Novel aminoimidazole derived proline organocatalysts for aldol reactions

Article abstract of DOI:10.1016/j.tet.2012.09.071

A series of l-proline amides with 2-aminoimidazole have been synthesized and found to be highly efficient organocatalysts for aldol reactions when an appropriate acid was added to control and activate the acceptor carbonyl group. Under optimized reaction conditions, high yields (over 80%) and high selectivities (ee 98%, de 98/2) were obtained in intermolecular aldol reaction even with only 1 equiv of ketone. Likewise, these systems also can catalyze intramolecular aldol reactions with good results.

Full text of DOI:10.1016/j.tet.2012.09.071

Tetrahedron 68 (2012) 10230e10235
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel aminoimidazole derived proline organocatalysts for aldol reactions
€
*
€
Gongkun Tang, Umit Gun, Hans-Josef Altenbach
Department of Organic Chemistry, Wuppertal University, Gaußstr. 20, 42097 Wuppertal, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2012
Received in revised form 12 September 2012
Accepted 13 September 2012
Available online 18 September 2012
A series of L-proline amides with 2-aminoimidazole have been synthesized and found to be highly ef-
ficient organocatalysts for aldol reactions when an appropriate acid was added to control and activate the
acceptor carbonyl group. Under optimized reaction conditions, high yields (over 80%) and high selec-
tivities (ee 98%, de 98/2) were obtained in intermolecular aldol reaction even with only 1 equiv of ketone.
Likewise, these systems also can catalyze intramolecular aldol reactions with good results.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Imidazole
Enantioselectivity
Organocatalysis
Proline
1. Introduction
second principle is exemplified by proline derived amines8 or
MacMillan’s imidazolidinone systems.9
Although there has been an impressive development in asym-
metric aldol reactions using organocatalysts like proline and pro-
line analogues, there are still some limitations, such as high catalyst
loading, large excess of ketone and moderate yield.1,2 In recent
years, significant contributions, which mainly focus on increasing
the hydrophobicity of organocatalysts have been made2a,3 and
a series of new catalysts have been described,4 however with only
limited success in decreasing the amount of catalyst and excess of
ketone.5 Moreover, very often the synthesis of new catalysts is te-
dious and problematic.4a,b Therefore, practical and efficient new
organocatalysts remain in high demand.
In this context we had the idea that proline derivatives like 1a,
1b or 1c, 1d, 1e, 1f might be potential catalysts when protonated
(Fig. 1). Especially imidazole systems seemed to be very interesting,
€
as imidazole has a bifunctional structure with Bronsted acid (acidic
€
proton on Nꢀ1) and Bronsted base (imine) sites and is incorporated
in many important biological molecules.10 Amazingly enough,
The activation model for proline catalysis through enamine/
iminium intermediates, as given by List,6 has been widely accepted
and has become a dominating principle for designing new orga-
nocatalysts. In the catalytic cycle, the proton from the carboxyl
group plays a crucial role in the rate-determining step.7 Further-
more, the proton can also activate the acceptor carbonyl group to
promote reaction. Therefore, proline derivatives or analogues with
other acidic groups in the side chain or basic groups, which can be
protonated by extra acid have been evaluated in the search for ef-
fective catalysts. Successful examples for the first idea are the sul-
fonylcarboxamide systems of Berkessel3d and the tetrazole systems
of Ley3e or our recently described proline sulfonimides.3k The
* Corresponding author. E-mail address: altenbach@uni-wuppertal.de (H.-J.
Altenbach).
Fig. 1. The designed organocatalysts 1aef.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.071

G. Tang et al. / Tetrahedron 68 (2012) 10230e10235
10231
Table 1
imidazole has only seldom been combined with a chiral scaffold for
use as an organocatalyst, only recently a -proline amide with
Screening of organocatalysts for the aldol reactiona
L
2-aminoimidazole has been introduced for an asymmetric Michael
addition reaction.11
2. Results and discussion
In this paper for the first time, we report guanidine and ami-
noimidazole derivatives linked to L-proline by a stable amide bond
(Fig. 1). Catalyst 1d was synthesized as outlined in Scheme 1 with
DCC and DMAP. Catalysts 1a, 1b and 1c, 1e, 1f were prepared like
1d from Z-L-proline and corresponding imidazole or guanidine
derivatives in dry dichloromethane at room temperature. After
reaction, the mixture was filtrated with silica gel to remove DCU
and DMAP. If necessary, further purification was done by flash
column chromatography. Finally, the protection group was re-
moved with H2, Pd/C.
