Gold(i)-catalyzed nucleophilic cyclization of β-monosubstituted: O -(alkynyl)styrenes: A combined experimental and computational study

Article abstract of DOI:10.1039/c9ob02126d

The stereospecific gold(i)-catalyzed nucleophilic cyclization of β-monosubstituted o-(alkynyl)styrenes to produce C-1 functionalized 1H-indenes including challenging substrates and nucleophiles, such as β-(cyclo)alkyl-substituted o-(alkynyl)styrenes and a variety of alcohols as well as selected electron-rich aromatics, is reported. DFT calculations support the stereochemical outcome of the process that involves the formation of a key cyclopropyl gold carbene intermediate through a regiospecific 5-endo cyclization.

Full text of DOI:10.1039/c9ob02126d

Organic &
Biomolecular Chemistry
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Gold(I)-catalyzed nucleophilic cyclization of
β-monosubstituted o-(alkynyl)styrenes: a
combined experimental and computational study†
Cite this: Org. Biomol. Chem., 2019,
17, 9924
a
Cintia Virumbrales, a Marta Solas, a Samuel Suárez-Pantiga,
b
Manuel A. Fernández-Rodríguez, ‡a Marta Marín-Luna,
Carlos Silva López b,c and Roberto Sanz
*
a
The stereospecific gold(I)-catalyzed nucleophilic cyclization of β-monosubstituted o-(alkynyl)styrenes to
produce C-1 functionalized 1H-indenes including challenging substrates and nucleophiles, such as
β-(cyclo)alkyl-substituted o-(alkynyl)styrenes and a variety of alcohols as well as selected electron-rich
aromatics, is reported. DFT calculations support the stereochemical outcome of the process that involves
the formation of a key cyclopropyl gold carbene intermediate through a regiospecific 5-endo cyclization.
Received 1st October 2019,
Accepted 4th November 2019
DOI: 10.1039/c9ob02126d
rsc.li/obc
divergent reaction pathways are observed depending on the sub-
stitution pattern of the enynes.5 In this area, our group has been
Introduction
The ability of gold(I) to act as a soft carbophilic Lewis acid to studying in the last few years the behaviour of o-(alkynyl)sty-
activate alkynes for a subsequent inter or intramolecular renes, a particular type of 1,3-dien-5-yne.6 Although most of the
nucleophilic attack has led to the development of a plethora of previously reported studies on these substrates are devoted to
useful synthetic methodologies during the last few years.1
the synthesis of naphthalene derivatives through 6-endo
In this field, cycloisomerizations of enynes are one of the cyclizations,7 in 2010 we first showed that 5-endo cycloisomeriza-
most representative transformations catalyzed by gold com- tions and alkoxycyclizations are also possible by using
plexes, allowing the construction of complex structures under β,β-disubstituted styrenes.8 With this methodology, alkoxy- and
very mild conditions usually involving simple and readily avail- hydroxy-functionalized indene derivatives, which are relevant
able starting materials.2 Favoured by the low oxophilicity of scaffolds due to their appearance in biologically active molecules
gold(I) complexes, the nucleophilic cyclization of enynes in the and their applications in materials science,9 could be efficiently
presence of alcohols or water, alkoxy- or hydroxycyclization obtained. Considering the presence of the two substituents at
reactions, respectively, is a useful strategy that allows the for- the β-position, we had proposed a gold-stabilized homoallylic
mation of functionalized carbo and heterocyclic compounds.3
carbocation as a likely key intermediate (Scheme 1a).10 Varying
For 1,5-enynes, 5-endo cyclizations are almost always involved the nature of the two substituents at the β-position of the
likely due to the much more favourable generation of a bicyclo o-(alkynyl)styrenes, we have also achieved the synthesis of dihydro-
[3.1.0]hexane intermediate compared to a bicyclo[2.1.0]pentane benzo[a]fluorenes11 and dihydroindeno[2,1-a]indenes.12 After our
system that would arise from an exo-cyclization.4 In many cases, pioneering work, other authors have also developed related 5-endo
cyclizations of β,β-disubstituted o-(alkynyl)styrenes under gold-,
other transition metal-, and even metal free-catalysis.13
aÁrea de Química Orgánica, Departamento de Química, Facultad de Ciencias,
Universidad de Burgos, Pza. Misael Bañuelos, s/n, 09001 Burgos, Spain.
