Partie Expérimentale
General. 1H NMR and
(1H: 250 MHz,
13C:
13C
NMR were recorded on a Brüker AC-250 FT
62.9 MHz) and Brüker DPX-300 FT (1H: 300 MHz,
13C:
75.6 MHz) using deuteried solvent as internal reference unless otherwise
indicated. The chemical shifts () and coupling constants (J) are expressed
in ppm and Hz respectively. IR spectra were recorded on a Perkin-Elmer
Paragon 1000 FT-IR spectrophotometer. The absorbance is given in cm-1.
Mass spectra were recorded on a VG Autospec-Q by EI (70 eV); m/z (%).
High
resolution
mass
spectra
were
recorded
on
a
FTICR
mass
spectrometer Brüker 4.7T BioApex II. The GC analyses were performed
through apolar column SPB1 30m x 0.32 mm x 0.1 µm, and also through
a chiral beta Dex 120 (30 m x 0.25 mm x 0.25 µm).Elemental analysis
were performed by Service Central d’Analyse at Vernaison (CNRS-France).
Melting points were not corrected and determined by using a digital
apparatus. Merck silica gel 60 (70-230 mesh) were used for flash
chromatography. Solvents and reagents were dried and purified by
standard procedures as usually described in Purification of Laboratory
Chemicals, 3rd ed (Perrin, D. D. and Armarego, W. L. F., Pergamon
Press).
Benzyl-(4,5-dimethyl-2-nitro-phenyl)-amine :
NO2
In a 250 mL flask, equipped with a condenser, is
introduced the 4,5-dimethyl-nitroaniline (10 g, 60.2
NHCH2Ph
C15H16N2O2
Mol. Wt.: 256,30
mmoles), K2CO3 (12 g, 86.2 mmoles) and DMF (80 mL).
The reaction mixture is heated to 120°C, then benzyl
bromide (11.5 mL, 96.8 mmoles) is added drop by drop. The reaction is
watched by TLC (80 % EP- 20 % AcOEt). The crude mixture is diluted in
DCM (250 mL). The organic phase is washed 4 times with water, and then
dried over MgSO4 before solvent was removed under vacuum. The crude
product is purified through silica gel chromatography (220 g) eluted with :
(95 % EP- 5 % AcOEt). The product is obtained as a orange powder (30
%). - 1H RMN (250 MHz, CDCl3) : 7.95 (s, 1 H, CH-C-NO2), 7.44-7.27
(m, 5 H, CH (Ph)), 6.61 (s, 1 H, CH-C-NH), 4.52 (d, J=5.8 Hz, 2 H, CH2),
2.20 (s, 3 H, CH3), 2.17 (s, 3 H, CH3). -
13C
RMN (62.9 MHz, CDCl3) :
147.5, 144.0, 137.8, 130.2, 129.0, 127.7, 127.2, 126.6, 125.0, 114.6,
47.2 (CH2), 20.9 (CH3), 18.7 (CH3).
N-Benzyl-4,5-dimethylbenzene-1,2-diamine 9 :
In a 100 mL flask, equipped with a condenser, X is
NH2
introduced (1.8 g, 7 mmoles) with tin powder (4.6 g, 38.9
NHCH2Ph
mmoles) in HCL 35 %,(20 mL). The reaction turns at R.T.,
C15H18N2
Mol. Wt.: 226,32
and is followed by TLC (80 % EP- 20 % AcOEt). Reaction mixture is
basified with NaOH 10 %. DCM is added, then the mixture is filtred over
celite. Organic phase is extracted, then dried over MgSO4. Solvant is
removed under vaccum to furnish a beige powder (54 %). - 1H RMN (250
MHz, CDCl3) : 7.45-7.26 (m, 5 H, CH(Ph) ), 6.56 (s, 1 H, CHAr), 6.51 (s,
1 H, CHAr), 4.29 (s, 2 H, CH2), 3.26 (br, NH2), 2.16 (s, 3 H, CH3), 2.15 (s,
3 H, CH3) ;-
13C
RMN (62.9 MHz, CDCl3) : 139.7, 135.6, 131.9, 128.6,
127.8, 127.2, 126.4, 118.4, 114.6, 49.0 (CH2), 19.3 (CH3), 18.8 (CH3).
General procedure to condensate carboxylic acid on diamine :
The carboxylic acid (27 mmol) was reacted with 4.5-dimethyl-1.2phenylenediamine (3.1 g, 23 mmol) in a 4 M aqueous solution of HCl (40
mL) under reflux for 1-7 days. The solution was then basified (pH=12)
with a 4 M aqueous solution of NaOH (4M, 10% or sometimes with
Na2CO3), then filtrated to recover the precipitate. The crude product was
purified by flash column chromatography (CH2Cl2-MeOH 96/4) or only
washed with Et20. Then the powder is dried in a desiccator containing
P2O5.
(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl-( R )-methanol :
The powder is recristalized in chloroform (26 %). - 1H
H
N
Ph
(R)
N
OH
C16H16N2O
Mol. Wt.: 252,31
RMN (200 MHz, DMSO-d6) : 12.09 (br, 1H, NH),
7.48-7.23 (m, 7 H, CH), 6.44 (br, 1 H, OH), 5.85 (s, 1 H, CH(OH), 2.25
(s, 6 H, CH3); -13C RMN (62.9 MHz, DMSO-d6) :  155.9, 142.4, 128.0 ,
127.2 , 126.2, 118.4 , 111.3 , 69.8 (CH(OH)), 19.8 (CH3).
