Synthesis of (R)- and (S)-2-N-methylamino-2,3-dimethylbutanamides and (R)- and (S)-(5-isopropyl-1,5-dimethyl-4,5-dihydro-1H-imidazol-4-on-2-yl)pyridine s

Article abstract of DOI:10.1016/j.tetasy.2008.01.016

Both (R)- and (S)-2-N-methylamino-2,3-dimethylbutanamides have been prepared by the reductive benzylation of (R)- and (S)-2-amino-2,3-dimethylbutanamides, followed by reductive methylation and hydrogenolytic removal of the benzyl group. The reductive benz

Full text of DOI:10.1016/j.tetasy.2008.01.016

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 384–390
Synthesis of (R)- and (S)-2-N-methylamino-2,3-dimethylbutanamides
and (R)- and (S)-(5-isopropyl-1,5-dimethyl-4,5-dihydro-
1H-imidazol-4-on-2-yl)pyridines
a
b
c
c
Pavel Drabina,a, Milos Sedlak, Ales Ruzˇicka, Andrei V. Malkov and Pavel Kocovsky
*
ˇ
´
ˇ
˚
ˇ
ˇ
´
a
ˇ
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice, Na´m. Cs. legiı´ 565,
53210 Pardubice, Czech Republic
Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Na´m. Cs. legiı´ 565,
b
ˇ
53210 Pardubice, Czech Republic
cDepartment of Chemistry, WestChem, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom
Received 13 December 2007; accepted 11 January 2008
Abstract—Both (R)- and (S)-2-N-methylamino-2,3-dimethylbutanamides have been prepared by the reductive benzylation of (R)- and
(S)-2-amino-2,3-dimethylbutanamides, followed by reductive methylation and hydrogenolytic removal of the benzyl group. The reductive
benzylation is chemoselective, and not accompanied by dibenzylation even with the application of excess benzaldehyde. Acylation of the
(R)- and (S)-2-N-methylamino-2,3-dimethylbutanamides with picolinic acid and subsequent ring closure gave the respective (R)- and
(S)-(5-isopropyl-1,5-dimethyl-4,5-dihydro-1H-imidazol-4-on-2-yl)pyridines. Their complexes with Cu(I) catalyze the Kharash–Sosnovsky
allylic oxidation with overall yields as high as 99% but with low enantioselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
tion compounds were tested as catalysts for the Henry
reaction.2b,c
The importance of new nitrogen heterocyclic compounds
and their complexes with metal ions lies in their potential
applicability as suitable catalysts in many chemical pro-
cesses.1 If, in addition, the complex involves a heterocyclic
system containing in its structure a stereogenic centre, it
can be used as a homogeneous or heterogeneous catalyst
for asymmetric syntheses.1 The 4,5-dihydro-1H-imidazol-
5-ones prepared by us also belong among chiral nitro-
gen-containing ligands.2 In our previous work, we found
out that Rh(III) complexes of substituted 2,6-bis(4,5-
dihydro-1H-imidazol-5-on-2-yl)pyridines exhibit excellent
catalytic activity in the deallylation reactions of allyl-
malonates with various alkyl groups.3 Analogous Fe(III)
complexes catalyze the ring closure of substituted 2-
chloro-1,6-dienes giving 1-methylidene-2-propylcyclopen-
tanes.4 Since the 4,5-dihydro-1H-imidazol-5-ones prepared
contain a stereogenic centre, they were prepared in their
enantiomerically pure forms, and their Cu(II) coordina-
In the 2,6-bis(4,5-dihydro-1H-imidazol-5-on-2-yl)pyridines
1 and 2-(4-isopropyl-1,4-dimethyl-4,5-dihydro-1H-imida-
zol-5-on-2-yl)pyridines 2 that we originally prepared, the
stereogenic centre is adjacent to the nitrogen atom partici-
pating in the coordination with a metal atom (the 4-posi-
tion of 4,5-dihydro-1H-imidazole skeleton) (Fig. 1).
Recently an example has been described where a relocation
of the stereogenic centre in the ligand to a position more
remote from the chelate-forming centre positively affected
the enantioselectivity of a catalytic process.5 In order to
verify this possibility in the case of our ligands, the aim
of the this work was to prepare enantiomerically pure (5-
isopropyl-1,5-dimethyl-4,5-dihydro-1H-imidazol-4-on-2-yl)-
pyridine ligands 7. These ligands differ from our earlier
derivatives in having their stereogenic centre at the 5-posi-
tion of the 4,5-dihydro-1H-imidazole cycle, that is, at a
position more remote from the chelate-forming centre than
that present in our earlier ligands.1,2 Another aim of this
work was to compare the enantioselectivity of the newly
suggested ligands with our earlier derivatives using a suit-
able model asymmetric reaction. Since the synthesis of
*
Corresponding author. Tel.: +420 466037010; fax: +420 466037068;
e-mail: pavel.drabina@upce.cz
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.016

P. Drabina et al. / Tetrahedron: Asymmetry 19 (2008) 384–390
385
Figure 1. ORTEP representation and projection of crystal structure of compound (R)-(+)-6.
