Design, synthesis, and application of chiral electron-poor guanidines as hydrogen-bonding catalysts for the Michael reaction

Article abstract of DOI:10.1016/j.tetasy.2010.04.033

The first chiral electron-poor guanidine organocatalysts were synthesized. The presence of a tunable electron-withdrawing group on the guanidine moiety allows for the modulation of the catalysts' activity. The application of this new class of organocatalysts to the Michael reaction is demonstrated.

Full text of DOI:10.1016/j.tetasy.2010.04.033

Tetrahedron: Asymmetry 21 (2010) 751–755
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Design, synthesis, and application of chiral electron-poor guanidines
as hydrogen-bonding catalysts for the Michael reaction
*
Karen Thai, Michel Gravel
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK, Canada S7N 5C9
a r t i c l e i n f o
a b s t r a c t
Article history:
The first chiral electron-poor guanidine organocatalysts were synthesized. The presence of a tunable
electron-withdrawing group on the guanidine moiety allows for the modulation of the catalysts’ activity.
The application of this new class of organocatalysts to the Michael reaction is demonstrated.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 29 March 2010
Accepted 20 April 2010
Available online 18 May 2010
1. Introduction
most successful catalysts in this class, the bifunctional chiral thio-
ureas developed by Takemoto and co-workers can be used to effi-
Guanidine, a functional group present in arginine, exists in the
protonated form as a guanidinium ion, which forms highly selec-
tive hydrogen-bonding and electrostatic interactions with anionic
functionalities such as carboxylate and phosphate.1 Following Nat-
ure’s precedent, several chiral guanidines have been utilized as
Brønsted base catalysts.2,3 For most of the reactions catalyzed by
guanidines, it is proposed that in situ generation of a guanidinium
ion is followed by activation of an electrophile through hydrogen-
bonding as well as electrostatic interactions. An inherent disadvan-
tage of this approach to hydrogen-bonding catalysis is the require-
ment for specific nucleophile–electrophile combinations that are
compatible with and sufficiently activated by guanidinium ions
(e.g., silyl enol ether nucleophiles and basic functional groups un-
dergo protonation under typical acidic conditions). In contrast to
the use of in situ-generated guanidinium ions, we hypothesized
that guanidines bearing tunable electron-withdrawing groups
could directly act as hydrogen-bond donors. To the best of our
knowledge, there have been no reports of electron-poor guanidines
behaving as hydrogen-bonding catalysts.4 In this paper, we (1) de-
tail the design and modular synthesis of a new class of guanidine
organocatalysts, (2) demonstrate their catalytic activity, (3) dem-
onstrate their tunability through modification of the electron-
withdrawing group and (4) perform a preliminary assessment of
their potential for catalyzing Michael addition reactions.
ciently catalyze a number of reactions including Michael
additions,7 Friedel–Crafts alkylations8 and aza-Morita–Baylis–Hill-
man reactions.9 A double hydrogen-bonding mode of activation
was proposed for the Michael addition of malonate derivatives
onto
a
,b-unsaturated imides (Fig. 1a).7b
S
Ar
N
H
N
H
EWG
N
NMe2
Ar
O
O
N
H
N
H
NMe2
N
R
(b)
(a)
Figure 1. (a) Activation of imides through hydrogen-bonding interactions using
thiourea. (b) Structure of proposed electron-poor guanidine catalysts.
Similarly, we envisioned that electron-poor guanidines (Fig. 1b)
would also catalyze reactions through hydrogen-bonding interac-
tions. Significantly, the additional electron-withdrawing group
(EWG) present in the guanidine would allow fine tuning of the
hydrogen-bonding ability of the catalyst, allowing a greater flexi-
bility to catalyze a variety of reactions.
The potential of Brønsted acid catalysis in the hydrogen-bond-
ing activation of electrophiles has received considerable attention
in organocatalysis over the past decade. In particular, the develop-
ment of chiral hydrogen-bond donors has given rise to a broadly
applicable class of catalysts for enantioselective synthesis.5 In re-
cent years, various groups have reported the use of thioureas as
catalysts in a number of enantioselective reactions.6 Among the
2. Results and discussion
The required guanidine catalysts were conveniently synthe-
sized in a one-pot transformation from the appropriate isothiocya-
nates (Table 1).10–13 Very few examples of unsymmetrical
guanidines bearing electron-withdrawing groups have been
reported;13 to the best of our knowledge, this represents the first
synthesis of chiral and electron-poor guanidines. This simple
protocol gives access to highly functionalized chiral guanidine cat-
alysts from readily available starting materials. Although the
* Corresponding author. Tel.: +1 306 966 7785; fax: +1 306 966 4730.
