Diastereoselective reductive N-alkylation of (R,R)-trans-1,2-diaminocyclohexane with prochiral ketones using the Ti(OiPr)4/NaBH4 system

Article abstract of DOI:10.1016/j.tetasy.2009.05.004

A simple and convenient one-pot method for the reductive N-alkylation of (R,R)-trans-1,2-diaminocyclohexane by prochiral ketones using a Ti(OⁱPr)₄/NaBH₄ system to obtain the corresponding alkyl amine derivatives in 76-95%

Full text of DOI:10.1016/j.tetasy.2009.05.004

Tetrahedron: Asymmetry 20 (2009) 1247–1253
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Diastereoselective reductive N-alkylation of (R,R)-trans-1,2-diaminocyclohexane
with prochiral ketones using the Ti(OiPr)4/NaBH4 system
*
Manasi Dalai, Mariappan Periasamy
School of Chemistry, University of Hyderabad, Central University P.O., Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and convenient one-pot method for the reductive N-alkylation of (R,R)-trans-1,2-diaminocyclo-
hexane by prochiral ketones using a Ti(OiPr)4/NaBH4 system to obtain the corresponding alkyl amine
derivatives in 76–95% yields with good diastereoselectivity (dr = up to 23:1:1) is reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 March 2009
Accepted 1 May 2009
Available online 3 June 2009
1. Introduction
and Ti(OiPr)4, followed by reaction with NaBH4 under ambient con-
ditions (Scheme 1). After completion of the reaction followed by
Amines and their derivatives are highly versatile building
blocks for various organic molecules and are essential precursors
for the synthesis of a variety of biologically active compounds such
as pharmaceuticals1 and agrochemicals.2 Over the last 10 years,
numerous different methods have emerged for the preparation of
amines such as hydrogenations,3–6 hydrosilylations of imines or
imine derivatives, and nucleophilic 1,2-additions of organometallic
reagents to the C@N double bond.7–10 The reductive alkylation of
amines is a very convenient and important tool for chemists to tar-
get the synthesis of primary, secondary, and tertiary amines. trans-
1,2-Diaminocyclohexane derivatives have been shown to be useful
chiral reagents and ligands for catalysis with applications in asym-
metric synthesis.11 In continuation of our research efforts toward
the synthesis of various chiral secondary amines12,13 and macrocy-
cles14 containing the trans-1,2-diaminocyclohexyl moiety, we were
looking for a convenient method of N-alkylation of this readily
accessible15 versatile C2-symmetric chiral amine with prochiral ke-
tones. Recently, there have been reports on the reductive mono-N-
alkylation of primary amines with ketones using the Ti(OiPr)4 and
NaBH4 reagent system.16–20 Accordingly, we have examined the
use of this reagent system for the synthesis of chiral secondary dia-
mines 4a–4i containing the trans-1,2-diaminocyclohexane moiety.
Herein we report the results of this investigation (Scheme 1).
extraction of the product, the crude N-alkylated diamine 4a was
obtained in an 8:1:1 diastereomeric ratio. The separation of the
major diastereomer was achieved by flash column chromatogra-
phy (silica gel, 230–400 mesh, hexane/EtOAc 97/3) in 61% chemical
yield. The configuration of this major diastereomer was assigned as
1R,2R,10R,100R by comparison with the reported specific rotation va-
lue.22 The absolute configuration at the newly formed stereogenic
centers of the major diastereomer 4a was further confirmed by sin-
gle-crystal X-ray analysis of its trifluoroacetamide derivative 5
(Fig. 1).23 The absolute configuration at the newly formed stereo-
genic centers of the major diastereomer 4c was confirmed to be
(1R,2R,10R,100R) by single-crystal X-ray analysis (Fig. 2).24
We next examined the titanium(IV)-reductive N-alkylation
reaction of (R,R)-trans-1,2-diaminocyclohexane 1 with various pro-
chiral ketones under the experimental conditions. The results are
summarized in Table 1. The expected three diastereomeric prod-
ucts were obtained in good to excellent chemical yields (76–
95%), with diastereomeric ratios (dr) of 2:1:0 to 23:1:1. For exam-
ple, the reaction of chiral amine 1 with a-tetralone gave the corre-
sponding N-alkylated product 4d in a 13:1:1 diastereomeric ratio
(Table 1, entry 4). One major diastereomer and two minor diaste-
reomers of the alkylated product 4d were separated by column
chromatography. The best diastereoselectivity was achieved with
2-acetylthiophene (Table 1, entry 5, dr 23:1:1). The separation of
the major diastereomer was achieved via column chromatography
in 84% yield. Also, in the case of p-nitro and p-chloroacetophe-
nones, the corresponding N-alkylated products were obtained in
4:1:1 and 7:1:1 dr, respectively (Table 1, entries 2 and 3). In these
cases, the major diastereomers were isolated in pure form by col-
umn chromatography. In the case of the reaction with ketones such
as 2-acetylnaphthalene, p-methyl acetophenone, and p-methoxy-
acetophenone, only the major diastereomers were obtained in pure
form for identification by column chromatography besides the
mixture of diastereomers. In the reaction with 2-acetylpyridine
2. Results and discussion
Initially, the titanium(IV)-reductive N-alkylation reaction of
(R,R)-trans-1,2-diaminocyclohexane
1 with acetophenone was
carried out using the Ti(OiPr)4/NaBH4 system16 (Table 1, entry 1).
