Unlocking the 5-exo Pathway with the AuI-Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes

Article abstract of DOI:10.1002/chem.202001296

The first general regio- and stereoselective 5-exo gold(I)-catalyzed alkoxycyclization of a specific class of 1,5-enynes such as 1,3-dien-5-ynes has been described, despite 1,5-enynes being known to almost invariably proceed via endo cyclizations under gold-catalysis. The configuration of the terminal alkene in the starting 1,3-dien-5-yne plays a crucial role on the regiochemical outcome of the reaction. A wide variety of interesting alkoxy-functionalized alkylidenecyclopentenes have been synthesized from 1-monosubstituted (E)-1,3-dien-5-ynes. On the contrary, the corresponding Z isomers evolve affording formal 6-endo cyclization products. In addition, mechanistic exploration supports a highly stabilized carbocation as a key intermediate instead of a highly constrained cyclopropyl gold carbene from E isomers, and also accounts for the well differentiated reactivity observed between both E/Z geometrical isomers as well as for the stereochemical outcome of the reaction.

Full text of DOI:10.1002/chem.202001296

Accepted Article
Accepted Article
Title: Unlocking the 5-exo Pathway with the Au(I)-Catalyzed
Alkoxycyclization of 1,3-Dien-5-ynes
Authors: Cintia Virumbrales, Samuel Suárez-Pantiga, Marta Marín-
Luna, Carlos Silva López, and Roberto Sanz
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To be cited as: Chem. Eur. J. 10.1002/chem.202001296
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01/2020

10.1002/chem.202001296
Chemistry - A European Journal
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Unlocking the 5-exo Pathway with the Au(I)-Catalyzed
Alkoxycyclization of 1,3-Dien-5-ynes
Cintia Virumbrales,[a] Samuel Suárez-Pantiga,[a] Marta Marín-Luna,[b,c] Carlos Silva López,*[b] and
Roberto Sanz*[a]
[a]
Dr. C. Virumbrales, Dr. Suárez-Pantiga, Prof. Dr. R. Sanz
Área de Química Orgánica. Departamento de Química
Universidad de Burgos
Pza. Misael Bañuelos, s/n, 09001-Burgos. Spain
E-mail: rsd@ubu.es
[b]
[c]
Dr. M Marín-Luna, Dr. C. Silva-López
Departamento de Química Orgánica and CITACA, Agri-Food Research and Transfer Cluster, Campus da Auga
Universidade de Vigo
32004-Ourense, Spain
Current address: Dr. M. Marín-Luna
Departamento de Química Orgánica
Regional Campus of International Excellence “Campus Mare Nostrum”, Universidad de Murcia
Campus de Espinardo, 30100-Murcia, Spain
Supporting information for this article is given via a link at the end of the document.
Abstract: The first general regio- and stereoselective 5-exo gold(I)-
catalyzed alkoxycyclization of a specific class of 1,5-enynes such as
1,3-dien-5-ynes has been described, despite 1,5-enynes being
known to almost invariably proceed via endo cyclizations under gold-
catalysis. The configuration of the terminal alkene in the starting 1,3-
dien-5-yne plays a crucial role on the regiochemical outcome of the
cyclizations, is strongly favoured over the formation of
bicyclo[2.1.0]pentanes, resulting from the alternative exo
pathway.[7]
Along the last years, there has been some controversy about the
nature of the reactive intermediates, mainly regarding the Au−C
bond, in this type of gold-catalyzed cyclizations, ranging from
simple carbocations till gold carbene complexes.[8] Based on
thorough mechanistic studies, Fürstner suggested that
organogold intermediates have a highly cationic character.[8a,c]
Toste and Goddard proposed a description for the gold carbene
bonding in which strongly -donating and weakly -acidic
ligands, such as NHCs, were expected to increase the carbene-
like reactivity.[9] Recently, Echavarren has characterized
spectroscopically cationic gold(I) carbenes for first time in
solution.[10] Moreover, DFT calculations have been carried out to
rationalize some of the observed experimental results,[11] and the
direct isolation or in situ detection of intermediates is also
helping to shed light on this matter.[12]
reaction.
