L-Menthol as new scaffold for designing chiral phase-transfer catalysts

Article abstract of DOI:10.1016/j.tetasy.2005.07.011

We herein report, a new class of chiral phase-transfer catalysts derived from l-menthol. The moderately good enantioselectivity exhibited by these catalysts have been explained based on single crystal X-ray data and molecular modelling studies.

Full text of DOI:10.1016/j.tetasy.2005.07.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2599–2605
L-Menthol as new scaffold for designing chiral
phase-transfer catalysts
Sanjeev Kumar,a,* Masilamani Elizabeth Sobhiab and Uma Ramachandrana,*
aDepartment of Pharmaceutical Technology, National Institute of Pharmaceutical Education and Research (NIPER),
S.A.S. Nagar, Sec-67, Mohali 160 062, Punjab, India
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Sec-67,
Mohali 160 062, Punjab, India
Received 25 May 2005; accepted 6 July 2005
Abstract—We herein report, a new class of chiral phase-transfer catalysts derived from L-menthol. The moderately good enantio-
selectivity exhibited by these catalysts have been explained based on single crystal X-ray data and molecular modelling studies.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of both enantiomers, it can be used as a versatile, chiral
synthon.
Since, the first successful chiral phase-transfer catalyst
(PTC) was reported by Dolling,1 their applications have
increased many fold.2 Many laboratories across the
world are currently engaged in research in this area.3
For the preparation of quaternary ammonium salts
from L-menthol, it was converted to L-menthylamine.9
This amine was dimethylated using methyl iodide in
80% yield and was quaternalized with different alkyl
halides (viz. benzyl bromide and 2-bromomethylnaph-
thalene). The quaternization was found to be very slug-
gish; taking almost 96 h for completion. However, the
quaternary ammonium salts 2a and 2b, were obtained
in good yields (Scheme 1). When the above catalysts
were used in the benzylation of benzophenone imine
tert-butyl glycinate 16, the product was obtained with
very poor enantioselectivites (Scheme 3, Table 1, entries
1–2).
However, most of the research in the development of
chiral PTCs from the chirality pool is centered on cin-
chona alkaloids. Reports on high enantiomeric excess
of up to 94% in C-alkylation reactions using prolinol
derived chiral PTCs4 had to be retracted on reinvestigation
by Dehmlow et al.5 Camphor based chiral PTCs yielded
only 39% enantiomeric excess for similar reaction.6
Thus, the initial efforts on shifting from cinchona alka-
loids to other naturally occurring templates met with
limited success. Recently, there have been reports of
some successful catalysts based on tartaric acid
derivatives.7
Br
R
i
ii
N
NH2
N
1
2
2. Results and discussion
a) R = Ph (80%), b) 2-Naphthyl (65%)
Scheme 1. Reagents and conditions: (i) MeI, KOH, CH2Cl2, 2 h, 80%;
(ii) RBr, CH3CN, 96 h.
We report herein, our initial findings in designing new
chiral PTCs from naturally occurring L-menthol. Men-
thol and its derivatives have been widely used as chiral
auxiliaries and chiral ligands in the field of asymmetric
synthesis.8 Due to its low cost and ease of availability
Attempts at making N,N-dibenzyl salt 4 from N,N-
dibenzyl menthylamine 3 were not successful (Scheme 2).
We then converted this amine to the amide 5 using chloro-
acetyl chloride in presence of N,N-dimethylaniline in
dichloromethane. Chloride 5 was first aminated using
*
Corresponding authors. Tel.: +91 172 214682 87; fax: +91 172
214692; e-mail: umaram@yahoo.com
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.011

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S. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2599–2605
Table 1. Benzylation of N-(diphenylmethylene)glycine tert-butyl ester
Entry Catalyst Time (h) Yielda (%) %Selectivityb (R:S)
O
O
HN
O
ii
i
NHMe
X
1
2
3
4
5
6
7
8
9
2a
2c
7
36
32
15
6
2
12
7
87
83
89
87
94
88
80
82
78
52:48
52:48
62:34
83:17
74:26
74:26
63:37
81:19
81:19
N
H
N
5
8
N
H
10
11
12
13
14
15
9
O
HN
O
iii
N
R
N
H
8
8
10) R = Ph, X = Br. 11) R =H, X = I. 12) R = 1-Naphthyl, X = Br.
a Yields of isolated product.
b Based on chiral HPLC using Chiralcel OD-H column.
Ph
X = Br
Ph
O
13)
15)
HN
OH
X = Br
14)
OH
X = I
Ph
Ph
Ph
I
i
Scheme 5. Reagents and conditions: (i) NH2Me, 1,3-dioxane, 4 h,
90%; (ii) 5, K2CO3, CH3CN, 8 h, 93%, (iii) RCH2X, CH3CN.
ii
NH2
N
N
Ph
3
4
Ph
Scheme 2. Reagents and conditions: (i) BnBr, NEt3, CH2Cl2, 4 h, 94%;
(ii) MeI, CH3CN.
R
OtBu
OtBu
i
Ph2C
Ph2C
N
N
O
O
17a-g
16
Bn
OtBu
OtBu
i
Ph2C
Ph2C
N
N
Scheme 6. Reagents and conditions: (i) RBr, 10 (10 mol %), 50% aq
KOH, ꢀ20 ꢁC.
O
O
17d
16
A systematic study of various quaternary groups on
compound 9 was undertaken. Catalyst 11, having
N,N-dimethyl moieties decreased the enantioselectivity
(74:26). Compound 12 with N,N-methyl(methylnaph-
thyl) groups showed similar enantiocontrol (74:26).
