Gold-catalyzed cycloaromatization of 2, 4-dien-6-yne carboxylic acids: Synthesis of 2, 3-disubstituted phenols and unsymmetrical Bi- and terphenyls

Full text of DOI:10.1002/anie.200901269

Communications
DOI: 10.1002/anie.200901269
Gold Catalysis
Gold-Catalyzed Cycloaromatization of 2,4-Dien-6-yne Carboxylic
Acids: Synthesis of 2,3-Disubstituted Phenols and Unsymmetrical
Bi- and Terphenyls**
Patricia Garcꢀa-Garcꢀa, Manuel A. Fernꢁndez-Rodrꢀguez, and Enrique Aguilar*
Cycloaromatization reactions of conjugated polyenyne sys-
tems, such as the Bergman (enediynes), Saito–Myers (enyne–
allene), or Moore (enyne–ketene) cyclizations, have become
reliable methods for the formation of aromatic compounds
(Scheme 1).[1] The specific and limited substitution pattern of
limited to a specific substitution or require high temperatures,
high catalyst loadings, or long reaction times.
The notorious ability of gold derivatives to activate triple
bonds for attack by different nucleophiles[5] has resulted in the
development of an impressive array of organic transforma-
tions[6]—predominantly intramolecular cyclizations.[7] One
such example is the synthesis of substituted naphthalenes
under mild conditions by a 6-endo-dig gold(I)-catalyzed
cycloaromatization of aromatic 1,5-enynes bearing a sub-
stituent on their alkyne terminus.[8]
We have recently described an efficient and simple
procedure for the synthesis of captodative dienynes 1 and
2,[9] which could be appropriate substrates for metal-catalyzed
transformations. In this sense, non-activated nitriles regiose-
lectively attack the metal-complexed triple bond of 1 which
leads, after cyclization, to tetrasubstituted pyridines 3 in an
intermolecular hetero-dehydro-Diels–Alder reaction.[10]
However, when the analogous dienyne carboxylic acid 2a
was treated under very similar reaction conditions, a mixture
of the corresponding pyridine 3b and 2,3-disubstituted phenol
4a[11] was obtained (Scheme 2). Remarkably, the cycloaroma-
Scheme 1. Cycloaromatization reactions of conjugated polyenynes.
the starting materials as well as the harsh reaction conditions
traditionally required for these transformations can be
partially overcome by stoichiometric, metal-based triggering
reactions.[2] Ruthenium- and tungsten-catalyzed 6p cycloaro-
matizations via metal vinylidene species have also been
reported.[3] Furthermore, Rh, Fe, and Pt catalysts are able to
promote the cyclization of conjugated enynes containing
internal alkyne units.[4] However, all of these processes are
Scheme 2. Gold-catalyzed reaction of push-pull dienynes 1a and 2a.
tization of 2a to form 4a is very different from the above-
mentioned cyclizations involving 6p electrons. In the present
[*] Dr. P. Garcꢀa-Garcꢀa, Dr. E. Aguilar
Instituto Universitario de Quꢀmica Organometꢁlica
“Enrique Moles”, Universidad de Oviedo
C/Juliꢁn Claverꢀa, 8, 33006 Oviedo, Asturias (Spain)
Fax: (+34)985-103-450
À
case, a new C C bond is formed between carbon atoms 2 and
7 of the p-conjugated system, instead of the more common
creation of a bond between carbon atoms 1 and 6 (Scheme 1).
Herein we report our study of this novel transformation as
well as a related cyclization-decarboxylation sequence that
occurs with noncaptodative dienyne carboxylic acids.
E-mail: eah@uniovi.es
Dr. M. A. Fernꢁndez-Rodrꢀguez
Instituto de Quꢀmica Avanzada de Catalunya (IQAC-CSIC)
C/Jordi Girona 18-26, 08034 Barcelona (Spain)
The initial experiments were carried out with dienyne 2a
to allow optimization of several parameters. In contrast to the
situation in acetonitrile, reaction takes place at room temper-
ature in other solvents to exclusively form phenol derivative
4a. Thus, CH2Cl2 led to better results than toluene, THF,
diethyl ether, hexane, or methanol.[12] Cationic gold(I) com-
plexes, generated in situ with silver salts, were also able to
catalyze the reaction (Table 1, entries 3–11). The counterion
of the silver salt was found to be important: AgSbF6 provided
[**] We thank MICINN (Spain; grant CTQ2007-61048), MCyT (Spain;
predoctoral fellowship to P. G.-G. and Juan de la Cierva contract to
M.A.F.-R.), Principado de Asturias (project IB08-088), and Funda-
ciꢂn Ramꢂn Areces for financial support. We acknowledge Prof. B.
Kꢃnig for providing us with a copy of Ref. [1b], and Prof. J. Barluenga
for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901269.
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Table 1: Catalyst screening for the cyclization of 2a.
