Improved conditions for the addition of alkoxides to di(ethylene glycol) di-p-tosylate: Application to the stereospecific synthesis of the trans-isomers of dicyclohexano-18-crown-6

Article abstract of DOI:10.1016/S0040-4039(01)00331-8

Conditions are defined for the efficient preparation of polyethers by direct condensation of ditosylates and alkoxides, and this approach is shown to provide a facile method for the synthesis of the trans-syn-trans (C) and trans-anti-trans (D) isomers of

Full text of DOI:10.1016/S0040-4039(01)00331-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2945–2948
Improved conditions for the addition of alkoxides to di(ethylene
glycol) di-p-tosylate: application to the stereospecific synthesis of
the trans-isomers of dicyclohexano-18-crown-6†,‡
Vincent J. Huber* and Mark L. Dietz
Chemistry Division, Argonne National Laboratory, Argonne, IL 60439, USA
Received 7 December 2000; revised 19 February 2001; accepted 20 February 2001
Abstract—Conditions are defined for the efficient preparation of polyethers by direct condensation of ditosylates and alkoxides,
and this approach is shown to provide a facile method for the synthesis of the trans-syn-trans (C) and trans-anti-trans (D) isomers
of dicyclohexano-18-crown-6 (DCH18C6), one which both provides significantly improved yields and avoids the difficult
separations required by certain previously described synthetic methods. © 2001 Elsevier Science Ltd. All rights reserved.
The complexation properties of crown ethers have been
intensely studied1–3 since their initial identification by
Pedersen.4 Of the numerous crown compounds now
known, dicyclohexano-18-crown-6 (DCH18C6) has
been among the most thoroughly investigated.1–3 This
compound can exist in five distinct isomeric forms
(1–5), each varying with respect to cis-trans isomerism
at the point of ring fusion and syn-anti isomerism
between cyclohexano substituents across the macro-
cyclic cavity. Two of these stereoisomers, the cis-syn-cis
(A) and cis-anti-cis (B) forms (1 and 2, respectively),
are readily obtained by catalytic hydrogenation of
dibenzo-18-crown-6.5 These two isomers have attracted
considerable interest as metal ion complexants or
extractants, and it is now well established that they can
differ significantly in both complexation and extraction
behavior for a given metal ion.2,6–8 Analogous investi-
gations of the trans-syn-trans (C) and trans-anti-trans
(D) stereoisomers (3 and 4, respectively), among them
our own studies of the influence of steric and stereo-
chemical factors on the magnitude of synergistic inter-
actions
between
crown
ethers
and
various
organophosphorus ligands,9,10 have been hampered by
the lack of satisfactory methods for their preparation.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
1
2
3
O
O
O
O
O
O
O
O
O
O
4
5
Keywords: crown ether; stereospecific synthesis.
* Corresponding author. Present address: Molecumetics, Ltd., 2023 120th Avenue, N.E., Bellevue, WA 98005, USA. Tel.: +(425) 646-8865;
fax: +(425) 646-8890; e-mail: huber@molecumetics.com
†
Work performed under the auspices of the Office of Basic Energy Sciences, Division of Chemical Sciences, US Department of Energy under
contract number W-31-109-ENG-38.
The submitted manuscript has been created by the University of Chicago as Operator of Argonne National Laboratory (‘Argonne’) under
‡
Contract No. W-31-109-ENG-38 with the US Department of Energy. The US Government retains for itself, and others acting on its behalf, a
paid-up, nonexclusive, irrevocable worldwide license in said article to reproduce, prepare derivative works, distribute copies to the public, and
perform publicly and display publicly, by or on behalf of the Government.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00331-8

2946
V. J. Huber, M. L. Dietz / Tetrahedron Letters 42 (2001) 2945–2948
isomers was expected to be considerably easier than
OR
that described by Stoddart,12 however, since 7 would
OBn
OH
not be present in the product mixture.
i
ii
iv
6
3 + 4
O
O
Diol 6 was first protected as its monobenzyl ether 11.21
The construction of the lower polyether chain was then
attempted by condensing two equivalents of cyclohex-
anol 11 with either (2-bromoethyl)ether (8) or
di(ethylene glycol) di-p-toluene sulfonate (9). Signifi-
cant differences in the outcome of the reaction were
observed depending on the electrophile, base and reac-
tion conditions used (Table 1).22 As shown, attempts to
alkylate 8 with 11 in refluxing THF were unsuccessful.
