 6.32, N 19.55%.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-[1-{2-(dimethylamino)naph-
thalen-1-yl}naphthalen-2-yl]thiourea 13. Compound 13 was
synthesized following the literature procedure.9d
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-mesitylurea 18.
Compound 18 was prepared from the corresponding amine
(373 mg, 2.62 mmol, 1.00 eq.) and mesitylisocyanate (422 mg,
2.62 mmol, 1.00 eq.), and isolated as a colourless crystalline solid
(513 mg, 65%). Mp 168–169 ◦C. [a]589 = −43.1, [a]546 = −50.9,
1-[3,5-Bis(trifluoromethyl)phenyl]-3-{[(1S,5R)-5-(dimethylamino)-
1,3,3-trimethylcylohexyl]methyl}urea 14. Compound 14 was
prepared from the corresponding amine (26 mg, 131 lmol,
1.00 eq.) and 3,5-bis(trifluoromethyl)phenyl isocyanate (23 lL,
131 lmol, 1.00 eq.), and isolated as a colourless solid (according
to 1H-NMR, the product contains ∼20% unidentified impurities).
1H-NMR (300 MHz, CDCl3): d = 0.81–1.48 (m; 15H); 1.65–1.93
(m; 2H), 2.15 (s; 1H), 2.72 (s; 6H), 3.18–3.34 (m; 1H), 6.84–6.94
(m; 1H), 7.34 (s; 1H), 7.97 (s; 2H), 9.31 (s; 1H). FT-IR (ATR,
neat): m[cm−1] = 3290 (w), 2959 (w), 2678 (w), 1697 (m), 1566,
1555, 1473, 1387 (all m), 1275, 1172, 1126 (all s), 1032, 999, 946,
878, 844, 800 (all w), 732 (m), 702 (m), 680 (s). HRMS (ESI):
calcd for [C21H30F6N3O] ([M + H]+): 454.229, found: 454.230.
1
[a]405 = −103.9, [a]365 = −136.1 (c = 1.02, CHCl3). H-NMR
(300 MHz, CDCl3): d = 0.89–1.32 (m; 4H), 1.55–1.74 (m; 3H),
1.99–2.02 (m; 1H), 2.08 (s; 6H), 2.22 (s; 6H), 2.25 (s; 3H),
2.30–2.38 (m; 1H), 3.33–3.43 (m; 1H), 4.97 (br s; 1H), 5.91 (br s;
1H), 6.87 (s; 2H). 13C-NMR (75 MHz, CDCl3): d = 18.0, 20.9,
21.6, 24.7, 25.3, 33.8, 39.8, 51.5, 66.5, 129.0, 131.8, 137.0, 157.6.
FT-IR (CsI): m[cm−1] = 3343 (m), 2937 (m), 2859 (w), 1638 (s),
1559 (s), 1458 (w), 1316 (w), 1264 (w), 1051 (w), 846 (m), 707 (w).
HRMS (ESI): calcd for [C18H29N3NaO] ([M + Na]+): 326.221,
found: 326.221. Elemental analysis: anal. calcd for C18H29N3O: C
71.25, H 9.63, N 13.85, found: C 70.87, H 9.60, N 13.75%.
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1S,2S,4S,5S)-5-(dimethyl-
amino)bicyclo[2.2.1]hept-2-yl}thiourea 15. Compound 15 was
isolated as a pale yellow solid (52%).† Mp 54 ◦C. [a]589 = −40.9,
[a]546 = −49.0, [a]405 = −90.1 (c = 0.88, CHCl3). 1H-NMR
(300 MHz, CD3OD): d = 1.24–1.28 (m; 1H), 1.45–1.60 (m; 1H),
1.56 (s; 2H), 1.65–1.74 (m; 1H), 1.88–1.98 (m; 1H), 2.21 (s; 6H),
2.29 (s; 1H), 2.33 (s; 1H), 2.65 (s; 1H), 4.59 (br s; 1H), 7.62 (s;
1H), 8.11 (s; 2H). The signals of the NH-protons could not be
detected. 13C-NMR (75 MHz, CD3OD): d = 28.0, 29.2, 38.5,
41.4, 41.8, 45.1, 57.4, 70.4, 117.7, 123.7, 124.8, 132.7, 143.2,
182.7. FT-IR (CsI): m[cm−1] = 3519 (s), 3288 (s), 3195 (m), 1590
(s), 1474 (w), 1387 (m), 1350 (m), 1280 (m), 1181 (m), 1135 (m),
887 (w), 682 (m). HRMS (ESI): calcd for [C18H22F6N3S] ([M +
H+]): 426.144, found: 426.143. Elemental analysis: anal. calcd for
C18H21F6N3S·1/2H2O: C 49.76, H 5.10, N 9.67, found: C 49.50,
H 5.32, N 9.45%.