E-mail address: michel.gravel@usask.ca (M. Gravel).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.033

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K. Thai, M. Gravel / Tetrahedron: Asymmetry 21 (2010) 751–755
Table 1
anesulfonyl electron-withdrawing group were screened as
catalysts in the Michael addition of malononitrile to ,b-unsatu-
rated imide 2a (Table 2).
Synthesis of chiral guanidines10
a
EWG
N
To our delight, all four families of electron-poor guanidines
were shown to catalyze this transformation. Indeed, no reaction
was detected in the absence of a catalyst. This catalytic activity
stands in contrast to a recent report on the inability of an achiral
tosyl-guanidine to bind sulfoxides, acetate, and chloride ion.14
Although the reaction rates are low, thiourea-catalyzed Michael
addition reactions of this type were also reported to be quite
sluggish.7b
1. EWG-NH2, NaH, DMF
Ar
Ar-NCS
N
H
N
H
2.
, EDCI
NMe2
1a-o
H2N
NMe2
Entry
Ar
EWGa
Yieldb (%)
Guanidines bearing an unsubstituted phenyl aromatic moiety
were generally quite active catalysts; however, the enantioselec-
tivity of the reaction was poor (entries 1–4). In contrast to the fre-
quently used 3,5-bis(trifluoromethyl)phenyl substituent in
thiourea catalysis,7–9 the corresponding guanidine derivatives
were less reactive, and provided only marginal enantioselectivity
(entries 5–7). Consequently, we decided to examine the perfor-
mance of catalysts containing electron-rich aromatic rings (entries
8–14). Satisfyingly, both the rate and the enantioselectivity of the
reaction were improved relative to the use of catalysts bearing
an electron-poor aryl group. Intrigued, we examined the possibility
of introducing additional steric bulk on the aromatic moiety (entry
15). The mesityl-bearing catalyst showed no improvement in
either reactivity or asymmetric induction relative to the p-
methoxyphenyl- or p-methylphenyl-derived catalysts.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a Ph
CN
Ms
Ts
48
70
50
40
45
92
32
33
64
84
62
50
37
49
47
b Ph
c Ph
d Ph
Tf
e 3,5-(CF3)2–C6H3
f 3,5-(CF3)2–C6H3
g 3,5-(CF3)2–C6H3
h 4-MeO–C6H4
i 4-MeO–C6H4
j 4-MeO–C6H4
k 4-MeO–C6H4
l 4-Me–C6H4
CN
Ms
Ts
CN
Ms
Ts
Tf
CN
Ms
Ts
m 4-Me–C6H4
n 4-Me–C6H4
o 2,4,6-(CH3)3–C6H2
Ts
a
Ms = CH3SO2; Ts = p-CH3–C6H4SO2; Tf = CF3SO2.
Yield of pure isolated product.
b
As anticipated at the outset, the ability to fine tune the hydro-
gen-bonding character of electron-poor guanidines by varying
the nature of the electron-withdrawing substituent is well illus-
reaction generally affords clean conversion to the desired product,
the low yields obtained in some cases are a reflection of the diffi-
culty in purifying the most polar guanidines. Nevertheless, the
modular nature and straightforward synthesis of these guanidines
allow rapid catalyst optimization. Ultimately, catalyst 1j proved to
be optimal (vide infra) and was obtained in high yield.
