Synthesis and evaluation of guanidinyl pyrrolidines as bifunctional catalysts for enantioselective conjugate additions to cyclic enones

Article abstract of DOI:10.1039/b812038b

Guanidinyl pyrrolidines derived from 'S'-proline are effective catalysts for the enantioselective conjugate addition of malonate, nitroalkane and other carbon and heteroatom nucleophiles to cyclohexenone and cyclopentenone in the absence of basic additive

Full text of DOI:10.1039/b812038b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and evaluation of guanidinyl pyrrolidines as bifunctional catalysts
for enantioselective conjugate additions to cyclic enones†
Sunil V. Pansare* and Rajinikanth Lingampally
Received 14th July 2008, Accepted 19th September 2008
First published as an Advance Article on the web 17th November 2008
DOI: 10.1039/b812038b
Guanidinyl pyrrolidines derived from ‘S’-proline are effective catalysts for the enantioselective
conjugate addition of malonate, nitroalkane and other carbon and heteroatom nucleophiles to
cyclohexenone and cyclopentenone in the absence of basic additives. The stereoselectivity is strongly
dependant on catalyst loading as well as reaction concentration.
a base-containing catalyst would enhance the reaction rate by
Introduction
assisting in the deprotonation of the nucleophile. This would
The organocatalytic Michael addition of carbon nucleophiles to a
potentially offer some improvements over catalyst systems which
variety of acceptors has been extensively investigated in recent
require a large excess of malonate and prolonged reaction times
years.1 One particular class of these reactions, the conjugate
for appreciable turnover. A cursory examination of the acidity
of carbon nucleophiles suggested that a guanidine moiety10
would be well suited as the base for deprotonation of malonate
and nitroalkane nucleophiles. Hence, we chose to prepare the
guanidinyl pyrrolidines 1–3 as catalyst candidates for this study.
It may be noted that relatively few studies10 have examined chiral
guanidines as bases in conjugate addition reactions in general and
even fewer studies have investigated guanidine-catalyzed conjugate
additions of malonates to enones.10h,i
The synthesis of catalysts 1–3 is readily achieved by reaction
of (S)-N-Boc-aminomethylpyrrolidine with the appropriate im-
idazolium species followed by deprotection of the pyrrolidine
(Scheme 1).
addition of carbon nucleophiles to a,b-unsaturated ketones, is
of special interest. The ready availability of starting materials,
the simplicity of the process, and the synthetic versatility of the
Michael adducts have all contributed to the notable interest in
the asymmetric catalysis of this reaction. Remarkable progress in
the enamine-mediated2 and the iminium ion3 mediated conjugate
addition reactions has been witnessed in recent years. However, the
organocatalytic conjugate addition of malonates and nitroalkanes
to cyclic and acyclic enones is an enduring challenge and the
search for new and efficient organocatalysts for these reactions
continues.4–9 Herein, we report preliminary results on the applica-
tion of pyrrolidinyl guanidines as catalysts for the malonate-enone
and nitroalkane-enone conjugate addition reactions.
Studies on the iminium ion mediated organocatalytic conjugate
addition of malonates to enones have employed catalysts based on
functionalized imidazolidinones4 and modified prolines.5 Mod-
erate to good enantioselectivities are obtained, but reactions with
the imidazolidinone catalysts are sluggish and are often conducted
with malonate as the solvent. The proline-based catalysts usually
require amine additives for optimum performance. Similarly,
modified prolines/amine additives,6 peptides/amine additives7
and imidazolidinone catalyst systems8 have been examined for
the asymmetric conjugate addition of nitroalkanes to enones. The
imidazolidinone catalysts provide better stereoselectivities in these
reactions but often require a large excess of the nitroalkane. A
few organocatalysts that do not rely on iminium ion formation
have also been examined for malonate and nitroalkane conjugate
additions.9
Scheme 1
Considering that proline and peptide based catalysts work best
with amine additives, we reasoned that an efficient catalyst system
could probably be developed by appending a basic moiety to
the pyrrolidine framework. In addition, it seemed plausible that
Preliminary experiments involved screening of the guanidinyl
pyrrolidines 1–3 for efficacy in the conjugate addition of dibenzyl
malonate to cyclohexenone in a variety of solvents to provide (S)-
4a4 (Table 1).