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-(pyridine-3-yl)thio-
urea 19. Compound 19 was prepared from the corresponding
amine (300 mg, 2.11 mmol, 1.00 eq.) and 3-pyridylisothiocyanate
(235 lL, 2.11 mmol, 1.00 eq.), and isolated as a yellow foam
1
(415 mg, 71%). H-NMR (300 MHz, CDCl3): d = 1.14–1.27 (m;
5H), 1.65–1.92 (m; 3H), 2.31 (m; 1H), 2.45 (s; 6H), 2.86–2.92 (m;
1H), 4.26 (br s; 1H), 6.14 (br s; 1H), 7.13–7.17 (m; 1H), 7.94–7.96
(m; 1H), 8.23–8.24 (m; 1H), 8.53 (s; 1H). 13C-NMR (75 MHz,
CDCl3): d = 22.6, 24.2, 24.3, 32.4, 39.9, 54.5, 67.0, 123.0, 131.0,
136.0, 144.7, 145.3, 181.5. FT-IR (ATR): m[cm−1] = 3234 (br),
3027 (br), 2931 (s), 2857 (sh), 2783 (w), 1538 (s), 1481 (m), 1425
(m), 1316 (s), 1229 (m), 1185 (w), 1160 (sh), 1096 (m), 1062 (w),
1043 (w), 1025 (w), 991 (sh), 954 (w), 938 (w), 910 (w), 883 (m),
851 (w), 804 (s), 725 (m). HRMS (EI): calcd for [C14H23N4S]
([M + H]+): 279.164, found: 279.165.
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}urea 16. Compound
16 was prepared from the corresponding amine (140 mg,
1.23 mmol, 1.00 eq.), KOCN (99.8 mg, 1.23 mmol, 1.00 eq.)
and acetic acid (73.6 mg, 1.23 mmol, 1.00 eq.), and isolated as a
colourless semisolid (120 mg, 53%). 1H-NMR (300 MHz, CDCl3):
d = 1.25–1.33 (m; 4H), 1.74–1.91 (m; 2H), 1.97–2.12 (m; 2H), 2.78
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-methylthiourea 20.
Compound 20 was prepared from the corresponding amine
(103 mg, 725 mmol, 1.00 eq.) and methylisothiocyanate (50 lL,
725 mmol, 1.00 eq.), and isolated as an off-white amorphous solid
(100 mg, 64% yield). Mp 101 C. H-NMR (300 MHz, CDCl3):
d = 1.05–1.39 (m; 4H), 1.68–1.96 (m; 3H), 2.33 (s; 6H), 2.40–2.61
◦
1
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(m; 2H), 2.96 (d, J = 4.5 Hz; 3H), 3.91 (m; 1H), 6.70 (s; 1H), 7.10
(s; 1H). 13C-NMR (75 MHz, CDCl3): d = 21.8, 24.5, 24.9, 30.9,
33.1, 40.0, 55.5, 66.9, 182.8. FT-IR (ATR): m[cm−1] = 3259 (m),
2930 (s), 2855 (m), 1548 (s), 1447 (m), 1352 (m), 1269 (m), 1237
(w), 1208 (w), 1184 (w), 1089 (w), 1040 (m), 883 (w), 717 (m), 644
(w). HRMS (EI): calcd for [C10H21N3S] ([M]+): 216.153, found:
216.153.
d = 21.4, 24.3, 25.3, 29.3, 32.6, 36.0, 39.6, 41.8, 53.4, 56.8, 67.2,
180.8. FT-IR (ATR): m[cm−1] = 3273 (br), 2904 (s), 2849 (sh),
2784 (m), 1521 (s), 1473 (w), 1450 (m), 1399 (w), 1370 (w), 1356
(sh), 1340 (w), 1306 (m), 1294 (m), 1250 (w), 1228 (w), 1203 (m),
1186 (w), 1149 (w), 1114 (w), 1088 (m), 1060 (m), 1039 (m), 979
(w), 957 (w), 914 (m), 872 (w), 836 (sh), 730 (s). HRMS (EI): calcd
for [C19H34N3S] ([M + H]+): 336.247, found: 336.247. Elemental
analysis: anal. calcd for C19H33N3S: C 68.01, H 9.91, N 12.52,
found: C 67.65, H 9.78, N 12.58%.
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-benzylurea
21.
Compound 21 was prepared from the corresponding amine
(47.8 mg, 336 mmol, 1.00 eq.) and benzylisocyanate (50 lL,
336 mmol, 1.00 eq.), and isolated as an off-white amorphous solid
(49 mg, 53%). Mp 135–140 ◦C. 1H-NMR (300 MHz, CDCl3): d =
1.02–1.23 (m; 4H), 1.60–1.82 (m; 3H), 2.19 (s; 6H), 2.26–2.34 (m;
2H), 3.33–3.41 (m; 1H), 4.23–4.36 (m; 2H), 5.47 (t, J = 5.3 Hz;
1H), 5.65 (d, J = 3.9 Hz; 1H), 7.17–7.33 (m; 5H). 13C-NMR
(75 MHz, CDCl3): d = 21.7, 24.5, 25.0, 33.8, 39.7, 51.3, 52.8, 66.8,
126.9, 127.3, 128.4, 139.6, 158.9. FT-IR (ATR): m[cm−1] = 2929
(br), 1616 (s), 1571 (s), 1491 (m), 1454 (m), 1319 (w), 1261 (w),
1237 (w), 1070 (w), 1045 (w), 745 (w), 698 (m), 637 (w). HRMS
(EI): calcd for [C16H25N3O] ([M]+): 275.200, found: 275.200.