Only 11 was returned from the reaction and none of the
dibromide was recovered. Presumably, the elimination
of dibromide 8 was faster than its alkylation with 11.
The alkylation of 9 with 11, also in refluxing THF, did
lead to a small amount (ꢀ30% yield) of 12, along with
a number of impurities. Analysis of the product mixture
showed that a significant amount (43% yield) of vinyl
ether 10 was present23 in addition to 12 and unreacted
11. More detailed characterization of the mixture was
hampered by the difficulty in isolating compounds of
suitable purity for further analysis. The addition of
DMF led to an increase in the isolated yield of 12,
although 10 was again a significant impurity. Using
DMSO as the reaction solvent and NaH as the base
further improved the isolated yield of the desired
product. Interestingly, using a NaH dispersion in min-
eral oil consistently led to a significant (21%) improve-
ment in the yield of 12 over that obtained with dry
NaH.
2
11
12, R = Bn
13, R = H
iii
Scheme 1. (i) BnBr, NaH, DMSO, 65%. (ii) See Table 1. (iii)
10% Pd/C, H2, MeOH, rt, 48 h, quantitative. (iv) 60% NaH,
DMSO, 13, rt, 16 h, 64% (3+4).
Prior syntheses of these isomers have been effected
using a variety of strategies.11–13 While elegant, these
methodologies either lead to complex product mixtures
or afford yields insufficient for extended study. Gener-
ally, the C isomer (3) is more readily obtained; in one
instance,12 it crystallized from the crude product mix-
ture, while in a second,13 it was the predominant isomer
obtained, even when racemic trans-1,2-cyclohexanediol
was employed as the starting material. In contrast, the
isolation of the D isomer (4) has proven problematic.
In fact, only a chiral synthesis of (+)-4 using a ‘half
crown’ strategy,14 bridged through the western cyclo-
hexyl moiety, starting from (+)-(1R,2R)-trans-1,2-cyclo-
hexanediol ((+)-6) has been shown to give the
compound in a meaningful yield (12%).13 The yields of
both isomers were likely affected negatively by the poor
addition of alkoxides to ditosylates,15–20 and in some
cases, the formation of 1,4,7-trioxa[4.7.0]bicyclo-
tridecane (7), which tends to co-crystallize and co-elute
with 4.12
Hydrogenolysis of 12 cleanly gave diol 13.24 Condensa-
tion of the resulting diol with one equivalent of the
ditosylate gave a mixture of the C and D diastereomers.
The combined yield of both diastereomers from this
step was 64% (36% C and 28% D).25 Thus, the overall
yield for all four synthetic steps was 40% for isomer C
and 31% for isomer D, a nearly four- and threefold
increase, respectively, over the best previously reported
yields for these compounds.
We envisioned a straightforward four-step synthesis of
3 and 4 (Scheme 1) roughly analogous to that set
forward by Stoddart et al.,11 whereby monoprotection
of 6 would allow the convenient assembly of the ‘half
crown’ bridged through the southern polyether moiety.
Removal of the protecting groups, followed by comple-
tion of the northern polyether moiety, would yield a
mixture of 3 and 4. The isolation of the C and D
OH
OH
O
OBn
O
O
R
O
2
O
O
6
8, R = Br
9, R = TsO
7
10
Table 1. Condensation of 11 with di(ethylene glycol)-derived electrophiles
Entry
Base
8/9
Solvent
Temp.