the newly suggested (R)- and (S)-(5-isopropyl-1,5-di-
methyl-4,5-dihydro-1H-imidazol-4-on-2-yl)pyridines 7 un-
avoidably starts from (R)- and (S)-2-N-methylamino-2,3-
dimethylbutanamides 6, it was crucial for this research to
develop their synthesis. The procedure chosen needs a
strategy entirely different from that used for the racemic
2-N-methylamino-2,3-dimethylbutanamides6,7 (see Chart
1).
for the monomethylation of primary amino groups was
described for the esters of amino acids,10 which involved
the reduction of the corresponding imine of benzophenone,
followed by reductive amination with formaldehyde and
hydrogenolysis.10 In our case, the first reductive amination
of 2-amino-2,3-dimethylbutanamides, that is, by using the
benzaldehyde/NaBH3CN system, was employed to prepare
2-N-methylamino-2,3-dimethylbutanamides 6. We found
that in this case, thanks to the lower reactivity but higher
selectivity of the benzaldehyde as compared with formalde-
hyde, the Eschweiler–Clark reaction only produced
monobenzyl derivatives. Monobenzylation was observed
even in the presence of an excess of benzaldehyde
(1.3 equiv); on the other hand, this excess proved to be
favourable for achieving very good conversions (85–97%).
Subsequently, the N-benzyl derivatives 4 were submitted
to an analogous reaction with formaldehyde, to afford
the racemic and enantiomerically pure (R)- and (S)-N-
benzyl-N-methyl derivatives 5, in P90% yields. The benzyl
group in the latter product 5 was removed quantitatively
by hydrogenolysis on palladium at a mild overpressure of
hydrogen (ca. 5 kPa). This sequence was also used to pre-
pare racemic 2-N-methylamino-2,3-dimethylbutanamide
and (R)- and (S)-2-N-methylamino-2,3-dimethylbutana-
mides 6 in 75–80% overall yields (Scheme 1). The structure
of compound (R)-(+)-6 was confirmed by X-ray diffraction
analysis.
2. Results and discussion
2.1. Synthesis of 2-N-methylamino-2,3-dimethylbutanamides 6
The enantiomerically pure (R)- and (S)-2-amino-2,3-di-
methylbutanamides can be easily prepared by the partial
hydrolysis of (R)- and (S)-2-amino-2,3-dimethylbutanenitr-
iles, respectively; these were obtained by the resolution of
their racemate with tartaric acid.8 On the other hand,
neither the resolution of racemate of 2-N-methylamino-
2,3-dimethylbutanamide 6 nor that of 2-N-methylamino-
2,3-dimethylbutanenitrile by means of chiral acids was
successful. The strategy chosen for preparing compounds
7 consists of selective methylation of the amino group in
the enantiomerically pure 2-amino-2,3-dimethylbutana-
mides, whereas direct methylation by alkylating agents,
such as methyl iodide or dimethyl sulfate, may lead to
the non-selective formation of mixtures of various methyl-
ated products. Also the direct Eschweiler–Clark methyl-
ation with formaldehyde in the presence of reducing
agents (HCOOH, NaBH3CN) is not appropriate, since it
usually results in double methylation, producing the
respective tertiary amine.9 A chemoselective procedure
The molecular arrangement of compound (R)-(+)-6 pre-
sented in Figure 1 shows that individual molecules are
interconnected by hydrogen bonds between the nitrogen
atom of one of the amide groups and the oxygen atom of
the next one. This leads to a double-layer structure of
CH3
R
R
R
N
N
N
N
N
N
O
O
N
O
N
N
N
N
O
1a R = Me
1b R = Bz
2a R = Me
2b R = Bz
2c R = Py-2-CH2-
( )-7
(R)-(+)-7
(S)-(−)-7
Chart 1. 4,5-Dihydro-1H-imidazol-5(4)-one chiral ligands.

386
P. Drabina et al. / Tetrahedron: Asymmetry 19 (2008) 384–390
Ph
PhCHO, NaBH3CN
MeOH, AcOH
Ph
CH2O, NaBH3CN
MeOH, AcOH
N
CH3
H2N
HN
CONH2
CONH2
( )-3
CONH2
( )-4
( )-5
(R)-(−)-5
(S)-(+)-5
(R)-(−)-4
(S)-(+)-4
(R)-(+)-3
(S)-(−)-3
H2/Pd
MeOH
1. Py-2-COOH,
DIC, DMAP
CH3
N
HN
CH3
N
CONH2
2. NaOH, MeOH
N
( )-6
(R)-(+)-6
(S)-(−)-6
O
( )-7
(R)-(+)-7
(S)-(−)-7
Scheme 1.
linearly connected molecules, the alkyl groups of the mole-
cules in these two layers being oriented mutually against
each other. This arrangement in the solid phase is very
similar to the crystal structure of (S)- and (rac)-valine with
an analogous type of double-layer arrangement.11
N-ethyl-N0-(c-dimethylaminopropyl)carbodiimide prolonged
the reaction time, owing to the rearrangement of the
O-acylurea into its non-reactive N-acyl isomer (see Fig. 2).
