An efficient optical resolution of nitrogen-centered chiral β-hydroxy-tetraalkylammonium salts via complexation with (R)-BINOL

Article abstract of DOI:10.1016/j.tetlet.2007.04.078

The optical resolution of nitrogen-centered chiral β-hydroxy-tetraalkylammonium bromides is demonstrated by using chiral BINOL as a complexing agent. Determination of the enantiopurities and absolute configurations of the resolved N-chiral tetraalkylammonium salts are described.

Full text of DOI:10.1016/j.tetlet.2007.04.078

Tetrahedron Letters 48 (2007) 4183–4185
An efficient optical resolution of nitrogen-centered chiral
b-hydroxy-tetraalkylammonium salts via
complexation with (R)-BINOL
Eiji Tayama* and Hiroyuki Tanaka
Graduate School of Science and Technology, Niigata University, Niigata 950-2181, Japan
Received 27 March 2007; revised 13 April 2007; accepted 16 April 2007
Available online 20 April 2007
Abstract—The optical resolution of nitrogen-centered chiral b-hydroxy-tetraalkylammonium bromides is demonstrated by using
chiral BINOL as a complexing agent. Determination of the enantiopurities and absolute configurations of the resolved N-chiral
tetraalkylammonium salts are described.
Ó 2007 Elsevier Ltd. All rights reserved.
While asymmetric synthesis of carbon-centered chiral
molecules has rapidly been advanced, the chemistry of
N-centered chiral tetraalkylammonium salts still
remains largely unexplored mainly due to the severely
limited accessibility thereof. In 1899, Pope et al.
reported the first preparation of enantio-enriched
N-centered chiral tetraalkylammonium salt via fractional
crystallization of its (+)-champhorsulfonate followed by
anion exchange.1 However, the enantio-purity and
absolute configuration of the enantiomer was not deter-
mined.2 Since then, only a few examples of N-chiral
enantiomers derived from amine N-oxides have been
reported,3 whereas there have been some examples of
diastereoselective quaternarization of C-centered chiral
tertiary amines to afford the C- and N-chiral diastereo-
mers in the enantio-enriched forms.4 The direct optical
resolution of racemic N-centered chiral tetraalkylammo-
nium salts has never been achieved.
the unique complexation of some tetraalkylammonium
salts with BINOL.5 Now we wish to report the efficient
optical resolution of N-centered chiral b-hydroxy-tetra-
alkylammonium salts 1 using (R)-BINOL as the com-
plexing agent (Scheme 1).
First, we carried out the optical resolution of N-allyl-
N-benzyl-N-(2-hydroxyethyl)-N-methylammonium bro-
mide monohydrate (1a)6 by complexation with (R)-BI-
NOL. When a mixture of 1a (1.0 equiv) and (R)-
BINOL (0.50 equiv) in dichloromethane7 was stirred at
room temperature for 24 h, a 1:1 complex (2a) of 1a with
(R)-BINOL was precipitated.8 The complex 2a was iso-
lated by filtration in 75% yield [determined from the
amount of (R)-BINOL] as colorless crystals, then com-
plex 2a was dissolved in a mixture of diethyl ether and
During the course of our continuing studies on asym-
metric Stevens rearrangements,4a we needed N-chiral
N-allylic quaternary ammonium salts (Stevens sub-
strates) as the enantio-enriched forms. Thus, we were
interested in optical resolution via complexation with
enantio-pure (R)-2,20-dihydroxy-1,10-binaphthol [(R)-
BINOL] in view of the recent publications concerning
Keywords: Ammonium salts; Optical resolution; Complexation;
Scheme 1. Optical resolution of N-centered chiral b-hydroxy-tetra-
alkylammonium salt 1a by diastereoselective complexation with (R)-
BINOL.
Diastereoselectivity; Nitrogen.
*
Corresponding author. Tel./fax: +81 25 262 7741; e-mail: tayama@
gs.niigata-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.078