Acetophenone was reacted with the chiral primary diamine 1
* Corresponding author. Tel.: +91 40 23134814; fax: +91 40 23012460.
E-mail address: mpsc@uohyd.ernet.in (M. Periasamy).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.004

1248
M. Dalai, M. Periasamy / Tetrahedron: Asymmetry 20 (2009) 1247–1253
R
R
Ar
NH
NH
Ar
Ar
R
OTi(OiPr3)
NH2
NH2
O
Ti(OiPr4), THF
R
rt, 12 h
NaBH4, EtOH
rt, 12 h
N
N
3
+
H
H
Ar
2
-1
OTi(OiPr3)
R
(R,R)
Ar
(1R,2R,1'R,1''R)-4
R = Me
a: Ar = Ph
g: Ar = 2-pyridyl
d
: RCOAr = tetralone
b: Ar = 4-NO2-C6H4
c: Ar = 4-Cl-C6H4
e
h: Ar = 4-Me-C6H4
: Ar = 2-thiophenyl
f: Ar = 2-naphthyl
i: Ar = 4-MeO-C6H4
Scheme 1.
the major diastereomer could not be isolated in pure form by col-
umn chromatography and the diastereoselectivity for this reaction
was poor (Table 1, entry 7). The configurations of the major diaste-
reomers of the N-alkylated products 4b, 4d, and 4e were assigned
as 1R,2R,10R,100R by comparison with the specific rotation value of
the known diamine 4a.22
We have also studied the effect of solvents and temperature on
the diastereoselective titanium(IV)-reductive N-alkylation reaction
Table 1
Ti(IV)-reductive N-alkylation reaction of (R,R)-trans-1,2-diaminocyclohexane 1 with various prochiral ketonesa
Entry
Starting ketone
Product amineb
Yieldc (%)
drd
Ar
R
Me
Me
1
Ph
Me
87
8:1:1
NH HN
4a
Me
Me
NH HN
2
4-NO2–C6H4
Me
80
4:1:1
4b
O2N
NO2
Me
Me
NH HN
3
4-Cl–C6H4
Me
89
7:1:1
4c
Cl
Cl
4
a-Tetralone
94
13:1:1
NH HN
4d
Me
Me
5
2-Thiophenyl
Me
89
23:1:1
NH HN
4e
S
S

M. Dalai, M. Periasamy / Tetrahedron: Asymmetry 20 (2009) 1247–1253
1249
Table 1 (continued)
Entry
Starting ketone
Product amineb
Yieldc (%)
drd
Ar
R
Me
Me
Me
Me
NH HN
6
7
8
2-Naphthyl
Me
Me
Me
76
7:1:1
2:1:0e
4:1:0
4f
2-Pyridyl
90
NH HN
4g
N
N
Me
Me
NH HN
4h
4-Me–C6H4
95
Me
Me
Me
Me
NH HN
9
4-MeO–C6H4
Me
79
8:1:1
4i
MeO
OMe
a
All reactions were carried out using 1.0 mmol of diamine 1, 2.2 mmol of ketone 2, and 4.0 mmol of Ti(OiPr)4 in 5.0 mL of dry THF at room temperature for 12 h and for
in situ reduction, 5.0 mmol of NaBH4 in 5.0 mL of absolute EtOH was used at rt and stirred for 12 h.
b
Products were identified using spectroscopic data (IR and 1H and 13C NMR).
c
Yields are of the isolated product and correspond to the three diastereomers.
d
Diastereomeric ratio (dr) was determined by 1H NMR analysis of the crude product mixture. The major diastereomer was obtained in pure form by column chroma-
tography of the crude diastereomeric products 4a, 4b, 4c, 4d, and 4e.
e
A mixture containing the major diastereomer (87.5%) and the minor diastereomer (12.5%) was isolated by column chromatography for spectroscopic analysis.
of (R,R)-trans-1,2-diaminocyclohexane with
a
-tetralone (Scheme
Since the re face is more hindered, the borohydride prefers to
approach intermediate 6 through the si face (Fig. 3).
