Cinchona alkaloid phase-transfer catalysts revisited: Influence of substituted aryl groups on the enantioselectivity of glycine ester enolate alkylation

Article abstract of DOI:10.1016/j.tet.2005.05.012

We report herein, the influence of substituted aryl groups in quaternary ammonium salts derived from cinchona alkaloids on enantioselectivity of the alkylation of glycine ester enolates.

Full text of DOI:10.1016/j.tet.2005.05.012

Tetrahedron 61 (2005) 7022–7028
Cinchona alkaloid phase-transfer catalysts revisited: influence of
substituted aryl groups on the enantioselectivity of glycine ester
enolate alkylation
*
Sanjeev Kumar and Uma Ramachandran
Department of Pharmaceutical Technology, National Institute of Pharmaceutical Education & Research (NIPER), Sector-67, Mohali,
Punjab 160 062, India
Received 17 December 2004; revised 15 April 2005; accepted 5 May 2005
Abstract—We report herein, the influence of substituted aryl groups in quaternary ammonium salts derived from cinchona alkaloids on
enantioselectivity of the alkylation of glycine ester enolates.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
explored the combination of electronic and steric factor by
way of ortho-fluoro-dimeric cinchona-derived PTCs.6
Dimers and trimers of cinchona alkaloids have also been
reported by other workers.7
Asymmetric synthesis using phase-transfer catalysts (PTCs)
represent one of the important methodologies in organic
chemistry. Since, the pioneering work by Dolling et al.1
chiral PTCs derived from cinchona alkaloids have been
applied to various organic reactions.2
In 1989, O’Donnell’s group reported the enantioselective
PTC alkylations of N-(diphenylmethylene)glycine tert-
butyl ester (8) for the synthesis of a-amino acids in
enantiomerically pure form using catalyst 1a derived from
cinchonidine.3 The enantioselective catalytic activity was
improved by Lygo and Corey using third generation
versions of these catalysts containing an N-9-anthracenyl-
methyl group either with a free OH (1b) or with an O-allyl
group (1c), respectively.4
When the nitrogen on the bicyclic ring of the cinchona
alkaloids are quaternized by the addition of the bulky and
rigid anthracenylmethyl group, it seems to give the highest
rigidity and steric effect to the catalyst’s framework and
leads to highly enantioselective alkylations as compared to a
benzyl group. Jew et al. found that an ortho fluoro
substituent on the benzyl group in the quaternary
ammonium salt dramatically increased the enantio-
selectivity in the alkylation of a glycine anion equivalent
which was attributed to the electronic effect.5 They also
2. Results and discussion
We designed new catalysts having diaryl substitution at the
3- and 4-positions of the N-benzyl group in cinchonidinium
salts to check how substituted aryl groups affect the
asymmetric induction in the benzylation reaction as
compared to those having flat linear aryl systems like
naphthylmethyl and anthracenylmethyl groups.
For the preparation of new cinchona-derived quaternary
ammonium salts, the corresponding 2-, 3- and 4-(bromo-
methyl)phenyl(diaryl)methanols were prepared, starting
from o-, m- and p-toluic acid methyl esters (Scheme 1).
Keywords: Cinchona alkaloids; Phase-transfer catalysts; Asymmetric
alkylations.
*
Corresponding author. Tel.: C91 172 2214682/87; fax: C91 172
2214692; e-mail: umaram54@yahoo.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.012

S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 7022–7028
7023
As shown in Table 1, substitution at the meta- and para-
position with diphenyl moieties gave slight increases in the
enantioselectivity as compared to the unsubstituted
N-benzyl group (entries 1–3). The use of bulkier sub-
stituents, that is, di(1-naphthyl) moieties in place of
di(phenyl) showed an increase in enantiomeric excess
(entries 4–5). The meta-di(1-naphthyl) substituted catalyst
5b gave higher enantiomeric excess as compared to the
para-substituted counterpart 7b (Scheme 2).
Scheme 1. Reagents: (i) ArBr, Mg, THF; (ii) NBS, CCl4.
2-, 3- and 4-(Bromomethyl)phenyl(diaryl)methanols thus,
prepared were used for quaternization of cinchona alkaloids.
This reaction was done in a mixture of acetonitrile and
toluene (80:20) at 80 8C. While meta- and para-(bromo-
methyl)phenyl(diaryl)methanols formed the quaternary
salts in 80–92% yields, the ortho-(bromomethyl)phenyl-
(diaryl)methanol failed to quaternize cinchonidine.
Scheme 2. Benzylation of imine 8 using various catalysts.
The catalyst 5b was O(9)-allylated with allyl bromide in the
presence of K2CO3 to give the catalyst 6 in 88% yield. The
use of catalyst 6 gave high enantiomeric excess (92%)
favouring the (S)-isomer when the reaction was carried at
K20 8C.