The introduction of another L-menthyl unit linked
through the amide bond as in catalyst 13 did not
improve the enantioselectivity (Table 1, entry 7). Fur-
ther, substitution on the phenyl ring as in catalysts 14
and 15 showed almost same level of selectivity (81:19,
Table 1, entry 8 and 9). In all the above cases, the abso-
lute stereochemistry of the benzylated product 17d was
found to be R as detected by chiral HPLC.2
Scheme 3. Reagents and conditions: (i) BnBr, cat. (10 mol %), 50% aq
KOH, ꢀ20 ꢁC.
N-methylbenzyl amine to give 6 in 93% yield, which was
quaternized with benzyl bromide to afford quaternary
ammonium salt 7 in 92% yield (Scheme 4).
O
i
ii
Cl
NH2
O
N
H
5
O
iii
N
Our endeavors at using L-menthol as a chiral synthon
for developing a chiral phase-transfer catalyst has high-
lighted a few important points. Catalysts 7 and 10–15
are novel and though these catalysts are highly flexible,
they seem to show significant stereoselectivity in alkyl-
ation reactions based on ion-pair mechanism. This sug-
gested that the structure may have obtained some sort of
rigidity by internal hydrogen bonding(s).
N
N
H
N
H
Br
6
7
Scheme 4. Reagents and conditions: (i) chloroacetyl chloride, N,N-
dimethylaniline, CH2Cl2, 3 h, 80%; (ii) N-methyl benzyl amine,
K2CO3, CH3CN, 2 h, 93%; (iii) BnBr, CH3CN, 3 h, 92%.
To understand how the groups are placed around the
quaternary nitrogen atom, we decided to obtain X-ray
crystal data (Fig. 1). Attempts at crystallizing the best
catalyst 10 were unsuccessful; however, the dimethylated
analogue 11 was crystallized from acetone. The crystal
data of catalyst 11 shows that the two amide groups
are far apart and that there is no possibility of internal
hydrogen bonding.10
Using 7 as PTC for the benzylation of N-(diphenylmeth-
ylene)glycine tert-butyl ester, we obtained the benzyl-
ated product in 24% enantiomeric excess with a
preference for the (R)-isomer (Table 1, entry 3).
Encouraged by the above results, we designed a catalyst
having two menthyl units linked by an amide function
following Scheme 5. Quaternization of compound 9 with
benzyl bromide gave quaternary ammonium salt 10,
which further enhanced the level of enantioselectivity
(83%, Table 1, entry 4).
However, it is possible that some intermolecular interac-
tions may be playing a part in stabilizing particular ori-
entations of the ion-pair formed between the enolate of

S. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2599–2605
2601
for the asymmetric alkylation of 16 with various alkyl
halides, using the similar conditions, and at ꢀ20 ꢁC
are given in Table 2 (Scheme 6). Good stereoselectivity
ranging between 81% and 86% was observed with these
alkylating agents (Table 2, entries a–h) for the asymmet-
ric synthesis of a-amino acids.
3. Conclusion
In conclusion, these are encouraging preliminary studies
for helping design better phase-transfer catalysts using
L-menthol scaffold.
4. Experimental
4.1. General
Figure 1. ORTEP diagram of catalyst 11.
Melting points are uncorrected. 1H and 13C spectra were
recorded at 300 and 75 MHz Bruker Advance Spectro-
meter respectively, with chemical shifts in ppm and tet-
ramethylsilane as the internal standard. Infra-red
absorption spectra were recorded on a Nicolet Impact
410 spectrometer, the frequencies in the IR spectra are
indicated in cmꢀ1. Mass spectra data were recorded on
a Finnigan-MAT LC–MS spectrometer. Elemental anal-
yses were recorded on a Elementa Vario EL. HPLC was
performed on a Shimadzu SPD-10A using chiral phase
column DIACEL Chiralcel, OD-H). TLC was per-
formed on plates pre-coated (0.25 mm) with silica gel
60, Merck F-254. The plates were visualized by the use
of a combination of UV 254 nm) and iodine. Column
chromatography was carried out with silica gel Merck
60 (80–230 mesh).
the substrate and the positively charged quaternary
nitrogen, during benzylation/alkylation reaction. One
can also postulate that the original form of the catalyst
may be undergoing conformational changes due to the
formation of ammonium ylides (by the abstraction of
the a-H of amide by the base). Thus, factors that are
responsible for the control of the enantioselectivity are
yet to be fully understood.
As expected, catalyst 10, which has an aromatic group
for quaternalization as compared to catalyst 11, which
has alkyl units, have shown better selectivity.11
Taking catalyst 10, phase-transfer alkylation with vari-
ous alkyl halides was carried out. The results obtained
4.2. Synthesis of N-[(1R,2S,5R)-2-isopropyl-5-methyl-
cyclohexyl]-N,N-dimethylamine 1
Table 2. Alkylation of imine 16 using catalyst 10
Entry RXa
Time Yieldc
%Selectivityd,e
(h)
(%)
(R:S)
To a solution of menthylamine (5.0 g, 32.1 mmol) at
ꢀ10 ꢁC in dichloromethane (25 mL) was added methyl
iodide (11.3 g, 79.61 mmol) and 50% aqueous KOH
(10.7 mL). After stirring the reaction mixture for 2 h at
ꢀ5 ꢁC, CH2Cl2 (50 mL) was added and the organic
phase washed with water (3 · 20 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, hexane–
a
b
CH3CH2Ib
CH3(CH2)4CH2Ib
7
7
66, 17a 82:18
78, 17b 86:14
Br
c
4
92, 17c 85:14
Br
Br
d
6
87, 17d 83:17
e
f
5
91, 17e 83:17
F
EtOAc, 90:10) to give
1
as oil (4.7 g, 80%).