The formation of a titanium complex of the diimine intermedi-
ate 8 before reduction cannot be ruled out (Fig. 3). However, such
an intermediate would also lead to the same stereochemical out-
come (Fig. 3).
2). The results are given in Table 2. When the reaction was carried
out in absolute MeOH at room temperature, the chemical yield and
diastereoselectivity of the product diamine 4d decreased (Table 2,
entry 1). When absolute EtOH was used as the solvent, the chem-
ical yield decreased from 94% to 73%. When CH2Cl2 was used, there
was a significant decrease in the chemical yield from 94% to 41%
(Table 2, entry 4). In THF, the reaction proceeded well and the
product diamine 4d was obtained in 94% chemical yield with
13:1:1 dr (Table 2, entry 3). When the reaction was carried out
at ꢀ78 °C in THF, both the chemical yield and the diastereoselectiv-
ity decreased (Table 2, entry 5).
The transformations reported here may be rationalized by con-
sidering the steps and stereochemical models shown in Scheme 3
and Figure 3. The initially formed titanium(IV) complex 3 (Scheme
1 and 2) would undergo further elimination to give the chiral dii-
mine intermediate 6 or 7.17 The (E,E) intermediate 6 is expected
to be more favorable in which the aryl group is far away from
the cyclohexyl moiety.
3. Conclusion
In conclusion, we have developed a one-pot method for the syn-
thesis of chiral diamines 4a–4i containing an (R,R)-trans-1,2-diam-
inocyclohexyl moiety via a Ti(IV) isopropoxide-mediated reductive
N-alkylation reaction of chiral diamine 1 with prochiral ketones in
good to excellent yields with moderate to good diastereoselectivi-
ties. The secondary chiral N-alkyl amines have been used as ligands
for asymmetric deprotonation of epoxides.21 Previously, the 1,2-
diaminocyclohexane derivative 4a containing a chiral N-alkyl
group was prepared by the opening of an aziridine with (S)-a-

1250
M. Dalai, M. Periasamy / Tetrahedron: Asymmetry 20 (2009) 1247–1253
N
N
COCF3
COCF3
5
Figure 1. ORTEP diagram of compound 5.
Figure 2. ORTEP diagram of the compound 4c.
O
OTi(OiPr3)
H
NH2
NH
NH
NaBH4
Ti(OiPr4)
N
N
+
EtOH, rt, 12 h
NH2
solvent, rt, 12 h
H
OTi(OiPr3)
2d
(R,R)-1
(1R,2R,1'R,1''R)-4d
3d
Scheme 2.

M. Dalai, M. Periasamy / Tetrahedron: Asymmetry 20 (2009) 1247–1253
1251
Table 2
Ti(IV)-reductive N-alkylation reaction of (R,R)-trans-1,2-diaminocyclohexane 1 with
-tetralone under various experimental conditionsa
4. Experimental
a
Infrared spectra were recorded on JASCO FT-IR spectrophotom-
eter Model 5300. 1H NMR and 13C NMR spectra were recorded on
Bruker AV-400 spectrometers with chloroform-D as a solvent and
TMS as the reference (d = 0 ppm). Coupling constants J are given
in hertz. Elemental analyses were carried out on a Flash EA 1112
series analyzer. Optical rotations were measured in an AUTOPOL-
IV automatic polarimeter (readability 0.001). Chromatography
was carried out using Acme’s silica gel (100–200 mesh and 230–
400 mesh). Solvents were dried using the standard procedures.
The reagents were used as received after further distillation. The
commercial cis/trans mixture of 1,2-diaminocyclohexane was re-
solved following a literature procedure.15
Entry
Solvent
Temperature
Productb
Yieldc (%)
drd
1
2
3
4
5
MeOH
EtOH
THF
CH2Cl2
THF
rt
rt
rt
rt
4d
4d
4d
4d
4d
64
73
94
41
66
12:1:1
13:1:1
13:1:1
12:1:1
12:1:1
ꢀ78 °C
a
All reactions were carried out using 1.0 mmol of diamine 1, 2.2 mmol of
a
-tetralone, and 4.0 mmol of Ti(OiPr)4 in 5.0 mL of dry solvent at rt for 12 h and for
in situ reduction, 5.0 mmol of NaBH4 in 5.0 mL of absolute EtOH was used at rt and
stirred for 12 h.
b
The products were identified using spectroscopic data (IR and 1H and 13C NMR).
c
Yields are of the isolated product and correspond to the three diastereomers.
d
Diastereomeric ratio (dr) was determined by 1H NMR analysis of the crude
product mixture.