Time (h)
Yield (%)
1
2
3
4
5
KH
KH
8
9
9
9
9
THF
THF
33% THF/DMF
DMSO
DMSO
Reflux
Reflux
Reflux
Rt
14
14
14
24
24
0a
30b
42
64
85
KH
NaHc
NaHd
Rt
a Only 6 was recovered from the reaction mixture.
b Major product was the vinyl ether.
c Dry NaH was used.
d Unwashed 60% NaH was used.

V. J. Huber, M. L. Dietz / Tetrahedron Letters 42 (2001) 2945–2948
2947
NaH suspension. That is, displacement of the tosylate
from 9 can occur via either elimination or substitution.
The immiscibility of mineral oil with DMSO, by mini-
mizing the concentration of NaH and Na–DMSO
present in solution at any given time, apparently leads
to a low background concentration of the alkoxide,
which favors substitution over elimination. There is, as
yet, no ready explanation for the considerable differ-
ence between the results obtained with DMSO and
DMF when the mineral oil suspension of NaH is
employed. Further studies are needed to precisely define
the role of the solvent and other factors (e.g. tempera-
ture and cation) in this reaction. Work addressing these
opportunities is now in progress.
OH
a
+
O
2
O
O
O
16
14
15
Scheme 2. (a) 14 (2.5 mmol), base (5.0 mmol), 9 (1.25 mmol),
solvent (5 mL).
Repeating the reaction sequence starting with enan-
tiomerically pure (1S,2S)-trans-1,2-cyclohexanediol
gave 4 directly. The only adjustments from the proce-
dure described above were to further decrease the ratio
of the diol to benzyl bromide to 1:1. The yield of (+)-11
was 37%; however, the isolated yield of its dibenzyl
analog was 59%. The recovery of the chiral dibenzyl
ether gave a convenient means of recovering and recy-
cling the chiral diol not converted to 11. The modest
yield of (+)-11 notwithstanding, the yields of the chiral
intermediates and products are consistent with those in
the racemic synthesis. The overall yield of (+)-4 was
19%.26
In summary, we have demonstrated that the efficiency
of alkylation of ditosylates with alkoxides can be sig-
nificantly enhanced by employing unwashed 60% NaH/
DMSO. The result is an improved method for the
preparation of polyethers in general and of the trans
isomers of DCH18C6 in particular.
Acknowledgements
In an attempt to determine the origin of the improve-
ment in the yield of 12 observed when a mineral oil
dispersion of NaH was employed in the alkylation of 9,
the product distributions obtained in the reaction of
cyclohexanol 14 with 9 (Scheme 2) were determined for
various combinations of NaH (dry or as a 60% suspen-
sion) and solvents.27 The results of these experiments
are summarized in Table 2. As shown, increasing the
solvent polarity leads to an improvement in the yields
of the desired product, triether 15, although a consider-
able percentage of cyclohexanol and vinyl ether 16 are
also present in the product mixture. Also, using a 60%
suspension of NaH with DMSO leads to a modest
increase (13%) in the yield of 15 versus dry NaH under
identical conditions. Although this increase is smaller
than that observed in the synthesis of the DCH18C6
stereoisomers, it was reproducible over several experi-
ments. Conducting the alkylation using dry NaH in
either THF or DMSO yields essentially identical
product distributions. Interestingly, however, the com-
bination of 60% NaH and DMF leads to a significant
decline in the yield of 15. Taken together, these results
suggest that the poor solubility of mineral oil in DMSO
may account for the improved yields observed with the
Drs. H. K. Jacobs and A. S. Gopalan of New Mexico
State University are thanked for their assistance in
obtaining optical rotations. Dr. R. E. Barrans is
thanked for helpful discussions.
References
1. Izatt, R. M.; Bradshaw, J. S.; Nielsen, S. A.; Lamb, J. D.;
Christensen, J. J. Chem. Rev. 1985, 85, 271.
2. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R.
L. Chem. Rev. 1991, 91, 1721.
3. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R.
L. Chem. Rev. 1995, 95, 2529.
4. Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 2495.
5. Gokel, G. W.; Korzeniowski, S. H. Macrocyclic
Polyether Syntheses; Springer-Verlag: New York, 1982.
