Cu(I)-catalyzed oxidative cyclization of alkynyl oxiranes and oxetanes

Article abstract of DOI:10.1021/ja209866a

In the presence of a Cu(I) catalyst and a pyridine oxide, alkynyl oxiranes and oxetanes can be converted into functionalized five- or six-membered α,β-unsaturated lactones or dihydrofuranaldehydes. This new oxidative cyclization is proposed to proceed via an unusual allenyloxypyridinium intermediate.

Full text of DOI:10.1021/ja209866a

Communication
pubs.acs.org/JACS
Cu(I)-Catalyzed Oxidative Cyclization of Alkynyl Oxiranes and
Oxetanes
Colombe Gronnier,† Søren Kramer,‡ Yann Odabachian,† and Fabien Gagosz*,†
†Dep
́
artement de Chimie, UMR 7652, CNRS/Ecole Polytechnique, 91128 Palaiseau, France
‡Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
S
* Supporting Information
be used to generate an unusual allenyloxy intermediate 6 by an
ABSTRACT: In the presence of a Cu(I) catalyst and a
pyridine oxide, alkynyl oxiranes and oxetanes can be
converted into functionalized five- or six-membered α,β-
unsaturated lactones or dihydrofuranaldehydes. This new
oxidative cyclization is proposed to proceed via an unusual
allenyloxypyridinium intermediate.
SN2′-type addition of an oxidizing agent 5 at the terminal position
of the alkyne. Subsequent activation of 6 by an electrophilic metal
could potentially induce the addition of a nucleophile at carbon
C(1) of the allene moiety and ultimately lead to the formation of
α,β-unsaturated keto compound 8 via 7. In contrast to what was
previously reported (eq 1), this approach would allow the
introduction of both the oxygen atom and the nucleophile at the
same terminal position of the alkyne (eq 2).
Alkynyl oxiranes such as 9, which are prone to undergo
metal-mediated SN2′-type additions,5 were first chosen as model
substrates to study the feasibility of this general approach
(Scheme 1). In this case, the addition of an oxidizing agent at
mong the variety of gold-catalyzed transformations that
1
Ahave been developed to date, those concerning the oxo
functionalization of alkynes have attracted special interest.2 They
indeed allow an unconventional and efficient access to a range
of molecules that cannot be easily synthesized using other
methods. These transformations, which take advantage of the
π-acid/electron-donor dual reactivity of gold species, involve
the formation of an α-oxo gold carbene intermediate that is
generated after an initial intra- or intermolecular nucleophilic
addition of an oxygen donor (amine oxide, sulfoxide, nitro, etc.)
onto a gold-activated alkyne.3 In the case of a terminal alkyne 1,
this process leads to the regioselective formation of a gold
carbene 2, which can then be trapped by a nucleophile to
furnish the functionalized keto derivative 3 (eq 1).
Scheme 1. First Attempt at Oxidative Cyclization with
Alkynyl Oxirane Model Substrate 9 (LG = Nu in eq 2)
the terminal position of the alkyne could produce a metal alkoxide
such as 10 that would play the role of the functionalizing nucleo-
phile in our scenario (LG = Nu in eq 2).
On the basis of recent work concerning the oxidative func-
tionalization of alkynes using gold(I) complexes and pyridine
oxides3d−i and the already reported possibility of activating
alkynyl oxiranes with gold species,6 substrate 9 was treated with
7
4 mol % XPhosAuNTf2 and 2 equiv of pyridine oxide in
refluxing chloroform (Scheme 1). The reaction was slow and
led to the formation of multiple products, among which the two
isomeric oxidized products 12 and 13, which differ by the
presence of a carbonyl functionality at either C(1) or C(2),
could be identified.
Although this transformation was inefficient and unselective,
the formation of the unsaturated lactone 12 validated our approach
(eq 2), since both the oxygen atom and the functionalizing
Following our continuous interest in metal-mediated trans-
formations of alkynes,4 we were intrigued by the possibility of
developing an alternative oxidative functionalization of alkynes
based on the use of terminal alkynes of type 4 (eq 2). We
conceived that the presence of a leaving group (LG) in 4 might
Received: October 20, 2011
Published: December 19, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
nucleophile were introduced at the terminal position of the alkyne
in this case. The competitive formation of the isomeric furan-3-
one 13 could be explained by nucleophilic trapping of the
alternative α-oxo gold carbene intermediate 11 by the epoxide
moiety following a process similar to that presented in eq 1.