4.1. General procedure for the N-alkylation reaction of (R,R)-
trans-1,2-diaminocyclohexane 1
phenylethylamine catalyzed by lithium perchlorate in a three-step
reaction sequence in moderate chemical yield and diastereoselec-
tivity.22 Easy access to the chiral amines 4a–4i following the meth-
od described here should be helpful for further synthetic
exploitations.
A
mixture of the (R,R)-trans-1,2-diaminocyclohexane
1
(0.12 mL, 1 mmol), ketone 2 (2.2 mmol), and Ti(OiPr)4 (1.2 mL,
4 mmol) in dry THF (5 mL) was stirred for 12 h at room temperature
Ar
R
R
H
Ar
OTi(OiPr)3
H
H
..
O
H
..
Ti(OiPr)4
Ar
NH2
N
R
+
N
..
H
N
..
NH2
..
-Ti(OiPr)3OH
iPrOH
N
or
N
Ar
R
-
..
H
Ar
N
OTi(OiPr)3
H
2 equiv.
H
H
R
H
R
Ar
R
Ar
7
6
(R,R)-1
2
3
not preferred
preferred
NaBH4
EtOH
H
R
H
Ar
N
H
R
N
H
H
H Ar
'
''
4
(1R,2R,1R,1 R)-
Scheme 3.
without titanium complexation
si face
si face
attack
R
R
H
H2C
attack
R
H
Ar
BH4
BH4
Ar
H
BH4
R
N
N
N
Ar
H
C
..
si face
H
R
N
..
N
N
attack
H
H
R
Ar
BH4
CH2
H
si face
attack
H
H
Ar
Ar
re face
BH4
''
(1R,2R,1'R,1 R)-4
attack
6
6
major diastereomer
with titanium complexation
R
H
H
H
R
Ar
H
BH4
BH4
N
Ar
N
N
TiLn
si face
H
N
R
Ar
attack
H
BH4
H
H
R
Ar
''
(1R,2R,1'R,1 R)-4
8
Figure 3. Stereochemical models.

1252
M. Dalai, M. Periasamy / Tetrahedron: Asymmetry 20 (2009) 1247–1253
under a N2 atmosphere. Then NaBH4 (190 mg, 5 mmol) and
absolute EtOH (5 mL) were added at 0 °C under a N2 atmosphere
and the resulting mixture was stirred for an additional 12 h at
room temperature. The reaction mixture was then quenched by
adding water (1 mL). The solvent was evaporated and the residue
was stirred with Et2O (15 mL) for 15 min. The resulting inorganic
precipitate was filtered and washed with Et2O (10 mL). Next, H2O
(10 mL) was added to the filtrate and the organic layer was sepa-
rated and the remaining aqueous layer was extracted with Et2O
(10 mL). The combined organic extracts were washed with brine
(10 mL), dried over anhydrous Na2SO4, and the solvent was re-
moved at reduced pressure. The crude product was purified by col-
umn chromatography on silica gel.
cmꢀ1): 3306, 2924, 1595, 1489, 1369, 1091, 829; 1H NMR
(400 MHz; CDCl3): dH 7.30–7.25 (m, 8H), 3.79 (q, J = 6.6 Hz, 2H),
2.26–2.22 (m, 2H), 1.79–1.75 (m, 2H), 1.56–1.54 (m, 2H), 1.46 (br
s, 1H), 1.44 (br s, 1H), 1.28 (d, J = 6.6 Hz, 6H), 1.12–1.07 (m, 2H),
0.92–0.83 (m, 2H); 13C NMR (100 MHz; CDCl3) dC 146.2, 132.2,
128.5, 128.4, 127.9, 126.8, 60.5, 55.6, 32.7, 24.9, 24.1.
