Short and simple synthesis of chelating bis-ethers and bis-amines in the bicyclo[3.3.1]nonane series

Article abstract of DOI:10.1016/j.tetlet.2006.02.038

A remarkably simple process for the synthesis of a series of rigid bicyclic diethers and diamines is described.

Full text of DOI:10.1016/j.tetlet.2006.02.038

Tetrahedron Letters 47 (2006) 2581–2583
Short and simple synthesis of chelating bis-ethers and bis-amines
in the bicyclo[3.3.1]nonane series
Felix H. V. Chau and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
Received 27 January 2006; revised 1 February 2006; accepted 6 February 2006
Available online 23 February 2006
Abstract—A remarkably simple process for the synthesis of a series of rigid bicyclic diethers and diamines is described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Some years ago Tilichenko et al.1 described the coupling
of propiophenone with 37% aqueous formaldehyde and
ethanolic sodium hydroxide to give a 1:1 mixture of dia-
stereomeric ketones 1. When we carried out the reaction
at 70 ꢁC by slow addition (over 45 min) of formalin to a
solution of propiophenone and base, a 95% yield of 1
was obtained readily and reproducibly on a 1 mol scale
(which requires only a 1-L flask). Further reaction of 1
with formalin in ethanolic sodium hydroxide for 1 h at
50 ꢁC gave after cooling, dilution with ethanol, and fil-
tration of the precipitate essentially pure crystalline
bicyclic bis-hemiketal 2 in 55% yield; mp 184–185 ꢁC
after recrystallization from C6H6 (see Scheme 1). Treat-
ment of 2 with a catalytic amount of concd H2SO4 (ca.
2 mol %) in 2:1 EtOH–CHCl3 at reflux gave upon cool-
ing the crystalline ethyl ketal 3 (90% yield from the first
two crops, additional after neutralization of H2SO4 and
further concentration), mp 176–178 ꢁC.2 Upon slow
recrystallization of 3 from benzene, large monoclinic
crystals were obtained, which, when individually sub-
jected to measurement of optical rotation, were found
23
invariably to show ½aꢀD of either ca. +240 or ꢁ240 (in
CHCl3 solution). That these crystals were nearly enantio-
merically pure was demonstrated by the fact that fur-
ther recrystallization of either dextrorotatory 3 or
levorotatory 3 raised the specific optical rotation only
slightly.
O
O
NaOH
EtOH
PhCOCH2CH3
+
The ready availability of racemic 3 in quantity combined
with the fact that this rigid molecule undergoes sponta-
neous resolution by simple crystallization, suggests that
this system could be useful for enantioselective synthetic
purposes. Crystals of 3 may be described as of the con-
glomerate type because the crystalline enantiomers are
less soluble (and have a higher melting point) than those
of the racemate.3 Multigram quantities of the enantio-
mers of 3 were easily obtained by various recrystalliza-
tion techniques. The simplest of these involved the
induction of crystallization by seeding of a clear (parti-
cle-free), concentrated solution of the racemate in hot
benzene with crystals of one of the pure enantiomers,
arbitrarily chosen as dextro, although obviously either
of the enantiomers could be used. After allowing the
solution to cool very slowly to 23 ꢁC, filtration of the
crystals afforded (+)-3 of ca. 90% enantiomeric purity.
Ph
Ph
H2CO (aq)
Me Me
1
NaOH
EtOH
H2CO (aq)
Me
Me
EtO
O
OEt
Ph
HO
O
OH
EtOH
H2SO4
Ph
Me
O
Me
O
Ph
Ph
( )-3
( )-2
recryst./C6H6
(+)-3 seed
recryst ./
C6H6
(–)-3
(+)-3
+
mother liquors
(–)-3 seed
Scheme 1. Efficient and simple preparation of the (+)- and (ꢁ)-
enantiomers of bis-ketal 3.
Recrystallization of this material from benzene afforded
23
*
crystals of >98% enantiomeric purity; ½aꢀD +245
Corresponding author. Tel.: +1 617 495 4033; fax: +1 617 495
0376; e-mail: corey@chemistry.harvard.edu
(CHCl3), mp 206–208 ꢁC.4 The mother liquors were
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.038

