Tandem br?nsted acid promoted and nazarov carbocyclizations of enyne acetals to hydroazulenones

Article abstract of DOI:10.1002/anie.201205823

Ring the changes: Enyne acetals were easily converted into hydroazulene skeletons by a new and efficient metal-free route involving a Br?nsted acid promoted carbocyclization and a subsequent stereospecific Nazarov cyclization (see scheme). The versatility of this transformation also allowed assembly of interesting heteroaromatic tricyclic systems. Copyright

Full text of DOI:10.1002/anie.201205823

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DOI: 10.1002/anie.201205823
Dominoreaktionen
Tandem Brønsted Acid Promoted and Nazarov Carbocyclizations of
Enyne Acetals to Hydroazulenones**
Luz Escalante, Carlos Gonzꢀlez-Rodrꢁguez, Jesffls A. Varela, and Carlos Saꢀ*
The presence of hydroazulen(on)e skeletons in many bioac-
tive natural products, such as guanacastepene[1] or pleocarpe-
none,[2] has resulted in sustained interest in their synthesis. A
wide variety of approaches have been described.[3] The most
common approaches, other than the use of rearrangement
reactions,[3,4] have started from the five-membered ring, on
which the seven-membered ring has been assembled by ring
enlargement, reductive cyclization, metathesis, or aldol con-
densation.[3,5] Alternative methods have involved the con-
struction of the five-membered ring on the seven-membered
ring and have employed metathesis, aldol condensation, ring
expansion, or Nazarov cyclization.[3,6]
Highly efficient approaches in which both rings are
created in one pot have also been developed, most of them
involve
metal-catalyzed
cycloaddition
reactions
(Scheme 1).[7–14] Thus Wender et al. have used both intra-
molecular Rh-catalyzed [5+2] cycloaddition (Scheme 1,
path a)[7a] and intermolecular tandem Rh-catalyzed [5+2]/
Nazarov cyclization;[7b] Trost et al. have explored [5+2]
cyclization protocols using Ru catalysts;[8] MascareÇas and
co-workers have employed Pd- and Pt-catalyzed [4+3] cyclo-
addition[9] (Scheme 1, path b);[10] and Ahmar et al.,[11a] Brum-
mond et al.[11b] and Mukai et al.[11c] have reported various
approaches employing allenic reactions of the Pauson–Khand
type (Scheme 1, path c).[12] Strategies based on the cyclization
of acyclic dienynes, mediated[13a] or catalyzed[13b] by metal
carbenes, have also been reported (Scheme 1, paths d and
e).[14]
Scheme 1. Metal-catalyzed and tandem enyne acetal-Nazarov Brønsted
acid promoted carbocyclizations to hydroazulen(on)es.
Initially, we subjected enyne acetal 1a (Table 1), to the
optimized reaction conditions identified in our previous work
(heating in DCE in the presence of excess trifluoroacetic
acid).[16] Cyclization proceeded smoothly to give an almost
equimolar mixture of enones 2a and 3a in excellent combined
yield (Table 1, entry 1). When the reaction was carried out at
room temperature a similar yield was obtained but there was
a higher proportion of 2a (Table 1, entry 2). The major
regioisomer was the single-bond-fused bicycle 2a, which is the
thermodynamically less-stable isomer.[21] This bicycle can
potentially be further functionalized in the seven-membered
ring for future applications;[6f,22] therefore we proceeded to
seek reaction conditions to optimize this regioselectivity.
The use of HBF4 instead of TFA as acid resulted in an
increase in the 2a/3a ratio to 3:1 (Table 1, entries 3 and 4).
