Synthesis and competency of a novel dicationic phase-transfer catalyst

Article abstract of DOI:10.1016/j.tetasy.2003.10.036

Synthesis and characterization of a novel phase-transfer catalyst, 6,6′ di(triethylammoniummethyl)-2,2′-dihexyloxybi-1,1′- naphthalene, are reported. Preliminary catalytic studies on the alkylation of a glycine derivative show the catalyst to be an effect

Full text of DOI:10.1016/j.tetasy.2003.10.036

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 151–154
Synthesis and competency of a novel dicationic phase-transfer
catalyst
Walter E. Kowtoniuk, Michelle E. Rueffer and Darren K. MacFarland*
Department of Chemistry, Gettysburg College, 300 North Washington Street, Gettysburg, PA 17325, USA
Received 29 September 2003; accepted 22 October 2003
Abstract—Synthesis and characterization of a novel phase-transfer catalyst, 6,60 di(triethylammoniummethyl)-2,20-dihexyloxy-
bi-1,10-naphthalene, are reported. Preliminary catalytic studies on the alkylation of a glycine derivative show the catalyst to be an
effective phase-transfer catalyst but with no enantioselectivity.
Ó 2003 Published by Elsevier Ltd.
1. Introduction
cedure by Lemaire gave diamine 6.22 Purification by
column chromatography using a gradient eluant of ether
followed by 100:100:1 CH2Cl2/MeOH/NH3 and finally
Asymmetric phase-transfer catalysis represents an
important developing field for many reactions.1–3 In
particular the possibility of designer peptides through
the controlled synthesis of unnatural amino acids is of
significant interest.4–8 Most reports of successful phase-
transfer catalysts revolve around quaternization of
Cinchona alkaloids.4–6;9–13 Recent reports have intro-
duced the binaphthyl moiety into the mix.8;14–17 The
majority of these catalysts have a single quaternized
ammonium site, with only very few exceptions.7;18 In
contrast a dicationic catalyst has the potential to pseudo-
chelate an anion, perhaps then influencing its nucleo-
philic attack and generating enantioselectivity. Herein
we report the synthesis and catalytic competency of a
novel compound with two quaternary ammonium
groups positioned to act cooperatively.
23
2:2:1 CH2Cl2/MeOH/NH3 gave pure diamine. Quat-
ernization with ethyl iodide gave 1a initially, but upon
further reflux, the salt decomposed to give tetraethyl-
ammonium iodide. This led us to replace ethyl iodide
with ethyl tosylate, which required longer reaction times,
but gave 1b in good yield. Gradient chromatography on
alumina (ethyl acetate followed by 20:1 ethyl acetate/
methanol and finally 1:1 ethyl acetate/methanol) sur-
prisingly yielded 1c (Fig. 1).
Preliminary catalytic testing on glycine imino ester 7
alkylation (Scheme 2) showed compound 1 to be a good
phase-transfer catalyst with rates comparable to those
reported in the literature for the same reaction.8;15;16
Table 1 summarizes our results. Integration of the chiral
column HPLC traces showed enantioselectivities to be
below 5% for all substrates and conditions. Following
literature procedures8;15;16 we used a variety of active
alkyl halides: methyl iodide, benzyl bromide, allyl bro-
mide, and 2-(bromomethyl)naphthalene. Even methyl
iodide, reported in the literature to give slow rates even
with fivefold excess, gave a significant yield in 1 h. After
1 h the methyl iodide was fully consumed, presumably
hydrolyzed to methanol.
2. Results and discussion
The diammonium salt 1 can be synthesized in five steps
from (R)-1,10-bi-2,20-naphthol19 (BINOL) (Scheme 1).
After a standard Williamson ether synthesis, bromina-
tion follows the procedure of Persoons and Bjornholm.20
Double cyanation of the dibromodihexyloxy derivative
4 with CuCN gives dicyanodihexyloxy BINOL deriva-
tive 5.21 Reduction of 5 proved difficult, owing to both
over- and under-reduction, but modification of a pro-
To test the ability of our compound to act as a solid–
liquid and a liquid–liquid phase-transfer catalyst, both
50% KOH (for liquid–liquid catalysis) and CsOHÆH2O
(for solid–liquid catalysis) were used as base. Solid
CsOH consistently gave faster rates, though the KOH
solution was still effective.
* Corresponding author. E-mail: dmacfarl@gettysburg.edu
0957-4166/$ - see front matter Ó 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2003.10.036