To evaluate the potential of these guanidines as chiral hydro-
gen-bonding organocatalysts, we began our explorations with the
Michael addition reaction. Various chiral guanidine catalysts bear-
ing a nitrile, methanesulfonyl, p-toluenesulfonyl, or trifluorometh-
trated in these results. Guanidines bearing
a nitrile group
(EWG = CN) were found to be generally very reactive in compari-
son to the corresponding sulfonyl-substituted guanidines (entries
1, 5, 8, and 12). However, the enantioselectivity of the reaction
using this family of catalysts was very poor. In contrast, the reac-
tion rate dropped dramatically when methanesulfonyl-guanidines
(EWG = Ms) containing neutral or electron-poor aromatic substitu-
ents were employed (entries 2 and 6). Promising results were ob-
tained using toluenesulfonyl-bearing guanidines, furnishing the
Table 2
Screening of guanidine catalysts for the Michael reaction
EWG
N
NC
Ph
CN
O
Ar
N
H
N
H
O
O
O
1a-o
(10 mol %)
NMe2
N
Ph
N
CH2(CN)2 (2 equiv), toluene, rt
2a
3b
Entry
Catalyst
Time (h)
Conversiona (%)
erb (S:R)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
168
120
144
96
82
18
71
85
61
11
22
84
51
42
37
73
36
35
40
50:50
57:43
62:38
56:44
64:36
56:44
56:44
63:37
76:24
81:19
68:32
67:33
74:26
79:21
76:24
168
216
168
120
120
168
168
168
168
120
168
a
Determined by 1H NMR spectroscopy of the crude reaction mixture.
Determined by HPLC using a chiral stationary phase (see Section 4).
b

K. Thai, M. Gravel / Tetrahedron: Asymmetry 21 (2010) 751–755
753
product in moderate enantioselectivity (entries 10, 14, and 15).
Guanidine catalyst 1j, bearing p-methoxyphenyl and p-toluenesul-
fonyl groups, was found to be the best catalyst for this reaction,
furnishing the product (S)-3a in an 81:19 enantiomeric ratio (entry
10). Interestingly, all the catalysts predominantly furnished the (S)-
enantiomer of product 3a, whereas the corresponding thiourea cat-
alysts gave rise to the opposite enantiomer.7a,b These results sug-
gest a significantly different organization of the reactants in the
transition state for guanidine- versus thiourea-catalyzed reactions.
We then turned our attention to the optimization of the reac-
tion conditions using catalyst 1j (Table 3). The use of THF as sol-
vent resulted in decreased reactivity and enantioselectivity, as
predicted based on its coordinating character (entry 1). In contrast,
an increase in the rate of the reaction was observed using CH2Cl2 or
benzene (entries 2 and 3). However, toluene was deemed more
suitable for this reaction, furnishing the addition product 3a with
an improved enantiomeric ratio (entry 4). A small increase in
reaction was achieved when the reaction was performed at a con-
centration of 0.5 M in the imide substrate, without significant de-
crease in the enantioselectivity (entry 6). Further increase of the
concentration resulted in a significant drop of the enantiomeric ra-
tio (entries 7 and 8).
The scope of the reaction was investigated with various aryl and
alkyl b-substituents under the optimized conditions. As illustrated
in Table 4, aryl-substituted imides 2a–g underwent the conjugate
addition to furnish 3a–g in good yields and moderate enantioselec-
tivity. The enantioselectivity and the reactivity of para-substituted
imides 2b,e–g were similar despite the difference in electronic prop-
erties of the aromatic system. However, in the case of imide 2f, the
rate of the reaction was somewhat lower, due to the electron-rich
nature of the substrate. Compared to the para-substituted aryl sys-
tems, meta- and ortho-chlorinated aryl-substituted imides are more
reactive (entries 3 and 4). Interestingly, the ortho-chlorinated aryl-
substituted imide gave rise to increased yield and enantioselectivity
(entry 3). Although the reasons behind this observation are unclear
at the moment, disruption of conjugation in the Michael acceptor
enantioselectivity was observed when
a catalyst loading of
20 mol % was used (entry 5). An improvement in the rate of the
Table 3
Optimization of reaction conditions
Ts
H3CO
N
NC
Ph
CN
O
N
H
N
H
O
O
O
1j
NMe2 (10 mol %)
N
Ph
N
CH2(CN)2 (2 equiv), toluene, rt
2a
3b
Entry
Solvent
Concentration (M)
Conversiona (%)
Time (h)
erb (S:R)
1
2
3
4
THF
0.2
0.2
0.2
0.2
0.2
0.5
1.0
2.0
57
>95
60
42
49
79
79
83
168
120
168
168
168
168
168
72
62:38
76:24
78:22
81:19
85:15
84:16
76:24
70:30
CH2Cl2
Benzene
Toluene
Toluene
Toluene
Toluene
Toluene
5c
6c
7c
8c
a
b
c
Determined by 1H NMR spectroscopy of the crude reaction mixture.
