Synthesis of Barbaralones and Bullvalenes Made Easy by Gold Catalysis

Article abstract of DOI:10.1002/anie.201606101

The gold(I)-catalyzed oxidative cyclization of 7-ethynyl-1,3,5-cycloheptatrienes gives 1-substituted barbaralones in a general manner, which simplifies the access to other fluxional molecules. As an example, we report the shortest syntheses of bullvalene, phenylbullvalene, and disubstituted bullvalenes, and a readily accessible route to complex cage-type structures by further gold(I)-catalyzed reactions.

Full text of DOI:10.1002/anie.201606101

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International Edition: DOI: 10.1002/anie.201606101
German Edition: DOI: 10.1002/ange.201606101
Fluxional Molecules
Synthesis of Barbaralones and Bullvalenes Made Easy by Gold
Catalysis
Sofia Ferrer and Antonio M. Echavarren*
Abstract: The gold(I)-catalyzed oxidative cyclization of
7-ethynyl-1,3,5-cycloheptatrienes gives 1-substituted barbar-
alones in a general manner, which simplifies the access to other
fluxional molecules. As an example, we report the shortest
syntheses of bullvalene, phenylbullvalene, and disubstituted
bullvalenes, and a readily accessible route to complex cage-
type structures by further gold(I)-catalyzed reactions.
Scheme 1. Synthesis of barbaralone (1a) from ethyl cyclohepta-2,4,6-
triene-1-carboxylate (4).
F
luxional molecules, such as barbaralone (1a), bullvalone
(2a), and bullvalene (3a) have been central to the under-
standing of the phenomena of valence tautomerism (see
Figure 1).[1,2] These molecules undergo low energy [3.3]-
sigmatropic rearrangements, which in the case of bullvalene
1-Methylbarbaralone (1w) was prepared by a procedure
similar to that shown in Scheme 1 using ethyldiazomethane in
the reaction with cycloheptatriene carbamoyl chloride to
form the homologue of 5.[9b] Although some ingenious
syntheses of highly substituted bullvalenes have been
designed,[8] most bullvalenes have been prepared from
parent 3a. Thus, for example, phenylbullvalene (3b) was
obtained in three steps (26% yield) from 3a by dibromina-
tion, dehydrobromination with KOtBu, and reaction of the
resulting bromobullvalene with Ph2CuLi.[7d]
Figure 1. Barbaralone (1a), bullvalone (2a), and bullvalene (3a).
Current synthetic art does not allow preparation of
substituted barbaralones in a general way,[14] which limits
the access to fluxional homologues and other theoretically
interesting molecules.[12,15] We have recently found that
7-aryl-1,3,5-cycloheptatrienes undergo a gold(I)-catalyzed
retro-Bꢀchner reaction to form highly reactive aryl gold(I)
carbenes (a decarbenation reaction).[16] However, 7-ethynyl-
1,3,5-cycloheptatrienes (6) react differently to form fluxional
barbaralyl gold(I) intermediates 7; after a series of complex
rearrangements 7 finally leads to indenes 8 and/or 9, depend-
ing on the gold catalyst (Scheme 2).[17] Since the gold-
catalyzed oxidation of alkynes has been shown to take place
readily with oxidants such as sulfoxides, or amine-N-oxides to
form a-oxo gold(I) carbenes,[18,19] we envisioned that the
oxidation of intermediates 7 could lead to 1-substituted
barbaralones 1 (Scheme 2). However, if the oxidation takes
place directly on 7-ethynyl-1,3,5-cycloheptatrienes (6), the
two regioisomeric a-oxo gold(I) carbenes 10a and 10b would
be formed,[18] of which only 10b would lead to barbaralones
1 by intramolecular cyclopropanation.
lead to 1209600 degenerate tautomers,[3–5] whereas a lower
number of constitutional isomers are possible for substituted
bullvalenes[6–8] and only two exist for barbaralone (1a).[9]
Syntheses of these fluxional molecules requires multistep
procedures that proceed with low overall yield, often using
explosive and toxic diazomethane. Thus, the optimized syn-
thesis of barbaralone (1a), en route to bullvalene (3a),[10]
starts with the Bꢀchner reaction of ethyl diazoacetate with
benzene to form 4,[11,12] which is converted into 1a in four
steps via diazomethyl ketone 5 (Scheme 1).[10] Bullvalene (3a)
can be prepared from 1a in four additional steps by two
different procedures by homologation of 1a to bullvalone
(2a) with diazomethane.[2,10] Barbaralone (1a) has also been
prepared from (cyclooctatetraene)tricarbonyliron in two
steps in approximately 36% yield.[13]
[*] S. Ferrer, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Barcelona Institute of Science and Technology
Av. Paꢀsos Catalans 16, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
Herein, we report a general and straightforward synthesis
of 1-substituted barbaralones 1 from alkynes and commer-
cially available tropylium tetrafluoroborate in just two steps
by oxidative cyclization of 7-ethynyl-1,3,5-cycloheptatrienes.
