Asymmetric organocatalysis with novel chiral thiourea derivatives: Bifunctional catalysts for the Strecker and nitro-Michael reactions

Article abstract of DOI:10.1002/ejoc.200500420

Novel bifunctional organocatalysts bearing both a thiourea moiety and an imidazole group on a chiral scaffold were synthesized and applied to the Strecker synthesis and nitro-Michael reaction. The addition of acetone to nitroolefins in the presence of these novel bifunctional organocatalysts gave enantioselectivities (up to 87 % ee) that are superior to those generated by the proline and/or homo-proline tetrazole catalysts described in the literature. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500420

FULL PAPER
DOI: 10.1002/ejoc.200500420
Asymmetric Organocatalysis with Novel Chiral Thiourea Derivatives:
Bifunctional Catalysts for the Strecker and Nitro-Michael Reactions
Svetlana B. Tsogoeva,*[a] Denis A. Yalalov,[a] Martin J. Hateley,[b] Christoph Weckbecker,[b]
and Klaus Huthmacher[b]
Keywords: Strecker synthesis / Michael addition / Asymmetric catalysis / Chiral thioureas / Bifunctional organocatalysts
Novel bifunctional organocatalysts bearing both a thiourea
moiety and an imidazole group on a chiral scaffold were syn-
thesized and applied to the Strecker synthesis and nitro-
Michael reaction. The addition of acetone to nitroolefins in
the presence of these novel bifunctional organocatalysts
gave enantioselectivities (up to 87% ee) that are superior to
those generated by the proline and/or homo-proline tetrazole
catalysts described in the literature.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
organocatalysts for conjugate addition reactions, for exam-
ple in the Michael addition of acetone to β-nitrostyrene, is
demonstrated.
Introduction
The continually increasing number of contributions to
the field of asymmetric synthesis with chiral bifunctional
catalysts undoubtedly confirms the importance of this area
of research for chemists from both academia as well as in-
dustry.[1,2]
Results and Discussion
A large body of results from Jacobsen’s laboratory clearly
demonstrated peptide-like thiourea based molecules to be
excellent bifunctional chiral catalysts for the asymmetric
Strecker synthesis,[3–5] enantioselective hydrophosphonyl-
ation of imines,[6] Acyl-Pictet–Spengler[7] and nitro-Man-
nich[8] reactions.
Furthermore, examples of enantioselective Michael ad-
ditions,[9–13] Aza-Henry,[14] Baylis–Hillman[15,16] reactions
and dynamic kinetic resolution of azlactones[17] have re-
cently been reported in which chiral bifunctional organoca-
talysts have been employed.
Our investigation began with the preparation of novel
thiourea compounds 13–16 from four different chiral
amines: (R)-(+)-1-phenylethylamine (1), (S)-1-(2-naphthyl)
ethylamine (2), (S)-3,3-dimethyl-2-aminobutane (3) and (S)-
1-cyclohexylethylamine (4) by known methods[5,20,21] as
summarised in Scheme 1. These derivatives were then exam-
ined for their ability to mediate the enantioselective Strecker
reaction.
As a model transformation we studied the addition of
hydrogen cyanide to aldimines 19 and 20 in the presence of
0.1 equiv. of the appropriate thiourea derivative, with the
reaction proceeding for 2.5 h at –40 °C and subsequently
for a further 16 h at –20 °C (Scheme 2).
However, the design and development of new, effective
and easily accessible bifunctional chiral organic catalysts
continues to be a major challenge.
The results obtained show that the nature of the sub-
strate influences both the reaction rate and enantio-
selectivity to a large extent. Notably, catalysts 13–16 af-
forded low to moderate conversions (up to 47%) and
enantioselectivities (up to 39% ee) with substrate 19 over
2.5 h at –40 °C (Entries 1, 3, 5, 7 of Table 1). Better enantio-
selectivities (up to 68% ee), but worse conversions (up to
24%) were observed under the same reaction conditions
with the aldimine substrate 20. The bulkier N-benzhydryl
subunit present in substrate 20 seems to have a beneficial
effect on the enantioselectivity (Entries 2 and 6 of Table 1).