Amino-guanidines 1,2 and 3 catalyzed the conjugate addition
of dibenzyl malonate to cyclohexenone in substoichiometric
amounts (15 mol%), to provide 4 in good to moderate yield. Al-
though reasonable yields were obtained with catalysts 1 and 3 the
enantiomeric excess was negligible (0–12%, Table 1, entries 1–6). In
contrast, catalyst 2 provided (S)-4a with higher enantioselectivity
Department of Chemistry, Memorial University, St. John’s, Newfoundland,
Canada, A1B 3X7. E-mail: spansare@mun.ca; Fax: +1 (709) 737-3702;
Tel: +1 (709) 737-8535
† Electronic supplementary information (ESI) available: Experimental
details and characterization data for compounds 4–8 and spectra for
compounds 1–3 and intermediates. See DOI: 10.1039/b812038b
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Table 1 Addition of dibenzyl malonate to cyclohexenone
that dilution was not an option with this solvent (Table 2, entry 1,
31% ee). Experiments in dichloromethane and 1,2-dichloroethane
(DCE) were more fruitful and diluting the reaction mixture had
a significant, positive effect on enantioselection in these solvents.
For example, doubling the dilution in dichloromethane with 15
mol% of 2, increased the enantioselectivity from 61% to 82%
(entries 2 and 5, Table 2). Further dilution and a concomitant
decrease in catalyst loading improved the enantioselectivity to 86%
(Table 2, entry 6) but at the expense of the yield. A similar effect of
dilution was also observed in 1,2-dichloroethane but, in this case,
decreasing the catalyst loading was less detrimental to the overall
yield. Consequently, 1,2-dichloroethane was the solvent of choice
and under the optimized conditions, 4a was obtained in 64% yield
and 86% ee (Table 2, entry 12).
The precise reasons for the effect of dilution on the enan-
tioselection are not clear at this time. We hypothesize that at
higher reaction concentrations, deprotonation of the malonate
by 2 is faster than iminium ion formation and this results in a
direct conjugate addition of malonate anion to cyclohexenone
with low enantioselectivity. The poor enantioselectivity observed
in malonate as the reaction medium supports this proposal. As the
effective concentration of malonate is lowered, the rate ofmalonate
deprotonation by free catalyst 2 is sufficiently reduced to allow
iminium ion formation, and conjugate addition to an iminium
species involving 2 proceeds with higher enantioselectivity. These
observations suggest a bifunctional role for guanidinyl pyrrolidine
2, namely, iminium ion formation and malonate deprotonation. It
is also plausible that dilution favours double hydrogen bonding
between the malonate anion and the guanidinium ion, which
results in a directed addition of the malonate.
Entrya
Catalyst
Solvent
Time (h)
Yield (%)
Ee(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
1
3
3
3
2
2
2
2
2
2
2
2
toluene
CH2Cl2
DMF
toluene
CHCl3
DMF
—
DMF
toluene
CHCl3
THF
168
92
168
36
36
36
20
48
48
48
48
48
48
48
94
91
82
41
35
75
99
56
68
46
84
70
41
45
4
12
6
5
3
< 1
4
21
36
49
50
58
61
63
DCE
CH2Cl2
t-BuOH
a 1.2 eq. malonate. b Chiral HPLC analysis.
in 1,2-dichloroethane, dichloromethane and t-butyl alcohol
(Table 1, entries 12–14). Also, with 2 as the catalyst, dibenzyl
malonate provided higher enantioselectivity compared to its
dimethyl5b (4b, 59% ee) and diethyl5b (4c, 52% ee) congeners
whereas di-t-butyl malonate failed to react. Interestingly, the
enantioselectivity was negligible (4%, entry 7, Table 1) when
dibenzyl malonate was used as the solvent. These observations
clearly indicated an important role for the solvent as well as
the concentration of the reactants. We therefore conducted
an optimization study with dibenzyl malonate, cyclohexenone
and catalyst 2. The effect of catalyst loading and reaction
concentration was examined in this study (Table 2).
We next investigated the conjugate addition of nitroalkanes to
cyclohexenone and cyclopentenone. These results are summarized
in Table 3.
