Angewandte
Chemie
would involve the convenient preparation of oxetanes
substituted with aliphatic, aromatic, and heterofunctional
groups. Another structural feature of 2 is the tert-butyl group,
which can be considered a special case of a gem-dimethyl
group on a small aliphatic (ethyl) side chain. As the tert-butyl
group is frequently encountered in medicinal chemistry,[6] its
replacement by a 3-methyl-oxetan-3-yl unit and the study of
concomitant property changes constitute a particularly inter-
esting aspect of this work.
We chose structures 3–5 to examine the effect of replacing
the tert-butyl group by an oxetane-containing unit. Structures
6–9 were prepared so as to carry out an “oxetane scan”, in
which the oxetanyl unit was placed at different topological
distances from the basic amine. We focused on strategies in
which an oxetane ring is conveniently introduced in a modular
building block approach rather than built up de novo for each
molecule.[7] The targeted oxetane derivatives were assembled
using oxetan-3-one[8–10] (1) as the starting material
(Scheme 1). The existing procedure for the preparation of
oxetan-3-one[8,11] involves a five-step sequence, with prepara-
tive GC as a final purification step, and proceeds in 13%
overall yield. Consequently, we developed an efficient and
scalable route that could provide useful quantities of oxetan-
3-one (1). The newroute commences with the conversion of
dihydroxyacetone into its dimethylacetal (MeOH, toluene p-
sulfonic acid, trimethylorthoformate). Monotosylation of the
isolated 1,3-dihydroxy-2,2-dimethoxypropane, followed by
treatment with NaH, furnished 2,2-dimethoxyoxetane (37%
overall yield).[12] Hydrolysis of the acetal proved difficult.
However, heating a solution of 2,2-dimethoxypropane in the
presence of Montmorillonite K10 at reflux provided the
desired oxetan-3-one in 62% yield. This four-step sequence
affords the target compound in an overall yield of 23% after
purification by distillation.[13]
Scheme 1. a) (Me2N)(CH2)4(C6H4)-p-Li, THF, À788C, 71%;
b) Ph3PCHCO2Et, CH2Cl2, RT, 89%; c) Ph3PCHCHO, CH2Cl2, RT, 81%;
d) 1. NEt3, MeNO2, RT; 2. NEt3, MsCl, CH2Cl2, À788C, 81%;
e) 1. NaH, Et2O, 08C; 2. TsCl, 08C; 3. LiAlH4, À788C, 58%; f) DAST,
CH2Cl2, À788C, 40%; g) (Me2N)(CH2)4(C6H4)-p-B(OH)2, cat. [{Rh-
(cod)Cl}2], KOH, aq dioxane, RT, 83%; h) DIBAL-H, À788C;
i) [(Ph3P)3RhCl], toluene, 1058C, 33% (2 steps); j) 4-tBuBnMgBr,
TMSCl, CuI, THF, À188C, 70%; k) Me2NH, NaCNBH3, MeOH, 28%
(2 steps); l) 4-tBuPhB(OH)2, cat. [{Rh(cod)Cl}2], KOH, aq dioxane, RT,
78%; m) 1. MeNO2, NEt3, RT; 2. NEt3, MsCl, CH2Cl2, À788C, 58%;
n) 1. H2, Pd(OH)2/C, CH2O, RT, MeOH; 2. NaCNBH3, CH2O, MeOH,
34% o) 1. HNMe2, DBU, THF, À188C; 2. 4-tBuPhCHPPh3; p) H2, Pd/
C, MeOH, 36% (3 steps); q) (E)-4-tBuC6H4CHCHB(OH)2, cat. [{Rh-
(cod)Cl}2], KOH, aq dioxane, RT; 34% (overall sequence). Ms=metha-
nesulfonyl, Ts=toluene-p-sulfonyl, DAST=(diethylamino)sulfur tri-
fluoride, cod=cycloocta-1,5-diene, DIBAL-H=diisobutylaluminum hy-
dride, TMS=trimethylsilyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
Bn=benzyl.
The addition of an aryl lithium compound to oxetan-3-one
(1) furnished the 3-aryl-3-hydroxyoxetane 10, which in turn
was converted into the 3-aryl-3-fluorooxetane 4 by treatment
with DAST (Scheme 1). Alternatively, the 3-hydroxy-oxetane
10 can be reduced to 3 in a one-pot procedure involving
tosylation followed by reduction (LiAlH4). These two proto-
cols thus provide the simple aryl oxetanes.
conditions to better differentiate the solubilities of amines
with slightly different basicities, and to avoid complications
resulting from the tendency of charged lipophilic compounds
to form micelles under neutral pH conditions (a tendency
observable for some of these compounds). At basic pH, 2 is
essentially insoluble, whereas the oxetane derivatives 3–5
remain highly soluble (Table 1). The solubility data closely
parallel the lipophilicity data represented by logD and
logP values. The latter constitutes the intrinsic lipophilicity
of the neutral base derived from the experimental pKa and
logD values, which correspond to the octanol/water distribu-
tion coefficients measured at pH 7.4. The replacement of the
remote tert-butyl group by the 3-methyl-3-oxetanyl group
results in a lowering of the logD (and logP) value by one unit.
Interestingly, the magnitude of this decrease in lipophilicity is
comparable with the increase in lipophilicity when going from
ethylbenzene (logP ꢀ 3.2) to tert-butylbenzene (logP
ꢀ 4.1).[14] The introduction of an oxetanyl module into a
methylene unit thus constitutes a “liponeutral” bulk increase.
We next developed routes to oxetanes bearing a quater-
nary center at C-3. Oxetan-3-one (1) undergoes reaction with
stabilized ylides to furnish the a,b-unsaturated ester 11 and
aldehyde 12. The analogous nitroalkene 13 was obtained in
81% yield from condensation of 1 with nitromethane. It is
worth noting that all of these unsaturated compounds, to the
best of our knowledge, have not been previously reported and
yet are easily handled and stored. Given the ease with which
11–13 were prepared, the stage was set to examine these as
Michael acceptors. We were pleased to find that all three
compounds readily undergo 1,4-addition by various nucleo-
philes, including amines, aryl and vinyl boronic acids (cata-
lyzed by Rh complexes), as well as organocuprates, thus
making them useful building blocks.
With compounds 3–9 in hand, we examined the physical
and pharmacological properties imparted by the oxetane ring.
The thermodynamic solubilities measured in buffered sol-
utions at pH 9.9 are shown in Table 1. We chose these
Angew. Chem. Int. Ed. 2006, 45, 7736 –7739
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7737