When the reaction temperature was lowered to À158C the
regioselectivity increased to 4.5:1, but a lower yield was
obtained (Table 1, entry 5). No reaction occurred if the
amount of HBF4 was reduced from 3 to 1 equivalents
(Table 1, entry 6). With BF3·OEt2 or H2SO4 as acid, yields
were low to moderate and 3a was slightly favored over 2a
(Table 1, entries 7 and 8). Formation of enone 3a was also
favored when triflimide was employed, and it was the
exclusive product when triflic acid was used,[20c] although in
both cases yields were low (Table 1, entries 9 and 10).[23]
When the aldehyde corresponding to acetal 1a was used as
the starting compound and HBF4 as the acid, both the yield
and the 2a/3a ratio decreased (compare Table 1, entries 4 and
11), undoubtedly because the reaction intermediate was less
As a contribution to the development of metal-free,
environmentally less hazardous synthetic methods,[15] we
recently described an efficient intramolecular cyclization of
alkynals promoted by Brønsted acids.[16,17] Herein we report
its use in tandem with a Nazarov cyclization[7b,18] to construct
hydroazulenone skeletons
2
from enyne acetals 1[19]
(Scheme 1).[20]
[*] L. Escalante, Dr. C. Gonzꢀlez-Rodrꢁguez, Dr. J. A. Varela, Prof. C. Saꢀ
Departamento de Quꢁmica Orgꢀnica y Centro Singular de Inves-
tigaciꢂn en Quꢁmica Biolꢂgica y Materiales Moleculares (CIQUS)
Universidad de Santiago de Compostela
15782 Santiago de Compostela (Spain)
E-mail: carlos.saa@usc.es
Homepage: http://www.usc.es/gi1603/saa
[**] We thank the MICINN [Projects CTQ2011-28258, Consolider
Ingenio 2010 (CSD2007-00006)] and Xunta de Galicia (2007/XA084
and CN2011/054) for financial support. L.E. thanks Fundayacucho
(Venezuela) and Xunta de Galicia for predoctoral grants and C. G.-R.
thanks the MICINN for a Juan de la Cierva Contract (JCI-2011-
09946).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205823.
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Table 1: Brønsted acid promoted carbocyclization of enyne acetal 1a to
hydroazulenones 2a and 3a.[a]
Table 2: Hydroazulenones and azahydroazulenones prepared by tandem
carbocyclizations of b-substituted enyne acetals 1a–j.[a,b]
Entry
Brønsted acid
T [8C]
t [h]
2a/3a[b]
Yield [%][c]
Entry
1
Enyne acetal
Hydroazulenone[c]
2/3
Yield[d] [%]
1
2
3
4
5
6
7
8
TFA (20 equiv)
TFA (20 equiv)
HBF4 (3 equiv)
HBF4 (3 equiv)
HBF4 (3 equiv)
HBF4 (1 equiv)
BF3·OEt2 (3 equiv)
H2SO4 (3 equiv)
TfOH (3 equiv)
Tf2NH (3 equiv)
HBF4 (3 equiv)
90[d]
20[d]
20
0.5
3
0.5
1
1.3
72
1.5
0.7
0.4
0.4
0.6
1.2:1
1.8:1
2.5:1
3:1
4.5:1
–
1:1.6
1:1.6
0:1
1:2.6
2.3:1
93
96
84
89
63
–
39
60
39
47
52
0
3:1
89
À15
20
20
20
20
0
9
1.5:1
(1:1.5)
45
2
3
4
10
(62)[e]
11[e]
0
[a] Reaction conditions: 1a (0.3 mmol), CH2Cl2 (3 mL). [b] Regioisomers
2a and 3a are easily separated by chromatography. [c] Combined yields
of the isolated products. [d] DCE as solvent. [e] With the aldehyde
corresponding to acetal 1a as starting compound (0.3 mmol).
DCE=1,2-dichloroethane, Tf=trifluoromethanesulfonyl, TFA=tri-
fluoroacetic acid.
2:1
1:0
66
62
electrophilic.[24] In view of these results, in most subsequent
experiments we used the reaction conditions of entry 4
(referred to below as optimized conditions A) or entry 2
(optimized conditions B).
