Synthesis of Indenes by Tandem Gold(I)-Catalyzed Claisen Rearrangement/Hydroarylation Reaction of Propargyl Vinyl Ethers

Article abstract of DOI:10.1021/acs.joc.9b00646

The tandem gold(I)-catalyzed propargyl Claisen rearrangement/hydroarylation reaction of suitable propargyl vinyl ethers, followed by in situ reduction of the resulting carbonyl group, provides functionalized indenes in good to excellent yields. The reacti

Full text of DOI:10.1021/acs.joc.9b00646

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of Indenes by Tandem Gold(I)-Catalyzed Claisen
Rearrangement/Hydroarylation Reaction of Propargyl Vinyl Ethers
†
†
‡
Antonia Rinaldi, Vittoria Lange, Enrique Gomez-Bengoa, Giovanna Zanella,‡ Dina Scarpi,*,†
́
́
and Ernesto G. Occhiato*,†
†
̀
Dipartimento di Chimica “U. Schiff”, Universita degli Studi di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
‡
́
Departamento de Química Organica I, Universidad del País Vasco/UPV-EHU, Manuel de Lardizabal 3, 20018 Donostia-San
́
Sebastian, Spain
S
* Supporting Information
ABSTRACT: The tandem gold(I)-catalyzed propargyl Claisen rearrange-
ment/hydroarylation reaction of suitable propargyl vinyl ethers, followed by in
situ reduction of the resulting carbonyl group, provides functionalized indenes
in good to excellent yields. The reaction occurs at room temperature in
dichloromethane in the presence of 3 mol % [IPrAuCl]/AgBF4 as the best
catalytic system. Instead, cyclization of the allene intermediate either does not
take place or is very slow with phosphine ligands. A variety of substituents and
functional groups present on the substrate are tolerated. The effect of the aryl
ring substituents and the results of a density functional theory computational
study suggest that the final hydroarylation is the rate-determining step of this
cascade process. Further in situ chain elongation, prior final work up of the
tandem process, can be carried out by Wittig olefination of the aldehyde
functionality, thus incrementing the diversity of the products obtained.
INTRODUCTION
■
The development of efficient methods for the synthesis of
indenes1a,b continues to attract interest from the organic
chemists’ community as these compounds show a variety of
biological activities, including antitumor, anticonvulsant,
antiallergic, anti-hypercholesterolemic, fungicidal, herbicidal,
and antimicrobial activities.2 The indene framework is also
found in natural products (Figure 1),3 and it finds application
in material science4 and in the preparation of ligands for metal
complexes, for example, ligands for tailored metallocene
complexes used to catalyze olefin polymerization.5
Metal-catalysis has been widely exploited to build this
important carbocyclic structure through a variety of
processes,1a,c−j including those based on the 1,2- or 1,3-
migration and carbocyclization of propargylic esters and
carbonates.6 Given the high efficiency of Au(I) in activating
triple bonds,7 gold-catalysis has been exploited for the
synthesis of indenes by the latter approach8a,b,9 too. Other
methods based on gold(I)-catalysis include for example the
carbocyclization of 1-alkynyl-2-(methoxymethyl)benzene de-
rivatives,8c,d the carbocyclization of 1,5- and 1,6-enynes
embodying an aryl ring,8e−g the Csp −H bond activation in
3
Figure 1. Examples of natural compounds embedding the indene
core.
diarylacetylene derivatives,8h the formal (3 + 2) cycloaddition
between allenes and aryl gold(I)-carbenes,8i tandem trans-
formations of 1,5-diynes embodying an aryl ring via a gold-
vinylidene intermediate,8j and a few other multicomponent
processes.8k,l
We have recently reported that suitably substituted
propargyl vinyl ethers 1 undergo a propargyl Claisen
Received: March 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00646
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Article
rearrangement10 followed by a Nazarov cyclization when
subjected to gold(I)-catalysis, which efficiently provided
functionalized cyclopentadienes 2 fused with various N-hetero-
and carbocycles [Schema 1a].11
Moreover, we demonstrate that further in situ elaboration of
the aldehyde functionality is possible by Wittig olefination,
thus enlarging the variety of products which can be obtained
by this methodology.
In this process, the gold-catalyzed [3,3]-rearrangement
generates a gold-allene complex which, once formed,
immediately undergoes the 4π-electrocyclization plausibly via
the corresponding pentadienyl cation to form the final
product.12 While in cyclization processes involving the initial
rearrangement of propargylic esters, the final products are
cyclopentenones o cyclopentadienyl alkanoates,9 this tandem
propargyl Claisen rearrangement/Nazarov reaction provides
cyclopentadienes bearing, on one side chain, an aldehyde
group which can be easily subjected to further in situ
elaboration for incrementing the structural diversity of the
products.
RESULTS AND DISCUSSION
The synthesis of the substrates (Scheme 2) for the gold-
catalyzed reaction was carried out by treatment of the
■
Scheme 2. Synthesis of Substrates 6a−r
Given the importance of indenes, and in continuation of our
study on gold-catalyzed rearrangement processes involving
propargyl alcohol derivatives,11,13 we decided to evaluate
whether the same approach could be used for the construction
of such important ring systems by exploiting the rearrangement
of 3-aryl-substituted propargyl vinyl ethers 3 [Scheme 1b]. The
Scheme 1. Tandem Processes Involving an Au(I)-Catalyzed
Propargyl Claisen Rearrangement
corresponding propargylic alcohols 5 with ethyl vinyl ether
in the presence of Hg(OAc)2.10d,14,15 While we used this
methodology for small-scale preparations, for example, in the
evaluation of the scope of the gold-catalyzed tandem process,
we looked for an alternative approach to vinyl ethers 6 when
these were needed in larger amount, as in the case of model
substrate 6a, in order to avoid the use of the mercury salt.16
Out of the many approaches we experimented, the best is
depicted in Scheme 3. As shown, converting 5a into the
Scheme 3. Synthesis of Substrate 6a
corresponding acetate and then treating with InCl3 in
nitromethane at 50 °C in the presence of 2-bromo-1-ethanol,
provided bromide 7a in 78% yield over the two steps.17 The
next elimination step was carried out by treatment of 7a with a
strong base (t-BuOK in toluene) which provided model
compound 6a in 91% yield.18
achievement of this synthetic objective through a cascade
process in which the allene is generated in situ by a [3,3]-
rearrangement was not guaranteed, though. The final
cyclization in the tandem propargyl Claisen rearrangement/
Nazarov reaction [Scheme 1a] was a fast process, but in the
present case, the cyclization of the allene intermediate
[Scheme 1b] involves the temporary disruption of the
aromaticity of the aryl ring. Thus, the conditions (gold ligand,
temperature, and counterions) required for the initial Claisen
rearrangement could be unsuitable for the hydroarylation step.
In this paper, we report on an experimental and computational
study of the tandem gold(I)-catalyzed Claisen rearrangement/
hydroarylation reaction of 3-aryl-substituted propargyl vinyl
ethers and we show that, with the right choice of the catalytic
system, it efficiently provides polyfunctionalized indenes.
We used substrate 6a to find the best reaction conditions for
the gold(I)-catalyzed process, and the results of the screening
of various gold(I)-catalysts and gold(I)-precatalyst/silver salt
combinations are reported in Table 1. The reactions were
carried out by adding a solution of the substrate in
dichloromethane (DCM) to a solution of the catalyst (3 mol
%) generated by mixing the gold and silver salts in the same
solvent at 25 °C.
−
The [Ph3PAu]+BF4 and [Ph3PAu]+TfO− catalysts (entries
1 and 2) have been shown to catalyze the Claisen
rearrangement of propargyl vinyl ethers.10a With 3 mol % of
B
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a
On the other hand, AgBF4 alone (entry 17) was able to
catalyze the Claisen rearrangement, but not the cyclization,
and similarly in the presence of the IPrAuCl salt alone (entry
16), only the [3,3]-rearrangement occurred.
Table 1. Optimization of the Reaction Conditions
We tested other NHC gold complexes (entries 12−15) and
quite surprisingly, among these, only the SIPr ligand was
effective, although the reaction was slightly slower than with
IPr ligand (the 8a/9a ratio was 1:1 after 15 min).21 With ICy,
ItBu, and IMes ligands, only allene 9a was formed.
Interestingly, in the Au(I)-catalyzed tandem [3,3]-rearrange-
ment/hydroarylation of propargylic acetates to form indenes,
other NHC ligands, as well as Ph3P, were able (although not as
efficiently as IPr) to promote the hydroarylation step.8b
Having found the best reaction conditions, these were used
to evaluate the scope with 3-aryl-substituted propargyl vinyl
ethers bearing various groups (R3) on the aromatic ring and
substituents (R1, R2) on the carbinolic position (Scheme 4).
To avoid both partial degradation of aldehydes 8 and double
bond migration to the exocyclic position during chromatog-
raphy on silica gel (which generates α,β-unsaturated
aldehydes), the reaction products were reduced in situ to the
corresponding alcohols 10 by NaBH4 after dilution of the
DCM solution with MeOH (method A).22 As an alternative,
c
product ratio
time
b
entry
catalyst
(min)
6a
8a
9a
1
2
3
4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgOTf
[Ph3PAuCl]/AgSbF6
[(p-CF3C6H4)3PAuCl]/AgOTf
30
30
120
30
30
30
30
40
25
60
120
55
55
55
55
55
60
100
100
93
7
d
e
5
tBu3PAuNTf2
100
100
6
7
8
9
10
11
12
13
14
15
16
17
[Cy3PAuCl]/AgOTf
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgOTf
[IPrAuCl]/AgBF4
f
100
f
100
100
100
50
e
IPrAu(CH3CN)BF4
e
IPrAuNTf2
50
[SIPrAuCl]/AgBF4
[ICyAuCl]/AgBF4
[ItBuAuCl]/AgBF4
[IMesAuCl]/AgBF4
IPrAuCl
100
100
100
22
100
100
g
78
Scheme 4. Scope of the Au(I)-Catalyzed Propargyl Claisen
Rearrangement/Hydroarylation Reaction
AgBF4
a
Conditions: reactions carried out on 0.2−0.3 mmol of 6a in CH2Cl2
b
(0.05 M) at 25 °C under N2 atmosphere. Prepared by mixing the
silver salt (3 mol %) and the gold chloride (3 mol %) in CH2Cl2
before addition of the substrate unless otherwise noted. IPr = 1,3-
bis(diisopropylphenyl)imidazol-2-ylidene, SIPr = 1,3-bis(2,6-diisopro-
pylphenyl)-4,5-dihydroimidazol-2-ylidene, IMes = 1,3-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene, ItBu = 1,3-di-t-butylimidazol-2-
c
ylidene, ICy = 1,3-bis(cyclohexyl)imidazol-2-ylidene. Product ratio
1
based on integration of H NMR resonances in the crude reaction
d
e
mixture. Complete degradation of the starting material. Commer-
f
cially available. Some degradation of the starting material occurred.
Devinylation of 6a to alcohol 5a occurred.
g
these catalysts in CH2Cl2 substrate 6a was quickly (less than
30 min) converted into allene 9a.19 However, we did not
observe even traces of indene 8a in the crude reaction mixtures
by prolonging the reaction times. Only when using AgSbF6 as
the source of the non-coordinating anion we observed, after 2
h, the formation of a small relative amount (entry 3) of
aldehyde 8a.