2.2. Synthesis of (5-isopropyl-1,5-dimethyl-4,5-dihydro-1H-
imidazol-4-on-2-yl)pyridines 7
The preparation of substituted 2-aryl-5-alkyl-1,5-dimethyl-
4,5-dihydro-1H-imidazol-4-one derivatives can be effected
in two steps; 2-N-methylaminoalkanamide is treated with
the corresponding aroyl chloride, and the resulting 2-N-benzo-
yl-2-N-methylaminoalkanamide is subsequently cyclized
by a base.2c,7 We expected that (R)- and (S)-(5-isopropyl-
1,5-dimethyl-4,5-dihydro-1H-imidazol-4-on-2-yl)pyridines
can be prepared in the same way, involving N-acylation with
activated pyridine-2-carboxylic acid. Due to steric hin-
drance, 2-N-methylamino-2,3-dimethylbutanamides 6 are
rather unreactive and can only be acylated with very reac-
tive reagents. However, the requisite pyridine-2-carbonyl
chloride is not available, and the previously described2b acti-
vation of pyridine-2-carboxylic acid by means of ethyl
chloroformate proved to be unsuccessful in this case.
Furthermore, the recently described N-acylation via amino-
lysis of methyl pyridine-2-carboxylate catalyzed by Lewis
acids12 also failed in our case. The best way for the acylation
of aminoamides 6 with pyridine-2-carboxylic acid proved to
be activation with N,N0-diisopropylcarbodiimide. However,
the application of this procedure gave a mixture of acylation
and ring-closure products 7. Therefore, the acylation prod-
ucts were not isolated and the crude products immediately
submitted to the base-catalyzed ring closure, giving rise to
the cyclic products 7 (Scheme 1). However, the removal of
N,N0-diisopropylurea, arising as a byproduct, proved to
be a problem. Complete purification was achieved only after
repeated recrystallization of compounds 7 from cyclohex-
ane. In principle, this problem could be circumvented by
using N-ethyl-N0-(c-dimethylaminopropyl)carbodiimide, as
the corresponding urea can easily be removed by extraction
into water.13 However, in our case the application of
Figure 2. ORTEP representation of structure of compound (R)-(+)-7.
2.3. Asymmetric allylic oxidation catalyzed by Cu(I) com-
plexes of 1, 2 and 7
The newly prepared chiral ligands 7 were tested for their
catalytic activity in the allylic oxidation of olefins (Kha-
rash–Sosnovsky reaction) and compared with the previ-
ously reported derivatives of 4,5-dihydro-1H-imidazol-5-
ones (1 and 2).2a,b,3 It is well known that this reaction
is effectively catalyzed by Cu(I) complexes of nitrogen
ligands.14 The Cu(I) complexes of ligands 1, 2 and 7 were
prepared in situ by reducing the ligand/Cu(OTf)2 com-
plexes with phenylhydrazine. Five- to seven-membered
cycloalkenes and tert-butyl peroxybenzoate oxidant were
utilized. The reactions were performed in acetone, which
has been generally accepted as the most appropriate
solvent.14h The reaction times were in the order of days
(1–42 days), which represents a distinct retardation as com-
pared with the catalysis by analogous oxazoline deriva-
tives.14 With respect to this slow course of the reaction, it
was impossible to carry out any more significant study of
temperature effect upon enantioselectivity (reaction tem-
peratures 0 and 20 °C). The very slow reaction course is

P. Drabina et al. / Tetrahedron: Asymmetry 19 (2008) 384–390
387
probably caused by a substantial steric hindrance exhibited
4. Experimental
by the alkyl groups bound to the asymmetric centre. All the
ligands studied 1, 2 and 7 (Table 1) showed very low selec-
tivity (0–22% ee). The results given in Table 1 indicate that
ligand (R)-(+)-7 is rather less enantioselective than analo-
gous ligands with the chiral centre at 4-position (1 and
2). For instance, the oxidation product of cyclopentene
9a was obtained with catalysis by ligand (R)-(+)-7 in 9%
ee (Table 1, entry 1), while the catalysis by ligands 1a
and 2a gave 14% and 15% ee, respectively (Table 1, entries
3 and 13).