25
½aꢁD ¼ ꢀ55.8 (c 1.9, CHCl3); IR (film) m 2932, 2563,
Br
1605, 1515, 1462, 1392, 1370, 1170, 1026, 956 cmꢀ1
;
11
84, 17f
82.5:17.5
N
1H NMR (CDCl3): d 0.72 (d, J = 10.71, 3H), 0.87 (d,
J = 6.51, 3H), 0.92 (d, J = 6.49, 3H), 1.0–1.22 (m,
4H), 1.29 (m, 1H), 1.60–1.79 (m, 4H), 2.20 (s, 6H);
MS (APCI): m/z (%) 184 (M++1, 100).
HBr
Br
g
8
86, 17g 81:19
a The reaction was carried out with RX (2.0 equiv) and aqueous KOH
(50%, 12 equiv) in the presence of 10 (10 mol %) in toluene/CH2Cl2
(7:3) at ꢀ20 ꢁC.
4.3. Synthesis of benzyl[(2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexyl]dimethylammonium bromide 2a
b RX (5.0 equiv) was used.
To a solution of 1 (0.500 g, 2.72 mmol) in acetonitrile
was added benzyl bromide (0.932 g, 5.54 mmol) and
the reaction mixture was stirred at 80 ꢁC for 96 h. After
removing the solvent in vacuo the residue was
crystallized with EtOAc–hexane to afford 2a as white
c Yields of isolated products.
d Based on chiral HPLC using Chiralcel OD-H column.
e The absolute configuration was determined by comparision of the
HPLC retention time with that of an authentic sample, which was
independently checked with the known procedure.2,3

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S. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2599–2605
crystalline solid (0.695 g, 80%). Mp 158–159 ꢁC.
was evaporated, the residue diluted with water (15 mL)
and then extracted with CH2Cl2 (3 · 50 mL). The com-
bined organic extract was dried over anhydrous Na2SO4
25
½aꢁD ¼ ꢀ43.4 (c 0.4, CHCl3); IR (KBr) m 3019, 2958,
2870, 1467, 1455, 1372, 1346, 1163 cmꢀ1 1H NMR
;
(CDCl3): d 1.04 (d, J = 1.94, 6H), 1.18 (d, J = 5.39,
3H), 1.53–2.24 (m, 9H), 3.04 (s, 3H), 3.15 (s, 3H), 4.38
(m, 1H), 4.91 (d, J = 12.4, 1H), 4.84 (d, J = 12.6, 1H),
7.43 (d, J = 7.24, 3H), 7.76 (d, J = 7.14, 2H); 13C
NMR (CDCl3): d 19.9, 22.0, 22.8, 26.3, 27.3, 30.5,
31.7, 40.9, 46.7, 64.3, 74.2, 127.4, 129.0, 130.5, 133.6.
MS (APCI): m/z (%) 274 (M+ꢀ80, 35), 184 (100). Anal.
Calcd for C19H32BrN: C, 64.40; H, 9.10; N, 3.95.
Found: C, 63.97; H, 10.32; N, 3.12.
and concentrated in vacuo to afford 6 as oil (0.655 g,
25
93%). ½aꢁD ¼ ꢀ53.0 (c 1, CHCl3); IR (film) m 3310,
3018, 2952, 2922, 2863, 1660, 1516, 1454, 1369, 1125,
1027 cmꢀ1 1H NMR (CDCl3): d 0.75 (d, J = 6.84,
;
3H), 0.88 (d, J = 6.80, 6H), 0.84–0.86 (m, 2H), 1.01–
1.16 (m, 2H), 1.47 (br s, 1H), 1.78–1.95 (m, 4H), 2.27
(s, 3H), 2.96 (d, J = 16.2, 1H), 3.04 (d, J = 16.3, 1H),
3.55 (s, 2H), 3.76 (m, 1H), 6.97 (d, J = 9.47, 1H),
7.27–7.31 (m, 5H); 13C NMR (CDCl3): d 15.8, 20.9,
21.9, 23.5, 26.6, 29.45, 31.3, 31.6, 34.8, 42.8, 43.0, 47.7,
46.0, 60.7, 62.0, 127.2, 128.2, 128.5, 137.5, 169.4; MS
(APCI): m/z (%) 318 (M++2, 20), 317 (100).
4.4. Synthesis of (2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexyl(dimethyl)2-naphthylammonium bromide 2b
The procedure described for compound 2a was fol-
lowed; 2b was obtained as a white crystalline solid
4.7. Synthesis of dibenzyl[(2S,1R,5R)-2-isopropyl-5-
methylcyclohexylcarbamoylmethyl]methylammonium
bromide 7
(0.750 g, 65%) from 1 and 2-(bromomethyl)naphthalene.