A
wide variety of interesting alkoxy-functionalized
have been synthesized from 1-
alkylidencyclopentenes
monosubstituted (E)-1,3-dien-5-ynes. Contrary, the corresponding Z
isomers evolve affording formal 6-endo cyclization products. In
addition, mechanistic exploration supports
a highly stabilized
carbocation as a key intermediate instead of a highly constrained
cyclopropyl gold carbene from E isomers, and also accounts for the
well differentiated reactivity observed between both E/Z geometrical
isomers as well as for the stereochemical outcome of the reaction.
Introduction
In this field we have described the gold-catalyzed
methoxycyclization reactions of 1,1-disubstituted 1,3-dien-5-
ynes[13] that selectively undergo 5-endo cyclizations,[14] leading
to 5-alkoxymethyl cyclopentadienes (Scheme 1b).[15] Related
ortho-(alkynyl)styrenes, a particular type of 1,3-dien-5-ynes, also
led to interesting cycloisomerization processes under gold-
catalysis triggered by an initial 5-endo cyclization (Scheme
1b).[16] Additionally, we have recently reported the regio and
diastereospecific 5-endo nucleophilic cyclization of -
monosubstituted o-(alkynyl)styrenes (Scheme 1c).[17] In our
experience, the involved gold intermediates are well described
as homoallylically stabilized carbocations with different degrees
of gold carbene-type contribution mainly due to the substrate
structure but not to the ancillary ligand electronic properties.
Herein, we report the first general example of a gold(I)-catalyzed
5-exo cyclization of 1,5-enynes consisting on the
alkoxycyclization of 1-monosubstituted 1,3-dien-5-ynes[18] that
takes place in a regio- and diastereospecific manner thus initially
supporting the intermediacy of an elusive cyclopropyl gold
carbene on a strained bicyclo[2.1.0]pentane skeleton (Scheme
1d).
The gold-catalyzed activation of 1,n-enynes toward the inter or
intramolecular attack of nucleophiles is nowadays a well-
established strategy for the construction of densely
functionalized carbocyclic scaffolds, which usually operates in a
highly selective manner.[1] Whereas 1,6-enynes could react
through 5-exo-dig or 6-endo-dig processes,[2] mainly depending
on the terminal or internal nature of the alkyne and the
substituents of the alkene, as well as the nature of the metal
ligands, 1,5-enynes almost exclusively evolve via endo-dig
cyclizations.[3] Moreover, the addition of nucleophiles on enynes,
mainly the addition of alcohols and water (alkoxy- and
hydroxycyclizations), nicely expands the versatility of gold(I)-
catalyzed reactions allowing the preparation of functionalized
carbo and heterocyclic compounds.[4] This reactivity is likely
favoured by the low oxophilicity of gold(I) complexes. Despite of
the abundant studies in gold-catalyzed cyclization of 1,5-enynes,
the elusive 5-exo cyclization was described only in two examples
and merely as a by-product of the most favored endo pathway
(Scheme 1a).[5,6] This scenario is likely due to the fact that the
generation of bicyclo[3.1.0]hexanes, derived from endo
1
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10.1002/chem.202001296
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Scheme 2. Initial approach and preliminary result with enyne (E)-1a.
this methoxycyclization, only one was obtained indicating an
exquisite control of the stereoselectivity of the reaction.
Based on this result, we decided to evaluate a variety of gold(I)
catalysts (Table 1). First, different bis(triflimidate) gold(I)
complexes were tested (entries 1–4). Although the 5-exo
product was obtained as single stereoisomer in all cases,
phosphine-based ligands (entries 2–4) performed less efficiently
than a NHC-carbene ligand such as IPr (entry 1), and only the
use of JohnPhosAuNTf2 achieved comparable yields (entry 3).
Nevertheless, a related cationic acetonitrile gold(I) complex
bearing a bulkier biarylphosphine like XPhos (entry 5) was
proved to be less efficient. We also evaluated the nature of the
counteranion by treating IPrAuCl with silver salts as chloride
scavengers (entries 6–9). Best results were obtained by using
tosylate and particularly hexafluoroantimoniate as weakly
coordinating counteranion providing access to the desired 5-exo
product almost quantitatively (entries 8 and 9). The catalytic
system IPrAuCl/AgSbF6 has demonstrated to be highly efficient
even in toluene (entry 10) or neat methanol (entry 11).
Scheme 1. 5-endo Nucleophilic additions to 1,5-enynes (well-known reactivity).
