Synthesis of (±)-epi-Jungianol by the Gold(I)-Catalyzed Propargyl Claisen Rearrangement/Hydroarylation Cascade Reaction of Propargyl Vinyl Ethers

Article abstract of DOI:10.1002/ejoc.202001555

The synthesis of (±)-epi-jungianol was successfully carried out by the gold(I)-catalyzed propargyl Claisen rearrangement/hydroarylation cascade reaction of suitably substituted propargyl vinyl ethers as the key step to form the indane skeleton. Two routes were compared, which involved substrates with a different degree of substitution on the vinyl moiety. The one based on a propargyl vinyl ether bearing an unsubstituted vinyl moiety, despite entailing two additional steps, provided the final compound in a higher overall yield. A method for the preparation of acid sensitive propargyl vinyl ethers with an α-alkyl-substituted vinyl moiety and their reactivity under gold catalysis is also reported.

Full text of DOI:10.1002/ejoc.202001555

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Synthesis of (�)-epi-Jungianol by the Gold(I)-Catalyzed
Propargyl Claisen Rearrangement/Hydroarylation Cascade
Reaction of Propargyl Vinyl Ethers
[a]
[a]
[a]
[a]
Antonia Rinaldi, Vittoria Langé, Dina Scarpi, and Ernesto G. Occhiato*
Dedicated to Professor Franco Cozzi on the occasion of his 70th birthday.
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The synthesis of (�)-epi-jungianol was successfully carried out
by the gold(I)-catalyzed propargyl Claisen rearrangement/
hydroarylation cascade reaction of suitably substituted prop-
argyl vinyl ethers as the key step to form the indane skeleton.
Two routes were compared, which involved substrates with a
different degree of substitution on the vinyl moiety. The one
based on a propargyl vinyl ether bearing an unsubstituted vinyl
moiety, despite entailing two additional steps, provided the
final compound in a higher overall yield. A method for the
preparation of acid sensitive propargyl vinyl ethers with an α-
alkyl-substituted vinyl moiety and their reactivity under gold
catalysis is also reported.
1. Introduction
Cascade reactions allow for structural modifications on the
organic compounds through the formation of several chemical
bonds in one-pot, which results in the reduction of the number
of steps in the synthesis of complex compounds. To this end,
[1]
gold-catalysis, has been extensively exploited, especially in
[2]
cycloisomerization processes, to construct various cyclic and
heterocyclic frameworks through cascade reactions triggered
by activation of a triple bond, which have ultimately led to the
[3]
total synthesis of several natural compounds. In the context of
our studies on Au(I)-catalyzed synthesis of hetero- and
[4]
carbacycles, we have recently reported that propargyl vinyl
ethers 1 (Scheme 1, a) are suitable substrates for a cascade
process which entails the Au(I)-catalyzed propargyl Claisen
rearrangement of 1 and the hydroarylation reaction of the
Au(I)-allene complex intermediate to give differently substituted
Scheme 1. Au(I)-catalyzed propargyl Claisen rearrangement/hydroarylation
cascade reactions and synthetic approach to (�)-epi-jungianol.
,[5,6]
indenes 2 bearing an aldehyde appendage at C3.
To
demonstrate the usefulness of this approach in the synthesis of
target compounds, we focused our attention on epi-jungianol 5
Me) would be a more advanced intermediate in the synthesis of
5. However, ketones 4 (R=alkyl) would derive from the Au(I)-
catalyzed propargyl Claisen rearrangement/hydroarylation reac-
tion of propargyl vinyl ethers 3 bearing an α-alkyl group on the
vinyl moiety for which there are no available synthetic
(Scheme 1, b), an epimer of jungianol (which has 1,3-trans
configuration) isolated in 1977 from a South American plant,
[7]
Jungia malvaefolia, by Bolhmann et al. To date, only two
[8,9]
[10]
synthetic approaches of both epimers have been reported,
and in one of these, gold catalysis has been instrumental for
methods. In this paper we describe our approach to prepare
such substituted vinyl ethers, their behavior under gold(I)-
catalysis, and the application to the synthesis of epi-jungianol
via Au(I) catalysis. The alternate approach from a propargyl vinyl
ether of type 1 is also reported.
[9]
the construction of the indane ring. Although, as we will show
later, epi-jungianol can be prepared via a suitably substituted
aldehyde 2, we envisaged that the corresponding ketone 4 (R=
[a] Dr. A. Rinaldi, V. Langé, Dr. D. Scarpi, Prof. Dr. E. G. Occhiato
Dipartimento di Chimica “U. Schiff”
2
. Results and Discussion
Università degli Studi di Firenze
Via della Lastruccia 13, 50019, Sesto Fiorentino (FI), Italy
E-mail: ernesto.occhiato@unifi.it
https://www.unifi.it/p-doc2-2019-200010-O-3f2a3d31332e29-0.html
In our previous studies, in most cases we prepared vinyl ethers
1
by treatment of the propargyl alcohols with ethyl vinyl ether
[5,6]
in the presence of Hg(OAc)2,
but to avoid the use of this toxic
Supporting information for this article is available on the WWW under
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salt we also found convenient to react the corresponding
propargyl acetates with 2-bromo-1-ethanol in the presence of
Part of the “Franco Cozzi’s 70th Birthday” Special Collection.