E-mail: rsd@ubu.es
bDepartamento de Química Orgánica, Universidade de Vigo, AS Lagoas (Marcosende)
s/n, 36310 Vigo, Spain
cCITACA - Clúster de Investigación y Transferencia Agroalimentaria del Campus
Auga, Universidad de Vigo, 32004-Ourense, Spain
In this context, we decided to study the gold-catalyzed
nucleophilic cyclizations of β-monosubstituted o-(alkynyl)
styrenes.14 With this goal in mind, we have recently reported the
methoxycyclization of β-aryl o-(alkynyl)styrenes that takes place in
a regiospecific 5-endo mode (Scheme 1b).15 However, for these
substrates, the regiochemistry of the potential cyclization is not
obviously predicted.16 Considering the carbocationic-like inter-
mediates that would account for the competitive 5-endo and
6-endo cyclizations, both types of ring closures must locate the
positive charge at secondary carbon atoms (Scheme 1c). In fact,
at least for β-alkyl-substituted substrates (R1 = Alk), the 6-endo
†Electronic supplementary information (ESI) available: Experimental procedures
and analytical data (1H NMR, 13C NMR and HRMS) for all new compounds. See
DOI: 10.1039/c9ob02126d
‡Current address: Departamento de Química Orgánica y Química Inorgánica,
Campus Científico-Tecnológico, Facultad de Farmacia, Universidad de Alcalá,
Autovía A-II, Km 33.1, 28805 Alcalá de Henares, Madrid, Spain.
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o-(alkynyl)styrenes 1 that diastereospecifically led to 1-methoxy-
benzyl-1H-indenes 2 in high yields and typically short reaction
times (Table 1, entries 1–3, 5–7, 11–14, 16, 19, 20 and 22–24).15
We established IPrAuNTf2,17 bearing a NHC ligand and the
weakly coordinating counteranion Tf2N− as the best catalyst,
whereas complexes possessing phosphine or phosphite
ligands provided lower conversion and/or yields (see the ESI†
for further details). Herein, we have expanded the scope of this
process to new substrates such as 1e,f,m (entries 9, 10 and 21),
and to different mixtures of geometrical isomers of starting
materials (entries 4, 8, 15, 17 and 18). So, different starting
substrates 1a–g, bearing a representative selection of aromatic
substituents in the alkenes, including the electron-donating
and electron-withdrawing groups, were suitable for this meth-
oxycyclization (entries 1–11). In addition, apart from a phenyl
group, the alkyne moiety can also support (cyclo)alkyl, hetero-
aromatic, alkenyl, and arylthio groups as the substituents
(entries 12–24). Remarkably, starting from geometrically pure
(E)-1, the corresponding 1-methoxybenzyl-1H-indenes 2 were
Table 1 Au(I)-Catalyzed methoxycyclization of β-aryl o-(alkynyl)sty-
renes 1.15 Stereospecific synthesis of 1-methoxybenzyl-1H-indenes 2a
Yieldc
[%]
Entry
1
Ar
R
E/Z
2
drb
Scheme 1 Au(I)-Catalyzed alkoxycyclizations of β,β-disubstituted
o-(alkynyl)styrenes (previous work) and nucleophilic cyclization of
β-monosubstituted o-(alkynyl)styrenes.
1
2
3
4
5
6
1a
1a
Ph
Ph
Ph
Ph
Ph
Ph
>20/1 2a
>20/1 93
1/1 86
>20/1 86
1/1 2a
>20/1 2b
1/1 2b
>20/1 2c
1b 4-MeC6H4
1b 4-MeC6H4
1c
1c
1/1
16/1
93
86
79
4-MeOC6H4 Ph
4-MeOC6H4 Ph
1/8
diast-2c 5/1
7
8
9
1d 4-ClC6H4
1d 4-ClC6H4
Ph
Ph
Ph
>20/1 2d
>20/1 85
cyclization should give rise to a more stabilized intermediate. In
addition, although the analysis of the stereospecificity of these
processes could facilitate the mechanistic proposal regarding the
nature of the involved gold intermediates, whose structures are
typically described as intermediates between cyclopropyl gold car-
benes and gold-stabilized homoallylic carbocations,4 we have
also carried out DFT calculations in order to further understand
the source of regio- and stereoselectivity in these processes.
Herein, we report a detailed experimental and compu-
tational study on the nucleophilic cyclizations of
β-monosubstituted o-(alkynyl)styrenes under gold catalysis,
including β-alkyl substituted substrates and a variety of O- and
C-centered nucleophiles.