Gold salts with Ph3P and electron-rich phosphine ligands
were all competent catalysts in the tandem Claisen rearrange-
ment/Nazarov cyclization of enynyl vinyl ethers,11 but as it is
evident from entries 1−3 and 5−6, they seem unable to
promote the final hydroarylation step with substrate 6a.
Instead, with the NHC (NHC = N-heterocyclic carbene)
ligand IPr and various anions (entries 7−11), we always
observed the formation of indene 8a. In particular, the best
combination was the [IPrAuCl]/AgBF4 catalytic system (entry
9).20 With 3 mol % of this catalyst, we observed (by 1H NMR)
the immediate (less than 5 min) conversion of the substrate
into allene 9a, half of which already cyclized to indene 8a (8a/
9a ratio = 1:1 after 5 min). After 15 min, the ratio was 3.2:1,
and in 25 min, the reaction was complete. With 1 mol % of the
catalyst, the reaction was complete in 3 h. Commercial
[IPrAu(CH3CN)]+BF4− (entry 10) catalyzed the reaction, too,
ruling out any role of the silver salt in the hydroarylation step.
a
b
Numbering refers to the indene skeleton; commercial [IPrAu-
c
d
(CH3CN)]BF4 was used; 6 mol % of the catalyst was used; in
mixture with 7-F isomer (15%); reaction carried out at 40 °C.
e
C
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upon completion of the reaction, the crude aldehydes were
isolated after an aqueous work-up, dissolved in MeOH, and
then reduced (method B).
The only substrates which seem unsuitable for this gold(I)-
catalyzed cascade process are those bearing an aryl ring at the
carbinolic position (Scheme 5). Simple phenyl-substituted
By using the former procedure (method A), simple indene
10a was obtained in 80% yield after chromatography.
Scheme 5. Gold(I)-Catalyzed Process with Substrates 6q
and 6r
Electron-donor groups on the aromatic ring made the
reaction faster and, with the exception of the o-methyl
substituted substrate 6c, which reacted in 1.5 h, alcohols
10b−10f were all obtained in 15 min. m-Methyl- and m-
methoxy-substituted substrates (6d and 6f, respectively) of
course provided a mixture of isomers deriving from ring
closure at the ortho and para position. However, in the case of
the m-methoxy-substituted compound, attack to the para
position prevailed (86:14 ratio in the crude reaction mixture)
and pure isomer 10f could be isolated by chromatography in
good yields.23a With aromatic rings bearing amino- and alkoxy-
substituted methyl groups (6g and 6h, respectively), the
reaction proceeded smoothly, too, providing alcohols 10g and
10h in good yields (62 and 75% yield, respectively). In the case
of 6h, the reaction was carried out with the commercial
[IPrAu(CH3CN)]+BF4− and, as for the model compound 6a, it
was just slightly slower than with the [IPrAuCl]/AgBF4
catalytic system. The latter, as well as the preformed catalyst,
was used to carry out the reaction with the propargyl vinyl
ether bearing a dioxolane moiety in the para position (6i). The
reaction was slow (2 h for a complete conversion of the allene
intermediate), and in both cases, we observed an almost
complete trans-acetalization during the gold(I)-catalyzed step.
Thus, compound 10i could be obtained in 63% yield after
chromatography.24
propargyl vinyl ether 6q, under various conditions, always
quantitatively provided the corresponding allene 9q. We
thought the lack of reactivity could be due to the stabilization
by the phenyl ring of the positively charged gold(I)-complex
intermediate [Scheme 1b] making it less reactive, but the result
obtained with dichloro-substituted substrate 6r (Scheme 5)
instead suggests that it is either the greater stability of the aryl-
substituted allene intermediate or the steric hindrance in the
ring closure step by the aryl ring being the possible reason.
A plausible mechanism for the tandem Claisen/hydro-
arylation reaction and the energies calculated relative to
complex II are reported in Scheme 6. Upon coordination of
the triple bond to the cationic gold(I) complex, a very fast
[3,3]-rearrangement of II occurs and conversion of the
substrate into allene V is immediate.10d,26 This is exper-
imentally observed for all types of substrates, suggesting that
the Claisen rearrangement is not the rate-determining step of
the process. The calculated transition state energies for the
rearrangement steps (TS1 and TS2) are in fact low with both
IPr and Ph3P ligands (<10−12 kcal/mol), whereas the ring
closure of allene−gold(I) complex IV, which is in equilibrium
with the free allene V, presents a higher barrier (17.8 kcal/mol
with both ligands) and thus is the rate-determining step. When
the cyclization is slow or does not take place, allene V can be
isolated.
As expected on the basis of the above results, which suggest
that the hydroarylation could be the rate-determining step of
the process (see later), the hydroarylation of the allene
intermediate was in fact very slow with electron-withdrawing
groups on the aromatic ring (6j−6l). In two cases (6k, bearing
a m-F group, and 6l, bearing a p-CO2Me group) either the long
reaction times or the heating led to an almost equimolar
mixture of isomers as a consequence of the shift of the double
bond to the position 1 in the five-membered ring. Such an
isomerization could be observed, to a very minor extent and
regardless the presence or absence of a silver salt in the
reaction mixture, also for other substrates for which, however,
the adoption of method B allowed us to overcome the
problem.25 As in the case of the m-OMe-substituted substrate,
also with m-F-substituted propargyl vinyl ether 6k, the ring
The cyclization step takes place as an electrophilic aromatic
substitution to form VI, and during this step, a partial positive
charge develops on the aromatic ring (TS3), which explains
the effect of the substituents we observed when assessing the
scope of the reaction (interestingly, in the Au(I)-catalyzed
tandem [3,3]-rearrangement/hydroarylation of propargylic
acetates to form indenes, the reaction was very fast irrespective
of the substituent present on the aryl ring, providing the
products in 5 min).8b After proton elimination from C7a (to
restore aromaticity) and protodeauration of VII, indene VIII is
eventually formed. We carried out an experiment with
deuterated [D]-6a (Scheme 7) and found out that all
deuterium was incorporated in the product at position C1,
meaning that, contrarily to what observed in the tandem
Claisen/Nazarov reaction we have recently studied [Scheme
1a], no [1,2]-H shift from position 1 to position 2 occurs.11
Another important difference with the tandem Claisen/
Nazarov process is that we were never able to observe (and
isolate) the allene intermediates in that case, as the cyclization
was a fast step, especially with carbocyclic substrates.11
Two important points in the present cascade process are the
1
closure occurred predominantly (85% by H NMR analysis of
the crude reaction mixture) at the para position.23b
Finally, a few substrates with different substitution at the
carbinolic position were evaluated, and in all cases, the reaction
provided the target compounds (10m−p) in good to excellent
yield. Benzyl-substituted indene 10n, however, which was
obtained isomerically almost pure (95%) from 6n after 3 h in
the presence of 6 mol % of the catalyst, underwent a slight
double bond isomerization during the chromatography on
silica gel, and it was eventually obtained as a 9:1 mixture of
isomers. With the gem-dimethyl-substituted substrate 6o,
because of the double substitution at the propargylic moiety,
the reaction was slower (3.5 h) than with the model substrate
6a but provided the target compound 10o in an excellent 93%
yield. Similarly, the reaction of 6p was slow (16 h), and it was
carried out in the presence of 6 mol % of the catalyst, but it
nevertheless provided compound 10p in 92% yield.
−
role of the BF4 counterion and the effect of the IPr gold(I)-
ligand, which together form the best combination (entry 9,
D
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Article
a
Scheme 6. Catalytic Cycle with Calculated Energies
a
Energies in kcal/mol are calculated relative to II (in blue for Ph3P ligand, in red for IPr ligand). DFT calculations were carried out with the
Gaussian16 set of programs and the M06 functional.
Scheme 7. Control Experiment
Scheme 8. Calculated Energies for the Dissociation of
Complex IV
Table 1). Tetrafluoroborate is a weakly coordinating anion27
and this could favor coordination of LAu+ cationic complex to
allene V to re-generate allene−gold complex IV. Concerning
the ligands, because the calculated energies (Scheme 6) are
almost the same for both IPr and Ph3P ligands, explaining the
efficiency of the NHC gold ligand compared to the phosphine
ligands, with which ring closure of allene intermediate V does
not take place or is very slow, is more difficult. It has been
suggested that, in the rearrangement of a model propargyl
acetate to form the corresponding allene, the latter is the
resting state with a NHC ligand (IMe) and that allene
coordination to gold is favored with the IMe ligand compared
to a phosphine.9d We calculated the energies associated to the
dissociation equilibrium of complex IV (Scheme 8) and found
that the phosphine ligand is able to stabilize more efficiently
the LAu+ species, as the uphill energy is only +3.9 kcal/mol
compared with +7.3 kcal/mol for the NHC carbene. Thus, the
equilibrium is more shifted to the left with the latter ligand
with which the formation of allene−gold(I) complex
intermediate IV from allene V is more favored.
Finally, to demonstrate that aldehyde intermediates 8 can be
directly employed just after their formation for further chain
elongation without prior work-up of the gold-catalyzed step,
we studied the Wittig reaction of 8o and 8p with selected
phosphorus ylides (Scheme 9). The reactions were carried out
by transferring by a syringe the DCM solution containing the
crude aldehyde to a tetrahydrofuran (THF) solution of the
Scheme 9. Sequential Au(I)-Catalyzed Tandem Process/
Wittig Olefination of Substrates 6o−p
The reason why, apart from SIPr, the other NHC catalysts
are unable to promote cyclization, is instead unclear at the
moment.
E
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DCM (60 mL) under nitrogen atmosphere was cooled to 0 °C (ice
bath); Et3N (2.5 mL, 18.0 mmol) and 4-dimethylaminopyridine (36
mg, 0.30 mmol) were then added, followed by dropwise addition of
Ac2O (1.5 mL, 12.0 mmol). After 10 min, the ice bath was removed
and the resulting mixture was stirred at room temperature for 3 h. A
satd solution of NaHCO3 (60 mL) was added and the mixture was
left under vigorous stirring for 5 min; after separation of the layers, the
aqueous one was extracted with DCM (2 × 30 mL) and the
combined organic extracts were dried over anhydrous K2CO3. After
filtration and evaporation of the solvent, the crude acetate was
purified by flash chromatography (eluent: n-hexane/EtOAc, 8:1; Rf =
preformed ylide at 0 °C and leaving under stirring until
complete consumption of 8. With simple Ph3PCH2, the
reaction led to the terminal olefin 11 in 70% yield after
chromatography. No isomerization of the double bonds was
observed. Similarly, the reaction occurred quantitatively with a
substituted ylide prepared from n-hexylphosphonium iodide,
which provided Z olefin 12 in 80% yield. Finally, after
rearrangement and cyclization of 6p, the crude aldehyde 8p
was reacted with ylide 13, prepared from the corresponding
commercial phosphonium bromide, which furnished com-
pound 14 in 71% yield.
1
0.41), affording the pure acetate (1.11 g, 98%) as a colorless oil. H
NMR (400 MHz, CDCl3): δ 7.45−7.43 (m, 2H), 7.33−7.28 (m, 3H),
5.68 (q, J = 6.8 Hz, 1H), 2.11 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H).
