Chiral lariat ethers based on spontaneously resolved 3-(2-cyanophenoxy) propane-1,2-diol

Full text of DOI:10.1134/S1070428014040319

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 4, pp. 611–613. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © R.R. Fayzullin, Z.A. Bredikhina, D.R. Sharafutdinova, O.B. Bazanova, A.A. Bredikhin, 2014, published in Zhurnal Organicheskoi
Khimii, 2014, Vol. 50, No. 4, pp. 622–624.
SHORT
COMMUNICATIONS
Chiral Lariat Ethers Based on Spontaneously Resolved
3-(2-Cyanophenoxy)propane-1,2-diol
R. R. Fayzullin, Z. A. Bredikhina, D. R. Sharafutdinova, O. B. Bazanova, and A. A. Bredikhin
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: robert.fayzullin@gmail.com
Received January 27, 2014
DOI: 10.1134/S1070428014040319
Lariat ethers are macrocyclic polyethers (crown
ethers) containing one ore more side arms with
electron-donating groups [1]. Such substituents may
enhance the selectivity and efficiency of binding guest
molecules or ions (lariat effect) [2, 3]. We previously
demonstrated lariat effect in the complexation of o-
and p-methoxyphenoxymethyl-15-crowns-5 with alkali
metal salts in the crystalline and gas phases [3]. It was
found that only the o-methoxyphenoxymethyl substit-
uent ensures efficient binding of sodium cation.
tallization is accompanied by spontaneous optical
resolution, as chiral building block in the synthesis of
a family of scalemic lariat ethers [5] (for spontaneous
resolution and its applied aspects, see [7]). However,
the ethers thus obtained contained no chemically reac-
tive functional groups and therefore neither covalent
grafting to a surface nor further functionalization of
these compounds was possible.
3-(2-Cyanophenoxy)propane-1,2-diol (I) is an ex-
ample of compounds for which an efficient stereo-
selective crystallization procedure has also been devel-
oped [8]. We selected diol I as synthetic precursor of
chiral lariat ethers having a cyano group which may be
subject to further chemical transformations. Racemic
diol rac-I and crystalline seeds of scalemic diols (R)-I
and (S)-I were synthesized from 2-hydroxybenzonitrile
and racemic or enantiomerically pure 3-chloropropane-
1,2-diol, respectively. Both enantiomers (R)-I and (S)-I
were isolated by preferential crystallization of rac-I
Lariat ethers attract particular interest as models of
natural ionophores and as chiral synthetic receptors.
Lariat ether-based resolving agents were shown to
ensure enantioselective extraction and derivatization of
racemates [4, 5]. Despite known advances in the syn-
thesis of lariat ethers [6], the number of available
nonracemic crown compounds remains insufficient.
We have recently reported on the use of 3-(2-methoxy-
phenoxy)propane-1,2-diol (guaifenesin), whose crys-
CN
CN
CN
Preferential
crystallization
+
O
OH
O
OH
O
OH
OH
OH
O
OH
rac-I
(R)-I
(S)-I
O
NC
NaH
O
O
O
O
(R)-I
+
Ts
Ts
O
O
O
O
O
II
NaH
(R)-III
NaH
(S)-I
+
II
(S)-III
rac-I
+
II
rac-III
611

FAYZULLIN et al.
612
374
[C18H25NO6 + Na]+
(a)
100
80
60
40
20
0
473
[C18H25NO6 + C8H12N]+
350
370
390
410
430
450
470
473
490 m/z
(b)
100
80
60
40
20
0
[C18H25NO6 + C8H12N]+
374
[C18H25NO6 + Na]+
350
370
390
410
430
450
470
490 m/z
MALDI mass spectra of mixtures of lariat ether (R)-III with (a) (R)-1-phenylethanamine and (b) (S)-1-phenylethanamine hydrochlorides.
[8]. Crown ethers rac-III, (S)-III, and (R)-III were
obtained in moderate yields (~21–25%) by cyclization
of diols I with tetraethylene glycol bis-p-toluenesul-
fonate (II) in the presence of NaH in THF under high
dilution conditions. The products were isolated by col-
umn chromatography, and their structure was proved
(S)-IV + H]+ is formed with an appreciably higher
probability than [(R)-III + (R)-IV + H]+. Presumably,
this is the result of chiral discrimination in the ex-
amined system.