Determined by HPLC using a chiral stationary phase (see Section 4).
20 mol % catalyst loading.
Table 4
Scope of the reaction
Ts
H3CO
N
NC
R
CN
O
N
H
N
H
(20 mol %)
NMe2
O
O
O
1j
N
R
N
CH2(CN)2 (2 equiv)
toluene (0.5 M)
2a-i
3a-i
Entry
R
Time (h)
Yielda (%)
erb (S:R)
1
2
3
4
5
6
7
8
9
a Ph
168
168
168
168
168
168
168
240
72
56
50
86
73
58
41
53
48
98
84:16
73:27
84:16
74:26
75:25
76:24
73:27
78:22
56:44
b p-ClC6H4
c o-ClC6H4
d m-ClC6H4
e p-FC6H4
f p-MeC6H4
g p-MeOC(O)C6H4
h 2-Furyl
i Me
a
Yield of pure isolated product.
Determined by HPLC using a chiral stationary phase (see Section 4).
b

754
K. Thai, M. Gravel / Tetrahedron: Asymmetry 21 (2010) 751–755
may be a factor. Furyl-substituted acceptor 2h furnished the desired
product 3h in good yield and moderate enantioselectivity, with ex-
tended reaction time. Methyl b-substituted 2i furnished the corre-
sponding Michael product 3i in good yields (entry 9). Although the
rate of the reaction was significantly higher in this case, the product
was obtained in nearly racemic form.
units of g/100 mL. The enantiomeric excess was determined, when
necessary, using an HPLC system. CHIRALPAKÒ IB, IC, and ASH col-
umns were purchased from Daicel Chemical Industries, Ltd.
4.2. General procedure for the synthesis of the guanidine
catalysts
The mode of catalysis for this reaction may be similar to the one
shown in Figure 1a. However, the bulky nature of the additional
electron-withdrawing group would force the guanidine substitu-
ents out of planarity. The resulting twisted geometry may only pro-
vide single-point activation, and a transition state favoring the
opposite enantiomer to that obtained using the corresponding
thiourea catalyst. Alternatively, a ground state in which one NH
forms an intramolecular hydrogen bond to the sulfonyl moiety
could also favor single-point activation over double hydrogen
bonding.14
4.2.1. N-(((1R,2R)-2-(Dimethylamino)cyclohexylamino)(4-meth
oxyphenylamino)methylene)-4-methylbenzenesulfonamide
(1j)
At first, NaH (19 mg, 0.49 mmol, 60% in mineral oil) was added
to a stirring solution of p-toluenesulfonamide (83 mg, 0.49 mmol)
in dry DMF (1.6 mL) under an inert atmosphere at room tempera-
ture. After 5 min, 4-methoxyphenyl isothiocyanate (45 lL,
0.32 mmol) was added and the reaction mixture was heated to
80 °C until the complete consumption of the isothiocyanate was
observed by thin layer chromatography. The mixture was then
cooled to room temperature, and (1R,2R)-1-amino-2-(dimethyl-
3. Conclusion
amino)cyclohexane1 (46 mg, 0.32 mmol) in dry DMF (200
lL)
was added, followed by EDCI (68 mg, 0.36 mmol). After 20 h at
room temperature, the reaction was quenched with distilled water
(2 mL) and the reaction mixture was extracted with EtOAc
(3 ꢁ 3 mL). The combined organic extracts were dried over Na2SO4
and then concentrated in vacuo. The crude product was purified by
column chromatography (1:1 EtOAc/hexanes, 5% Et3N, Rf = 0.30) to
In conclusion, we designed a new class of hydrogen-bonding
catalysts derived from electron-poor guanidines. The modular ap-
proach to the synthesis of these chiral guanidines allows flexibility
and rapid screening of various reactions and substrates. Fine tun-
ing of the properties of the catalysts is achieved through the elec-
tron-withdrawing group present on the guanidine moiety.