The acetate (941 mg, 5.0 mmol) was then dissolved in
nitromethane (20 mL) under nitrogen atmosphere, and 2-
bromoethanol (1.1 mL, 15.0 mmol) was added followed by
anhydrous InCl3 (55 mg, 0.25 mmol). The resulting mixture was
heated at 50 °C (external) for 2 h. After cooling, the solvent was
removed under vacuum and purification of the crude residue by flash
chromatography (eluent: n-hexane/EtOAc, 20:1; Rf = 0.30), afforded
CONCLUSIONS
■
In conclusion, the tandem gold(I)-catalyzed propargyl Claisen
rearrangement/hydroarylation reaction of aryl-substituted
propargyl vinyl ethers is an efficient way to obtain function-
alized indenes. The reaction occurs at room temperature in
DCM in the presence of [IPrAuCl]/AgBF4 as the best catalytic
system for both the propargyl Claisen rearrangement and the
subsequent allene cyclization (the hydroarylation step).
Instead, cyclization of the allene intermediate does not take
place (or it is very slow) with phosphine ligands, which is
probably due to the higher stabilization of the free cationic
gold(I) in the equilibrium involving coordination/decoordina-
tion of the allene intermediate to gold(I), as suggested by
density functional theory (DFT) computations. Various groups
and substituents on the aryl ring and at the carbinolic position
of the propargyl vinyl ether are tolerated. The effect of the
substituents on the aryl ring suggests that the final hydro-
arylation is the rate-determining step of this cascade process
with a calculated free activation energy of about 18 kcal/mol
for both the NHC and phosphine ligand. Further functional-
ization can be achieved prior final work of the tandem process
by carrying out a Wittig reaction on the aldehyde functionality,
thus incrementing the diversity of the products obtained.
1
pure 7a (1.01 g, 80%) as a pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.45−7.42 (m, 2H), 7.33−7.30 (m, 3H), 4.48 (q, J = 6.8
Hz, 1H), 4.10 (dt, J = 10.8, 6.4 Hz, 1H), 3.81 (dt, J = 10.8, 6.4 Hz,
1H), 3.57−3.49 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H). 13C {1H} NMR
(100.4 MHz, CDCl3): δ 131.7, 128.4, 128.3, 122.5, 88.5, 85.4, 68.5,
66.1, 30.3, 22.1. GCMS (CI) m/z (%): 255 ([M + 1]+, 3) and 253
([M + 1]+, 3), 153 (15) and 151 (17), 129 (100). Anal. Calcd for
C12H13BrO: C, 56.94; H, 5.18. Found: C, 57.02; H, 5.23.
(3-Viniloxy-but-1-ynyl)-benzene (6a). To a solution of 7a (1.0 g,
3.95 mmol) and 18-crown-6 (10 mg, 1 mol %) in anhydrous toluene
(5.9 mL) under nitrogen atmosphere, solid t-BuOK (532 mg, 4.74
mmol) was added in one portion, and the mixture was left under
vigorous stirring for 5 h. After cooling, the mixture was filtered
through a short pad of silica gel (980 mg) and the pad was washed
with n-hexane/EtOAc, 20:1 (4 mL). The solvent was then removed
under vacuum, and purification of the crude residue by flash
chromatography (eluent: n-hexane/EtOAc, 20:1; Rf = 0.21) afforded
1
pure 6a (619 mg, 91%) as a pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.45−7.42 (m, 2H), 7.32−7.28 (m, 3H), 6.50 (dd, J =
14.0, 6.4 Hz, 1H), 4.77 (q, J = 6.4 Hz, 1H), 4.48 (dd, J = 14.0, 1.6 Hz,
1H), 4.16 (dd, J = 6.4, 1.6 Hz, 1H), 1.60 (d, J = 6.8 Hz, 3H). 13C{1H}
NMR (100.4 MHz, CDCl3): δ 149.6, 131.8, 128.5, 128.2, 122.4, 89.8,
87.9, 85.6, 65.1, 21.9. GCMS (EI) m/z (%): 172 (M+, 24), 157 (100),
128 (43). Anal. Calcd for C12H12O: C, 83.69; H, 7.02. Found: C,
83.45; H, 6.82.
Compound 6a was also prepared according to the general
procedure reported below. Vinylation of alcohol 5a (150 mg, 1.02
mmol) afforded pure 6a (135 mg) after chromatography in 77% yield.
General Procedures for the Synthesis of the 3-Aryl-
Substituted Propargyl Vinyl Ethers. In a screw-cap vial,
Hg(OAc)2 (0.45 mmol) was added in one portion to a solution of
substrate 5 (1 mmol) in ethyl vinyl ether (2.5 mL) under nitrogen
atmosphere, and the reaction mixture was heated at 50 °C (external)
for 24 h. The mixture was then cooled to room temperature and a
solution of satd Na2CO3 (5 mL) was added. The product was
extracted with Et2O (3 × 5 mL), and the combined organic extracts
were dried over anhydrous K2CO3. After filtration and evaporation of
the solvent, the crude reaction mixture was purified by flash column
chromatography to give pure 6 which was stored at 4 °C as a solution
in n-hexane until use.
EXPERIMENTAL SECTION
■
General Information. Anhydrous solvents were prepared
accordingly to the standard techniques. Commercially available
reagents were used without further purification. Chromatographic
separations were performed under pressure on silica gel (Merck 70−
230 mesh) by using flash column techniques; Rf values refer to TLC
carried out on 0.25 mm silica gel plates (F254) with the same eluent as
indicated for column chromatography. 1H NMR (400 MHz) and 13
C
NMR (100.4 MHz) spectra were recorded on Varian Inova and
Mercury (400 MHz) spectrometers in the specified deuterated
solvent at 25 °C. Solvent reference lines were set at 7.26 and 77.00
(CDCl3) and 3.31 and 49.00 (CD3OD) in 1H and 13C NMR spectra,
respectively. Mass spectra were carried out either by direct inlet of a
10 ppm solution in CH3OH on a LCQ Fleet Ion Trap LC/MS system
(Thermo Fisher Scientific) with an electrospray ionization (ESI)
interface in the positive ion mode or by EI at 70 eV or by methanol
CI on a Varian GC/MS Saturn 2200 instrument equipped with a CP-
sil8 Varian column. High-resolution mass spectrometry (HRMS)
analyses were performed under conditions of ESI-MS through direct
infusion of a 1 μM solution in MeOH in a TripleTOF 5600+ mass
spectrometer (Sciex, Framingham, MA, U.S.A.), equipped with a
DuoSpray interface operating with an ESI probe. Microanalyses were
carried out with a CHN Thermo FlashEA 1112 Series elemental
analyzer. Alcohols 5a, 5m, and 5q are commercially available.
Compounds [D]-5a,28 5b,29−32 5c,29 5d,29,30 5e,29,30 5f,31 5j,29 5k,29
5l,31 5n,30 5o,33 5p,32 and 6q10d are known. n-Hexyltriphenylphos-
phonium iodide was prepared as reported.34
1-Methyl-4-(3-viniloxy-but-1-ynyl)-benzene (6b). Vinylation of
compound 5b (150 mg, 0.95 mmol) afforded 6b, which was purified
by flash chromatography (n-hexane + 1% Et3N; Rf = 0.28). Pure 6b
1
was obtained as a colorless oil (108 mg, 61%). H NMR (400 MHz,
CDCl3): δ 7.33 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.50
(dd, J = 14.0, 6.8 Hz, 1H), 4.77 (q, J = 6.8 Hz, 1H), 4.48 (dd, J =
14.0, 2.0 Hz, 1H), 4.16 (dd, J = 6.8, 2.0 Hz, 1H), 2.35 (s, 3H), 1.60
(d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 149.7,
138.6, 131.7, 129.0, 119.3, 89.7, 87.2, 85.8, 65.2, 21.9, 21.5. GCMS
[3-(2-Bromoethoxy)-but-1-ynyl]-benzene (7a). A solution of
( )-4-phenyl-3-butyn-2-ol 5a (872 μL, 6.0 mmol) in anhydrous
F
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The Journal of Organic Chemistry
Article
(EI) m/z (%): 186 (M+, 5), 171 (100), 143 (9), 128 (13). Anal.
Calcd for C13H14O: C, 83.83; H, 7.58. Found: C, 83.48; H, 7.63.
1-Methyl-2-(3-viniloxy-but-1-ynyl)-benzene (6c). Vinylation of
compound 5c (185 mg, 1.15 mmol) afforded 6c, which was purified
by flash chromatography (n-hexane; Rf = 0.30). Pure 6c was obtained
as a colorless oil (133 mg, 62%). 1H NMR (400 MHz, CDCl3): δ 7.41
(d, J = 7.6 Hz, 1H), 7.25−7.18 (m, 2H), 7.15−7.11 (m, 1H), 6.52
(dd, J = 14.0, 6.8 Hz, 1H), 4.82 (q, J = 6.8 Hz, 1H), 4.49 (dd, J =
14.0, 1.6 Hz, 1H), 4.18 (dd, J = 6.8, 1.6 Hz, 1H), 2.43 (s, 3H), 1.63
(d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 149.6,
140.3, 132.0, 129.4, 128.5, 125.5, 122.1, 91.8, 89.7, 84.5, 65.1, 22.0,
20.7. GCMS (EI) m/z (%): 186 (M+, 12), 171 (39), 157 (100), 129
(33). Anal. Calcd for C13H14O: C, 83.83; H, 7.58. Found: C, 84.00;
H, 7.32.
Vinylation of compound 5g (343 mg, 1.25 mmol) afforded 6g,
which was purified by flash chromatography (n-hexane/EtOAc, 5:1 +
1% Et3N; Rf = 0.28). Pure 6g was obtained as a pale yellow oil (286
mg, 76%). 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8.4 Hz, 2H),
7.21 (d, J = 8.0 Hz, 2H), 6.48 (dd, J = 14.0, 6.8 Hz, 1H), 4.87 (br s,
1H), 4.76 (q, J = 6.8 Hz, 1H), 4.46 (dd, J = 14.0, 2.0 Hz, 1H), 4.31−
4.26 (m, 2H), 4.15 (dd, J = 6.8, 2.0 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H),
1.45 (s, 9H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 155.8, 149.6,
139.5, 132.0, 127.2, 121.3, 89.8, 87.9, 85.4, 79.6, 65.1, 44.4, 28.4, 21.8.
HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C18H23NO3Na,
324.1570; found, 324.1569.