25
Mp 182–183 ꢁC; ½aꢁD ¼ ꢀ58.1 (c 0.35, CHCl3); IR (KBr)
m 3010, 2954, 2924, 2866, 1477, 1455, 1370, 1258,
To a solution of 6 (0.350 g, 1.10 mmol) in toluene
(10 mL) was added benzyl bromide (0.378 g,
2.21 mmol). After stirring the reaction mixture for 3 h
at 100 ꢁC, toluene was evaporated under vacuum. The
residue was diluted with hexane (10 mL), stirred at rt
1
1162 cmꢀ1; H NMR (CDCl3): d 1.04 (s, 6H), 1.21 (s,
3H), 1.58–1.71 (m, 5H), 1.91 (m, 2H), 2.25 (m, 2H),
3.05 (s, 3H), 3.18 (s, 3H), 4.44 (br s, 1H), 5.07 (d, J =
12.2, 1H), 5.01 (d, J = 12.4, 1H), 7.53 (t, J = 7.59,
2H), 7.77–7.92 (m, 4H), 8.29 (s, 1H); 13C NMR
(CDCl3): d 20.0, 22.0, 22.1, 22.8, 26.2, 27.3, 30.5, 31.6,
41.1, 46.7, 64.0, 124.4, 126.8, 127.6, 127.6, 128.4,
128.8, 129.5, 132.7, 133.6, 134.2; MS (APCI): m/z (%)
324 (M+ꢀ80, 100), 185 (35). Anal. Calcd for
C22H32BrN: C, 67.68; H, 8.26; N, 3.59. Found: C,
66.74; H, 9.32; N, 3.02.
and filtered to afford 7 as an off-white solid (0.506 g,
25
92%). Mp 98–99 ꢁC. ½aꢁD ¼ ꢀ16.0 (c 1.65, CHCl3); IR
(KBr) m 3421, 3188, 3041, 2954, 2869, 1673, 1556,
1456, 1365, 1288, 1257, 1212, 1111 cmꢀ1 1H NMR
;
(CDCl3): d 0.81 (d, J = 6.87, 3H), 0.88 (d, J = 6.88,
3H), 0.91 (d, J = 7.21, 3H), 1.04–1.28 (m, 3), 1.43 (t,
J = 11.31, 2H), 1.68 (d, J = 10.79, 2H), 1.92–2.04 (m,
2H), 3.07 (s, 3H), 3.86 (m, 1H), 4.17 (d, J = 14.52,
1H), 4.56 (d, J = 14.52, 1H), 4.67 (d, J = 12.39, 1H),
4.75 (d, J = 12.33, 1H), 5.21 (d, J = 12.33, 1H), 5.31
(d, J = 12.39, 1H), 7.44–7.60 (m, 10H), 8.75 (d,
J = 8.91, 1H); 13C NMR (CDCl3): d 15.7, 21.1, 22.0,
23.4, 26.6, 31.9, 34.1, 41.9, 46.2, 47.4, 51.0, 59.3, 65.6,
65.8, 126.6, 129.5, 131.1, 133.2, 162.7; MS (APCI): m/z
(%) 408 (M+ꢀ80, 25), 407 (100), 317 (42). Anal. Calcd
for C27H39BrN2O: C, 66.52; H, 8.06; N, 5.75. Found:
C, 65.43; H, 8.76; N, 4.98.
4.5. Synthesis of 2-chloro-N-[(1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl]acetamide 5
To a cooled (ꢀ20 ꢁC) mixture of menthylamine (5.0 g,
32.1 mmol) and N,N-dimethylaniline (5.07 g, 41.8 mmol)
in CH2Cl2 (30 mL) was added chloroacetyl chloride
(4.36 g, 38.6 mmol) dropwise over a period of 10 min
under argon. After stirring the reaction mixture for
3 h, it was diluted with water (15 mL) and the aqueous
layer extracted with CH2Cl2 (3 · 50 mL), dried over
Na2SO4 and concentrated under vacuum. The residue
was purified by column chromatography (SiO2, hex-
4.8. Synthesis of N-[(1R,2S,5R)-2-isopropyl-5-methyl-
cyclohexyl]-2-(methyl amino)acetamide 8
ane–EtOAc, 95:5) to afford 5 as white solid (6.56 g,
25
80%). Mp 69–70 ꢁC; ½aꢁD ¼ ꢀ52.9 (c 0.65, CHCl3); IR
To a solution of 5 (5.0 g, 22.0 mmol) in 1,3-dioxane
(15 mL) at 0 ꢁC was added a solution of methylamine
(10 mL, prepared by bubbling methylamine in 1,3-
dioxane for 1 h). After stirring the reaction mixture for
4 h at 0 ꢁC, the solvent was removed under reduced pres-
sure. The residue was dissolved in CH2Cl2 (50 mL),
washed with water, brine, dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by
(KBr) m 3275, 3089, 2953, 2863, 1651, 1567, 1445,
1365, 1346, 1240, 1161, 1111 cmꢀ1; H NMR (CDCl3):
1
d 0.79 (d, J = 6.81, 3H), 0.90 (t, J = 5.37, 6H), 1.03–
1.19 (m, 4H), 1.48 (br s, 1H), 1.71–1.98 (m, 4H), 3.79
(m, 1H), 4.05 (s, 2H), 6.29 (d, J = 9.42, 1H); 13C
NMR (CDCl3): d 16.1, 21.0, 22.0, 23.7, 26.8, 31.7,
34.3, 42.6, 42.7, 47.7, 50.4, 164.8; MS (APCI): m/z (%)
232 (M+, 18), 231 (100).
column chromatography (MeOH–CHCl3, 5:95) to af-
25
ford 8 as oil (4.39 g, 90%). ½aꢁD ¼ ꢀ91.6 (c 0.24, CHCl3);
4.6. Synthesis of N1-[(2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexyl]-2-benzyl(methyl)aminoacetamide 6
IR (film) m 3293, 2953, 2922, 2870, 1647, 1528, 1451,
1
1369, 1288, 1115 cmꢀ1; H NMR (CDCl3): d 0.78 (d,
J = 6.94, 3H), 0.88 (t, J = 6.01, 6H), 0.88–1.96 (m,
9H), 2.41 (s, 3H), 3.22 (s, 2H), 3.76 (m, 1H), 6.93 (d,
J = 9.43, 1H); 13C NMR (CDCl3): d 16.0, 21.1, 22.1,
3.7, 26.8, 31.8, 34.5, 36.7, 43.1, 47.9, 49.3, 54.6, 170.3;
MS (APCI): m/z (%) 228 (M++2, 10), 227 (100).