152
W. E. Kowtoniuk et al. / Tetrahedron: Asymmetry 15 (2004) 151–154
Br
ii
iii
i
OH
OH
OHex
OHex
OHex
OHex
Br
4
2
3
NC
NC
H2N
H2N
Et3N
+
iv
OHex
OHex
OHex
OHex
v
OHex
OHex
+
Et3N
6
1
5
Scheme 1. Synthesis of phase-transfer catalyst 1. Reagents and conditions: (i) 1-bromohexane, NaOH, acetone; (ii) Br2, CH2Cl2, 0 °C; (iii) CuCN,
DMF; (iv) LAH, THF; (v) EtOTos, dioxane, Na3PO4.
ions. The catalytic alkylation of the imino ester 7
Et3N
+
showed that the compound was an efficient phase-
transfer catalyst. Further studies on other related com-
pounds are currently under way.
1a: X- = I-
O
O
1b: X- = TosO-
1c: 2X- = HPO42-/PO4
3-
+
Et3N
Figure 1. Chiral phase-transfer catalyst 1.
3. Experimental
3.1. General
O
O
Ph
Ph
Ph
RX
OtBu
+
N
N
All chemicals were purchased from Aldrich and used as
received, except THF, which was distilled from sodium
metal just prior to use. (R)-BINOL was synthesized
from 2-naphthol24 and resolved19 according to literature
procedures. NMR spectra were obtained on a Bruker
Avance 400. GC/MS data were obtained on a Varian
Saturn 2100T. Optical rotations were obtained on a
Perkin–Elmer 341 polarimeter. IR spectra were obtained
on a ThermoNicolet 200. Elemental analyses were
performed by Desert Analytics. HPLC analysis was
performed on a Chiracel OD column.
OtBu
Ph
CH2Cl2/base
catalyst 1c 5%
R
H
7
Scheme 2. General imino ester alkylation with phase-transfer catalyst
1c.
The catalyst was soluble in dichloromethane and ace-
tonitrile; the alkylation reaction ran well in both sol-
vents. In toluene, however, the catalyst was insoluble
with the alkylation proceeding only at the background
rate.
3.2. Synthesis of (R)-2,20-dihexyloxybi-1,10-naphthalene 3
In conclusion, we have reported the synthesis of a
novel phase-transfer catalyst, the first of its class of
6,60 substituted 2,20-dihexyloxybi-1,10-naphthalene dicat-
To a solution of (R)-BINOL (6.0 g, 20.1 mmol) in ace-
tone (150 mL) was added NaOH (1.76 g, 44.1 mmol,
Table 1. Results of imino ester alkylation with 5% catalyst loading
Alkyl halide RX
Solvent
Base
Temperature (°C)
Time (min)
% Completion
PhCH2Br
PhCH2Br
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50% KOH
CsOH
0
0
60
20
60
20
60
20
60
60
60
60
79.6
89.4
77.5
82.7
43.0
82.3
68.9
22.2
93.4
33.7
PhCH2Br
PhCH2Br
50% KOH
CsOH
20
0
CH2CHCH2Br
CH2CHCH2Br
CH3I
50% KOH
CsOH
CsOH
0
0
0
CH3I
Bromomethylnaphthalene
Bromomethylnaphthalene
50% KOH
CsOH
50% KOH
0
0
0