1,6-Di-{3-(1R,2R)-2-dimethylaminocyclohexyl}ureado hexane
25. Compound 25 was prepared from the corresponding amine
(300 mg, 2.11 mmol, 2.27 eq.) and 1,6-diisocyanatohexane
(156 mg, 0.93 mmol, 1.00 eq.), and isolated as a colourless foam
1
(330 mg, 79%). H-NMR (300 MHz, CDCl3): d = 0.92–1.78 (m;
24H), 2.15 (s; 12H), 2.26–2.30 (m; 2H), 3.02–3.08 (m; 4H), 3.27–
3.37 (m; 2H), 4.96–4.98 (m; 2H), 5.35–5.36 (m; 2H). 13C-NMR
(75 MHz, CDCl3): d = 21.4, 24.6, 25.2, 26.3, 29.8, 34.0, 39.9, 40.1,
51.3, 66.7. FT-IR (ATR): m[cm−1] = 3315 (br), 2926 (s), 2854 (sh),
2774 (m), 1632 (s), 1562 (s), 1453 (w), 1314 (w), 1262 (m), 1238 (m),
1188 (w), 1084 (w), 1043 (m), 871 (sh), 848 (w), 729 (m). HRMS
(EI): calcd for [C24H49N6O2] ([M + H]+): 453.392, found: 453.391.
1-{(1R,2R)-2-Dimethylaminocyclohexyl}-3-cyclohexylthiourea
22. Compound 22 was prepared from the corresponding amine
(390 mg, 2.74 mmol, 1.00 eq.) and cyclohexylisothiocyanate
(375 lL, 2.74 mmol, 1.00 eq.), and isolated as a colourless foam
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-{(R)-1-phenylethyl}-
urea 26a. Compound 26a was prepared from the corresponding
amine (315 mg, 2.21 mmol, 1.00 eq.) and (R)-1-phenylethyl
isocyanate (310 lL, 2.21 mmol, 1.00 eq.), and isolated as a
(600 mg, 77%). Mp 59–60 ◦C. [a]589 = +23.4, [a]546 = +27.9, [a]405
=
1
+45.0, [a]365 = +29.3 (c = 1.01, CHCl3). H-NMR (300 MHz,
CDCl3): d = 1.01–1.41 (m; 9H), 1.54–1.83 (m; 6H), 1.91–2.01 (m;
2H), 2.21 (s; 6H), 2.28–2.43 (m; 2H), 3.50–3.55 (m; 1H), 3.73 (br s;
1H), 6.28 (s; 1H). 13C-NMR (75 MHz, CDCl3): d = 22.1, 24.4,
24.7, 24.8, 24.9, 25.4, 32.8, 32.9, 33.1, 40.2, 52.8, 56.1, 67.3, 181.1.
FT-IR (ATR): m[cm−1] = 3259 (br), 3050 (w), 2926 (s), 2852 (s),
2783 (m), 1539 (s), 1473 (w), 1448 (m), 1360 (m), 1321 (m), 1271
(w), 1254 (m), 1239 (w), 1207 (w), 1187 (w), 1152 (w), 1081 (w),
1061 (w), 1040 (w), 978 (w), 946 (w), 889 (w), 872 (w), 847 (w), 734
(m). HRMS (EI): calcd for [C15H29N3S] ([M]+): 283.208, found:
283.209. Elemental analysis: anal. calcd for C15H29N3S: C 63.55,
H 10.31, N 14.82, found: C 63.26, H 10.22, N 14.75%.
colourless crystalline solid (445 mg, 70%). Mp 137 ◦C. [a]589
=
−33.3, [a]546 = −38.6, [a]405 = −66.5, [a]365 = −77.0, [a]334 = −82.1
(c = 1.015, CHCl3). 1H-NMR (300 MHz, CDCl3): d = 0.88–1.30
(m; 4H), 1.37 (d, J = 6.82 Hz; 3H), 1.54–1.71 (m; 3H), 1.91 (s;
6H), 2.03–2.11 (m; 1H), 2.37–2.43 (m; 1H), 3.11–3.19 (m; 1H),
4.64 (dq, J = 6.53, 6.82 Hz; 1H), 5.11 (d, J = 6.53 Hz; 1H),
5.35 (br s; 1H), 7.16–7.25 (m; 1H), 7.28 (d, J = 4.41 Hz; 4H).
13C-NMR (75 MHz, CDCl3): d = 21.1, 23.8, 24.5, 25.2, 33.5, 39.4,
50.5, 51.7, 66.5, 125.8, 127.0, 128.5, 144.6, 158.8. FT-IR (KBr):
m[cm−1] = 3359 (s), 3298 (s), 3060 (w), 2970 (m), 2933 (s), 2858 (s),
2820 (m), 2778 (m), 1670 (w), 1622 (s), 1570 (s), 1449 (m), 1375
(w), 1321 (w), 1262 (m), 1239 (m), 1190 (w), 1095 (m), 1027 (w),
872 (m), 764 (m), 706 (s). HRMS (ESI): calcd for [C17H28N3O]
([M + H]+): 290.223, found: 290.223. Elemental analysis: anal.
calcd for C17H27N3O: C 70.55, H 9.40, N 14.52, found: C 70.05,
H 9.22, N 14.45%.