1-Benzyloxymethyl-4-(3-vinyloxy-but-1-ynyl)-benzene (6h). Al-
cohol 5h was prepared as reported for 5g, by Sonogashira coupling of
1-benzyloxymethyl-4-bromobenzene (664 mg, 2.4 mmol) and ( )-3-
butyn-2-ol (1.2 equiv). Purification by flash column chromatography
(n-hexane/EtOAc, 4:1; Rf = 0.25) afforded pure enynyl alcohol 5h
1-Methyl-3-(3-vinyloxy-but-1-ynyl)-benzene (6d). Vinylation of
compound 5d (163 mg, 1.01 mmol) afforded 6d, which was purified
by flash chromatography (n-hexane + 1% Et3N; Rf = 0.40). Pure 6d
1
(288 mg, 45%) which was used immediately in the next step. H
1
NMR (400 MHz, CDCl3): δ 7.43−7.39 (m, 2H), 7.38−7.34 (m, 4H),
7.33−7.29 (m, 3H), 4.79−4.72 (m, 1H), 4.56 (s, 2H), 4.55 (s, 2H),
1.56 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ
138.7, 138.0, 131.7, 128.4, 127.8, 127.7, 127.5, 121.8, 90.9, 83.9, 72.3,
71.6, 58.9, 24.4.
was obtained as a pale yellow oil (129 mg, 68%). H NMR (400
MHz, CDCl3): δ 7.27−7.24 (m, 2H), 7.22−7.17 (m, 1H), 7.14−7.12
(m, 1H), 6.51 (dd, J = 14.0, 6.4 Hz, 1H), 4.77 (q, J = 6.8 Hz, 1H),
4.48 (dd, J = 14.0, 1.6 Hz, 1H), 4.17 (dd, J = 6.4, 1.6 Hz, 1H), 2.33 (s,
3H), 1.60 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3):
δ 149.6, 137.9, 132.3, 129.4, 128.8, 128.1, 122.2, 89.8, 87.5, 85.8, 65.1,
21.9, 21.2. GCMS (EI) m/z (%): 186 (M+, 35), 171 (100), 143 (82),
128 (43). Anal. Calcd for C13H14O: C, 83.83; H, 7.58. Found: C,
83.47; H, 7.82.
1-Methoxy-4-(3-vinyloxy-but-1-ynyl)-benzene (6e). Vinylation of
compound 5e (193 mg, 1.1 mmol) afforded 6e, which was purified by
flash chromatography (n-hexane/EtOAc, 50:1 + 1% Et3N; Rf = 0.40).
Pure 6e was obtained as a colorless oil (91 mg, 41%). 1H NMR (400
MHz, CDCl3): δ 7.39−7.35 (m, 2H), 6.85−6.81 (m, 2H), 6.50 (dd, J
= 14.4, 6.8 Hz, 1H), 4.76 (q, J = 6.8 Hz, 1H), 4.47 (dd, J = 14.0, 2.0
Hz, 1H), 4.15 (dd, J = 6.8, 1.6 Hz, 1H), 3.80 (s, 3H), 1.59 (d, J = 6.8
Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 159.7, 149.7, 133.2,
114.5, 113.9, 89.7, 86.5, 85.6, 65.3, 55.3, 22.0. GCMS (EI) m/z (%):
203 ([M + 1]+, 28), 202 (M+, 100), 188 (63), 159 (28). Anal. Calcd
for C13H14O2: C, 77.20; H, 6.98. Found: C, 76.96; H, 7.12.
1-Methoxy-3-(3-vinyloxy-but-1-ynyl)-benzene (6f). Vinylation of
compound 5f (200 mg, 1.14 mmol) afforded 6f, which was purified by
flash chromatography (n-hexane + 1% Et3N; Rf1= 0.17). Pure 6f was
obtained as a pale yellow oil (134 mg, 58%). H NMR (400 MHz,
CDCl3): δ 7.23−7.19 (m, 1H), 7.04−7.02 (m, 1H), 6.97−6.95 (m,
1H), 6.89−6.86 (m, 1H), 6.49 (dd, J = 14.0, 6.8 Hz, 1H), 4.77 (q, J =
6.8 Hz, 1H), 4.47 (dd, J = 14.0, 2.0 Hz, 1H), 4.17 (dd, J = 6.8, 2.0 Hz,
1H), 3.80 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.4
MHz, CDCl3): δ 159.2, 149.6, 129.3, 124.3, 123.4, 116.5, 115.1, 89.8,
87.7, 85.5, 65.1, 55.3, 21.8. GCMS (EI) m/z (%): 203 ([M + 1]+, 45),
202 (M+, 100), 188 (44), 159 (25). Anal. Calcd for C13H14O2: C,
77.20; H, 6.98. Found: C, 77.55; H, 7.01.
Vinylation of compound 5h (224 mg, 0.84 mmol) afforded 6h,
which was purified by flash chromatography (n-hexane/EtOAc, 20:1;
Rf = 0.30). Pure 6h was obtained as a pale yellow oil (148 mg, 60%).
1H NMR (400 MHz, CDCl3): δ 7.45−7.42 (m, 2H), 7.38−7.36 (m,
4H), 7.33−7.31 (m, 3H), 6.51 (dd, J = 14.0, 6.4 Hz, 1H), 4.78 (q, J =
6.8 Hz, 1H), 4.559 (s, 2H), 4.555 (s, 2H), 4.49 (dd, J = 14.0, 2.0 Hz,
1H), 4.18 (dd, J = 6.8, 2.0 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H). 13C{1H}
NMR (100.4 MHz, CDCl3): δ 149.6, 138.8, 138.0, 131.8, 128.4,
127.8, 127.7, 127.5, 121.6, 89.8, 87.9, 85.5, 72.2, 71.6, 65.1, 21.8.
GCMS (EI) m/z (%): 292 (M+, 3), 277 (100), 91 (19). Anal. Calcd
for C20H20O2: C, 82.16; H, 6.89. Found: C, 81.99; H, 7.05.
2-[4-(3-Vinyloxy-but-1-ynyl)-phenyl]-[1,3]dioxolane (6i). Alcohol
5i was prepared as reported for 5g, by Sonogashira coupling of 2-(4-
bromophenyl)-[1,3]dioxolane (515 mg, 2.2 mmol) and ( )-3-butyn-
2-ol (1.2 equiv). Purification by flash column chromatography (n-
hexane/EtOAc, 2:1; Rf = 0.27) afforded pure enynyl alcohol 5i (467
1
mg, 97%) which was used immediately in the next step. H NMR
(400 MHz, CDCl3): δ 7.43−7.39 (m, 4H), 5.79 (s, 1H), 4.76−4.69
(m, 1H), 4.12−3.99 (m, 4H), 2.33 (d, J = 4.8 Hz, 1H), 1.53 (d, J =
6.4 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 137.9, 131.6,
126.4, 103.2, 91.5, 83.6, 65.3, 58.7, 24.3.
Vinylation of compound 5i (186 mg, 0.85 mmol) afforded 6i,
which was purified by flash chromatography (n-hexane/EtOAc, 10:1;
Rf = 0.25). Pure 6i was obtained as a pale yellow oil (150 mg, 72%).
1H NMR (400 MHz, CDCl3): δ 7.46−7.40 (m, 4H), 4.49 (dd, J =
14.0, 6.8 Hz, 1H), 5.80 (s, 1H), 4.77 (q, J = 6.8 Hz, 1H), 4.47 (dd, J =
14.0, 2.0 Hz, 1H), 4.16 (dd, J = 6.8, 2.0 Hz, 1H), 4.13−4.01 (m, 4H),
1.60 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ
149.6, 138.2, 131.8, 126.4, 123.2, 103.2, 89.8, 88.4, 85.3, 65.3, 65.1,
21.8. GCMS (CI) m/z (%): 245 ([M + 1]+, 100), 73 (91). Anal.
Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.50; H, 6.92.
1-Bromo-4-(3-vinyloxy-but-1-ynyl)-benzene (6j). Vinylation of
compound 5j (225 mg, 1.0 mmol) afforded 6j, which was purified
by flash chromatography (n-hexane + 1% Et3N; Rf = 0.50). Pure 6j
[4-(3-Vinyloxy-but-1-ynyl)-benzyl]-carbamic Acid tert-Butyl Ester
(6g). To a solution of (4-bromobenzyl)-carbamic acid tert-butyl ester
(918 mg, 3.2 mmol) in anhydrous Et3N (16 mL) were added
(Ph3P)2PdCl2 (5 mol %), CuI (3 mol %) and ( )-3-butyn-2-ol (1.2
equiv), under nitrogen atmosphere, and the reaction mixture was
stirred at 50 °C (external) for 3 h. A second portion of ( )-3-butyn-
2-ol (0.5 equiv), CuI (1.5 mol %), and (Ph3P)2PdCl2 (2.5 mol %) was
then added. Heating was continued at 50 °C for 16 h. The mixture
was cooled to room temperature and water (16 mL) was added. The
product was extracted with Et2O (3 × 16 mL), and the combined
organic extracts were washed once with brine (50 mL) and dried over
anhydrous K2CO3. After filtration and evaporation of the solvent, the
crude reaction mixture purified by flash column chromatography (n-
hexane/EtOAc, 2:1 + 1% Et3N; Rf = 0.29) afforded pure enynyl
alcohol 5g (696 mg, 79%) which was used immediately in the next
1
was obtained as a pale yellow oil (191 mg, 76%). H NMR (400
MHz, CDCl3): δ 7.45−7.42 (m, 2H), 7.31−7.27 (m, 2H), 6.48 (dd, J
= 14.0, 6.8 Hz, 1H), 4.75 (q, J = 6.4 Hz, 1H), 4.47 (dd, J = 14.0, 2.0
Hz, 1H), 4.17 (dd, J = 6.8, 2.0 Hz, 1H), 1.59 (d, J = 6.4 Hz, 3H).
13C{1H} NMR (100.4 MHz, CDCl3): δ 149.6, 133.2, 131.5, 122.8,
121.3, 89.9, 89.1, 84.5, 65.0, 21.7. GCMS (EI) m/z (%): 252 (M+, 19)
and 250 (M+, 18), 237 (100) and 235 (86), 128 (55). Anal. Calcd for
C12H11BrO: C, 57.39; H, 4.42. Found: C, 57.54; H, 4.21.
1-Fluoro-3-(3-vinyloxy-but-1-ynyl)-benzene (6k). Vinylation of
compound 5k (150 mg, 0.92 mmol) afforded 6k, which was purified
by flash chromatography (n-hexane; Rf = 0.40). Pure 6k was obtained
1
step. H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.4 Hz, 2H), 7.21
(d, J = 8.0 Hz, 2H), 4.87 (br s, 1H), 4.77−4.72 (m, 1H), 4.33−4.24
(m, 2H), 2.08 (br s, 1H), 1.54 (d, J = 6.4 Hz, 3H), 1.45 (s, 9H).
13C{1H} NMR (100.4 MHz, CDCl3): δ 155.8, 139.3, 131.8, 127.3,
121.5, 91.0, 83.7, 58.8, 44.4, 28.4, 24.4.
1
as a colorless oil (119 mg, 68%). H NMR (400 MHz, CDCl3): δ
7.31−7.27 (m, 1H), 7.24−7.21 (m, 1H), 7.16−7.13 (m, 1H), 7.07−
7.01 (m, 1H), 6.50 (dd, J = 14.0, 6.8 Hz, 1H), 4.78 (q, J = 6.4 Hz,
G
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The Journal of Organic Chemistry
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1H), 4.49 (dd, J = 14.0, 2.0 Hz, 1H), 4.19 (dd, J = 6.8, 2.0 Hz, 1H),
1.61 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ
162.3 (d, JCF = 246.0 Hz), 149.6, 129.8 (d, JCF = 9.0 Hz), 127.6 (d, JCF
= 3.0 Hz), 124.1 (d, JCF = 10.0 Hz), 118.6 (d, JCF = 23.1 Hz), 115.9
(d, JCF = 21.1 Hz), 89.9, 88.8, 84.3 (d, JCF = 4.0 Hz), 64.9, 21.7.