Our results show that the quaternary ammonium salts 5–7
containing the triaryl carbinol units provide better steric
screens as compared to the naphthylmethyl group (1d,
49%)8 in the asymmetric benzylation of 8. Among them,
O(9)-allyl-N-[3-(hydroxy-di-naphthalen-1-yl-methyl)-
benzyl]cinchonidinium bromide (6) seems to give the best
steric screen as well as cation rigidity for the formation of
close ion-pairs between the bridgehead nitrogen and the
enolate of 8. However, it is less effective than 1c which has
an anthracenylmethyl group in the quaternary ammonium
salt.
Taking catalyst 6, phase-transfer alkylation of 8 with
various alkyl halides was carried out. The results obtained
for the asymmetric alkylation of 8 with various alkyl
halides, using the similar conditions, and at K20 8C are
given in Table 2. High enantiomeric excesses up to 94%
were obtained with a wide variety of alkylating agents
(entries 1–10) for the asymmetric synthesis of a-amino
acids (Scheme 3).
The catalysts 5–7 were evaluated in the enantioselective
phase-transfer benzylation of N-(diphenylmethylene)glycine
tert-butyl ester. The reaction was carried out in toluene/
dichloromethane (7:3) at 0 8C and at K20 8C using 50%
aqueous KOH as a base under argon (Table 1).
3. Conclusion
In conclusion, we studied various cinchona alkaloids
quaternized by triarylcarbinol units in asymmetric PTC
Table 1. Benzylation of imine 8 using catalysts 1a and 5–7
Entry
Catalyst
Time (h)
Temp (8C)
Yielda (%)
%eeb [config]c
1
2
3
4
5
6
7
1a
5a
7a
7b
5b
6
10
12
18
18
16
5
0
0
0
0
0
0
K20
89
83
74
80
86
90
92
66 (S)
73 (S)
72 (S)
80 (S)
84 (S)
90 (S)
92 (S)
6
7
a Yields of isolated product.
b Based on HPLC analysis using Chiralcel OD-H column with hexanes/2-propanol (99.5:0.5) as eluent.
c The absolute configuration was determined by comparision of the HPLC retention time with that of an authentic sample, which was independently
synthesized by the reported procedure.4

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S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 7022–7028
Table 2. Alkylation of imine 8 using catalyst 6
Entry
RXa
Time (h)
Product
Yieldb(%)
%eec [config]d
1
2
CH3CH2Ie
8
8
9a7a
9b7a
68
78
92 (S)
94 (S)
CH3(CH2)4CH2Ie
3
3
9c7a
92
93 (S)
4
5
7
6
9d7a
9e4b
90
93
93 (S)
92 (S)
6
7
6
9f7a
9g
93
87
91 (S)
f
10
92
8
9
10
8
9h
85
89
91f
9i4
89 (S)
a The reaction was carried out with RX (2.0 equiv) and aqueous KOH (50%, 12 equiv) in the presence of 6 (10 mol%) in toluene/CH2Cl2 (7:3) at K20 8C.
b Yields of isolated products.
c Based on chiral HPLC using a Chiralcel OD-H column.
d The absolute configuration was determined by comparision of the HPLC retention time with that of an authentic sample, which was independently
synthesized by the reported procedure.4–7
e RX (5.0 equiv) was used.
f
Absolute configuration not determined.
was performed 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).
Scheme 3. Alkylation of imine 8 using catalyst 6.
4.2. General procedure for the synthesis of 2- or -3 or
4-methylphenyl(diphenyl)methanol
reactions. O(9)-Allyl-N-[3-(hydroxy-di-naphthalen-1-yl-
methyl)-benzyl]cinchonidinium bromide (6) proved to be
the best as it gave very high ees in the alkyated products of
8. The applications to other types of phase-transfer catalytic
reactions using 6 are currently being investigated. Further, it
would be interesting to synthesize and study the catalysts
where R3 aryl carbinol units can be heteroaromatic or
further substituted aromatic systems.
Under argon, to a suspension of magnesium turnings (5.9 g,
246 mmol) in dry tetrahydrofuran (100 mL) was added
bromobenzene (26.3 mL, 249 mmol) dropwise at such a rate
so as to maintain a gentle reflux over a period of 0.5 h. After
stirring the reaction mixture for 1 h at rt, a solution of 2-, 3-
or 4-toluic acid methyl esters (15 g, 99.8 mmol) in
tetrahydrofuran (25 mL) was added dropwise and the
stirring continued for 5 h at 50 8C. The reaction mixture
was cooled to rt, poured onto ice and acidified with 2 N HCl.
The aqueous layer was extracted with chloroform (3!
60 mL) and the combined organic layers dried over Na2SO4
and concentrated. Purification of the residue oil by column
chromatography on silica gel (hexane/EtOAc, 95:5) gave 2-
or -3 or 4-methylphenyl(diphenyl)methanols as white solids
(70–84%).