A longer reaction time (16 h at –20 °C) provided high
conversions with the aldimine substrate 19 (93–100%, En-
tries 1, 3, 5, 7 of Table 1) and low to good conversions with
the bulkier substrate 20 (12–73%, Entries 2, 4, 6, 8 of
Table 1). At the same time, the enantiomeric excess values
Based on our previous results and the observation[18] that
imidazole as a base is essential for thiourea catalytic ac-
tivity, we report here on the syntheses and application of
some novel chiral imidazole-based thiourea catalysts for C–
C bond formation reactions. Initially, these bifunctional or-
ganocatalysts were tested in the asymmetric Strecker reac-
tion,[19] one of the most direct and efficient methods for
the asymmetric synthesis of natural and unnatural α-amino
acids. Furthermore, the high potential of these bifunctional
[a] Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: +49-551-399-660
E-mail: stsogoe@gwdg.de
[b] Degussa AG, Feed Additives,
Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany
Eur. J. Org. Chem. 2005, 4995–5000
© 2005 Wiley-VCH Verlag GmbH & Co. KgaA, Weinheim
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S. B. Tsogoeva, D. A. Yalalov, M. J. Hateley, C. Weckbecker, K. Huthmacher
FULL PAPER
Scheme 1.
version of substrate 19 to that generated by catalyst 13
(Table 1, Entry 10 vs. Entry 1), only 10% conversion and
4% ee were observed with catalyst 24 for substrate 20
(Table 1, Entry 11 vs. Entry 2). This represents a 63% re-
duction in the conversion and a 20% reduction in the ee
value compared to the imidazole-based chiral thiourea 13.
These results indicate that for a high conversion the catalyst
should possess both an imidazole group and a thiourea
Scheme 2.
moiety.
In order to explain the low enantioselectivities observed
we examined the reaction of aldimine substrates 19 and 20
of all products were reduced during the course of the reac-
tion, indicating that racemization of the product takes place
under the reaction conditions.
The contribution of the thiourea and imidazole subunits in the absence of catalyst under the standard reaction con-
to the activity of the catalyst was then investigated. Replac- ditions (–20 °C, 16 h). The rate of the noncatalysed racemic
ing the thiourea moiety of 13 with an imidazole ring (com- reaction was found to be very low for the N-benzhydryl
pound 23, Scheme 3) led to a reduction in the conversion of imine 20 but significant for the N-benzyl benzaldehyde im-
aldimine 19 from 96% to 74%, as well as a corresponding ine 19 (5% and 54% conversion, respectively, Entries 12,
reduction in enantiomeric excess of the product from 12% 13 in Table 1). Taking these results into consideration we
to 3% (Table 1, Entry 1 vs. Entry 9). Whereas thiourea de- speculated that complete suppression of the noncatalysed
rivative 24, which has no imidazole moiety (prepared ac- racemic reaction pathway might occur at a reduced tem-
cording to Scheme 3), provides a comparatively high con- perature. Indeed, a slight enhancement in the ee value from
Table 1. Strecker reactions catalyzed by thiourea derivatives 13–16 and compounds 23 and 24.
Entry
Catalyst
Substrate
2.5 h at –40 °C
conv. [%][a]
16 h at –20 °C
ee [%][a]
conv. [%][a]
ee [%][a]
1
2
3
4
5
6
7
8
13
13
19
20
19
20
19
20
19
20
19
19
20
20
19
19
27
24
14
2
47
17
16
0
8
20
0
0
6
22
63
39
–
24
68
13
–
2
2
–
–
96
73
93
12
100
71
99
47
74
97
10
5
12
24
17
15
10
20
5
2
3
4
4
14
14
15
15
16
16
9
23
10
11
12
13
14
24
24
none
none
13
–
–
–
54
–
–
50[b]
31[b]
[a] Determined by HPLC after reaction proceeded for 16 h at –20 °C. Reported conversions and ee values are the average of 2 runs.
[b] Reaction was carried out at –78 °C for 120 h.
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Asymmetric Organocatalysis with Novel Chiral Thiourea Derivatives
FULL PAPER
Scheme 3.
12% to 31% was observed when the conversion of 19 was Table 2. Michael addition of acetone to trans-β-nitrostyrene in dif-
ferent solvents.
carried out at –78 °C (Table 1, Entry 1 vs. Entry 14). Unfor-
tunately, this improved enantioselectivity was paid for by a
much lower reaction rate (50% conversion in 120 h).
The novel thiourea derivatives 13–16 subsequently
proved to be effective catalysts in the nitro-Michael reac-
tion. The addition of acetone to trans-β-nitrostyrene was
chosen as a model reaction to determine the catalytic ac-
tivity of the thiourea compounds. Barbas and coworkers
were the first to report the organocatalytic version of this
reaction. Using -proline as the catalyst in DMSO[22] they
were only able to isolate the product in the racemic form.