We first studied the reaction of 7-(phenylethynyl)cyclo-
hepta-1,3,5-triene (6b) with different gold(I) catalysts in the
presence of diphenylsulfoxide (Ox1), and the N-oxides of
pyridine (Ox2), 3,5-dichloropyridine (Ox3), or 8-methylquino-
line (Ox4) as oxidants (Table 1). Using Johnphos gold(I)
complex A in combination with Ox3, 1-phenylbarbaralone
Prof. A. M. Echavarren
Departament de Quꢁmica Analꢁtica i Quꢁmica Orgꢂnica
Universitat Rovira i Virgili
C/ Marcel·li Domingo s/n, 43007 Tarragona (Spain)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201606101.
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Table 1: Gold(I)-catalyzed oxidative reaction of 6b to give 1-phenyl-
barbaralone (1b).
Entry
[Cat.]
Oxid.
Time
[h]
1b
8b
Yield [%][a]
Yield [%][a]
1
2
3
4
5
6
7
8
A
A
A
A
B
C
D
D
D
D
E
E
F
F
Ox1
Ox2
Ox3
Ox4
Ox3
Ox3
Ox1
Ox2
Ox3
Ox4
Ox1
Ox3
Ox1
Ox3
Ox3
Ox3
2.5
16
2.5
16
3
3
3
24
3
3
2.5
2.5
5
5
2.5
24
12
5
58
–
28
–
36
42
–
–
–
–
–
50 (50)[b]
23
30
32
(83)[b]
2
64
7
20
30
14
61
Scheme 2. Two different pathways for the formation of barbaralones
1 by gold(I)-catalyzed oxidative cyclization of 7-ethynyl-1,3,5-cyclo-
heptatrienes (6).
9
10
11
12
13
14
15
16
(1b) was obtained in 50% yield, together with 2-phenyl-1H-
indene (8b; Table 1, entry 3). Related gold(I) complexes B
and C led to 1b in lower yields in the presence of Ox3 (Table 1,
entries 5 and 6). The best yields of 1b were obtained using
[IPrAu(MeCN)][SbF6] (D) and either Ox1 or Ox3 (Table 1,
respectively entries 7 and 9). Oxidants Ox2 and Ox4 led to
very poor results (Table 1, respectively entries 8 and 10).
Interestingly, whereas phosphite gold(I) complex E afforded
low yields (Table 1, entries 11 and 12), pycolinate gold(III)
complex provided 1b in a similar yield in the presence of Ox3
(Table 1, entry 14). Reactions of alkynes with pyridine-N-
oxides can also be performed with Brønsted acids[20] or ZnII
catalysts.[21] However, in our system, a complex reaction
mixture was obtained in the presence of methanesulfonic acid
(Table 1, entry 15) and starting material was recovered when
Zn(OTf)2 was used as the catalyst (Table 1, entry 16).
–
61
–
MeSO3H[c]
Zn(OTf)2
complex mixture
starting material
[d]
1
[a] Yields determined by H NMR using mesitylene as an internal
standard. [b] Yield of isolated products. [c] 4 equiv [d] 10 mol%. Catalyst
(cat.), oxidant (oxid.).