4. Experimental
4.1. General
1
Melting points are uncorrected. H and 13C spectra were
recorded at 300 and 75 MHz using a Bruker Advance
spectrometer, respectively, with chemical shifts in ppm and
tetramethylsilane as the internal standard. Infra-red absorp-
tion spectra were recorded on a Nicolet Impact 410
spectrometer; the frequencies in the IR spectra are indicated
in cmK1. Mass spectral data were recorded on a Finnigan-
MAT LCMS spectrometer. Elemental analyses were
recorded on an Elementa Vario EL. HPLC was performed
on a Shimadzu SPD-10A using a chiral phase column
(DAICEL Chiralcel OD and Chiralcel OD-H, 254 nm). TLC
4.2.1. 2-Methylphenyl(diphenyl)methanol (3a). 19.2 g,
yield 70%; mp 100–101 8C; IR (KBr) n 3468, 3058, 3027,
2929, 2863, 1598, 1509, 1445, 1328, 1153, 1007 cmK1; 1H
NMR (CDCl3) d 2.33 (s, 3H), 2.77 (s, 1H), 7.09–7.33 (m,
14H); MS (APCI): m/z 257 (MCKOH, 100). Anal. Calcd
for C, 87.56; H, 6.61. Found C, 87.14; H, 6.78.

S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 7022–7028
7025
4.2.2. 3-Methylphenyl(diphenyl)methanol (3b). 22.5 g,
yield 82%; mp 62–63 8C; IR (KBr) n 3462, 3049, 2928,
4.4.1. 3-Methylphenyl-di(1-naphthyl)methanol (3d).
27 g, yield 72%; mp 180–183 8C decomp.; IR (KBr) n
3550, 3043, 2922, 1599, 1505, 1395, 1341, 1222, 1148,
1050, 1011 cmK1; 1H NMR (CDCl3) d 2.29 (s, 3H), 3.60 (s,
1H), 6.84 (d, JZ7.1 Hz, 2H), 7.09–7.24 (m, 8H), 7.38 (t,
JZ7.3 Hz, 2H), 7.77 (d, JZ8.1 Hz, 2H), 7.84 (d, JZ
8.1 Hz, 2H), 8.25 (d, JZ8.5 Hz, 2H); 13C NMR (CDCl3) d
21.7, 85.2, 124.3, 125.1, 125.3, 125.5, 127.8, 127.9, 128.3,
128.6, 128.8, 129.1, 131.4, 135.1, 137.6, 142.2, 146.8; MS
(APCI): m/z (%) 357 (MCKOH, 100). Anal. Calcd for C,
89.81; H, 5.92. Found C, 89.67; H, 5.98.
1594, 1490, 1440, 1321, 1154, 1010 cmK1 1H NMR
;
(CDCl3) d 2.31 (s, 3H), 2.79 (s, 1H), 7.09–7.33 (m, 14H);
MS (APCI): m/z 274 (MC), 257. Anal. Calcd for C, 87.56;
H, 6.61. Found C, 87.18; H, 6.71.
4.2.3. 4-Methylphenyl(diphenyl)methanol (3c). 23.1 g,
yield 84%; mp 72–73 8C; IR (KBr) n 3466, 3058, 1597,
1
1489, 1444, 1325, 1156, 1009 cmK1; H NMR (CDCl3) d
2.13 (s, 3H), 2.96 (s, 1H), 7.17–7.32 (m, 14H); MS (APCI)
m/z 274 (MC), 257, 197, 105. Anal. Calcd for C, 87.56; H,
6.61. Found C, 87.23; H, 6.67.
4.4.2. 4-Methylphenyl-di(1-naphthyl)methanol (3e).
25.4 g, yield 68%; mp 188–190 8C decomp.; IR (KBr) n
3546, 3041, 2916, 1599, 1506, 1395, 1342, 1311, 1183,
1154, 998 cmK1; 1H NMR (CDCl3) d 2.33 (s, 3H), 3.57 (s,
1H), 6.85 (d, JZ7.1 Hz, 2H), 7.11–7.26 (m, 8H), 7.37 (t,
JZ7.1 Hz, 2H), 7.77 (d, JZ8.0 Hz, 2H), 7.83 (d, JZ
8.0 Hz, 2H), 8.26 (d, JZ8.5 Hz, 2H); 13C NMR (CDCl3) d
20.4, 84.5, 123.6, 124.6, 124.8, 125.7, 126.8, 127.1, 127.6,
128.0, 128.1, 128.5, 129.6, 130.7, 134.4, 136.0, 141.6,
143.3; MS (APCI): m/z (%) 357 (MCKOH, 100). Anal.
Calcd for C, 89.81; H, 5.92. Found C, 89.59; H, 6.01.
4.3. General procedure for the synthesis of 2-, 3- or
4-(bromomethyl)phenyl(diphenyll)methanol
To a solution of 3- or 4-methylphenyl(diphenyl)methanol
(5.0 g, 18.2 mmol) in CCl4 (50 mL) at 70 8C was added
N-bromosuccinimide (3.24 g, 18.2 mmol) and benzoyl
peroxide (88 mg, 0.36 mmol) in two portions. The solution
was stirred under reflux for 5 h and cooled to rt, washed
successively with 10% NaHCO3, water and brine, dried over
anhydrous Na2SO4 and the solvent evaporated in vacuo to
afford the product as oils in 79–85% yield, which was used
without purification for the next step.
4.5. General procedure for the synthesis of 3- and
4-bromomethylphenyl-di(1-naphthyl)methanol
4.3.1. [2-(Bromomethyl)phenyl](diphenyl)methanol (4a).