As a result, considerable effort has been directed towards
the development of a catalytic asymmetric version of this
reaction over the past several years, although only low
enantioselectivities (up to 31% ee) have been obtained so
far.[23–25] The best results to date have been achieved very
recently using a homo-proline tetrazole catalyst in the ad-
dition of acetone to trans-β-nitrostyrene with up to 42%
ee.[13b]
We first screened a range of solvents for the reaction cat-
alysed by the novel bifunctional organocatalyst 13 (Table 2,
Entries 1–5). The optimum result was observed in nonpolar
toluene, providing high conversion (89%) and very good
enantioselectivity (87% ee) (Table 2, Entry 1). This repre-
sents a 45% improvement in the ee value over the reported
homo-proline tetrazole catalyst.[13b] Interestingly, the results
in CH2Cl2 and CHCl3 resemble those in toluene, with the
sole exception of the reduced conversion achieved in
CH2Cl2 (Table 2, Entries 2, 3). In more polar solvents (ace-
tone, MeOH) the adduct was obtained with lower conver-
sions and enantioselectivities, since these solvents might in-
hibit the hydrogen-bonding interaction between trans-β-ni-
trostyrene and the thiourea moiety of 13 (Table 2, Entries
4, 5).
Entry
Solvent
Conversion
[%][a]
ee [%][b]
(R)
1
2
3
4
5
toluene
CH2Cl2
CHCl3
acetone
MeOH
89
58
86
48
39
87
86
85
79
56
1
[a] Determined from the H NMR spectrum of the crude reaction
mixture. [b] Enantioselectivities were determined by chiral HPLC
analysis (Daicel Chiralpak AS) in comparison with authentic race-
mic material.
4 of Table 3). The stereoselectivity of this reaction has been
shown to be dependent on the presence of a suitable combi-
nation of the absolute configurations of the stereogenic
centres in the catalyst molecule.
Table 3. Michael addition of acetone to trans-β-nitrostyrene.
Entry
Catalyst
Yield
[%][a]
55[c]
49
60
61
n.r
n.r.
n.r
ee [%][b]
(R)
1
2
3
4
5
6
7
13
14
15
16
87
73
73
77
–
–
–
imidazole
23
24
[a] Yield of isolated product after column chromatography on SiO2.
[b] Enantioselectivities were determined by chiral HPLC analysis
(Daicel Chiralpak AS) in comparison with authentic racemic mate-
rial. [c] Yield and % ee were determined after 40 h.
It is necessary to note that the urea derivative of com-
pound 13 gave a lower conversion (78%) and enantio-
selectivity (72% ee) in toluene with respect to thiourea 13,
which is in agreement with results reported in the literature
(the interaction in the catalyst-substrate complex is stronger
for thiourea than for urea).[5]
When the bifunctional thioureas 14–16 with the S-con-
figuration in the naphthyl-, tert-butyl- and cyclohexylethyl-
The similarity of the results using the thiourea catalysts
amine moieties were studied as catalysts in the same reac- 14–16 is also noteworthy, suggesting that the functionality
tion, we found that the Michael product was formed with attached to the thiourea moiety has little effect on the out-
slightly reduced enantioselectivities (73–77% ee, Entries 2– come of this reaction.
Eur. J. Org. Chem. 2005, 4995–5000
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S. B. Tsogoeva, D. A. Yalalov, M. J. Hateley, C. Weckbecker, K. Huthmacher
FULL PAPER
In order to gain an insight into the mechanism of cataly- the nitrostyrene molecule enantioselectively from one face
sis, imidazole alone as well as compounds 23 and 24 were of the double bond. According to our results and the pro-
tested as catalysts. Whereas thioureas 13–16 gave the posed model, the Re approach is favoured for acetone. The
Michael product in up to 61% yield (Entries 1–4), no reac- nitrostyrene substrate is held in place by hydrogen bonding
tion was observed in the presence of imidazole, or com- between the nitro group and the thiourea moiety. The hy-
pounds 23 and 24 (Entries 5–7, Table 3). These experiments drogen bonding strength is, evidently, affected by the sol-
show that neither the imidazole ring nor the thiourea moi- vent polarity and this is consistent with the observed range
ety are able to facilitate the Michael addition on their own, of conversions and enantioselectivities found in the various
and thus the prerequisite for successful conversion to prod- solvents investigated (Table 2).
uct is that the catalyst possess both functionalities. Both of
these groups most probably act in a synergistic manner
within the catalyst.
Conclusions
Once the optimal catalyst and solvent conditions had
The novel imidazole-based chiral thiourea derivatives
13–16 have been shown to catalyse the nitro-Michael reac-
tion with much higher stereoselectivity than the Strecker
synthesis. In the case studied (addition of acetone to trans-
β-nitrostyrene) these novel catalysts gave superior results in
terms of enantioselectivity (up to 87% ee) than the known
proline derivatives described in the literature.
been established, various nitroolefins were then evaluated
as substrates (Table 4).
Table 4. Michael addition of acetone to nitroolefins under op-
timised conditions.