6. Lemaire, M.; Guy, A.; Chomel, R.; Foos, J. J. Chem.
Soc., Chem. Commun. 1991, 1152.
7. Nazarenko, A. Y.; Sukhan, V. V. Zh. Neorg. Khim. 1992,
37, 950.
8. Dietz, M. L.; Bond, A. H.; Clapper, M.; Finch, J. W.
Radiochim. Acta 1999, 85, 119.
9. Dietz, M. L.; Bond, A. H.; Hay, B. P.; Chiarizia, R.;
Huber, V. J.; Herlinger, A. W. J. Chem. Soc., Chem.
Commun. 1999, 1177.
Table 2. The alkylation of 9 with 14 in the presence of NaH
Entry
Base
Solvent
Temp.
Yield 14, 16, 15 (%)
10. Bond, A. H.; Chiarizia, R.; Huber, V. J.; Dietz, M. L.;
Herlinger, A. W.; Hay, B. P. Anal. Chem. 1999, 71, 2757.
11. Stoddart, J. F.; Wheatley, C. M. J. Chem. Soc., Chem.
Commun. 1974, 390.
12. Burden, I. J.; Coxon, A. C.; Stoddart, J. F.; Wheatley, C.
M. J. Chem. Soc., Perkin Trans. 1 1977, 220.
13. Hayward, R. C.; Overton, C. H.; Whitham, G. H. J.
Chem. Soc., Perkin 1 1976, 2413.
c
1
2
3
4
5
6
NaHa THF
NaHa THF
NaHa DMSO
NaHa DMF
NaHb DMSO
NaHb DMF
Rt
Reflux
Rt
Rt
Rt
55, 15, 30
29, 16, 55
28, 17, 55
15, 17, 68
51, 13, 36
Rt
a Dry NaH was used.
b 60% NaH was used.
14. Green, R. N. Tetrahedron Lett. 1972, 1793.
15. Naemura, K.; Nishikawa, Y.; Fuji, J.; Hirose, K.; Tobe,
Y. Tetrahedron: Asymmetry 1997, 8, 873–882.
c The reaction was not complete at 48 h. A number of unidentified
peaks were also present.

2948
V. J. Huber, M. L. Dietz / Tetrahedron Letters 42 (2001) 2945–2948
16. Aspinall, H. C.; Greeves, N.; Lee, W.-M.; McIver, E. G.;
Smith, P. M. Tetrahedron Lett. 1997, 38, 4679–4682.
17. Hyun, M. H.; Cho, Y. J.; Chang, G. Y.; Jyung, K. K. J.
Kor. Chem. Soc. 1996, 40, 287–290.
18. Kanakamma, P. P.; Mani, N. S.; Maitra, U.; Nair, V. J.
J. Chem. Soc., Perkin Trans. 1 1995, 1, 2339–2344.
19. Naemura, K.; Miyabe, H.; Shingai, Y.; Tobe, Y. J.
Chem. Soc., Perkin Trans. 1 1993, 1073–1077.
reaction vessel was evacuated, then back-filled with H2,
and the resulting mixture stirred for 72 h. The mixture
was then filtered through a pad of Celite and the filtrate
evaporated in vacuo to give a waxy semi-solid. The
residue was suspended in DCM (35 mL) and the resulting
mixture was washed with water (2×25 mL). The clear
organic solution was then dried over MgSO4 and evapo-
rated in vacuo, giving a colorless oil. 1H NMR was
consistent with that of the expected product. The crude
product was used without further purification.
20. Bradshaw, J. S.; An, H.; Krakowiak, K. E.; Wu, G.;
Izatt, R. M. Tetrahedron 1990, 46, 6985–6994.
21. Spectral and physical properties are consistent with those
described in: Masaki, Y.; Miura, T.; Ochiai, M. Bull.
Chem. Soc. Jpn. 1996, 69, 195.