To a suspension of 5 (0.500 g, 2.15 mmol) and K2CO3
(0.596 g, 4.31 mmol) in acetonitrile (10 mL) was added
N-methylbenzylamine (0.260 g, 2.14 mmol). After stir-
ring the reaction mixture for 2 h at 80 ꢁC, the solvent

S. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2599–2605
2603
4.9. Synthesis of N1-[(2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexyl]-2-[(2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexylcarbamoylmethyl(methyl)amino]acetamide 9
1.90 (d, J = 9.42, 4H), 2.09 (s, 2H), 3.58 (s, 6H), 3.80
(m, 2H), 4.61 (d, J = 13.6, 2H), 4.67 (d, J = 13.6, 2H),
7.58 (d, J = 9.09, 2H); 13C NMR (CDCl3): d 15.7, 21.0,
21.9, 23.4, 26.7, 31.8, 34.1, 42.1, 46.4, 51.1, 52.7, 64.6,
161.5; MS (APCI): m/z (%) 436 (M+ꢀ127, 60), 316,
241, 154. Anal. Calcd for C26H50IN3O2: C, 55.41; H,
8.94; N, 7.46. Found: C, 55.20; H, 8.84; N, 7.35.
To a suspension of 8 (3.0 g, 13.2 mmol) and K2CO3
(1.83 g, 13.2 mmol) in acetonitrile (30 mL) was added 5
(3.4 g, 14.7 mmol). After stirring the reaction mixture
for 8 h at 60 ꢁC, the solvent was evaporated, the residue
diluted with water (25 mL) and extracted with CH2Cl2
(3 · 50 mL). The combined organic extract was dried
over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography
4.12. Di[(2S,1R,5R)-2-isopropyl-5-methylcyclohexyl-
carbamoylmethyl][1-naphthylmethyl](methyl)ammonium
bromide 12
(EtOAc–hexane, 50:50) to afford 9 as an off-white solid
The procedure described for compound 10 was fol-
lowed; 12 was obtained as white solid (0.632 g, 83%)
25
(5.19 g, 93%). Mp 123–124 ꢁC; ½aꢁD ¼ ꢀ72.1 (c 0.33,
CHCl3); IR (KBr) m 3352, 3252, 3078, 2953, 2870, 1633,
from 7 (0.500 g, 1.18 mmol) and 2-(bromomethyl)-naph-
25
1
1531, 1446, 1386, 1305, 1130 cmꢀ1; H NMR (CDCl3):
thalene (1.305, 1.47 mmol). Mp 94–95 ꢁC; ½aꢁD ¼ ꢀ46.4
d 0.78 (m, 22H), 1.11 (m, 4H), 149–1.87 (m, 7H), 1.85 (t,
4H), 1.95 (d, J = 12.04, 3H), 2.36 (s, 3H), 3.04 (d,
J = 15.8, 2H), 3.11 (d, J = 15.8, 2H), 3.81 (m, 2H), 6.33
(d, J = 9.26, 2H); 13C NMR (CDCl3): d 15.9, 21.3, 22.1,
23.6, 27.0, 31.8, 34.4, 43.1, 43.9, 47.9, 49.7, 61.5, 168.6;
MS (APCI): m/z (%) 423 (M++2, 26), 422 (100).
(c 0.37, CHCl3); IR (KBr: m 3207, 3053, 2944, 2922,
2869, 1681, 1557, 1455, 1365, 1288, 1247, 1180 cmꢀ1
;
1H NMR (CDCl3): d 0.80 (t, J = 7.33, 6H), 0.92 (d,
J = 6.55, 12H), 1.09–2.17 (m, 18H) 3.14 (s, 3H), 3.81
(m, 2H), 4.33 (d, J = 13.86, 1H), 4.57 (s, 2H), 4.88 (d,
J = 12.93, 1H), 5.78 (d, J = 12.4, 1H), 5.86 (d, J =
12.5, 1H), 6.38 (d, J = 9.39, 2H), 7.57 (q, J = 7.28,
1H), 7.71 (t, J = 7.13, 1H), 7.94 (d, J = 7.14, 1H), 8.03
(d, J = 7.86, 1H), 8.16 (d, J = 8.37, 1H), 8.23 (d, J =
8.80, 1H), 8.47 (d, J = 8.47, 1H); 13C NMR (CDCl3):
d 15.8, 21.1, 21.3, 22.0, 23.5, 26.9, 31.9, 34.1, 41.9,
42.1, 46.5, 48.7, 51.4, 61.8, 62.6, 123.4, 125.2, 126.8,
128.5, 129.4, 132.4, 134.0, 162.2; MS (APCI): m/z (%)
562 (M+ꢀ80, 45), 422 (100). Anal. Calcd for
C36H56BrN3O2: C, 67.27; H, 8.78; N, 6.54. Found: C,
66.36; H, 9.03; N, 6.42.