Eur. J. Org. Chem. 2021, 1266–1273
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[
11]
InCl in nitromethane at 50°C, followed by elimination of HBr
because we discovered that only one (the major) of the two
diastereomers of 11a underwent elimination of HBr. Also, in
this case we tried many different reaction conditions, but it was
always the same diastereomer that gave target product 12a,
while the other, whose relative stereochemistry could not be
assigned, did not react and it was recovered unaltered. Under
the best conditions (5 h at 25°C, with 1.2 eq of t-BuOK and
5 mol% 18-crown-6) compounds 12a and 12b were obtained
in 50 and 51% yield respectively after chromatography on
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[12]
by t-BuOK in toluene. In order to extend this approach to the
synthesis of propargyl vinyl ethers 3 with an α-alkyl group on
the vinyl moiety, we first prepared three 1-bromo-2-alkanols
8a–c, Scheme 2) according to reported procedures, i.e. by
reacting the corresponding methyl ketones 6 with Br in
(
2
[13]
MeOH and then reducing by NaBH the formed α-bromoke-
4
[14]
tones 7 to the bromoalcohols 8. Compounds 8a and 8b were
used to find the best reaction conditions with model acetate 10
for the synthesis of the propargyl vinyl ethers 12 (Scheme 3)
and to study the Au(I)-catalyzed reaction of the latter, while 1-
bromo-2-propanol 8c (R=Me) was used for the synthesis of
epi-jungianol.
[15]
alumina.
To explain the lack of reactivity of the minor
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diastereomer, as the process is likely an E elimination in which
2
the base removes a proton antiperiplanar to the leaving
bromide anion, we reasoned that only with one of the two
diastereomers of 11 a transition state without too much steric
hindrance be possible. To prove this, we reacted dimethyl-
substituted propargyl alcohol 13 with bromoalcohol 8a in the
In the InCl -catalyzed reaction with acetate 10, secondary
alcohols 8a–b proved less reactive than 2-bromo-1-ethanol.
3
[5]
By heating in nitromethane at 60°C, with 5 mol% of the
catalyst, the reaction of 10 with 8a (2 equiv.) was slow and,
after 2.5 h, only about 60% of the starting material was
converted into 11a, without reacting furtherly. The reaction
was thus stopped and, after chromatography, 11a was
obtained in 50% yield, while recovering unreacted 10 (36%).
This was reacted again under the same conditions obtaining at
the end 11a in 67% overall yield as a 1.4:1 mixture of
diastereomers. With the same approach 11b was obtained in
[
16]
presence of FeCl3
to obtain ether 14 (44% yield)
[17]
(Scheme 4). This was subjected to the elimination conditions
with t-BuOK and, as expected, it did not react at all.
[18]
With model compound 12a in hand we could finally study
its behavior under gold(I)-catalysis and the results are reported
in Table 1.
Compared to simple propargyl vinyl ethers of type 1,
substituted vinyl ether 12a (i.e. of type 3) was much more
sensitive to the presence of acids, reasonably because of the α-
alkyl group which makes the β position of the vinyl moiety
7
0% yield as 1.3:1 mixture of diastereomers. We tested many
other conditions to carry out this coupling, including adding
more InCl , changing the reactant ratios, using the correspond-
3
ing α-chloroacetate instead of the acetate 10, and using a
different catalyst (pTsOH) with both alcohol 9 and acetate 10,
without any significant improvement.
The next reaction with t-BuOK in toluene at 25°C and in the
presence of catalytic 18-crown-6 proved quite troublesome
Scheme 4. (a) 8a, FeCl
18-crown-6 (5 mol%), toluene, 25°C, 5 h.
3
(5 mol%), CH
3
NO
2
, 25°C, 7 h; (b) t-BuOK (1.2 equiv.),
[
a]
Table 1. . Optimization of the reaction conditions.
Scheme 2. (a) Br (1.1 equiv.), MeOH, 0!10°C, 2.5 h [ref. 13]; (b) NaBH
2
4
(
6 equiv.), EtOH, 0°C, 3 h [ref. 14].
[b]
[b]
Entry Catalyst
Solvent/additive
4a [%]
6a [%]
[
c]
1
2
3
4
5
6
7
8
9
IPrAu(CH
IPrAu(CH
3
CN)BF
CN)BF
4
4
DCM
50
74
87
(dec.)