5.5 g, yield 85%; IR (neat) n 3452, 3046, 1593, 1478, 1444,
The procedure discussed in Section 4.3 was followed.
1
1325, 1156, 1006 cmK1; H NMR (CDCl3) d 4.52 (s, 2H),
4.5.1. [3-(Bromomethyl)phenyl][di(1-naphthyl)]metha-
nol (4d). 4.9 g, yield 82%; mp 159–163 8C decomp.; IR
(KBr) n 3541, 3046, 1598, 1507, 1359, 1342, 1216, 1149,
5.18 (s, 1H), 7.10–7.33 (m, 14H); MS (APCI): m/z 337
(MCKOH), 335, 257, 255.
1
1008 cmK1; H NMR (CDCl3) d 3.6 (s, 1H), 4.4 (s, 2H),
4.3.2. [3-(Bromomethyl)phenyl](diphenyl)methanol (4b).
5.2 g, yield 80%; IR (neat) n 3442, 3029, 2923, 1598, 1442,
6.83 (d, JZ7.1 Hz, 2H), 7.19–7.41 (m, 10H), 7.79 (d, JZ
7.9 Hz, 2H), 7.84 (d, JZ8.0 Hz, 2H), 8.2 (br s, 2H); 13C
NMR (CDCl3) d 34.2, 85.6, 122.4, 125.8, 125.9, 126.0,
126.1, 128.4, 128.5, 128.7, 128.8, 128.9, 129.1, 129.2 (2C),
129.3, 129.8, 131.6, 135.5, 138.1, 142.2, 148.0; MS (APCI):
m/z (%) 437 (MCKOH, 74), 435 (74), 390 (40), 357 (100).
1
1356, 1148, 1012 cmK1; H NMR (CDCl3) d 2.82 (s, 1H),
4.48 (s, 2H), 7.22–7.48 (m, 14H); MS (APCI): m/z (%) 354
(MC), 352 (MC), 337, 274.
4.3.3. [4-(Bromomethyl)phenyl](diphenyl)methanol (4c).
5.1 g, yield 79%; IR (neat) n 3432, 3059, 2923, 1598, 1445,
1409, 1386, 1228, 11545, 1018 cmK1; 1H NMR (CDCl3) d
2.81 (br s, 1H), 4.52 (s, 2H), 7.24–7.48 (m, 14H); MS
(APCI): m/z 354 (MC), 352 (MC), 273, 105.
4.5.2. 4-Bromomethylphenyl-di(1-naphthyl)methanol
(4e). 5.3 g, yield 87%; mp 168 8C decomp.; IR (neat) n
3542, 3040, 2922, 2863, 1504, 1498, 1340, 1229, 1155 cmK1
;
1H NMR (CDCl3) d 3.62 (s, 1H), 4.41 (s, 2H), 6.82 (d, JZ
7.1 Hz, 2H), 7.15–7.26 (m, 8H), 7.39 (t, JZ7.1 Hz, 2H),
7.76 (d, JZ8.0 Hz, 2H), 7.83 (d, JZ8.0 Hz, 2H), 8.23 (d,
JZ8.2 Hz, 2H); 13C NMR (CDCl3) d 32.5, 85.6, 124.1,
124.7, 125.7, 125., 125.9, 126.0 (2C), 128.6, 128.7, 128.7,
128.8, 128.9, 129.2, 129.3, 129.5, 129.7, 131.6, 135.5,
137.0, 142.1, 147.6; MS (APCI): m/z (%) 437 (MCKOH,
74), 435 (100), 391 (35), 357 (25).
4.4. General procedure for the synthesis of 3- or
4-methylphenyl-di(1-naphthyl)methanol
Under argon, to a suspension of magnesium turnings (5.9 g,
246 mmol) in dry tetrahydrofuran (100 mL) was added a
solution of 1-bromonaphthalene (51.2 g, 247 mmol) in
tetrahydrofuran (40 mL) slowly at such a rate so as to
maintain a gentle reflux over a period of 0.5 h. After stirring
the reaction mixture for 2 h at 50 8C, a solution of 3- or
4-toluic acid methyl ester (15 g, 99.8 mmol) in tetrahydro-
furan (25 mL) was added drop wise and the stirring
continued for 8 h at 60 8C. The reaction mixture was cooled
to rt, poured onto ice and acidified with 2 N HCl. The
aqueous layer was extracted with chloroform (2!100 mL)
the combined organic layers dried over Na2SO4 and
concentrated in vacuo. Purification of the residue by
crystallization from toluene/hexane gave the product as
white solid (68–72%).
4.6. General procedure for the synthesis of quaternary
ammonium salts from cinchona alkaloids
A suspension of cinchonidine (1.0 g, 3.39 mmol) and 3- or
4-(bromomethyl)phenyl][di(aryl)]methanol (3.73 mmol) in
acetonitrile/toluene (50:50, 20 mL) was stirred at 80 8C
under argon for 6 h. The reaction mixture was cooled to rt,
the solvent was removed in vacuo and the residue was
purified by column chromatography (SiO2, MeOH/CHCl3
5:95) to afford the products [7a–b, 9a–b] as crystalline
solids (80–92%).

