An efficient gold-catalyzed domino process for the construction of tetracyclic ketoethers

Article abstract of DOI:10.1002/chem.201302985

Au, yeah! Catalytic amounts of gold(III)chloride allow a mild and efficient oxidative domino cyclization/cycloaddition of enyne carbonyl compounds 1 and 4 to give the tetracycles 2 or 5, respectively, in the presence of pyridine N-oxide 3 (see scheme; DCE = 1,2-dichloroethane). Copyright

Full text of DOI:10.1002/chem.201302985

COMMUNICATION
DOI: 10.1002/chem.201302985
An Efficient Gold-Catalyzed Domino Process for the Construction of
Tetracyclic Ketoethers
Tobias Groß and Peter Metz*[a]
In the last decade gold has emerged as a transition metal
that can catalyze a variety of synthetically useful transfor-
mations with high efficacy,[1] in particular cyclizations and
cycloadditions.[2] Pioneering work[3,4] on metal-catalyzed
benzannulations with diyne or enyne carbonyl compounds
A showed that naphthalenes D are obtained from the
diynes with AuIII-catalysts and the corresponding dihydro-
bonyl compounds under RhII catalysis[9] or through photoly-
sis of a,b-epoxyketones.[10] In more recent work on transi-
tion-metal catalysis, the transformation of enyne benzalde-
hydes A to polyoxacycles F by RhI catalysis at high temper-
ature[11] as well as PtII catalysis was reported, whereby the
latter provides the tetracycle only as a byproduct.[12] An
AuIII-catalyzed reaction of a benzaldehyde substrate of type
A with a terminal allene to give a tetracycle of type F was
described as well.[13] In all these cases, water apparently acts
as external oxidant. Alternatively, an iodine-mediated trans-
formation to F under alkaline conditions can be performed
for enyne benzaldehydes A, which might be problematic
naphthalenes D from the enynes with CuACTHNUTRGENUG(N OTf)2 (Scheme 1).
with ketones
A
(R=alkyl) bearing a-C H bonds.[14]
À
N-Bridged polycyclic ketones H corresponding to F were
prepared from nitrones G by means of gold catalysis[15] via
an intramolecular redox process to generate the ketone
function.[16]
Herein we report an efficient gold-catalyzed domino reac-
tion of enyne aldehydes and ketones A as well as related
substrates to afford tetracyclic ketoethers F and heteroaro-
matic analogues by using pyridine N-oxides[17] as external
oxidants.[18] In addition, we show that an alternative tether-
ing[3] of the reactive units in A (cf. 4) also allows a domino
reaction to constitutionally isomeric tetracycles under these
conditions.[10]
Alkyne 1a easily available through Sonogashira coupling
of 2-iodoacetophenone and 4,4-dimethyl-6-hepten-1-yne[19]
was selected to determine suitable reaction conditions
(Table 1). Catalyst screening started with IPrAuCl/AgNTf2
and PPh3AuCl/AgNTf2 with pyridine N-oxide 3a as an oxi-
dant in dichloroethane (entries 1 and 2). These combinations
already produced the desired tetracycle 2a, albeit with mod-
erate yields. The relative configuration of 2a was unambigu-
ously determined by X-ray diffraction analysis.[20] Even
AgNTf2 alone showed a corresponding reactivity, although
to a lesser extent and accompanied by the formation of de-
Scheme 1. Metal-catalyzed domino reactions of diyne and enyne carbonyl
compounds A and the corresponding nitrones G. [M]=metal catalyst,
[O]=oxidant.
The isobenzopyrylium intermediate B reacts here with net
[4+2] cycloaddition,[3–6] which can also result from 1,3-dipo-
lar cycloaddition (cf. C) and subsequent 1,2-shift.[7] In con-
trast, dienones or enones E were formed by AuIII-catalysis
with diyne and enyne benzaldehydes A bearing a geminal
diester group between the C,C multiple bonds.[8] Previously,
polycycles of type F were accessible only from a-diazocar-