Entry
Catalyst
Solvent
Yieldb [%]
anti/sync
ee [%] (anti)d
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1c
1d
1e
1f
1c
1d
1e
1f
1c
1d
1e
1f
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCM
DCM
DCM
DCM
THF
72
79
88
92
93
93
93
94
95
94
95
94
91
93
96
96
94
96
90
92
90
91
78
85
81
80
71
85
40/60
75/25
78/22
91/9
89/11
92/8
88/12
76/24
80/20
84/16
77/23
81/19
85/15
78/22
70/30
83/17
75/25
78/22
90/10
95/5
7
5
91
94
94
92
82
86
88
88
72
67
65
72
77
78
72
83
94
92
92
90
96
98
96
96
94
98
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
THF
THF
THF
EtOAc
EtOAc
EtOAc
EtOAc
MeOH
MeOH
MeOH
MeOH
H2O
H2O
H2O
H2O
H2O/EtOAc
H2O/EtOAc
1c
1d
1e
1f
90/10
94/6
92/8
96/4
91/9
94/6
94/6
96/4
1c
1d
1e
1f
Scheme 1. Synthesis of 1d.
1ce
1de
4-Nitrobenzaldehyde and cyclohexanone in DMSO were utilized
to evaluate the catalysts 1aef (Table 1). The reaction with catalysts
1a,1b gave good yield (72% and 79%) but low selectivity (7% and 5%)
(entries 1 and 2, Table 1), whereas catalysts 1c, 1d and 1e, 1f gave
better results in yield and selectivity. The yield with 1c and 1d
reached 88% and 92% with enantiomeric excess (ee) 91% and 94%,
respectively (entries 3 and 4, Table 1). Catalysts 1e and 1f gave
a little higher yield and similar selectivity. It seems as if the pro-
tonated guanidine systems are less able to form hydrogen bonding
to the carbonyl group than the 2-aminoimidazole systems, proba-
bly due to their higher basicity.
Besides the reaction in DMSO, we screened other solvents like
DCM, THF, EtOAc, MeOH and also water with catalysts 1cef. Water
is widely used as solvent in organocatalysis for its peculiar prop-
erties, but its special role is still in debate.12 It has been reported
that the selectivity of organocatalytic reactions in water is higher
than that with organic solvents.13 In our case the results show that
in organic solvents, where the reaction is in a homogeneous phase,
always higher yields are obtained than in heterogeneous reactions
with water (Table 1). The yields of reactions with catalyst 1c, 1d, 1e
and 1f in organic solvents are always above 88%, whereas the yields
with water reach only 85%.
Even more importantly, we have found that the solvent has
a significant effect on diastereoselectivity. The anti/syn ratio of the
reaction product with 1c in DMSO, DCM, THF, EtOAc was much
lower than the obtained 90/10 and 92/8 ratio in methanol and
water (entries 3, 7, 11, 15, 19, 23, Table 1). 1d and 1e, 1f gave
analogous results to 1c. For the different selectivity in diverse
solvents, we suspect that the added acid, which combines with the
imidazole function to control and activate the carbonyl group, is
more active in protic solvents. However, the yield is not obviously
affected.
a
The reaction was performed with 1 (0.1 mmol), TFA (0.1 mmol), 4a (0.51 mL,
5.0 mmol) and 5a (151 mg, 1.0 mmol), solvent (0.5 mL) at room temperature for
24 h.
b
Combined yields of isolated diastereomers.
c
Determined by 1H NMR of the crude product.
d
e
Determined by chiral-phase HPLC analysis of the anti product.
Solvent is 0.25 mL H2O and 0.25 mL EtOAc.
generally better than in aprotic solvents and considering the ad-
vantages of water, we chose water as the solvent for further studies.
In the reactions described above, the ketone was applied in excess
as usual, being also a cosolvent. Using cheap and biodegradable
ethyl acetate, however, excess ketone was not necessary to obtain
good yields and selectivities. Considering the similarity of results
between 1cef, only 1c and 1d were applied in the tests. With
1 equiv of cyclohexanone 1c gave 71% yield and 94% ee (entry 27,
Table 1), 1d gave even better results (85% with 98% ee) (entry 28,
Table 1).
With these promising results from reactions with 1 equiv of
ketone in water and EtOAc, we screened different acids and
lower catalyst loading. As in water/ethylacetate the yield with 1d
was higher than with 1c, catalyst 1d was chosen for the fol-
lowing tests (Table 2). In the search with the same amount of
catalyst (10 mol %) but different acids, it was found that the
selectivity of reaction is generally increased when the added acid
becomes stronger in acidity. However, there is an exceptiondthe
catalysts on addition with HCl did not lead to higher selectivity.
Compared with trifluoroacetic acid and trifluoromethanesulfonic
acid, the selectivity of reaction with HCl is only 82% (entries 4, 5,
6, Table 2). Under these conditions quite some condensation
product was detected after the reaction, as elimination takes
place.