4.5. (1R,2R,10R,100R)-N,N0-Di(1,2,3,4-tetrahydro-1-
naphthalenyl)-1,2-cyclohexanediamine 4d
1H NMR analysis of the crude product mixture revealed that the
diastereomeric ratio (dr) is 13:1:1. The mixture containing three
diastereomeric products was isolated in 94% yield by column chro-
matography. The major diastereomer (1R,2R,10R,100R)-4d was iso-
lated in pure form by column chromatography (silica gel; 100–
200 mesh, hexane/EtOAc, 90/10) as a colorless liquid and the two
minor diastereomers were obtained together as a 1:1 mixture
using hexane/EtOAc (85/15) as an eluent in 9% yield. Major diaste-
4.2. (1R,2R,10R,100R) -N,N0-Di(1-phenylethyl)-1,2-
cyclohexanediamine 4a
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) was 8:1:1. The mixture containing
three diastereomeric products was isolated in 87% yield by flash
column chromatography. The major diastereomer was isolated in
pure form by flash column chromatography (silica gel; 230–400
mesh, hexane/EtOAc 97/3) as a colorless liquid. Major diastereo-
reomer (1R,2R,10R,100R)-4d: yield: 85% (0.32 g); ½a 2D5
¼ ꢀ115:1 (c
ꢁ
1.0, CHCl3); IR (neat, cmꢀ1): 3301, 3059, 2930, 2855, 1603, 1578,
1489, 739; 1H NMR (400 MHz; CDCl3) dH 7.34 (d, J = 6.6 Hz, 2H),
7.14–7.10 (m, 4H), 7.04 (d, J = 6.6 Hz, 2H), 3.77 (br s, 2H), 2.77–
2.60 (m, 4H), 2.33–2.30 (m, 4H), 1.86–1.66 (m, 10H), 1.33–1.12
(m, 6H); 13C NMR (100 MHz; CDCl3) dC 140.3, 137.4, 129.2, 128.8,
126.3, 125.7,59.2, 51.8, 32.6, 29.3, 28.0, 25.3, 18.5; CHN calcd: C,
83.4; H, 9.1; N, 7.5; found: C, 83.2; H, 9.1; N, 7.8.
mer (1R,2R,10R,100R)-4a: Yield: 61% (0.196 g); ½a 2D5
¼ ꢀ40:4 (c 1.1,
ꢁ
CHCl3), lit.22 for (1S,2S,10S,100S)-isomer ½a 2D5
¼ þ40:5 (c 1.0, CHCl3);
ꢁ
IR (neat) (cmꢀ1): 3308, 3061, 2926, 1602, 1493, 1448, 1122, 700;
1H NMR (400 MHz; CDCl3) dH 7.29–7.10 (m, 10H), 3.76 (q,
J = 6.6 Hz, 2H), 2.23–2.17 (m, 2H), 1.77–1.74 (m, 4H), 1.51–1.48
(m, 2H), 1.26 (d, J = 6.6 Hz, 6H), 1.06–1.02 (m, 2H), 0.88–0.78 (m,
2H); 13C NMR (100 MHz; CDCl3) dC 147.6, 128.3, 126.7, 126.6,
60.4, 56.1, 32.6, 25.0, 24.0.
4.6. (1R,2R,10R,100R)-N,N0-Di[1-(2-thienyl)ethyl]-1,2-
cyclohexanediamine 4e
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) is 23:1:1. The mixture containing
three diastereomeric products was isolated in 89% yield by column
chromatography. The major diastereomer (1R,2R,10R,100R)-4e was
isolated in pure form by column chromatography (silica gel;
100–200 mesh, hexane/EtOAc, 90/10) as a colorless liquid and
the two minor diastereomers were obtained together as a 1:1 mix-
ture using (75/15) hexane/EtOAc in 5% yield. Major diastereomer
4.3. (1R,2R,10R,100R)-N,N0-Di[1-(4-nitrophenyl)ethyl]-1,2-
cyclohexanediamine 4b
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) is 4:1:1. The mixture containing three
diastereomeric products was isolated in 80% yield by column chro-
matography. The major diastereomer (1R,2R,10R,100R)-4b was iso-
lated in pure form by column chromatography (silica gel; 100–
200 mesh, hexane/EtOAc, 90/10) as a colorless liquid and the two
minor diastereomers were obtained together as a 1:1 mixture
using hexane/EtOAc (75/15) as eluent in 19% yield. Major diaste-
(1R,2R,10R,100R)-4e: Yield: 84% (0.28 g); ½a 2D5
¼ ꢀ27:9 (c 1.0, CHCl3);
ꢁ
IR (neat, cmꢀ1): 3299, 3073, 2969, 2926, 2855, 1510, 1449; 1H NMR
(400 MHz; CDCl3) dH 7.18–7.16 (m, 2H), 6.95–6.93 (m, 4H), 4.20 (q,
J = 6.4 Hz, 2H), 2.33–2.31 (m, 2H), 2.00 (br s, 2H), 1.92–1.89 (m,
2H), 1.65–1.62 (m, 2H), 1.43 (d, J = 6.4 Hz, 6H), 1.20–1.15 (m,
2H), 1.05–1.00 (m, 2H); 13C NMR (100 MHz; CDCl3) dC 152.7,
126.4, 123.4, 122.5, 60.1, 51.5, 32.5, 25.0, 24.4; CHN calcd: C,
64.6; H, 7.8; N, 8.4; S, 19.2; found: C, 64.8; H, 7.9; N, 8.2; S, 19.1.