4.1. General
Racemic and enantiomerically pure 2-amino-2,3-di-
methylbutanamides 3 were prepared according to the
method reported by Wepplo.8 The other reagents for the
syntheses were purchased reagent grade and were used
without further purification. The 1H and 13C NMR spectra
were recorded on a Bruker Avance 500 spectrometer at
500.13 (1H) and 125.76 MHz (13C) in DMSO-d6. The H
1
and 13C chemical shifts were referenced to the central peaks
of the solvent (d = 2.55 and 39.60, respectively). The mass
spectra were recorded on an instrument set from Agilent
Technologies (gas chromatograph 6890N with mass detec-
tor 5973 Network). The elemental analyses were performed
on FISONS Instruments EA 1108 CHN. The optical rota-
tion was measured on a Perkin–Elmer 341 instrument, con-
centration c is given in g/100 ml. The enantiomeric purity
of cyclopent-2-enyl benzoate 9a was determined by means
of HPLC using a Chiralcel OD-H column (Daicel)
(99.5:0.5 hexane/propan-2-ol, 0.5 ml/min, 220 nm) and
the enantiomeric purity of cyclohex-2-en-1-ol and cyclo-
hept-2-en-1-ol was determined by means of GC using a
Supelco b-DEX 120 column.
3. Conclusion
The enantiomerically pure 2-N-methylamino-2,3-dimethyl-
butanamides 6 can be prepared by selective methylation of
amino group in (R)- and (S)-2-amino-2,3-dimethylbutana-
mides in high yields (75–80%). The chemoselective intro-
duction of methyl group relies on two reductive
aminations, the first being reductive benzylation and the
second reductive methylation. This method makes use of
the fact that the reductive benzylation is not accompanied
by dibenzylation even in the presence of excess benzalde-
hyde. Hydrogenolytic removal of the benzyl group gave
the required enantiomerically pure compounds 6, which
were transformed into enantiomerically pure (R)- and
(S)-(5-isopropyl-1,5-dimethyl-4,5-dihydro-1H-imidazol-4-
on-2-yl)pyridines 7. The coordination compounds of 7 with
Cu(I) catalyze the allyl oxidation with high chemoselectiv-
ity (699%) but very low enantioselectivity (622% ee).
4.2. Synthesis of compounds 4–7
4.2.1. ( )-2-N-Benzylamino-2,3-dimethylbutanamide ( )-4.
A mixture of ( )-2-amino-2,3-dimethylbutanamide ( )-3
(3.7 g, 28 mmol), benzaldehyde (3.86 g, 36 mmol, 1.3 equiv)
and acetic acid (2.75 ml) in methanol (60 ml) was treated
Table 1. Asymmetric allylic oxidation of cycloalkenes 8a–c catalyzed by Cu(I) complexes of chiral ligands 1, 2 and 7
5 mol % Cu(OTf)2, L*
PhNHNH2, Acetone
O
O
+
*
O
O OC(CH3)3
n
n
9a, n = 0
9b, n = 1
9c, n = 2
8a, n = 0
8b, n = 1
8c, n = 2
Entry
Ligand
Olefin
Temp (°C)
Time (d)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
(R)-(+)-7
8a
8b
8a
8b
8c
8c
8a
8a
8b
8c
8c
8a
8a
8c
8a
20
20
20
20
20
0
20
0
20
20
0
8
13
2.5
7
5
24
1
42
2
2
25
31
19
8
56
80
99
50
82
58
98
13
81
65
47
10
65
24
30
9
<3
15
13a
18a
18a
16
(R)-(+)-7
2a
2a
2a
2a
2b
2b
21
2b
2b
14a
17a
22a
<3
14
2b
2c
20
20
20
20
1a
1a
<3a
12
1a
11
a Analysis of the corresponding allyl alcohol by means of GC; 9b and 9c were transformed into the corresponding allyl alcohols by reduction with LiAlH4
(8 equiv) in THF (24 h, rt).

388
P. Drabina et al. / Tetrahedron: Asymmetry 19 (2008) 384–390
with NaBH3CN (3.0 g, 48 mmol, 1.3 equiv) added for
5 min. After 48-h stirring at room temperature, the solvent
was evaporated in vacuo, and the evaporation residue was
mixed with 5% aqueous solution of NaOH (50 ml). The
mixture obtained was extracted with CH2Cl2 (3 ꢀ 70 ml),
and the combined extracts were evaporated until dry. The
crude product was made rid of benzyl alcohol in vacuum
at 110 °C and then recrystallized from a mixture of cyclo-
hexane and CHCl3 (10:1). Yield 5.25 g (85%); mp 122–
mp 80–81 °C; 1H NMR (DMSO-d6, d ppm): 0.92 (d,
3J = 6.7 Hz, 3H, iPrCH3), 1.01 (d, 3J = 6.7 Hz, 3H,
iPrCH3), 1.16 (s, 3H, CH3), 2.05 (s, 3H, NCH3), 2.16 (sp,
2
3J = 6.7 Hz, 1H, iPrCH), 3.60–3.43 (2 ꢀ d, J = 14.3 Hz,
2H, CH2), 6.90 (br s, 1H, CONH2), 7.20 (br s, 1H, CONH2),
3
3
7.27 (t, J = 7.2 Hz, 1H, PhH4), 7.36 (t, J = 7.4 Hz, 2H,
PhH3,5), 7.43 (d, 3J = 7.5 Hz, 2H, PhH2,6). 13C NMR
(DMSO-d6, d ppm): 12.4; 17.8; 17.9; 32.1; 35.4; 55.5; 68.8;
126.7; 127.9; 128.4; 140.2; 174.1; EI-MS: m/z 190, 174, 160,
120, 91 (100%), 65, 56; Anal. Calcd for C14H22N2O: C,
71.76; H, 9.46; N, 11.95. Found: C, 71.92; H, 9.38; N, 12.05.