1,3-Bis{(1R,2R)-2-(dimethylamino)cyclohexyl}thiourea
23.
Compound 23 was isolated as an off-white foam (330 mg, 60%).†
1H-NMR (300 MHz, CDCl3): d = 0.99–1.33 (m; 8H), 1.61–1.84
(m; 6H), 2.21 (s; 12H), 2.33–2.41 (m; 4H), 3.60–3.69 (m; 2H), 7.17
(br s; 2H). 13C-NMR (75 MHz, CDCl3): d = 21.9, 24.5, 25.0, 33.0,
39.1, 55.7, 66.7, 182.6. FT-IR (KBr): m[cm−1] = 3265 (br), 2931
(s), 2857 (s), 2783 (m), 1540 (s), 1457 (m), 1362 (m), 1323 (m),
1270 (m), 1240 (w), 1187 (w), 1165 (w), 1085 (w), 1038 (m), 957
(w), 871 (m), 739 (m). HRMS (EI): calcd for [C17H34N4S] ([M]+):
326.250, found: 326.251.
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-{(S)-1-phenylethyl}-
urea 26b. Compound 26b was prepared from the corresponding
amine (225 mg, 1.58 mmol, 1.00 eq.) and (S)-1-phenylethyl
isocyanate (223 lL, 1.58 mmol, 1.00 eq.), and isolated as a
colourless crystalline solid (345 mg, 75%). Mp 146 ◦C. [a]589
=
−57.2, [a]546 = −67.7, [a]405 = −137.1, [a]365 = −179.5, [a]334
=
1
1-Adamantan-1-yl-3-{(1R,2R)-2-dimethylaminocyclohexyl}thio-
urea 24. Compound 24 was prepared from the corresponding
amine (300 mg, 2.11 mmol, 1.00 eq.) and 1-adamantylisothio-
cyanate (408 mg, 2.11 mmol, 1.00 eq.), and isolated as a colourless
amorphous solid (550 mg, 78%). Mp 78–79 ◦C. [a]589 = −69.0,
[a]546 = −81.8, [a]405 = −158.6, [a]365 = −194.8 (c = 1.00, CHCl3).
1H-NMR (300 MHz, CDCl3): d = 0.93–1.35 (m; 4H), 1.55–1.66
(m; 7H), 1.80–1.82 (m; 2H), 1.94 (s; 6H), 2.05 (s; 3H), 2.17 (s;
6H), 2.31–2.38 (m; 1H), 2.93–2.97 (m; 1H), 3.45–3.55 (m; 1H),
6.09 (br s; 1H), 6.61 (br s; 1H). 13C-NMR (75 MHz, CDCl3):
−230.2 (c = 1.00, CHCl3). H-NMR (300 MHz, CDCl3): d =
0.88–1.29 (m; 4H), 1.42 (d, J = 6.93 Hz; 3H), 1.56–1.77 (m; 3H),
2.09–2.14 (m, 1H), 2.16 (s; 6H), 2.36–2.42 (m; 1H), 3.19–3.28 (m;
1H), 4.79 (dq, J = 6.93, 6.85 Hz; 1H), 4.98 (br s; 1H), 5.18 (br s;
1H), 7.17–7.31 (m; 5H). 13C-NMR (75 MHz, CDCl3): d = 21.4,
23.1, 24.5, 25.2, 33.6, 39.9, 50.0, 51.9, 66.8, 126.0, 127.0, 128.5,
144.6, 158.4. FT-IR (KBr): m[cm−1] = 3335 (s), 3302 (s), 2976
(m), 2921 (s), 2859 (m), 2821 (m), 2777 (m), 1674 (w), 1622 (s),
1559 (s), 1456 (m), 1372 (w), 1330 (m), 1255 (m), 1235 (m), 1208
(m), 1106 (m), 1074 (m), 1052 (w), 1020 (m), 873 (w), 830 (w),
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745 (w), 703 (s). HRMS (ESI): calcd for [C17H27N3NaO] ([M +
Na]+): 312.205, found: 312.206. Elemental analysis: anal. calcd
for C17H27N3O: C 70.55, H 9.40, N 14.52, found: C 70.32, H 9.34,
N 14.47%.
CDCl3): d = 21.8, 24.5, 24.8, 26.8, 32.9, 35.7, 36.0, 39.9, 51.2,
55.2, 60.3, 66.5, 127.2, 127.9, 128.4, 136.8, 172.5, 182.5. FT-IR
(ATR): m[cm−1] = 3308 (br), 3060 (w), 2930 (s), 2857 (m), 2782
(w), 1626 (s), 1535 (s), 1494 (w), 1477 (w), 1450 (m), 1413 (m),
1364 (m), 1320 (m), 1267 (w), 1237 (w), 1186 (w), 1081 (m), 1030
(w), 950 (w), 873 (w), 733 (m), 701 (s). HRMS (ESI): calcd for
[C23H39N4OS] ([M + H]+): 419.285, found: 419.284. Elemental
analysis: anal. calcd for C23H38N4OS: C 65.99, H 9.15, N 13.38,
found: C 65.60, H 9.15, N 13.15%.