(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl-(S)-methanol :
Quantitative yield and the powder is beige. MP
H
N
Ph
(S)
N
OH
C16H16N2O
Mol. Wt.: 252,31
(EtOH)=153-156°C. -1H RMN (200 MHz, DMSO-d6) :
7.48-7.23 (m, 7 H, CH), 5.59 (br, 1 H, OH), 5.02 (s,
1 H, CH(OH), 2.26 (s, 6 H, CH3) ; -13C RMN (62.9
MHz, DMSO-d6) :  142.4, 140.1, 129.6, 128.0,
127.5, 127.2, 126.5, 126.3,
114.9, 72.3 (CH(OH)), 19.8 (CH3). MS EI
m/z (%) 252 (65), 234 (45), 219 (15), 147 (25), 107 (100), 79 (68), 77
(55), 51 (17). C16H16N2O + 2 H2O (260.31) calc. C 66.7, H 6.94, N 9.7 ;
found C 65.95, H 5.99, N 9.56.
1-(5,6-dimethyl-1H-benzoimidazol-2-yl) -(S)-ethanol:
Quantitative yield
H
N
-1H RMN (250 MHz, CDCl3) : 7.23 (s, 2 H, CH), 4.87
(S)
N
OH
C11H14N2O
Mol. Wt.: 190,24
(q, J=6.7 Hz, 1 H, CH(OH)), 2.26 (s, 6 H, CH3), 1.46
(d, J=6.7 Hz, 3 H, CH3); -13C RMN (62.9 MHz,
CDCl3) : 157.6, 136.8, 129.5, 114.8, 63.5 (CH(OH)), 22.8 (CH 3(CH)),
19.8 (CH3).
General procedure for benzylation reaction:
First, sodium hydroxide 60% (900 mg, 22.5 mmoles) is washed by
pentane, which is removed after. Then, dried THF (100 mL) is added and
the medium is cooled to 0°C. The Benzimidazole (19.8 mmoles) is added
by small portion, watching H2 liberation. The reaction mixture is heated to
30°C, and then benzyl bromide (2.6 mL, 21.8 mmoles) is added drop by
drop. The reaction is followed by TLC. The reation mixture is diluted with
DCM (100 mL), and then the organic phase is extracted 5 times with
water (5 x 25 mL). Organic phase is dried over MgSO4, and then solvents
are removed by vaccum. The crude product is recristalized in ethanol.
(1-benzyl-5,6-dimethyl-1H-benzoimidazol-2-yl)-(S)-phenylmethanol :
pathway A : X with (S) mandelic acid. Yellow powder
Ph
Ph
N
pathway B : Benzylation reaction of Y. After a
(S)
N
(20 %).
OH
C23H22N2O
Mol. Wt.: 342,43
filtration and a pentane washing, is obtained a white
powder (40 %). MP (EtOH)= 195-198°C. - 1H RMN
(250 MHz, CDCl3) : 7.64-7.15 (m, 12 H), 6.53 (s, 1 H, CH-OH), 5.45
(dd, J= 16.47 Hz, 2 H, CH2), 2.71 (s, 3 H, CH3), 2.67 (s, 3 H, CH3) ; -
13C
RMN (62.9 MHz, CDCl3) : 154,8, 140.1, 139,9, 135.7, 134.4, 132.1,
131.1, 128.5, 127.9, 127.4, 126.7, 126.2, 119.5, 110.3, 70.1 (CH(OH)),
47.3 (CH2), 20.5 (CH3), 20.2 CH3. MS EI m/z (%) 343 (18), 342 (72),
341 (11), 252 (16), 251 (84), 233 (18), 175 (41), 105 (23), 91 (100), 77
(27), 65 (15). C23H22N2O + 0.5 x H2O (351.43) calc.: C 78.5, H 6.5, N 8;
found C 78.22, H 6.21, N 8.09.
1-(1-Benzyl-5,6-dimethyl-1H-benzoimidazol-2-yl) -(S)-ethanol:
Yield 38 %.-1H RMN (250 MHz, CDCl3) :  7.34
Ph
(s, 1 H, CH(Ar)), 7.33-7.13 (m, 3 H, CH(Ph)),
N
(S)
N
OH
C18H20N2O
Mol. Wt.: 280,36
7.00-6.98 (m, 2 H, CH(Ph)), 6.90 (s, 1 H,
CH(Ar)), 5.30 (s, 2 H, CH2), 4.11 (q, J= 6.7 Hz, 1
H, CH(CH3)), 2.39 (s, 3 H, CH3), 2.37 (s, 3 H, CH3), 1.6 (d, J=6.7Hz, 3 H,
CH3); -13C RMN (62.9 MHz, CDCl3) :  155.8, 140.3, 134.3, 132.2, 131.2,
128.9, 127.7, 126 CH, 119.7, 110.1, 63.5 (CH(CH3)), 46.9 (CH2), 22.6
(CH3), 20.6 (CH3), 20,3 (CH3).
1-Benzyl-2-(1-(S)-benzyloxy-ethyl)-5,6Ph
dimethyl-1H-benzoimidazole:
N
(S)
N
OCH2Ph
C25H26N2O
Mol. Wt.: 370,49
Yield 34 %.-1H RMN (250 MHz, CDCl3) :  7.57 (s, 1 H, CH), 7.3-7.16
(m, 8 H, CH(Ph)), 6.98-6.96 (m, 3 H, CH), 5.52 (dd, J=16.7 Hz, 2 H,
CH2(N)), 5.01 (q, J=6.7 Hz, 1 H, CH), 4.42 (dd, J=11.5 Hz, 2 H, CH2(O)),
2.37 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 1.63 (d, J=6.7 Hz, 3 H, CH3); -13C
RMN (62.9 MHz, CDCl3) : 153.3, 140.8, 137.7, 136.6, 136.5, 131.3,
128.8, 128.4, 127.8, 127.7, 127.5, 126, 121.4, 120, 11.9, 110.3, 71.8,
70.5 (CH2(OH)), 47,1 (CH2(N)), 25.9 (CH3), 20.5 (CH3), 19.7 (CH3).