Thus, we have synthesized both racemate and pure
R and S enantiomers of [(2-cyanophenoxy)methyl]-15-
crown-5 (III) from accessible enantiomerically pure
3-(2-cyanophenoxy)propane-1,2-diol (II) due to its
ability to undergo spontaneous resolution upon crys-
tallization. According to the MALDI mass spectral
data, crown ether (R)-III is capable of binding chiral
amines and is likely to exhibit chiral discrimination.
1
by MALDI mass spectrometry and H and 13C NMR
spectroscopy.
Our preliminary data showed formation of supra-
molecular complexes by crown ether (R)-III and enan-
tiomers of 1-phenylethanamine hydrochloride IV·HCl.
Analysis of the intensities of ion peaks belonging to
diastereoisomeric complexes [C18H25NO6 +C8H12N]+
(m/z 473.2574) relative to the [C18H25NO6 +Na]+ ion
peak (m/z 374.1586) in the MALDI mass spectrum
(see figure) suggests that the complex ion [(R)-III +
The synthesis of racemic and enantiopure 3-(2-cy-
anophenoxy)propane-1,2-diols and the procedure for
stereoselective crystallization of (R)-I and (S)-I were
described in [8].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

CHIRAL LARIAT ETHERS BASED ON SPONTANEOUSLY RESOLVED
613
column, 0.46×25 cm, grain size 20 μm, 22°C, eluent
hexane–propan-2-ol (9:1), flow rate 1 mL/min. The
MALDI mass spectra were recorded on a Bruker
UltraFlex III TOF/TOF instrument; Nd:YAG laser,
λ 355 nm. The precise m/z values were determined at
a resolution of 10 000 using PEG-400 for external
calibration. Samples were applied to a metal target by
the dried drop method using a 0.1 M solution of
p-nitroaniline (matrix) in MeCN (0.5 μL) and a 0.1 M
solution of an equimolar mixture of enantiomers of
crown ether III and 1-phenylethanamine hydrochloride
IV·HCl in MeOH (0.5 μL).
(R)-[(2-Cyanophenoxy)methyl]-15-crown-5
(R)-(III). A solution of 2.7 g (14 mmol) of diol (R)-I
{mp 72–73°C, [α]D20 = +9.6 (c = 1, t-BuOMe)} in
200 mL of anhydrous THF was added dropwise over
a period of 20 min under stirring at room temperature
to a suspension of 1.68 g (70 mmol) of sodium hydride
in 150 mL of anhydrous THF. The mixture was heated
for 3 h under reflux and cooled to 50°C, a solution of
7.04 g (14 mmol) of tetraethylene glycol bis-p-toluene-
sulfonate (II) in 300 mL of THF was added over
a period of 1 h, 150 mL of THF was then added, and
the mixture was heated for 70 h under reflux. The pre-
cipitate was filtered off, the filtrate was concentrated
under reduced pressure, and the oily residue was puri-
fied by column chromatography on silica gel (0.125–
0.25 mm) using propan-2-ol–hexane (1:4 to 4:1) as
eluent. Yield 1.13 g (23%), light yellow oily substance,
REFERENCES
1. Gokel, G.W., Chem. Soc. Rev., 1992, vol. 21, p. 39;
Gokel, G.W., Leevy, W.M., and Weber, M.E., Chem. Rev.,
2004, vol. 104, p. 2723.
[α]D20 = –5.4 (c = 1, CHCl3), ee 97% [HPLC, tmin
=
2. Nakatsuji, Y., Nakamura, T., Okahara, M., Di-
shong, D.M., and Gokel, G.W., Tetrahedron Lett., 1982,
vol. 23, p. 1351; Gatto, V.J. and Gokel, G.W., J. Am.
Chem. Soc., 1984, vol. 106, p. 8240; Gatto, V.J.,
Arnold, K.A., Viscariello, A.M., Miller, S.R.,
Morgan, C.R., and Gokel, G.W., J. Org. Chem., 1986,
vol. 51, p. 5373; Tsukube, H., Adachi, H., and Moro-
sawa, S., J. Chem. Soc., Perkin. Trans. 1, 1989, p. 89.