93
50
26
13
-
[c]
3
DCM / 0.25 eq K
2
CO
3
[
c]
IPrAu(CH CN)BF4
3
DCM / 1.0 eq K CO3
2
IPrAu(CH
IPrAu(CH
IPrAu(CH
3
3
3
CN)BF
CN)BF
CN)BF
4
4
4
toluene
[
d]
DCM
7
[c]
DCM /4 Å MS
71
39
60
83
29
61
40
17
[
d]
IPrAuNTf2
[IPrAuCl]/AgOTf
[IPrAuCl]/AgSbF
DCM
DCM
DCM
[
[
e]
e]
[d]
[d]
6
[
(
a] Conditions: Reactions carried out on 0.2–0.3 mmol of 12a in CH
2
Cl
atmosphere. [b] Product ratio based on
2
0.05 M) at 25°C under N
2
1
integration of H NMR resonances in the crude reaction mixture. [c] From
bottle. [d] Distilled from CaH before use. [e] Catalyst prepared by mixing
the silver salt (3 mol%) and the gold chloride (3 mol%) in CH Cl before
2 2
addition of the substrate unless otherwise noted. IPr=1,3-bis(diisopropyl-
2
Scheme 3. (a) Ac
2
O, DMAP, Et
NO
3
N, DCM, 25°C, 2 h; (b) Bromohydrin 8a–b
(
2 equiv.), InCl (5 mol%), CH
crown-6 (5 mol%), toluene, 25°C, 5 h.
3
3
2
, 60°C, 2.5 h; (c) t-BuOK (1.2 equiv.), 18-
phenyl)imidazol-2-ylidene.
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[8b]
more electron-rich. In fact, during the gold-catalyzed reactions,
compound,
the hydrogenation occurred with high stereo-
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we observed degradation of the substrate and formation of
ketone 6a (Table 1) because of the acidity of the reaction
medium and, possibly, the concurrent presence of water. In
analogy to substrates of type 1, the only cationic gold complex
capable to promote not only the propargyl Claisen rearrange-
ment of 12a but also the next hydroarylation of the formed
selectivity providing the cis isomers only, which was the one we
hoped for in view of the epi-jungianol synthesis. This was
demonstrated by analysis of a NOESY-2D spectrum of 16a in
which NOE cross-peaks between both the methyl group at
1.30 ppm and one of the protons of the appendage at position
3 (2.54 ppm) with the same proton at C2 (1.10 ppm) of the five-
membered ring were consistent with the cis stereochemical
attribution.
+
allene intermediate to give 4a was [IPrAu] . Under the standard
conditions for the process (entry 1), the relative amount of
1
ketone 6a was about 50% (by H NMR). To prevent the
The synthesis of epi-jungianol is reported in Schemes 6–8.
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[19]
formation of ketone 6a and thus degradation of the starting
material before its Au(I)-catalyzed reaction, we carried out the
reaction by adding to the mixture 0.25 and 1 equiv. of
Starting from known 2-bromo-6-methylanisole 17, we pre-
pared propargyl alcohol 18 (74%) by Sonogashira coupling
(Scheme 6) and this was acetylated to quantitatively give 19.
Coupling with 1-bromo-2-propanol 8c under the optimized
conditions provided ether 20 in 62% yield and elimination with
t-BuOK gave propargyl vinyl ether 21 in 49%. Also, in this case,
only the major diastereomer reacted. The Au(I)-catalyzed
reaction of 21, followed by hydrogenation of the crude reaction
anhydrous K CO3 (entries 2 and 3, respectively), in order to
2
reduce the possible acidity deriving from the process and/or
the solvent. With 1 eq. of K CO , the degradation of the
2
3
substrate was reduced as the relative amount of ketone 6a was
3%. Replacing the solvent with toluene caused an almost
1
complete degradation of the substrate (entry 4). At the end we
found that with no additives, but by simply employing as the
solvent freshly distilled CH Cl over CaH2 (entry 5) we could
2
2
abate the relative amount of ketone 6a to 7% and obtain a
1
conversion into product 4a of 93% by H NMR, whereas in the
presence of molecular sieves (entry 6) results were again poor.
In freshly distilled CH Cl , we also evaluated the efficiency of the
2
2
catalyst by changing the counterion, as their conjugate acids
possess a different acidity. With IPrAuNTf (entry 7) an extensive
2
degradation was observed (61% of ketone 6a), and also with
both [IPrAuCl]/AgOTf (entry 8) and [IPrAuCl]/AgSbF6 (entry 9)
we did not obtain acceptable results.