Experimental Section
General: All solvents were purified by standard procedures and dis-
tilled prior to use. Reagents obtained from commercial sources
were used without further purification. TLC chromatography was
performed on precoated aluminium silica gel SIL G/UV254 plates
(Marcherey–Nagel & Co.) or silica gel 60-F254 precoated glass
plates (Merck). All reactions were conducted under argon or nitro-
1
gen. H NMR spectra were recorded with a Varian Unity 300. EI
[a] Yield of isolated product after column chromatography on SiO2.
[b] Enantioselectivities were determined by chiral HPLC analysis
(Daicel Chiralpak AS) in comparison with authentic racemic mate-
rial. [c] Yield and % ee were determined after 40 h.
mass spectra were measured with a Finnigan MAT 95: Alpha AXP
DEC station 3000–300LX. ESI mass spectra were recorded with
a LCQ Finnigan spectrometer. High-resolution mass spectra were
measured with a Bruker APEX IV 7T FT-ICR instrument. A Per-
kin–Elmer 241 polarimeter was used for optical rotation measure-
ments.
The introduction of electron-withdrawing or electron-do-
nating groups on the aromatic ring of the nitroolefins did
not affect the enantioselectivities (83–87% ee, Table 4, En-
tries 1–4) or the yields (46–62%) significantly.
Compound 5: CS2 (1.26 mL) and DCC (680 mg, 3.3 mmol) were
added to a solution of (R)-1-phenylethylamine (1) (0.42 mL,
399.8 mg, 3.3 mmol) in dry ether (4.2 mL) at –10 °C. The reaction
mixture was allowed to warm slowly to room temperature over a
period of 3 h and then was stirred for a further 12 h at room tem-
perature. After separation of the precipitated thiourea by filtration,
the solvent was removed under vacuum. The residue was taken up
in ether and more of the thiourea was removed by filtration. Evapo-
ration of the solvent and rapid filtration through silica gel (with
Although further studies are needed to firmly elucidate
the reaction mechanism of this Michael addition, we postu-
late the sequence shown in Scheme 4.[25] Acetone in the
hexane) gave product 5 (506 mg, 94%) as a liquid. [α]2D0 = –4.3 (c
1
enol/enolate form, stabilised by the imidazole group, attacks = 1.0, acetone). H NMR (300 MHz, CDCl3): δ = 7.30–7.43 (m, 5
Scheme 4. Proposed transition state.
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Asymmetric Organocatalysis with Novel Chiral Thiourea Derivatives
FULL PAPER
H), 4.93 (q, 1 H), 1.69 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 140.11, 128.84, 128.14, 125.35, 56.98,
535 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 8.20 (s, 1 H), 7.68
(br. s, NH), 7.25 (br. s, NH), 7.10–7.20 (m, 5 H), 7.11 (s, 2 H),
24.90 ppm. EI-MS (70 eV); m/z (%): 163.1 (16) [M+], 105.1 (100), 5.36–5.37 (m, 1 H), 4.16 (m, 1 H), 3.13–3.21 (m, 1 H), 2.17–2.20
77.1 (13), 51.0 (6).
(m, 1 H), 1.55–1.71 (m, 4 H), 1.39 (d, J = 6.9 Hz, 3 H), 1.2–1.41
(m, 2 H), 1.11–1.32 (m, 1 H) ppm. 13C NMR (75.5 MHz, [D6]
DMSO): δ = 181.2, 152.24, 145.04, 144.37, 127.98, 126.22, 125.94,
125.81, 72.47, 56.51, 51.85, 48.50, 33.45, 31.17, 24.21, 23.65,
22.03 ppm. ESI-MS (positive ion): m/z = 356.1 [M + H]+, 710.9
[2M + H]+. HRMS (ESI): calcd. for C19H25N5S [M + H]+
356.19034; found 356.19032.
Compound 6: This compound was prepared in 51% (1.3 g) yield as
a white solid, analogously with the above procedure, starting from
(S)-1-(2-naphthyl)ethylamine (2). [α]2D0 = +24.9 (c = 0.095, CHCl3).
1H NMR (300 MHz, [D6]DMSO): δ = 7.91–7.99 (m, 4 H), 7.53–
7.56 (m, 3 H), 5.42 (q, J = 6.9 Hz, 1 H), 1.71 (d, J = 6.6 Hz, 3 H)
ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 137.47, 132.60,
132.45, 128.60, 127.80, 127.48, 126.49, 126.32, 124.20, 123.53,
56.51, 23.86 ppm.