4.10. Synthesis of benzyl{di[(2S,1R,5R)-2-isopropyl-5-
methylcyclohexylcarbamoylmethyl]}methylammonium
bromide 10
To a solution of 9 (0.500 g, 1.18 mmol) in acetonitrile
(20 mL) was added benzyl bromide (0.608 g,
3.55 mmol). After stirring the reaction mixture for 10 h
at 75 ꢁC, acetonitrile was evaporated under reduced
pressure. The residue was diluted with hexane (15 mL),
stirred at rt and filtered to afford 10 as an off-white solid
25
(0.618 g, 88%). Mp 79–80 ꢁC; ½aꢁD ¼ ꢀ43.7 (c 0.37,
4.13. Synthesis of tri[(2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexylcarbamoylmethyl](methyl)ammonium
iodide 13
CHCl3); IR (KBr) m 3205, 3055, 2952, 2926, 2856,
1
1676, 1552, 1455, 1288, 1111 cmꢀ1; H NMR (CDCl3):
d 0.79 (d, J = 5.04, 6H), 0.88–0.97 (m, 14H), 1.05 (m,
4H), 1.32 (m, 2H), 1.46 (m, 2H), 1.69 (m, 4H), 1.93
(m, 4H), 3.40 (s, 3H), 3.81 (m, 2H), 4.14 (d, J = 14.25,
1H), 4.28 (s, 2H), 4.57 (d, J = 14.27, 1H), 5.31 (s, 2H),
7.45–7.51 (m, 3H), 7.63 (d, J = 7.73, 2H), 8.37 (t,
J = 6.85, 2H); 13C NMR (CDCl3): d 15.7, 19.0, 21.0,
21.9, 23.3, 26.6, 29.6, 31.8, 34.0, 41.9, 46.3, 49.6, 50.9,
61.0, 61.2, 65.5, 126.5, 128.7, 129.3, 130.8, 131.0,
133.1, 162.5; MS (APCI): m/z (%) 513 (M+ꢀ80, 33),
512 (100), 423 (20), 422 (58). Anal. Calcd for
C32H54BrN3O2: C, 64.85; H, 9.18;N, 7.09. Found: C,
64.01; H, 10.02; N, 6.84.
To a solution of 9 (0.150 g, 0.355 mmol) in acetonitrile
(15 mL) was added 5 (0.082 g, 0.355 mmol) and sodium
iodide (0.053 g, 0.355 mmol) and the reaction mixture
stirred at 80 ꢁC for 48 h. Evaporation of the solvent
afforded the residue, which was purified by preparative
TLC (MeOH–CHCl3, 8:92) to give 13 (0.210 g, 68%)
25
as yellowish solid. Mp 210–211 ꢁC; ½aꢁD ¼ ꢀ98.2 (c
0.24, CHCl3); IR (KBr) m 3445, 3066, 2956, 2929,
2870, 1668, 1548, 1384, 1180, 1112, 1056, 978 cmꢀ1
;
1H NMR (CDCl3): d 0.75 (d, J = 6.39, 9H), 0.89 (m,
18H), 0.98 (m, 6H), 1.25 (m, 3H), 1.45 (m, 3H), 1.68
(m, 6H), 1.86 (m, 6H), 2.12 (m, 3H), 3.61 (s, 3H), 3.76
(m, 3H), 4.71 (dd, J = 13.53, 9.78, 6H), 7.03–7.24 (m,
3H); 13C NMR (CDCl3): d 15.9, 15.8, 21.0, 21.2, 21.9,
22.1, 23.4, 23.6, 26.8, 29.7, 31.9, 34.1, 34.3, 42.2, 42.8,
46.7, 47.3, 50.1, 50.5, 51.2, 60.1, 62.8, 161.7, 169.3; MS
(APCI): m/z (%) 618 (M+ꢀI, 45), 617 (100), 603 (20).
Anal. Calcd for C37H69BrN4O3: C, 63.68; H, 9.97; N,
8.03. Found: C, 62.86; H, 10.84; N, 7.64.
4.11. Synthesis of di[(2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexylcarbamoylmethyl](dimethyl)ammonium
iodide 11
To a solution of 9 (0.500 g, 1.18 mmol) in acetonitrile
(20 mL) was added methyl iodide (0.502 g, 3.53 mmol).
After stirring the reaction mixture for 3 h at rt, acetoni-
trile was removed under vacuum. The residue was crys-
tallized from acetone to afford 11 as white crystalline
4.14. Synthesis of 3-(hydroxy-diphenyl-methyl)-benzyl-
{di-[(2S,1R,5R)-2-isopropyl-5-methylcyclohexylcarbamoyl-
methyl]}(methyl) ammonium bromide 14
25
solid (0.561 g, 84%). Mp 191–192 ꢁC; ½aꢁD ¼ ꢀ57.1 (c
0.26, CH2Cl2); IR (KBr) m 3212, 2958, 2869, 1678,
1
1546, 1448, 1380, 1286 cmꢀ1; H NMR (CDCl3): d 0.75
(d, J = 6.90, 6H), 0.88–1.05 (m, 16H), 1.34 (t,
To a solution of 9 (0.250 g, 0.592 mmol) in acetonitrile
J = 11.55, 2H), 1.46 (m, 2H), 1.70 (d, J = 10.65, 4H),
(10 mL) was added [3-(bromomethyl)phenyl](diphenyl)-

2604
S. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2599–2605
methanol (0.314 g, 0.88 mmol). After stirring the reac-
tion mixture for 12 h at 75 ꢁC, acetonitrile was evapo-
rated in vacuo and the residue purified by column
chromatography (CHCl3–MeOH, 90:10) to afford 14
(CDCl3): d 0.87 (t, J = 6.8, 3H), 1.26–1.23 (m, 8H),
1.44 (s, 9H), 1.86 (m, 2H), 3.98 (t, J = 6.7, 1H), 7.18
(dd, J = 5.1, 2.0, 2H), 7.32–7.43 (m, 5H), 7.64–7.79
(m, 3H); MS (MALDI): m/z 380 (M++1). Rt HPLC
(Chiralcel OD, 95.5:0.5, hexane/2-propanol, tS =
10.5 min, tR = 12.2 min).