GCMS (EI) m/z (%): 190 (M+, 26), 189 ([M − 1]+, 18), 175 (100),
146 (35), 127 (15). Anal. Calcd for C12H11FO: C, 75.77; H, 5.83.
Found: C, 75.59; H, 5.87.
14.0, 2.0 Hz, 1H), 4.23 (dd, J = 6.4, 2.0 Hz, 1H). 13C{1H} NMR
(100.4 MHz, CDCl3): δ 149.4, 137.7, 131.8, 128.7, 128.6, 128.3,
127.4, 122.2, 90.6, 88.3, 85.9, 71.2. GCMS (CI) m/z (%): 235 ([M +
1]+, 100).
1,2-Dichloro-4-(3-phenyl-1-vinyloxy-prop-2-ynyl)-benzene (6r).
Phenylacetylene (439 μL, 4.0 mmol) was added dropwise to a
solution of n-BuLi (1.6 M in hexanes, 2.75 mL, 4.4 mmol) in
anhydrous THF (9 mL) cooled at −78 °C (internal), keeping the
temperature below −70 °C. After 30 min, a solution of 3,4-
dichlorobenzaldehyde (840 mg, 4.8 mmol) in anhydrous THF (1.5
mL) was slowly added and, after further 5 min, the cooling bath was
removed, and the reaction mixture was stirred at room temperature
until complete consumption of the starting material (2.5 h). A satd
solution of NH4Cl (6 mL) was added under vigorous stirring,
followed by water (5 mL). The phases were separated and the
aqueous one was extracted by Et2O (3 × 10 mL). The combined
organic extracts were dried over anhydrous Na2SO4. After filtration
and evaporation of the solvent, crude 5r was isolated and purified by
flash chromatography (eluent: n-hexane/EtOAc, 10:1; Rf = 0.20),
affording pure enynyl alcohol 5r (1.02 g, 93%) which was used
immediately in the next step. 1H NMR (400 MHz, CDCl3): δ 7.71 (d,
J = 2.0 Hz, 1H), 7.49−7.45 (m, 4H), 7.37−7.32 (m, 3H), 5.65 (d, J =
4.8 Hz, 1H), 2.41 (d, J = 5.2 Hz, 1H). 13C{1H} NMR (100.4 MHz,
CDCl3): δ 140.7, 132.7, 132.4, 131.8, 130.6, 128.9, 128.7, 128.4,
126.0, 121.9, 87.6, 87.3, 63.8.
Vinylation of compound 5r (278 mg, 1.0 mmol) afforded 6r, which
was purified by flash chromatography (n-hexane/EtOAc, 75:1; Rf =
0.25). Pure 6r was obtained as a yellow oil (169 mg, 56%). 1H NMR
(400 MHz, CDCl3): δ 7.69 (d, J = 2.0 Hz, 1H), 7.50−7.47 (m, 3H),
7.44−7.42 (m, 1H), 7.37−7.33 (m, 3H), 6.55 (dd, J = 14.0, 6.4 Hz,
1H), 5.69 (s, 1H), 4.58 (dd, J = 14.0, 2.0 Hz, 1H), 4.27 (dd, J = 6.4,
2.0 Hz, 1H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 149.1, 137.9,
132.80, 132.78, 131.9, 130.6, 129.3, 129.0, 128.4, 126.6, 121.7, 91.3,
89.0, 84.6, 69.8. GCMS (CI) m/z (%): 305 ([M + 1]+, 70) and 303
([M + 1]+, 100), 304 (20). Anal. Calcd for C17H12Cl2O: C, 67.35; H,
3.99. Found: C, 67.55; H, 4.01.
4-(3-Vinyloxy-but-1-ynyl)-benzoic Acid Methyl Ester (6l). Vinyl-
ation of compound 5l (260 mg, 1.28 mmol) afforded 6l, which was
purified by flash chromatography (n-hexane/EtOAc, 25:1; Rf = 0.21).
1
Pure 6l was obtained as a pale yellow oil (232 mg, 79%). H NMR
(400 MHz, CDCl3): δ 7.99−7.95 (m, 2H), 7.50−7.47 (m, 2H), 6.48
(dd, J = 14.0, 6.4 Hz, 1H), 4.78 (d, J = 6.8 Hz, 1H), 4.47 (dd, J =
14.0, 2.0 Hz, 1H), 4.18 (dd, J = 6.4, 2.0 Hz, 1H), 3.91 (s, 3H), 1.60
(d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 166.4,
149.5, 131.7, 129.8, 129.4, 127.0, 90.8, 89.9, 84.8, 64.9, 52.5, 21.7.
GCMS (EI) m/z (%): 230 (M+, 3), 215 (100). Anal. Calcd for
C14H14O3: C, 73.03; H, 6.13. Found: C, 72.88; H, 6.39.
(3-Vinyloxyhex-1-ynyl)-benzene (6m). Vinylation of commercially
available compound 5m (158 μL, 0.86 mmol) afforded 6m, which was
purified by flash chromatography (n-hexane/EtOAc, 50:1; Rf = 0.40).
1
Pure 6m was obtained as a pale yellow oil (143 mg, 83%). H NMR
(400 MHz, CDCl3): δ 7.46−7.41 (m, 2H), 7.34−7.28 (m, 3H), 6.51
(dd, J = 14.0, 6.8 Hz, 1H), 4.64 (t, J = 6.8 Hz, 1H), 4.48 (dd, J = 14.0,
2.0 Hz, 1H), 4.15 (dd, J = 6.8, 2.0 Hz, 1H), 1.94−1.79 (m, 2H),
1.62−1.52 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100.4
MHz, CDCl3): δ 149.9, 131.8, 128.4, 128.2, 122.5, 89.6, 87.2, 86.3,
69.1, 37.5, 18.5, 13.7. GCMS (EI) m/z (%): 200 (M+, 6), 171 (100),
157 (20), 128 (29). Anal. Calcd for C14H16O: C, 83.96; H, 8.05.
Found: C, 84.12; H, 7.98.
(4-Phenyl-3-viniloxybut-1-ynyl)-benzene (6n). Vinylation of com-
pound 5n (363 mg, 1.63 mmol) afforded 6n, which was purified by
flash chromatography (n-hexane/EtOAc, 75:1; Rf = 0.34). Pure 6n
1
was obtained as a colorless oil (210 mg, 52%). H NMR (400 MHz,
CDCl3): δ 7.42−7.39 (m, 2H), 7.35−7.26 (m, 8H), 6.51 (dd, J =
14.4, 6.8 Hz, 1H), 4.84 (t, J = 6.8 Hz, 1H), 4.51 (dd, J = 14.4, 2.0 Hz,
1H), 4.18 (dd, J = 6.8, 2.0 Hz, 1H), 3.27−3.14 (m, 2H). 13C{1H}
NMR (100.4 MHz, CDCl3): δ 149.6, 136.5, 131.7, 129.8, 128.5,
128.3, 128.2, 126.8, 122.3, 89.9, 87.3, 86.6, 70.0, 41.9. GCMS (CI)
m/z (%): 249 ([M + 1]+, 100), 205 (22). Anal. Calcd for C18H16O:
C, 87.06; H, 6.49. Found: C, 86.85; H, 6.72.
(3-Viniloxy-but-1-ynyl)-benzene ([D]-6a). Vinylation of com-
pound [D]-5a (300 mg, 2.04 mmol) afforded [D]-6a, which was
purified by flash chromatography (n-hexane/EtOAc, 50:1; Rf = 0.30).
Pure [D]-6a was obtained as a colorless oil (223 mg, 63%). 1H NMR
(400 MHz, CDCl3): δ 7.48−7.42 (m, 2H), 7.34−7.28 (m, 3H), 6.51
(dd, J = 14.4, 6.4 Hz, 1H), 4.49 (dd, J = 14.4, 2.0 Hz, 1H), 4.18 (dd, J
= 6.8, 2.0 Hz, 1H), 1.61 (s, 3H). 13C{1H} NMR (100.4 MHz,
CDCl3): δ 149.6, 131.7, 128.5, 128.2, 122.3, 89.7, 87.8, 85.6, 64.7 (t,
(3-Methyl-3-vinyloxybut-1-ynyl)-benzene (6o). Vinylation of
compound 5o (191 mg, 1.19 mmol) afforded 6o, which was purified
by flash chromatography (n-hexane/EtOAc, 75:1; Rf = 0.30). Pure 6o
J
CD = 22.8 Hz), 21.7. GCMS (CI) m/z (%): 174 ([M + 1]+, 28), 146
(100).
General Procedure for the Gold(I)-Catalyzed Propargyl
1
was obtained as a colorless oil (164 mg, 74%). H NMR (400 MHz,
CDCl3): δ 7.45−7.42 (m, 2H), 7.33−7.29 (m, 3H), 6.76 (dd, J =
14.0, 6.4 Hz, 1H), 4.52 (dd, J = 14.0, 1.2 Hz, 1H), 4.16 (dd, J = 6.4,
1.2 Hz, 1H), 1.62 (s, 6H). 13C{1H} NMR (100.4 MHz, CDCl3): δ
147.4, 131.7, 128.5, 128.3, 122.4, 91.5, 90.2, 85.2, 72.6, 29.3. GCMS
(EI) m/z (%): 186 (M+, 14), 171 (100), 128 (13). Anal. Calcd for
C13H14O: C, 83.83; H, 7.58. Found: C, 84.02; H, 7.43.
Claisen Rearrangement/Hydroarylation Reaction Followed
by in Situ Reduction. The solution of 6 in n-hexane was
concentrated and dried under vacuum just prior use.
−
Gold(I) complex [IPrAu]+BF4 was prepared by adding an
equimolar amount of AgBF4 (as a 0.3 M solution in toluene) to a
0.003 M solution of IPrAuCl in DCM and leaving the mixture under
stirring for 1 min at 25 °C before adding the substrate.
(3,5-Dimethyl-3-viniloxyhex-1-ynyl)-benzene (6p). Vinylation of
compound 5p (193 mg, 0.96 mmol) afforded 6p, which was purified
by flash chromatography (n-hexane/EtOAc, 15:1; Rf = 0.80). Pure 6p
Method A. To a solution of gold(I) complex [IPrAu]+BF4− (3 mol
%) in DCM (3 mL; 0.003 M) stirred at 25 °C under nitrogen
atmosphere was added a solution of propargyl vinyl ether 6 (0.3
mmol) in DCM (3 mL; final concentration 0.05 M), and the reaction
mixture was stirred at 25 °C. After complete consumption of 6 (TLC
monitoring), the mixture was diluted with MeOH (12 mL) and
NaBH4 (0.3 mmol) was immediately added. After 10 min, the
reduction was completed. The solvent was then evaporated, water was
added to the residue (15 mL), and the product was extracted with
DCM (3 × 15 mL). The combined organic extracts were dried over
anhydrous K2CO3. After filtration and evaporation of the solvent, the
oily residue was purified by flash chromatography to give the
corresponding indene 10.