1-{(S)-1-(Dimethylcarbamoyl)-2,2-dimethylpropyl}-3-{(1R,2R)-
2-(dimethylamino)cyclohexyl}thiourea 27a. Compound 27a
was prepared from the corresponding isothiocyanate (337 mg,
1.68 mmol, 1.00 eq.) and the (1R,2R)-N,N-dimethyl-1,2-
diaminocyclohexane (275 mg, 1.93 mmol, 1.15 eq.), and isolated
as a colourless foam (350 mg, 61%). Mp 146 ◦C. [a]589 = +7.3,
[a]546 = +8.9, [a]405 = +10.6, [a]365 = −2.9 (c = 0.71, CHCl3).
1H-NMR (300 MHz, CDCl3): d = 0.93 (s; 9H), 1.02–1.12 (m; 4H),
1.58–1.76 (m; 3H), 2.13 (s; 6H), 2.21–2.29 (m; 2H), 2.85 (s; 3H),
3.15 (s; 3H), 3.50 (m; 1H), 5.50 (d, J = 8.97 Hz; 1H), 6.66 (br s;
1H), 7.03 (d, J = 8.97 Hz; 1H). 13C-NMR (75 MHz, CDCl3):
d = 21.9, 24.5, 24.9, 26.6, 32.9, 35.4, 35.9, 38.4, 40.1, 55.4, 59.9,
66.5, 171.9, 182.3. FT-IR (ATR): m[cm−1] = 3307 (br), 2928 (s),
2857 (sh), 2781 (w), 1624 (s), 1536 (s), 1477 (w), 1416 (w), 1396
(m), 1364 (m), 1319 (w), 1253 (w), 1238 (w), 1188 (w), 1139 (m),
1118 (w), 1083 (m), 1062 (w), 1036 (m), 947 (m), 914 (m), 872
(sh), 825 (w), 730 (s). HRMS (ESI): calcd for [C17H35N4OS] ([M +
H]+): 343.253, found: 343.253. Elemental analysis: anal. calcd for
C17H34N4OS: C 59.61, H 10.00, N 16.36, found: C 59.20, H 9.88,
N 16.19.
1-{(S)-1-(Benzylcarbamoyl)-2,2-dimethylpropyl}-3-{(1R,2R)-2-
(dimethylamino)cyclohexyl}thiourea 27d. Compound 27d was
prepared from the corresponding isothiocyanate (430 mg,
1.64 mmol, 1.00 eq.) and (1R,2R)-N,N-dimethyl-1,2-diamino-
cyclohexane (275 mg, 1.93 mmol, 1.18 eq.), and isolated as
an off-white foam (490 mg, 74%). Mp 89–91 ◦C. 1H-NMR
(300 MHz, CDCl3): d = 1.00 (s; 9H), 1.09–1.85 (m; 4H), 1.61–1.76
(m; 3H), 2.16 (s; 6H), 2.22–2.24 (m; 1H), 2.54 (m; 1H), 3.98
(m; 1H), 4.20 (dd, J = 5.38, 14.88 Hz; 1H), 4.42 (dd, J = 6.10,
14.88 Hz; 1H), 4.70 (m; 1H), 4.86 (br m; 1H), 7.17–7.24 (m; 7H).
13C-NMR (75 MHz, CDCl3): d = 22.0, 24.5, 24.6, 27.0, 32.9, 34.4,
39.8, 43.1, 54.9, 66.5, 127.0, 127.6, 128.3, 138.1, 171.3, 182.2.
FT-IR (ATR): m[cm−1] = 3264 (br), 3061 (m), 2933 (s), 2862 (m),
2793 (w), 1644 (s), 1537 (s), 1474 (w), 1452 (m), 1399 (w), 1359
(m), 1309 (m), 1232 (w), 1182 (w), 1088 (m), 1028 (sh), 991 (w),
949 (w), 909 (m), 873 (sh), 851 (w), 824 (w), 728 (s). HRMS (ESI):
calcd for [C22H37N4OS] ([M + H]+): 405.269, found: 405.269.
1-{(S)-1-(Diethylcarbamoyl)-2,2-dimethylpropyl}-3-{(1R,2R)-
2-(dimethylamino)cyclohexyl}thiourea 27b. Compound 27b
was prepared from the corresponding isothiocyanate
(440 mg, 1.93 mmol, 1.00 eq.) and (1R,2R)-N,N-dimethyl-
1,2-diaminocyclohexane (313 mg, 2.20 mmol, 1.14 eq.), and
isolated as a colourless foam (515 mg, 72%). Mp 120–121 ◦C.