124 °C; 1H NMR (DMSO-d6,
d
ppm): 0.89 (d,
3J = 6.9 Hz, 3H, iPrCH3), 0.95 (d, 3J = 6.9 Hz, 3H,
iPrCH3), 1.10 (s, 3H, CH3), 1.88 (sp, 3J = 6.9 Hz, 1H,
iPrCH), 2.17 (br s, 1H, NH), 3.65–3.51 (m, 2H, CH2),
4.2.5. (R)-2-N-Benzyl-N-methylamino-2,3-dimethylbutana-
20
3
7.09 (br s, 1H, CONH2), 7.26 (t, J = 7.0 Hz, 1H, PhH4),
mide (ꢁ)-5. Yield 93%; mp 96–99 °C; ½aꢂD ¼ ꢁ13:1 (c
3
7.31 (br s, 1H, CONH2), 7.35 (t, J = 7.5 Hz, 2H, PhH3,5),
0.42, THF); 1H NMR (DMSO-d6, d ppm): 0.91 (d,
3J = 6.8 Hz, 3H, iPrCH3), 1.01 (d, 3J = 6.8 Hz, 3H,
iPrCH3), 1.16 (s, 3H, CH3), 2.05 (s, 3H, NCH3), 2.16 (sp,
3
7.39 (t, J = 7.1 Hz, 2H, PhH2,6); 13C NMR (DMSO-d6, d
ppm): 15.8; 17.0; 17.7; 35.4; 47.5; 64.6; 126.5; 127.9; 128.2;
141.6; 178.1; EI-MS: m/z 176, 132, 106, 91 (100%), 65; Anal.
Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72. Found:
C, 70.95; H, 9.29; N, 12.63.
2
3J = 6.8 Hz, 1H, iPrCH), 3.59–3.43 (2 ꢀ d, J = 14.2 Hz,
2H, CH2), 6.91 (br s, 1H, CONH2), 7.22 (br s, 1H,
3
CONH2), 7.27 (t, J = 7.2 Hz, 1H, PhH4), 7.36 (m, 2H,
PhH3,5), 7.43 (d, 3J = 7.5 Hz, 2H, PhH2,6). 13C NMR
(DMSO-d6, d ppm): 12.4; 17.8; 17.9; 32.1; 35.4; 55.5;
68.8; 126.7; 127.9; 128.4; 140.2; 174.1; EI-MS: m/z 190,
174, 160, 120, 91 (100%), 65, 56; Anal. Calcd for
C14H22N2O: C, 71.76; H, 9.46; N, 11.95. Found: C,
72.04; H, 9.33; N, 11.84.
4.2.2. (R)-2-N-Benzylamino-2,3-dimethylbutanamide (ꢁ)-4.
20
Yield 96%; mp 146–149 °C; ½aꢂD ¼ ꢁ16:8 (c 0.40, THF);
3
1H NMR (DMSO-d6, d ppm): 0.87 (d, J = 6.7 Hz, 3H,
3
iPrCH3), 0.95 (d, J = 6.7 Hz, 3H, iPrCH3), 1.10 (s, 3H,
3
CH3), 1.88 (sp, J = 6.7 Hz, 1H, iPrCH), 2.21 (br s, 1H,
2
NH), 3.63–3.51 (2 ꢀ d, J = 12.9 Hz, 2H, CH2), 7.07 (br
3
s, 1H, CONH2), 7.26 (t, J = 7.1 Hz, 1H, PhH4), 7.30 (br
4.2.6. (S)-2-N-Benzyl-N-methylamino-2,3-dimethylbutana-
20
3
s, 1H, CONH2), 7.35 (t, J = 7.3 Hz, 2H, PhH3,5), 7.39 (t,
mide (+)-5. Yield 92%; mp 94–97 °C; ½aꢂD ¼ þ12:9 (c
3J = 7.1 Hz, 2H, PhH2,6). 13C NMR (DMSO-d6, d ppm):
15.8; 17.0; 17.7; 35.4; 47.5; 64.6; 126.5; 127.9; 128.2;
141.6; 178.1; EI-MS: m/z 176, 132, 106, 91 (100%), 65;
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72.
Found: C, 70.83; H, 9.38; N, 12.87.