As the enantioselectivity of the reaction with 1c and 1d in protic
solvents (94%, 92% in methanol and 96%, 98% in water) was
As an important result it turned out that trifluoroacetic acid is
better than trifluoromethanesulfonic acid, especially with regard to

10232
G. Tang et al. / Tetrahedron 68 (2012) 10230e10235
Table 2
Table 3
Screening added acids and catalysts loading for aldol reactiona
The aldol reaction with various ketones and aldehydesa
Catalyst Reaction Yieldb anti/sync ee [%]
[mol %] time [h] [%]
(major)d
pHe
Entry
Aldehyde Ar
Ketone
R1, R2
Yield of
anti/sync
ee [%]
Entry Acid
6 [%]b
(major)d
1
2
3
4
5
6
7
p-NO2C6H4
o-NO2C6H4
m-NO2C6H4
p-ClC6H4
p-CH3OC6H4
p-NO2C6H4
p-NO2C6H4
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)2e
H, H
6a 83
6b 81
6c 80
6d 63
6e 58
6f 84
6g 60
98/2
95/5
95/5
99/1
97/3
60/40
98
96
97
97
96
91
84
1
2f
3
4
5
6
7
8
9
No
10
48
24
24
24
18
18
36
48
72
80
65
78
85
88
69
83
82
80
68/32
85/15
83/17
96/4
88/12
84/16
98/2
48
69
73
98
97
82
98
95
95
Succinic acid 10
AcOH
2.44
2.57
0.69
0.58
0.54
0.91
1.13
1.44
10
10
10
10
5
CF3COOH
CF3SO2OH
HCl
CF3COOH
CF3COOH
CF3COOH
a
2.5
1
89/11
87/13
The reaction was performed with 1d (0.05 mmol), TFA (0.05 mmol),
4
(1.0 mmol) and 5 (151 mg, 1.0 mmol), solvent (in 0.25 mL H2O and 0.25 mL EtOAc) at
a
room temperature for 36 h.
The reaction was performed with 1d, 4a (0.10 mL, 1.0 mmol) and 5a (151 mg,
b
Combined yields of isolated diastereomers.
1.0 mmol), acid solution (0.25 mL), EtOAc (0.25 mL) at room temperature for the
time corresponded in the table.
c
Determined by 1H NMR of the crude product.
d
b
Determined by chiral-phase HPLC analysis of the anti product.
Combined yields of isolated diastereomers.
c
Determined by 1H NMR of the crude product.
d
Determined by chiral-phase HPLC analysis of the anti product.
The added acid solutions were made with same mole amount of catalyst in
Table 4
e
Intramolecular aldol reaction catalyzed by catalyst 1da
0.25 mL water.
f
Succinic acid is 5 mol %.
diastereoselectivity with 1d (entries 4 and 5, Table 2). Besides this,
the anti/syn ratio decreases when the catalyst loading is reduced.
With 1 mol % loading, an anti/syn ratio (87/13) is obtained with
excellent comparable yields of 80% and enantioselectivities of more
than 95% (entries 9, Table 2).
In the following the pH in the reactions from Table 2 was in-
vestigated, in order to find a relationship between the pH of water
solution and reaction selectivity. A solution of the corresponding
acid in water was made and the pH of the acid solution was mea-
sured. In Table 2 it can be seen that the pH for reactions with high
selectivity of product is mainly between 0.5 and 1.4. When the pH
of the solution is lower than 0.5, elimination of water leading to
condensation product is occurring with decrease of selectivity of
the aldol addition product. When the pH of solution is higher than
1.5, the selectivity is also going down.
Entry
Solvent
Yieldb [%]
ee [%](major)c
1
2
3
4
THF
95
96
97
93
65
67
71
73
DMSO
Methanol
H2O
a
The reaction was performed with 1d (0.05 mmol), TFA (0.05 mmol),
7
(1.0 mmol) and solvent (0.5 mL) at room temperature for 24 h.
b
Yield is after purification.
Determined by chiral-phase HPLC analysis.
c
Finally, the optimized conditions were used to test different
aldehydes and ketones. Firstly, different substituted benzalde-
hydes were investigated and it was found that regarding selec-
tivity electron poor and electron rich substituted systems gave
similar results, only the yields were lower with 4-chloro and 4-
methoxybenzaldehyde compared to the nitro-substituted benzal-
dehydes. After testing different aldehydes, other ketones, namely
cyclopentanone and acetone, were also investigated. Notably, in
comparison to cyclohexanone, the selectivity of the reaction with
the five-membered ketone and also with acetone was lower (en-
tries 6 and 7, Table 3).
After proving that 1d was a highly efficient catalyst for in-
termolecular aldol reactions, this catalyst was also tested in an
intramolecular aldol reaction, namely in the final aldol reaction
step in the well known HajoseParrisheEdereSauereWiechert
process for the synthesis of 814da valuable intermediate for steroid
synthesis. 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexane-dione 715 was
treated in different solvents with 5 mol % of catalyst 1d. Aldol
addition and condensation was accomplished in 24 h at room
temperature. The enantioselectivity was highest (ee 73%) in the
reaction in water (entry 4, Table 4), even better than the reported
Fig. 2. The proposed transition state with organocatalysts 1cef.