The guanidinyl pyrrolidine 2 was again the catalyst of choice
in these reactions and a small excess (2–5 eq.) of the nitroalkane
was beneficial for enantioselectivity. Compared with the malonate
Although tert-butyl alcohol had provided the highest enantiose-
lectivity in the solvent screening study, it was immediately apparent
Table 2 Optimization studies with catalyst 2
Entrya
Cat. (mol%)
Solvent
Vol. (mL)
Malonate (M)
Time (h)
Yield (%)
Ee (%)b
1
2
3
4
5
6
7
8
9
15
15
5
t-BuOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
DCE
DCE
DCE
DCE
2
1
2
2
2
4
2
5
7
2
4
3
0.3
0.6
0.3
0.3
0.3
0.15
0.3
0.12
0.09
0.3
0.15
0.2
48
48
90
120
90
156
48
164
185
140
156
140
88
41
16
50
61
27
92
99
87
78
47
64
31
61
74
82
82
86
73
79
81
84
86
86
10
15
10
15
20
20
10
10
10
10
11
12
DCE
a 0.5 mmol cyclohexenone, 1.2 eq. malonate. b By chiral HPLC.
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Table 3 Asymmetric conjugate additions of nitroalkanes to cycloalkenones
Entrya
5b
a
n
R
Cat. (mol%)
Vol. (mL)
Nitroalkane (M)
Time (h)
Yield (%)
Ee (%)c
1
2
3
4
5
6
7
8
9
10
2
H
H
H
H
CH3
CH3
(CH2)4
(CH2)5
H
15
5
2
1
3
3
4
2
4
4
2
4
1.25
2.5
0.8
0.8
0.25
0.5
0.6
0.25
1.5
120
192
168
164
156
120
240
192
96
31
15
97
54
43
52
44
42
50
88
72
72
56
66
65
58
41
45
50d
26
15
10
10
15
10
10
15
10
b
2
c
d
e
f
2
2
1
1
CH3
0.3
96
a CH2Cl2 as solvent, DCE for entries 4, 5 and 9. b 5 eq. of nitroalkane 2 eq. for entries 5, 6 and 8. c Chiral HPLC. d 13C NMR of ketal with (2R,3R)-2,3-
butanediol.
study, the trend in stereoselection was less predictable and lowering
catalyst loading and increasing dilution did not always increase
enantioselectivity. (5a, entries 1, 3 and 4). Curiously, increasing
the size of the nitroalkane did not result in an increase in
enantioselectivity as has been observed in some studies and the
enantioselectivity with nitrocyclopentane and nitrocyclohexane
is lower than the acyclic nitroalkanes.11 It is also noteworthy
that an increase in catalyst loading and reaction time for the
nitromethane/cyclohexenone reaction provided 5a in excellent
yield (97%, Table 3, entry 3). This suggests that 5a is stable
under the reaction conditions and may not be reacting further
as indicated in studies with the tetrazolyl proline catalyst.6d
Significantly, all of the malonate and the nitroalkane addition
products have the ‘S’ configuration whereas the earlier proline-
derived catalysts4,5b,6–8 provide the ‘R’ products in the majority of
cases. A possible explanation of this observation is initial iminium
ion formation followed by addition of malonate or nitronate that
is hydrogen-bonded to the protonated guanidine12 as shown in
Fig. 1.
guanidine 2 to provide the conjugate addition products 6–8
respectively (Fig. 2). The stereoselectivities for these reactions
were strongly dependant on the amount of catalyst employed and
low catalyst loading was necessary for appreciable enantioselec-
tion. This observation highlights the basicity of the guanidine
pendant in catalyst 2. Presumably, these nucleophiles are rapidly
deprotonated due to their higher acidity, and the non-iminium ion
mediated conjugate addition pathway predominates as the catalyst
loading increases. Low catalyst loading increases enantioselection
but reduces the product yield. For example, the triketone 6 (Fig. 2)
was obtained in 99% yield and 39% ee when 15 mol% of catalyst 2
were employed. A similar reaction with 1 mol% of 2 provided
6 with 80% ee but reduced yield (12%) in spite of a longer
reaction period. While this highlights the inherent potential in 2
for asymmetric induction, a balance between iminium ion forming
ability and basicity seems necessary, especially when nucleophiles
with low pKa values are employed.
Fig. 2 Results with other nucleophiles.