4184
E. Tayama, H. Tanaka / Tetrahedron Letters 48 (2007) 4183–4185
Figure 1. Molecular structure of a 1:1 complex 2a (hydrogen and
solvent atoms are omitted for cleanly).
water. By extractive separation, enantio-enriched 1a was
obtained in 97% yield from the aqueous solution by
evaporation of water.9 The (R)-BINOL was recovered
from the diethyl ether solution (96% recovery from
2a). The enantiomer excess (ee) of the resolved 1a was
determined to be 82% ee by chiral HPLC analysis [Dai-
cel Chiralpak AD–H column, n-hexane/ethanol/trifluo-
roacetic acid/diethylamine = 90:10:0.1:0.1 as eluent,
flow rate = 0.50 mL/min, tR = 23.0 min for (S)-1a and
25.9 min for (R)-1a].10 The enantiomerically pure 1a
was obtained from diastereomerically pure 2a which
was obtained by recrystallization of 2a from ethanol,
or further optical resolutions of the resolved 1a with
(R)-BINOL.11 The absolute configuration of 1a was
determined as the S configuration on the nitrogen atom
by a single crystal X-ray diffraction (Fig. 1).12
Scheme 2. Separation of the both enantiomers of 1a by complexation
with (R)- or (S)-BINOL.
Table 1. Optical resolution of various types of tetraalkylammonium
salts 1
25
c
Entry
Ar
R
Yieldb
(%)
½aꢀ589
eed
(%)
(c 1.00,
EtOH)
1
2
3
4
5
6
2-Me–Ph
2-F–Ph
4-F–Ph
2-Br–Ph
Ph
H
H
H
H
Me
Ph
b
c
d
e
f
64
52
37
48
58
0e
ꢁ5.3
ꢁ5.3
ꢁ3.9
ꢁ3.8
ꢁ5.2
—
83
83
89
84
>95
—
The crystal structure of complex 2a reveals that the bro-
mide ion acts (or serves) as a bridge between the hydr-
oxyl group of tetraalkylammonium cation of (S)-1a
and one hydroxyl group of (R)-BINOL.13,14 Similar
types of intermolecular hydrogen bonds have been
reported in previous studies on tetraalkylammonium
salt–phenol complexation.5
Ph
g
a
Configurations were determined by the analogy with (S)-1a.
b Isolated yield.
c Include ca. 0.2 errors.
Interestingly enough, the present resolution method
allows us to obtain the both enantiomers of 1a from
the single racemic sample as depicted in Scheme 2. The
filtrate obtained after the 1st optical resolution was
concentrated under reduced pressure and the residue
was dissolved in a mixture of diethyl ether and water.
Extractive separation of the aqueous solution gave the
recovered ammonium salt 1a and the salt was treated
with (S)-BINOL in dichloromethane to resolve the other
enantiomer. Significantly enough, the other enantiomer
(R)-1a was obtained also in high enantio-purity (>95%
ee).
d Determined by the specific rotations based on the highest specific
rotations obtained by 3 times optical resolutions. The results include
ca. 5% errors.
e Not precipitated.
column were unsuccessful. Thus, the ee of the salts ob-
tained by the single resolution were determined by the
25
specific rotation values ð½aꢀ589Þ based on the highest spe-
cific rotation values obtained by 3 times optical resolu-
tions.15 No precipitations were observed in using N-
cinnamyl derivative 1g.
The scope of substrates was further explored as shown
in Table 1. Enantio-enriched N-chiral tetraalkylammo-
nium salts 1b–1f were obtained in the same way as
described above. Unfortunately, the determination of
ee-values for 1b–1f by HPLC analysis using chiral
In conclusion, we report that the first preparative meth-
od for a nitrogen-centered chirality was successfully
demonstrated by optical resolution of N-chiral b-hydr-
oxy-tetraalkylammonium salts 1. This work is likely to
stimulate advanced idea in the rapidly developing asym-