Alkoxycyclizations of 1,1-disubstituted-1,3-dien-5-ynes and -monosubstituted
o-(alkynyl)styrenes (our prior work). 5-exo Alkoxycyclizations of (E)-1-
monosubstituted 1,3-dien-5-ynes (this work).
Results and Discussion
We selected dienyne 1a, bearing an internal alkyne moiety, as
model substrate for which the expected endo-cyclization would
give rise to a cyclopropylgold carbene intermediate A that could
lead to different products derived from formal 6-endo or 5-endo
cyclization modes. Considering our previous results (see
Scheme 1b,c),[15-17] -methoxybenzyl cyclopentadiene 2´a
should be the preferred product (Scheme 2). An alternative exo-
cyclization would lead to a highly strained cyclopropylgold
carbene intermediate B and was unprecedented in the literature
(Scheme 2).
Surprisingly, when we submitted (E)-1a to our standard
methoxycyclization conditions under gold-catalysis,[17] we
selectively obtained methoxyalkylidencyclopentene derivative 2a
instead of the cyclopentadiene derivative 2´a resulting from the
expected 5-endo alkoxycyclization (Scheme 2). This result
clearly suggested that a 5-exo cyclization had taken place. In
addition, although four diastereoisomers could be generated in
Table 1. Optimization of the gold-catalyzed methoxycyclization of (E)-1a.[a]
Entry
Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Conversion[b]
Yield [%][b]
1
2
3
4
IPrAuNTf2
100
60[c]
100
100
77
34
37
69
Ph3PAuNTf2
(t-Bu)3PAuNTf2
JohnPhosAuNTf2
2
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substituents R3 on the internal alkene of the starting enyne (E)-1.
In this regard, modification of the cyclohexane unit into a
tetrahydropyran or N-tosyl-tetrahydropyridine ring provides
5
XPhos(MeCN)AuSbF6
IPrAuCl/AgNTf2
IPrAuCl/AgBF4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
MeOH
100
100
100
100
100
100
100
27
64
67
85
90
88
79
6
access
to
the
hydrocyclopenta[c]pyran
(2p,q)
and
7
hydrocyclopenta[c]pyridine (2r) cores in good yields. In addition,
the X-ray structure of compound 2r could be obtained further
supporting the proposed stereochemistry.[20] Importantly, the
presence of a cyclic structure on the internal alkene in the
starting enyne (E)-1 is not required to promote the reaction as
demonstrated with the 5-exo methoxycyclization of linear enynes
8
IPrAuCl/AgOTs
IPrAuCl/AgSbF6
IPrAuCl/AgSbF6
IPrAuCl/AgSbF6
9
10
11
1t
and
1u,
which
afforded
the
expected
methoxyalkylidencyclopentene derivatives 2t and 2u in high
yields (Scheme 3).
[a] Reaction conditions: (E)-1a (0.1 mmol), MeOH (0.5 mmol), catalyst (3
mol%), solvent (1 mL), RT, 20 min. [b] Calculated by 1H NMR using 1,3,5-
trimethoxybenzene as internal standard. [c] Complete conversion was
achieved after 1 h.
Next, other alcohols other than methanol were also tested as
nucleophiles (Table 2). Under standard reaction conditions, a
diverse range of alkoxyalkylidencyclopentene derivatives 4 are
easily obtained in good yields by reaction of model enyne (E)-1a
with simple primary alcohols such ethanol or butanol (entries 1
and 2), as well as others more functionalized such as allyl
alcohol or ethyleneglycol, bearing an alkene or an extra hydroxyl
group, respectively (entries 3 and 4). To further demonstrate the
general applicability of these alcohols in the 5-exo cyclization,
selected enynes (E)-1 bearing different R2 substituents were
evaluated as reaction partners (entries 5–9). In all cases the
reaction proceeds efficiently. In addition, the cyclohexane ring is
not required to promote the 5-exo cyclization, as linear dienyne
1t successfully underwent the alkoxycyclization with ally alcohol
(entry 9).
