Gold-catalyzed one-step practical synthesis of oxetan-3-ones from readily available propargylic alcohols

Article abstract of DOI:10.1021/ja1033952

A general solution for the synthesis of various oxetan-3-ones is developed. This reaction uses readily available propargylic alcohols as substrates and proceeds without the exclusion of moisture or air ("open flask"). Notably, oxetan-3-one, a highly valuable substrate for drug discovery, can be prepared in one step from propargyl alcohol in a fairly good yield. The facile formation of the strained oxetane ring provides strong support for the intermediacy of α-oxo gold carbenes. This safe and efficient generation of gold carbenes via intermolecular alkyne oxidation offers a potentially general entry into α-oxo metal carbene chemistry without using hazardous diazo ketones.

Full text of DOI:10.1021/ja1033952

Published on Web 06/03/2010
Gold-Catalyzed One-Step Practical Synthesis of Oxetan-3-ones from Readily
Available Propargylic Alcohols
Longwu Ye, Weimin He, and Liming Zhang*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received April 21, 2010; E-mail: zhang@chem.ucsb.edu
Oxetan-3-ones1 contain a strained four-membered ring and
possess considerable synthetic/medicinal utility. They have been
incorporated into steroid skeletons,2 used to prepare oxetanocin
derivatives,3 and converted into 3-aminooxetanes4 including 3-ami-
nooxetane-3-carboxylic acid.4a Moreover, Rogers-Evans, Carreira
and co-workers have shown that the oxetane ring can serve as a
surrogate of a gem-dimethyl group,5a resemble a carbonyl group,5b
and offer alternatives to 1,3-heteroatom-substituted cyclohexanes
in spirocyclic structures5c in drug discovery; in these studies, the
parent oxetan-3-one serves as an essential starting material for
introducing the oxetane ring. However, syntheses of oxetan-3-ones
typically demand multiple synthetic steps and/or highly function-
alized substrates.1 For example, oxetan-3-one itself was prepared
in four5a or five4 steps with 23% or 13% overall yield, respectively,
highlighting the challenge of constructing this strained skeleton and
the lack of efficient preparative methods.
7) and was chosen to screen catalysts. Among the different gold
catalysts examined (entries 8-11), (2-biphenyl)Cy2PAuNTf2 gave
a better result than Ph3P (entry 9). Of note, without using any gold
catalyst, no oxetan-3-one 2 was observed under the acidic reaction
conditions, and PtCl2 was not effective in promoting this reaction
(entry 12). One of the side products in these reactions was mesylate
3, likely due to the reaction of gold carbene A with MsOH. To our
delight, the use of HNTf2 minimized this side reaction, leading to a
further improved yield (entry 13), and oxetan-3-one 2 was isolated in
71% yield. Little product (<5%) was observed without using acid.
Table 1. Reaction Conditions Optimizationa
entry
L
R
acidb
conditions
yieldc
Scheme 1. Synthesis of Oxetan-3-ones from Propargylic Alcohols?
1
2
3
4
5
6
7
8
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
IPr
3,5-Cl2
3-Br
4-Et
4-Ac
2-Br
2,4-Cl2
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
Tf2NH
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
toluene, 80 °C
DCE, rt, 3 h
58%
50%
22%
44%
58%
61%
62%
33%
66%
53%
47%
<5%
73%f
d
R1
d
R1
d
9
Le
R1
d
R1
10
11
12
13
(4-CF3Ph)3P
Et3P
d
R1
d
R1
PtCl2
R-Diazo ketones have been used to prepare oxetan-3-ones (Scheme
1),6 but those diazo substrates are in general hazardous and their
preparations are nontrivial. We have recently developed a practical
and efficient synthesis of dihydrofuran-3-ones via gold-catalyzed
intermolecular oxidation of terminal alkynes,7 where a C-C triple bond
is converted into a reactive R-oxo gold carbene intermediate in the
proposed catalytic cycle. This strategy would render alkynes equiValent
to R-diazo ketones in accessing R-oxo metal carbene chemistry,8 which
could offer significant synthetic and economic benefits. We speculated
that this equivalency could substitute the R-diazo ketone moiety in
oxetan-3-one synthesis6 with a simple C-C triple bond (Scheme 1);
as a result, readily available propargylic alcohols could serve as direct
substrates. Herein, we report a successful implementation of the design
and the development of a practical solution to oxetan-3-one synthesis;
moreover, the ease of forming this strained ring provides convincing
support for the formation of R-oxo gold carbene intermediates via
intermolecular alkyne oxidation.
Propargylic alcohol 1 was chosen as a substrate for our initial
study. To our delight, the expected oxetan-3-one (i.e., compound
2) was indeeded formed under the optimal reaction conditions we
previously developed7 (Table 1, entry 1) and, moreover, in a fairly
good NMR yield. A variety of other oxidants were examined, and
some results are shown in entries 2-7. 3-Methoxycarbonyl-5-
bromopyridine N-oxide (4) led to a slightly improved yield (entry
Le
R1
d
a [1] ) 0.05 M; DCE: 1, 2-dichloroethane. b 1.2 equiv. c Estimated by
d
1H NMR using diethyl phthalate as internal reference. R1
)
3-MeO2C-5-Br. e (2-Biphenyl)Cy2P. f 71% isolated yield.
With the optimal reaction conditions in hand, we then probed
the reaction scope using various secondary propargylic alcohols as
substrates. As shown in Table 2, this reaction proceeded smoothly
in the presence of various functional groups. For example, remote
Ph (entry 2) and vinyl (entry 3) groups were tolerated, suggesting
that their reaction with the gold carbene moiety were insignificant;
moreover, a Ph group at the propargylic position (entry 4) did not
interfere with the carbene O-H insertion to a significant extent. A
MOM-protected HO group (entry 5) was compatible with the acidic
reaction conditions, confirming the buffering effect of N-oxide 4.
However, some deprotection of N-Boc groups was observed at room
temperature; a serviceable yield (60%, entry 6) was obtained when
the reaction was run at -20 °C. In addition, substrates containing an
azido (entry 7) and a bromo (entry 8) group were suitable as well.
Expansion of this oxetanone formation chemistry to tertiary
propargylic alcohols was initially met with low yields likely due
to the increased tendency of forming propargylic cations under the
acidic reaction conditions. To overcome this problem, an electron-
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8550 J. AM. CHEM. SOC. 2010, 132, 8550–8551
10.1021/ja1033952  2010 American Chemical Society