W. E. Kowtoniuk et al. / Tetrahedron: Asymmetry 15 (2004) 151–154
153
2.1 equiv) in water. 1-Bromohexane (7.27 g, 44.1 mmol)
3.5. Synthesis of (R)-6,60-di(aminomethyl)-2,20-dihexyl-
was then added and the solution refluxed with stirring
for 18 h. The reaction was monitored by TLC (1:1
ether/hexanes eluant) with additional bromohexane
added if needed. The reaction mixture was then cooled
and solvent removed in vacuo. The resulting oil was
taken into ether and extracted with 1 M NaOH. After
drying over CaCl2, solvent was removed to yield the
oxybi-1,10-naphthalene 6
(R)-6,60-Dicyano-2,20-dihexyloxybi-1,10-naphthalene
5
(3.0 g, 6.0 mmol) was taken into freshly distilled THF;
pelletized LAH (3.0 g, 59 mmol) was also taken into a
separate flask of freshly distilled THF and vigorously
stirred until the pellet was fully dispersed. Both solutions
were degassed with bubbling nitrogen for 20 min and the
dinitrile solution added via cannula to the LAH solu-
tion. The mixture was stirred for 90 min; longer reaction
times yielded over-reduction. The reaction was quen-
ched with water, 15% NaOH, Celite, and toluene fol-
lowing a simple formula: g LAH ¼ mL H2O ¼ mL 15%
NaOH ¼ g Celite. Celite was added to aid filtering;
toluene (25 mL) was added. The role toluene plays is
unclear but it is a critical addition. This quenched
mixture was stirred for 1 h and then filtered. Solvents
were removed in vacuo to yield the product as a pale
yellow, highly viscous oil (2.7 g, 88%). If further purifi-
cation was needed, column chromatography on silica
was performed using a gradient eluant (ether; 100:100:1
CH2Cl2/MeOH/NH3; 2:2:1 CH2Cl2/MeOH/NH3). 1H
NMR: d 7.9 (d, 2H, ArH), 7.7 (s, 2H, ArH), 7.4 (d, 2H,
ArH), 7.1 (m, 4H, ArH), 3.95 (s, 4H, NH2 CH2), 3.9 (m,
4H, OCH2), 0.6–1.7 (m, 11H, hexyl). 13C NMR: d 154.4,
138.1, 133.3, 129.3, 128.7, 126.0, 125.9, 125.1, 120.7,
1
product as an oil (9.11 g, 95.6%). H NMR: d 7.9 (d,
2H, ArH), 7.8 (d, 2H, ArH), 7.4 (d, 2H, ArH), 7.3 (m,
2H, ArH), 7.2 (m, 4H, ArH), 3.9 (m, 4H, OCH2), 0.7–
1.4 (m, 11H, hexyl). 13C NMR: d 154.5, 134.2, 129.3,
129.0, 127.7, 125.5, 123.4, 120.7, 115.9, 69.8, 31.3, 29.4,
25.3, 22.4, 13.9. MS: 455 (Mþ+H); ½aŠ +36 (c 1.0,
D
THF).
3.3. Synthesis of (R)-6,60-dibromo-2,20-dihexyloxybi-1,10-
naphthalene 4
(R)-2,20-Dihexyloxybi-1,10-naphthalene
3
(8.35 g,
18.6 mmol) was dissolved in CH2Cl2 (150 mL) and
cooled to 0 °C. Bromine was added in increments,
starting with 1.8 equiv. The reaction was followed by
GC/MS, with bromine added until the reaction went to
completion. The reaction mixture was then extracted
with 10% sodium hydrosulfite and brine. After drying
over CaCl2 and filtering, the solvent was removed to
116.1, 69.8, 46.5, 31.3, 30.0, 25.3, 22.7, 13.9. ½aŠ )8.6 (c
D
0.6, THF). MS: 513 (Mþ). Anal. Calcd: %C 79.67
(79.65), %H 8.71 (8.65), %N 5.30 (5.46).
1
yield the product as an oil (11.3 g, 99%). H NMR: d
8.0 (d, 2H, ArH),7.8 (d, 2H, ArH), 7.4 (d, 2H, ArH),
7.3 (dd, 2H, ArH), 7.0 (d, 2H, ArH), 3.9 (m, 4H,
OCH2), 0.7–1.4 (m, 11H, hexyl). 13C NMR: d 154.8,
132.6, 130.2, 129.7, 129.4, 128.4, 127.1, 120.0, 117.2,
116.4, 69.5, 31.3, 29.7, 29.2, 25.3, 22.5, 13.9. MS: 612
(Mþ).
3.6. Synthesis of (R)-6,60-bis(triethylammoniummethyl)-
2,20-dihexyloxyBINOL hydrogen phosphate/phosphate 1c