reomer (1R,2R,10R,100R)-4b: Yield: 61% (0.25 g); ½a 2D5
¼ ꢀ21:0 (c
ꢁ
1.0, CHCl3); IR (neat, cmꢀ1); 3306, 3930, 1601, 1516, 1344, 1109,
856; 1H NMR (400 MHz; CDCl3) dH 8.22 (d, J = 8.4 Hz, 4H), 7.48
(d, J = 8.4 Hz, 4H), 4.00 (q, J = 6.6 Hz , 2H), 2.17 (br s, 2H), 1.82–
1.84 (m, 4H), 1.63–1.50 (m, 2H), 1.35 (d, J = 6.6 Hz, 6H), 1.12–
0.96 (m, 2H), 0.92–0.81 (m, 2H); 13C NMR (100 MHz; CDCl3) dC
155.5, 146.8, 127.4, 123.6, 60.8, 55.9, 32.6, 24.8, 24.1; CHN calcd:
C, 64.06; H, 6.8; N, 13.5; O, 15.6; found: C, 64.07; H, 6.9; N, 14.6;
O, 14.5.
4.7. (1R,2R,10R,100R)-N,N0-Di[1-(2-naphthyl)ethyl]-1,2-
cyclohexanediamine 4f
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) is 7:1:1. The mixture of three diaste-
reomeric products was isolated by column chromatography (silica
gel; 100–200 mesh, hexane/EtOAc, 90/10). Yield: 76% (0.32 g). A
small quantity (0.030 g) of the major isomer was obtained in pure
form as a colorless liquid which solidified on standing. Major dia-
4.4. (1R,2R,10R,100R)-N,N0-Di[1-(4-chlorophenyl)ethyl]-1,2-
cyclohexanediamine 4c
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) is 7:1:1. The mixture containing three
diastereomeric products was isolated in 89% yield by column chro-
matography. The major diastereomer (1R,2R,10R,100R)-4c was iso-
lated in pure form by column chromatography (silica gel; 100–
200 mesh, hexane/EtOAc, 93/7) as a colorless liquid which solidi-
fies slowly. The two minor diastereomers were obtained together
as a 1:1 mixture using hexane/EtOAc (85/15) as an eluent in 20%
yield; major diastereomer (1R,2R,10R,100R)-4c: yield: 69%
stereomer (1R,2R,10R,100R)-4f: Mp: 73–75 °C; ½a 2D5
¼ ꢀ9:1 (c 0.5,
ꢁ
CHCl3); IR (neat, cmꢀ1): 3306, 3053, 2926, 2854, 1601, 1508,
1367, 746; 1H NMR (400 MHz; CDCl3) dH 7.87 (d, J = 8.4 Hz, 6H),
7.83 (s, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.50 (m, 4H), 4.06 (q,
J = 6.4 Hz, 2H), 2.43–2.37 (m, 2H), 1.89 (br s, 1H), 1.85 (br s, 1H),
1.62–1.53 (m, 4H), 1.48 (d, J = 6.4 Hz, 6H), 1.16–1.11 (m, 2H),
1.02–0.91 (m, 2H); 13C NMR (100 MHz; CDCl3) dC 147.7, 136.2,
135.4, 130.7, 130.4, 130.3, 128.5, 128.0, 127.9, 127.5, 63.3, 59.1,
35.4, 27.6, 26.8; CHN calcd: C, 85.3; H, 8.1; N, 6.6; found: C, 85.1;
H, 8.2; N, 6.7.