3. Conclusion
In summary, an easy approach to a series of highly efficient chiral
aminoimidazole catalysts in only two steps has been established and
the effect of solvent and added acid on the selectivity of aldol re-
actions has been examined. Especially, the amides from
L-proline
value using D-proline as a catalyst Fig. 2.
with 2-aminobenzimidazole have been found to be effective

G. Tang et al. / Tetrahedron 68 (2012) 10230e10235
10233
organocatalysts for aldol reactions in water. After protonation, these
efficient catalysts may form active H-bond, with which the carbonyl
group can be activated and the stereoselectivity can be controlled. It
has also been found that the selectivity of reaction is greatly de-
termined by the added acid. The reaction with catalyst 1d and tri-
fluoroacetic acid gives highly selective reactions in test reactions of
cyclohexanone and substituted benzaldehydes (de 98/2, ee 98%) and
good yields without using excess of ketone. These catalysts can be
expected to be also suited for other organocatalytic reactions, in
which activation of the acceptor carbonyl group is needed.
and the filtrate concentrated in vacuum. The crude product was
purified by flash column chromatography (MeOH/DCM¼1:4) to give
white solid product (0.69 g, 90% yield). ½a D20
ꢃ
ꢀ3.0 (c 0.40, MeOH). 1H
NMR (400 MHz, DMSO-d6): d 8.50e7.91 (1H, br), 7.72e7.50 (1H, br),
3.90e3.82 (1H, t, J¼8.6 Hz), 3.51e3.30 (3H, m), 3.20e3.10 (1H, m),
2.08e1.80 (3H, m), 1.56e1.48 (1H, m). 13C NMR (400 MHz, DMSO-
d6):
d
189.0, 177.3, 66.9, 47.9, 27.2, 26.4. HRMS (ESI): m/z [MþHþ]
calcd for C6H13N4O 157.1089, found 157.1084.
4.2.3. (S)-Benzyl-2-(pyrimidin-2-ylcarbamoyl) pyrrolidine-1-carbo-
xylate (2b). To a solution of N-carbobenzyloxy-L-proline (2.49 g,
4. Experimental section
4.1. General information
10.0 mmol, 1.0 equiv) and 2-aminopyrimidine (1.04 g, 11.0 mmol,
1.1 equiv) in CH2Cl2 (30.0 mL) N,N0-dicyclohexyl-carbodiimide
(2.26 g, 11.0 mmol,1.1 equiv) and 4-dimethylamino pyridine (1.34 g,
11.0 mmol) were added at 0 ꢂC under N2 atmosphere. The reaction
mixture was stirred for 30 min at 0 ꢂC, then stirred at room tem-
perature for 24 h. The reaction mixture was filtrated through silica
gel pad (SiO2 15 g) to remove dicyclohexylurea. Further purification
was by flash column chromatography. The target product (2.37 g,
73% yield) was obtained as a white solid. 1H NMR (400 MHz, CHCl3-
Chemicals were purchased from commercial suppliers and used
without further purification. Solvents were either purchased from
commercial suppliers or purified by standard techniques. All re-
actions were magnetically stirred and monitored by thin-layer
chromatography (TLC) using silica gel 60 F254 aluminium pre-
coated plates from Merck (0.25 mm) and compounds were visu-
alized by irradiation with UV light and/or by treatment with
a Ninhydrin solution followed by heating. The pH of acid solutions
was measured with Mettler DL25 with buffer standards of pH
4.01ꢁ0.02 and pH 7.00. Flash column chromatography was per-
formed on silica gel (MN Kieselgel 60 M, 0.04e0.063 mm,
230e400 mesh). 1H NMR and 13C NMR spectra were recorded on
Bruker Avance DPX 400 MHz spectrometer or Bruker Avance DPX
600 MHz spectrometer. Chemical shifts were reported in ppm
(parts per millions) according to residual solvent signals of CDCl3
d):
7.00 (1H, s), 5.10 (2H, m), 4.95e4.85 (1H, s), 3.70e3.40 (2H, m),
2.40e1.90 (4H, m). 13C NMR (400 MHz, CHCl3-d):
158.1, 136.1,
d
8.50e7.91 (1H, br), 8.60 (2H, d, J¼4.85 Hz), 7.50e7.10 (5H, m),
d
128.2, 127.8, 127.6, 116.3, 67.2, 61.1, 46.9, 28.0, 24.1. HRMS (ESI): m/z
[MþNaþ] calcd for C17H18N4NaO3 349.1277, found 349.1271.
4.2.4. (S)-N-(1,4,5,6-Tetrahydropyrimidin-2-yl) pyrrolidin-2-carbox-
amide (1b). To a solution of 2b (1.63 g, 5.0 mmol) in MeOH
(20 mL) was added 10% Pd/C, followed by two drops of concen-
trated HCl was added to the solution. The mixture was stirred at
room temperature for 14 h under an atmosphere of hydrogen. Then
excess of Na2CO3 was added to the solution, the reaction mixture
was filtered through Celite and the filtrate concentrated in vacuum.