Guanidines bearing methanesulfonyl, trifluoromethanesulfonyl,
p-toluenesulfonyl, and nitrile groups were all found to catalyze
yield a viscous yellow oil (112 mg, 84%). ½a D22
¼ ꢀ8:2 (c 2.4, CHCl3);
ꢂ
FTIR mmax 3311, 2935, 2300, 1575, 1511, 1248, 1211, 1141, 1090,
1034 cmꢀ1 1H NMR (500 MHz, CDCl3) d 8.96 (br s, 1H), 7.83 (d,
.
the Michael addition reaction of malononitrile onto
a,b-unsatu-
J = 7.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H),
6.86 (d, J = 9.7 Hz, 2H), 5.64 (br s, 1H), 3.94 (s, 3H), 3.50–3.40 (m,
1H), 2.44–2.37 (M, 4H), 2.21–2.05 (m, 7H), 1.82–1.70 (m, 2H),
1.64–1.54 (m, 1H), 1.31–1.21 (m, 1H), 1.18–1.07 (m, 2H), 1.03–
0.92 (m, 1H); 13C NMR (125 MHz, CDCl3) d 162.7, 155.2, 141.8,
141.5, 129.3, 126.2, 123.8, 115.0, 55.9, 55.7, 40.0, 36.7, 33.2, 31.6,
25.3, 24.7, 21.6, 15.5; HRMS (EI+) m/z calcd for C23H32N4O3S
[M]+: 444.2188, found: 444.2189.
rated imides. A preliminary assessment of this new class of organ-
ocatalysts provided the conjugate addition products in good yields
and moderate enantiomeric ratio. To the best of our knowledge,
this is the first example of chiral electron-poor guanidine catalysts
acting through hydrogen-bonding interactions without prior pro-
tonation to form a guanidinium species. The design and synthesis
of more structurally rigid guanidines that will allow for double
hydrogen-bonding interactions is under way. In addition, the
investigation of 2-methoxyphenyl-Michael substrates, shown by
Takemoto et al. to be ideal Michael acceptors, will be explored.7c
4.3. General procedure for the guanidine-catalyzed Michael
addition reaction
4. Experimental
4.1. General
4.3.1. (S)-1-(4,4-Dicyano-3-phenylbutanoyl)pyrrolidine-2-one
(3a)
Malononitrile (32 mg, 0.48 mmol) was added to a stirring solu-
tion of
a,b-unsaturated imide 2a (52 mg, 0.24 mmol) and guani-
Anhydrous dimethylformamide (DMF) was dried over calcium
hydride, then distilled under a nitrogen atmosphere; anhydrous
CH2Cl2 was dried using a solvent purification system and stored
under nitrogen over 3 Å molecular sieves. Unless otherwise noted,
all reactions were performed under an inert atmosphere of
nitrogen.
Thin layer chromatography (TLC) was performed on Silica Gel
60 F254 and was visualized with UV light and 5% phosphomolybdic
acid (PMA) and/or KMnO4. Silica Gel 60 (40–63 lm) was used for
dine catalyst 1j (20 mg, 0.048 mmol) in toluene (480 mL) at room
temperature. After 168 h, the reaction mixture was concentrated
in vacuo and the product was purified by column chromatography
(2:1 Et2O/hexanes, Rf = 0.25) to yield a colorless oil (38 mg, 56%).
1H NMR (500 MHz, CDCl3) d 7.44–7.38 (m, 5H), 4.57 (d, J = 5.5 Hz,
1H), 3.85–3.78 (m, 3H), 3.62–3.60 (m, 2H), 2.68–2.66 (m, 2H),
2.13–2.02 (m, 2H). HPLC [CHIRALPAKÒ AS-H, EtOH/hexanes = 20/
80, 0.1 mL/min, k = 254 nm, retention times: (major) 34.8 min,
(minor) 38.3 min].
column chromatography. NMR spectra were measured in CDCl3
solution at 500 MHz for 1H and 125 MHz for 13C. The residual sol-
vent protons (1H) or the solvent carbons (13C) were used as internal
standards for chemical shifts. High-resolution mass spectra
(HRMS) were obtained on a double focusing high-resolution spec-
trometer. EI ionization was accomplished at 7 eV and CI at 50 eV
with ammonia as the reagent gas. IR spectra were recorded on a
Fourier transform interferometer using a diffuse reflectance cell
(DRIFT); only diagnostic and/or intense peaks are reported. Unless
otherwise stated, all samples were prepared on KBr film for IR
analysis. Optical rotations were determined from an average of five
measurements at ambient temperature using a 1-mL, 10-dm cell;
the units are 10ꢀ1 deg cm2 gꢀ1, the concentrations are reported in
4.3.2. (S)-1-[3-(4-Chlorophenyl)-4,4-dicyanobutanoyl]
pyrrolidin-2-one (3b)
Colorless oil. 1H NMR (500 MHz, CDCl3) d 7.41 (d, J = 8.6 Hz, 2H),
7.35 (d, J = 8.6 Hz, 2H), 4.56 (d, J = 5.8 Hz, 1H), 3.87–3.42 (m, 3H),
3.63–3.50 (m, 2H), 2.69–2.55 (m, 2H), 2.13–2.00 (m, 2H). HPLC
[CHIRALPAKÒ IB, iPrOH/hexanes = 20/80, 0.1 mL/min, k = 254 nm,
retention times: (minor) 29.0 min, (major) 31.2 min].