0.42, THF); 1H NMR (DMSO-d6, d ppm): 0.92 (d,
3J = 6.7 Hz, 3H, iPrCH3), 1.01 (d, 3J = 6.7 Hz, 3H,
iPrCH3), 1.16 (s, 3H, CH3), 2.05 (s, 3H, NCH3), 2.14 (sp,
2
3J = 6.7 Hz, 1H, iPrCH), 3.59–3.44 (2 ꢀ d, J = 14.2 Hz,
2H, CH2), 6.91 (br s, 1H, CONH2), 7.23 (br s, 1H,
3
CONH2), 7.27 (t, J = 6.8 Hz, 1H, PhH4), 7.36 (m, 2H,
4.2.3. (S)-2-N-Benzylamino-2,3-dimethylbutanamide (+)-4.
PhH3,5), 7.43 (d, 3J = 7.4 Hz, 2H, PhH2,6). 13C NMR
(DMSO-d6, d ppm): 12.5; 17.9; 18.0; 32.2; 35.4; 55.5;
68.8; 126.7; 127.9; 128.4; 140.3; 174.1; EI-MS: m/z 190,
174, 160, 120, 91 (100%), 65, 56; Anal. Calcd for
C14H22N2O: C, 71.76; H, 9.46; N, 11.95. Found: C,
71.87; H, 9.21; N, 11.75.
20
Yield 97%; mp 146–148 °C; ½aꢂD ¼ +16.7 (c 0.41, THF); 1H
NMR (DMSO-d6, d ppm): 0.87 (d, 3J = 6.6 Hz, 3H,
3
iPrCH3), 0.95 (d, J = 6.6 Hz, 3H, iPrCH3), 1.10 (s, 3H,
3
CH3), 1.88 (sp, J = 6.6 Hz, 1H, iPrCH), 2.20 (br s, 1H,
2
NH), 3.64 – 3.51 (2 ꢀ d, J = 12.8 Hz, 2H, CH2), 7.07 (br
3
s, 1H, CONH2), 7.26 (t, J = 6.9 Hz, 1H, PhH4), 7.30 (br
3
s, 1H, CONH2), 7.35 (t, J = 7.2 Hz, 2H, PhH3,5), 7.39 (t,
4.2.7. ( )-2-N-Methylamino-2,3-dimethylbutanamide ( )-6.
Catalyst (5% palladium on carbon 0.23 g, 0,1 mmol Pd)
was added to a solution of compound ( )-5 (2.34 g,
10 mmol) in methanol (60 ml), and hydrogen (ca. 5 kPa)
was bubbled through the mixture for a period of 48 h,
whereupon the mixture was bubbled with argon, filtered
and the product was isolated by evaporation of methanol.
3J = 7.2 Hz, 2H, PhH2,6). 13C NMR (DMSO-d6, d ppm):
15.8; 17.0; 17.7; 35.4; 47.5; 64.6; 126.5; 127.9; 128.2;
141.6; 178.1; EI-MS: m/z 176, 132, 106, 91 (100%), 65;
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72.
Found: C, 70.68; H, 9.33; N, 12.83.
1
4.2.4. ( )-2-N-Benzyl-N-methylamino-2,3-dimethylbutana-
mide ( )-5. A mixture of compound ( )-4 (5.25 g,
24 mmol), 37% aqueous formaldehyde solution (4.2 g,
52 mmol), acetic acid (2 ml) and methanol (80 ml) was trea-
ted with NaBH3CN (1.95 g, 33 mmol) added over 5 min.
The mixture was stirred at room temperature 24 h, where-
upon another formaldehyde solution (6.2 g, 52 mmol) was
added. After 16 h, methanol was evaporated in vacuum,
and the evaporation residue was mixed with 5% aqueous
solution of NaOH (50 ml). The mixture formed was
extracted with CH2Cl2 (4 ꢀ 70 ml), and the combined
Yield 1.35 g (94%); mp 58–60 °C; H NMR (DMSO-d6, d
ppm): 0.82 (d, 3J = 6.9 Hz, 3H, iPrCH3), 0.88 (d, 3J =
6.9 Hz, 3H, iPrCH3), 1.00 (s, 3H, CH3), 1,76 (sp, 3J =
6.9 Hz, 1H, iPrCH), 1.87 (br s, 1H, NH), 2.15 (s, 3H,
NCH3), 6.96 (br s, 1H, CONH2), 7.18 (br s, 1H, CONH2).
13C NMR (DMSO-d6, d ppm): 15.1; 16.8; 17.6; 30.0; 35.4;
64.4; 177.9; EI-MS: m/z 129, 100 (100%), 85, 69, 56; Anal.
Calcd for C7H16N2O: C, 58.30; H, 11.18; N, 19.42. Found:
C, 58.47; H, 11.03; N, 19.36.
4.2.8. (R)-2-N-Methylamino-2,3-dimethylbutanamide (+)-6.