(Scheme 3). The reaction is effective when R is an aromatic
ring (4a–d), with either electron-withdrawing (4b) or elec-
tron-donating (4c) substituents. It also leads to good yields for
alkynyl- (4e), alkenyl- (4 f,g), linear or branched alkyl- (4h,i),
and silyl-substituted (4j) dienyne carboxylic acids. In all cases,
complete regioselectivity was observed in the cycloaromati-
zation.[17]
Entry
[M]
cat. mol%
4a[a]
1
AuCl3
3
41
2
3
4
5
6
7
8
9
10
11
12
13
14
AgSbF6
AuCl/AgSbF6
[AuClPPh3]/AgSbF6
[AuClPEt3]/AgSbF6
[AuClP(p-MeOC6H4)3]/AgSbF6
[AuClP(o-MeC6H4)3]/AgSbF6
[AuClP(p-CF3C6H4)3]/AgSbF6
[AuClP(C6F5)3]/AgSbF6
[AuCl{P(1-naphthyl)(tBu)2}]/AgSbF6
[AuClP(OPh)3]/AgSbF6
[AuClP(p-CF3C6H4)3]/AgSbF6
[AuClP(p-CF3C6H4)3]/AgSbF6
[AuClP(p-CF3C6H4)3]/AgSbF6
5
3
3
3
3
3
3
3
3
3
3
1
27[b]
(37)
61 (45)
(33)
(33)
62
72[c]
54
47
44
64[c,d]
69[c]
70[c]
0.5
[a] Yield of isolated product; in parenthesis, yield obtained without
premixing the gold precatalyst with the silver salt. [b] Reaction carried
out under argon (reaction time: >5 h). [c] Reaction time: entry 8,
<5 min; entry 12, 20 min; entry 13, 30 min; entry 14, 2 h. [d] Reaction
performed at 08C.
Scheme 3. Scope of the cyclization of dienynes 2. [a] 3 mol% catalyst
loading. [b] Partial decomposition of the starting dienyne acid 2j was
observed during reaction set-up.
higher yields of 4a than did AgOTf or AgBF4.[13] AgSbF6 by
itself also promotes the reaction, although it leads to a lower
yield after a longer reaction time and requires strictly
anhydrous conditions (entry 2), otherwise hydration of the
triple bond was observed. Two crucial factors for achieving
good reaction yields are: a) premixing the gold catalyst
(3 mol%) with the silver salt (entry 4) and b) the premixing
time: an optimum time of 30 minutes leads to the best
yields.[13] With these conditions established, the reactivity of
cationic gold(I) catalysts was modulated by incorporating a
phosphite and several phosphine ligands[14] with a broad range
of electron-donating abilities and steric effects. Thus, aliphatic
phosphines (entry 5), aromatic phosphines with electron-
donating (entries 6 and 7) and electron-withdrawing substitu-
ents (entries 8 and 9), sterically hindered phosphines
(entry 10), as well as an aromatic phosphite (entry 11) were
tested. Among them, the [AuClP(p-CF3C6H4)3]/AgSbF6
system afforded the best result (entry 8). The high activity
of the catalytic system for this transformation is noteworthy
since it allows the use of low catalyst loadings and mild
reaction conditions. Thus, reducing the catalyst loading to
0.5 mol% afforded phenol 4a in nearly the same yield
(entries 13 and 14); such a catalyst loading is one order of
magnitude lower than the amount employed in most gold-
catalyzed processes.[6,7,15] The mild conditions and the short
reaction times are especially noteworthy compared to other
related cyclizations:[16] reactions occur in less than 5 minutes
at room temperature (entry 8) or in 20 min at 08C (entry 12)
for a 3 mol% catalyst loading.
A mechanism that would explain the formation of phenols
4 is depicted in Scheme 4. Initial coordination of the gold
catalyst to the triple bond to form intermediate Ia, which is
stabilized by the electron-donating ability of the alkoxy group
through resonance structure Ib, is followed by a s-trans-s-cis
isomerization to give intermediates IIa or IIb. An intra-
molecular regioselective nucleophilic attack of the carboxylic
group to the more electrophilic of the two sp-hybridized
carbon atoms should take place to give the eight-membered
After establishing the optimum conditions (entries 13 and
14) for the desired transformation, the scope and limitations
of this novel approach to synthesize 2,3-disubstituted phenols
was analyzed by testing a wide variety of dienyne acids 2
Scheme 4. Proposed mechanism for the 2,7-cycloaromatization of 2.
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cyclic intermediates III.[18] The alkoxy group is important in
silylated biphenyl 7d, which is amenable to further elabo-
ration. The reaction time for this transformation must be
controlled (< 2 h) to avoid desilylation.
promoting such a cyclization: in the case of dienyne acid 2e
1
À ꢀ À
(R = C C Ph, R = Et), which exhibits two triple bonds of
different electronic nature, the nucleophilic attack of the
carboxylic group takes place chemoselectively at the ethoxy-
substituted triple bond. Both the activation and subsequent
nucleophilic attack of triple bonds are well documented for
gold-mediated transformations.[6,7,18] The alkoxy group would
also promote the evolution of intermediate IIIa by an
intramolecular attack on the activated carbonyl group,
thereby forming bicyclic species IV.[19] A final aromatization
would trigger the ring opening of the four-membered cycle in
intermediate IV to give the final product 4, and would
regenerate the catalyst, which may be incorporated into a new
cycle. The catalytic cycle in Scheme 4 represents the first
transition-metal-catalyzed cycloaromatization reaction of
dienyne carboxylic acids.