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S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 7022–7028
4.6.1. N-[3-(Hydroxy-diphenyl-methyl)-benzyl]cincho-
nidinium bromide (5a). Yield 88%; mp 209–210 8C
decomp.; [a]3D0 K71.24 (c 0.52, MeOH); IR (KBr) n 3424,
3173, 3061, 2955, 1614, 1454, 1294, 1158, 1146, 1034,
1016, 928 cmK1; 1H NMR (CDCl3C CD3OD) d 1.28–1.31
(m, 1H), 1.73 (m, 1H), 2.00–2.22 (m, 3H), 2.56 (br s, 1H),
3.14–3.25 (m, 1H), 3.47–3.51 (m, 1H), 3.86 (t, JZ8.5 Hz,
1H), 4.52 (m, 1H), 4.98 (d, JZ10.4 Hz, 1H), 5.05 (d, JZ
4.4 Hz, 1H), 5.09 (d, JZ9.9 Hz, 1H), 5.45–5.56 (m, 2H),
6.59 (s, 1H), 7.18–7.33 (m, 14H), 7.56–7.65 (m, 2H), 7.69
(d, JZ7.4 Hz, 1H), 7.75 (s, 1H), 7.82 (d, JZ4.5 Hz, 1H),
8.02 (d, JZ7.6 Hz, 1H), 8.08 (d, JZ7.3 Hz, 1H), 8.82 (d,
JZ4.5 Hz, 1H); 13C NMR (CDCl3CCD3OD) d 21.3, 24.5,
26.2, 37.5, 50.9, 60.4, 63.6, 64.3, 67.9, 81.0, 117.2, 119.7,
122.6, 124.2, 126.3, 126.9, 127.6, 127.6, 128.2, 129.0,
129.5, 130.1, 132.0, 132.8, 136.2, 145.4, 146.4, 146.9,
148.4, 149.2; MS (APCI): m/z (%) 568 (MCKBr, 32), 567
(100), 549 (29). Anal. Calcd for C39H39BrN2O2: C, 72.33;
H, 6.07; N, 4.33. Found: C, 71.57; H, 6.14; N, 4.26.
(0.160 g, 1.33 mmol) in CH2Cl2 (10 mL) was added K2CO3
(0.184 g, 1.33 mmol). The resulting mixture was stirred
vigorously at rt for 12 h. The mixture was diluted with water
(10 mL) and extracted with CH2Cl2 (3!20 mL), the
combined organic extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography (SiO2, CH2Cl2/MeOH, 90:10)
to afford 6 as yellow solid (0.463 g, 88%); mp 195–196 8C
(decomp.); [a]3D0 K44.26 (c 0.30, MeOH); IR (KBr) n 3393,
3040, 2929, 1608, 1450, 1340, 1287, 1166, 1063, 1040,
928 cmK1; 1H NMR (CDCl3) d 1.87–2.03 (m, 3H), 2.8 (m,
1H), 3.24 (br s, 1H), 3.72 (br s, 1H), 4.06–4.49 (m, 3H), 4.72
(m, 2H), 4.98 (m, 1H), 4.99 (d, JZ9.8 Hz, 1H), 5.16 (d, JZ
9.7 Hz, 2H), 5.30 (d, JZ17.3 Hz, 1H), 5.53–5.59 (m, 2H),
5.97 (m, 1H), 6.63 (m, 1H), 6.80 (m, 1H), 6.93 (d, JZ
7.05 Hz, 2H), 7.26–7.61 (m, 11H), 7.72–7.90 (m, 7H), 8.09
(d, JZ8.4 Hz, 1H), 8.33 (m, 2H), 8.70 (m, 2H), 8.86 (d, JZ
4.2 Hz, 1H); 13C NMR (CDCl3) d 22.4, 25.1, 26.6, 37.6,
50.2, 59.4, 62.2, 65.6, 70.1, 85.0, 118.3, 119.0, 119.6, 124.5,
124.6, 125.2, 125.3, 126.3, 128.3, 128.4, 128.7, 129.1,
129.7, 129.9, 130.2, 130.8, 131.2, 132.2, 133.4, 135.0,
135.9, 139.8, 141.6, 148.3, 149.2; MS (APCI): m/z (%) 707
(MCKBr, 100). Anal. Calcd for C50H47BrN2O2: C, 76.23;
H, 6.01; N, 3.56. Found: C, 75.79; H, 6.24; N, 3.49.