The crude product was purified by flash column chromatography
(1H NMR;
d
¼7.26 ppm, 13C NMR;
d
¼77.0 ppm), DMSO-d6 (1H NMR;
d
¼2.50 ppm, 13C NMR;
d
¼39.43 ppm) and CD3OD (1H NMR;
d
¼3.30 ppm, 13C NMR;
¼49.0 ppm). All spectra were acquired and
d
processed using Bruker TOPSPIN (1.3) or MestRenova. Optical ro-
tations were measured on a PerkinElmer 241 polarimeter. High
resolution mass analysis was measured on a micrOTOF series 168
instrument. Chiral HPLC studies were carried out on a Merck-
Hitachi LaChrom instrument (Autosampler LaChrom L-7200,
Pump LaChrom L-7100, detector LaChrom L-7490).
(MeOH/DCM¼1:4) to give the product (0.89 g, 91% yield). ½a D20
ꢀ1.5
ꢃ
(c 1.00, MeOH). 1H NMR (400 MHz, Methanol-d4):
d 4.18e4.14 (1H,
m), 3.54e3.48 (2H, m), 3.44e3.36 (2H, m), 3.10e3.00 (2H, m),
2.20e2.10 (3H, m), 2.08e1.98 (2H, m), 1.65e1.58 (1H, m). 13C NMR
(400 MHz, Methanol-d4):
d 191.9, 176.9, 69.3, 49.2, 40.5, 37.7, 29.1,
28.7, 27.8. HRMS (ESI): m/z [MþHþ] calcd for C9H17N4O 197.1402,
4.2. Synthesis of catalysts 1aef
found 197.1397.
4.2.1. (S)-Benzyl-2-(N-(benzyloxycarbonyl)
carbamimidoylcarba-
4.2.5. (S)-Benzyl-2-(1H-imidazol-2-ylcarbamoyl) pyrrolidine-1-car-
moyl) pyrrolidine-1-carboxylate (2a). N-Cbz-guanidine was syn-
boxylate (2c). To a solution of N-carbobenzyloxy-L-proline (2.49 g,
thesized following a literature report.16
10.0 mmol, 1.0 equiv) and 2-aminoimidazole sulfate (2.36 g,
11.0 mmol, 1.1 equiv) in CH2Cl2 (30.0 mL) N,N0-dicyclohexylcarbo-
diimide (2.26 g, 11.0 mmol, 1.1 equiv) and 4-dimethylamino pyri-
dine (2.68 g, 22.0 mmol) were added at 0 ꢂC under N2 atmosphere.
The reaction mixture was stirred for 30 min at 0 ꢂC, then at room
temperature for 24 h. The reaction mixture was filtrated through
silica gel pad (SiO2 15 g) to remove dicyclohexylurea. Further pu-
rification was done by flash column chromatography (Methanol/
DCM¼1:15). The target product (2.4 g, 78% yield) was obtained as
To a solution of N-carbobenzyloxy-L-proline (2.49 g, 10.0 mmol,
1.0 equiv) and N-Cbz-guanidine (2.21 g, 11.0 mmol, 1.1 equiv) in
CH2Cl2 (30.0 mL) N,N0-dicyclohexylcarbo-diimide (2.26 g,
11.0 mmol, 1.1 equiv) and 4-dimethylamino pyridine (1.34 g,
11.0 mmol) were added at 0 ꢂC under N2 atmosphere. The reaction
mixture was stirred for 30 min at 0 ꢂC, then stirred at room tem-
perature for 24 h. The reaction mixture was fast filtrated through
silica gel pad (SiO2 15 g) to remove dicyclohexylurea. Further pu-
rification was through flash column chromatography (Methanol/
DCM¼1:15) to give product (3.77 g, 89%). 1H NMR (400 MHz, CHCl3-
a white solid. 1H NMR (400 MHz, CHCl3-d):
d 7.46e7.08 (5H, m),
6.82 (2H, s), 5.21e4.92 (2H, m), 4.53e4.43 (1H, dd, J¼3.62 Hz),
d):
d 7.42e7.20 (10H, m), 5.23e5.15 (1H, m), 5.15e5.14 (2H, d,
3.73e3.50 (2H, m), 2.42e2.22 (1H, m), 2.19e1.82 (3H, m). 13C NMR
J¼2.55 Hz), 5.14e4.99 (1H, m), 4.45e4.32 (2H, m), 3.72e3.41 (2H,
(400 MHz, CHCl3-d): d 173.6, 156.9, 142.6, 140.4, 129.3, 128.9, 128.7,
m), 2.32e1.99 (2H, m), 1.99e1.82 (2H, m). 13C NMR (400 MHz,
119.2, 108.2, 68.3, 61.6, 40.1, 32.4, 24.6. HRMS (ESI): m/z [MþHþ]
CHCl3-d):
d
171.7, 158.6, 155.9, 146.9, 136.0, 128.4, 128.4, 128.1, 128.0,
calcd for C16H19N4O3 315.1457, found 315.1452.