General procedure for a bromination reaction:
X (4.28 mmoles) is dissolved in anhydrous DMF (10 mL). NBS is also
dissolved (897 mg, 5 mmoles) in anhydrous DMF (4 mL), and then is
added drop by drop. The reaction is followed by TLC (80 % PE – 20 %
AcOEt). The reaction mixture is diluted in DCM (150 mL), washed 4 times
with water (4 x 50 mL). The organic phase is dried over MgSO4, and then
solvents were removed under vacuum. The crude product is purified
through a silica gel chromatography (60 g) eluted with (90 % EP – 10 %
AcOEt).
(1-benzyl-4-bromo-5,6-dimethyl-1H-benzoimidazol-2-yl)-(S)phenyl-methanol:
Yield 38 %. - 1H RMN (250 MHz, CDCl3) : 7.48-7.04
Ph
Ph
N
(S)
N
Br
OH
C23H21BrN2O
Mol. Wt.: 421,33
(m, 10 H, CH(Ar)), 6.70-6.68 (m, 1 H, CH(Ar)), 6.25
(s, 1 H, CH-OH), 5.15 (dd, J=16.775 Hz, 2 H, CH2),
2.45 (s, 3 H, CH3), 2.29 (s, 3 H, CH3) ; -
13C
RMN
(62.9 MHz, CDCl3) : 155.1, 139.5, 135.4, 135.3, 130.5, 128.6, 127.9,
127.5, 126.5, 126.2, 115.0, 109.9, 70.2 ( CH-OH), 47.8 (CH2), 23.1
(CH3), 19.0 (CH3) ; MS EI : 422 (20 ), 420 (20), 331 (28), 329 (28), 255
(15), 253 (16), 105 (23), 91 (100), 77 (23), 65 (13).
Acetic acid (1-benzyl-4-bromo-5,6-dimethyl-1H-benzoimidazol-2yl)-(S)-phenyl-methyl ester:
Corrected yield 58 %. - 1H RMN (250 MHz, CDCl3) :
Ph
7.29-7.22 (m, 9.5 H, CHAr), 6.90-6.86 (m, 1.5 H,
Ph
N
(S)
N
Br
OAc
C25H23BrN2O2
Mol. Wt.: 463,37
CHAr), 5.26 (dd, J= 16.7 Hz, 2 H, CH2), 2.51 (s, 3 H,
CH3), 2.36 (s, 3 H, CH3), 1.85 (s, 3 H, CH3CO). – 13C
RMN (62.9 MHz, CDCl3) : 169.5, 151.2, 135.4,
133.8, 130.8, 128.8, 128.7, 128.5, 127.6, 126.7, 125.6, 109.6, 71.0
(CH(OH)), 47.6 (CH2), 22.1 (CH3), 20.4 (CH3), 19.1 (CH3(CO)); MS FAB
(Na): m/z (%) 488 (15), 487 (52), 486 (17), 485 (52), 466 (26), 465
(96), 464 (48), 463 (100), 462 (24), 421 (26), 419 (26), 406 (18), 405
(59), 404 (23), 403 (60), 329 (29), 313 (16), 307 (22).
1-(1-benzyl-4-bromo-5,6-dimethyl-1H-benzoimidazol-2-yl)-(S)ethanol:
Yellow powder, yield 45 %.- 1H RMN (250 MHz,
Ph
CDCl3) : 7.27-7.23 (m, 3 H, CH), 6.98-6.95 (m,
N
OH
2 H, CH), 6.80 (s, 1 H, CH), 5.45 (dd, J= 16.7Hz,
C18H19BrN2O
Mol. Wt.: 359,26
2 H, CH2), 5.16 (m, 1 H, CHCH3), 2.46 (s, 3H,
(S)
N
Br
CH3), 2.34 (s, 3 H, CH3), 1.68 (d, J= 6.7 Hz, 3 H, CH3) ; - 13C RMN (62.9
MHz, CDCl3) : 156.5, 136.1, 134.1, 133.3, 130.6, 120.1, 127.9, 126.1,
115.4, 109.8, 64.5 (CH(CH3)), 45.5, (CH2), 22.7, (CH3), 22.2 (CH3), 19.2
(CH3(CH)).
1-Benzyl-2-(1-(S)-benzyloxy-ethyl)-4-bromo-5,6-dimethyl-1Hbenzoimidazole:
Pale yellow powder, yield 44 %.-
Ph
(S)
Br
RMN (250
MHz, CDCl3) : 7.65-7.53 (m, 8 H, CH), 7.36-7.32
N
N
1H
OCH2Ph
C25H25BrN2O
Mol. Wt.: 449,38
(m, 2 H, CH), 7.25 (s, 1 H, CH), 5.96 (dd, J=16.7
Hz, 2 H, CH2(N)), 5.53 (q, J=7 Hz, 1 H, CH(CH3),
4.82 (dd, J=11.6 Hz, 2 H, CH2(O)), 2.85 (s, 3 H, CH3), 2.73 (s, 3 H, CH3),
1.97 (d, J=7 Hz, 3 H, CH3) ; -
13C
RMN (62.9 MHz, CDCl3) : 153.9,
140.1, 137.6, 136.3, 134.5, 133.4, 130.4, 128.9, 128.4, 127.9, 127.8,
127.6, 125.9, 115.5, 109.9, 75.3 (CH(CH3)), 71.4 (CH2(O)), 47.5
(CH2(N)), 22.1 (CH3), 20.3 (CH3), 19.1 (CH3(CH)).
Acetic acid (1-benzyl-5,6-dimethyl-1H-benzoimidazol-2-yl)-(S)phenyl-methylester:
In a 50 mL flask, YY (1.6 g, 4.6 mmoles), DMAP (cat.)