C O M M U N I C A T I O N S
withdrawing carboxylate group was installed to the alkyne terminus.
Expectedly, the gold catalysis proceeded much slower, and mild
heating was required to complete the reaction within 24 h;
moreover, the combination of 4-acetylpyridine N-oxide and
IPrAuNTf2 worked better. As shown in Table 3, high to excellent
yields were observed with various substrates. For asymmetric
substrates, low diastereoselectivities were observed (entries 2
and 3).
With chiral propargylic alcohols readily available,11 this chemistry
provides easy access to chiral oxetan-3-ones. For example, enantio-
merically enriched alcohol 5b11c (80% ee) was converted into oxetan-
3-one 6b (81% ee) with no apparent racemization detected.
Scheme 2. A One-Step Synthesis of Oxetan-3-Ones and Its
Synthetic Conversion without Purification
Table 2. Reaction Scope with Secondary Propargyl Alcoholsa
In conclusion, we have developed a general solution for the synthesis
of various oxetan-3-ones. This reaction uses readily available prop-
argylic alcohols as substrates and proceeds without the exclusion of
moisture or air (“open flask”). Notably, oxetan-3-one, a highly valuable
substrate for drug discovery, can be prepared in one step from propargyl
alcohol in a fairly good yield. The facile formation of the strained
oxetane ring provides strong support for the intermediacy of R-oxo
gold carbenes. This efficient generation of gold carbenes via intermo-
lecular alkyne oxidation would potentially offer a general entry into
R-oxo metal carbene chemistry without using hazardous diazo ketones.
a [5] ) 0.05 M. b Isolated yields. c 2-Bromopyridine N-oxide and
MsOH were used instead. d Temperature: -20 °C; time: 16 h.
Table 3. Reaction Scope With Tertiary Propargyl Alcoholsa
Acknowledgment. We thank NSF (CAREER award CHE-
0969157), NIGMS (R01 GM084254), and UCSB for generous
financial support.
Supporting Information Available: Experimental procedures,
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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a [7] ) 0.1 M. b Isolated yields. c Reaction temperature: 60 °C.
d Reaction temperature: 40 °C.
The synthetic utility of this chemistry is underscored by a one-
step preparation of oxetan-3-one. As discussed above, the synthesis
of this highly useful O-heterocycle4,5 requires multiple steps and
is low yielding. It is commercially available but expensive.9 To
our delight, this volatile heterocycle was formed in 71% NMR yield
directly from cheap propargyl alcohol following this chemistry, and
the catalyst loading could be lowered to 1 mol % with little effect
to the yield (Scheme 2); moreover, a 51% NMR yield was
achievable with cheaper and lesser amounts of reagents and a higher
substrate concentration. Coupled with a subsequent Wittig reaction5a
upon simple workup or a Strecker reaction10 directly, this reaction
led to oxetane derivatives 9 and 10 in 62% and 60% overall yields,
respectively [5 mol % of (2-biphenyl)Cy2PAuNTf2 used].
JA1033952
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