128.0, 67.6, 67.1, 61.8, 47.3, 29.3, 24.4. HRMS (ESI): m/z [MþHþ]
calcd for C22H25N4O5 425.1825, found 425.1819.
4.2.6. N-1H-Imidazol-2-yl-L-prolinamide (1c). To a solution of 2c
(1.57 g, 5.0 mmol) in MeOH (20 mL) was added 10% Pd/C. The
mixture was stirred at room temperature for 14 h under an atmo-
sphere of hydrogen. The reaction was filtered through Celite and
the filtrate concentrated in vacuum. The crude product was purified
by flash column chromatography (MeOH/DCM¼1:4) to give the
4.2.2. (S)-N-Carbamimidoylpyrrolidine-2-carboxamide (1a). To a so-
lution of 2a (2.12 g, 5.0 mmol) in MeOH (20 mL) was added 10% Pd/
C. The mixture was stirred at room temperature for 14 h under an
atmosphere of hydrogen. The reaction was filtered through Celite

10234
G. Tang et al. / Tetrahedron 68 (2012) 10230e10235
product (0.74 g, 82% yield). ½a D20
ꢃ
ꢀ48.6 (c 0.53, MeOH). 1H NMR
was purified by flash column chromatography (Methanol/
(400 MHz, Methanol-d4):
d
6.72e6.68 (2H, d, J¼1.82 Hz), 3.60e3.50
DCM¼1:4) to give the deprotection product (1.14 g, 88% yield). ½a D20
ꢃ
(1H, m), 3.00e2.90 (2H, m), 2.18e2.08 (1H, m), 1.90e1.75 (1H, m),
ꢀ81.5 (c 1.10, MeOH). 1H NMR (400 MHz, Methanol-d4):
d 6.90e7.30
1.72e1.65 (2H, m). 13C NMR (400 MHz, Methanol-d4):
d
175.6, 142.8,
(1H, d, J¼7.76 Hz), 6.54e6.52 (1H, d, J¼2.37 Hz), 6.35 (1H, dd,
J¼2.39, 7.46 Hz), 3.50 (1H, m), 3.38 (3H, s), 2.60 (2H, m), 1.75 (1H,
m), 1.50 (1H, m), 1.35 (2H, m). 13C NMR (400 MHz, Methanol-d4):
118.9, 118.9, 61.7, 47.9, 31.8, 26.9. HRMS (ESI): m/z [MþHþ] calcd for
C8H13N4O 181. 1089, found 181.1084.
d
176.4, 157.7, 148.0, 115.3, 112.1, 108.8, 98.6, 62.0, 56.2, 47.9, 31.8,
4.2.7. (S)-Benzyl-2-(1H-benzo[d]imidazol-2-ylcarbamoyl)pyrroli-
26.9. HRMS (ESI): m/z [MþHþ] calcd for C13H17N4O2 261.1352,
dine-1-carboxylate (2d). To a solution of N-carbobenzyloxy-
L-pro-
found 261.1352.
line (2.49 g, 10.0 mmol, 1.0 equiv) and 2-amino-1H-benzimidazole
(1.46 g, 11.0 mmol, 1.1 equiv) in CH2Cl2 (30.0 mL) N,N0-dicyclohex-
ylcarbo-diimide (2.26 g, 11.0 mmol, 1.1 equiv) and 4-dimethylamino
pyridine (2.68 g, 22.0 mmol) were added at 0 ꢂC under N2 atmo-
sphere. The reaction mixture was stirred for 30 min at 0 ꢂC, then at
room temperature for 24 h. The reaction mixture was filtrated
through silica gel pad (SiO2 15 g) to remove dicyclohexylurea.
Further purification was done by flash column chromatography
(Methanol/DCM¼1:15) to give 2d as white solid product (3.31 g,
4.2.11. (S)-Benzyl-2-(5,6-dimethyl-1H-benzo[d] imidazol-2-
ylcarbamoyl)pyrrolidine-1-carboxylate (2f). 2-Amino-5,6-dimethyl-
1H-benzo[d]imidazole was obtained following the reported opera-
tion using 2-amino-5,6-dimethyl-1H-benzo[d]imidazole as starting
material.17 To a solution of Cbz-
L-proline (2.49 g, 10.0 mmol,
1.0 equiv) and 2-amino-5,6-dimethyl-1H-benzo[d]imidazole (1.77 g,
11.0 mmol, 1.1 equiv) in CH2Cl2 (30.0 mL) N,N0-dicyclohex-
ylcarbodiimide (2.26 g, 11.0 mmol, 1.1 equiv) and 4-dimethylamino
pyridine (1.34 g, 11 mmol, 1.1 equiv) were added at 0 ꢂC under N2
atmosphere. The reaction mixture was stirred for 30 min at 0 ꢂC,
then at room temperature for 24 h. The reaction mixture was fil-
trated through silica gel pad (SiO2 15 g) to remove dicyclohexylurea.
