Synthesis of Di-, Tri-, and tetrasubstituted oxetanes by rhodium-catalyzed O-H insertion and C-C bond-forming cyclization

Article abstract of DOI:10.1002/anie.201408928

Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl-and alkyl-substituted oxetanes and fused oxetane bicycles. Enantioenriched alcohols provided enantioenriched oxetanes with complete retention of configuration. The oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chemistry.

Full text of DOI:10.1002/anie.201408928

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Angewandte
Communications
DOI: 10.1002/anie.201408928
Oxetanes
Synthesis of Di-, Tri-, and Tetrasubstituted Oxetanes by Rhodium-
ꢀ
ꢀ
Catalyzed O H Insertion and C C Bond-Forming Cyclization**
Owen A. Davis and James A. Bull*
Abstract: Oxetanes offer exciting potential as structural motifs
and intermediates in drug discovery and materials science.
Here an efficient strategy for the synthesis of oxetane rings
incorporating pendant functional groups is described. A wide
variety of oxetane 2,2-dicarboxylates were accessed in high
yields, including functionalized 3-/4-aryl- and alkyl-substituted
oxetanes and fused oxetane bicycles. Enantioenriched alcohols
provided enantioenriched oxetanes with complete retention of
configuration. The oxetane products were further derivatized,
while the ring was maintained intact, thus highlighting their
potential as building blocks for medicinal chemistry.
adjuncts to improve solubility, lipophilicity, and other phys-
icochemical properties toward drug-like molecules. Pioneer-
ing studies by Carreira and co-workers demonstrated oxetane
motifs to be effective polar replacements for gem-dimethyl
groups and carbonyl derivatives.[7,9] Furthermore, compared
to larger oxygen heterocycles, the small ring displays a meta-
bolic robustness which is linked to its inherent lower lipo-
philicity.[10]
Classical oxetane synthesis includes intramolecular Wil-
liamson ether synthesis[11] and Paterno–Bꢀchi [2+2] photo-
cycloadditions (Scheme 1a).[12] More recently, ring-opening/
O
xetanes are widely used compounds in numerous
branches of science. As strained cyclic ethers, they find uses
in polymer and materials science, as monomers for cationic
ring-opening polymerizations,[1] and as crosslinkers.[2] Oxe-
tanes are employed as intermediates in synthetic chemistry in
processes featuring ring expansion,[3] ring opening,[4] or
rearrangement processes.[5] The oxetane motif is also found
in natural products and other biologically active compounds
(Figure 1).[6]
Scheme 1. Approaches to oxetane derivatives. LG=leaving group,
LiHMDS=1,1,1,3,3,3-hexamethyldisilazane, Ts=toluene-4-sulfonyl.
Figure 1. Biologically important oxetane-containing compounds.
Recently, oxetanes have received considerable attention
in drug discovery and have been widely adopted in medicinal
chemistry.[7,8] In this context, they are considered stable
closing from epoxides using sulfoxonium ylides has been
developed,[13] though this approach has not been extended to
more functionalized derivatives. Current medicinal chemistry
investigations are largely focused on 3-substituted oxetanes
(Scheme 1b). These are often derived from Carreiraꢁs oxetan-
3-one,[7,14] or from 3-iodooxetane by Suzuki cross-coupling[15]
or other methods.[16,17] We recently reported a cyclization
[*] O. A. Davis, Dr. J. A. Bull
Department of Chemistry, Imperial College London
South Kensington, London SW7 2AZ (UK)
E-mail: j.bull@imperial.ac.uk
Homepage: http://www3.imperial.ac.uk/people/j.bull
ꢀ
strategy for oxetane synthesis involving C C bond formation
in order to prepare 2-(arylsulfonyl)oxetanes as fragments for
[**] We thank the EPSRC for a Career Acceleration Fellowship (EP/
J001538/1; to JAB) and Imperial College London. We are grateful to
Prof. Alan Armstrong for generous support. We thank the EPSRC
National Mass Spectrometry Facility, Swansea.
fragment-based drug discovery (Scheme 1c).[18]
We considered that efficient methods to access more
highly substituted and chiral oxetanes would afford interest-
ing novel appendages or core scaffolds for drug discovery.[19]
Oxetanes offer six possible vectors from which to develop
a compound in three dimensions,[20] and such derivatives
would constitute new chemical space for exploration in
medicinal chemistry. However, the synthesis of diversely
substituted oxetanes bearing functional groups remains
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408928.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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ꢀ
a challenge. We proposed that applying a C C bond-forming
strategy would provide access to such oxetane derivatives.
a 1.0 mmol scale.[22] This sequence constitutes an efficient
two-step oxetane synthesis from readily available starting
materials.