With the optimized reaction conditions in hand we proceeded to
study a wide range of enynes (E)-1 (Scheme 3). Aryl, heteroaryl,
alkyl, and even a carboxylate substituent on the alkyne are well
tolerated and the reaction proceeds smoothly (2a-d). Although
the terminal alkyne 1e also evolved through the 5-exo cyclization
pathway, the formation of the expected methoxyalkylidene 2e
product was not observed. Instead, isomerization of the double
bonds into inner positions takes place affording 2’e along with a
minor amount of ketone 3, derived from a competitive addition of
methanol to the terminal alkyne and subsequent hydrolysis
(Scheme 3). Curiously, when the starting dienyne (E)-1f, bearing
a
TMS-substituted alkyne, was used, compound 2e was
obtained.[19] We also evaluated the nature of the substituent on
the terminal alkene moiety (R2). The transformation has shown
to be general with phenyl rings bearing different functional
groups 2g-j, as well as other arenes such as naphthyl 2k or
heteroarenes such as thienyl 2l. Remarkably, when R2 is a
methyl group the reaction also proceeds, with only a minor loss
of the stereochemical control of the process, giving rise to 2m in
77%. The methoxycyclization was successfully accomplished
with other alkyl groups as R2 substituents such as cyclopropyl,
2n, or even with dienyne 1o, possessing a hydroxymethyl
substituent (Scheme 3). We also varied the nature of
Scheme 3. 5-exo Methoxycyclization of 1,3-dien-5-ynes (E)-1. Synthesis of alkylidencyclopentenes 2a-u. Yields are of isolated material after column
chromatography. [a] The starting enyne 1 was used as a 20:1 mixture of geometrical isomers. [b] Obtained as a ca. 14:1 mixture of diastereoisomers.
3
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Table
2.
Alkoxycyclization
reactions
of
(E)-1.
Synthesis
of
alkoxyalkylidencyclopentenes 4.[a]
Scheme
4.
Cyclization
of
dienyne
(E,Z)-1s.
Isolation
of
methoxyalkylidencyclopentene 2s and tetrahydronaphthalene 5s.
Entry Enyne R2
R3
R4
Product Yield [%][b]
tuent R2 of the enyne possesses a minimal influence. For
instance, phenyl group provides unaltered ratio (entries 1, 4 and
5). When halogen- or methoxy-substituted aryl rings were tested
only a slightly changed ratio of products was detected. Even
when R2 is a less bulky group, such as methyl (entries 3 and 6),
the 2:5 proportion is determined by the E/Z ratio of the starting
enyne 1.
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1h
1h
1k
1k
1t
Ph
Ph
Ph
Ph
−(CH2)4−
−(CH2)4−
−(CH2)4−
−(CH2)4−
Et
4aa
4ab
61
72
70
74
71
68
60
61
79
n-Bu
CH2=CHCH2 4ac
HO-(CH2)2
Et
4ad
4ha
4hd
4kb
4kd
4-MeOC6H4 −(CH2)4−
4-MeOC6H4 −(CH2)4−
HO-(CH2)2
n-Bu
Table 3. Au(I)-catalyzed cyclization of dienynes (E/Z)-1. Selective access to
methoxyalkylidencyclopentenes 2 and tetrahydronaphthalenes 5.[a]
1-naphthyl
1-naphthyl
Ph
−(CH2)4−
−(CH2)4−
Et
HO-(CH2)2
CH2=CHCH2 4tc
[a] Reaction conditions: (E)-1 (0.3 mmol), R4OH (0.6 mmol), IPrAuCl/AgSbF6
(3 mol%), CH2Cl2 (1 mL), RT, 20 min. [b] Isolated yield after column
chromatography.
Yield [%][c]
Entry 1 R2
R3
E/Z
t (min) 2:5[b]
2
5
38
64
Taking into account our recent report about the diastereospecific
alkoxycyclization of -monosubstituted o-(alkynyl)styrenes,[17] in
which the configuration of the starting alkene was transferred to
the final cyclized product, we wondered at this point what could
be the result when using starting dienynes 1 as a mixture of
geometrical isomers. So, as enyne 1s was obtained as a 7/1
mixture of E/Z isomers, we decided to subject this product to the
reaction conditions to explore the influence of the configuration
of the terminal alkene on the reaction outcome. Interestingly, two
well-differentiated main products were observed: the 5-exo
methoxycyclized product 2s and the tetrahydronaphthalene
derivative 5s resulting from a formal 6-endo cycloisomerization
(Scheme 4). These compounds were obtained in a similar ratio
corresponding to the mixture of geometrical isomers of the
starting enyne 1s. Formation of compound 5s could be
reasoned by a direct 6-endo cycloisomerization or alternatively
by an initial 5-endo cyclization affording a bicyclo[3.1.0]hexane
intermediate (see Scheme 2), which rapidly evolves through ring
expansion followed by aromatization to deliver the
tetrahydronaphthalene derivative, similarly to the reported
cycloisomerization reaction of the related 1,1-disubstituted 1,3-
dien-5-ynes.[14a] According to this result, we hypothesized that
enyne (E)-1 would provide exclusively the 5-exo product 2
whereas, by contrast, tetrahydronaphthalene 5 would arise from
the Z-isomer of 1.