Ph
N
Ph
and triethylamine (325 µL, 2.3 mmoles) are mixed in
OAc
freshly distilled DCM (20 mL). Acetic anhydride (216
(S)
N
C25H24N2O2
Mol. Wt.: 384,47
µL, 2.3 mmoles) is added drop by drop. The reaction is
followed by TLC (80 % EP – 20 % AcOEt). For a completion reaction, one
more equivalent of acetic anhydride could be added. Water and NaHCO3
are added to the reaction mixture, which is extracted with DCM. The
organic phase is dried over MgSO4, and then the solvent is removed
undere vacuum. X is obtained as a white powder (93 %) - 1H RMN (250
MHz, CDCl3) : 7.30-7.23 (m, 7.3 H, CH(Ar)), 7.08 (s, 1 H, CH(OH), 69.769.2 (m, 2.7 H, CH(Ar)), 5.70 (dd, J=17.07 Hz, 2 H, CH2), 2.36 (s, 3 H,
CH3), 2.31 (s, 3 H, CH3), 1.92 (s, 3 H, CH3 (Ac)).
General procedure for the Suzuki - Mukyama cross coupling:
Bromo derivatives, Cs2CO3, [Pd(PPh3)2Cl2] and the corresponding boronic
acid were heated in toluene (8 mL) and water (2 mL) at 85°C under an
inert atmosphere. DCM was added, and the organic phase was washed
seven times with water and then dried over Mg(SO4)2. After a column
chromatography through silica gel (DCM 99.5 % - 5 % MeOH) a solid was
precipated in ethanol, and the compound was isolated as powder in 60%
yield.
1-(1-Benzyl-5,6-dimethyl-4-phenyl-1H-benzoimidazol-2-yl)-(S)ethanol:
In a 25 mL flask equipped with a condenser, X (200
Ph
mg, 556 µmoles), PdCl2(PPh3)2 (80 mg, 5 mol%),
N
N
OH
C24H24N2O
Mol. Wt.: 356,46
Cs2CO3 (540 mg, 1.6 mmoles) and phenylboronic acid
(75 mg, 615 µmoles) are mixed. DMF (10 mL) is
added, and then N2 is
Ensuite on fait buller de l'azote quelques
minutes dans le milieu réactionnel, avant de chauffer à 95°C. The
reaction
mixture
is
pale
yellow,
and
then
becomes
black
with
palladium(0). The reaction is followed by TLC (99 % DCM - 1 % MeOH).
The crude reaction is diluted with DCM (100 mL), washed several times
with water. The organic phase is dried over MgSO4, and then the solvant
is removed under vacuum. The crude product is purified through a silica
gel chromatography (10 g) eluted with ( 99.5 % DCM - 0.5 % MeOH) to
furnish a pale yellow oil (30 %). - 1H RMN (250 MHz, CDCl3) : 7.45-7.27
(m,
8
H,
CH),
7.08
-7.05
(m,
2
H,
CH),
7.00
(s,
1
H,
CH(benzoimidazole)), 5.41 (m, 2 H, CH2), 4.96 (q, J=6.4 Hz, CH(CH3)),
2.38 (s, 3 H, CH3), 2.19 (s, 3 H, CH3), 1.46 (d, J=6.4 Hz, 3 H, CH3(CH)).
Ethyl-2-methyl-2-phenylcyclopropane-1-carboxylate:
2
Ph
1
3
First : Complex preparation. In a Schlenk flask, under argon,
CO2Et
(CuOTf)2C6H6 (7.5 mg, 15 µmoles) is introduced with the
ligand
in
DCM
solution
(1
mL).
Next
degassed
by
frozen/unfrozen cycle under vacuum, reaction mixture is stirred 1h (the
solution is pale green). The alpha-methylstyrene (1 mmole) is added. One
frozen/unfrozen cycle is accomplished. The EDA (136 µL, 1.3 mmoles) is
diluted in DCM (1 mL), and then added over 6h with a styringe pump. An
nitrogen emission is observed by a bulleur. The reaction is monitored by
TLC (95 % EP – 5 % AcOEt), and also with GC (from 70°C to 280°C with a
rampe of 8°C.min-1). EDA could be added to completion reaction. The
solvant is removed and the crude product is purified through a silica gel
chromatography (8g) (99 % EP – 1 % AcOEt). -IR (CDCl3)  cm-1 : 3100,
2253, 1719, 1466, 1383, 1297, 1185, 1085, 907, 734. 1H NMR (200 MHz,
CDCl3) : isomer trans  7.1-7.4 (m, 5 H, Ph), 4.25 (m, 2 H, CH2CH3), 2.00
(m, 1 H, H-C1), 1.58 (s, 3 H, CCH3), 1.45 (m, 1 H, H-C3), 1.31 (t, J= 7 Hz,
3 H, CH2CH3) ; 1H NMR (200 MHz, CDCl3) isomer cis :  7.1-7.4 (m, 5 H,
Ph), 3.85 (m, 2 H, CH2CH3), 1.92 (m, 1 H, H-C1), 1.79 (m, 1 H, H-C3),
1.49 (s, 3 H, CCH3), 1.15 (m, 1 H, H-C3), 0.95 (m, 3 H, CH2CH3) ; Chiral
GC (isotherm at 125°C) diastereoisomer cis : 56.910 / 59.079 min et
diastereoisome trans : 70.687 / 71.913 min.
5,6-Dimethyl-2-pyrrolidin-2-yl-1H-benzoimidazole (BIP) :
L-proline (3.4 g, 27 mmol) was reacted with 4.5-
N
N
H
N
H
dimethyl-1.2-phenylenediamine (3.1 g, 23 mmol) in a
4 M aqueous solution of HCl (40 mL) under reflux for 4
days. The solution was then neutralized with a 4 M aqueous solution of
NaOH, then extracted with CH2Cl2. The crude product was purified by flash
column chromatography (DCM 96 % - 4 % MeOH) to afford 1 as a brown
powder (1.9 g, 70% corrected yield). 1 can be precipitated in cold water,
filtrated and washed with diethyl ether to give a beige powder which was
used as such in the aldol reaction. 1 was recrystallized from MeOH/H2O.
mp 94°C (for the beige powder); IR (KBr): = cm-1 3280 (NH), 2970,
2871, 2282, 1634, 1444, 1310, 825.