1/8
diast-2d 8/1 80
1e
1f
1g
4-FC6H4
3-MeOC6H4 Ph
1-Naphthyl Ph
>20/1 2e
>20/1 92
5,5/1 71
>20/1 88
>20/1 91
10
11
12
13
14
15
16
17
18d
19e
20
21
22f
23
24
6/1
2f
>20/1 2g
>20/1 2h
<1/20 diast-2h >20/1 87
>20/1 2i >20/1 75
1h Ph
1h Ph
n-Bu
n-Bu
n-Bu
n-Bu
1i
1i
1j
1j
1k
1k
1l
4-MeC6H4
4-MeC6H4
4-MeOC6H4 n-Bu
4-MeOC6H4 n-Bu
4-ClC6H4
4-ClC6H4
1-Naphthyl n-Bu
1/1
9/1
1/1
2i
2j
2j
1/1
9/1
1/1
90
70
80
n-Bu
n-Bu
>20/1 2k
<1/20 diast-2k >20/1 88
>20/1 2l
>20/1 74
>20/1 91
>20/1 90
>20/1 82
>20/1 87
>20/1 90
1m 4-MeC6H4
1n Ph
c-C3H5g >20/1 2m
c-C6H9
3-Thh
SPh
>20/1 2n
>20/1 2o
>20/1 2p
1o
Ph
1p Ph
a Reaction conditions:
1 (0.3 mmol) in CH2Cl2 (1 mL) at RT.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Isolated yield of the product based on the starting material.
d Reaction conditions = 2 h at refluxing DCE. Conducting the process
at RT, the competitive attack of methanol on the triple bond takes
place. e Reaction time = 6 h. f Reaction time = 48 h. g Cyclohexen-1-yl.
h 3-Thienyl.
Results and discussion
Methoxycyclization reactions
As reported in our prior publication,15 we had described the
regiospecific 5-endo methoxycyclization of selected β-aryl
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Table 2 Au(I)-Catalyzed methoxycyclization of β-alkyl o-(alkynyl)sty-
renes 3. Stereospecific synthesis of 1-methoxyalkyl-1H-indenes 4a
obtained as single diastereoisomers. Control experiments
using a variety of enynes 1 as ∼1/1 mixtures of geometrical
isomers led to the corresponding indenes 2 as ∼1/1 mixtures
of diastereoisomers (entries 2, 4, 15 and 17). Moreover, when
selected (Z)-1 styrenes were subjected to the same reaction con-
ditions, the other diastereoisomer of 2 (diast-2) was selectively
obtained (entries 6, 8, 13 and 19). These results prove the dia-
stereospecificity of the process as the stereochemical infor-
mation of the alkene is transferred to the final product.18
Then, we turned our attention to β-alkyl monosubstituted o-
(alkynyl)styrenes 3. (E)-3a, bearing a methyl group as the sub-
stituent at the β-position, was selected as the model substrate
and was subjected to the same reaction conditions as
described earlier for β-aryl o-(alkynyl)styrenes 1. In this case, a
preliminary analysis of the most likely pathway of cyclization,
simply considering the stability of the presumed carbocationic
intermediates, reveals that the carbocation arising from a
6-endo ring closure (secondary benzylic, Scheme 1b) should be
more stable than the corresponding carbocation resulting
from the 5-endo cyclization (secondary alkylic, R1 = Me in
Scheme 1b). Nevertheless, 1-methoxyalkyl-1H-indene derivative
4a was selectively obtained in high yield as a single diastereo-
isomer, and without the presence of competitive naphthalene
derivatives derived from a competitive 6-endo cyclization
(Scheme 2). The stereochemistry of 4a was established consid-
ering our previous and related results,16 which involve a net
anti-addition of a heteroatomic nucleophile and an activated
alkyne to the olefin.3
Entry
3
Alk
R
E/Z
4
drb
Yieldc [%]
1
3a Me
3a Me
3b Me
3b Me
3c n-Pr
3d n-Pr
3e n-Bu
Ph
Ph
n-Bu
n-Bu
Ph
>20/1 4a
1/2
>20/1 85
diast-4a 2/1 88
2
3d
4d
5
>20/1 4b
1/1
>20/1 87
diast-4b 1,5/1
81
>20/1 73
>20/1 84
>20/1 72
>20/1 87
>20/1 84
>20/1 4c
6d
7
c-C3H5 >20/1 4d
Ph >20/1 4e
c-C3H5 >20/1 4f
>20/1 4g
1/1 4g
8d
9
3f
n-Bu
3g n-C6H13 Ph
3g n-C6H13 Ph
3h c-C6H11 Ph
10
11
12
13d
14d
1/1
89
>20/1 4h
>20/1 4i
>20/1 4j
>20/1 90
>20/1 85
>20/1 88
3i
3j
3j
c-C3H5
c-C3H5
c-C3H5
Ph
n-Bu
n-Bu
1,6/1
4j
1,6/1
83
a Reaction conditions: 3 (0.3 mmol) in CH2Cl2 (1 mL) at RT. The reac-
tion times can be reduced up to 1–2 h by using 5 mol% of catalyst.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Isolated yield of the product based on the starting material.