To assess the generality of this oxidative cyclization,
various 7-ethynyl-1,3,5-cycloheptatrienes (6a–v) were pre-
pared[17] and the combinations of catalyst and oxidant that
provided the best results in the preliminary studies (con-
ditions: A) cat. D, Ox1; B) cat. D, Ox3; C) cat. A, Ox3) were
tested on these substrates (Table 2). The most simple
substrate, 7-ethynyl-1,3,5-cycloheptatriene (6a), produced
barbaralone (1a) in 97% yield. The reaction was compatible
with 7-(arylethynyl)-1,3,5-cycloheptatrienes 6c–o bearing
different o-, m-, or p- substituents on the phenyl ring, such
as methyl-, tert-butyl-, fluorine-, chlorine-, methoxy-, or
trifluoromethyl-, affording the corresponding 1-substituted
barbaralones (1c–o) in moderate to good yields. Substrates
6p–q, possessing a naphthyl or a thiophenyl substituent, gave
barbaralones 1p–q in yields up to 88%. This catalytic
procedure was extendible to alkynyl cycloheptatrienes with
aliphatic or alkyl groups (6s–v), including n-butyl, n-hexyl,
2-phenylethyl, and cyclopropyl, giving the desired barbar-
alones 1s–v in moderate to excellent yields. The reaction was
also applicable to a substrate containing two alkynes (6r),
affording dibarbaralone 1r in 60% yield. The process was
efficiently scalable, providing up to 850 mg of barbaralone
(1a) in one run in 96% yield. Mechanistically, the formation
of aryl substituted barbaralones 1b–r strongly suggests that
the oxidation takes place on barbaralyl gold(I) intermediates
7 (Scheme 2), rather than on the alkyne, which would favor
formation of unproductive intermediate 10a by benzylic
oxidation.[18]
The introduction of a methyl substituent was found to
shift the sigmatropic equilibrium toward the 1-substituted
isomer (Scheme 3).[6c,9b] Our NMR data show that 1-substi-
tuted barbaralones are in all cases the most stable tautomers,
as confirmed by the X-ray diffraction structures of 1a–d, 1q,
and 1r (Table 2).[22]
With the synthesis of barbaralones (1) in hand, and the
preparation of bullvalenes (3) in mind, we examined the
applicability of this oxidative cyclization for the synthesis of
bullvalone (2a) using propargyl cycloheptatriene as substrate
(11). Thus, the reaction of propargyl cycloheptatriene (11)
with different gold(I) catalysts in the presence of the
previously employed oxidants was investigated (Table 3).
However, instead of the desired bullvalone, arising from a
2
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Table 2: Gold(I)-catalyzed oxidative synthesis of barbaralones 1a–v.
Table 3: Gold(I)-catalyzed oxidative reaction of propargyl cyclohepta-
triene (11) to give 1-formylbarbaralane (12).
Entry
[Au]
Oxid.
Time
[h]
12
Yield [%][a]
1
2
3
4
5
6
8
9
A
A
A
A
B’
B’
D
D
E’
E’
Ox1
Ox2
Ox3
Ox4
Ox1
Ox3
Ox1
Ox3
Ox1
Ox3
18
15
18
15
17
17
4
18
6
24
27
–
5
–
91 (87)[b]
7
90 (87)[b]
8
92
–
10
11
1
[a] Yields determined by H NMR spectroscopy using mesitylene as an
internal standard. [b] Yield of isolated products.
(2a) in 24% yield along with an isomeric aldehyde (34%).[2,10]
Reduction of 2a followed by acetylation led to the corre-
sponding acetate (40%, two steps), which was pyrolyzed at
3458C to give a 1:1 ratio of bullvalene (3a) and cis-9,10-
dihydronaphthalene.[2,23] An improved procedure was
reported via bullvalone tosylhydrazone, providing bullvalene
(3a) in approximately 5% yield from 2a in four steps.[10,24]
In our new approach, bullvalene (3a) and phenylbullva-
lene (3b) were prepared from barbaralones 1a–b by a three-
step procedure. A homologation reaction of 1a and 1b with
the lithium anion of (trimethylsilyl)diazomethane[25] gave
bullvalones 2a and 2b in 37 and 22% yield, respectively
(Scheme 4). Formation of the corresponding enol triflates
using LDA and Cominsꢁ reagent, or LiHMDS and PhNTf2
followed by immediate reduction with nBu3SnH and
Pd(PPh3)4 as catalyst,[26] afforded 3a and 3b[27] in 44% and
60% yield, respectively, whose structures were confirmed by
X-ray diffraction.[22] This new synthesis of bullvalene (3a) is
the most efficient to date as it requires a total of five steps
(10% overall yield) from commercially available tropylium
tetrafluoroborate and ethynyl magnesium bromide.
Conditions: A) cat. D, Ox1; B) cat. D, Ox3; C) cat. A, Ox3.
Scheme 3. Equilibrium between 1-methyl- and 5-methylbarbaralones.[9b]
5-endo-dig oxidative cyclization, in all cases we observed the
recovered starting material or formation of 1-formylbarbar-
alane (12),[22] the product of a 5-exo-dig process. While
Johnphos gold(I) complex A gave poor results regardless of
the oxidant used (Table 3, entries 1–4), good yields were
obtained with tBuXPhos gold(I) catalyst (B’) and [IPrAu-
(MeCN)]SbF6 (D) with Ox1 (Table 3, entries 5 and 8). A
better yield of aldehyde 12 was obtained using phosphite
gold(I) complex E’ and Ox1 (Table 3, entry 10).