1H
NMR (250 MHz, DMSO-d6): 
7.30 (2H ,s), 4.46-4.41 (1H, m), 3.06-2.98 (2H, m), 2.34 (6H, s), 2.222.13 (1H, m), 2.02-1.98 (1H, m), 1.85-1.77 (2H, m).13C NMR (75.55 MHz,
DMSO-d6):  155.2, 136.9, 131.2, 115.1, 56.3, 46.5, 32.2, 25.5, 20.2.
MS (EI) 215 (75, M+), 216 (20), 187 (55), 186 (37), 173 (100), 172 (95),
160 (75), 147 (30), 145 (20). Anal. Calcd for C13H17N3+1.5H2O: C 64.46,
H 8.26, N 17.35. Found: C 64.50, H 7.85, N 17.25.
2-(1-Isopropyl-pyrrolidin-2-yl)-5,6-dimethyl-1H-benzoimidazole
BIP-iPr: 1 (50 mg, 0.23 mmol) and TFA (18 µL, 0.23
N
N
H
N
mmol) were stirred in acetone for 10 min, then
NaBH3CN (30 mg, 0.5 mmol) was added by portion.
After 24h at RT, the resulting solution was treated with water and Na2CO3.
The reaction mixture was extracted with diethyl acetate and the resulting
organic layer dry over MgSO4. The solvent was evaporated in vacuo to
afford 6 as a white powder (39 mg, 65 %). mp 160-178°C; IR (KBr): =
cm-1 2966, 1635, 1417, 1309. 1H NMR (300 MHz, CDCl3): 7.25 (2H, s),
4.11-4.08 (1H, m), 3.15-3.05 (1H, m), 2.85-2.75 (1H, m), 2.60-2.40 (1H,
m), 2.28 (6H, s), 2.25-2.15 (1H, m).
13C
NMR (75.55 MHz, DMSO-d6):
159.2, 131.3, 115.4, 59.7, 53, 50.3, 33.8, 24.7, 22.2, 20.7,19.4. MS
(FAB+) 280 ([M+Na]+), 258 (100, [M+H]+), 257 (26), 256 (80), 214
(65), 212 (22). HRMS for C16H24N3 ([M+H]+): 258.196543, Found:
258.197023.
(3S,5R)-5-(5,6-dimethyl-1H-benzoimidazol-2-yl)pyrrolidin-3-ol :
OH
N H
N
H
Yield 55 %; IR (KBr): = cm-1. 1H NMR (300 MHz,
MeOD):  7.29 (2H ,s), 4.67-4.39 (2H, m), 3.32-
N
H
2.94 (2H, m), 2.59-1.97 (8H, m CH2 + s CH3).
13C
NMR (74.57 MHz, MeOD):  158.5, 138.3, 132.2, 115.9 CH, 115.8 CH,
73.4 CH, 56.1 CH2, 56.0 CH, 42.6 CH2, 20.4 (2xCH3). MS (EI) 232 (100,
[M+H]+), 147 (56). HRMS for C13H18N3O ([M+H]+): 232,144987. Found:
232,144558. C 67.51, H 7.41, N 18.17, O 6.92.
(2R,3R)-2-(5,6-dimethyl-1H-benzoimidazol-2-yl)pyrrolidin-3-ol :
Yield XX %; IR (KBr): = cm-1. 1H NMR (300 MHz,
HO
N H
N
H
MeOD):  7.
N
H
MS
(EI)
13C
(100,
NMR (74.57 MHz, MeOD):  158.5,.
[M+H]+),.
HRMS
for
CyHxN3O
([M+H]+):. Found:.
(S)-4-(5,6-dimethyl-1H-benzoimidazol-2-yl)thiazolodine :
N H
N
H
S
N
H
Yield XX %; IR (KBr): = cm-1.
1H
NMR (250 MHz,
MeOD):  7.38 (1H ,s), 7.25 (1H, s), 5.11 (2H, d,
J=0.6 Hz), 4.38 (1H, dd, J=4,6 Hz, J=7.3 Hz), 3.32
(1H, m), 3.00 (1H, m), 2.38 (3H, s, CH3), 2.35 (3H, s, CH3).
13C
NMR
(74.57 MHz, MeOD):  154.3, 140.5, 133.9, 133.5, 133.1, 119.6 CH,
111.0 CH, 49.1 CH, 44.4 CH2, 33.3 CH2, 20.5 CH3, 20.3 CH3. MS (EI) 233
(25), 187 (100), 186 (65), 160 (50), 159 (55). Anal. Calcd for C12H15N3S:
C 61.77, H 6.48, N 18.01, S 13.74. Found:.
(S)-5,6-dimethyl-2-(1-methylpyrrolidin-2-yl)-1Hbenzoimidazole :
Reference6. Quantitative yield; IR (KBr): = cm-1.
N H
N
H
(3H, m).
1H
NMR (300 MHz, CDCl3):  7.31 (2H ,s), 3.68-3.63 (1H,
N
m), 3.22-3.15 (1H, m), 2.41-2.25 (11H, m), 1.92-1.87
13C
NMR (62.9 MHz, CDCl3):  156.6, 131.5 CH, 65.1 CH, 57.2
CH2, 41.6 CH3, 33.3 CH2, 23.9 CH2, 20.7 CH3. MS (EI) 229 (27), 173
(100), 172 (22), 160 (20), 42 (20). Anal. Calcd for C14H19N3: C 73.33, H
8.35,
N
18.32.
Found:.
HRMS
for
C14H19N3:
229.157898,
Found:
229.157974.
1-Methyl-2-(S)-pyrrolidin-2-yl-1H-benzoimidazole :
Yield 58 %; IR (KBr): = cm-1. 1H NMR (300 MHz, DMSO-
N H
N
d6):  7.57 (2H, d, J=7.2 Hz), 7.49 (2H, d, J=7.2 Hz),
N
H
7.24-713 (2H, m), 4.47 (1H, t, J=7.2 Hz), 3.80 (3H, s,
CH3), 3.01-2.82 (2H, m, CH2), 2.18-2.10 (2H, m, CH2), 1.90-1.72 (2H, m,
CH2).