In conclusion, new organocatalysts incorporating iminium ion
forming (pyrrolidine) and strongly basic (guanidine) function-
alities were prepared and examined in the conjugate addition
reactions of cyclohexenone and cyclopentenone with a variety of
nucleophiles. The enantioselectivity for the addition of dibenzyl
malonate to cyclohexenone (86% ee) is, to the best of our
knowledge, the highest reported for the organocatalytic variant
of this reaction in the absence of an externally added base.16
It is also noteworthy that the malonate conjugate additions do
not require a large excess of the malonate and good yields
Fig. 1 Proposed model for the origin of stereoselectivity with amino
guanidine catalyst 2.
The conjugate addition of other carbon and heteroatom
nucleophiles such as dibenzoylmethane,13 malononitrile,14 and
naphthalene-2-thiol15 was also effectively catalyzed with amino
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of the products with cyclohexenone are obtained in reasonable
time (Table 2, 1.2 eq. of malonate, average time 115 h, average
yield 63%). Qualitatively, this implies an increased reaction rate
compared to the functionalized imidazolidinone catalysts4 used
for this reaction (malonate as reaction medium (8 eq.), 78% yield,
150 h). The observations from this study provide some insight into
the reactivity of amine-guanidine bifunctional catalyst motifs and
lay the foundation for designing second generation catalysts with
modulated nucleophilic and basic character. Current efforts focus
on reactions of other nucleophiles and enones catalyzed by 2 and
related amino-guanidines.
pressure. The residue was dissolved in ethyl acetate (5 mL) and
the solution was extracted with water (2 mL). The aqueous
phase was cooled (<5 ◦C), basified with NaOH pellets and the
basic solution was extracted with CH2Cl2 (3 ¥ 10 mL). The
combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure to give 50 mg (47%) of 1 as a colourless
oil. This material was directly used further.
1H NMR (500 MHz, CDCl3): d 3.50 (s, 4H, NCH2CH2N), 3.28-
3.23 (m, 1H, CHN), 3.20-3.16 (dd, 1H, J = 3.5, 13.5 CHCH2N),
2.98-2.93 (dd, 1H, J = 8.2, 13.5 CHCH2N), 2.88-2.83 (m, 1H,
CH2N), 2.77-2.72 (m, 1H, CH2N), 1.84-1.71 (m, 2H, CH2CH2),
1.63-1.56 (m, 1H, CH2CH2), 1.40-1.31 (m, 1H, CH2CH2); visible
peaks for tautomer: 3.73-3.7 (m); 13C NMR (125.8 MHz, CDCl3):
d 163.4 (NCN), 59.0 (NCH2CH2N), 48.5 (br, NCH), 46.8 (br, 2 x
NCH2), 29.4 (br, CH2CH2), 26.4 (br, CH2CH2); visible peaks for
minor tautomer: d 63.9, 49.5, 46.5, 41.9, 31.9; MS (APCI): m/z
169.2 (M + 1, 100); IR: (neat): 3261, 2960, 1608, 1559, 1456, 1263,
1199 cm-1; HRMS (CI): m/z 169.1454 (169.1453 calc. for C8H17N4
Experimental section
General
All commercially available reagents and solvents were used with-
out purification. Commercial precoated silica gel (Merck 60F-254)
plates were used for TLC. Silica gel for column chromatography
was 230–400 mesh. All melting points are uncorrected. IR spectra
were recorded on a Bruker TENSOR 27 spectrometer. 1H NMR
and 13C NMR spectra were recorded on a Bruker AVANCE-500
instrument. Coupling constants (J) are given in Hz. Mass spectra
were obtained on an Agilent 1100 series LC/MSD chromato-
graphic system. High-resolution mass spectra were obtained on
a Waters GCT Premier Micromass mass spectrometer. Optical
rotations were measured at the sodium D line on a JASCO-DIP
370 digital polarimeter at ambient temperature.
23
(M + H)); [a]D = -33.2 (c 1, CHCl3).
4,5-Dihydro-1-methyl-N-(((S)-pyrrolidin-2-yl)methyl)-1H-
imidazol-2-amine (2)
To a solution of (S)-N-Boc-2-aminomethyl pyrrolidine17 (3 g,
15 mmol) in isopropanol (50 mL) was added 4,5-dihydro-1-methyl-
2-(methylthio)-1H-imidazole hydroiodide ((prepared from N-
methyl ethylenediamine by conversion to 1-methyl imidazolidin-
2-thione and subsequent reaction with iodomethane), 3.87 g,
15 mmol) at room temperature and the solution was heated to
reflux at 95 ◦C for 2 days. The solution was concentrated
under reduced pressure to provide 6.13 g (99%) of (S)-tert-butyl
2-((4,5-dihydro-1-methyl-1H-imidazol-2-ylamino)methyl)pyrro-
lidine-1-carboxylate hydroiodide (2a) as a pale yellow solid.