d Reaction time = 2 h.
cyclopropyl ring does not interfere with the addition to the
more hindered β-position, although this type of cyclopropyl
ring opening has been well-established.19 In this way, the
corresponding 1-(1-methoxy-1-cyclopropylmethyl)-1H-indenes
4i,j were diastereospecifically obtained in high yields
(entries 12–14). It is also interesting to point out that the intra-
molecular [4 + 2] cycloaddition of 6-aryl-1,6-enynes, developed
by Echavarren and co-workers,20 resulted in stereospecificity
except for substrates bearing cyclopropyl groups as the
substituents of the alkene,21 whereas in our case this type of
alkene moiety does not interfere in the stereoinformation
transfer.
So, we proceeded to study the methoxycyclization of a series
of β-alkyl o-(alkynyl)styrenes 3. As shown in Table 2, the
process proceeded efficiently for a variety of starting enynes
3a–h bearing different (cyclo)alkyl substituents at the olefin
and aryl or (cyclo)alkyl groups at the alkyne (entries 1–11).
Regarding the stereospecific nature of this cyclization, starting
from the pure (E) isomer the corresponding 1-(1-methoxy)alkyl
indene derivatives 4 were obtained as single diastereoisomers
(entries 1, 3, 5–9 and 11), whereas the use of o-(alkynyl)sty-
renes 3 as mixtures of geometrical isomers led to the isolation
of the corresponding indenes 4 with the same diastereomeric
ratio as the starting enynes (entries 2, 4 and 10). The reactivity
of β-cyclopropyl substituted o-(alkynyl)styrenes 3i and 3j is
noteworthy, as the competitive attack of methanol on the
Computational results: reaction mechanism
Aiming to shed light on the experimentally observed stereospe-
cificity of the methoxycyclization reaction of both β-aryl- and
β-alkyl-monosubstituted o-(alkynyl)styrenes 1 and 3, and to
elucidate its mechanism, we performed a thorough compu-
tational study at the M06/Def2-SVP theoretical level selecting a
simplified o-(alkynyl)styrene 3 with Alk = R = Me as the theore-
tical model. The influence of the solvent was taken into
account via the polarizable continuum model (PCM, employ-
ing dichloromethane parameters).
A
number of alternative mechanistic pathways were
explored, and only the pathway with the lowest energy is
shown here; non-competitive alternatives can be found in the
ESI.† Computational results indicate that (S*,S*)-1H-indene for
this substitution pattern (as in diast-4 in Table 1, but consider-
Scheme 2 Selective 5-endo Au(I)-catalyzed methoxycyclization of (E)-
3a to indene 4a.