1
2
3
4
5
6
7
8
1a Ph
−(CH2)4−
1.2/1
1/10
1.2/1
10
60
10
10
10
10
60
240
1.3/1 41
1/8
1i 3-MeOC6H4 −(CH2)4−
9
1m Me
−(CH2)4−
1.1/1 40[d] 35
1s Ph
−CH2(NTs)(CH2)2− 1/20
1/20
−
68
33
1t Ph
Et
2/1
1.7/1 51
1v Me
Et
1/1.2
3/1
1/1.6 33[d] 47
1w 3-ClC6H4
1x 2-FC6H4
−(CH2)4−
−(CH2)4−
2.5/1 51
2.5/1 52
21
33
2.5/1
[a] Reaction conditions: (E/Z)-1 (0.3 mmol), MeOH (1.5 mmol),
IPrAuCl/AgSbF6 (3 mol%), CH2Cl2 (1 mL), RT. [b] Calculated by 1H NMR in the
crude reaction mixture. [c] Isolated yield after column chromatography. [d]
Obtained as a ca. 13:1 mixture of diastereoisomers.
In summary, according to the observed results, there is a
correlation between the proportion of 5-exo and 6-endo products
and the ratio of E/Z geometrical isomers of the starting enyne 1.
The position of the substituent in the terminal alkene moiety
therefore plays a decisive role into favouring the 5-exo or the 6-
endo pathway. Whereas (E)-enynes prefer the 5-exo cyclization
mode affording methoxyalkylidencyclopentene 2, the (Z)-enynes,
similarly to their parent 1,1-disubstituted 1,3-dien-5-ynes,[14a]
give rise to the benzene derivatives 5.
Aiming to shed light onto the different reactivity displayed by 1,3-
dien-5-ynes (E)-1 and (Z)-1 and to provide reasonable
mechanisms ruling their transformations toward compounds 2
and 5, respectively, we performed a thorough computational
study at the DFT level. We are including here only the lowest
energy mechanistic pathway and a brief account of the key
steps of the alternative routes, i.e. 5-exo, 5-endo and 6-endo
To test our hypothesis, the reactivity of a selection of dienynes 1,
as mixtures E/Z isomers, was studied under the standard
protocol (Table 3). In all cases, both compounds 2 and 5 were
obtained in a proportion comparable to the E/Z ratio of the
starting material, and only minimal differences are noticeable.
Remarkably, some examples implied a significant increase in the
reaction time. These results clearly indicate that the E/Z ratio
determines the final outcome. Notably, the nature of the substi-
4
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cyclization modes of the starting gold-complexes (SCE and SCZ)
and of the role of methanol present in the reaction medium
(Scheme 5). Full mechanistic disclosure with greater level of
detail is provided in the Supporting Information.
overcome an energy barrier of 92 kJ mol−1 (TS1′) hence
resulting non-competitive with respect to alternative computed
pathways.
The mechanism would then evolve with the interception of the
carbocation intermediate E1 by a methanol molecule. Our
results envisaged a clear preference between the two suitable
approach trajectories of methanol onto the most reactive allylic
position C2. Thus, methanol would approach through the
opposite side of the molecular plane in which the methyl group is
placed since it is less cluttered therefore minimizing the steric
In the case of (E)-1, after the coordination of the gold complex to
the alkyne moiety forming SCE, the initial 5-exo transition
structure TSE5exo leading to the intermediate E1 is less energetic
in 14.3 and 21.3 kJ mol−1 than those involving a 5-endo
(TSE5endo) and 6-endo (TSE6endo) cyclization mode, respectively.