Further purification was done by flash column chromatography
(Methanol/DCM¼1:20).
91% yield). 1H NMR (600 MHz, CHCl3-d):
d 7.4 89 (2H, s), 7.41e7.35
(3H, m), 7.28e7.22 (3H, m), 6.99 (1H, s), 5.29e5.27 (1H, d,
J¼12.2 Hz), 5.17e5.06 (1H, m), 4.77e4.74 (2H, d, J¼17.6 Hz),
3.74e3.55 (2H, m), 2.18e2.12 (2H, m), 2.10e2.01 (1H, m), 1.90e1.89
(1H, m). 3C NMR (600 MHz, CHCl3-d):
d 173.9, 173.2, 155.4, 154.2,
147.5, 147.4, 136.3, 135.8, 128.4, 128.3, 128.0, 128.0, 127.8, 127.7,
122.4, 122.2, 67.3, 60.7, 60.2, 47.3, 46.9, 31.4, 29.8, 24.4,23.6. HRMS
(ESI): m/z [MþHþ] calcd for C20H21N4O3 365. 1614, found 365.1608.
1H NMR (600 MHz, CHCl3-d):
d 7.46e7.32 (3H, m), 7.28e7.24
(2H, m), 7.24e7.20 (1H, m), 7.06e7.00 (1H, m), 5.80e5.60 (1H, m),
5.20e5.00 (1H, m), 4.70e4.60 (1H, m), 3.90e3.75 (2H, m),
2.40e2.32 (6H, d, J¼12.2 Hz), 2.35e2.25 (2H, m), 2.20 (1H, m),
4.2.8. N-1H-Benzimidazol-2-yl- -prolinamide (1d). To a solution of
L
2d (1.82 g, 5.0 mmol) in MeOH (20 mL) was added 10% Pd/C. The
mixture was stirred at room temperature for 14 h under an atmo-
sphere of hydrogen. The reaction was filtered through Celite and
the filtrate concentrated in vacuum. The crude product was purified
by flash column chromatography (MeOH/DCM¼1: 4) to give the
1.95e1.80 (1H, m). 13C NMR (600 MHz, CHCl3-d):
d 173.3, 155.5, 146.
8, 146.7, 136.3, 136.0, 131.3, 131.2, 128.4, 128.3, 128.1, 128.0, 127.8,
127.7, 127.6, 127.4, 67.3, 67.2, 60.9, 60.5, 47.3, 46.9, 31.5, 29.9, 24.4,
23.7. HRMS (ESI): m/z [MþHþ] calcd for C22H25N4O3 393.1927,
found 393.1921.
product (1.04 g, 91% yield) as a white solid. ½a D20
ꢀ50.8 (c 0.46,
ꢃ
MeOH). 1H NMR (600 MHz, CHCl3-d):
d
7.55e7.35 (2H, m),
4.2.12. N-(5,6-Dimethyl-1H-benzimidazol-2-yl)-L-prolinamide(1f). To
7.25e7.20 (2H, m), 4.00e3.95 (1H, t, J¼4.5 Hz), 3.15e2.95 (2H, m),
a solution of 2f (1.96 g, 5.0 mmol) in MeOH (20 mL) was added 10%
Pd/C. The mixture was stirred at room temperature for 14 h under an
atmosphere of hydrogen. The reaction was filtered through Celite
and the filtrate concentrated in vacuum. The crude product was
purified by flash column chromatography (Methanol/DCM¼1:4).
2.33e2.22 (1H, m), 2.12e2.02 (1H, m), 1.82e1.74 (2H, m). 13C NMR
(600 MHz, CHCl3-d):
d 175.8, 146.2, 129.0, 128.5, 122.0, 114.5, 114.2,
60.4, 47.2, 30.8, 26.1. HRMS (ESI): m/z [MþHþ] calcd for C12H15N4O
231. 1246, found 231.1240.