1H NMR (500 MHz, CDCl3): d 8.83 (s, 1H, NH), 8.54 (s, 1H,
NH), 3.84-3.83 (m, 1H, CHN), 3.80-3.76 (m, 2H, CH2NCO),
3.68-3.59 (m, 3H, NCH2CH2N, CHCH2N), 3.42-3.35 (m, 2H,
NCH2CH2N), 3.27-3.24 (m, 1H, CHCH2N), 3.14 (s, 3H, NCH3),
2.26 (m, 1H, CH2CH2), 2.04-1.89 (m, 2H, CH2CH2), 1.89-1.85
(m, 1H, CH2CH2), 1.47 (s, 9H, C(CH3)3); 13C NMR (125.8 MHz,
CDCl3): d 158.5 (NCO), 156.9 (NCN), 81 (OC(CH3)3, 56.9
(CHN), 50.3 (CH2NCO), 48.2 (CHCH2N), 47.1 (CH2N), 41.4
(NCH3), 33.2 (CH2N), 29.7 (CH2CH2), 28.4 (C(CH3)3), 23.7
(CH2CH2); MS (APCI): m/z 283.3 (M + 1, 100); IR (neat): 3199,
2967, 2228, 2024, 1669, 1405 cm-1; HRMS (CI): m/z 282.2054
(282.2056 calc. for C14H26N4O2 (M - HI)).
4,5-Dihydro-N-(((S)-pyrrolidin-2-yl)methyl)-1H-
imidazol-2-amine (1)
To a solution of (S)-N-Boc-2-aminomethyl pyrrolidine17 (1.25 g,
6.25 mmol) in isopropanol (50 mL) was added 2-methylthio-
2-imidazoline hydroiodide ((prepared from ethylenediamine by
conversion to imidazolidine-2-thione and subsequent reaction
with iodomethane), 1.53 g, 6.25 mmol) at room tempera-
ture and the solution was heated to reflux at 95 ◦C for
2 days. The solution was concentrated under reduced pres-
sure and the residue was purified by flash chromatography
over silica gel (dichloromethane/methanol 98/2) to provide
1.40 g, (57%) of (S)-tert-butyl 2-((4,5-dihydro-1H-imidazol-2-
ylamino)methyl)pyrrolidine-1-carboxylate hydroiodide (1a) as a
white foam.
1H NMR (500 MHz, CDCl3): d 8.57 (s, 1H, NH), 8.36 (s,
1H, NH), 7.59 (s, 1H, NH), 3.77 (s, 4H, NCH2CH2N), 3.68-
3.65 (br m, 1H, CHN), 3.39-3.34 (m, 1H, CH2NCO), 3.34-3.29
(dd, 1H, J = 6, 15 CHCH2N), 3.23-3.12 (m, 2H, CH2NCO,
CHCH2N), 2.02-1.87 (m, 4H, CH2CH2), 1.47 (s, 9H, C(CH3)3);
13C NMR (125.8 MHz, CDCl3): d 161.1 (NCO), 156.3 (NCN),
81.4 (C(CH3)3, 57.6 (CHN), 47.2 (CH2NCO), 46.5 (CH2N), 43.6
(CH2N), 43.3 (CH2N), 30.4 (CH2CH2), 28.8 (C(CH3)3), 23.8
(CH2CH2); MS (APCI): m/z 269.2 ((M - HI) + 1, 100); IR:
(neat) 2960, 1663, 1291, 1199, 1175, 1127 cm-1; HRMS (CI): m/z
268.1897 (268.1899 calc. for C13H24N4O2 (M - HI)).
To a stirred solution of the above hydroiodide (1.5 g, 3.61 mmol)
in dry CH2Cl2 (5 mL), was added trifluoroacetic acid (5 mL)
at 0 ◦C. The solution was brought to room temperature after
30 min., stirred for 3 h and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate (5 mL) and the solution
was extracted with water (2 mL). The aqueous phase was cooled
◦
(<5 C), basified with NaOH pellets and the basic solution was
extracted with CH2Cl2 (3 ¥ 10 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure to
give 624 mg (93%) of 2 as a colourless oil. This was directly used
further.