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ing Alk = R = Me) is thermodynamically more stable than the tational exploration;22 the 5-exo mode is usually disregarded as
(S*,R*)-diastereoisomer (as in 4 in Table 1, also considering non-competitive mechanistic branch. We nevertheless
a
Alk = R = Me) by 13.8 kJ mol−1 (see the ESI†). This thermo- included the three routes for the sake of completeness. At the
dynamic preference could be in agreement with the isolated starting intermediate, the INT-0 stereoisomer is more stable by
1H-indene derivatives formed when starting from the (Z)-o- 2.2 kJ mol−1 with respect to diast-INT-0. Both 5-endo cycliza-
(alkynyl)styrenes 3 but cannot explain why, when (E)-isomers tion transition states toward cyclopropylcarbenes INT-IA and
are employed as reactants, the (S*,R*)-1H-indenes 4 are the iso- diast-INT-IA are ∼20 kJ mol−1 less energetic than the alterna-
lated products. This seems to indicate that the observed stereo- tive 6-endo cyclization furnishing the dihydronaphthalene
specificity is kinetically governed. With this in mind, we INT-IB and its enantiomer. The formation of the intermediate
started to explore the competitive initial cyclizations of both (diast-)INT-IA from enynes is well-known and has been
(E)- and (Z)-alkynyl–gold complexes INT-0 and diast-INT-0, reported in similar cycloisomerizations.22 In fact, the related
respectively. All the geometrically plausible modes for the homoallylic carbocation, postulated as an intermediate for the
cyclization of this conjugated system have been considered transformations of β,β-disubstituted o-(alkynyl)styrenes (see
computationally: 5-endo, 6-endo and also the 5-exo modes were Scheme 1), is computed to be ∼50–60 kJ mol−1 less stable than
calculated (Scheme 3, top). It is worth noting that the first two (diast-)INT-IA, therefore, strongly suggesting the occurrence of
modes, 5-endo and 6-endo, have been broadly observed in a cyclopropyl carbene as a more likely intermediate (see the
similar substrates both experimentally and through compu- ESI†).
In good agreement with the previous studies, our compu-
tational results predict that a starting 5-exo cyclization of INT-0
and diast-INT-0 towards the carbocation intermediate INT-IC
(and its enantiomer) results in higher energies than the endo
alternative, particularly for the Z isomer, with an associated
activation energy of almost 50 kJ mol−1 higher than what is
needed for the (Z)-5-endo cyclization (diast-TS-IC).
Lastly, we also considered the interconversion between
(diast-)INT-IA and INT-IB via transition structures TS-II and
diast-TSII as a viable route. This process is nevertheless very
costly as the computed energy barriers reveal. For the trans-
formation (diast-)INT-1A → INT-IB, the computed barriers are
ΔG=TSÀII = 125.3 and ΔGd=iastÀTSÀII = 114.3 kJ mol−1, respectively,
and for the reverse sequence INT-1B → (diast-)INT-IA: ΔGT=SÀII
= 120.7 and ΔG=diastÀTSÀII = 120.0 kJ mol−1 (Scheme 3, bottom).
This initial exploration strongly suggests that the formation
of either the dihydronaphthalene INT-IB or the indene deriva-
tive INT-IC, and a subsequent methanol attack are unfavour-
able, and an alternative pathway through the cyclopropyl-
carbene INT-IA and diast-INT-IA operates in the experiment.
Once INT-IA and diast-IA are formed, which already contain
the indene core, two alternative pathways are conceivable to
furnish the observed 1-metoxyalkyl-1H-indene derivatives 4.
(diast-)INT-IA could either cleave its C1–C6 bond leading to a
homoallylic secondary carbocation intermediate, prone to be
intercepted by a methanol molecule or, in contrast, methanol
could attack directly onto the cyclopropylcarbene intermediate
(diast-)INT-IA in an SN2-like reaction featuring an intra-
molecular leaving group. It is worth noting that the loss of
stereospecificity would be observed, should the homoallylic
cation be involved in the reaction mechanism, due to 4 and
diast-4 becoming available via the rotation of the C1–C2 bond.
Gratifyingly, our simulations predict that the methanol attack
onto the C1 atom of intermediate (diast-)INT-IA is kinetically
more favourable than the proposed cyclopropyl ring-opening
process (see the ESI†). Two transition structures were located
for this SN2 process since methanol can attack onto any of the
two faces of the C1 atom: one in which the nucleophile
approaches opposite to gold in an anti-SN2 trajectory (TS-III),
Scheme 3 Computed initial plausible 5-endo, 6-endo and 5-exo cycli-
zations of INT-0 and diast-INT-0 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 INT-0 (diast-INT-0 does not proceed through a
6-endo TS according to our calculations).