With these optimized conditions, the introduction of
substituents onto bromoethanol was examined in order to
form chiral oxetanes. Aryl substituents were examined using
readily available b-bromohydrins to prepare 2,2,4-substituted
oxetanes (Table 1).[22] For the phenyl-substituted bromo-
ꢀ
ꢀ
Here we report a mild and efficient O H insertion and C C
bond-forming cyclization strategy for oxetane synthesis
(Scheme 1d). Functionalized di-, tri-, and tetrasubstituted
oxetane derivatives are rapidly generated as building blocks
and potential scaffolds of interest for medicinal chemistry.
Further elaboration of these motifs is also reported.
A key aspect of our strategy was to develop a mild and
widely applicable approach to the cyclization precursor. The
Table 1: Synthesis of diethyl 4-aryl-2,2-oxetane dicarboxylates.
ꢀ
activation of X H bonds (X = N, O, S) through metal-
catalyzed diazo decomposition and carbenoid insertion is
[21]
ꢀ
a powerful approach to C X bond construction.
We
envisaged that insertion of a diazo compound that bears
ꢀ
anion-stabilizing groups into the O H bond of functionalized
Entry
Ar
Yield 5 [%][a]
Yield 6 [%][b]
alcohols could rapidly deliver the required cyclization pre-
cursors. We targeted the synthesis of oxetane 2,2-dicarbox-
ylates to facilitate the cyclization and install the ester
functionality for further manipulation. A functional-group-
1
79
84
a
b
2[c]
84 (85% ee)
83 (85% ee)
3
4
76
95
77
81
ꢀ
tolerant O H insertion would permit a convergent strategy
with the required leaving group in place, as well as the
incorporation of useful functionality to decorate the oxetane
core.
c
ꢀ
We initially attempted an O H insertion reaction using
ethylene glycol and diazomalonate 1 (Scheme 2). This trans-
formation provided ether 2a in 77% yield using catalytic
5
6
70
76
d
e
f
88[d]
77[e]
7
8
9
68
73
71
83
88
82
g
ꢀ
[a] O H insertion conditions: 4 (1.0–3.0 mmol), 1 (1.5 equiv),
[Rh2(OAc)4] (0.5 mol%), PhH, 0.1m, 808C. [b] Cyclization conditions: 5
(0.5–1.0 mmol), NaH (1.2 equiv), DMF, 0.025m, 258C, 16 h.
[c] Enantioenriched (S)-4a (85% ee). [d] Reaction on 9.0 mmol scale.
[e] Reaction on 6.5 mmol scale.
ꢀ
Scheme 2. O H insertion/cyclization strategy to diethyl 2,2-oxetane-
dicarboxylate. See the Supporting Information for details of optimiza-
tion for each substrate. [a] Using 1 as limiting reagent (10 equiv
ethylene glycol). [b] TsCl, Et3N, Me3N·HCl. [c] Using alcohol as limiting
reagent (1.5 equiv 1). [d] Using conditions optimized for bromide
substrate. DMF=N,N-dimethylformamide.
ꢀ
hydrin 4a, the Rh-catalyzed O H insertion gave a high
yield under the conditions developed above. However, the
cyclization required a longer reaction time (16 h) and higher
temperature (258C) to achieve an excellent yield (Table 1,
entry 1).[22] The sequence was then performed with enan-
tioenriched b-bromohydrin (S)-4a.[24a] As expected, the
ee value was perfectly retained through both steps to access
enantioenriched oxetane (R)-6a (Table 1, entry 2). This
reduces the requirements for enantioselective oxetane syn-
thesis to enantioselective bromohydrin synthesis.[24]
The p-tolyl derivative gave high yields through both steps,
as did aryl fluoride, chloride, and bromide derivatives
(Table 1, entries 3–7). To demonstrate the scalability of the
procedure, chlorophenyl derivative 6d was prepared on
a larger scale, affording over 1.5 g of the oxetane. Electron-
rich and electron-poor aromatic substituents gave similarly
high yields (Table 1, entries 8 and 9).
[Rh2(OAc)4] and excess ethylene glycol.[22] Treatment with
TsCl afforded 2b in high yield. Alternatively, tosylate 2b was
ꢀ
accessed by O H insertion on ethylene glycol monotosylate
to obtain the cyclization precursor.