We will discuss later the reasons behind this preference. An
analysis of the Wiberg indices at E1 revealed that this structure
should be envisioned as a hybrid of two resonant forms of the
gold-carbene A and the allylic carbocation B (Scheme 6a). This
may be the main reason for the non-observation of 5-exo
cyclizations of structurally related -monosubstituted o-
(alkynyl)styrenes, since the stability due to aromaticity would be
jeopardized during the cyclization step, incurring in a higher
energetic penalty.[17] It is noteworthy that our computational
studies predict that the strained cyclopropyl carbene isomer, the
bicyclo[2.1.0]pentane intermediate E1′ (123.8 kJ mol−1), would
not be formed during the reaction course (Scheme 6b). In fact,
we computed this isomerisation step finding that it requires to
contacts at the transition structure (GTS = 42.7 kJ mol−1 vs.
E2
GTS’E2 = 67.9 kJ mol−1). In line with the experimental evidence,
the computed trajectory selectivity in the methanol attack affords
the alkoxycyclopentene derivative E3 in which both methoxy and
methyl group are placed in trans relative spatial disposition.
Interestingly, both TSE2 and E3 are almost isoenergetic,[21] the
reverse process, the departure of MeOH being a competitive
step. However, this reversibility is satisfactorily solved with the
excess of MeOH (2−5 equiv) in the reaction medium. The
subsequent proton capture by the Tf2N− counteranion at the E3
affords intermediate E4 which finally affords diastereoisomer 2a
after a protodeauration step.
Scheme 5. Proposed mechanism for the gold(I)-mediated formation of the alkylidenecyclopentene E4 and the tetrahydronaphthalene Z4 from the 1,3-dien-5-ynes
SCE and SCZ at the PCM(DCM)/M06/Def2-SVP theoretical level. Gibbs free energies are reported in kJ mol−1 (1 atm and 298 K), relative to SCE. Tf2N− was
chosen as counteranion to allow for a comparative analysis with the computational results of previous studies.[17] Colours refer to the alternative initial cyclizations:
5-exo (red), 5-endo (blue), 6-endo (green).
5
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Figure 1. Computed transition structures TSE5exo and TSZ5exo. Distances are
shown in angstroms (Å) and angles in degrees (°).
pointed as a key factor in determining the cyclization modes in
gold-catalyzed enyne cycloisomerization reactions,[8] rarely steric
factors have been decisive. Remarkably, in this case, the
position (E/Z) of the substituent has a crucial role in determining
the cyclization mode.
Scheme 6. a) Resonance forms of intermediate E1; b) computed
transformation of intermediate E1 into the strained cyclopropyl carbene isomer
E1′. Energies are shown in kJ mol−1 and distances in angstroms (Å).
For the sake of completeness, we also explored the influence of
the size of the substituent at the alkene moiety and the presence
of the cyclohexene fragment in the bicyclic system in the
energetic barriers of the three possible initial cyclization modes
(Table 4). We observed that the 5-exo cyclization mode is
favourable in all (E)-1,3-dien-5-enynes studied regardless of the
substitution at C1. Remarkably, the energetic barrier decreases
as the size of the substituent increases. This could be related to
the electron delocalization along the polyene at the transition
structure, which is greater when a phenyl group is present.
Additionally, such electron delocalization would be the main
reason behind the preference of 5-exo with respect to the 5-
endo transition structure, where the electron delocalization is
lower. In all cases, the transition structure involving a 6-endo
cyclization mode is the highest energy one. Likewise, the 5-endo
cyclization is preferred rather than the 5-exo for (Z)-
diastereoisomers due to steric congestion around the reactive
site. Interestingly, and contrary to the observed tendency with
(E)-enynes, (Z)-enynes with bulkier substituents such as phenyl
group (Table 4, entry 3) have a higher energetic barrier for the 5-
exo cyclization over the related (Z)-methyl substituted enyne
despite of the electron delocalization effect of this substituent.
This clearly supports that TSZ5exo, bearing a substituent in
position in, is considerably much more exposed to steric factors
than TSE5exo possessing the substituent in position out. We also
decided to study the possible effect of the cyclohexane moiety
(Table 4, entry 4). In absence of a cyclic structure including the
central double bond, computational results predict that the 5-exo
cyclization is even easier for the corresponding (E)-1 whereas
similar energetic barriers are computed for the 5-endo transition
structure (entries 2 vs. 4).