as off-white solid (0.376 g, 82%). Mp 124–125 ꢁC;
25
½aꢁD ¼ ꢀ42.7 (c 0.25, CHCl3); IR (KBr) m 3418, 3213,
3058, 2955, 2929, 2863, 1679, 1551, 1448, 1369, 1288,
1180, 1155, 1111, 1015 cmꢀ1
;
1H NMR (CDCl3): d
4.18. tert-Butyl (2S)-2-[(diphenylmethylene)amino]pent-
4-enoate 17c
0.73 (d, J = 7.15, 6H), 0.87 (d, J = 6.44, 12H), 0.97–
1.08 (m, 4H), 1.25 (m, 2H), 1.42 (m, 2H), 1.67 (d,
J = 11.05, 4H), 1.87 (m, 6H), 3.33 (s, 3H), 3.74 (m,
2H), 4.04 (d, J = 13.67, 2H), 4.30 (d, J = 13.81, 1H),
4.40 (d, J = 14.00, 1H), 5.10 (q, J = 11.04, 2H), 7.26–
7.51 (m, 14H), 7.47 (s, 1H), 8.07 (d, J = 8.85, 2H); 13C
NMR (CDCl3): d 15.7, 20.9, 22.1, 22.8, 26.5, 29.4,
31.8, 34.0, 41.8, 46.4, 48.5, 51.0, 61.03, 61.30, 65.6,
81.6, 125.3, 127.6, 127.8, 128.2, 128.4, 129.0, 129.2,
132.7 146.1, 150.0, 161.9; MS (APCI): m/z (%) 695
(M+ꢀ80, 30), 694 (70), 423 (35), 422 (100). Anal. Calcd
for C45H64BrN3O: C, 69.75; H, 8.32; N, 5.42. Found: C,
68.83; H, 9.09; N, 4.92.
Yield 92%; IR (film) m 3061, 2928, 2930, 1734, 1624,
1598, 1576, 1446, 1367, 1277, 1152 cmꢀ1 1H NMR
;
(CDCl3): d 1.44 (s, 9H), 2.65 (m, 2H), 4.0 (dd, J = 7.6,
5.5, 1H), 4.99–5.09 (m, 2H), 5.72 (m, 1H), 7.17 (m,
2H), 7.47–7.30 (m, 6H), 7.64 (m, 2H); MS (MALDI):
336 [M++1]. Rt HPLC (Chiralcel OD-H, 99.5:0.5, hex-
ane/iso-propanol, tS = 10.5 min, tR = 12.0 min).
4.19. tert-Butyl-N-(diphenylmethylene)-L-phenylalaninate
17d
1
Yield 87%; H NMR (CDCl3): d 1.41 (s, 9H), 3.22–3.09
4.15. Synthesis of 4-(hydroxy-diphenyl-methyl)-
benzyl{di[(2S,1R,5R)-2-isopropyl-5-methyl-
cyclohexylcarbamoylmethyl]}(methyl)ammonium
bromide 15
(m, 2H), 4.08 (dd, J = 4.98, 9.08, 1H), 6.53–7.62 (m,
15H); Rt HPLC (Chiralcel OD-H, 254 nm, 0.5 mL, hex-
ane/iso-propanol, tS = 25.4 min, tR = 17.5 min).
4.20. tert-Butyl (2S)-3-(4-fluorophenyl)-2-[(diphenyl-
methylene)amino]propanoate 17e
The procedure described for compound 10 was fol-
lowed; 15 was obtained as white solid (0.390 g, 85%),
from 9 and 4-bromomethylphenyl-diphenylmethanol.
Yield 91%; IR (neat) m 2977, 2928, 1726, 1626, 1508,
25
Mp 132–133 ꢁC; ½aꢁD ¼ ꢀ38.0 (c 0.20, CHCl3); IR
1446, 1369, 1285, 1148 cmꢀ1 1H NMR (CDCl3): d
;
(KBr) m 3421, 3210, 3047, 2955, 2922, 2863, 1681,
1.45 (s, 9H), 3.15 (dd, J = 13.4, 8.6, 1H), 3.22 (dd,
J = 13.4, 4.8, 1H), 4.06 (dd, J = 8.6, 4.8, 1H), 6.69 (d,
J = 7.1, 2H), 6.85–7.02 (m, 4H), 7.30–7.41 (m, 6H),
7.56–7.58 (m, 2H); Rt HPLC (Chiralcel OD, 99.5:0.5,
hexane/iso-propanol, tS = 8.1 min, tR = 13.5 min).