[a]589 = −46.4, [a]546 = −55.9, [a]405 = −135.9, [a]365 = −209.7 (c =
1.01, CHCl3). 1H-NMR (300 MHz, CDCl3): d = 0.94 (s; 9H), 1.02
(t, J = 7.13 Hz; 3H), 1.09–1.12 (m; 4H), 1.20 (t, J = 7.13 Hz; 3H),
1.58–1.78 (m; 3H), 2.14 (s; 6H), 2.25–2.33 (m; 2H), 2.91–3.03 (m;
1H), 3.25–3.34 (m; 1H), 3.45–3.49 (m; 1H), 3.54–3.67 (m; 2H),
5.44 (d, J = 8.96 Hz; 1H), 6.60 (br s; 1H), 6.95 (d, J = 8.96 Hz;
1H). 13C-NMR (75 MHz, CDCl3): d = 12.7, 14.5, 21.8, 24.5, 24.8,
26.7, 32.9, 36.1, 39.8, 40.0, 42.7, 55.2, 59.7, 66.5, 170.6, 182.2.
FT-IR (ATR): m[cm−1] = 3320 (br), 2934 (s), 2861 (m), 2788 (w),
1622 (s), 1540 (s), 1458 (s), 1364 (s), 1321 (m), 1265 (m), 1216 (w),
1187 (w), 1138 (w), 1084 (w), 1035 (w), 949 (m), 873 (m), 840 (m),
787 (w), 747 (m). HRMS (ESI): calcd for [C19H39N4OS] ([M +
H]+): 371.284, found: 371.284. Elemental analysis: anal. calcd for
C19H38N4OS: C 61.58, H 10.34, N 15.12, found: C 61.28, H 10.30,
N 15.01%.
1-{(S)-1-(Diisobutylcarbamoyl)-2,2-dimethylpropyl}-3-{(1R,2R)-
2-(dimethylamino)cyclohexyl}thiourea 27e. Compound 27e
was prepared from the corresponding isothiocyanate (598 mg,
2.10 mmol, 1.00 eq.) and the (1R,2R)-N,N-dimethyl-1,2-
diaminocyclohexane (320 mg, 2.25 mmol, 1.07 eq.), and isolated
as a colourless foam (600 mg, 67%). Mp 59–61 ◦C. [a]589 = −34.9,
[a]546 = −42.6, [a]405 = −107.3, [a]365 = −174.3 (c = 1.03, CHCl3).
1H-NMR (300 MHz, CDCl3): d = 0.80–0.88 (m; 12H), 0.97 (s;
9H), 1.03–1.24 (m; 4H), 1.59–1.79 (m; 3H), 1.85–2.05 (m; 2H),
2.13 (s; 6H), 2.19–2.35 (m; 2H), 2.58–2.65 (m; 1H), 3.05–3.12 (m;
1H), 3.37–3.65 (m; 3H), 5.53 (br s; 1H), 6.43 (s; 1H), 6.92 (d,
J = 8.6 Hz; 1H). 13C-NMR (75 MHz, CDCl3): d = 19.3, 20.2,
20.4, 20.5, 21.7, 24.5, 25.0, 26.5, 26.9, 27.9, 32.9, 36.9, 39.9, 53.5,
55.3, 56.2, 59.8, 66.6, 172.2, 182.1. FT-IR (ATR): m[cm−1] = 3315
(br), 3054 (br), 2954 (s), 2928 (s), 2865 (m), 2825 (w), 2782 (w),
1617 (s), 1527 (s), 1465 (s), 1445 (s), 1385 (m), 1363 (s), 1338 (w),
1320 (w), 1301 (w), 1268 (w), 1238 (m), 1207 (m), 1188 (w), 1140
(m), 1119 (w), 1096 (m), 1085 (m), 1062 (w), 1035 (m), 946 (sh),
900 (w), 872 (sh), 848 (w), 821 (m), 753 (sh). HRMS (EI): calcd
for [C23H46N4OS] ([M]+): 426.339, found: 426.339. Elemental
analysis: anal. calcd for C23H46N4OS: C 64.74, H 10.87, N 13.13,
found: C 64.34, H 10.84, N 13.09%.
1-{(S)-1-(N-Benzyl-N-methylcarbamoyl)-2,2-dimethylpropyl}-
3-{(1R,2R)-2-(dimethylamino)cyclohexyl}thiourea 27c. Com-
pound 27c was prepared from the corresponding isothiocyanate
(430 mg, 1.56 mmol, 1.00 eq.) and the (1R,2R)-N,N-dimethyl-1,2-
diaminocyclohexane (260 mg, 1.83 mmol, 1.17 eq.), and isolated
as a colourless foam (483 mg, 74%). Mp 58–59 ◦C. [a]589 = −17.5,
[a]546 = −21.8, [a]405 = −60.2, [a]365 = −99.2 (c = 1.01, CHCl3).
1H-NMR (500 MHz, CDCl3): d = 1.06 (s; 9H), 1.18–1.32 (m; 4H),
1.69–1.87 (m; 3H), 2.28 (s; 6H), 2.36–2.42 (m; 1H), 2.56–2.58 (m;
1H), 3.19 (s; 3H), 3.84 (m; 1H), 4.50 (d, J = 14.6 Hz; 1H), 4.69 (d,
J = 14.6 Hz; 1H), 5.48 (d, J = 8.5 Hz; 1H), 7.11 (br s; 1H), 7.20
(br d, J = 8.5 Hz; 1H), 7.22–7.34 (m; 5H). 13C-NMR (125 MHz,
1-{(R)-1-(N-Benzyl-N-methylcarbamoyl)-2,2-dimethyl propyl}-
3-{(1R,2R)-2-(dimethylamino)cyclohexyl}thiourea 28. Com-
pound 28 was prepared from the corresponding isothiocyanate
(552 mg, 2.00 mmol, 1.00 eq.) and the (1R,2R)-N,N-dimethyl-1,2-
diaminocyclohexane (310 mg, 2.18 mmol, 1.09 eq.), and isolated
as a colourless foam (530 mg, 64%). Mp 64–65 ◦C. [a]589 = +47.7,
[a]546 = +58.9, [a]405 = +149.1, [a]365 = +216.7 (c = 1.00, CHCl3).