On the contrary, for the (Z)-1 dienyne, the 5-exo cyclization of
SCZ is disfavoured compared to the alternative 5-endo mode
(GTS
= 104.0 kJ mol−1 and GTS
= 88.0 kJ mol−1,
Z5exo
Z5endo
respectively). The transition structure for
a
seemingly
straightforward 6-endo cyclization could not be located on the
potential energy surface. At this point, the resulting bicycle Z1 is
prone to either react with a methanol molecule or undergo a ring
expansion. Opposite to that observed for o-(alkynyl)styrene
compounds,[17] the ring expansion process, involving the
cleavage of the C2−C6 single bond on route to Z3, is highly
favoured with respect to the nucleophilic attack by methanol
onto C1 (TS = 37.0 kJ mol−1 and GTS’ = 74.0 kJ mol−1,
Z2
Z2
respectively). This can easily be justified resorting to the gain of
aromaticity at the 6-memberred ring occurring after the
deprotonation of Z3, which affords the tetrahydronaphthalene
derivative, Z4. Then, upon protodeauration, this latest
intermediate would afford tetrahydronaphthalene 5.
Our calculations revealed that for both simulated reaction
profiles the initial cyclization step is the rate-determining: the 5-
exo cyclization involving the (E)-dienyne-gold complex SCE and
the 5-endo one for its diastereoisomer.
In this scenario, we wondered why the 5-exo cyclization is not
competitive for the (Z)-1 species under gold(I)-catalysis. To
answer this question, we analyzed both transition structures for
the 5-exo cyclization, TSE5exo and TSZ5exo (Figure 1).
Both TSE5exo and TSZ5exo are found to be structurally very close
and with characteristics reminiscent of a C=C double bond
attack to the central carbon atom of a gold-activated allene.[22]
The forming C−C bond lengths are comparable (2.13 and 2.17 Å,
for TSE5exo and TSZ5exo, respectively), however, the spatial
orientation of the methyl group differs notably. Whereas in
TSE5exo the methyl group at C1 is located out of the forming ring,
that group turns in in the case of TSZ5exo, therefore increasing
the steric hindrance around the reactive site. This steric factor
would be enough to avoid the 5-exo cyclization of (Z)-1, as well
as in the cases of related 1,1-dialkyl substituted 1,3-dien-5-ynes,
as reported previously,[14] and to favour the 5-endo alternative
that is less sterically congested. Although electronic effects
derived from the substitution pattern of the alkene have been
6
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Table 4. Gibbs free energies (kJ mol−1) of the transition structures of the three
possible cyclization modes of gold(I)-activated 1,5-enynes (E)-1 and (Z)-1. E
and Z refers to the stereoisomerism of the C1−C2 double carbon bond at the
initial 1,5-enyne. Energies are relative to the corresponding previous
intermediate SC.
Entry
1
Enyne
1a
R2
Product
6a
Yield [%][b]
68
Ph
2
1j
4-ClC6H4
2-Th
6j
62
3
1l
6l
63
4[c]
5
1m
1n
Me
6m
6n
36[d,e]
61
c-C3H5
2-FC6H4
6[f]
1x
6x
47[d]
G5-exo
G5-endo
G6-endo
Entry
R2
R3
E
Z
E
Z
E
Z
[a] Reaction conditions: (E)-1 (0.3 mmol), MeOH (1.5 mmol), IPrAuCl/AgSbF6
(3 mol%), DCM (1 mL), RT, 20 min; then, DDQ (1.5 mmol), RT, 1h. [b] Isolated
yield after column chromatography. [c] Used as a 1.2:1 mixture of (E/Z)-
isomers. [d] The corresponding tetrahydronaphthalenes 5m and 5x were also
obtained derived from the corresponding (Z)-1. [e] Obtained as a ca.10:1
mixture of geometrical isomers likely due to subsequent isomerisation of the
final unsaturated ketone. [f] Used as a 2.5:1 mixture of (E/Z)-isomers.
1
2
3
4
H
−(CH2)4−
−(CH2)4−
−(CH2)4−
Me
79.6
105.6
96.7
[a]
[a]
[a]
Me
Ph
Me
72.7
69.3
56.1
104.0
112.0
96.5
87.3
86.4
87.5
88.0
91.1
89.6
94.0
94.0
95.3
−
−
−
Conclusion
[a] Computational results predict that the cyclization does not proceed
involving this transition structure.