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Fig. 1 Computed transition structures TS-III and diast-TS-III at the
PCM(DCM)/M06/Def2-SVP theoretical level. Relevant distances are
shown in angstroms.
ively); in contrast, this situation is inverted when comparing
the breaking C—C bond, which is longer in TS-III than in
diast-TS-III. It is remarkable that this favoured trajectory is
independent on the absolute configuration of the C1 atom
since it determines the absolute configuration of the stereo-
genic centers present at the subsequent intermediates
INT-II·H and diast-INT-II·H, and, therefore, the stereospecifi-
city of the process. Whereas the transition structure TS-III
evolves towards intermediate INT-II·H, its diastereoisomer
diast-INT-II·H is obtained from diast-TS-III. It is noteworthy
that this situation would be inverted in the case of proceeding
through TS′-III and diast-TS′-III. The subsequent proton
capture step by the counteranion Tf2N− leads to the corres-
ponding intermediates INT-II and diast-INT-II, that afford the
1H-indene derivatives 4 and diast-4, which show the stereospe-
cificity observed experimentally after
process (for the full mechanism, see the ESI†).
a protodeauration
Scheme 4 Proposed mechanism for the gold(I)-mediated formation of
1-methoxyalkyl-1H-indenes INT-II and diast-INT-II from cyclopropyl-
carbene INT-IA and diast-INT-IA 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 INT-0. Some structures and connections are not
shown for clarity. In order to study the transfer of stereochemical infor-
mation, the computational study was performed with the diastereo-
isomers shown in this scheme; the corresponding enantiomeric forms
report analogous profiles.
Other nucleophilic cyclizations
Considering the stereospecific nature of the methoxycycliza-
tion of β-monosubstituted o-(alkynyl)styrenes 1 and 3, we won-
dered at this point if other nucleophiles could also be suitable
for this transformation thus allowing diastereoselective access
to a variety of 1-functionalized indenes. With enyne (E)-1a as a
model substrate, different O-centered nucleophiles were
and the less common syn-SN2 alternative TS′-III (Scheme 4). essayed under the same reaction conditions as described for
Our results indicate that the methanol attacks onto any of the methanol (Table 3, entries 1–9).24 Successful results were
diastereoisomers, INT-IA and diast-INT-IA, and proceeds fol- obtained employing a selection of primary alcohols, which
lowing the anti-SN2 trajectory (TS-III) rather than the syn-SN2 gave rise to alkoxy-functionalized indenes 5a–d in high yields
alternative (TS′-III). Similar reactions have been previously and with high diastereospecificity (entries 1–4). Secondary
studied and the authors also found the same methanol alcohols were also able to efficiently participate in the alkoxy-
approach preference, the larger orbital overlap, whereby, a cyclization process, although slightly longer reaction times
stronger interaction between C1 and the incoming oxygen were required (entries 5 and 6). With s-BuOH, an almost equi-
atom from methanol seems to be responsible of this selective molecular mixture of diastereoisomers was obtained due to
anti path.23
the new stereogenic center introduced by the external alcohol
Both computed favoured transition structures TS-III and (entry 6). Interestingly, a carboxylic acid like acetic acid also
diast-TS-III are shown in Fig. 1. Our computational results turned out to be a suitable nucleophilic partner giving rise to
predict that the distance of the forming O—C bond is shorter acetate 5g in high yield (entry 7). In addition, 1,3-cyclohexane-
in TS-III species than in diast-TS-III (2.05 and 2.22 Å, respect- dione selectively led to the O-functionalized product 5h
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Table 3 Au(I)-Catalyzed alkoxy and hydroxycyclization of β-monosubstituted o-(alkynyl)styrenes (E)-1 and (E)-3. Synthesis of alkoxy- and hydroxy-
functionalized 1H-indenes 5 and 6a
Entry
Starting material
R1
R2
R3OH
Product
drb
Yieldc [%]
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1h
1h
1h
3e
3e
3f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
n-Bu
n-Bu
4-FC6H4
4-MeC6H4
n-Pr
n-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
EtOH
n-BuOH
H2CvCHCH2OH
PhCH2OH
i-PrOH
s-BuOH
AcOH
–(CH2)3C(O)CHvC(OH)–
(S)-MeCH(CO2Et)OH
H2CvCHCH2OH
AcOH
(S)-MeCH(CO2Et)OH
H2CvCHCH2OH
AcOH
H2CvCHCH2OH
H2O
H2O
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
6a
6b
6c
6d
>20/1
>20/1
>20/1
>20/1
>20/1
1,1/1e
>20/1
>20/1
1,4/1h
>20/1
>20/1
1,5/1h
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
91
86
82
71
80
73
80k
86
70i
84
71k
69i
72
72k
82
62
74
63
68
4
5d
6d
7
8f
9g
Ph
10d
11j
12g, j
13j
14j
15
16l
17l
18
19l
n-Bu
n-Bu
n-Bu
Ph
Ph
c-C3H5
Ph
c-C3H5
c-C3H5
Ph
1e
1m
3d
3e
H2O
H2O
a Reaction conditions: 1 or 3 (0.3 mmol), R3OH (0.6 mmol) in CH2Cl2 (1 mL) at RT, or H2O (2.1 mmol) in a 1 : 1 mixture of CH2Cl2 and 1,4-
dioxane (1.6 mL) at RT. b Determined by 1H NMR analysis of the crude reaction mixture. c Isolated yield of the product based on the starting
material 1. d Reaction time = 3 h. e This dr refers to the mixture of diastereoisomers with respect to the new stereogenic center introduced by
s-BuOH. The two other minor diastereoisomers were also observed (<10%). f 1,3-Cyclohexanedione was used as R3OH. g (S)-Ethyl lactate was used
as R3OH. h This dr refers to the mixture of diastereoisomers with respect to the new stereogenic center introduced by ethyl lactate. The two other
minor diastereoisomers were also observed (<10%). i Referred to the overall yield for the two major independently isolated and enantiomerically
pure diastereoisomers. j Reaction time = 6 h. k Minor amounts (∼10%) of the corresponding hydroxycyclized compounds 6 were also obtained.