1
was obtained as a colorless oil (164 mg, 75%). H NMR (400 MHz,
CDCl3): δ 7.45−7.42 (m, 2H), 7.34−7.30 (m, 3H), 6.78 (dd, J =
14.0, 6.4 Hz, 1H), 4.50 (dd, J = 14.0, 0.8 Hz, 1H), 4.14 (dd, J = 6.4,
0.8 Hz, 1H), 2.06−1.99 (m, 1H), 1.82−1.69 (m, 2H), 1.59 (s, 3H),
1.05 (d, J = 6.4 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H). 13C{1H} NMR
(100.4 MHz, CDCl3): δ 147.3, 131.6, 128.4, 128.3, 122.5, 91.1, 89.8,
86.4, 75.7, 50.1, 27.9, 24.9, 24.1, 23.9. GCMS (EI) m/z (%): 228 (M+,
8), 185 (100). Anal. Calcd for C16H20O: C, 84.16; H, 8.83. Found: C,
84.05; H, 9.02.
(3-(Vinyloxy)prop-1-yne-1,3-diyl)dibenzene (6q).10d Vinylation of
compound 5q (284 μL, 1.5 mmol) afforded 6q, which was purified by
flash chromatography (n-hexane/EtOAc, 50:1; Rf = 0.40). Pure 6q
was obtained as a pale yellow oil (189 mg, 60%). H NMR (400
Method B. To a solution of gold(I) complex [IPrAu]+BF4− (3 mol
%) in DCM (3 mL; 0.003 M) stirred at 25 °C under nitrogen
atmosphere was added a solution of propargyl vinyl ether 6 (0.3
1
MHz, CDCl3): δ 7.62−7.59 (m, 2H), 7.50−7.47 (m, 2H), 7.47−7.30
(m, 6H), 6.58 (dd, J = 14.0, 6.4 Hz, 1H), 5.75 (s, 1H), 4.58 (dd, J =
H
DOI: 10.1021/acs.joc.9b00646
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−
mmol) in DCM (3 mL; final concentration 0.05 M), and the reaction
mixture was stirred at 25 °C. After complete consumption of 6 (TLC
monitoring), water (6 mL) was added and, after separation of the
layers, the aqueous one was extracted with DCM (3 × 6 mL) and the
combined organic extracts were dried over anhydrous Na2SO4. After
filtration and evaporation of the solvent, the oily residue was dissolved
in MeOH (12 mL) and NaBH4 (0.3 mmol) was added. After 10 min,
the reduction was completed. The solvent was then evaporated, water
was added to the residue (15 mL), and the product was extracted with
DCM (3 × 15 mL). The combined organic extracts were dried over
anhydrous K2CO3. After filtration and evaporation of the solvent, the
oily residue was purified by flash chromatography to give the
corresponding indene 10.
(85 mg, 0.42 mmol) and using [IPrAu]+BF4 as the catalyst. The
reaction was complete in 15 min. Purification by flash chromatog-
raphy (n-hexane/EtOAc, 4:1; Rf = 0.35) afforded pure 10e (68 mg,
79%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.21 (d, J =
8.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.4, 2.4 Hz, 1H),
6.14−6.12 (m, 1H), 3.91 (t, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.45−3.39
(m, 1H), 2.81−2.77 (m, 2H), 1.29 (d, J = 7.6 Hz, 3H). 13C{1H}
NMR (100.4 MHz, CDCl3): δ 158.3, 151.8, 138.4, 137.1, 135.1,
119.3, 111.5, 109.6, 61.0, 55.6, 43.8, 31.1, 16.6. GCMS (EI) m/z (%):
186 ([M − 18]+, 100), 171 (48). Anal. Calcd for C13H16O2: C, 76.44;
H, 7.90. Found: C, 76.26; H, 7.99.
2-(6-Methoxy-3-methyl-3H-inden-1-yl)-ethanol (10f). Com-
pound 10f was prepared following Method A, starting from 6f (86
mg, 0.42 mmol) and using [IPrAu]+BF4− as the catalyst. The reaction
was complete in 15 min. Purification by flash chromatography (n-
hexane/EtOAc, 4:1; Rf = 0.10) afforded pure 10f (64 mg, 74%) as a
2-(3-Methyl-3H-inden-1-yl)-ethanol (10a). Compound 10a was
prepared following Method A, starting from 6a (252 mg, 1.48 mmol)
and using [IPrAu]+BF4− as the catalyst. The reaction was complete in
25 min. Purification by flash chromatography (n-hexane/EtOAc, 12:1;
1
pale yellow oil. H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.0 Hz,
1
Rf = 0.16) afforded pure 10a (204 mg, 80%) as a pale yellow oil. H
1H), 6.87 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 8.0, 1.6 Hz, 1H), 6.29−
6.27 (m, 1H), 3.92 (q, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.45−3.39 (m,
1H), 2.82−2.77 (m, 2H), 1.49 (t, J = 5.6 Hz, 1H), 1.28 (d, J = 7.6 Hz,
3.H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 159.0, 145.5, 142.1,
138.7, 138.6, 123.1, 110.4, 105.1, 61.0, 55.6, 43.2, 31.0, 16.5. GCMS
(EI) m/z (%): 186 ([M − 18]+, 94), 171 (100). Anal. Calcd for
C13H16O2: C, 76.44; H, 7.90. Found: C, 76.55; H, 8.01.
NMR (400 MHz, CDCl3): δ 7.44−7.41 (m, 1H), 7.35−7.22 (m, 3H),
6.27 (m, 1H), 3.96−3.91 (m, 2H), 3.48 (qd, J = 7.6, 2.0 Hz, 1H),
2.86−2.81 (m, 2H), 1.32 (d, J = 7.6 Hz, 3H). 13C{1H} NMR (100.4
MHz, CDCl3): δ 149.9, 144.0, 138.8, 137.2, 126.3, 125.0, 122.7,
119.0, 61.0, 43.9, 31.0, 16.3. GCMS (EI) m/z (%): 156 ([M − 18]+,
62), 141 (100), 115 (35). Anal. Calcd for C12H14O: C, 82.72; H, 8.10.
Found: C, 82.53; H, 8.22.
[1-(2-Hydroxyethyl)-3-methyl-3H-inden-ylmethyl]-carbamic
Acid tert-Butyl Ester (10g). Compound 10g was prepared following
Method A, starting from 6g (60 mg, 0.20 mmol) and using
2-(3,5-Dimethyl-3H-inden-1-yl)-ethanol (10b). Compound 10b
was prepared following Method A, starting from 6b (88 mg, 0.48
[IPrAu]+BF4 as the catalyst. The reaction was complete in 15 min.
−
−
mmol) and using [IPrAu]+BF4 as the catalyst. The reaction was
Purification by flash chromatography (n-hexane/EtOAc, 2:1; Rf =
0.25) afforded pure 10g (38 mg, 62%) as a colorless oil. H NMR
complete in 15 min. Purification by flash chromatography (n-hexane/
EtOAc, 5:1; Rf = 0.37) afforded pure 10b (80 mg, 89%) as a pale
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.24 (s, 1H), 7.22 (d, J =
7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.21−6.18 (m, 1H), 3.94−3.89
(m, 2H), 3.43 (q, J = 7.2 Hz, 1H), 2.83−2.79 (m, 2H), 2.41 (s, 3H),
1.30 (d, J = 7.6 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ
150.2, 141.4, 138.6, 136.3, 134.8, 127.0, 123.7, 118.7, 61.0, 43.7, 31.1,
21.5, 16.4. GCMS (EI) m/z (%): 170 ([M − 18]+, 100), 155 (83),
128 (12). Anal. Calcd for C13H16O: C, 82.94; H, 8.57. Found: C,
82.73; H, 8.65.
1
(400 MHz, CDCl3): δ 7.33 (s, 1H), 7.27−7.26 (m, 1H), 7.21−7.18
(m, 1H), 6.26−6.24 (m, 1H), 4.84 (br s, 1H), 4.39−4.29 (m, 2H),
3.91 (q, J = 6.4 Hz, 2H), 3.47−3.41 (m, 1H), 2.83−2.79 (m, 2H),
1.54 (t, J = 5.6 Hz, 1H), 1.47 (s, 9H), 1.29 (d, J = 7.6 Hz, 3H).
13C{1H} NMR (100.4 MHz, CDCl3): δ 155.9, 150.4, 143.4, 138.6,
137.4, 135.8, 125.8, 122.2, 119.0, 61.0, 44.9, 43.8, 31.0, 28.4, 16.3.
HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C18H25NO3Na,
326.1727; found, 326.1740.
2-(3,7-Dimethyl-3H-inden-1-yl)ethanol (10c). Compound 10c
was prepared following Method A, starting from 6c (72 mg, 0.39
2-(5-Benzyloxymethyl-3-methyl-3H-inden-1-yl)-ethanol (10h).
Compound 10h was prepared following Method A, starting from
6h (72 mg, 0.25 mmol) and using commercially available [IPrAu-
−
mmol) and using [IPrAu]+BF4 as the catalyst. The reaction was
−
(CH3CN)]+BF4 as the catalyst. The reaction was complete in 50
complete in 1.5 h. Purification by flash chromatography (n-hexane/
Et2O, 3:1 + 1% Et3N; Rf = 0.20) afforded pure 10c (52 mg, 71%) as a
min. Purification by flash chromatography (n-hexane/Et2O + 1%
Et3N, 3:1; Rf = 0.12) afforded pure 10h (55 mg, 75%) as a colorless
1
colorless oil. H NMR (400 MHz, CDCl3): δ 7.26−7.24 (m, 1H),
1
7.13−7.09 (m, 1H), 7.03−7.01 (m, 1H), 6.21 (m, 1H), 3.97−3.92
(m, 2H), 3.41−3.36 (m, 1H), 3.03−2.99 (m, 2H), 2.57 (s, 3H), 1.56
(t, J = 6.0 Hz, 1H), 1.28 (d, J = 7.6 Hz, 1H). 13C{1H} NMR (100.4
MHz, CD3OD): δ 152.0, 142.9, 141.7, 137.8, 131.6, 130.2, 125.9,
121.6, 62.5, 44.3, 34.8, 20.3, 17.1. GCMS (EI) m/z (%): 188 (M+,
10), 170 ([M − 18]+, 9), 157 (70), 144 (100), 115 (26). Anal. Calcd
for C13H16O: C, 82.94; H, 8.57. Found: C, 82.78; H, 8.71.
oil. H NMR (400 MHz, CD3OD): δ 7.40−7.24 (m, 10H), 6.25−
6.23 (m, 1H), 4.58 (s, 2H), 4.54 (s, 2H), 3.84 (t, J = 7.2 Hz, 2H),
3.45−3.39 (m, 1H), 1.27 (d, J = 7.6 Hz, 3H). 13C{1H} NMR (100.4
MHz, CD3OD): δ 151.5, 145.4, 140.3, 139.6, 137.9, 136.0, 129.4,
129.0, 128.7, 127.5, 123.7, 119.7, 73.6, 73.0, 61.7, 44.9, 31.9, 16.7.
HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C20H22O2Na,
317.1512; found, 317.1529.