composition products (entry 3). The goldI species
[21]
Me4tBuXPhosAuNTf2
provided 2a in very high yield
(entry 4). Fortunately, AuCl already caused a similarly effi-
cient transformation in only a fraction of the time (entry 5),
and its higher oxidized counterpart AuCl3 led to a further
increase in yield in just 10 min (entry 6). Even with a catalyst
loading of only 0.1 mol% AuCl3, 2a was isolated in almost
quantitative yield, but only after a significantly prolonged
reaction time (entry 7).[22] Dichloromethane and nitrome-
thane proved to be suitable solvents as well (entries 8 and
[a] T. Groß, Prof. Dr. P. Metz
Fachrichtung Chemie und Lebensmittelchemie
Organische Chemie I
Technische Universitꢀt Dresden
Bergstrasse 66, 01069 Dresden (Germany)
Fax : (+49)351-463-33162
E-mail: peter.metz@chemie.tu-dresden.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302985.
Chem. Eur. J. 2013, 19, 14787 – 14790
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Table 1. Reaction optimization.
Table 2. Scope of the gold-catalyzed domino reaction.
No.
1
Substrate
Product
Conditions Yield
[%][a]
RT
85
30 min
No.
Catalyst [mol%]
Oxidant
Time
Yield [%][a]
1
2
3
4
5
6
7
IPrAuCl/AgNTf2 (1)
PPh3AuCl/AgNTf2 (2)
AgNTf2 (1)
Me4tBuXPhosAuNTf2 (1)
AuCl (1)
AuCl3 (1)
AuCl3 (0.1)
AuCl3 (1)
AuCl3 (1)
3a
3a
3a
3a
3a
3a
3a
3a
3 h
2 h
19 h
6.5 h
15 min
10 min
22 h
30 min
1.5 h
1 d
1 d
2 h
20 min
55 min
30 min
2.4 h
50
54
20
95
85
96
98
94
93
–
–
70
64
47
40
RT
62
2
3
4
1 h
508C
71
8[b]
9[c]
10
11
12
13
14
15
16
2 h
3a
[e]
PtCl2 (12)
3a[d]
3a[d]
3b[g]
3c
[f]
Rh
N
AuCl3 (2)
AuCl3 (1)
AuCl3 (1)
AuCl3 (1)
AuCl3 (1)
508C
75
16 h
3d
UHP[d]
–
[h]
–
[a] Yield of isolated product. [b] Dichloromethane as solvent. [c] Nitro-
methane as solvent. [d] 1.2 equivalents. [e] Traces of 2a according to
GCMS analysis. [f] No conversion according to GC/MS analysis.
[g] 1.6 equivalents. [h] Unselective formation of many products. DCE:
1,2-dichloroethane, IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene,
Tf=trifluoromethanesulfonyl, oct=octanoate, UHP=urea hydrogen per-
oxide complex.
658C
71
5
6
18 h
508C
88
15 min
9). Platinum(II)chloride and rhodium(II)octanoate turned
out to be unreactive (entries 10 and 11). Variation of the ox-
idant showed that in addition to the hygroscopic N-oxide 3b
also the oxidized Hantzsch ester 3c,[21] unsubstituted pyri-
dine-N-oxide (3d), and even the urea hydrogen peroxide
complex can be used with less efficiency (entries 12–15),
whereas an unselective product formation was observed in
the absence of any oxidant (entry 16).
RT
80
7
2 h
508C
8
64 (83)[b]
28 h
Table 2 illustrates the scope of the gold-catalyzed domino
reaction under optimized conditions. Similarly to ketone 1a,
aldehyde 1b was converted rapidly and with high yield into
tetracyclic ketoether 2b, the relative configuration of which
was also confirmed by X-ray diffraction analysis (entry 1).[20]
The methyl-substituted aromatic ketone 1c already reacted
at room temperature as well (entry 2). When a methoxy
group that can additionally interact with the Lewis acid
AuCl3 is present at the aromatic nucleus, the reaction tem-
perature should be slightly increased to achieve a marked
turnover (entries 3–6). However, then even a-branching
(1 f) and an electron-deficient aromatic moiety (1g) are
well-tolerated in the ketones. Interestingly, substrate 1h
lacking a geminal dimethyl substitution between alkyne and
olefin reacted almost as efficiently as ketone 1a (entry 7).
Thus, a Thorpe–Ingold or gem-disubstituent effect[23] is not
508C
22 h
9
67
508C
5.5 h
10
11
79
508C
2 h
70 (90)[b]
[a] Yield of isolated product. [b] Based on recovered starting material.
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Chem. Eur. J. 2013, 19, 14787 – 14790