To our delight, tosylate 2b cyclized successfully to oxetane
ꢀ
3 through the formation of the C C bond by using NaH in
DMF. Despite extensive examination of the reaction con-
ditions, the yield of 43% could not be improved.[22] Therefore,
we examined alternative leaving groups, using functionalized
ethanol derivatives. Following optimization, bromide 2c was
ꢀ
obtained in 90% yield by O H insertion using 2-bromoetha-
nol.[23] Iodoethanol was also successful but with reduced
yields because of the instability of iodide 2d. The bromide
leaving group was shown to be most effective for the
cyclization and full optimization was conducted with bromide
2c. The developed conditions (NaH (1.2 equiv) in DMF
(0.025m) for 1 h at 08C) afforded oxetane 3 in 73% yield on
Next, alkyl substituents were examined to generate
trisubstituted 4-alkyloxetanes (Table 2). Under the conditions
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Table 2: Synthesis of diethyl 4-alkyl-2,2-oxetane dicarboxylates.
Entry
X
Y
Yield 8 [%][a]
Yield 9 [%][b]
1
2
3
4
Br
Br
Br
Br
CH2OBn
CH2OPh
CH2Br
a
b
c
67
89
65
81
45/7
92
51[c]
80
CH2Cl
d
(Y=Cl/Br, 9d/9c)
5
6
7
8
9
Cl
Cl
Cl
Br
Br
CH2Cl
e
f
g
h
i
86
97
77 (9d)
75
71
CH2OiPr
CH2OTBS
CF3
65
28[d]
98[f]
43
CH3
82[g]
[e]
Scheme 3. Synthesis of tetrasubstituted oxetanes. a) Bromohydrin for-
ꢀ
[a] O H insertion conditions: 7 (1.0–3.0 mmol), 1 (1.5 equiv),
[Rh2(OAc)4] (0.5 mol%), PhH, 0.1m, 808C. [b] Cyclization conditions: 8
(0.4–1.0 mmol), NaH (1.2 equiv), DMF, 0.025m, 258C, 16 h. [c] Heated
at 808C for 3 d. [d] Yield over two steps from 3-bromo-1,1,1-trifluoro-
acetone. [e] From technical grade 1-bromo-2-propanol (7i) containing
20 wt% 2-bromo-1-propanol. [f] Mixture of regioisomers (4:1). [g] Mix-
ture of regioisomers (4-Me/3-Me oxetanes 5.4:1). Bn=benzyl,
TBS=tert-butyldimethylsilyl.
ꢀ
mation. b) O H insertion. c) Cyclization.
The scope of substituted oxetanes was then expanded to
a variety of sterically congested tetrasubstituted oxetanes
using olefins as precursors (Scheme 3). 2,2,4,4-Substituted
derivative 12a was prepared from a-methylstyrene in three
steps, including bromohydrin formation with NBS/H2O. We
next investigated the 2,2,3,4-substituted derivatives from
trans-stilbene; bromohydrin 10b was formed as a single
diastereoisomer. This was converted to the corresponding 3,4-
anti-substituted oxetane 12b through the same process, with
stereospecific intramolecular displacement from benzylic
bromide 11b. We then considered cyclic alkenes to access
fused oxetane derivatives. Treating cyclohexene with NBS/
H2O afforded the anti-substitution in bromohydrin 10c, as
required for the proposed cyclization. Installation of the
malonate group occurred effectively to provide 11c, and
cyclization proceeded without incident to afford the
oxabicyclo[4.2.0]octane derivative 12c in an excellent yield.
From cyclopentene, the fused [3.2.0] ring system of bicycle
12d could be effectively obtained. Moreover, from 2,5-
dihydrofuran, dioxabicyclo[3.2.0]heptane 12e was readily
prepared in excellent yields. These oxetane-containing bicy-
cles, readily accessible from simple alkenes in three steps, may
provide interesting rigid motifs for medicinal chemistry.
Elaboration of the oxetane products was then examined
toward oxetane-containing fragments and building blocks.
Initial investigations into the derivatization of the diester
functionality were undertaken with oxetane 6d (Scheme 4).