1551, 1450, 1369, 1255 cmꢀ1 1H NMR (CDCl3): d
;
0.76 (dd, J = 1.2, 2.5, 6H), 0.87–0.89 (m, 14H), 1.02–
1.06 (m, 4H), 1.19–1.32 (m, 4H), 1.44 (br s, 1H), 1.68
(d, J = 10.64, 4H), 1.91 (m, 4H), 3.37 (s, 3H), 3.79 (m,
2H), 4.12 (d, J = 13.93, 1H), 4.30 (s, 2H), 4.56 (d,
J = 13.89, 1H), 5.23 (s, 2H), 7.27–7.30 (m, 10H), 7.42
(d, J = 8.18, 2H), 7.56 (d, J = 8.14, 2H), 8.16 (t,
J = 6.45, 2H); 13C NMR (CDCl3): d 15.7, 21.1, 22.0,
23.4, 26.7, 29.6, 31.9, 34.1, 42.0, 46.4, 48.5, 51.1, 61.1,
61.3, 65.6, 81.7, 125.5, 127.6, 127.8, 128.1, 129.03,
132.8, 146.1, 150.1, 162.0; MS (APCI): m/z (%) 659
(M+ꢀ80, 45), 694 (85), 423 (35), 422 (100). Anal. Calcd
for C45H64BrN3O: C, 69.75; H, 8.32;N, 5.42. Found: C,
68.94; H, 9.37; N, 4.98.
4.21. tert-Butyl 2-[(diphenylmethylene)amino]-3-pyridin-
3-ylpropanoate 17f
25
Yield: 84%; ½aꢁD ¼ ꢀ184.3 (c 1, CH2Cl2), IR (neat) m
2958, 2869, 1739, 1450, 1425, 1286, 1173 cmꢀ1 1H
.
NMR (CDCl3): d 1.44 (s, 9H), 3.25 (dd, J = 5.3, 3.3,
2H), 4.95 (dd, J = 5.9, 3.3, 1H), 6.87 (d, J = 6.2, 2H),
7.23 (dd, J = 4.9, 2.8, 1H), 7.39–7.58 (m, 7H), 7.76 (d,
J = 7.0, 2H), 8.44 (s, 1H), 8.48 (d, J = 4.7, 1H) 13C
NMR (CDCl3): d 27.9, 36.6, 67.1, 81.4, 122.9, 127.4,
128.2, 128.4, 128.6, 129.9, 130.3, 132.3, 133.8, 136.1,
137.3, 139.1, 147.6, 170.8; MS (MALDI): m/z 386
(M+). Rt HPLC (Chiralcel OD-H, 98:2, hexane/iso-pro-
panol, tS = 20.4 min, tR = 22.8 min). Anal. Calcd for
C25H26N2O2: C, 77.69; H, 6.78; N, 7.25. Found: C,
77.58; H, 6.84; N, 7.18.
4.16. tert-Butyl (2S)-2-[(diphenylmethylene)amino]-
butanoate 17a
Yield 66%; IR (film) m 3060, 2926, 2854, 1732, 1662,
1
1625, 1446, 1367, 1284, 1154 cmꢀ1; H NMR (CDCl3):
d 0.87 (t, J = 7.6, 3H); 1.44 (s, 9H), 1.87–1.91 (m,
2H), 4.01 (dd, J = 8.0, 5.2, 1H), 7.17 (dd, J = 4.4, 1.6,
2H), 7.30–7.44 (m, 6H), 7.65 (m, 2H); (MALDI): m/z
324 (M++1). Rt HPLC (Chiralcel OD, 95.5:0.5, hex-
ane/2-propanol, tS = 11.6 min, tR = 13.3 min).
4.22. tert-Butyl (2S)-2-[(diphenylmethylene)amino]-3-
(1-naphthyl)propanoate 17g
Yield 86%; IR (film) m 3054, 2975, 1730, 1622, 1576,
4.17. tert-Butyl (2S)-2-[(diphenylmethylene)amino]-
octanoate 17b
1446, 1367, 1287, 1150 cmꢀ1 1H NMR (CDCl3): d
;
1.46 (s, 9H), 3.56 (dd, J = 12.9, 8.2, 1H), 3.86 (dd,
J = 12.9, 3.8, 1H), 4.30 (dd, J = 8.2, 3.8, 1H), 6.68 (br
s, 2H), 6.96 (t, J = 7.5, 2H), 7.12–7.34 (m, 8H), 7.39
(ddd, J = 8.7, 6.9, 1.2, 1H), 7.50–7.72 (m, 4H); Rt HPLC
Yield 78%; IR (film) m 2954, 2929, 2856, 1735, 1627,
1456, 1448, 1391, 1365, 1249, 1153 cmꢀ1 1H NMR
;

S. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2599–2605
2605
B.-S.; Park, Y.; Park, H.-g. Org. Lett. 2002, 4, 4245–4248;
(Chiralcel OD, 95.5:0.5, hexane/2-propanol, tS =
24.3 min, tR = 21.6 min).
´
´
(c) Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron:
Asymmetry 2002, 13, 927–931; (d) Belokon0, Y. N.;
Davies, R. G.; North, M. Tetrahedron Lett. 2000, 41,
7245–7248; (e) Kita, T.; Georgieva, A.; Hashimoto, Y.;
Nakata, T.; Nagasawa, K. Angew. Chem., Int. Ed. 2002,
41, 2832–2834.
Acknowledgements
This work was supported with grant from National Insti-
tute of Pharmaceutical Education Research (NIPER).
We thank Prof. Guru Row, Indian Institute of Science,
Bangalore, India, for the crystallographic data.
4. Eddine, J. J.; Cherqaooui, M. Tetrahedron: Asymmetry
1995, 6, 1225–1228.
5. Dehmlow, V. E.; Klauck, R.; Duttmann, S.; Neumann, B.;
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