E. Tayama, H. Tanaka / Tetrahedron Letters 48 (2007) 4183–4185
4185
studies were applied for optical resolution of rac-BINOL,
see: (a) Ha, W.; Shan, Z. Tetrahedron: Asymmetry 2006,
17, 854–859; (b) Toda, F.; Yoshizawa, K.; Hyoda, S.;
Toyota, S.; Chatziefthimiou, S.; Mavridis, I. M. Org.
Biomol. Chem. 2004, 2, 449–451; (c) Wang, Y.; Sun, J.;
Ding, K. Tetrahedron 2000, 56, 4447–4451; (d) Toda, F.;
Tanaka, K.; Stein, Z.; Goldberg, I. J. Org. Chem. 1994, 59,
5748–5751; (e) Tanaka, K.; Okada, T.; Toda, F. Angew
Chem. Int. Ed. Engl. 1993, 32, 1147–1148.
metric chemistry of N-centered chiral molecules. The
further applications for organic synthesis are in progress
in our laboratory.
Acknowledgments
This work was supported by a Grant-in-Aid for Young
Scientists (17750034) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan and
Award in Synthetic Organic Chemistry, Japan and
UNION TOOL Scholarship Foundation.
6. Prepared from N-methylaminoethanol in 3 steps. [(i)
benzoyl chloride, NaHCO3, THF, rt; (ii) LiAlH4, THF,
0 °C to rt; (iii) allyl bromide, rt]. For more details, see the
Supplementary data.
7. Use of ethanol as solvent provided the comparable result.
1
8. The H NMR spectra of 2a in deuterated solvents (e.g.,
dimethylsulfoxide-d6, acetone-d6, and acetonitrile-d3) did
not show any diastereomerically separated peaks.
9. Compound 1a was stable for several days in a freezer
without racemization.
10. The specific analysis condition (eluent system) of 1a was
found by the analysis request to Daicel Chemical Indus-
tries, Ltd CPI Company, Chiral Separation Service.
11. Further optical resolution of (S)-1a (82% ee) with (R)-
BINOL (0.85 equiv) in dichloromethane improved the
enantio-purity to 93–95% ee. After one more optical
resolution of the resolved (S)-1a, the enantio-purity
was improved to >95% ee (determined by HPLC
analysis).
12. CCDC-640938 contains the supplementary crystallo-
graphic data for this Letter. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
13. Use of a chloride salt as substrate provided the corre-
sponding 1:1 complex with the similar yield and selectivity,
but an iodide salt did not.
14. By our preliminary studies, it was found that a b-hydroxy
group of ammonium salt is necessary for complexation
with BINOL.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.04.078.
References and notes
1. Pope, W. J.; Peachey, S. J. J. Chem. Soc. 1899, 1127–1131.
2. Recently, the absolute configuration was determined by a
single crystal X-ray diffraction, see: Torbeev, V. Y.;
Lyssenko, K. A.; Kharybin, O. N.; Antipin, M. Y.;
Kostyanovsky, R. G. J. Phys. Chem. B 2003, 107, 13523–
13531.
3. (a) Toda, F.; Mori, K.; Stein, Z.; Goldberg, I. Tetrahedron
Lett. 1989, 30, 1841–1844; (b) Meisenheimer, J.; Glawe,
H.; Greeske, H.; Schorning, A.; Vieweg, E. Liebig Ann.
Chemie. 1926, 449, 188–213; (c) Meisenheimer, J. Chem.
Ber. 1908, 41, 3966–3976.
4. (a) Tayama, E.; Nanbara, S.; Nakai, T. Chem. Lett. 2006,
35, 478–479; (b) Shimomoto, A.; Yonezawa, H.; Taki-
zawa, S.; Sasai, H. Jpn. Kokai Tokkyo Koho JP
2006076911 A 20060323, 2006; (c) Glaeske, K. W.; West,
F. G. Org. Lett. 1999, 1, 31–33.
15. The highest specific rotation values were obtained by 3
25
times optical resolutions; 1b: ½aꢀ589 ꢁ6.4 (c 1.00, EtOH),
25
25
1c: ½aꢀ589 ꢁ6.4 (c 1.00, EtOH), 1d: ½aꢀ589 ꢁ4.4 (c 1.00,
25
25
EtOH), 1e: ½aꢀ589 ꢁ4.5 (c 1.00, EtOH), 1f: ½aꢀ589 ꢁ5.2 (c
1.00, EtOH). For more details, see the Supplementary
data.
5. Previous papers have shown that BINOL and some of
quaternary ammonium salts form 1:1 complexes. These