4.3.3. (S)-1-[3-(2-Chlorophenyl)-4,4-dicyanobutanoyl]
pyrrolidin-2-one (3c)
The crude was purified by column chromatography (1:1 hex-
anes/EtOAc, Rf = 0.12) to yield a colorless oil (86% yield); FTIR mmax

K. Thai, M. Gravel / Tetrahedron: Asymmetry 21 (2010) 751–755
755
1739, 1691, 1478, 1460, 1438, 1390, 1362, 1323, 1288, 1253, 1225,
4.3.8. (S)-1-[4,4-Dicyano-3-(furan-2-yl)butanoyl]pyrrolidin-2-
one (3h)
1193, 1039, 1024, 913, 761 cmꢀ1; 1H NMR (500 MHz, CDCl3) d 7.42
(dd, J = 7.5, 1.5 Hz, 1H), 7.36 (dd, J = 7.5, 1.5 Hz, 1H), 7.24–7.16 (m,
2H), 4.51 (d, J = 7.0 Hz, 1H), 4.48–4.44 (m, 1H), 3.71–3.65 (m, 2H),
3.60–3.47 (m, 2H), 2.54–2.50 (m, 2H), 2.00–1.92 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 175.9, 170.4, 134.3, 134.2, 130.6, 130.3,
128.5128.0, 111.8, 111.4, 45.6, 38.5, 37.4, 33.5, 27.5, 17.4; HRMS
(EI+) m/z calcd for C16H14ClN3O2 [M]+: 315.0774, found:
315.0789. HPLC [CHIRALPAKÒ AS-H, EtOH/hexanes = 15/75,
0.1 mL/min, k = 254 nm, retention times: (major) 26.5 min, (minor)
30.7 min].
Colorless oil. 1H NMR (500 MHz, CDCl3) d 7.47–7.42 (m, 1H),
6.47–6.36 (m, 2H), 4.57 (d, J = 5.8 Hz, 1H), 4.02 (dt, J = 5.7 Hz,
1H), 3.81 (t, J = 7.2 Hz, 2H), 3.62 (d, J = 18.9, 5.7 Hz, 1H), 3.52 (d,
J = 18.9, 8.2 Hz, 1H), 2.68–2.58 (m, 2H), 2.14–2.02 (m, 2H). HPLC
[CHIRALPAKÒ IC, iPrOH/hexanes = 15/75, 0.1 mL/min, k = 254 nm,
retention times: (minor) 40.8 min, (major) 48.7 min].
4.3.9. (S)-1-[4,4-Dicyano-3-methylbutanoyl]pyrrolidin-2-one
(3i)
Colorless oil. 1H NMR (500 MHz, CDCl3) d 4.41 (d, J = 4.9 Hz, 1H),
3.80 (t, J = 7.2 Hz, 2H), 3.18 (dd, J = 18.6, 4.9 Hz, 1H), 3.08 (dd,
J = 18.6, 8.7 Hz, 1H), 2.77–2.67 (m, 1H), 2.62 (t, J = 8.1 Hz, 2H),
2.14–2.04 (m, 2H), 1.36 (d, J = 6.7 Hz, 3H). HPLC [CHIRALPAKÒ
AS-H, EtOH/hexanes = 20/80, 0.1 mL/min, k = 254 nm, retention
times: 13.9 min, 15.5 min].