20
1
extracts were dried and evaporated until dry. Yield 5.10 g . Yield 86%; mp 87–89 °C; ½aꢂD ¼ þ13:9 (c 0.47, THF); H
(91%) of an oily product, which solidified after several days;
NMR (DMSO-d6, d ppm): 0.82 (d, 3J = 6.8 Hz, 3H,

P. Drabina et al. / Tetrahedron: Asymmetry 19 (2008) 384–390
389
3
iPrCH3), 0.88 (d, J = 6.8 Hz, 3H, iPrCH3), 0.99 (s, 3H,
ppm): 0.81 (d, 3J = 6.9 Hz, 3H, iPrCH3), 1.05 (d,
3J = 6.9 Hz, 3H, iPrCH3), 1.38 (s, 3H, CH3), 2.12
(sp, 3J = 6.9 Hz, 1H, iPrCH), 3.39 (s, 3H, NCH3), 7.71
(m, 1H, PyH4), 8.13 (m, 2H, PyH3,5), 8.85 (m, 1H,
3
CH3), 1.76 (sp, J = 6.8 Hz, 1H, iPrCH), 1.84 (br s, 1H,
NH), 2.15 (s, 3H, NCH3), 6.97 (br s, 1H, CONH2), 7.19
(br s, 1H, CONH2). 13C NMR (DMSO-d6, d ppm): 15.3;
16.9; 17.7; 30.2; 35.5; 64.6; 178.0; EI-MS: m/z 129, 100
(100%), 85, 69, 56; Anal. Calcd for C7H16N2O: C, 58.30;
H, 11.18; N, 19.42. Found: C, 58.53; H, 11.12; N, 19.27.
PyH6). 13C NMR (DMSO-d6,
d ppm): 15.1; 16.5;
19.3; 30.5; 32.5; 71.6; 126.6; 126.8; 137.7; 148.6;
149.0; 173.9; 192.6; EI-MS: m/z 231 (M+), 216, 188
(100%), 173, 105, 78; Anal. Calcd for C13H17N3O: C,
67.51; H, 7.41; N, 18.17. Found: C, 67.41; H, 7.57; N,
17.94.
4.2.9. (S)-2-N-Methylamino-2,3-dimethylbutanamide (ꢁ)-6.
20
.
Yield 90%; mp 85–86 °C; ½aꢂD ¼ ꢁ14:2 (c 0.48, THF);
1H NMR (DMSO-d6, d ppm): 0.82 (d, J = 6.9 Hz, 3H,
3
3
iPrCH3), 0.88 (d, J = 6.8 Hz, 3H, iPrCH3), 0.99 (s, 3H,
4.3. X-ray
3
CH3), 1,75 (sp, J = 6.9 Hz, 1H, iPrCH), 1.86 (br s, 1H,
NH), 2.15 (s, 3H, NCH3), 6.95 (br s, 1H, CONH2),
7.17 (br s, 1H, CONH2). 13C NMR (DMSO-d6, d ppm):
15.2; 16.8; 17.6; 30.1; 35.4; 64.6; 177.9; EI-MS: m/z 129,
100 (100%), 85, 69, 56; Anal. Calcd for C7H16N2O: C,
58.30; H, 11.18; N, 19.42. Found: C, 58.41; H, 11.09; N,
19.24.
Crystallographic data (excluding structure factors) for
structures (R)-(+)-6 and (R)-(+)-7 have been deposited
with the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC 670558 (R)-(+)-6 and
CCDC 670559 (R)-(+)-7. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/conts/retrieving.htlm
or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge, CB2 1EZ, UK; fax: +44
1223336033 or deposit@ccdc.cam.ac.uk. The X-ray data
were collected on a Nonius KappaCCD diffractometer fit-
4.2.10. ( )-(5-Isopropyl-1,5-dimethyl-4,5-dihydro-1H-imida-
zol-4-on-2-yl)pyridine ( )-7. At 0 °C, a solution of picol-
inic acid (0.92 g, 7.5 mmol) and DMAP (0.91 g,
7.5 mmol) in dry CH2Cl2 (15 ml) was mixed with diisopro-
pylcarbodiimide (1.18 ml, 7.5 mmol). After 30-min stirring,
a solution of compound ( )-6 (1.08 g, 7.5 mmol) in CH2Cl2
(15 ml) was added, and the mixture was stirred for another
3–4 h at 0 °C and then 4 days at room temperature. The
suspension formed was extracted with 5% aqueous solution
of acetic acid (30 ml). After evaporating CH2Cl2, the evap-
oration residue was suspended in 1 M NaOH (50 ml), the
suspension was stirred for 1 h, neutralized with acetic acid
and then extracted with diethyl ether (3 ꢀ 30 ml). The
crude product obtained by evaporating the diethyl ether
was recrystallized from cyclohexane. Yield 1.01 g (58%);
mp 106–108 °C; 1H NMR (DMSO-d6, d ppm): 0.81 (d,
3J = 7.0 Hz, 3H, iPrCH3), 1.06 (d, 3J = 7.0 Hz, 3H,
iPrCH3), 1.39 (s, 3H, CH3), 2.13 (sp, 3J = 7.0 Hz, 1H,
iPrCH), 3.38 (s, 3H, NCH3), 7.71 (m, 1H, PyH4), 8.13
(m, 2H, PyH3,5), 8.85 (m, 1H, PyH6). 13C NMR (DMSO-
d6, d ppm): 15.1; 16.5; 19.2; 30.4; 32.5; 71.4; 126.4; 126.7;
137.6; 148.5; 148.9; 173.7; 192.4; EI-MS: m/z 231 (M+),
216, 188 (100%), 173, 105, 78; Anal. Calcd for
C13H17N3O: C, 67.51; H, 7.41; N, 18.17. Found: C,
67.27; H, 7.63; N, 18.46.