2-(3,6-Dimethyl-3H-inden-1-yl)ethanol (10d). Compound 10d
was prepared following Method A, starting from 10d (91 mg, 0.49
(1-[1,3]Dioxolan-2-ylmethyl-3-methyl-3H-inden-5-yl)-methanol
(10i). Compound 10i was prepared following Method B, starting from
6i (105 mg, 0.43 mmol) and using commercially available
−
mmol) and using [IPrAu]+BF4 as the catalyst. The reaction was
−
[IPrAu(CH3CN)]+BF4 as the catalyst (6 mol %). The reaction
complete in 15 min. Purification by flash chromatography (n-hexane/
EtOAc, 5:1; Rf = 0.20) afforded 10d (71 mg, 77%) as a colorless oil.
1H NMR (400 MHz, CDCl3) (1:1 mixture of 3,6- and 3,4-dimethyl-
substituted products): δ 7.31 (d, J = 7.6 Hz, 1H), 7.24−7.15 (m, 3H),
7.07−7.05 (m, 1H), 7.03−7.02 (m, 1H), 6.26−6.23 (m, 1 H both
compounds), 3.97−3.88 (m, 2 H both compounds), 3.46−3.50 (m,
1H), 3.47−3.41 (m, 1H), 2.84−2.79 (m, 2 H both compounds), 2.45
(s, 3H), 2.42 (s, 3H), 1.32 (d, J = 7.2 Hz, 3H), 1.29 (d, J = 7.6 Hz,
3H). 13C{1H} NMR (100.4 MHz, CDCl3) (1:1 mixture of 3,6- and
3,4-dimethyl-substituted products): δ 147.6, 147.0, 144.2, 144.0,
138.7, 138.4, 137.61, 137.59, 135.9, 133.1, 126.9, 126.7, 125.8, 122.5,
119.7, 116.7, 61.05, 61.03, 43.49, 43.48, 31.03, 30.99, 21.5, 18.8, 16.4,
15.0. GCMS (EI) m/z (%): 170 ([M − 18]+, 87), 155 (100). Anal.
Calcd for C13H16O: C, 82.94; H, 8.57. Found: C, 82.88; H, 8.67.
2-(5-Methoxy-3-methyl-3H-inden-1-yl)-ethanol (10e). Com-
pound 10e was prepared following Method A, starting from 10e
was complete in 2 h. Purification by flash chromatography (n-hexane/
Et2O, 2:1 + 1% Et3N; Rf = 0.28) afforded pure 10i (67 mg, 63%) as a
1
colorless oil. H NMR (400 MHz, CDCl3): δ 7.42−7.26 (m, 3H),
6.34−6.33 (m, 1H), 5.18 (t, J = 4.8 Hz, 1H), 4.74−4.72 (m, 2H),
4.01−3.99 (m, 2H), 3.90−3.88 (m, 2H), 3.50−3.44 (m, 1H), 2.91−
2.88 (m, 2H), 1.31 (d, J = 7.6 Hz, 3H). 13C{1H} NMR (100.4 MHz,
CDCl3): δ 150.1, 144.2, 138.4, 137.6, 136.8, 125.4, 121.7, 119.3,
103.5, 65.0, 43.9, 32.9, 29.7, 16.1. GCMS (CI) m/z (%): 246 (M+,
34), 230 (100), 73 (52). HRMS (ESI/TOF) m/z: [M + Na]+ calcd
for C15H18O3Na, 269.1148; found, 269.1132.
2-(5-Bromo-3-methyl-3H-inden-1-yl)-ethanol (10j). Compound
10j was prepared following Method A, starting from 6j (62 mg, 0.25
−
mmol) and using [IPrAu]+BF4 as the catalyst. The reaction was
complete in 6 h. Purification by flash chromatography (n-hexane/
EtOAc, 4:1; Rf = 0.32) afforded pure 10j (35 mg, 56%) as a white
I
DOI: 10.1021/acs.joc.9b00646
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The Journal of Organic Chemistry
Article
1
foam. 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 1.6 Hz, 1H), 7.41
(dd, J = 8.0, 1.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.25−6.23 (m,
1H), 3.92 (t, J = 6.4 Hz, 2H), 3.48−3.42 (m, 1H), 2.81−2.76 (m,
2H), 1.29 (d, J = 7.6 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3):
δ 152.0, 143.0, 138.4, 137.4, 129.3, 126.2, 120.3, 119.3, 61.0, 43.9,
30.9, 16.1. GCMS (EI) m/z (%): 254 (M+, 5) and 252 (M+, 5), 161
(66), 133 (100), 105 (92). Anal. Calcd for C12H13BrO: C, 56.94; H,
5.18. Found: C, 56.45; H, 5.52.
afforded pure 10n (60 mg, 69%) as a colorless oil. H NMR (400
MHz, CD3OD): δ 7.30−7.10 (m, 9H), 6.17 (s, 1H), 3.77 (t, J = 7.2
Hz, 2H), 3.68−3.64 (m, 1H), 3.06 (dd, J = 13.2, 6.8 Hz, 1H), 2.74−
2.68 (m, 3H). 13C{1H} NMR (100.4 MHz, CD3OD): δ 147.0, 144.1,
139.7, 139.3, 133.1, 128.2, 127.1, 125.5, 125.1, 123.7, 122.3, 117.9,
59.7, 49.8, 37.2, 29.9. HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C18H18O, 251.1430; found, 251.1419.
2-(3,3-Dimethyl-3H-inden-1-yl)-ethanol (10o). Compound 10o
was prepared following Method A, starting from 6o (86 mg, 0.53
2-(6-Fluoro-3-methyl-3H-inden-1-yl)-ethanol (10k). Compound
10k was prepared following Method A, starting from 6k (98 mg, 0.52
−
mmol) and using [IPrAu]+BF4 as the catalyst. The reaction was
−
mmol) and using [IPrAu]+BF4 as the catalyst. The reaction was
complete in 3.5 h. Purification by flash chromatography (n-hexane/
Et2O, 2:1; Rf = 0.12) afforded pure 10o (93 mg, 93%) as a colorless
oil. H NMR (400 MHz, CDCl3): δ 7.35−7.32 (m, 1H), 7.29−7.20
(m, 3H), 6.16 (m, 1H), 3.95−3.89 (m, 2H), 2.81−2.77 (m, 2H), 1.61
(t, J = 5.6 Hz, 1H), 1.32 (s, 6H). 13C{1H} NMR (100.4 MHz,
CDCl3): δ 154.1, 143.2, 142.8, 136.3, 126.3, 125.3, 121.2, 119.2, 61.0,
48.4, 30.8, 24.7. GCMS (CI) m/z (%): 189 ([M + 1]+, 100), 172
(70), 146 (87). Anal. Calcd for C13H16O: C, 82.94; H, 8.57. Found:
C, 82.67; H, 8.72.
complete in 16 h. Purification by flash chromatography (n-hexane/
EtOAc, 4:1; Rf = 0.20) afforded 10k (74 mg, 74%) as a colorless oil.
1H NMR (400 MHz, CDCl3) (1.2:1 mixture of 3H-isomer and 1H-
isomer): δ 7.32−7.29 (m, 1H), 7.20−7.18 (m, 1H), 7.13−7.10 (m,
1H), 7.02−6.97 (m, 2H), 6.93−6.87 (m, 1H), 6.33 (s, 1H, 3H-
isomer), 6.20 (s, 1H, 1H-isomer), 3.94−3.89 (m, 2H, 3H-isomer),
3.73−3.68 (m, 2H, 1H-isomer), 3.55−3.51 (m, 1H, 1H-isomer),
3.46−3.40 (m, 1H, 1H-isomer), 2.82−2.75 (m, 2H), 2.19−2.11 (m,
1H + 3 H 3H-isomer), 1.79−1.73 (m, 1H), 1.28 (d, J = 7.6 Hz, 3 H
3H-isomer). 13C {1H} NMR (100.4 MHz, CDCl3) (1.2:1 mixture of
3H-isomer and 1H-isomer): δ 163.2 (d, JCF = 80.3 Hz), 160.8 (d, JCF
= 80.3 Hz), 150.1 (d, JCF = 8.0 Hz), 146.0 (d, JCF = 9.0 Hz), 145.1 (d,
1
2-(3-Isobutyl-3-methyl-3H-inden-1-yl)-ethanol (10p). Compound
10p was prepared following Method A, starting from 6p (105 mg,
−
0.46 mmol) and using [IPrAu]+BF4 as the catalyst (6 mol %). The
reaction was complete in 16 h. Purification by flash chromatography
(n-hexane/EtOAc, 4:1; Rf = 0.30) afforded pure 10p (97 mg, 92%) as
a colorless oil. H NMR (400 MHz, CDCl3): δ 7.30−7.18 (m, 4H),
6.17 (s, 1H), 3.92 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 1.82−1.70 (m,
2H), 1.27 (s, 3H), 1.22−1.15 (m, 1H), 0.81 (d, J = 6.8 Hz, 3H), 0.55
(d, J = 6.4 Hz, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 153.2,
143.5, 141.8, 136.8, 126.2, 125.1, 121.5, 119.0, 61.1, 52.3, 47.5, 30.9,
25.6, 25.3, 25.0, 24.3. GCMS (EI) m/z (%): 230 (M+, 4), 174 (25),
143 (100), 130 (34). Anal. Calcd for C16H22O: C, 83.43; H, 9.63.
Found: C, 83.26; H, 9.71.
(3-Methyl-3H-inden-1-yl)-acetaldehyde ([D]-8a). Aldehyde [D]-
8a was prepared following Method B (first step only), starting from
[D]-7a (38 mg, 0.12 mmol) and using [IPrAu]+BF4− as the catalyst (3
mol %). The reaction was complete in 35 min. After filtration and
evaporation of the solvent, the 1H NMR analysis of the crude mixture
showed the presence of aldehydes [D]-8a (77%) and 8a (23%). [D]-
J
CF = 2.0 Hz), 141.3 (d, JCF = 2.0 Hz), 139.2, 138.4 (d, JCF = 3.0 Hz),
133.0 (d, JCF = 4.0 Hz), 123.3 (d, JCF = 9.0 Hz), 119.6 (d, JCF = 9.0
Hz), 115.0 (d, JCF = 3.0 Hz), 113.1 (d, JCF = 22.1 Hz), 111.5 (d, JCF
1
=
23.1 Hz), 110.5 (d, JCF = 23.1 Hz), 106.2 (d, JCF = 23.1 Hz), 61.3,
60.9, 45.9 (d, JCF = 3.0 Hz), 43.3, 34.4, 30.8, 16.3, 13.0. GCMS (EI)
m/z (%): 192 (M+, 26), 161 (100), 148 (63). Anal. Calcd for
C12H13FO: C, 74.98; H, 6.82. Found: C, 74.89; H, 7.02.
1-(2-Hydroxyethyl)-3-methyl-3H-indene-5-carboxylic Acid Meth-
yl Ester (10l). Compound 10l was prepared following Method A but
heating at 40 °C (external), starting from 6l (58 mg, 0.25 mmol) and
using [IPrAu]+BF4− as the catalyst. The reaction was complete in 7 h.