l 3 mol% of catalyst was used.
without competitive C-alkylation (entry 8).25 Finally, when
We then shifted our attention towards nucleophilic counter-
ethyl L-lactate was employed as a nucleophile, a mixture of dia- parts that could give rise to the formation of new C–C bonds.
stereoisomers with respect to the new stereocenter introduced With enyne (E)-1a as the model substrate, electron-rich aro-
by the lactate moiety was obtained. However, we were able to matic compounds such as 1,3,5-trimethoxybenzene, 1,3-
isolate the major diastereoisomers in pure form thus allowing dimethoxybenzene, and 3,5-dimethoxyphenol enabled useful
the preparation of enantiopure 5i, although its absolute con- nucleophiles to participate in these Au-catalyzed cyclizations
figuration was not determined (entry 9). Then, other β-aryl or (Scheme 5). While the nucleophilic cyclization with 1,3,5-tri-
β-alkyl o-(alkynyl)styrenes 1 or 3 were treated with selected methoxybenzene gave rise selectively to indene 7a in high yield
alcohols, also leading to the corresponding O-functionalized and as a single diastereoisomer, the use of 1,3-dimethoxyben-
indenes 5j–o (entries 10–15).
zene as the nucleophilic counterpart led to indene 7b as an
We were also able to perform hydroxycyclization reactions ∼8 : 1 mixture of diastereoisomers. Moreover, when using 3,5-
with some new β-aryl o-(alkynyl)styrenes 1 and selected β-alkyl dimethoxyphenol as an external nucleophile, a regioisomeric
o-(alkynyl)styrenes 3d and 3e (entries 16–19). In these cases, a mixture of 7c and 7′c (∼2 : 1) was generated due to the pres-
mixture of CH2Cl2 and dioxane as the solvent was required to ence of two competitive nucleophilic positions in the aromatic
favour water participation, and longer reaction times were core. Nevertheless, single diastereoisomers of these indene
required with a higher amount of the catalyst in some cases. derivatives were obtained and the major one, 7c, could be iso-
In these hydroxycyclizations, a most clear superior activity of lated in pure form (Scheme 5). Finally, this reaction was suc-
IPrAuNTf2, compared with gold complexes bearing Ph3P or cessfully extended to a selection of o-(alkynyl)styrenes (E)-1
(PhO)3P ligands, was observed.26 In this way, several 1- that provide useful access to 1-diarylmethyl-1H-indenes 7d–g
(α-hydroxyalkyl)-1H-indenes 6a–d were synthesized in good as single diastereoisomers in good yields by their treatment
yields and also in a stereospecific manner.
with 1,3,5-trimethoxybenzene (Scheme 5).27
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evolves through an attack in the anti-SN2 trajectory of an O- or
C-based nucleophile, yielding functionalized 1H-indenes. This
cyclopropyl carbene intermediate also plays a decisive role in
the stereospecificity of the process allowing the transfer of the
stereochemical information of the alkene into the final
products.