We next screened various experimental conditions to
optimize the formation of 12. The main results of this study
are compiled in Table 1. Changing the nature of the gold
Scheme 2. Reaction Scope: Alkynyl Oxiranes
a
Table 1. Optimization of the Catalytic System
a
b
c
Isolated yields. d.r. of starting material = 1:1.25. cis:trans ratio of starting
material = 1:1.3.
range of common functional groups, including an ester (16e), an
amide (16b, 16g, and 16o), an alkyl or silyl ether (16f, 16m, and
16n), an alcohol (16d), or a halogen (16j and 16n). No variation
in efficiency was observed when the degree of substitution of the
epoxide was varied (from di- to tetrasubstituted epoxides), whereas
a cis-epoxide was found to react as rapidly as its trans isomer
(16l).15 Notably, the transformation was selective toward the
conversion of the alkynyl oxirane moiety, since simple terminal
alkyne or epoxide functionalities remained untouched during the
process (16m and 16n). The transformation was also successfully
applied to the synthesis of the natural product ( )-dihydroacti-
nidiolide (16c).16,17
a
b
1
9: 0.1 mmol. Determined by H NMR spectroscopy of the crude
reaction mixture using 1,3,5-trimethoxybenzene as an internal
standard. 91% isolated yield (9: 2 mmol).
c
catalyst did not markedly improve the efficiency of the reaction
(entries 1−3), and a maximum 38% yield of 12 was obtained
when IPrAuNTf2 was used as the catalyst (entry 3).9 Inter-
8
estingly, silver salts showed higher reactivity (entries 4−6), and
an improved 65% yield of 12 was obtained when 9 was reacted
with 10 mol % AgOTf in refluxing acetonitrile for 20 h (entry 6).
Notably, no trace of furan-3-one 13 was observed under these
conditions, thus highlighting the striking difference in reactivity
between gold and silver catalysts. We next attempted the reaction
with softer Lewis acidic copper(I) catalysts (entries 7−10). We were
delighted to observe that 12 could be selectively obtained in an
excellent yield of 92% when AgOTf was replaced by the
Cu(NCMe)4OTf complex (10 mol %) (entry 7). An additional
screening of various counteranions showed that the rate of the re-
action could be noticeably enhanced when the complex Cu-
(NCMe)4NTf2 (14) was used as the catalyst (entry 9).10,11 The
catalyst loading could even be reduced, and the desired lactone 12
was finally obtained in 98% yield when 9 was treated with 4 mol %
14 in refluxing acetonitrile for 8 h (entry 10). Furthermore, copper(II)
catalysts were less reactive,12 and no trace of 12 was observed with
HNTf213 or in the absence of a catalyst (entries 11−13).14
A mechanistic proposal for the oxidative cyclization of alkynyl
oxiranes is presented in Scheme 3. Potential dual coordination
Scheme 3. Mechanistic Proposal
Having in hand optimal reaction conditions for the oxidative
cyclization of 9 (Table 1, entry 10), we explored the scope of
this new transformation. As shown by the results compiled in
Scheme 2, a wide range of alkynyl oxiranes 15a−o could be
converted into the corresponding lactones 16a−o in yields of
53−97%. The reaction could be performed with cyclic (12,
16a−g) as well as acyclic (16h−o) alkynyl oxiranes possessing a
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Journal of the American Chemical Society
Communication
a
of the copper(I) complex to both the alkyne and epoxide moieties
in 1718 could induce nucleophilic addition of the pyridine oxide at
the terminal position of the alkyne and the consequent formation
of the allenyloxypyridinium intermediate 18. Subsequent intra-
molecular activation of the allene moiety by the copper alkoxide19
could lead to the formation of the cyclic vinylcopper intermediate
20, possibly via 19. A final proton loss20/protodemetalation se-
quence would deliver the cyclic lactone 21 with concomitant
regeneration of the catalyst.21,22
Table 2. Oxidative Cyclization of Alkynyl Oxetane 22
To highlight further the synthetic potential of this new oxidative
cyclization, we envisaged its application to the conversion of
homologous alkynyl oxetanes. This would lead to the formation of
the important six-membered unsaturated lactone structural unit,
which is frequently found in natural products. Oxetane 22 was
therefore submitted to the optimized reaction conditions used for
the oxidative cyclization of alkynyl oxiranes (Table 2, entry 1).