4.6.2. N-[4-(Hydroxy-diphenyl-methyl)-benzyl]cincho-
nidinium bromide (7a). Yield 92%; mp 205–206 8C
decomp.; [a]3D0 K75.5 (c 0.56, MeOH); IR (KBr) n 3194,
1592, 1508, 1446, 1422, 1381, 1321, 1281, 1183, 1159,
1110, 1018, 938 cmK1; 1H NMR (CDCl3C CD3OD) d 1.40
(t, JZ11.3 Hz, 1H), 1.88 (m, 1H), 2.06 (s, 1H), 2.14–2.29
(m, 2H), 2.27 (br s, 1H), 3.30 (s, 1H), 3.62–3.70 (m, 1H),
3.98 (t, JZ8.9 Hz, 1H), 4.43 (m, 1H), 4.97 (d, JZ10.4 Hz,
1H), 4.99 (d, JZ12.2 Hz, 1H), 5.12 (d, JZ12.4 Hz, 1H),
5.17 (d, JZ7.5 Hz, 1H), 5.48 (s, 1H), 5.61–5.72 (m, 1H),
6.65 (s, 1H), 7.25–7.34 (m, 12H), 7.50 (d, JZ8.2 Hz, 2H),
7.67 (d, JZ8.2 Hz, 2H), 7.80 (t, JZ7.7 Hz, 1H), 7.88 (t, JZ
7.8 Hz, 1H), 7.99 (d, JZ4.5 Hz, 1H), 8.13 (d, JZ8.2 Hz,
1H), 8.28 (d, JZ8.3 Hz, 1H), 8.96 (d, JZ4.5 Hz, 1H); 13C
NMR (CDCl3C CD3OD) d 22.5, 25.9, 28.0, 39.1, 52.8,
54.8, 62.1, 64.8, 66.4, 69.4, 82.6, 117.5, 121.4, 124.2, 126.2,
127.2, 128.3, 128.9, 129.3, 129.4, 129.8, 130.0, 131.7,
134.2, 138.7, 148.1, 148.4, 148.5, 150.5, 151.1; MS (APCI):
m/z (%) 568 (MCKBr, 20), 567 (48), 549 (100). Anal.
Calcd for C39H39BrN2O2: C, 72.33; H, 6.07; N, 4.33. Found:
C, 71.80; H, 6.23; N, 4.09.
4.6.5. Synthesis of N-[4-(hydroxy-di-naphthalen-1-yl-
methyl)-benzyl]cinchonidinium bromide (7b). Yield
83%; mp 196–197 8C decomp.; [a]3D0 K72.92 (c, 0.80,
MeOH); IR (KBr) n 3400, 2944, 1634, 1502, 1388, 1159,
1
1115, 1018, 920 cmK1; H NMR (CDCl3) d 1.49 (m, 1H),
1.54 (m, 1H), 1.99–2.07 (m, 2H), 2.63 (br s, 1H), 3.08–3.34
(m, 2H), 3.63 (br s, 1H), 3.87 (m, 1H), 4.62 (m, 1H), 4.78 (d,
JZ6.8 Hz, 1H), 4.99 (d, JZ11.8 Hz, 1H), 5.41–5.47 (m,
2H), 5.77 (d, JZ12.2 Hz, 1H), 6.77 (s, 1H), 6.80 (t, JZ
7.9 Hz, 1H), 7.12–7.16 (m, 3H), 7.26–7.47 (m, 6H), 7.67–
7.89 (m, 10H), 8.00–8.30 (m, 5H), 8.65 (s, 1H), 8.73 (d, JZ
4.6 Hz, 1H); 13C NMR (CDCl3) d 23.9, 24.7, 26.5, 37.6,
51.1, 54.7, 62.5, 66.3, 68.3, 84.9, 117.6, 118.7, 120.1, 122.7,
123.0, 124.3, 125.3, 125.9, 127.1, 127.7, 127.8, 128.6,
128.7, 129.1, 129.2, 129.6, 131.2, 132.1, 133.6, 135.0,
136.2, 136.9, 141.6, 144.9, 147.3, 149.6; MS (APCI): m/z
(%) 667 (MCKBr, 25), 650 (50), 649 (100). Anal. Calcd for
C47H43BrN2O2: C, 75.49; H, 5.80; N, 3.75. Found: C, 74.98;
H, 6.04; N, 3.58.
4.6.3. N-[3-(Hydroxy-di-naphthalen-1-yl-methyl)-ben-
zyl]cinchonidinium bromide (5b). Yield 80%; mp 188–
190 8C decomp.; [a]3D0 K59.43 (c 0.85, MeOH); IR (KBr) n
3215, 3047, 2944, 1597, 1508, 1454, 1391, 1336, 1314,
1232, 1164, 1038, 928 cmK1; 1H NMR (CDCl3) d 0.82–0.87
(m, 1H), 1.37 (m, 1H), 1.64 (br s, 1H), 1.89–2.02 (m, 3H),
2.92 (br s, 1H), 3.85 (m, 1H), 4.22 (m, 1H), 5.11–5.24 (m,
3H), 5.79 (m, 1H), 6.52 (m, 2H), 6.49 (m, 2H), 7.20–7.35
(m, 15H), 7.70–7.81 (m, 8H), 8.04 (m, 1H), 8.27 (m, 1H),
8.61 (d, JZ4.6 Hz, 1H); 13C NMR (CDCl3) d 21.5, 24.7,
26.3, 29.6, 50.6, 60.5, 63.6, 68.8, 84.9, 117.5, 120.1, 124.2,
124.5 (2C), 125.4, 126.4, 127.5, 128.1, 128.3, 128.6, 129.0,
129.3, 129.5, 130.1, 131.3, 132.8, 134.9, 135.0, 136.1,
141.4, 141.6, 147.5, 148.4, 149.8; MS (APCI): m/z (%) 667
(MCKBr, 20), 650 (42), 649 (100). Anal. Calcd for
C47H43BrN2O2: C, 75.49; H, 5.80; N, 3.75. Found: C,
74.89; H, 5.92; N, 3.62.