Compound 14: This compound was prepared from 10 by the same
procedure as described above for 13, to give 14 as a white solid in
a quantitative yield. [α]2D0 = +70.3 (c = 0.65, CH3OH). IR (KBr):
Compound 7: This compound was prepared from (S)-3,3-dimethyl-
2-aminobutane (3) in a manner analogous to 5 and was obtained
as a liquid in 80% (2.27 g) yield. [α]2D0 = +36.9 (c = 0.85, CHCl3).
1H NMR (300 MHz, [D6]DMSO): δ = 3.76 (q, J = 6.6 Hz, 1 H),
1.26 (d, J = 6.9 Hz, 3 H), 0.93 (s, 9 H) ppm. 13C NMR (75.5 MHz,
[D6]DMSO): δ = 62.73, 35.20, 25.33, 16.25 ppm.
ν = 3259, 3053, 2930, 2856, 1647, 1543, 1446, 1353, 1269, 1131,
˜
1107, 1005, 945, 856, 819, 760, 656, 578, 476 cm–1. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.18 (s, 1 H), 7.72–7.91 (m, 4 H), 7.39–
7.56 (m, 3 H), 7.08 (s, 2 H), 5.49–5.59 (m, 1 H), 4.12–4.18 (m, 1
H), 3.14–3.20 (m, 1 H), 2.21–2.24 (m, 1 H), 1.46–1.79 (m, 4 H),
1.39 (d, J = 6.9 Hz, 3 H), 1.20–1.39 (m, 2 H), 1.05–1.19 (m, 1
H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 181.30, 152.82,
145.90, 142.01, 132.78, 131.91, 127.68, 127.56, 127.31, 125.92,
125.42, 125.02, 123.93, 72.25, 56.71, 52.25, 33.54, 31.02, 24.15,
23.70, 22.07 ppm. ESI-MS (positive ion): m/z = 406.1 [M + H]+,
428.2 [M + Na]+, 810.8 [2M + H]+, 832.8 [2M + Na]+. HRMS
(ESI): calcd. for C23H27N5S [M + H]+ 406.20599; found 406.20621.
Compound 8: This compound was prepared from (S)-1-cyclohexyle-
thylamine (4) in a manner analogous to 5 and was isolated as a
liquid in 66% (1.74 g) yield. [α]2D0 = +53.5 (c = 0.095, CHCl3). H
1
NMR (300 MHz, [D6]DMSO): δ = 3.81 (q, 1 H), 1.62–1.76 (m, 5
H), 1.42–1.52 (m, 1 H), 1.29 (d, J = 6.6 Hz, 3 H), 0.96–1.26 (m, 5
H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 58.39, 42.83,
28.93, 27.39, 25.63, 25.27, 25.16, 18.45 ppm.
Compound 15: This compound was prepared from 11 (2.20 g,
8.56 mmol) by the same procedure as described above for 13, to
give 15 in a quantitative yield as a white solid. [α]2D0 = +151.8 (c =
Compound 9: (R)-1-Phenylethyl isothiocyanate (5) (1.43 g,
8.75 mmol) was added over a period of 1 h to a stirred solution of
(S,S)-1,2-diaminocyclohexane (17) (1 g, 8.75 mmol) in dry dichlo-
romethane (17 mL). The reaction mixture was stirred for a further
2 h at room temperature. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography on
SiO2 (EtOAc/EtOH, 3:1) to give 9 as a yellow solid in 57% (1.38 g)
yield. [α]2D0 = –85.0 (c = 1, CHCl3). 1H NMR (300 MHz, [D6]
DMSO): δ = 7.17–7.35 (m, 5 H), 5.42–5.49 (m, 1 H), 3.68–3.69 (m,
1 H), 2.41–2.49 (m, 1 H), 1.94–1.99 (m, 1 H), 1.76–1.83 (m, 1 H),
1.54–1.62 (m, 2 H), 1.41 (d, J = 6.9 Hz, 3 H), 0.99–1.26 (m, 4
H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 181.57, 144.39,
128.12, 126.48, 125.97, 59.43, 54.20, 52.21, 34.40, 31.37, 24.42,
24.29, 22.30 ppm. ESI-MS (positive ion): m/z = 278.1 [M + H]+,
554.9 [2M + H]+. ESI-MS (negative ion): m/z = 276.1 [M – H]–.
HRMS (ESI): calcd. for C15H23N3S [M + H]+ 278.16854; found
278.16866.