(0.269 g); Mp: 70–72 °C; ½a D25
¼ ꢀ17:5 (c 1.0, CHCl3); IR (neat,
ꢁ

M. Dalai, M. Periasamy / Tetrahedron: Asymmetry 20 (2009) 1247–1253
1253
4.8. (1R,2R,10R,100R)-N,N0-Di[1-(2-pyridyl)ethyl]-1,2-
cyclohexanediamine 4g
and DMAP (0.2 mmol) were added and the solution was stirred for
5 min. To this excess trifluoroacetic anhydride (TFAA) (2 mL) was
added slowly at 0 °C and the reaction mixture was stirred at room
temperature for 48 h. The mixture was extracted with CH2Cl2
(3 ꢂ 10 mL) and the combined organic layer was dried over anhy-
drous Na2SO4, filtered, and evaporated. The product was purified
by column chromatography (silica gel, hexane/EtOAc, 99/1). The
product was obtained as a white solid. Yield: 68% (0.35 g);
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) is 2:1:0. The mixture of diastereo-
meric products was isolated by column chromatography (silica
gel; 100–200 mesh, CHCl3/MeOH, 98/2) as a brownish liquid 4g
which solidified on standing. Yield: 90% (0.29 g). Upon further
purification a small quantity (0.050 g) of product containing major
diastereomer (1R,2R,10R,100R)-4g (87.5%) and the minor diastereo-
mer (12.5%) was obtained. Mp: 88–90 °C (for the mixture of diaste-
½
a 2D5
ꢁ
¼ þ34:7 (c 1.2, CHCl3) Mp: 150–152 °C; IR (neat, cmꢀ1):
3065, 2984, 2937, 1699, 1442, 1140, 744; 1H NMR (400 MHz;
CDCl3) dH 7.43–7.30 (m, 10H), 4.92 (q, J = 8 Hz, 2H), 4.27 (q,
J = 4 Hz, 2H), 2.30–2.28 (m, 2H), 1.69–1.66 (m, 4H), 1.54 (d,
J = 8 Hz, 6H), 1.33–1.28 (m, 2H); 13C NMR (100 MHz; CDCl3) dC
155.6 (q, J = 34 Hz), 137.1, 128.7, 128.6, 128.4, 116.0 (q,
J = 288 Hz), 56.5, 55.4, 29.0, 24.9, 18.4.
reomeric products, dr = 87.5:12.5:0): ½a D25
¼ ꢀ10:3 (c 1.0, CHCl3)
ꢁ
(for the mixture of diastereomeric products, dr = 87.5:12.5:0); IR
(KBr, cmꢀ1): 3294, 2934, 1593,1375, 856, 787; 1H NMR
(400 MHz; CDCl3) dH 8.40 (d, J = 4.6 Hz, 2H), 7.58–7.54(m, 2H),
7.24 (d, J = 7.8 Hz, 2H), 7.10–7.07 (m, 2H), 4.16 (q, J =6.8 Hz, 2H),
2.57–2.55 (m, 2H), 1.67–1.64 (m, 2H), 1.5 (m, 2H), 1.36 (d,
J = 6.8 Hz, 6H), 1.13–1.06 (m, 2H), 1.03–0.95 (m, 2H); 13C NMR
(100 MHz; CDCl3) dC 161.1, 148.8, 136.9, 122.6, 121.5, 59.1, 56.1,
30.2, 24.2, 21.1; CHN calcd: C, 74.0; H, 8.7; N, 17.2; found: C,
74.1; H, 8.7; N, 18.0.
Acknowledgments
We are thankful to the UGC for support under the University
with Potential for excellence (UPE), Center for Advanced Study
(CAS-SAP), and UGC-MHRD Chemistry Networking Center pro-
grams. Support of the DST under FIST program and award of the
DST-JC Bose National Fellowship grant to MP are gratefully
acknowledged. MD is thankful to the CSIR for the research
fellowship.
4.9. (1R,2R,10R,100R)-N,N0-Di[1-(4-methylphenyl)ethyl]-1,2-
cyclohexanediamine 4h
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) is 4:1:0. A mixture of two diastereo-
meric products was isolated by column chromatography (silica
gel; 100–200 mesh, hexane/EtOAc, 90/10) as a colorless liquid.
Yield: 95% (0.33 g). A small quantity (0.065 g) of the major diaste-
reomer was obtained in pure form. Major diastereomer
References
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12. Periasamy, M.; Srinivas, G.; Suresh, S. Tetrahedron Lett. 2001, 42,
7123.
(1R,2R,10R,100R)-4h: ½a 2D5
ꢁ
¼ ꢀ29:2 (c 1.2, CHCl3); IR (neat, cmꢀ1):
3306, 3015, 2961, 2924, 2857,1613, 1514, 1447, 1109, 818; 1H
NMR (400 MHz; CDCl3) dH 7.24 (d, J = 8.0 Hz, 4H), 7.12 (d,
J = 8.0 Hz, 4H), 3.8 (q, J = 6.4 Hz, 2H), 2.33 (s, 6H), 2.27–2.21 (m,
2H), 1.85 (br s, 1H), 1.81 (br s, 1H), 1.59–1.55 (m, 4H), 1.30 (d,
J = 6.4 Hz, 6H), 1.14–1.08 (m, 2H), 0.95–0.83 (m, 2H); 13C NMR
(100 MHz; CDCl3) dC 144.6, 136.2, 129.0, 126.5, 60.4, 55.8, 32.7,
25.0, 24.0, 21.1; CHN calcd: C, 82.2; H, 9.8; N, 8.0; found: C, 82.3;
H, 9.7; N, 7.6.