3. Bredikhin, A.A., Gubaidullin, A.T., Bredikhina, Z.A., and
Fayzullin, R.R., J. Mol. Struct., 2013, vol. 1032, p. 176;
Sharafutdinova, D.R., Fayzullin, R.R., Bazanova, O.V.,
Bredikhina, Z.A., Rizvanov, I.H., and Bredikhin, A.A.,
J. Anal. Chem., 2013, vol. 68, p. 1178.
4. Helgeson, R.C., Koga, K., Timko, J.M., and Cram, D.J.,
J. Am. Chem. Soc., 1973, vol. 95, p. 3021; Hyun, M.H.,
J. Sep. Sci., 2003, vol. 26, p. 242; Nakatsuji, Y., Naka-
hara, Y., Muramatsu, A., Kida, T., and Akashi, M., Tetra-
hedron Lett., 2005, vol. 46, p. 4331; Chisholm, C.D.,
Fülöp, F., Forró, E., and Wenzel, T.J., Tetrahedron:
Asymmetry, 2010, vol. 21, p. 2289.
5. Bredikhina, Z.A., Eliseenkova, R.M., Fayzullin, R.R.,
Novikova, V.G., Kharlamov, S.V., Sharafutdinova, D.R.,
Latypov, Sh.K., and Bredikhin, A.A., Arkivoc, 2011,
part (x), p. 16.
29.4 min, tmaj = 34.7 min]. 1H NMR spectrum, δ, ppm:
3.56–3.83 m (15H, CH2), 3.84–4.01 m (3H, CH2),
4.06–4.31 m (3H, CH, CH2), 6.98–7.02 m (2H, 4-H,
6-H), 7.49–7.56 m (2H, 3-H, 5-H). 13C NMR spec-
trum, δC, ppm: 70.18, 70.46, 70.51, 70.51, 70.56,
70.60, 70.79, 70.89, 70.95, 71.32 (CH2O); 77.76 (CH),
102.21 (C2), 112.47 (C6), 116.38 (CN), 120.82 (C4),
133.64 (C3), 134.23 (C5), 160.76 (C1). Mass spectrum:
m/z 374.1586 [M + Na]+. C18H25NO6. Calculated:
[M + Na]+ 374.1580.
(S)-[(2-Cyanophenoxy)methyl]-15-crown-5
(S)-(III) was synthesized in a similar way from diol
(S)-I {mp 72–73°C, [α]D20 = –9.8 (c = 1, t-BuOMe)}.
Yield 1.23 g (25%), [α]D20 = +5.7 (c = 1, CHCl3);
ee 98% [HPLC, tmaj = 28.1 min, tmin = 33.5 min]. The
NMR spectra of (S)-III were identical to those given
above for (R)-III. Mass spectrum: m/z 374.1583 [M +
Na]+. C18H25NO6. Calculated: [M + Na]+ 374.1580.
rac-[(2-Cyanophenoxy)methyl]-15-crown-5
rac-(III) was synthesized in a similar way. Yield
0.51 g (21%). The NMR spectra of rac-III were iden-
tical to those given above for (R)-III. Mass spectrum:
m/z 374.1584 [M + Na]+. C18H25NO6. Calculated:
[M + Na]+ 374.1580.
6. Abbas, A.A. and Elwahy, A.H.M., J. Heterocycl. Chem.,
2009, vol. 46, p. 1035.
7. Coquerel, G., Top. Curr. Chem., 2007, vol. 269, p. 1;
Levilain, G. and Coquerel, G., CrystEngComm, 2010,
vol. 12, p. 1983; Bredikhin, A.A., Bredikhina, Z.A., and
Zakharychev, D.V., Mendeleev Commun., 2012, vol. 22,
p. 171; Lorenz, H. and Seidel-Morgenstern, A., Angew.
Chem., Int. Ed., 2014, vol. 53, p. 1218.
8. Bredikhina, Z.A., Akhatova, F.S., Zakharychev, D.V., and
Bredikhin, A.A., Tetrahedron: Asymmetry, 2008, vol. 19,
p. 1430.
1
The H and 13C NMR spectra were recorded on
a Bruker Avance-400 spectrometer at 399.9 and
100.5 MHz, respectively, using CDCl3 as solvent and
reference. The optical rotations were measured on
a Perkin Elmer 341 polarimeter. HPLC analyses were
obtained on a Shimadzu LC-20AD chromatograph
equipped with a UV detector (λ 275 nm); Chiralcel OD
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014