0.38, CH OH). IR (KBr): ν = 3280, 3058, 2933, 2856, 1649, 1541,
˜
3
1447, 1397, 1365, 1269, 1202, 1134, 1101, 994, 947, 866, 763, 724,
1
573 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 12.6 (br. s, NH),
8.18 (s, 1 H), 7.13 (s, NH), 7.12 (s, 2 H), 6.86 (d, NH), 4.12–4.21
(m, 2 H), 3.14–3.21 (m, 1 H), 2.26–2.31 (m, 1 H), 1.58–1.74 (m, 4
H), 1.26–1.40 (m, 2 H), 1.00–1.12 (m, 1 H), 0.83 (d, J = 6.9 Hz, 3
H), 0.79 (s, 9 H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ =
151.54, 144.33, 72.52, 56.59, 56.37, 45.49, 34.31, 33.53, 31.16,
26.18, 24.14, 23.68, 15.38, 8.45 ppm. ESI-MS (positive ion): m/z =
336.2 [M + H]+, 358.2 [M + Na]+, 670.9 [2M + H]+, 692.9 [2M +
Na]+. HRMS (ESI): calcd. for C17H29N5S [M + H]+ 336.22164;
found 336.22170.
Compound 16: This compound was prepared from 12 in a manner
analogous to 13 and was isolated in a quantitative yield. [α]2D0
=
+126.0 (c = 0.96, CH OH). IR (KBr): ν = 3259, 3056, 2924, 2853,
˜
3
Compound 10: This compound was prepared in a 50% (384 mg)
yield analogously with the above procedure, starting from 6. 1H
NMR (300 MHz, [D6]DMSO): δ = 7.80–7.89 (m, 4 H), 7.44–7.52
(m, 3 H), 5.61–5.63 (m, 1 H), 3.76–3.77 (m, 1 H), 2.50–2.54 (m, 1
H), 1.98–2.00 (m, 1 H), 1.80–1.83 (m, 1 H), 1.51–1.61 (m, 2 H),
1.51 (d, J = 6.6 Hz, 3 H), 1.15–1.22 (m, 4 H) ppm. 13C NMR
(75.5 MHz, [D6]DMSO): δ = 181.65, 141.99, 132.78, 131.95,
127.72, 127.54, 127.33, 125.96, 125.46, 124.95, 123.99, 59.17, 33.91,
31.27, 24.37, 24.21, 22.23 ppm. ESI-MS (positive ion): m/z = 328.1
[M + H]+, 655.0 [2M + H]+.
1649, 1544, 1449, 1366, 1271, 1236, 1203, 1149, 1100, 987, 955,
1
914, 857, 811, 759, 722, 671, 573 cm–1. H NMR (300 MHz, [D6]
DMSO): δ = 12.6 (br. s, NH), 8.17 (s, 1 H), 7.12 (s, 2 H), 6.9–7.0
(m, 2 H, 2×NH), 4.2 (m, 1 H), 3.95 (m, 1 H), 3.2 (m, 1 H), 2.23
(m, 1 H), 1.42–1.8 (m, 10 H), 1.19–1.4 (m, 3 H), 0.98–1.18 (m, 4
H), 0.89 (d, J = 6.9 Hz, 3 H), 0.8–0.98 (m, 1 H) ppm. 13C NMR
(75.5 MHz, [D6]DMSO): δ = 151.64, 144.36, 72.40, 52.75, 42.45,
33.61, 31.16, 28.79, 28.38, 25.89, 25.57, 24.20, 23.74, 17.19 ppm.
ESI-MS (positive ion): m/z = 384.4 [M + Na]+. ESI-MS (negative
ion): m/z = 360.1 [M – H]–. HRMS (ESI): calcd. for C19H31N5S
[M + H]+ 362.23729; found 362.23741.
Compound 13: Na2SO4 (2 g) and imidazole-2-carbaldehyde (18)
(3.24 mmol) were added to a solution of 9 (899 mg, 3.24 mmol) in
anhydrous methanol (50 mL) at room temperature under argon.
The reaction mixture was stirred for 2 h at room temperature, then
filtered and the collected sodium sulphate was washed with anhy-
drous methanol (3×20 mL). The organic phase was concentrated
to afford product 13 in a quantitative yield as a white solid. [α]2D0
Compound 23: This compound was prepared from (S,S)-1,2-diami-
nocyclohexane (17) (300 mg, 2.63 mmol) and imidazole-2-carbal-
dehyde (18) (505 mg, 5.26 mmol) by the same procedure as de-
scribed above for 13, to give 19 in quantitative yield as a white
solid. [α]2D0 = +393.6 (c = 0.41, CH OH). IR (KBr): ν = 3025, 2921,
˜
3
2854, 1649, 1554, 1446, 1388, 1344, 1307, 1153, 1113, 1090, 996,
935, 857, 815, 753, 712, 507 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 8.04 (s, 2 H), 7.03 (s, 4 H), 3.30–3.39 (m, 2 H), 1.39–
= +98.2 (c = 0.44, CHCl ). IR (KBr): ν = 3255, 3061, 2929, 2855,
˜
3
1646, 1543, 1494, 1447, 1357, 1232, 1097, 946, 863, 756, 698,
Eur. J. Org. Chem. 2005, 4995–5000
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4999

S. B. Tsogoeva, D. A. Yalalov, M. J. Hateley, C. Weckbecker, K. Huthmacher
FULL PAPER
1.81 (m, 8 H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 150.86,
144.12, 123.72, 72.48, 32.37, 23.55 ppm. ESI-MS (positive ion):
m/z = 271.2 [M + H]+, 293.2 [M + Na]+. ESI-MS (negative ion):
m/z = 269.2 [M – H]–. HRMS (ESI): calcd. for C14H18N6
[M + H]+ 271.16657; found 271.16666.