13C
NMR (74.57 MHz, DMSO-d6):  156.2, 141.5, 136.3, 121.7 CH,
121.2 CH, 118.6 CH, 109.7 CH, 54.3 CH, 46.6 CH2, 30.1 CH2, 29.7 CH2,
25.8 CH2. MS (EI). Anal. Calcd for C12H15N3: C 71.61, H 7.51, N 28.88.
Found:.
(S)-1-benzyl-2-(1-benzylpyrrolidin-2-yl)-5,6-dimethyl-1Hbenzoimidazole :
Yield 85 %; IR (KBr): = cm-1. 1H NMR (300 MHz,
N H
N
N
DCM-d2):  7.44 (1H, s), 7.25-715 (8H, m), 6.986.97 (2H, m), 6.87 (1H, s), 5.95 (1H, d, J=17 Hz),
5.44 (1H, d, J=17 Hz), 4.05-3.93 (1H, m), 3.82 (1H,
d, J=13 Hz), 3.19 (1H, d, J=13 Hz), 3.05-2.95 (2H,
m), 2.30 (3H, s), 2.24 (3H, s), 2.15-2.07 (2H, m), 1.80-1.62 (3H, m).
13C
NMR (74.57 MHz, DCM-d2):  154.1, 141.6, 139.4, 135.5, 132.0, 131.0,
129.1 CH, 128.7, 128.4 CH, 127.6 CH, 127.1 CH, 126.3 CH, 119.8, 110,6
CH, 64.3 CH, 58.9 CH2, 53.5 CH2, 47.5 CH2, 30.6 CH2, 23.1 CH2, 20.6
CH3, 20.3 CH3. MS (EI). Anal. Calcd for C27H29N3: C 81.99, H 7.39, N
10.62. Found:.
General Procedure for aldol reaction. (Table 1, entry 11): BIP 1
(4.9 mg, 23 µmol) and TFA (1.8 µL, 23 µmol) were stirred with acetone (2
mL, 32.7 mmol) for 5 min, then p-nitrobenzaldehyde (177.6 mg, 1.17
mmol) was added. The reaction progress was monitored using TLC
(Hexanes–EtOAc 7/3). The crude reaction mixture was then purified by
flash column chromatography on silica gel to give the aldol adduct 4
(Hexanes–EtOAc 7/3). Enantiomeric excesses were determined through
1H-NMR
spectroscopy of the corresponding Mosher’s ester (vide infra) or
using chiral HPLC.
4-Hydroxy-4-(4-nitro-phenyl)-butan-2-one:
OH O
Known Compound1. 1H NMR (300 MHz, CD2Cl2):  8.18
(2H, d, J=9 Hz), 7.54 (2H, d, J=8.85 Hz), 5.28-5.22
(1H, m), 3.58 (1H, b), 2.87-2.82 (2H, m), 2.19 (3H,
O2N
s).
13C
NMR (75.47 MHz, CDCl3):  208.8, 150.8, 147.7, 129.4 CH, 124.0
CH, 69.3 CH, 51.8 CH2, 30.8 CH3. MS (FAB): 232 (100, [M+Na]+), 212
(40), 210 (35, [M+H]+). HRMS for C10H11NO4Na ([M+Na]+) Calcd:
232,058578. Found: 232,053874. Anal. Calcd for C10H11NO4: C 57.41, H
5.30, N 6.70, O 30.59.
3,4-dihydroxyl-4-(4-nitrophenyl)-butane-2-one :
OH O
Reference?. IR (KBr): = cm-1. anti isomer
1H
NMR
(250 MHz, CDCl3):  8.25 (2H, d, J=8.8 Hz, 2xCH),
O2N
OH
7.61 (2H, d, J=8.3 Hz, 2xCH), 5.10 (1H, d, J=4.6 Hz,
CH), 4.48 (1H, d, J=4.6 Hz, CH), 2.03 (3H, s, CH3).
13C
NMR (75.47 MHz,
CDCl3):  207.3, 146.5, 127.3 CH, 123.7 CH, 80.6 CH, 74.4 CH, 27.5 CH3.
syn isomer 1H NMR (250 MHz, CDCl3):  8.25 (2H, d, J=8.8 Hz, 2xCH),
7.61 (2H, d, J=8.3 Hz, 2xCH), 5.22 (1H, d, J=2.2 Hz, CH), 4.42 (1H, d,
J=2.4 Hz, CH), 2.37 (3H, s, CH3).
13C
NMR (75.47 MHz, CDCl3):  206.8,
147.4, 127.1 CH, 123.7 CH, 79.9 CH, 72.9 CH, 25.9 CH3. MS (EI). Anal.
Calcd for C10H11NO5: C 53.33, H 4.92, N 6.22, O 35.52. Found: C, H, O.

1-Hydroxy-2-methyl-1-(4-nitrophenyl)-pentane-3-one :
Known compound5. IR (KBr): = cm-1. anti isomer 1H
OH O
NMR (300 MHz, CDCl3):  8.22 (2H, d, J=8.8 Hz,
2xCH), 7.51 (2H, d, J=8.5 Hz, 2xCH), 4.88 (1H, d,
O2N
J=7.5 Hz, CH), 2.95-2.91 (1H, m, CH), 2.55-2.51 (1H, m, CH2), 2.49-2.43
(1H, m, CH2), 1.05-0.95 (6H, m, 2xCH3).