4.3.4. (S)-1-[3-(3-Chlorophenyl)-4,4-dicyanobutanoyl]
pyrrolidin-2-one (3d)
White precipitate; mp 123–125 °C; FTIR
1598, 1574, 1479, 1460, 1435, 1390, 1362, 1322, 1250, 1192, 1082
cmꢀ1 1H NMR (500 MHz, CDCl3) d 7.38–7.35 (m, 3H), 7.32–7.30
mmax 1738, 1687, 1682,
;
(m, 1H), 4.56 (d, J = 6.3 Hz, 1H), 3.84–3.75 (m, 3H), 3.63–3.53 (m,
2H), 2.62 (dddd, J = 8.4, 8.4, 4.2, 4.2 Hz, 2H), 2.12–2.02 (m, 2H);
13C NMR (125 MHz, CDCl3) d 175.9, 170.6, 138.5, 135.3, 130.8,
129.6, 128.5, 126.5, 111.9, 111.5, 45.6, 41.5, 39.0, 33.5, 28.8, 17.4;
HRMS (EI+) m/z calcd for C16H14ClN3O2 [M]+: 315.0775, found:
315.0775. HPLC [CHIRALPAKÒ AS-H, EtOH/hexanes = 15/85,
0.1 mL/min, k = 254 nm, retention times: (major) 26.4 min, (minor)
30.6 min].
Acknowledgments
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada (NSERC), the Canada Foundation for innovation (CFI),
and the University of Saskatchewan for financial support.
References
1. For reviews, see: (a) Best, M. D.; Tobey, S. L.; Anslyn, E. V. Coord. Chem. Rev.
2003, 240, 3–15; (b) Schug, K. A.; Lindner, W. Chem. Rev. 2005, 105, 67–113; (c)
Blondeau, P.; Segura, M.; Pérez-Fernández, R.; de Mendoza, J. Chem. Soc. Rev.
2007, 36, 198–210; (d) Berlinck, R. G. S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat.
Prod. Rep. 2008, 25, 919–954.
2. For reviews on guanidines in organic synthesis, see: (a) Ishikawa, T.; Isobe, T.
Chem. Eur. J. 2002, 8, 552–557; (b) Ishikawa, T.; Kumamoto, T. Synthesis 2006,
737–752.
3. For a review on the use of chiral guanidines as organocatalysts, see: (a) Leow,
D.; Tan, C.-H. Chem. Asian J. 2009, 4, 488–507. For selected examples, see:; (b)
Echavarren, A.; Galán, A.; Lehn, J.-M.; de Mendoza, J. J. Am. Chem. Soc. 1989, 111,
4994–4995; (c) Kurzmeier, H.; Schmidtchen, F. P. J. Org. Chem. 1990, 55, 3749–
3755; (d) Iyer, M. S.; Gigstad, K. M. J. Am. Chem Soc. 1996, 118, 4910–4911; (e)
Corey, E. J.; Grogan, J. M. Org. Lett. 1999, 1, 157–160; (f) Terada, M.; Ube, H.;
Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454–1455; (g) Sohtome, Y.; Hashimoto,
Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894–2897; (h) Uyeda, C.; Jacobsen, E.
N. J. Am. Chem. Soc. 2008, 130, 9228–9229; (i) Yu, Z.; Liu, X.; Zhou, L.; Lin, L.;
Feng, X. Angew. Chem., Int. Ed. 2009, 48, 5195–5198; (j) Jiang, Z.; Yang, Y.; Pan,
Y.; Zhao, Y.; Liu, H.; Tan, C.-H. Chem. Eur. J. 2009, 15, 4925–4930; (k) Lovick, H.
M.; Michael, F. E. Tetrahedron Lett. 2009, 50, 1016–1019; (l) Fu, X.; Loh, W.-T.;
Zhang, Y.; Chen, T.; Ma, T.; Liu, H.; Wang, J.; Tan, C.-H. Angew. Chem., Int. Ed.
2009, 48, 7387–7390.
4.3.5. (S)-1-[3-(4-Fluorophenyl)-4,4-dicyanobutanoyl]
pyrrolidin-2-one (3e)
Colorless oil. 1H NMR (500 MHz, CDCl3) d 7.40 (dd, J = 8.4,
5.0 Hz, 2H), 7.11 (t, J = 8.6 Hz, 2H), 4.57 (d, J = 5.5 Hz, 1H), 3.90–
3.72 (m, 3H), 3.64–3.51 (m, 2H), 2.69–2.54 (m, 2H), 2.15–1.99
(m, 2H). HPLC [CHIRALPAKÒ IB, EtOH/hexanes = 30/70, 0.1 mL/
min, k = 254 nm, retention times: (minor) 16.1 min, (major)
17.5 min].