[1] For reviews of metallic bifunctional catalysts, see: a) M. Shiba-
saki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187; b) H. Gröger,
Chem. Eur. J. 2001, 7, 5246; c) M. Shibasaki, H. Sasai, T. Arai,
Angew. Chem. 1997, 109, 1290; Angew. Chem. Int. Ed. Engl.
1997, 36, 1236.
[2] For reviews of bifunctional organic catalysts, see: a) P. I. Dalko,
L. Moisan, Angew. Chem. 2004, 116, 5248–5286; Angew. Chem.
Int. Ed. 2004, 43, 5138–5175; b) A. Berkessel, H. Gröger,
Asymmetric Organocatalysis: From Biomimetic Concepts to
Applications in Asymmetric Synthesis, Wiley-VCH, Weinheim,
2004.
[3] M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120,
4901–4902.
[4] M. S. Sigman, P. Vachal, E. N. Jacobsen, Angew. Chem. 2000,
112, 1336–1338; Angew. Chem. Int. Ed. 2000, 39, 1279–1281.
[5] P. Vachal, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012–
10014.
Compound 24: This compound was prepared from 9 (400 mg,
1.44 mmol) and benzaldehyde (0.147 ml, 1.44 mmol) in a manner
analogous to that used for 13 with the difference being that the
reaction mixture was stirred at 40–45 °C for 5 h. The desired prod-
uct 21 was obtained in a quantitative yield as a white solid. [α]2D0
=
+59.3 (c = 0.84, CH OH). IR (KBr): ν = 3311, 3057, 2973, 2925,
˜
3
2856, 2807, 1642, 1536, 1493, 1448, 1354, 1338, 1315, 1262, 1234,
1201, 1132, 1087, 1072, 1002, 946, 916, 828, 797, 773, 753, 719,
1
692, 649, 558 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 8.35 (s,
1 H), 7.7 (m, 2 H), 7.45 (m, 4 H), 7.1–7.18 (m, 4 H), 7.0 (br. s, 2
H, 2×NH), 5.32–5.36 (m, 1 H), 4.14–4.21 (m, 1 H), 3.14–3.22 (m,
1 H), 2.06–2.09 (m, 1 H), 1.55–1.74 (m, 4 H), 1.17–1.40 (m, 3 H),
1.31 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75.5 MHz, [D6]DMSO):
δ = 160.01, 144.77, 136.25, 130.26, 128.37, 127.84, 127.78, 126.30,
126.01, 125.71, 72.36, 56.27, 51.95, 48.38, 33.11, 31.15,
24.25, 23.61, 22.15 ppm. ESI-MS (positive ion): m/z = 366.2
[M + H]+, 388.1 [M + Na]+, 752.9 [2M + Na]+. HRMS (ESI):
calcd. for C22H27N3S [M + H]+ 366.19985; found 366.20006.
[6] G. D. Joly, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 4102–
4103.
[7] M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126,
10558–10559.
[8] T. P. Yoon, E. N. Jacobsen, Angew. Chem. 2005, 117, 470–472;
Angew. Chem. Int. Ed. 2005, 44, 466–468.
[9] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003,
125, 12672–12673; b) T. Okino, Y. Hoashi, T. Furukawa, X.
Xu, Y. Takemoto, J. Am. Chem. Soc. 2005, 127, 119–125; c) Y.
Hoashi, T. Okino, Y. Takemoto, Angew. Chem. 2005, 117,
4100–4103; Angew. Chem. Int. Ed. 2005, 44, 4032–4035.
[10] H. Li, Yi. Wang, L. Tang, L. Deng, J. Am. Chem. Soc. 2004,
126, 9906–9907.