25. DMSO (25 mL) was added to 60% NaH (1.28 g; 32.1
mmol) followed by a solution of 13 (1.94 g; 6.42 mmol) in
DMSO (10 mL). The resulting solution was stirred for 16
h at room temperature. Water (100 mL) was then added,
followed by brine (50 mL), and the resulting mixture was
extracted with ether (3×50 mL). The combined ether
extracts were washed with brine (25 mL), dried over
MgSO4, and concentrated in vacuo to yield a yellowish
semi-solid. The crude residue was crystallized from ether,
giving 0.86 g of 3. The supernate was evaporated and the
residue chromatographed (silica gel; 10% EtOAC/hex),
then recrystallized from 25% hexanes/ether, yielding 0.68
g of 4. The physical and spectroscopic properties of 3 and
4 agree with literature values (e.g. mp3=116°C, lit.11=
120–121°C; mp4=76–77°C, lit.11=77–80°C).
22. A solution of cyclohexanol 11 (3.00 g, 2 equiv.) in the
reaction solvent (10 mL) was added to a solution of base
(4 equiv.) in the reaction solvent (15 mL) followed by 8 (1
equiv.) or a solution of 9 (1 equiv.). The resulting mixture
was stirred until TLC indicated no further reaction.
Water was added and the mixture was partitioned
between additional water and ether. The ether phase was
separated and washed with brine, then dried over MgSO4
and concentrated in vacuo. The residue was purified by
column chromatography (silica gel; 10% EtOAc/hex).
The structural assignment of 12 was consistent with its
TLC behavior and its 1H and 13C NMR spectra. Com-
plete separation of 12 from residual 11 was not achieved
however, and ca. 2–7% of 11 (based on 1H NMR)
remains in the product mixture after column chromatog-
raphy. Yields of 12 have been adjusted to reflect the
26. (+)-4 was obtained as a white solid; mp=76–77°C
(lit.13=71–74°C); [h]D25=+35.4 (c=0.65, CHL) (lit.:13
[h]2D0=+39.2 (c=1, EtOH).
1
27. General procedure: cyclohexanol 14 (2.5 mmol) was
added to a mixture of NaH (5.0 mmol) in the solvent (5
mL), followed by addition of 9 (1.25 mmol). The result-
ing mixture was stirred at room temperature until the
reaction was complete as indicated by GC. An aliquot
(250 mL) of the reaction mixture was partitioned between
ether (2 mL) and water (2 mL) and the composition of
the ether phase evaluated by GC. Retention times of the
key products: 14 (3.2 min), 15 (20.2 min), 16 (11.4 min).
Compounds 15 and 16 were isolated and their structures
amount of 11 present. Key H NMR signals (300 MHz):
l (ppm) 1.20–1.39 (m, 10H), 1.60–1.79 (m, 4H), 1.95–2.10
(m, 4H), 3.18–3.35 (m, 4H), 3.60–3.70 (m, 2H), 3.72–3.80
(m, 2H), 4.67 (d, 4H, J=9 Hz), 7.20–7.41 (m, 10H).
23. Compound 10 was obtained as a colorless oil from the
purification of crude 12. Key 1H NMR signals (300
MHz): l (ppm) 1.20–1.39 (m, 5H), 1.60–1.75 (m, 2H),
1.99–2.04 (m, 2H), 3.22–3.37 (m, 2H), 3.72–3.86 (m, 5H),
4.01 (dd, 1 H, J1=2 Hz, J2=7 Hz), 4.18 (dd, 1 H, J1=2
Hz, J2=14 Hz), 4.68 (d, 2 H, J=4 Hz), 6.51 (dd, 1 H,
J1=2 Hz, J2=14 Hz), 7.28–7.38 (m, 5H).
1
confirmed by H and 13C NMR.28
28. Buchanan, G. W.; Moghimi, A.; Reynolds, V. M.;
24. 10% Pd/C (0.50 g) was added to a solution of 12 (2.82 g)
in CH3OH (50 mL) followed by HOAC (1 mL). The
Bourque, K. Can. J. Chem. 1995, 73, 566.
.
.