The product (1.09 g, 84% yield) was obtained as a white solid. ½a D25
ꢃ
4.2.9. (S)-Benzyl-2-(6-methoxy-1H-benzo[d]imidazol-2-ylcarbamoyl)
pyrrolidine-1-carboxylate (2e). 2-Amino-5-methoxy-1H-benzimid-
azole was obtained from 4-methoxybenzene-1,2-diamine following
ꢀ68.0 (c 1.02, CHCl3).1H NMR (600 MHz, Methanol-d4):
d 7.24 (2H, s),
3.50e3.45 (1H, dd, J¼3.15, 7.25 Hz), 3.20 (1H, m), 2.80 (1H, m), 2.60
(1H, m), 2.30 (6H, s), 2.20 (1H, m), 2.00 (1H, m),1.70 (2H, m).13C NMR
the reported operation.17 To a solution of N-carbobenzyloxy-
L-pro-
(600 MHz, Methanol-d4): d 176.6, 147.9, 134.3, 132.2, 114.9, 62.1, 47.9,
line (2.49 g, 10.0 mmol, 1.0 equiv) and 2-amino-5-methoxy-1H-
benzo[d]imidazole (1.79 g, 11.0 mmol, 1.1 equiv) in CH2Cl2 (30.0 mL)
N,N0-dicyclo-hexylcarbodiimide (2.26 g, 11.0 mmol, 1.1 equiv) and 4-
dimethylamino pyridine (1.34 g, 11.0 mmol,1.1 equiv) were added at
31.7, 26.8, 20.2. HRMS (ESI): m/z [MþHþ] calcd for C14H19N4O 259.
1559, found 259.1553.
4.3. Typical procedure for the intermolecular aldol reaction
0
ꢂC under N2 atmosphere. The reaction mixture was stirred for
30 min at 0 ꢂC, then at room temperature for 24 h. The reaction
mixture was filtrated through silica gel pad (SiO2 15 g) to remove
dicyclohexylurea. Further purification was through flash column
chromatography (Methanol/DCM¼1:10). 1H NMR (400 MHz, CHCl3-
To a mixture of catalyst 1 (0.05 mmol) and TFA (3.7
mL
0.05 mmol) in water (0.25 mL) and EtOAc (0.25 mL), cyclohexanone
(0.1 mL, 1.0 mmol) and 4-nitrobenzaldehyde (151 mg, 1.0 mmol)
were added. After the reaction mixture had been stirred for 36 h,
water (5 mL) was added, followed by extraction with diethyl ether.
The organic phase was dried over Na2SO4 and concentrated in
vacuum. The crude product was purified by flash column chro-
matography (Hexane/EtOAc) to afford the aldol product 6a.
d):
d 7.50e7.30 (4H, m), 7.20e6.80 (4H, m), 5.15e5.05 (2H, m),
4.60e4.40 (1H, m), 3.84 (3H, d, J¼7.80 Hz), 3.72e3.48 (2H, m),
2.38e2.20 (1H, m), 2.10e1.75 (3H, m). 13C NMR (400 MHz, CHCl3-d):
d
179.3,156.6,154.5,146.6,136.7, 128.3,128.0,127.7, 127.4, 111.9, 66.5,
59.4, 55.7, 46.8, 30.8, 23.3. HRMS (ESI): m/z [MþHþ] calcd for
C21H23N4O4 395.1719, found 395.1714.
4.4. Procedure for the intramolecular aldol reaction
4.2.10. N-(5-Methoxy-1H-benzimidazol-2-yl)-
L
-prolinamide (1e). To
To a mixture of catalyst 1d (0.05 mmol) and TFA (3.7 mL
a solution of 2e (1.97 g, 5.0 mmol) in MeOH (20 mL) was added 10%
Pd/C. The mixture was stirred at room temperature for 14 h under
an atmosphere of hydrogen. The reaction was filtered through
Celite and the filtrate concentrated in vacuum. The crude product
0.05 mmol) in H2O (0.25 mL) EtOAc (0.25 mL), 2-methyl-2-(3-
oxobutyl)-cyclohexane-1,3-dione (0.19 g, 1.0 mmol) were added.
After the mixture had been stirred for 24 h, water (5 mL) was added
to the reaction mixture, followed by extraction with EtOAc. The

G. Tang et al. / Tetrahedron 68 (2012) 10230e10235
10235
8. (a) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126,
3418e3419; (b) Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027e5029; (c) Hatano,
M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara, K. J. Am. Chem. Soc. 2008, 130,
16858e16860; (d) Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 739e748; (e)
Saha, S.; Moorthy, J. N. Tetrahedron Lett. 2010, 51, 912e916; (f) Chandrasekhar,
S.; Kumar, T. P.; Haribabu, K.; Reddy, C. R.; Kumar, C. R. Tetrahedron: Asymmetry
2011, 22, 697e702; (g) Yu, C.; Qiu, J.; Zheng, F.; Zhong, W. Tetrahedron Lett. 2011,
52, 3298e3302.
organic phase was dried over Na2SO4 and concentrated in vacuum.
The crude product was purified by flash column chromatography
(Hexane/EtOAc) to afford product 8.
Supplementary data
9. For selected examples of MacMillan’s imidazolidinone as organocatalysts: (a)
Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370e4371; (b)
Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126,
4108e4109; (c) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 6722e6724; (d) Chen, Y. K.; Yoshida, M.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2006, 128, 9328e9329; (e) Beeson, T. D.; Mastracchio, A.;
Hong, J.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582e585; (f)
Simmons, B.; Walji, A.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48,
4349e4353; (g) Allen, A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133,
4260e4263.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.09.071.
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