Experimental
General procedure for the methoxycyclization of o-(alkynyl)
styrenes 1 and 3
To a 10 mL oven-dried vial containing a magnetic stirring bar,
IPrAuNTf2 (0.009 mmol, 7.8 mg, 3 mol%), CH2Cl2 (0.6 mL)
and MeOH (1.5 mmol, 0.06 mL) were added in sequence at RT,
and the mixture was stirred for 5 min. A solution of the corres-
ponding starting o-(alkynyl)styrene 1 or 3 (0.3 mmol) in
CH2Cl2 (0.4 mL) was subsequently added. The resulting reac-
tion mixture was stirred at RT until complete consumption of
the styrene derivative was observed by GC–MS (1–6 h). The
mixture was filtered through a short pad of silica gel using a
100 : 1 mixture of hexane and EtOAc as the eluent, the solvent
was removed under reduced pressure, and the crude mixture
was purified by flash column chromatography on silica gel
using mixtures of hexane and EtOAc as eluents to obtain the
corresponding 1-(α-methoxybenzyl)-1H-indenes 2, and 1-(1-
methoxyalkyl)-1H-indenes 4 in the yields reported in Tables 1
and 2.
Computational methods
Scheme 5 Au-Catalyzed nucleophilic additions of electron-rich arenes
to (E)-1. Synthesis of 1-diarylmethyl-1H-indenes 7.
All the structures and energies here reported have been opti-
mized through the Kohn–Sham formulation of the density
functional theory (DFT)28 at the M06/Def2-SVP theoretical
level.29 This methodology has been found particularly efficient
for the description of Au(I) catalytic cycles, including energy
minima and transition structures.30 Solvent effects were calcu-
lated with the PCM continuum solvation model with dichloro-
methane parameters.31 The nature of all stationary points as
minima or transition structures on the potential energy
surface was confirmed by a frequency analysis at the same
level of theory. At all the stationary points, thermal contri-
butions to the electronic energy were computed through the
analytical second derivatives of the energy with respect to
atomic displacements and the application of the rigid rotor
and harmonic oscillator (RRHO) approximations to the par-
tition functions. The stability of the resulting wavefunctions
was checked for all the optimized structures.32 All calculations
were performed using the ultrafine grid implemented in
Gaussian 09 E.01.33
Conclusions
In summary, we have reported that gold-catalyzed nucleophilic
cyclizations of β-monosubstituted o-(alkynyl)styrenes occur in
a 5-endo regiospecific manner regardless of the nature of the
substituent at the β-position, despite the fact that a 6-endo
cyclization could be initially considered more favourable. The
process exhibits a broad scope both at the substrate and the
nucleophile, including O-centered nucleophiles, such as func-
tionalized primary and secondary alcohols and acetic acid,
and C-centered nucleophiles such as electron-rich arenes.
Remarkably, the reactions are generally stereospecific
affording interesting functionalized 1H-indene derivatives in
high yields and as single diastereoisomers, just by simply
transferring the stereochemical information of the alkene
moiety into the final product. The experimental results have
been further supported by theoretical calculations, of which
the conclusions are in agreement with the observed reactivity.
So, a cyclopropyl gold carbene is proposed as the key inter-
mediate for these reactions, which allows the positive charge
Conflicts of interest
to be greatly homoallylically stabilized. This intermediate There are no conflicts to declare.
9930 | Org. Biomol. Chem., 2019, 17, 9924–9932
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Paper
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Acknowledgements
We gratefully acknowledge Ministerio de Economía
y
Competitividad (MINECO) and FEDER (CTQ2016-75023-C2-1-P
and 2-P), and Junta de Castilla y León and FEDER (BU291P18)
and Xunta de Galicia (ED431C 2017/70 and ED431E 2018/07)
for financial support. C. V. and M. S. thank Universidad de
Burgos and Junta de Castilla y León and FSE, respectively, for
predoctoral contracts. M. M.-L. thanks Xunta de Galicia for a
postdoctoral contract (ED418B 2016/166-0).
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18 Only the reactions of substrate 1c, bearing a p-methoxyphe-
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stereospecificity that could be due to the greater stabiliz-
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Paper
Organic & Biomolecular Chemistry
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19 For examples of gold-catalyzed ring-opening reactions of 26 No hydroxycyclization takes place using Ph3PAuNTf2 or
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different products with extensive decomposition.
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with 2 equiv. of MeOH without any significant change.
25 This behaviour of 1,3-cyclohexanedione has been pre-
viously observed in related processes: A. M. Sanjuán,
104, 9047.
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This journal is © The Royal Society of Chemistry 2019