2582
F. H. V. Chau, E. J. Corey / Tetrahedron Letters 47 (2006) 2581–2583
heated to form a clear, particle-free solution and seeded
with crystals of (ꢁ)-3. In this way, enantiomerically pure
(ꢁ)-3 was obtained upon cooling and an additional
recrystallization. There seems to be no obvious reason
why this process should be limited with respect to scale.
95 ꢁC for 10 h followed by extractive isolation and col-
umn chromatography on silica gel (30% EtOAc in hex-
ane for elution) afforded the bis-O-methyloxime 7
23
(colorless oil, ½aꢀD ꢁ36.6 (CHCl3)) in 90% yield, as out-
lined in Scheme 3. Reaction of 7 with 2.2 equiv of
CH3SO2Cl and 2.5 equiv of Et3N in CH2Cl2 at ꢁ30 ꢁC
for 4 h produced, after extractive isolation, the corre-
sponding dimesylate (8) as a solid that was sufficiently
pure to use directly in the next step. Upon heating the
dimesylate 8 in dimethylformamide with 2 equiv of
H2O and 1 equiv of Et3N at 100 ꢁC for 12 h, concentra-
tion in vacuo, extractive isolation, and filtration through
a column of basic alumina using CH2Cl2 as solvent, the
The absolute configuration of (+)-3 was established by
X-ray crystallographic analysis of the corresponding
bis-2-bromoethylketal, (+)-4. The synthesis of this
derivative was carried out as follows. Hydrolysis of
(+)-3 using a 1:1:1 mixture acetone–THF–H2O contain-
ing 0.001 vol of concd H2SO4 at reflux for 30 min affor-
ded, after addition of Et3N, concentration under
reduced pressure and extractive isolation, 95% of (+)-
bis-N-methyloxyamino-carbinol 9 was obtained in 70%
23
23
2, ½aꢀD +225 (CHCl3). Reaction of (+)-2 with 2-bromo-
yield; mp 196–197 ꢁC, ½aꢀD ꢁ201 (CHCl3). Reduction
ethanol and CH3SO3H in CHCl3 solution provided (+)-
of 9 with 4 equiv of NaBH3CN in CH3OH with gradual
addition of 2 N-methanolic HCl at 0 ꢁC for 4 h gave,
after removal of methanol under reduced pressure and
23
4 as colorless plates, mp 148–149 ꢁC, ½aꢀD +170
(CHCl3), the three-dimensional structure and absolute
configuration of which followed from the X-ray data5
(Scheme 2).
extractive isolation, the bis-N-methoxyamine 10 as a
23
colorless solid, ½aꢀD ꢁ247 (CHCl3), mp 205–207 ꢁC
(99% yield). Addition of a solution of 10 in THF to
an excess of Li dissolved in liquid ammonia at reflux
and further reaction at ꢁ33 ꢁC for 20 min afforded, after
quenching of excess Li with isoprene, evaporation of
NH3 and THF, extractive isolation, and column chro-
matography on silica gel (1:1 EtOAc–hexane for elu-
Me
Me
EtO
O
OEt
Ph
HO
O
OH
Ph
H3O+
Me
O
Me
O
Ph
Ph
(+)-3
(+)-2
H+
tion), the bicyclic diamine 11 (83%) as colorless
23
BrCH2CH2OH
needles, ½aꢀD ꢁ179 (CHCl3). When the diamine 11 was
stored in CH2Cl2 solution it was gradually transformed
Me
BrCH2CH2O
O
OCH2CH2Br
into the azaadamantane derivative 12, mp 77–78 ꢁC,
Ph
O
Me
(+)-4
Ph
MeO
Ph
OMe
Ph
Me
N
N
HO
O
OH
Ph
Scheme 2. Absolute configurations of (+)-2, (+)-3, and (+)-4.
1. H2NOCH3
C5H5N
95 ˚C
2. MeSO2Cl
Et3N
Me Me
RO
7, R = H
8, R = SO2Me
Me
O
Ph
Treatment of the bis-ethyl ketal (+)-3 with triethylsilane
and a catalytic amount of BF3ÆEt2O in CH2Cl2 at 0 ꢁC
resulted in rapid reduction to the crystalline bicyclic
OR
(–)-2
23
ether (+)-5, ½aꢀD +190 (CHCl3), mp 156–158 ꢁC, ob-
H2O
HCONMe2
100
C
tained in >98% yield after sublimation at 140 ꢁC and
20 mmHg. When (+)-2 was treated with a catalytic
amount of p-TsOH in CH2Cl2 at 23 ꢁC or H2SO4 in
Me
Me
H
HO
H
OH
Ph
NaBH3CN
HOAc at 60 ꢁC for 15 min, it was transformed into the
Ph
23
N
N
crystalline tricyclic triether 6, (95%), ½aꢀD ꢁ175 (CHCl3),
Me
Me
N
N
Ph
Ph
OMe
OMe
OMe
OMe
the structure of which was confirmed by X-ray crystallo-
graphic analysis.6
10
9
Li
NH3–THF
Me
Me
Ph
Me
Me
Ph
Me
H
H
H
H
H
H
CH2Cl2
Ph
Ph
Ph
O
O
O
Me
O
N
Ph
Me
Me
N
Ph
N
N
Ph
H
O
H
5
6
11
12
H2CO
HCO2H
NaBH3CN
We have taken advantage of the ready availability of
(+)- and (ꢁ)-2 to synthesize diamine analogs of the
diether 4.
Me
Me
H
H
H
H
Ph
Ph
The chiral diethers and diamines in this series are pro-
mising bidentate C2-symmetric chiral ligands. Bidentate
coordination of a metal cation can generate a rigid
diazaadamantane structure. Reaction of (ꢁ)-2 (prepared
from (ꢁ)-3) with 3 equiv of MeONH2ÆHCl in pyridine at
N
N
Me
Me
N
N
Ph
Ph
Me
Me
Me
H
14
13
Scheme 3. Synthesis of chiral C2-symmetric bis-amines.