To a stirred solution of the above hydroiodide (0.25 g,
0.63 mmol) in dry CH2Cl2 (3 mL), was added trifluoroacetic acid
(1.5 mL) at 0 ◦C. The solution was brought to room temperature
after 30 min., stirred for 3 h and concentrated under reduced
1H NMR (500 MHz, CDCl3):
d 3.45–3.41 (m, 2H,
NCH2CH2N), 3.33-3.28 (m, 1H, CHN), 3.27-3.21 (m, 3H,
CHCH2N, NCH2CH2N), 3.04-3.00 (dd, 1H, J = 8.3, 12.7,
322 | Org. Biomol. Chem., 2009, 7, 319–324
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CHCH2N), 2.93-2.85 (m, 2H, CH2N), 2.73 (m, 3H, CH3N),
1.87-1.79 (m, 1H, CH2CH2), 1.77-1.73 (m, 1H, CH2CH2), 1.70-
1.62 (m, 1H, CH2CH2), 1.45-1.38 (m, 1H, CH2CH2); 13C NMR
(125.8 MHz, CDCl3): d 161.8 (NCN), 59.5 (CHN), 51.4 (NCH3),
48.1 (CHCH2N), 46.5 (NCH2CH2N), 41.7 (NCH2CH2N), 33.7
(CH2N), 29.2 (CH2CH2), 26.8 (CH2CH2); MS (APCI): m/z 183.1
(M + 1, 100); IR (neat): 2958, 2024, 1655, 1409, 1262, 1031 cm-1;
HRMS (CI): m/z 183.1605 (183.1610 calc. for C9H19N4 (M + H));
(CH2CH2); MS (APCI): m/z 197.1 (M + 1, 100); IR (neat): 2937,
2231, 2024, 1652, 1603, 1447, 1403, 1288, 1263, 1114 cm-1; HRMS
23
(CI): m/z 197.1774 (197.1766 calc. for C10H21N4 (M + H)); [a]D
-54.6 (c 1, CHCl3).
=
Acknowledgements
These investigations were supported by the Natural Sciences
and Engineering Research Council of Canada and the Canada
Foundation for Innovation.
23
[a]D = -50.4 (c 1, CHCl3).
N-(1,3-Dimethylimidazolidin-2-ylidene)((S)-pyrrolidin-
2-yl)methanamine (3)
References
To a solution of (S)-N-Boc-2-aminomethyl pyrrolidine17 (1.38 g,
6.9 mmol) in acetonitrile (25 mL) was added commercially
available 2-chloro-1,3-dimethylimidazolinium chloride (1.17 g,
6.9 mmol) and potassium carbonate (2.86 g, 21 mmol) at
room temperature and the solution was stirred at room tem-
perature for 2 days. The undissolved solids were removed
by filtration and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatogra-
phy over silica gel (dichloromethane/methanol 90/10) to pro-
vide 0.78 g (34%) of (S)-tert-butyl-2-((1,3-dimethylimidazolidin-
2-ylideneamino)methyl)pyrrolidine-1-carboxylate hydrochloride
(3a) as a white, gummy foam.
1 Recent reviews: (a) D. Almasi, D. A. Alonso and C. Najera, Tetrahedron
Asymm., 2007, 18, 295; (b) S. Tsogoeva, Eur. J. Org. Chem., 2007,
1701.
2 Recent review: (a) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List,
Chem Rev., 2007, 107, 5471.
3 (a) Recent reviews: G. Lelais, D. W. C. MacMillan, Enantioselective
Organocatalysis, 2007, p. 95. Publisher: Wiley-VCH Verlag GmbH
& Co. KGaA, Weinheim, Germany; (b) C. Palomo and A. Mielgo,
Angew. Chem. Int. Ed., 2006, 45, 7876; (c) B. List, Chem. Comm., 2006,
819.
4 N. Halland, P. S. Aburel and K. A. Jorgensen, Angew. Chem. Int. Ed.,
2003, 42, 661.
5 (a) A. Kawara and T. Taguchi, Tetrahedron Lett., 1994, 35, 8805; (b) K.