Herein we have described the first general 5-exo Au(I)-catalyzed
alkoxycyclization of a specific class of 1,5-enynes, such as 1.3-
dien-5-ynes, in a selective manner. This chemistry has been
hereby exploited to form a wide range of densely decorated
(bi)cyclic systems from a variety of 1-monosubstituted (E)-1,3-
dien-5-ynes. Furthermore, our protocol is compatible with
substituents of different nature at almost all possible positions of
the starting material and it even allows the formation of
heterocyclic systems. Mechanistic exploration has provided a
rationale for this unexpected chemistry, offering a complete
picture which explains the different reactivity of 1,3-dien-5-ynes
depending on their substitution pattern and the configuration of
the terminal alkene. Theoretical calculations has suggested the
intermediacy of a different organogold compound instead of
previously proposed bicyclo[2.1.0]pentane intermediate. This
species has a strong carbocationic contribution. This chemistry
has been found to be governed by a delicate balance of electron
delocalization and steric factors resulting in a manifold of
competing pathways which allows the reaction to be drastically
steered to the formation of different products via subtle changes
at the starting material. Remarkably the (Z)-1,3-dien-5-ynes
react into a divergent pathway affording tetrahydronaphthalene
6-endo products, so a change in the geometry of the terminal
double bond determines the cyclization mode. The origin of this
differential reactivity was disentangled pointing to steric factors
in the positions in and out of the key decisive 5-exo intermediate.
Finally, two-step one-pot derivatization of the 5-exo products is
possible and it has been exemplified through the formation of
alkylidenecyclopentenones, a desirable structural motif.
Finally, we explored a likely derivatization of new compounds 2.
Into this regard, we envisioned that an oxidation of the methoxy-
substituted allylic position will provide access to valuable 2-
cyclopentenone derivatives. Initial tests with 2a demonstrated
that the use DDQ as oxidant at room temperature affords the
desired 4-alkylidenecyclopentenone 6a in high yields (Scheme
7).[23]
Scheme 7. Oxidation of methoxyalkylidencyclopentene 2a. Synthesis of
unsaturated ketone 6a.
With this result in hand, we decided to evaluate the feasibility of
a one-pot procedure to synthesize 4-alkylidenecyclopentenones
in one single operational step from enynes 1. So, after the initial
methoxycyclization, the oxidation would take place sequentially
upon addition of DDQ to the reaction media (Table 5). To our
delight this protocol was successful in providing a variety of
interesting 4-alkylydinecyclopentenones 6. Enynes 1 bearing on
the alkene moiety an aryl (neutral or moderately deactivate,
entries 1, 2, and 6), a thienyl (entry 3) or a (cyclo)alkyl group
(entries 4 and 5) are well tolerated. As expected, when a mixture
of E/Z-isomers was used, the tetrahydronaphthalenes 5m and
5x, derived from the endo cyclization of the corresponding
enynes (Z)-1 (entries 4 and 6), were also observed.
Acknowledgements
Table 5. Au(I)-catalyzed methoxycyclization of selected enynes 1 followed by
DDQ-mediated oxidation. One-pot synthesis of unsaturated ketones 6.[a]
We gratefully acknowledge Ministerio de Ciencia e Innovación
and FEDER (CTQ2016-75023-C2-1-P and 2-P), Junta de
Castilla y León and FEDER (BU291P18) and Xunta de Galiza
(ED431C 2017/70 and ED431E 2018/07) for financial support. S.
S.-P. thanks Junta de Castilla y León and FEDER for a
postdoctoral contract.
7
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10.1002/chem.202001296
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FULL PAPER
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8
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Entry for the Table of Contents
Whereas endo processes are ubiquitous for the cyclizations of 1,5-enynes under Au(I)-catalysis, this work describes the first general
5-exo alkoxycyclization. (E)-1,3-Dien-5-ynes undergo a regio- and stereoselective 5-exo Au(I)-catalyzed cyclization delivering
alkylidencyclopentenes, whereas their Z-isomers evolve via a formal 6-endo cyclization. DFT calculations predict that a highly
stabilized carbocation plays a crucial role in the outcome of the process.
9
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