F. H. V. Chau, E. J. Corey / Tetrahedron Letters 47 (2006) 2581–2583
2583
23
chenko, V. G. Zh. Obshch. Khim. 1962, 32, 1192–1194; (c)
Tilichenko, M. N. Zh. Obshch. Khim. 1965, 35, 440–444.
2. Satisfactory NMR and mass spectral data were obtained
for all new compounds.
3. For a compilation of conglomerates and a general discus-
sion, see: Jaques, J.; Collet, A.; Wilen, S. H. Enantiomers
Racemates, and Resolutions; John Wiley and Sons: NY,
1981, p 43.
4. This mp was measured in a sealed tube. In an unsealed
tube, compound sublimes without melting at 170 ꢁC. All
optical rotations were measured in CHCl3 (c = 1.0–2.0). As
expected from conglomerate formation, the mp of the chiral
compound was considerably higher than that of the
racemate.
½aꢀD +117 (CHCl3). The conversion 11!2 was also
effected in >99% yield simply by reaction of 11 with
37% aqueous H2CO. It is noteworthy that the levorota-
tory 11 gives rise to dextrorotatory 12. Treatment of 12
with sodium cyanoborohydride followed by methanolic
HCl provided the mono-N-methyl derivative 13 (>99%)
as a thick oil. Bismethylation of 11 with formaldehyde-
formic acid produced in >95% yield the diamine 14.
The pKa values were measured for the C2-symmetric
diamines 11 and 14 in 9:1 ethanol–H2O and found to
be 8.7 for 11 and 8.5 for 14. We found the pKa for spar-
teine to be 10.7 under the same conditions. The lower
basicity (ca. 2 pK units) found for 11 and 14 relative
to sparteine is probably due to a combination of the
electron-withdrawing inductive effect of the a-phenyl
substituent and the large degree of steric screening,
which reduces solvation of the monoprotonated ammo-
nium ion.
5. X-ray data for compound 4: C25H30Br2O4; Mr 554.31;
plates, crystal size 0.40 · 0.35 · 0.10; space group P212121;
3
˚
a = 8.3100(10), b = 10.9260(10), c = 25.694(3) A; V (nm )
2332.9(4); Z = 4; Dx = 1.578; F(000) 1128; MoKa radia-
tion; 2h 5–55ꢁ; 6238 measured reflections; 5355 reflections
(independent). Rint 0.066; wR 0.0420; wR, F2 (all data)
3
˚
00705; S 0.7; Max. D/r (e A ) 0.635; Max. D/q 0.003. An x-
refinement (Flack, H. D. Acta Cryst. 1983, A39, 876) gave
an x parameter of ꢁ0.009(11), indicating the correct
absolute configuration. X-ray data have been submitted
to the Cambridge Crystallographic Data Centre for com-
pounds 4 and 6.
The remarkably easy access to the chiral bicyclic C2-
symmetric diethers and diamines described herein makes
these compounds to be of unusual interest for further
studies that are now in progress.
6. X-ray data for compound 6: C21H22O3; Mr 322.39; plates,
crystal size 0.65 · 0.25 · 0.07 mm; space group P21; a =
(nm3)
˚
9.6680(10), b = 8.3450(10); c = 10.978(2) A;
V
References and notes
852.3(2); Z = 2; Dx = 1.256; F(000) 344; MoKa radiation;
2h 6–60ꢁ; 9766 measured reflections; 4969 reflections
(independent); Rint 0.062; wR, F2 (all data) 0.1041;
1. (a) Tilichenko, M. N.; Astakhova, N. K. Dokl. Akad. Nauk
SSSR 1950, 74, 951–953; (b) Tilichenko, M. N.; Khar-
3
˚
S 0.8; Max. D/r (e A ) 0.168; D/q <0.001.