The oxidative process was rapid and efficient but surprisingly
delivered a 1:1.9 mixture of the desired lactone 23 and the
unexpected dihydrofuranaldehyde 24.23 We attempted to
optimize the formation of both 23 and 24, conceiving that
these compounds could originate from the same allenyloxypyr-
idinium intermediate. Lactone 23 could indeed be formed by a
6-endo cyclization via 25, analogously to the case of alkynyl
oxiranes, while the dihydrofuranaldehyde 24 might be
produced by a competitive 5-exo cyclization via 26. We first
changed the catalyst, hoping that the use of a more Lewis acidic
species would favor the formation of 23 by stronger
coordination of the metal to the allene moiety in 25. To this
end, alkynyl oxetane 22 was treated with AgNTf2 and pyridine
oxide in refluxing acetonitrile (Table 2, entry 2). Unfortunately,
even though an increased quantity of lactone 23 was formed
(23:24 = 1.1:1), the reaction remained unselective. We next
envisaged modifying the oxidant. The use of a more electron-
deficient pyridine oxide, such as 3-bromopyridine oxide (O2),
could favor the formation of 24 since the corresponding
3-bromopyridine group in 27 would act as a better leaving
group during the 5-exo cyclization step (eq 3). Conversely, the use
a
Determined by 1H NMR spectroscopy of the crude reaction mixture.
b
Determined by 1H NMR spectroscopy of the crude reaction mixture
c
using 1,2-dichloroethane as an internal standard. Isolated yield.
Scheme 4. Oxidative Cyclization of Alkynyl Oxetanes
of a more electron-rich pyridine oxide, such as 4-methoxypyridine
oxide (O3), should favor the formation of 23 because the positive
charge in 28 would be partially delocalized far from the reacting
allene center (eq 3). Gratifyingly, treatment of 22 with 4 mol %
Cu(NCMe)4NTf2 in the presence of either O2 or O3 led to the
efficient and completely selective formation of 24 (85%) or 23
(74%), respectively (Table 2, entries 3 and 4).24 These two sets of
experimental conditions were then applied to a series of alkynyl
oxetanes in order to delineate the scope of the transformation. As
shown in Scheme 4, a range of diversely substituted alkynyl oxetanes
29a−f could be selectively converted into the corresponding
dihydrofuranaldehydes 30a−d (72−88%) or lactones 31a−f (67−
89%) simply by varying the nature of the pyridine oxide.25,26
In summary, we have developed a new and efficient oxidative
cyclization of alkynyl oxiranes or oxetanes into the correspond-
ing α,β-unsaturated lactones. This copper(I)-catalyzed trans-
formation, which presumably proceeds via the formation of an
unusual allenyloxypyridinium intermediate, takes place under
mild conditions using a simple pyridine oxide as the oxidant
and is compatible with a wide range of common functional
groups. Additionally, an interesting divergence in product selec-
tivity was uncovered in the case of alkynyl oxetanes, as these
can be converted into either lactones or dihydrofuranaldehydes
depending on the nature of the pyridine oxide employed.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
gagosz@dcso.polytechnique.fr
■
ACKNOWLEDGMENTS
This article is dedicated to Dr. Charles Fehr (Firmenich). The
authors thank Prof. Samir Z. Zard for helpful discussions and
■
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Journal of the American Chemical Society
Communication
Synth. Catal. 2004, 346, 432. Also see: (f) Gonzal
Lopez, C.; Marco-Contelles, J.; Nieto Faza, O.; Soriano, E.; de Lera, A.
R. J. Org. Chem. 2009, 74, 2982.
́ ́
ez Perez, A.; Silva
Rhodia Chimie Fine (Dr. F. Metz) for generous gifts of HNTf2
and HOTf. We deeply appreciate the generous financial
support from the Ecole Polytechnique (C.G., Y.O., and S.K.),
the Carlsberg Foundation, the Danish National Research
Foundation, H. Lundbeck A/S, the OChem Graduate School,
and Aarhus University (S.K.).
́
(7) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
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CH3CN by adapting the procedure described in: Kubas, G. J. Inorg.
Synth. 1979, 19, 90 (see the SI for more details). For a seminal use of
14 in cycloisomerization reactions, see: Fehr, C.; Vuagnoux, M.; Buzas,
A.; Arpagaus, J.; Sommer, H. Chem.Eur. J. 2011, 17, 6214.
(11) Only degradation was observed when acetonitrile was replaced
with chloroform.
(12) Other copper(II) or iron(III) catalysts (10 mol %) gave lower
yields and longer reaction times: [CuCl2] 4 h, 37%; [CuCl2, 2AgBF4]
18 h, 78%; [CuCl2, 2AgOTf] 24 h, 71%; [Cu2O] 24 h, 0%; [FeCl3,
3AgOTf] 24 h, 17%.
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