R. Knudsen, C. E. T. Mitchell and S. V. Ley, Chem. Comm., 2006,
66.
1H NMR (500 MHz, CDCl3): d 9.6 (s,1H, NH), 3.94-3.93
(br m, 1H, CHN), 3.75-3.72 (m, 1H, CHCH2N), 3.64 (s, 4H,
NCH2CH2N), 3.52-3.48 (m, 1H, CHCH2N), 3.37-3.32 (m, 2H,
CH2NCO), 3.28 (s, 6H, NCH3), 2.33-2.29 (m, 1H, CH2CH2),
2.11-2.09 (1H, m, CH2CH2), 1.93-1.83 (m, 2H, CH2CH2), 1.45
(s, 9H, C(CH3)3); 13C NMR (125.8 MHz, CDCl3): d 158.9
(NCO), 156.1 (N=CN), 80.2 (OC(CH3)3), 57.1 (CHN), 49.7
(CHCH2N, NCH2CH2N), 47.3 (NCH3), 46.1 (NCH3), 35.3
(CH2NC(O)), 29.5 (C(CH3)3), 28.4 (NCH2CH2(pyrrolidine)), 23.7
(NCH2 (pyrrolidine)). Visible peaks for isomeric salt: d 157.3,
81.09, 56.1, 53.6, 47.8, 45.6, 30.9; MS (APCI): m/z 297.2 ((M -
HI) + 1, 100); IR (neat): 2972, 1684, 1632, 1392, 1166, 1109
cm-1; HRMS (CI): m/z 296.2203 (296.2212 calc. for C15H28N4O2
(M - HI)).
To a stirred solution of the above hydrochloride (0.320 g,
0.96 mmol) in dry CH2Cl2 (3 mL) was added trifluoroacetic acid
(1.5 mL) at 0 ◦C. The solution was brought to room temperature
after 30 min., stirred for 3 h and concentrated under reduced
pressure. The residue was dissolved in ethyl acetate (5 mL) and
the solution was extracted with water (2 mL). The aqueous phase
was cooled (<5 ◦C), basified with NaOH pellets and the basic
solution was extracted with CH2Cl2 (3 ¥ 10 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure to give 138 mg (73%) of 3 as a pale yellow
gum.
6 (a) S. Hanessian, Z. Shao and J. S. Warrier, Org. Lett., 2006, 8, 4787;
(b) S. Hanessian, S. Govindan and J. S. Warrier, Chirality, 2005, 17,
540; (c) S. Hanessian and V. Pham, Org. Lett., 2000, 2, 2975; (d) C.
E. T. Mitchell, S. E. Brenner, J. Garcia-Fortanet and S. V. Ley, Org.
Biomol. Chem., 2006, 4, 2039; (e) C. E. T. Mitchell, S. E. Brenner and
S. V. Ley, Chem. Comm., 2005, 5346.
7 (a) S. B. Tsogoeva, S. B. Jagtap and Z. A. Armedasova, Tet. Asymm.,
2006, 17, 989; (b) S. B. Tsogoeva and S. B. Jagtap, Synlett, 2004,
2624; (c) S. B. Tsogoeva, S. B. Jagtap, Z. A. Armedasova and V. N.
Kalikhevich, Eur. J. Org. Chem., 2004, 4014.
8 (a) A. Prieto, N. Halland and K. A. Jorgensen, Org. Lett., 2005, 7, 3897;
(b) N. Halland, R. G. Hazell and K. A. Jorgensen, J. Org. Chem., 2002,
67, 8331.
9 (a) J. Wang, H. Li, L. Zu, W. Jiang, H. Xie, W. Duan and W. Wang,
J. Am. Chem. Soc., 2006, 128, 12652; (b) M. Ostendorf, S. Van, der
Neut, F. P. J. T. Rutjes and H. Hiemstra, Eur. J. Org. Chem., 2000, 61,
3520; (c) T. Kumamoto, K. Ebine, M. Endo, Y. Araki, Y. Fushimi, I.
Miyamoto, T. Ishikawa, T. Isobe and K. Fukuda, Heterocycles, 2005,
66, 347.
10 Chiral guanidine catalysts in conjugate addition reactions: 1,3-
dicarbonyl/nitroalkene: (a) M. Terada, H. Ube and Y. Yaguchi, J.