4.7. General procedure for enantioselective catalytic
alkylation of 8 under phase-transfer conditions
To a mixture of N-(diphenylmethylene)glycine tert-butyl
ester9 (0.050 g, 0.17 mmol) and 6 (0.013 g, 0.017 mmol) in
toluene/dichloromethane (7:3, 2 mL) was added alkyl halide
(0.34 mmol). The reaction mixture was cooled to K20 8C,
50% aqueous KOH (0.25 mL) was added and the resulting
mixture stirred vigorously until the starting material had
been consumed (3–10 h). The suspension was diluted with
diethyl ether (30 mL), washed with water (2!10 mL), dried
over Na2SO4, filtered and concentrated under reduced
pressure to give crude product. Purification of the residue
by flash chromatography (SiO2, Hexane/EtOAc, 98:2)
afforded the desired products in 68–93% yield.
4.6.4. O(9)-Allyl-N-[3-(hydroxy-di-naphthalen-1-yl-
methyl)-benzyl]cinchonidinium bromide (6). To a sus-
pension of 5b (0.500 g, 0.668 mmol) and allyl bromide
4.7.1. tert-Butyl (2S)-2-[(diphenylmethylene)amino]
butanoate (9a).7a Oil, yield 68%; IR (film) n 3060, 2926,

S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 7022–7028
7027
2854, 1732, 1662, 1625, 1446, 1367, 1284, 1154 cmK1; 1H
NMR (CDCl3) 0.87 (t, JZ7.6 Hz, 3H), 1.44 (s, 9H), 1.87–
1.91 (m, 2H), 4.01 (dd, JZ8.0, 5.2 Hz, 1H), 7.17 (dd, JZ
4.4, 1.6 Hz, 2H), 7.30–7.44 (m, 6H), d 7.65 (m, 2H); MS
(MALDI): m/z 324 (MCC1); Rt HPLC (Chiralcel OD,
254 nm, 1 mL/min, 95.5:0.5, hexane/2-propanol, tSZ
11.6 min, tRZ13.3 min).
386 (MC); Rt HPLC (Chiralcel OD-H, 254 nm, 0.5 mL/min,
98:2, hexane/isopropanol, tSZ20.4 min, tRZ22.8 min).
Anal. Calcd for C25H26N2O2: C, 77.69; H, 6.78; N, 7.25.
Found: C, 77.58; H, 6.84; N, 7.18.
4.7.8. tert-Butyl (2S)-2-[(diphenylmethylene)amino]-3-
pyridin-4-ylpropanoate (9h). Yield 85%; [a]2D5 K180.03
(c 1, CH2Cl2); IR (neat) n 2941, 2856, 1736, 1456, 1253,
1
1168 cmK1; H NMR (CDCl3) d 1.44 (s, 9H), 3.24 (t, JZ
4.7.2. tert-Butyl (2S)-2-[(diphenylmethylene)amino]
octanoate (9b).4b Oil, yield 78%; IR (film) n 2954, 2856,
1735, 1627, 1456, 1448, 1391, 1365, 1249, 1153 cmK1; 1H
NMR (CDCl3) d 0.87 (t, JZ6.8 Hz, 3H), 1.26–1.23 (m, 8H),
1.44 (s, 9H), 1.86 (m, 2H), 3.98 (t, JZ6.7 Hz, 1H), 7.18 (dd,
JZ5.1, 2.0 Hz, 2H), 7.32–7.43 (m, 5H), 7.64–7.79 (m, 3H);
MS (MALDI): m/z 380 (MCC1); Rt HPLC (Chiralcel OD,
254 nm, 1 mL/min, 95.5:0.5, hexane/2-propanol, tSZ
10.5 min, tRZ12.2 min).
6.7 Hz, 2H), 4.97 (dd, JZ6.4, 5.9 Hz, 1H), 6.82 (d, JZ
6.8 Hz, 1H), 7.15 (d, JZ5.7 Hz, 2H), 7.40–7.54 (m, 7H),
7.74 (d, JZ7.2 Hz, 2H), 8.50 (d, JZ5.5 Hz, 2H); 13C NMR
(CDCl3) d 27.9, 36.5, 65.2, 81.2, 122.3, 127.2, 128.2, 128.2,
129.9, 130.8, 132.2, 133.8, 135.9, 137.2, 139.1, 148.6,
170.7; MS (MALDI): m/z 386 (MC); Rt HPLC (Chiralcel
OD-H, 254 nm, 0.5 mL/min, 98:2, hexane/isopropanol, tRZ
44.6 min, tSZ48.8 min). Anal. Calcd for C25H26N2O2: C,
77.69; H, 6.78; N, 7.25. Found: C, 77.54; H, 6.86; N, 7.16.