4.10. (1R,2R,10R,100R)-N,N0-Di[1-(4-methoxyphenyl)ethyl]-1,2-
cyclohexanediamine 4i
13. Periasamy, M.; Seenivasaperumal, M.; Padmaja, M.; Rao, V. D. Arkivoc 2004, 4.
14. Padmaja, M.; Periasamy, M. Tetrahedron: Asymmetry 2004, 15, 2437.
15. Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org. Chem.
1994, 59, 1969.
16. Kumpaty, H. J.; Bhattacharyya, S.; Rehr, E. W.; Gonzalez, A. M. Synthesis 2003,
14, 2206.
17. Salmi, C.; Letourneux, Y.; Brunel, J. M. Lett. Org. Chem. 2006, 3, 396.
18. Salmi, C.; Letourneux, Y.; Brunel, J. M. Lett. Org. Chem. 2006, 3, 384.
19. Loncle, C.; Salmi, C.; Letourneux, Y.; Brunel, J. M. Tetrahedron 2007, 63,
12968.
20. Tanuwidjaya, J.; Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2007, 72,
626.
The 1H NMR analysis of the crude product mixture revealed that
the diastereomeric ratio (dr) is 8:1:1. A mixture of three diastereo-
meric products was isolated by column chromatography (silica gel;
100–200 mesh, CHCl3/MeOH, 98/2) as a colorless liquid. Yield: 79%
(0.30 g). A small quantity (0.035 g) of the major diastereomer was
obtained in pure form. Major diastereomer (1R,2R,10R,100R)-4i:
½
a 2D5
ꢁ
¼ þ10:7 (c 0.6, CHCl3); IR (neat, cmꢀ1): 3293, 2932, 2857,
1610, 1512, 1248, 1033, 833; 1H NMR (400 MHz; CDCl3) dH 7.27
(d, J = 8.8 Hz, 4H), 6.86 (d, J = 8.8 Hz, 4H), 3.8 (s, 8H), 2.28–2.20
(m, 2H), 1.97 (br s, 2H), 1.86–1.77(m, 2H), 1.59–1.54 (m, 2H),
1.31(d, J = 6.4 Hz, 6H), 1.16–1.09 (m, 2H), 0.97–0.85 (m, 2H); 13C
NMR (100 MHz; CDCl3) dC 158.5, 139.7, 127.6, 113.8, 60.4, 55.5,
55.3, 32.7, 25.1, 24.0.
21. Bhuniya, D.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1996, 61,
6108.
22. Parrodi, C. A.; Moreno, G. E.; Quintero, L.; Juaristi, E. Tetrahedron: Asymmetry
1998, 9, 2093.
23. Crystal data for the compound 5: Molecular formula: C26H28F6N2O2, Mw = 514.5,
trigonal, space group: P3(1), a = 9.7315(3) Å, b = 9.7315(3) Å, c = 22.5776(17) Å,
a
l
= 90°, b = 90°,
c
= 120°
, q ,
V = 1851.69(16) Å3, Z = 3, c = 1.384 mg mꢀ3
= 0.118 mmꢀ1
, T = 298(2) K. Of the 4787 reflections collected, 4206
reflections were unique (Rint = 0.0198). Refinement on all data converged at
R1 = 0.0451, wR2 = 0.1068 (CCDC deposition number 720608).
5. Representative procedure for the synthesis of
(1R,2R,10R,100R)-2,2,2-trifluoro-N-(1-phenyl-ethyl)-N-{2-[(1-
phenyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-cyclohexyl}-
acetamide 5
24. Crystal data for the compound 4c: Molecular formula: C22H28N2Cl2,
Mw = 391.36, orthorhombic, space group: P2(1)2(1)2(1), a = 5.7190(11) Å,
b = 16.311(3) Å, c = 23.291(5) Å,
a
= 90°, b = 90°,
c
= 90°, V = 2172.5(7) Å3,
Z = 4, ,
q
c = 1.197 mg mꢀ3 = 0.307 mmꢀ1
,
l
T = 293(2) K. Of the 6359
reflections collected, 4630 reflections were unique (Rint = 0.1134). Refinement
on all data converged at R1 = 0.0414, wR2 = 0.0997 (CCDC deposition number
720607).
To a solution of (1R,2R,10R,100R) diamine 4a (0.32 g, 1 mmol) in
solvent DCE (5 mL) under N2 atmosphere, Et3N (0.3 mL, 2.1 mmol)