13C
NMR (75.47 MHz, CDCl3): 
215.6, 149.6, 127.4 CH, 123.7 CH, 75.6 CH(OH), 52.2 CH(CH3), 36.4 CH2,
14.5 CH3(CH2), 7.5 CH3(CH). syn isomer 1H NMR (300 MHz, CDCl3): 
8.22 (2H, d, J=8.8 Hz, 2xCH), 7.51 (2H, d, J=8.5 Hz, 2xCH), 5.23 (1H, d,
J=3 Hz, CH), 2.85-2.75 (1H, m, CH), 2.55-2.51 (1H, m, CH2), 2.49-2.43
(1H, m, CH2), 1.05-0.95 (6H, m, 2xCH3).
13C
NMR (75.47 MHz, CDCl3): 
215.6, 146.6, 126.8 CH, 123.5 CH, 71.9 CH(OH), 51.4 CH(CH3), 35.1 CH2,
9.9 CH3(CH2), 7.4 CH3(CH). MS (FAB): 260 (100, [M+Na]+), 238 (20,
[M+H]+),
212
(21).
HRMS
Cacld
for
C12H15NO4Na
([M+Na]+):
260,089878. Found: 260,090584. Anal. Calcd for C12H15NO4: C 60.75, H
6.37, N 5.9, O 26.97. Found: C, H, O.

2-[Hydroxy-(4-nitrophenyl)-methyl]cyclohexanone :
OH O
Known compound5. IR (KBr): = cm-1. anti isomer 1H
NMR (250 MHz, CDCl3):  8.19 (2H, d, J=10.3 Hz,
2xCH), 7.50 (2H, d, J=10.2 Hz, 2xCH), 4.88 (1H, dd,
O2N
J=6.2 Hz, J=3.7 Hz, CH), 4.09 (1H, d, J=4 Hz, CH), 2.64-2.28 (3H, m),
2.14-2.06 (1H, m), 1.83-1.30 (5H, m).
13C
NMR (75.47 MHz, CDCl3): 
214.7, 148.4, 127.9 CH, 123.6 CH, 74.0 CH(OH), 57.2 CH, 42.7 CH2, 30.7
CH2, 27.6 CH2, 24.7 CH2. syn isomer 1H NMR (250 MHz, CDCl3):  8.21
(2H, d, J=7.5 Hz, 2xCH), 7.49 (2H, d, J=7.5 Hz, 2xCH), 5.49 (1H, s, CH),
3.20 (1H, d, J=3 Hz, CH), 2.67-2.53 (3H, m), 2.16-2.07 (1H, m), 1.891.45 (5H, m).
13C
NMR (75.47 MHz, CDCl3):  213.9, 147.6, 126.6 CH,
123.4 CH, 70.1 CH(OH), 56.8 CH, 42.6 CH2, 27.8 CH2, 25.9 CH2, 24.8
CH2. MS (FAB): 272 (100, [M+Na]+), 232 (30), 212 (49). HRMS Cacld for
C13H15NO4Na ([M+Na]+): 272,089878. Found: 272,090203. Anal. Calcd
for C13H15NO4: C 62.64, H 6.07, N 5.62, O 25.67. Found: C, H, O.

2-[Hydroxy-(4-nitrophenyl)-methyl]cyclopentanone :
OH O
Known compound5. The anti/syn ratio was determined
by 1H NMR analysis. The enantioselectivites of the anti
and syn isomers were measured by chiral HPLC
O2N
analysis. Analytical data: (column OD, Hexane 9 – 1 iPrOH) retention
times tR = 19.4 (syn, minor), 24.1 (syn, major), 26.1 (anti, major), 27.9
(anti, minor). IR (KBr): = cm-1. anti isomer 1H NMR (300 MHz, DCM-d2):
 8.18 (2H, d, J=10.6 Hz, 2xCH), 7.53 (2H, d, J=10.2 Hz, 2xCH), 4.82
(1H, d, J=9.0 Hz, CH), 4.67 (1H, s, CH), 2.30-1.50 (7H, m).
13C
NMR
(75.47 MHz, CDCl3):  240.1, 150.8, 148.0, 126.8 CH, 123.9 CH, 74.8
CH(OH), 55.4 CH, 39.0 CH2, 27.2 CH2, 20.7 CH2. syn isomer 1H NMR (300
MHz, CDCl3):  8.18 (2H, d, J=7.2 Hz, 2xCH), 7.53 (2H, d, J=7.5 Hz,
2xCH), 5.38 (1H, m, CH), 2.59 (1H, d, J=4.9 Hz, CH), 230-1.50 (7H, m).
13C
NMR (75.47 MHz, CDCl3):  220.1, 149.4, 127.8 CH, 123.4 CH, 70.9
CH(OH), 56.3 CH, 39.2 CH2, 22.8 CH2, 20.7 CH2. MS (FAB): 258 (100,
[M+Na]+), 218 (37), 212 (42). HRMS Cacld for C12H13NO4Na ([M+Na]+):
258,074228. Found: 258,074435. Anal. Calcd for C12H13NO4: C 61.20, H
5.57, N 5.95, O 27.21. Found: C, H, O.
2-methyl-2-(3-oxobutyl)cyclohexane-1,3-dione :
Reference4. In a 25 mL flask, the 2-methylcyclohexane-1,3-
O
dione (252 mg, 2 mmoles) is suspended in CH3CN (3 mL),
O
O
and then triethylamine (1 mL) is added. Finally methylvinyl
ketone (200 µL, 2.4 mmoles) is added. The reaction is monitored by TLC
(Hexane 1 – 1 AcOEt). The solvents are removed under vacuum, and a
purification through a silica gel chromatography furnish an oil (396 mg,
100%); IR (KBr): = cm-1. 1H NMR (300 MHz, CDCl3):  2.79-2.59 (4H,
m, 2x CH2), 2.36 (2H, t, J=7 Hz), 2.13 (3H, s), 2.09-2.01 (2H, m, CH2),
1.99-1.85 (2H, m, CH2), 1.26 (3H, s, CH3).