4.3.6. (S)-2-(3-Oxo-3-(2-oxopyrrolidin-1-yl)-1-p-tolylpropy)
malononitrile (3f)
Colorless oil. FTIR mmax 1740, 1686, 1419, 1388, 1250, 1224, 730,
637; 1H NMR (500 MHz, CDCl3) d 7.29 (d, J = 7.8 Hz, 2H), 7.22 (d,
J = 8.2 Hz, 2H), 4.54 (d, J = 5.2 Hz, 1H), 3.82–3.78 (m, 3H), 3.59–
3.58 (m, 2H), 2.64–2.60 (m, 2H), 2.36 (s, 3H), 2.11–2.05 (m, 2H);
13C NMR (125 MHz, CDCl3) d 175.8, 171.1, 139.2, 133.5, 130.1,
128.1, 112.2, 111.8, 45.6. 41.5, 39.2, 33.6, 29.2, 21.4, 17.4; HRMS
(EI+) m/z calcd for C17H17N3O2 [M]+: 295.1321, found: 295.1322.
HPLC [CHIRALPAKÒ IB, iPrOH/hexanes = 10/90, 0.1 mL/min,
k = 254 nm, retention times: (minor) 43.3 min, (major) 46.4 min].
4. Recently, Nájera and co-workers reported the use of chiral 2-
aminobenzimidazoles as organocatalysts for the conjugate addition of 1,3-
dicarbonyl compounds to nitroalkenes in high yields and enantioselectivity:
Almaßsi, D.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera, C. J. Org. Chem. 2009, 74,
6163–6168.
5. For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520–1543; (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743;
(c) Akiyama, T. Chem. Rev. 2007, 107, 5744–5758.
6. For reviews, see: (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299–4306; (b)
Connon, S. J. Chem. Eur. J. 2006, 12, 5418–5427; (c) Zhang, Z. G.; Schreiner, P. R.
Chem. Soc. Rev. 2009, 38, 1187–1198; (d) Connon, S. J. Synlett 2009, 354–376.
7. (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032–
4035; (b) Okino, T.; Hashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem.
Soc. 2005, 127, 119–126; (c) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2006, 128, 9413–9419.
4.3.7. (S)-Methyl 4-(1,1-dicyano-4-oxo-4-(2-oxopyrrolidin-1-
yl)butan-2-yl)benzoate (3g)
Compound 3g was isolated by column chromatography (1:1
hexanes/EtOAc, Rf = 0.26) to yield a colorless oil (53% yield). FTIR
mmax 1724, 1688, 1613, 1437, 1421, 1390, 1363, 1286, 1193,
1113, 1020, 914, 860, 772, 599 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
8.10 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.59 (d,
8. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44,
6576–6579.
9. Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007, 349, 2129–2135.
10. Atwal, K. S.; Ahmed, S. Z.; O’Reilly, B. C. Tetrahedron Lett. 1989, 30, 7313–7316.
11. Thai, K.; Clement, C. W.; Gravel, M. Tetrahedron Lett. 2009, 50, 6540–6542.
12. Zhang, J.; Shi, Y. Tetrahedron Lett. 2000, 41, 8075–8078.
13. Pescatori, L.; Arduini, A.; Pochini, A.; Ugozzoli, F.; Secchi, A. Eur. J. Org. Chem.
2008, 109–120.
J = 5.7 Hz, 1H), 3.91–3.88 (m, 4H), 3.80–3.75 (m, 2H), 3.62–3.60
(m, 2H), 2.63–2.59 (m, 2H), 2.08–2.04 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 178.0, 170.6, 166.6, 141.3, 131.1, 130.7,
128.4, 111.8, 111.5, 52.5, 45.6, 41.6, 38.9, 33.5, 28.7, 17.4; HRMS
(EI+) m/z calcd for C18H17N3O4 [M]+: 339.1219, found: 339.1217.
HPLC [CHIRALPAKÒ AS-H, EtOH/hexanes = 40/60, 0.1 mL/min,
k = 254 nm, retention times: (minor) 18.0 min, (major) 20.8 min].