1H-NMR (300 MHz, CDCl3): d = 1.02 (s; 9H), 1.09–1.26 (m; 4H),
1.64–1.85 (m; 3H), 2.19–2.31 (m; 2H), 2.24 (s; 6H), 3.17 (s; 3H),
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3.48 (br s; 1H), 4.36 (d, J = 14.6 Hz; 1H), 4.76 (d, J = 14.6 Hz;
1H), 5.60 (d, J = 9.3 Hz; 1H), 6.45 (br s; 1H), 7.19–7.34 (m; 5H),
8.28 (br s; 1H). 13C-NMR (75 MHz, CDCl3): d = 23.3, 24.5, 24.9,
26.8, 33.0, 36.1, 36.2, 40.8, 51.1, 56.7, 60.8, 67.5, 127.3, 128.0,
128.5, 136.9, 172.1, 183.3. FT-IR (ATR): m[cm−1] = 3324 (br),
3059 (w), 3027 (w), 2929 (s), 2857 (m), 2823 (w), 2782 (m), 1620
(s), 1530 (s), 1494 (w), 1477 (w), 1448 (m), 1413 (m), 1363 (m),
1319 (m), 1268 (m), 1253 (w), 1234 (m), 1207 (w), 1189 (w), 1153
(w), 1108 (w), 1082 (m), 1028 (w), 947 (m), 910 (m), 873 (sh), 849
(w), 822 (w), 730 (s). HRMS (ESI): calcd for [C23H39N4OS] ([M +
H]+): 419.285, found: 419.284. Elemental analysis: anal. calcd for
C23H38N4OS: C 65.99, H 9.15, N 13.38, found: C 65.55, H 9.08,
N 13.38%.
Z = 4, l = 0.141 mm−1, 11 456 reflections measured, 3913 unique
(Rint = 0.073). The final R1 and wR2 were 0.048 and 0.091
(I>2r(I)).
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(2S)-dimethylamino-(1S)-
phenylpropyl}urea 9. C20H21F6N3O, M = 433.40, monoclinic,
˚
a = 10.5778(9), b = 18.5187(16), c = 11.1532(13) A, b =
◦
3
˚
100.72(1) , U = 2146.6(4) A , T = 293(2) K, space group P21,
Z = 4, l = 0.120 mm−1, 12 334 reflections measured, 4834 unique
(Rint = 0.097). The final R1 and wR2 were 0.063 and 0.116
(I>2r(I)).
1-(3,5-Dinitrophenyl)-3-{(1R,2R)-2-(dimethylamino)cyclohexyl}-
urea 17. C31H48N10O12, M = 752.79, monoclinic, a = 8.1767(6),
◦
˚
b = 22.874(2), c = 10.1933(6) A, b = 108.158(3) , U =
1-{(S)-1-(N-benzyl-N-methylcarbamoyl)-3,3-dimethylbutyl}-3-
{(1R,2R)-2-(dimethylamino)cyclohexyl}thiourea 29. Compound
29 was prepared from the corresponding isothiocyanate
(747 mg, 2.57 mmol, 1.00 eq.) and (1R,2R)-N,N-dimethyl-1,2-
diaminocyclohexane (400 mg, 2.81 mmol, 1.09 eq.), and isolated
3
˚
1811.5(2) A , T = 100(2), space group P21, Z = 2, l =
0.107 mm−1, 7412 reflections measured, 4031 unique (Rint
0.038). The final R1 and wR2 were 0.059 and 0.157 (I>2r(I)).
=
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-mesitylurea 18.
◦
1
as a colourless foam (832 mg, 75%). Mp 67–68 C. H-NMR
(300 MHz, CDCl3): d = 0.82, 0.99 (2s; 9H), 1.06–1.27 (m; 5H),
1.53–1.77 (m; 5H), 2.24, 2.26 (2s; 6H), 2.34–2.41 (m; 2H), 2.92, 3.11
(2s; 3H), 3.64–3.71 (br s; 1H), 4.42 (d, J = 14.84 Hz; 0.7H), 4.60
(d, J = 16.50 Hz; 0.3H), 4.68 (d, J = 14.84 Hz; 0.7H), 5.06 (d, J =
16.50 Hz; 0.3H), 5.63–5.68 (m; 1H), 6.66 (br s; 1H), 7.18–7.35 (m;
5H), 7.91 (br s; 1H). 13C-NMR (75 MHz, CDCl3): d = 22.0, 22.3,
24.5, 24.8, 29.7, 30.0, 30.7, 30.9, 33.2, 34.4, 35.0, 40.2, 46.2, 46.8,
51.3, 52.4, 53.5, 55.1, 55.3, 67.0, 127.1, 127.4, 127.6, 127.7, 128.6,
128.7, 136.5, 136.7, 174.2, 181.7, 182.0. FT-IR (ATR): m[cm−1] =
3318 (br s), 2931 (s), 2858 (m), 2823 (w), 2779 (m), 1629 (s), 1543
(s), 1494 (w), 1475 (w), 1450 (m), 1419 (w), 1362 (m), 1318 (w),
1270 (w), 1253 (w), 1206 (w), 1150 (w), 1084 (m), 1038 (w), 945
(w), 911 (m), 875 (w), 851 (w), 730 (s). HRMS (EI): calcd for
[C24H41N4OS] ([M + H]+): 433.300, found: 433.300.