The relative configuration of 2a corresponds to the
conrotatory ring closure of an E olefin, thus indicating that,
under the reaction conditions, the divinyl ketone intermediate
might undergo a Z-to-E isomerization prior to the Nazarov
cyclization (Scheme 1).[25]
5
6
2:1
0:1
84
77
Once the viability of the tandem diastereoselective
process had been established we explored its scope, initially
by applying it to the b-substituted enyne acetals 1b–e (see
Table 2), in which, as in 1a, the tether between the acetal and
the triple bond includes a quaternary carbon with two
COOMe substituents. Surprisingly, cyclization of 1b, the
trans isomer of 1a, under optimized conditions A gave
a lower yield and 2a/3a ratio than that of 1a (1.5:1; Table 2,
entry 2); this result indicates that a more complex equilibrium
of intermediates could affect the regioselectivity of the
reaction.[26] Not unexpectedly, the styrene-containing enyne
acetal 1c was one of the least reactive substrates (66%;
Table 2, entry 3), whereas the reaction of the b,b-disubstituted
1e was one of the more higher yielding reactions (84%,
Table 2, entry 5). The results of the reaction of 1d were better
than we expected; the presence of the bulky tert-butyl
b substituent resulted in an increased 2/3 ratio of 1:0
(Table 2, entry 4).
7
8
1:0
63
73
1[f]:1
9
1:3
2:1
76
80
We next investigated the effect of modifying the tether.
Satisfyingly, moderate to good yields and complete regiose-
lectivity were achieved with the appropriate substituents; the
reaction of the substrate containing geminal methyl groups
adjacent to the alkyne fragment gave only 3 f (Table 2,
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Table 3: Hydroazulenones prepared by tandem carbocyclization of
a-substituted enyne acetals 4a–e.[a,b]
Table 2: (Continued)
Entry
Enyne acetal
Hydroazulenone[c]
2/3
Yield[d] [%]
11
4.5:1
72
[a] Conditions A: 1 (0.3 mmol), HBF4 (0.9 mmol), CH2Cl2 (3 mL), 08C,
20–60 min. [b] X=C(CO2Me)2. [c] Only the major regioisomer is shown.
[d] Combined yields of the isolated products. [e] Conditions B: 4
(0.3 mmol), TFA (6.0 mmol), DCE (3 mL), RT, 30 min. [f] Compound 2h
was obtained as a 2:1 mixture of trans and cis diastereomers as a result of
the partial isomerization of the divinylketone intermediate (only the
major diastereomer is shown).[25] Ts =p-toluenesulfonyl.
Entry
1[e]
Enyne acetal
Hydroazulenone[c]
5/6
Yield[d] [%]
1:2
72
2
0:1
1:0
58
entry 6) and that of methyl ketal 1g gave only 2g (Table 2,
entry 7). Interestingly, when the substrate not containing the
CO2Me groups was used, thus eliminating the Thorpe–Ingold
effect,[27] the cyclization still occurred, but with slightly
reduced yield and no regioselectivity (Table 2, entry 8).[28]
The opposite regioselectivity was obtained (that is 3 was
favored) when the substrate with the C(CO2Me)2 unit placed
closer to the acetal fragment (Table 2 entry 9); this result
probably due to the change of the original conformation of
the seven-membered ring. Gratifyingly, this tandem reaction
could be used to prepare azabicycles, as confirmed by the
successful reactions of the tertiary amines (Z)-1j and (E)-1j,
which afforded cyclopenta[c]azepinones[29] with good yields
and a 2/3 ratio of up to 4.5:1 in the case of (E)-1j (Table 2,
entries 10 and 11).