Am. Chem. Soc., 2006, 128, 1454. Phosphite/nitroalkene:; (b) M.
Terada, T. Ikehara and H. Ube, J. Am. Chem. Soc., 2007, 129, 14112;
(c) X. Fu, Z. Jiang and C.-H. Tan, Chem. Commun., 2008, 5058.
Iminoacetate/acrylate: (d) D. Ma and D. K. Cheng, Tetrahedron:
Asymmetry, 1999, 10, 713; (e) A. Rayoda, N. Najima, T. Haga,
T. Kumamoto, W. Nakanishi, M. Kawahata, K. Yamaguchi and T.
Ishikawa, J. Org. Chem., 2008, 73, 133; (f) T. Ishikawa, Y. Araki, T.
Kumamoto, T. Isobe, H. Seki and K. Fukuda, Chem. Comm., 2001, 245.
Iminoacetate/methyl vinyl ketone: (g) D. Wannaporn and T. Ishikawa,
Mol. Diversity, 2005, 9, 321. Dithiomalonate/enone: (h) W. Ye, Z.
Jhiang, Y. Zhao, S. Li, Min Goh, D. Leow, Y.-T. Soh and C.-H. Tan,
Adv. Synth. Catal., 2007, 349, 2454. Malonate/enone: (i) T. Kumamoto,
K. Ebine, M. Endo, Y. Araki, Y. Fushimi, I. Miyamoto, T. Ishikawa, T.
Isobe and K. Fukuda, Heterocycles, 2005, 66, 347. Pyrrolidine/lactone:
(j) V. Alcazar, J. R. Morgan and J. de Mendoza, Tetrahedron Lett., 1995,
36, 3941; (k) A. Howard-Jones, P. J. Murphy and D. A. Thomas, J. Org.
Chem., 1999, 64, 1039; (l) K. Nagasawa, A. Georgieva, H. Takahashi
and T. Nakata, Tetrahedron, 2001, 57, 8959.
1H NMR (500 MHz, CDCl3): 3.96-3.92 (m, 1H, CHN), 3.84-
3.8 (dd, 1H, J = 9.2, 13, CHCH2N), 3.5-3.45 (m, 1H, CH2N),
3.4-3.37 (dd, 1H, J = 5.7, 13, CHCH2N), 3.24-3.14 (m, 3H,
CH2N, NCH2CH2N), 2.87 (s, 3H, CH3N), 2.82 (br s, 1H,
NH), 2.81-2.76 (m, 3H, NH), 2.45 (s, 3H, CH3N), 1.96-1.9 (m,
1H, CH2CH2), 1.82-1.74 (m, 2H, CH2CH2), 1.54-1.47 (m, 1H,
CH2CH2); 13C NMR (125.8 MHz, CDCl3): d 167.7 (NCN), 64.2
(CHN), 58.6 (CHCH2N), 51.3 (CH2N), 51.1 (NCH2CH2N), 49.4
(NCH2CH2N), 36.9 (NCH3), 36.7 (NCH3) 32.4 (CH2CH2), 26.1
11 This trend in enantioselection contrasts with that observed with other
catalyst systems, see references 6d, 7c.
12 For a review on guanidinium cation-anion binding, see: C. Schmuck,
Coord. Chem. Rev., 2006, 50, 3053.
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13 P. Kotrusz and S. Toma, ARKIVOC (Gainesville, FL, United States),
2006, 100.
16 Higher enantioselection for malonate conjugate additions is reported
only when piperidine is used as an additive with the proline tetrazole
catalyst5b.
17 Prepared from Boc-(S)-prolinol by conversion to the corresponding
azide via the mesylate and subsequent hydrogenation of the azide to
the amine. For representative procedures, see: E. Bellis, K. Vasilatou
and G. Kokotos, Synthesis, 2005, 2407.
14 S. Watanuki, S. Sakamoto, H. Harada, K. Kikuchi, T. Kuramochi, K.
Kawaguchi, T. Okazaki and S. Tsukamoto, Heterocycles, 2004, 62, 127.
15 (a) B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding and Y. Wu, Synlett,
2005, 603; (b) P. McDaid, Y. Chen and L. Deng, Angew. Chem. Intl.
Ed., 2002, 41, 338.
324 | Org. Biomol. Chem., 2009, 7, 319–324
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The Royal Society of Chemistry 2009
©