Construction of Tetracyclic Ketoethers
COMMUNICATION
imperative for a smooth formation of tetracycles 2, which
considerably extends the synthetic applicability of the
domino process reported here. Also electron-rich (1i–k) as
well as electron-deficient heteroaromatic substrates (1l) re-
acted at 508C to give the desired tetracyclic products in
good yields (entries 8–11).
out competing ring expansion.[25] Thus, the hydrobenzoazu-
lene ring systems of the dolastane and neodolastane diter-
penes (2a–h)[26a] as well as of the daphnane, tigliane, and
rhamnofolane diterpenes (5a–d)[26b] can be obtained by the
domino process reported here.
Mechanistically, formation of the tetracyclic ketoethers 2
and 5 can be rationalized as illustrated in Scheme 2 for 5.
An intramolecular 6-endo-dig attack of the carbonyl oxygen
atom on the gold-activated alkyne to give the isobenzopyry-
À
Since ketones with a-C H bonds can be used without
problems under the conditions found here, an alternative
tethering[3] of the reactive units was investigated too
(Table 3). Initially, ketone 4a was subjected to the condi-
Table 3. Alternative tethering of the reactive units.
No.
1
Substrate
Product
Conditions
Yield [%][a]
RT
1 h
–
[b], 90[c]
Scheme 2. Mechanism for the formation of the tetracyclic ketoethers ex-
emplified by products 5. [Au]=gold catalyst.
RT
2 h
2
73
71
lium intermediate I and a subsequent intramolecular 1,3-di-
polar cycloaddition (c.f. J) afford gold carbenoid K. Inter-
molecular oxidation of K with the N-oxide 3a leads eventu-
ally via adduct L to the isolated product 5 with regeneration
of the gold catalyst. Regardless of the nature of the substra-
tes[27a] and the gold catalyst,[27b,c] no products resulting from
an initiating 5-exo-dig cyclization were observed in our stud-
ies. Moreover, even in the absence of a gem disubstitution
in the tether, a [3+2] cycloaddition was involved for all sub-
strates, making its participation[7] also likely for the forma-
tion of products D from A (c.f. Scheme 1).
RT
5 h
3
4
508C
5 h
57 (84)[e]
[a] Yield of isolated product. [b] Unselective formation of many products.
[c] From 5b. [d] K2CO3, MeOH, RT, 18 h. [e] Based on recovered starting
material.
In summary, a mild and efficient oxidative domino cycli-
zation/cycloaddition of enyne aldehydes and ketones 1 and
4 to give the polyfunctional tetracycles 2 or 5, respectively,
tions optimized for 1a, but a variety of other products was
formed instead of tetracycle 5a (Table 3, entry 1). As the
terminal alkyne 4a was prepared by desilylation of the tri-
methylsilyl derivative 4b, we also studied 4b as a substrate
for the gold-catalyzed domino reaction (entry 2). Indeed,
TMS substitution of the alkyne allowed a rapid and efficient
transformation already at room temperature into the a-silyl-
ketone 5b, the relative configuration of which was secured
by X-ray diffraction analysis.[20] With potassium carbonate in
methanol a mild desilylation of 5b succeeded to give 5a in
high yield. As the reactions of substrates 4c[24] and 4d indi-
cate, again no geminal disubstitution in the alkyl bridge to
the olefin is necessary (entries 3 and 4). Although the cyclo-
propyl substrate 4d was heated to 508C to increase conver-
sion, its transformation to 5d proceeded smoothly and with-
succeeded using goldACTHNGUTERN(UNG III)chloride as the catalyst already
with low loading in the presence of pyridine N-oxide 3a. A
geminal disubstitution in the tether between alkyne and
alkene was not required, and instead of a terminal alkyne
not tolerated in 4, the corresponding trimethylsilyl deriva-
tive could be used without any problems.
Acknowledgements
We thank Dipl.-Chem. Anne Jꢀger for the X-ray diffraction analyses.
Keywords: catalysis · cycloaddition · domino reactions ·
gold · oxidation
Chem. Eur. J. 2013, 19, 14787 – 14790
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www.chemeurj.org
14789

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Published online: October 2, 2013
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Chem. Eur. J. 2013, 19, 14787 – 14790