C18H29N3O, M = 303.44, orthorhombic, a = 11.8168(3), b =
3
˚
˚
16.6626(6), c = 18.2008(5) A, U = 3583.71(19) A , T = 100(2) K,
space group P212121, Z = 8, l = 0.071 mm−1, 18 006 reflections
measured, 4342 unique (Rint = 0.093). The final R1 and wR2 were
0.052 and 0.084 (I>2r(I)).
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-methylthiourea 20.
C10H21N3S, M = 215.36, orthorhombic, a = 11.5762(4), b =
3
˚
˚
12.7340(4), c = 16.3923(6) A, U = 2416.41(14) A , T = 100(2) K,
space group P212121, Z = 8, l = 0.238 mm−1, 13 703 reflections
measured, 5270 unique (Rint = 0.038). The final R1 and wR2 were
0.035 and 0.066 (I>2r(I)).
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-{(R)-1-phenylethyl}-
urea 26a. C17H27N3O, M = 289.42, monoclinic, a = 8.7335(2),
◦
˚
b = 22.1650(6), c = 9.9252(3) A, b = 101.774(1) , U =
3
˚
1880.88(9) A , T = 100(2) K, space group P21, Z = 4, l =
X-Ray crystallography data‡
0.065 mm−1, 9471 reflections measured, 3892 unique (Rint
0.043). The final R1 and wR2 were 0.039 and 0.082 (I>2r(I)).
=
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(N-benzyl-N-
methylamino)cyclohexyl}urea 1f. C23H25F6N3O·CH3HCOHCH3,
M = 533.55, monoclinic, a = 14.2234(7), b = 8.9069(5), c =
1-{(1R,2R)-2-(Dimethylamino)cyclohexyl}-3-{(S)-1-phenylethyl}-
◦
urea 26b. C17H27N3O, M = 289.42, orthorhombic, a = 9.1661(4),
3
˚
˚
21.5226(13) A, b = 90.890(0) , U = 2726.3(3) A , T = 100(2)
K, space group P21, Z = 4, l = 0.110 mm−1, 13 589 reflections
measured, 6269 unique (Rint = 0.105). The final R1 and wR2 were
0.075 and 0.111 (I>2r(I)).
3
˚
˚
b = 11.3191(6), c = 15.5757(8) A, U = 1616.01(14) A , T =
293(2) K, space group P212121, Z = 4, l = 0.075, 7841 reflections
measured, 2021 unique (Rint = 0.044). The final R1 and wR2 were
0.034 and 0.068 (I>2r(I)).
1-{3,5-Bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(diallylamino)-
cyclohexyl}urea 1g. C21H25F6N3O, M = 449.44, triclinic, a =
Acknowledgements
˚
9.3840(10), b = 9.9690(10), c = 12.6230(10) A, a = 81.560(10),
◦
3
˚
b = 89.690(10), c = 71.130(10) , U = 1104.19(18) A , T = 293(2)
This work was supported by the German Research Council
(DFG, priority programme “Organocatalysis”), and the Fonds
der Chemischen Industrie. In particular, F.C. thanks the Fonds
der Chemischen Industrie for a doctoral fellowship. We gratefully
acknowledge the Degussa AG, Hanau for generous gifts of amino
acids.
K, space group P1, Z = 2, l = 0.119 mm−1, 6801 reflections
measured, 4749 unique (Rint = 0.043). The final R1 and wR2 were
0.067 and 0.149 (I>2r(I)).
N-[3,5-Bis(trifluoromethyl)phenyl]-Nꢀ -[(1R,3S)-3-{[({[3,5-bis-
(trifluoromethyl)phenyl]amino}oxomethyl)amino]methyl}-3,5,5-
trimethylcyclohexyl]urea 5a. C28H28F12N4O2·CH3OH,
M
=
712.59, orthorhombic, a = 10.0545(8), b = 15.0943(13), c =
References
3
˚
˚
21.3967 A, U = 3247.3(4) A , T = 100(2) K, space group P212121,
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‡ CCDC reference numbers 605365–605373. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b607574f
2 (a) R. Rink, J. H. Lutje Spelberg, R. J. Pieters, J. Kingma, M. Nardini,
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Org. Biomol. Chem., 2006, 4, 4319–4330 | 4329
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9 For other applications of (thio)urea–tertiary amine bifunctional
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4330 | Org. Biomol. Chem., 2006, 4, 4319–4330
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