4.7.3. tert-Butyl (2S)-2-[(diphenylmethylene)amino]pent-
4-enoate (9c).7a Oil, yield 92%; IR (film) n 3061, 2928,
4.7.9. tert-Butyl (2S)-2-[(diphenylmethylene)amino]-3-
(1-naphthyl)propanoate (9i).4 Yield 89%; IR (film) n
2930, 1734, 1624, 1598, 1576, 1446, 1367, 1277, 1152 cmK1
;
1H NMR (CDCl3) d 1.44(s, 9H), 2.65(m, 2H), 4.0 (dd, JZ7.6,
5.5 Hz, 1H), 4.99–5.09 (m, 2H), 5.72 (m, 1H), 7.17 (m, 2H),
7.30–7.47 (m, 6H), 7.64 (m, 2H); MS (MALDI): 336 [MCC
1]; Rt HPLC (Chiralcel OD-H, 254 nm, 0.5 mL/min, 99.5:0.5,
hexane/isopropanol, tSZ10.5 min, tRZ12.0 min).
3054, 2975, 1730, 1622, 1576, 1446, 1367, 1287, 1150 cmK1
;
1H NMR (CDCl3) d 1.46 (s, 9H), 3.56 (dd, JZ12.9, 8.2 Hz,
1H), 3.86 (dd, JZ12.9, 3.8 Hz, 1H), 4.30 (dd, JZ8.2, 3.8 Hz,
1H), 6.68 (br s, 2H), 6.96 (t, JZ7.5 Hz, 2H), 7.12–7.34 (m,
8H), 7.39(ddd, JZ8.7, 6.9, 1.2 Hz, 1H), 7.50–7.72 (m, 4H);Rt
HPLC (Chiralcel OD, 254 nm, 1 mL/min, 95.5:0.5, hexane/
2-propanol, tSZ24.3 min, tRZ21.6 min).
4.7.4. tert-Butyl (2S)-2-[(diphenylmethylene)amino]pent-
4-ynoate (9d).7a Oil, yield 90%; IR (film) n 3642, 3290,
2968, 1728, 1622, 1447, 1369, 1328, 1156 cmK1; 1H NMR
(CDCl3) d 1.44 (s, 9H), 1.96 (t, JZ2.4 Hz, 1H), 2.77 (m,
2H), 4.15 (dd, JZ5.4, 7.6 Hz, 1H), 7.23–7.48 (m, 8H),
7.63–7.67 (m, 2H); MS (MALDI): m/z 332 (MCK1); Rt
HPLC (Chiralcel OD, 254 nm, 1 mL/min, 99.8:0.2, hexane/
isopropanol, tSZ18.4 min, tRZ21.2 min).
Acknowledgements
This work was supported by grant from National Institute of
Pharmaceutical Education & Research (NIPER), Mohali,
India.
4.7.5. tert-Butyl-N-(diphenylmethylene)-L-phenylalani-
nate (9e).7a Yield 93%; 1H NMR d (CDCl3) 1.41 (s,
9H), 3.22–3.09 (m, 2H), 4.08 (dd, JZ5.0, 9.1 Hz, 1H),
6.53–7.62 (m, 15H); Rt HPLC (Chiralcel OD-H, 254 nm,
0.5 mL/min, 99.5:0.5, hexane/isopropanol, tSZ25.4 min
tRZ17.5 min).
References and notes
1. Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
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4.7.6. tert-Butyl (2S)-3-(4-fluorophenyl)-2-[(diphenyl-
methylene)amino]propanoate (9f).7a Yield 93%; IR
(neat) n 2977, 2928, 1726, 1626, 1508, 1446, 1369, 1285,
1148 cmK1; 1H NMR (CDCl3) d 1.45 (s, 9H), 3.15 (dd, JZ
13.4, 8.6 Hz, 1H), 3.22 (dd, JZ13.4, 4.8 Hz, 1H), 4.06 (dd,
JZ8.6, 4.8 Hz, 1H), 6.69 (d, JZ7.1 Hz, 2H), 6.85–7.02 (m,
4H), 7.30–7.41 (m, 6H), 7.56–7.58 (m, 2H); Rt HPLC
(Chiralcel OD, 254 nm, 1 mL/min, 99.5:0.5, hexane/iso-
propanol, tSZ8.1 min, tRZ13.5 min).
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din-3-ylpropanoate (9g). Yield: 87%; [a]2D5 K184.32 (c
1, CH2Cl2); IR (neat) n 2958, 2869, 1739, 1450, 1425, 1286,
1173 cmK1; 1H NMR (CDCl3) d 1.44 (s, 9H), 3.25 (dd, JZ
5.3, 3.3 Hz, 2H), 4.95 (dd, JZ5.9, 3.3 Hz, 1H), 6.87 (d, JZ
6.2 Hz, 2H), 7.23 (dd, JZ4.9, 2.8 Hz, 1H), 7.39–7.58 (m,
7H), 7.76 (d, JZ7.0 Hz, 2H), 8.44 (s, 1H), 8.48 (d, JZ
4.7 Hz, 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,
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