Purification by flash chromatography (n-hexane/EtOAc, 4:1; Rf =
1
0.18) afforded 10l (42 mg, 72%) as a colorless oil. H NMR (400
MHz, CDCl3) (1:1 mixture of 3H-isomer and 1H-isomer): δ 8.06 (s,
1H), 8.01−7.98 (m, 1H), 7.94 (s, 1H), 7.93−7.91 (m, 1H), 7.45 (d, J
= 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.44−6.42 (m, 1H), 6.30−
6.29 (m, 1H), 3.95−3.90 (m, 2H, 1H-isomer), 3.93 (s, 3H), 3.92 (s,
3H), 3.71 (t, J = 6.4 Hz, 2H, 3H-isomer), 3.62−3.57 (m, 1H, 1H-
isomer), 3.53−3.47 (m, 1H, 3H-isomer), 2.85−2.80 (m, 2H, 3H-
isomer), 2.22−2.14 (m, 1H, 1H-isomer), 2.17 (t, J = 1.6 Hz, 3H, 1H-
isomer), 1.81−1.74 (m, 1H, 1H-isomer), 1.32 (d, J = 7.6 Hz, 3H, 3H-
isomer). 13C{1H} NMR (100.4 MHz, CDCl3) (1:1 mixture of 3H-
isomer and 1H-isomer): δ 167.7, 167.6, 153.2, 149.7, 148.8, 145.8,
140.7, 138.9, 138.8, 134.3, 128.7, 128.5, 126.7, 126.6, 123.7, 122.5,
120.1, 118.7, 61.3, 61.0, 52.02, 51.98, 46.1, 44.0, 34.2, 30.8, 15.9, 12.9.
GCMS (EI) m/z (%): 233 ([M + 1]+, 13), 215 (35), 202 (56), 189
(100). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.31;
H, 7.09.
1
8a. H NMR (400 MHz, CDCl3): δ = 9.76 (t, J = 1.6 Hz, 1H), 7.64
(d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.22−4.16 (m, 1H),
3.72 (dt, J = 16.8, 1.2 Hz, 1H), 3.41 (dt, J = 16.8, 1.2 Hz, 1H), 3.04−
2.96 (m, 1H), 2.43 (s, 3H), 2.09−2.00 (m, 2H), 1.86 (s, 3H), 1.53−
1.46 (m, 1H), 1.28−1.16 (m, 1H), 1.00−0.88 (m, 1H) ppm.
3-Allyl-1,1-dimethyl-1H-indene (11). The solution of 6o in n-
hexane was concentrated and dried under vacuum just prior use. A
solution of gold(I) complex [IPrAu]+BF4− (3 mol %) was prepared by
adding AgBF4 (0.3 M solution in toluene, 62 μL, 0.019 mmol) to a
solution of IPrAuCl (12 mg, 0.019 mmol) in DCM (6.3 mL) at 25 °C
under nitrogen atmosphere and, after 1 min, a solution of propargyl
vinyl ether 6o (100 mg, 0.62 mmol) in DCM (6.3 mL) was added.
The resulting reaction mixture was stirred at 25 °C for 3.5 h.
A solution of commercially available methyltriphenylphosphonium
bromide (450 mg, 1.26 mmol) in anhydrous THF (24 mL) was
cooled to 0 °C and a 1.0 M solution of t-BuOK in THF (1.36 mL,
1.36 mmol) was then added dropwise. After 30 min, the crude
reaction mixture containing aldehyde 8o was slowly added, and the
resulting mixture was stirred at 0 °C. After complete consumption of
8o (TLC monitoring; 30 min), the mixture was quenched by the
addition of brine (50 mL) and the product was extracted by Et2O (2
× 30 mL) and DCM (30 mL), and the combined organic extracts
were dried over anhydrous Na2SO4. After filtration and evaporation of
the solvent, the oily residue was purified by flash chromatography (n-
hexane + 1% Et3N; Rf = 0.43) affording pure 11 (80 mg, 70%) as a
2-(3-Propyl-3H-inden-1-yl)-ethanol (10m). Compound 10m was
prepared following Method A, starting from 6m (80 mg, 0.40 mmol)
−
and using commercially available [IPrAu(CH3CN)]+BF4 as the
catalyst. The reaction was complete in 1 h. Purification by flash
chromatography (n-hexane/Et2O, 8:1 + 1% Et31N; Rf = 0.26) afforded
pure 10m (57 mg, 70%) as a colorless oil. H NMR (400 MHz,
CD3OD): δ 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.22 (t,
J = 7.2 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 6.29 (s, 1H), 3.84 (t, J = 7.2
Hz, 2H), 3.42−3.34 (m, 1H), 2.76 (t, J = 7.2 Hz, 2H), 1.91−1.80 (m,
1H), 1.47−1.33 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100.4 MHz, CD3OD): δ 147.9, 144.0, 139.1, 133.4, 125.2, 123.8,
121.8, 117.8, 59.8, 48.2, 33.2, 30.0, 19.8, 12.7. GCMS (EI) m/z (%):
202 (M+, 38), 171 (50), 158 (98), 129 (100). Anal. Calcd for
C14H18O: C, 83.12; H, 8.97. Found: C, 83.01; H, 9.15.
1
colorless oil. H NMR (400 MHz, CDCl3): δ 7.34−7.31 (m, 1H),
7.28−7.19 (m, 3H), 6.09−5.99 (m, 2H), 5.21−5.16 (m, 1H), 5.14−
5.11 (m, 1H), 3.28−3.24 (m, 2H), 1.32 (s, 6H). 13C{1H} NMR
(100.4 MHz, CDCl3): δ 154.1, 143.1, 142.2, 138.0, 135.6, 126.2,
125.0, 121.0, 119.4, 116.2, 48.1, 32.0, 24.7. GCMS (CI) m/z (%): 185
([M + 1]+, 100). Anal. Calcd for C14H16: C, 91.25; H, 8.75. Found: C,
90.93; H, 9.03.
2-(3-Benzyl-3H-inden-1-yl)-ethanol (10n). Compound 10n was
prepared following Method B, starting from 6n (87 mg, 0.35 mmol)
−
and using commercially available [IPrAu(CH3CN)]+BF4 as the
catalyst (6 mol %). The reaction was complete in 2 h. Purification by
flash chromatography (n-hexane/Et2O, 4:1 + 1% Et3N; Rf = 0.17)
J
DOI: 10.1021/acs.joc.9b00646
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1,1-Dimethyl-3-oct-2-enyl-1H-indene (12). Compound 12 was
prepared as reported for 11, starting from 6o (112 mg, 0.69 mmol)
and n-hexylphosphonium iodide34 (656 mg, 1.38 mmol). The Wittig
reaction was complete in 45 min. Purification by flash chromatog-
raphy (n-hexane; Rf = 0.50) afforded pure 12 (140 mg, 80%) as a
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1
colorless oil. H NMR (400 MHz, CDCl3): δ 7.32−7.18 (m, 4H),
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0.92−0.88 (m, 3H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 154.2,
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0.72 mmol). The Wittig reaction was complete in 30 min. Purification
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1
pure 14 (80 mg, 71%) as a pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.27−7.15 (m, 4H), 6.05 (t, J = 2.0 Hz, 1.6H), 5.85−5.78
(m, 1H), 5.67−5.60 (m, 1H), 4.95 (t, J = 4.8 Hz, 1H), 4.03−3.96 (m,
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335.1982; found, 335.1972.
Computational Methods. All structures were initially optimized
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solvent = DCM).40 The stationary points were characterized by
frequency calculations in order to verify that they have the right
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00646.
■
S
Copies of 1H and 13C NMR spectra of all new
compounds and Cartesian coordinates and energies of
the structures included in the manuscript (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: dina.scarpi@unifi.it (D.S.).
*E-mail: ernesto.occhiato@unifi.it (E.G.O.).
■
ORCID
́
Enrique Gomez-Bengoa: 0000-0002-8753-3760
Dina Scarpi: 0000-0001-7211-4881
Ernesto G. Occhiato: 0000-0003-2187-2409
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from University of Florence is acknowl-
edged. Dr Alessandro Pratesi and Dr Susanna Pucci are
acknowledged for technical assistance. Ente Cassa di Risparmio
di Firenze is acknowledged for granting a 400 MHz NMR
instrument. G.Z. and E.G.-B. thank the European Funding
Horizon 2020-MSCA (ITN-EJD CATMEC 14/06-721223)
and also SGiker (UPV/EHU) for human and technical
support.
K
DOI: 10.1021/acs.joc.9b00646
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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́
(11) Rinaldi, A.; Petrovic, M.; Magnolfi, S.; Scarpi, D.; Occhiato, E.
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̀
(a) Gatineau, D.; Goddard, J.-P.; Mouries-Mansuy, V.; Fensterbank,
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(12) Gold(I)-catalyzed cascade processes in which allene inter-
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rings fused to other ring systems through a final Nazarov cyclization
(21) IPr is a weaker ligand than the corresponding saturated SIPr
and therefore could leave the metal center more electron poor than its
saturated congener. Consequently, its metal complexes could be more
reactive in activating unsaturations toward nucleophilic attacks.
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step, too. (a) Lemiere, G.; Gandon, V.; Cariou, K.; Fukuyama, T.;
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(22) For this reason aldehyde 8a was characterized as crude reaction
1
mixture. Diagnostic H NMR signals are the quartet at 3.53 ppm for
the proton at C1 which couples with the methyl at the same position
and which resonates as a doublet at 1.33 ppm. 2-H is a singlet at 6.40
ppm and the CHO proton is found a 9.79 ppm as a triplet. See
1
Supporting Information for H and 13C NMR spectra.
(23) (a) The structure of isomer 10f was assigned on the basis of the
chemical shift and coupling constants of aromatic protons. The two
protons ortho to the methoxy group (at positions 4 and 6) are
shielded and resonate below 7.00 ppm. The 4-H is a doublet at 6.87
4
ppm with a very small J with the proton at position 6 (0.6 Hz) and
the latter is a doublet of doublets at 6.77 ppm with a larger vicinal
coupling constant (8 Hz) with 7-H which resonates as a doublet at
7.29 ppm. (b) The ratio between the 5-F and 7-F isomers was 85:15
in the crude reaction mixture. The structure of major isomer 10k was
assigned (for both double bond isomers) on the basis of the chemical
shift and coupling constants of aromatic protons. The two protons
ortho to the F atom at C4 and C6 resonates as dd (3JHF = 8.8 Hz and
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Synthesis of Bruceolline H. Org. Lett. 2016, 18, 3922−3925.
́
́
3
3
4JHH = 2.4 Hz) and ddd (4JHH = 2.4 Hz, JHH = 8.4 Hz, JHF = 8.7
Hz,), respectively. The proton at C7 resonates instead as a dd (4JHF
=
́
́
(c) Petrovic, M.; Scarpi, D.; Fiser, B.; Gomez-Bengoa, E.; Occhiato,
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3
5.2 Hz and JHH = 8.4 Hz).
(24) The structure of compound 10i was assigned by analysis of 1H,
13C and bidimensional NMR spectra (gCOSY and gHSQC) (see
Supporting Information). Diagnostic 1H NMR signals (in CDCl3) are
the triplet at 5.19 ppm for the proton of the dioxolane moiety which
couples with the side chain CH2 group at C3, which in turn is a
doublet at 2.90 ppm The benzylic protons at C6 is a doublet at 4.73
ppm for the coupling with the proton of the hydroxyl group.
(25) In some cases we observed a slow isomerization in CDCl3 (for
example when recording 13C NMR spectra overnight) and in such
cases we used CD3OD as the solvent for the characterization.
(26) The possibility that, in general, a concerted process be
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1
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