˚
ted with MoKa radiation (k = 0.71073 A) at 150(1) K. The
absorption correction was performed using a empirical
(SADABS for (R)-(+)-6)15a,b and gaussian procedure
[(R)-(+)-7],15c respectively, the structure was solved by di-
rect methods (SIR9216) and full-matrix least-squares refine-
ments on F2 were carried out using the program SHELXL
97.17 Flack parameter18 was optimized to zero value with
known chemical absolute configuration R for both
structures.
Crystallographic data for (R)-(+)-6. C7H16N2O, M =
144.22, T = 150(1) K. Monoclinic, space group P21
˚
with a = 6.0690(16), b = 9.5230(16), c = 7.693(2) A, b =
102.13(2)°, V = 434.70(18) Aꢁ3, Z = 2, Dx = 1.102 g cmꢁ3
˚
(Z = 2), F(000) = 160, l = 0.075 mmꢁ1 (corrected by SAD-
ABS (Tmin/Tmax 0.379483)), 7359 reflections measured
(hmax = 27.5°), 1038 independent (Rint = 0.074), 901 with
I > 2r(I), 92 parameters, S = 1.013, R1 (obs. data) =
0.0757, wR2 (all data) = 0.1ꢁ9434; max, min residual electron
˚
density = 0.579, ꢁ0.409 eA
.
Crystallographic data for (R)-(+)-7. C13H18N3O, M =
232.30, T = 150(1) K. Orthorhombic, space group
P212121 with a = 9.6820(9), b = 11.1320(9), c = 11.6440(4)
4.2.11. (R)-(5-Isopropyl-1,5-dimethyl-4,5-dihydro-1H-imida-
zol-4-on-2-yl)pyridine (+)-7. Yield 65%; mp 128–131 °C;
A, V = 1254.99(16) Aꢁ3, Z = 4, Dx = 1.224 g cmꢁ3 (Z =
˚
˚
20
½aꢂD ¼ þ68:1 (c 0.50, THF); 1H NMR (DMSO-d6, d
4), F(000) = 496, l = 0.080 mmꢁ1, Tmin = 0.979, Tmax
=
ppm): 0.81 (d, 3J = 6.8 Hz, 3H, iPrCH3), 1.05 (d,
3J = 6.8 Hz, 3H, iPrCH3), 1.39 (s, 3H, CH3), 2.12 (sp,
3J = 6.8 Hz, 1H, iPrCH), 3.41 (s, 3H, NCH3), 7.70 (m,
1H, PyH4), 8.13 (m, 2H, PyH3,5), 8.84 (m, 1H, PyH6).
13C NMR (DMSO-d6, d ppm): 15.2; 16.6; 19.4; 30.6;
32.7; 71.6; 126.6; 126.9; 137.8; 148.5; 149.1; 173.9; 192.6;
EI-MS: m/z 231 (M+), 216, 188 (100%), 173, 105, 78; Anal.
Calcd for C13H17N3O: C, 67.51; H, 7.41; N, 18.17. Found:
C, 67.47; H, 7.49; N, 18.20.
0.990; 3325 reflections measured (hmax = 27.5°), 1641 inde-
pendent (Rint = 0.0394), 1280 with I > 2r(I), 92 parame-
ters, S = 1.187, R1 (obs. data) = 0.0595, wR2 (all data) =
0.1307; mꢁax3, min residual electron density = 0.230,
˚
ꢁ0.230 e A
.
Acknowledgements
4.2.12. (S)-(5-Isopropyl-1,5-dimethyl-4,5-dihydro-1H-imida-
zol-4-on-2-yl)pyridine (ꢁ)-7. Yield 62%; mp 127–130 °C;
The authors wish to acknowledge the financial support of
the Ministry of Education, Youth and Sports (MSM 002
162 7501) and the University of Glasgow.
20
½aꢂD ¼ ꢁ68:0 (c 0.51, THF); 1H NMR (DMSO-d6, d

390
P. Drabina et al. / Tetrahedron: Asymmetry 19 (2008) 384–390
12. Guo, Z.; Dowdy, E. D.; Li, W.-S.; Polniaszek, R.; Delaney,
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