13C
NMR (75.47 MHz, CDCl3):
 210.0, 207.5, 64.3, 38.4 CH2, 37.8 CH2, 29.9 CH3, 29.6 CH2, 20.0 CH3,
17.6 CH2. MS (FAB+): 197 (100, [M+H]+). HRMS Cacld for C11H17O3
([M+H]+): 197,117770. Found: 197,118217. Anal. Calcd for C11H16O3: C
67.32, H 8.22, O 24.46. Found: C, H, O.
8-methyl-3,4,8,8-tetrahydronaphthalene-1,6(2H,7H)-dione :
O
Known Compound3. Synthesis; IR (KBr): = cm-1. 1H NMR
(250 MHz, CDCl3):  5.85 (1H ,s), 2.85-2.70 (2H, m), 2.652.40 (4H, m), 2.25-2.05 (3H, m), 1.85-1.65 (1H, m), 1.45
O
(3H, s).
13C
NMR (75.47 MHz, CDCl3):  165.8, 125.9 CH, 50.6, 37.7 CH2,
33.6 CH2, 31.8 CH2, 29.7 CH2, 23.3 CH2, 23.0 CH3. MS (FAB+): 179 (100,
[M+H]+). HRMS Calcd for C11H15O2 ([M+H]+): 179,107205. Found: 179,
107743. Anal. Calcd for C11H14O2: C 74.13, H 7.92, O 17.95. Found: C, H,
O.

2-methyl-2-(3-oxobutyl)cyclopentane-1,3-dione :
Reference4. In a 25 mL flask, the 2-methylcyclopentane-1,3-
O
dione (2 mmoles) is suspended in CH3CN (3 mL), and then
triethylamine (1 mL) is added. Finally methylvinyl ketone
O
O
(200 µL, 2.4 mmoles) is added. The reaction is monitored by
TLC (Hexane 1 – 1 AcOEt). The solvents are removed under vacuum, and
a purification through a silica gel chromatography furnish an oil (100%);
IR (KBr): = cm-1. 1H NMR (300 MHz, CDCl3):  2.89-2-.73 (4H, m, 2x
CH2), 2.47 (2H, t, J=7 Hz), 2.12 (3H, s), 1.91 (2H, t, J=5 Hz, CH2), 1.12
(3H, s, CH3).
13C
NMR (75.47 MHz, CDCl3):  215.7, 207.8, 55.1, 37.4
CH2, 34.7 CH2, 30.0 CH3, 27.8 CH2, 19.1 CH3. MS (FAB+): 183 (100,
[M+H]+). HRMS Calcd for C10H15O3 ([M+H]+): 183,102120. Found:
183,10190. Anal. Calcd for C10H14O3: C 65.91, H 7.74, O 26.34. Found: C,
H, O.
7-methyl-2,3,7,7-tetrahydro-6H-indene-1,5-dione :
O
Known Compound2. Synthesis; IR (KBr): = cm-1.
1H
NMR
(300 MHz, CDCl3):  5.98 (1H ,s), 3.05-2.92 (1H, m), 2.852.77 (2H, m), 2.58-2.47 (2H, m), 2.17-2.04 (2H, m), 1.98-
O
1.84 (1H, m), 1.33 (3H, s).
13C
NMR (75.47 MHz, CDCl3):  214,3, 196.0,
167.6, 121.8 CH, 94.4 CH2, 32.6 CH2, 27.6 CH2, 24.7 CH2, 18.4 CH3. MS
(FAB+): 165 (100, [M+H]+), 147 (31), 141 (54), 135 (33). HRMS Calcd
for C10H13O2 ([M+H]+): 165,091555. Found: 165,091101. Anal. Calcd for
C10H12O2: C 73.15, H 7.37, O 19.49. Found: C, H, O.
2-Ally-cyclopentane-1,3-dione:
Known Compound7. 1H NMR (300 MHz, MeOD-d4):  5.85O
5.74 (1H, m), 4.92-4.82 (3H, m), 2.85 (2H, d, J=6 Hz),
2.52 (4H, s).
13C
NMR (75.47 MHz, CDCl3): . MS (EI).
Anal. Calcd for C8H10O2: C 69.54, H 7.30, O 23.16.
O
2-allyl-2-(3-oxobutyl)cyclopentane-1,3-dione :
Known CompoundY. Synthesis; IR (KBr): = cm-1. 1H NMR
O
(300 MHz, CDCl3):  5.
13C
NMR (75.47 MHz, CDCl3):  2.
MS (FAB+): XXX (100, [M+H]+). HRMS Calcd for CxHyOz
O
O
([M+H]+):. Found:. Anal. Calcd for CxHyOz:. Found: C, H,
O.
7-allyl-2,3,7,7-tetrahydro-6H-indene-1,5-dione :
Known CompoundXX. Synthesis; IR (KBr): = cm-1. 1H NMR
O
(300 MHz, CDCl3):  5.
13C
NMR (75.47 MHz, CDCl3):  2.
MS (FAB+): ZZZ (100, [M+H]+). HRMS Calcd for CxHyOz
O
([M+H]+): 165,091555. Found: 165,091101. Anal. Calcd
for C10H12O2: C 73.15, H 7.37, O 19.49. Found: C, H, O.
Reference for compounds analyses or syntheses
1. Barbas, C. F. III; Bui, T.; Notz, W.; Sakthivel, K. J. Am. Chem. Soc.,
2001, 123, 5260-5267.
2. Hajos, Z. G. ; Parrish, D. R. Org. Syn, 1985, 63, 26.
3. Barbas, C. F. III Tetrahedron Lett., 2000, 41, 6951.
4. Duben, W. G.; Bunce, R. A. J. Org. Chem., 1983, 48, 4642-4648.
5. Yamamoto, H.; Saito, S.; Nakadai, M. Tetrahedron, 2002, 58, 81678177.
6. a) Balboni J. Med. Chem., 2000, 35, 979. b) Borch J. Org. Chem.,
1972, 37, 1673.
7. Balboni Chem. Eur. J., 2005, 35, 979.
Spectral Data