General Procedure for the Addition of Hydrogen Cyanide to Substi-
tuted Imines 19 and 20: A solution of hydrogen cyanide (1.5 mmol)
in dry toluene (1.5 mL) was added in one batch to a suspension of
catalyst (10 mol-%) and an aldimine (19 or 20, 1 mmol) in dry tolu-
ene (3.5 mL) under argon at –40 °C. The mixture was then stirred
at –40 °C for 2.5 h and subsequently at –20 °C for a further 16 h.
The crude reaction mixture was analysed by HPLC using a Daicel
Chiralpak AS 250 column at 22 °C (n-hexane/2-propanol, 90:10,
flow rate 1 mL/min, λ = 210 nm; amino nitrile (21): tR1 = 9.8 min,
tR2 = 8.7 min); amino nitrile (22): tR1 = 8.9 min, tR2 = 14.4 min.
[11] B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7,
1967–1969.
[12] W. Wang, J. Wang, H. Li, Angew. Chem. 2005, 117, 1393–1395;
Angew. Chem. Int. Ed. 2005, 44, 1369–1371.
[13] a) A. J. A. Cobb, D. A. Longbottom, D. M. Shaw, S. V. Ley,
Chem. Commun. 2004, 1808–1809; b) C. E. T. Mitchell, A. J. A.
Cobb, S. V. Ley, Synlett 2005, 611–614; c) A. J. A. Cobb, D. M.
Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org. Biomol.
Chem. 2005, 3, 84–96.
[14] T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett.
2004, 6, 625–627.
[15] D. J. Maher, S. J. Connon, Tetrahedron Lett. 2004, 45, 1301–
1305.
21: 1H NMR (300 MHz, [D6]DMSO): δ = 7.56–7.23 (m, 10 H), 5.0
(d, 1 H, NH), 3.89–3.75 (m, 2 H), 3.62–3.57 (m, 1 H) ppm. EI-MS
(70 eV): m/z (%) = 222.1(5), 116.0 (70), 91.0 (91), 77.0 (62), 65.0
(56), 51.0 (100).
1
22: H NMR (300 MHz, CDCl3): δ = 7.2–7.6 (m, 15 H), 5.25 (s, 1
[16] Y. Sohtome, A. Tanatani, Y. Hashimoto, K. Nagasawa, Tetra-
hedron Lett. 2004, 45, 5589–5592.
H), 4.60 (s, 1 H), 2.15 (d, 1 H) ppm. EI-MS (70 eV): m/z (%) =
298.2 (2), 221.1 (48), 182.1 (58), 167.1 (67), 116.0 (100), 77.0(18),
51.0(6).
[17] a) A. Berkessel, F. Cleemann, S. Mukherjee, T. N. Müller, J.
Lex, Angew. Chem. 2005, 117, 817–821; Angew. Chem. Int. Ed.
2005, 44, 807–811; b) A. Berkessel, S. Mukherjee, F. Cleemann,
T. N. Müller, J. Lex, Chem. Commun. 2005, 1898–1900.
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Weckbecker, K. Huthmacher, Bioorg. Med. Chem. 2005, 13,
5680–5685.
[19] A. Strecker, Ann. Chem. Pharm. 1850, 75, 27–45.
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7108.
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[23] D. Enders, A. Seki, Synlett 2002, 26–28.
General Procedure for the Preparation of the Michael Adduct, 1-
Nitro-2-phenylpentan-4-one (25): Acetone (0.27 mL) was added to
a stirred solution of trans-β-nitrostyrene (20 mg, 0.13 mmol) and
catalyst (15 mol-%) in toluene (0.5 mL), and the reaction mixture
was stirred at room temperature for 48 h. The solvent was evapo-
rated and the residue was purified by TLC or chromatography on
a SiO2-column (hexane/ethyl acetate, 1:1) to afford the desired
product. The enantiomeric excess of the product was determined
by chiral HPLC analysis (Daicel Chiralpak AS) in comparison with
authentic racemic material: n-hexane/2-propanol = 65:35, flow rate
1 mL/min, λ = 210 nm: tR(minor) = 13.43 min, tR(major) =
1
16.98 min. H NMR (300 MHz, [D6]DMSO): δ = 7.20–7.50 (m, 5
[24] H. J. Martin, B. List, Synlett 2003, 1901–1902.
[25] O. Andrey, A. Alexakis, A. Tomassini, G. Bernardinelli, Adv.
Synth. Catal. 2004, 346, 1147–1168.
H), 4.80 (m, 2 H), 3.80 (m, 1 H), 2.91 (d, J = 8.0 Hz, 2 H), 2.10
(s, 3 H) ppm. ESI-MS (positive ion): m/z = 230.1 [M + Na]+.
HRMS (ESI): calcd. for C11H13NO3 [M + Na]+ 230.07876; found
230.07878.
Received: June 10, 2005
Published Online: October 19, 2005
5000
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 4995–5000