The diester 6d could be reduced using LiBH4, generated
in situ, to give diol 13 in 91% yield (Scheme 4). From this diol,
monotosylation gave 14, then treatment with NaH afforded
the unusual bisoxetane spirocycle 15 through classical oxe-
tane cyclization. Monohydrolysis of the diester moiety
occurred quantitatively when treated with 1m NaOH, afford-
ing the monocarboxylate sodium salt 16. This compound
successfully underwent amide coupling with both primary
(17) and secondary (18) amines using HATU.[25,26] Krapcho
decarboxylation using LiCl afforded trans- and cis-2,4-sub-
stituted oxetanes in a 1:1 ratio (19a:19b), which were readily
separable.[22]
employed with the aryl substituents, both steps were effective.
Benzyl and phenyl ethers were well tolerated (Table 2,
entries 1 and 2).
ꢀ
The O H insertion reaction with 1,3-dibromo-2-propanol
(7c) occurred cleanly to generate dibromide 8c, but required
a longer reaction time and gave a slightly reduced yield,
presumably as a result of increased steric demands (Table 2,
entry 3). Treatment of 8c with NaH afforded bromomethyl-
oxetane 9c in a high yield, providing an alkyl bromide handle
for further derivatization (see below).
In order to generate the corresponding chloromethyl-
oxetane, bromide 8d was formed from 1-bromo-3-chloro-2-
propanol (7d). When the cyclization was attempted, both
chloromethyloxetane 9d (major product) and bromomethyl-
oxetane 9c were isolated (Table 2, entry 4). This result
demonstrated that chlorides were also viable leaving groups
for oxetane synthesis. Subsequently, 1,3-dichloro-2-propanol
(7e) was employed to generate dichloride 8e in high yield,
which successfully underwent cyclization to chloromethyl-
oxetane 9d (Table 2, entry 5). Similarly, a single chloride as
ꢀ
leaving group also gave high yields in both O H insertion and
cyclization steps (Table 2, entries 6 and 7), including TBS
ether 9g. 4-Trifluoromethyl-substituted oxetane 9h was
successfully prepared from 3-bromo-1,1,1,-trifluoroacetone
(Table 2, entry 8). We examined the installation of a methyl
substituent starting from commercially available 1-bromo-2-
propanol (7i), consisting of a 4:1 mixture with 2-bromo-1-
ꢀ
propanol (technical grade, Table 2, entry 9). The O H
insertion occurred in high yield and was equally effective
for both isomers. Pleasingly, the cyclization occurred for both
regioisomers to afford a mixture of 3-methyl- and 4-methyl-
substituted oxetanes in a high yield without a significant
change in ratio (5.4:1), indicating that the cyclization was not
limited to primary halides.
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Scheme 4. Derivatization of oxetanes 6d. Conditions: a) NaBH4, LiCl,
MeOH, THF, 08C!RT; b) nBuLi, THF, 08C, 1 h; then TsCl, THF,
308C; c) NaH, DMF, 08C!258C; d) NaOH, EtOH, 308C; e) amine
(BnNH2 for 17; morpholine for 18), HATU, DMF, 408C; f) LiCl,
DMSO, 1508C. HATU=N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]-
pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate
N-oxide, DMSO=dimethyl sulfoxide.
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underwent cycloaddition with phenyl acetylene to afford
triazole 21. Treatment of 9c with imidazole and NaI under
basic conditions displaced the primary bromide, thus afford-
ing 22 in a 62% yield.
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Scheme 5. Bromide displacement from oxetane 9c. a) NaN3, DMF,
608C; b) phenylacetylene, CuSO4·5H2O (10 mol%), sodium ascorbate
(30 mol%), H2O/CH2Cl2 (1:1), RT; c) imidazole, NaI, K2CO3, DMF,
808C.
In summary, we have developed an efficient protocol for
the preparation of 2,2-disubstituted, 2,2,4-trisubstituted, and
2,2,3,4-tetrasubstitued oxetanes. These oxetane structures
contain functionalities that can be further derivatized to an
array of oxetane containing motifs. We anticipate that these
will provide interesting new structural elements for synthesis,
materials science, and medicinal chemistry programs in
particular. Further advances of this strategy in the synthesis
of small rings will be reported in due course.
Received: September 9, 2014
Published online: October 14, 2014
Keywords: cyclization · diazo compounds · heterocycles ·
.
ꢀ
O H insertion · oxetanes
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[22] See the Supporting Information for further details and discus-
sion.
ꢀ
[23] For the previous example of O H insertion on bromoethanol,
ˇ
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[26] Relative configuration of oxetanes 16–18 determined by NOE
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14234 www.angewandte.org
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Angew. Chem. Int. Ed. 2014, 53, 14230 –14234