3[f]
85[g] (5 h)
4[f]
1:0
2:1
79[g] (14 h)
5
52
The tandem reaction was equally successful when applied
to a-substituted substrates 4 (Table 3), although to our initial
surprise the major product afforded by enyne acetal 4a was
hydroazulenone 6a, a bicyclic enone with both bridgeheads
saturated and cis stereochemistry (Table 3, entry 1). When the
a substituent was tert-butyl the reaction was totally regiose-
lective (Table 3, entry 2). In contrast, when the a substituent
was TMS, which was lost during the reaction, the other
regioisomer was formed with high selectivity (Table 3,
entry 3). Cyclization of the a,b-unsubstituted enyne acetal
4d gave a similar result but required a longer reaction time
(14 h vs. 5 h, Table 3, entry 4), thus suggesting that desilyla-
tion most likely occurred after the Nazarov cyclization[30,31]
Finally, the toluenesulfonamide 4e afforded cyclopenta[c]-
azepinones 5e and 6e with a moderate combined yield
(Table 3, entry 5).
We believe the mechanism of the tandem carbocycliza-
tions of enyne acetals 1 and 4 most likely starts with the
Brønsted acid induced formation of the electrophilic oxonium
species A (Scheme 2).[32] This cationic species would undergo
standard heteroalkyne metathesis to the oxete intermediate B
(through [2+2] cycloaddition),[17a] which upon ring opening
would give the divinyl ketone C. Subsequently, the Brønsted
acid would induce a stereospecific Nazarov reaction (4peÀ
electrocyclization)[18] of this unpolarized[25d] dienone C to give
one of two possible oxyallyl cations, D and E, depending
whether the starting compound had been b or a substituted.
Proton elimination and enol-to-ketone tautomerization
[a] Conditions A: 4 (0.3 mmol), HBF4 (0.9 mmol), CH2Cl2 (3 mL), 08C,
20–60 min. [b] X=C(CO2Me)2. [c] Only the major regioisomer is shown.
[d] Combined yields of the isolated products. [e] Conditions B: 4
(0.3 mmol), TFA (6.0 mmol), DCE (3 mL), RT, 30 min. [f] Conditions B
but at 908C. [g] A low yield of the cyclic enone 2k (15%, 24%) was also
obtained in the tandem carbocyclization of 4c and 4d, respectively.
TMS=trimethylsilyl.
would finally afford the observed bicyclo[5,3,0]decenones 2,
3, 5, and 6.
As expected, the regioselectivity of the reaction seems to
depend to a large extent on the position of the alkene
substituent, a or b, and on the nature of the tether, through its
influence on the conformation of the oxyallyl cation inter-
mediate.[6f,18b–e,33] In most cases, it is the single-bond-fused
product that is favored.
Finally, we investigated the effect of linked a and b
substituents by replacing the terminal alkene group with
thiophene systems (Scheme 3).[34] To our delight, the attrac-
tive tricyclic systems 8 and 10 were obtained in good yields
from the 2- and 3-thiophenyl species 7 and 9, respectively.
In summary, we have developed a new, simple, and
versatile method for the synthesis of hydroazulenones from
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from enyne acetals to hydroazulenones.
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Scheme 3. Preparation of hydroazulenothiophenones 8 and 10 by
tandem carbocyclization of enyne acetals 7 and 9, respectively.
linear enyne acetals. This metal-free procedure may be
described as taking place through tandem Brønsted acid
promoted carbocyclizations, a regioselective exo-carbocycli-
zation previously applied to alkynals,[16] and a stereospecific
Nazarov cyclization. The new approach complements pre-
viously described methods based on metal-catalyzed cycliza-
tions. Its full scope is currently being further investigated by
application to a number of challenging cyclizations.
Received: July 23, 2012
Published online: November 4, 2012
Keywords: Brønsted acids · carbocyclizations · enynes ·
.
hydroazulenone · Nazarov cyclizations
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monitoring by 1H NMR spectroscopy (controlled amounts of
HBF4 added in CD2Cl2) showed that a faster but more-complex
reaction occurred for the trans isomer (1b) than for the cis
isomer (1a) thus most probably indicating, a less controlled
reaction.
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[28] However, when (E)-1h was employed (not shown), a 3:1 ratio
was obtained, with moderately good yield. See the Supporting
Information for details.
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[32] For the alternative route from 1 to divinyl ketone C that is shown
in Scheme 2 (direct addition of the activated alkyne to the
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