(R)-6,60-Di(aminomethyl)-2,20-dihexyloxybi-1,10-naphtha-
lene 6 (4.0 g, 7.8 mmol), ethyl tosylate (18.7 g, 93.5
mmol, 12 equiv), and Na3PO4 (7.6 g, 46.5 mmol, 6 equiv)
were combined in dioxane and refluxed for 48 h. The
reaction mixture was then cooled and poured onto an
alumina column filled with ethyl acetate. The column
was eluted with 20:1 ethyl acetate/MeOH to remove any
amine impurities, then 4:1 ethyl acetate/MeOH, and
finally pure MeOH. The product was found in metha-
nol-rich cuts (3.6 g, 69%). 1H NMR: d 8.1 (s, 2H, ArH),
8.0 (d, 2H, ArH, J ¼ 9 Hz), 7.5 (d, 2H, ArH, J ¼ 9 Hz),
7.3 (d, 2H, ArH, J ¼ 9 Hz), 7.0 (d, 2H, ArH, J ¼ 9 Hz),
4.8 (d, 2H, CH2NEt3, J ¼ 14 Hz), 4.7 (d, 2H, CH2NEt3,
J ¼ 14 Hz), 4.0 (m, 4H, OCH2), 3.4 (br, 6H,
NCH2CH3), 0.7–1.5 (m, hexyl and NCH2CH3). 13C
NMR: d 156.0, 134.6, 133.2, 130.1, 128.8, 128.5, 126.4,
121.7, 119.3, 116.2, 69.4, 63.6, 61.3, 52.8, 31.9, 31.3,
30.9, 30.3, 30.0, 29.7, 29.4, 29.2, 25.3, 22.7, 22.4, 14.1,
13.9, 8.4. Anal. Calcd: %C 72.06 (70.9), %H 9.41 (9.19).
Analysis is consistent with a 60% HPO24À/40% PO43À
mixture of counter ions (calcd C 72.0, H 9.49).
3.4. Synthesis of (R)-6,60-dicyano-2,20-dihexyloxybi-1,10-
naphthalene 5
(R)-6,60-Dibromo-2,20-dihexyloxybi-1,10-naphthalene
4
(6.7 g, 11.0 mmol) and CuCN (3.94 g, 44.0 mmol) were
taken into DMF and degassed with nitrogen. The
nitrogen line was replaced with a vent needle and the
reaction mixture refluxed for 16 h. The reaction mixture
was then poured into a 1:1 H2O/concd NH3 solution
(500 mL) and stirred for 2 h to remove any copper salts.
Filtration yielded the crude product as a sticky solid.
This solid was extracted with ethyl acetate. The ethyl
acetate solution was then further extracted with 1 M
NH3 until the aqueous layer was colorless. After drying
over CaCl2 and filtering, the solvent was removed in
vacuo. The resulting crude product was recrystallized
from MeOH and again from heptane to yield white
1
needles (3.18 g, 57.4%). H NMR: d 8.25 (d, 2H, ArH),
8.0 (d, 2H, ArH), 7.5 (d, 2H, ArH), 7.3 (dd, 2H, ArH),
7.1 (d, 2H, ArH), 4.0 (m, 4H, OCH2), 0.7–1.4 (m, 11H,
hexyl). 13C NMR: d 156.9, 135.5, 134.4, 130.4, 127.7,
126.8, 126.1, 119.6, 119.0, 106.6, 69.2, 31.2, 29.7, 25.2,
22.4, 13.8. IR: 2221 cmÀ1 (CN). MS: 505 (Mþ). Anal.
Calcd: %C 81.03 (80.92), %H 7.29 (7.19), %N 5.31
(5.55).
3.7. Example procedure for catalytic trials
A 25 mL round bottomed flask was charged with
CH2Cl2 (2 mL), 50% KOH (1 mL), N-(diphenylmethyl-
ene)glycine t-butyl ester (0.148 g, 0.50 mmol), and benzyl

154
W. E. Kowtoniuk et al. / Tetrahedron: Asymmetry 15 (2004) 151–154
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bar. The mixture was cooled in an ice bath. Catalyst 1c
(0.039 g, 0.05 mmol) was first dissolved in CH2Cl2
(1 mL) and then added to the mixture at which point
timing was started. Samples were taken after 10, 20, 30,
60, and 180 min. Samples were quenched by the addition
of a 1:1 ether/water mixture (2 mL) followed by extrac-
tion of the ether layer. Samples were analyzed by HPLC
using a Chiralcel OD–H column and a 99:1 hexane/
isopropanol eluent to determine both yield and % ee.
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Acknowledgements
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