Various disubstituted bullvalenes 3c–e were also prepared
from phenyl bullvalone (2b) through sequential formation of
the enol triflate followed by Stille couplings (Scheme 4).[28]
The molecular structure of diphenyl bullvalene 3c was
determined by X-ray diffraction.[22] Bullvalenes 3c–e were
in equilibrium with the 3,6- and 3,7-disubstituted isomers at
À408C; the observed ratios of the respective compounds was
7.6:5.7:1, 5.2:1.5:1, and 3.8:2.3:1.[7d]
At this stage we considered accessing bullvalones (2) via
barbaralones (1) en route to bullvalenes (3). Homologation of
1a with diazomethane has been reported to give bullvalone
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intermediates 16a and 16b[29,30] and semipinacol-type rear-
rangement to give 17a and 17b (Scheme 5). To the best of our
knowledge, and despite the many different types of gold(I)-
catalyzed cycloisomerizations,[30] this formation of a five-
membered ring by cyclization-rearrangement is unprece-
dented.
Furthermore, alkylation of barbaralol 18[22] with propargyl
bromide gives 1,7-enyne 19, which undergoes an exo-dig
cyclization with gold(I) catalyst D to form intermediate 20,[30]
which then reacts with methanol as a nucleophile to form
tricyclic system 21 (Scheme 6).
Scheme 4. Synthesis of bullvalene (3a), phenylbullvalene (3b), and
disubstituted bullvalenes 3c–e.
Scheme 6. Formation of tricyclic derivative 21 from barbaralol (18).
Barbaralones 1a and 1b were converted into 14a and 14b
in two steps by the addition of ethynyl magnesium bromide
and subsequent gold(I)-catalyzed reaction of the correspond-
ing alcohols 13a and 13b, which proceeded by a new type of
cyclization/rearrangement (Scheme 5). Structures 14a and
14b were confirmed by X-ray diffraction.[22]
Unprecedented tetracyclic cages 14a and 14b are prob-
ably formed by coordination of gold(I) of the alkyne of the
minor tautomer of 13a and 13b to give 15a and 15b, followed
by intramolecular attack of the alkene to form delocalized
In summary, we have developed an efficient synthesis of
1-substituted barbaralones by gold(I)-catalyzed oxidative
cyclization of 7-(substituted ethynyl)-1,3,5-cycloheptatrienes.
This method has allowed accomplishment of the shortest
syntheses of bullvalene and other substituted bullvalenes.
Thus, parent bullvalene (3a) is obtained in five steps from
commercially available starting materials in 10% overall
yield, which compares favorably with previous procedures
that require nine or more steps and proceeded with very low
overall efficiency. The straightforward access to barbaralones
opens a way to obtain complex cage systems with unprece-
dented molecular architectures.
Acknowledgements
We thank MINECO (Severo Ochoa Excellence Accredita-
tion 2014–2018 (SEV-2013-0319) CTQ2013-42106-P), the
MEC (FPU fellowship to SF), the European Research
Council (Advanced Grant No. 321066), the AGAUR (2014
SGR 818), and the ICIQ Foundation. We also thank the ICIQ
X-ray diffraction unit and Dr. Michael E. Muratore for
helpful discussions.
Keywords: barbaralones · bullvalenes · cyclization reactions ·
gold · valence tautomerism
Scheme 5. Preparation of highly fused tetracyclic molecules 14a and
14b.
4
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[27] Phenylbullvalene 3b has been shown to be in a 3:1 equilibrium
with the 3-substituted isomer at À408C.[7d] We have confirmed
this result and have observed that the equilibrium can be shifted
to 5.6:1 at À908C.
[28] W. J. Scott, G. T. Crisp, J. K. Stille, J. Am. Chem. Soc. 1984, 106,
4630 – 4632.
[29] V. Lꢃpez-Carrillo, N. Huguet, ꢅ. Mosquera, A. M. Echavarren,
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[14] For cyclopentannulated barbaralones by photocycloaddition of
2-(pent-4-yn-1-yl)tropones, see: K. S. Feldman, J. H. Come, G. J.
Received: June 23, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Fluxional Molecules
S. Ferrer,
A. M. Echavarren*
&&&& — &&&&
Synthesis of Barbaralones and
Bullvalenes Made Easy by Gold Catalysis
Take the bull by the horns: A method that
accomplishes the shortest known syn-
theses of bullvalene and other substi-
tuted bullvalenes has been developed.
Gold(I)-catalyzed oxidative cyclization of
7-(substituted ethynyl)-1,3,5-cyclohepta-
trienes yields 1-substituted barbaralones,
allowing easy access to other fluxional
molecules.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!