We considered that the electronic requirements of the
substrate were crucial for the reaction, as found for the [4+2]
intermolecular reaction of captodative enynes with nitriles.[10]
To test our assumptions, we prepared dienyne carboxylic acids
6a–d, which contain a p-methoxyphenyl group instead of an
alkoxy group linked to the triple bond.[20] When 6a (Ar=
4-MeOC6H4, R = Ph) was treated under the typical reaction
conditions described in Scheme 3, m-terphenyl 7a was
isolated in low yield, with no traces of the phenol derivative
detected. Interestingly, 7a results from a sequence involving
cyclization—by creation of a bond between C1 and C6—and
decarboxylation. Consequently, a strong electron-donating
group linked to the triple bond appears to be a requisite to
promote 2,7-cycloaromatization.
This cyclization/decarboxylation sequence takes place
even with a non-activated substrate. Phenyl-substituted
dienyne carboxylic acid 6e (Ar= Ph, R = Ph) reacts to form
m-terphenyl 7e, although higher temperatures (refluxing
toluene) and catalyst loadings ([AuClP(p-CF3C6H4)3]
(10 mol%)/AgSbF6 (30 mol%)) were needed, and the con-
version did not proceed beyond 56%, probably because of
thermal decomposition of the catalyst.
The formation of biphenyl and terphenyl derivatives 7
would probably follow a similar pathway to that proposed for
phenols 4 at the earlier stages of the mechanism (metal
coordination, s-trans-s-cis isomerizacion, and nucleophilic
attack of a carboxylic acid). However, the absence of a
strong electron-donating group results in intermediate V (an
analogue of III), which undergoes an electrocyclic ring
closure between positions 1 and 6 to give VI. Aromatization
should then occur to form 7 by CO2 extrusion and the
regeneration of the gold catalyst (Scheme 6).
This 1,6-cyclization/decarboxylation sequence also proved
to be general, although higher catalyst loadings ([AuClP(p-
CF3C6H4)3] (5 mol%)/AgSbF6 (15 mol%)) and a higher
temperature (reflux in CH2Cl2) were required. Accordingly,
different p-methoxyphenyl-substituted dienyne carboxylic
acids 6a–c could be converted into unsymmetrical m-ter-
phenyl derivatives[21] 7a,b or biphenyl 7c in moderate yields
(Scheme 5). Notably, silyl-substituted dienyne carboxylic acid
6d (Ar= 4-MeOC6H4, R = TMS) provided high yields of
Scheme 6. Proposed mechanism for the 1,6-cycloaromatization of 6.
In summary, we have reported a novel gold-catalyzed 2,7-
cycloaromatization reaction of captodative dienyne carbox-
ylic acids which occurs at room temperature with short
reaction times, low catalyst loading, and with total regiose-
lective control. The reaction is dependent on the electronic
properties of the dienyne acid: if a strong electron-donating
group is not directly linked to the triple bond, a regioselective
1,6-cyclization-decarboxylation sequence takes place upon
warming, thereby leading to biphenyl or m-terphenyl deriv-
atives in moderate to high yields.
Experimental Section
General procedure for the synthesis of phenols 4: AgSbF6 (0.5–
1.0 mol%, 0.4–0.8 mg) was added to
a solution of [AuClP(p-
CF3C6H4)3] (0.5–1.0 mol%, 0.9–1.8 mg) in dry CH2Cl2 (2 mL) and
the reaction mixture was stirred for 30 min. A solution of the
corresponding dienynoic acid 2 (0.5 mmol) in dry CH2Cl2 (3 mL) was
added and the reaction mixture was stirred at RT until complete
disappearance of the dienynoic acid was observed by TLC (1–2 h).
The solvent was removed under reduced pressure and the crude
mixture was purified by flash chromatography on silica gel. The
corresponding phenols 4 were isolated in the yields reported in
Scheme 3.
Scheme 5. Cyclization of dienynes 6. [a] 56% conversion; reaction
conducted in toluene at reflux and with a higher catalyst loading
([AuClP(p-CF3C6H4)3] (10 mol)/AgSbF6 (30 mol%). TMS=trimethyl-
silyl.
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Received: March 6, 2009
compounds with relevant biological activity: a) O. Soltani, J. K.
Published online: May 8, 2009
De Brabander, Angew. Chem. 2005, 117, 1724 – 1727; Angew.
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[12] In particular, (2E,4Z)-6-methoxycarbonyl-5-phenyl-2,4-hexa-
dienoic acid (5), which results from the formal hydration of
2a, was isolated (81%) when the reaction was performed in
MeOH.
Keywords: cycloaromatization · gold · homogeneous catalysis ·
.
phenols · terphenyls
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[20] The strong electron-donating effect displayed by the methoxy
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