Since compound 4a, and 4b as well (Scheme 5), tend to
isomerize during chromatography like the analogous
[5]
aldehydes, to give the α,β-unsaturated ketone, we decided to
avoid trying to isolate products 4 as such and instead convert
them as crude reaction mixtures into stable alcohols 15a–b by
reduction with NaBH (83% and 73%, respectively, over the two
4
steps after chromatography) or ketone 16a by hydrogenation
over dry Pd/C (83% yield after chromatography over the two
Scheme 6. (a) 3-Butyn-2-ol, Pd(PPh
3
)
4
, CuI, pyrrolidine, 70°C, 16 h; (b) Ac
2
O
(2 equiv.), Et N, DMAP, DCM, 25°C, 3 h; (c) 1-bromopropan-2-ol (2 equiv.),
3
InCl
3
(5 mol%), CH
3
NO
2
, 60°C, 2.5 h; (d) t-BuOK (1.2 equiv.), 18-crown-6
steps). Interestingly, as reported for
a closely related
(5 mol%), toluene, 25°C, 5 h; (e) IPrAu(CH CN)BF (3 mol%), DCM, 25°C,
3
4
50 min; (f) H
2
, 10% Pd/C (16 mol%), NaHCO
3
, THF, 25°C, 1 h.
Scheme 7. (a) 2-Bromo-1-ethanol, InCl
3
(5 mol%), CH
3
NO
2
, 50°C, 1.5 h; (b) t-
BuOK (1.2 equiv), 18-crown-6 (5 mol%), toluene, 25°C, 16 h; (c) IPrAu(CH CN)
3
Scheme 5. (a) IPrAu(CH
3
CN)BF
4
(3 mol%), DCM, 25°C, 4.5 h; (b) NaBH
4
BF
4
(3 mol%), DCM, 25°C, 4 h; (d) CH
3
MgBr (1.5 equiv.), THF, À 65!-20°C,
(
4 equiv.), MeOH, 25°C, 20 min; (c) H
, 10% Pd/C (16 mol%), NaHCO
, THF,
1.5 h; (e) H
periodinane, DCM, 25°C, 2 h.
, 10% Pd/C (16 mol%), NaHCO
, THF, 25°C, 1 h; (f) Dess-Martin
2
3
2
3
2
5°C, 1 h.
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isomer 28. The final conversion of 29 into epi-jungianol by
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3
4
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6
7
[8b]
demethylation was carried out as described, providing pure
1
13
(
�)-5 in 78% yield after chromatography with H and C NMR
[8b]
spectra as reported.
3
. Conclusion
In conclusion, we have demonstrated that the gold(I)-catalyzed
propargyl Claisen rearrangement/hydroarylation reaction is a
cascade process useful for the synthesis of target compounds
embodying a cis 1,3-disubstituted indane moiety, as in the case
of epi-jungianol. Two types of propargyl vinyl ethers can be
prepared and subjected to gold(I) catalysis, i.e. with or without
an α-alkyl substituent on the vinyl moiety. Those bearing an α-
alkyl group are less stable (acid sensitive) and generally
obtained in lower yield than the unsubstituted ones, although
they provide a more advanced intermediate in the total
synthesis of the target compound. The route involving unsub-
stituted vinyl ethers is longer but allows for the preparation of a
common intermediate in the synthesis of epi-jungianol in
higher yield (27% over 8 steps).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
Scheme 8. (a) Methyltriphenylphosphonium bromide (2 equiv.), t-BuOK, THF,
0
°C, 2 h; (b) cat. PTSA, DCM, 25°C, 20 h; (c) CH
3
MgBr (1.5 equiv.), THF, À 65!
À 20°C, 1.5 h; (d) NaH, propanethiol, DMF, 130°C, 4.5 h.
mixture containing 22, provided our key intermediate 23 as a
single cis isomer in 72% yield after chromatography over two
steps (16% overall yield from 17).
The expected cis configuration was confirmed by the
presence of NOE cross-peaks in a NOESY-2D spectrum as in
compound 16a, i.e. between both the methyl group at
1
.27 ppm and one of the protons of the appendage at the
relative position 3 (2.49 ppm) with the same proton at C2
(1.16 ppm) of the five-membered ring.
Experimental Section
For the synthesis of 23 we relied also on the tandem Au(I)-
Anhydrous solvents were prepared accordingly to the standard
techniques. Commercially available reagents were used without
further purification. Melting points were recorded on a Büchi B-540
apparatus and are uncorrected. Chromatographic separations were
performed under pressure on silica gel (Merck 70–230 mesh), unless
catalyzed reaction of propargyl vinyl ethers of type 1 which
would afford an aldehyde that must be consequently converted
into ketone 23 (Scheme 7). Acetate 19 was thus reacted with 2-
bromo-1-ethanol in the presence of InCl which provided 24 in
3
otherwise stated, by using flash column techniques; R values refer
f
good yield (76%) after 1.5 h at 50°C. As expected in this case,
the next elimination step occurred smoothly giving vinyl
propargyl ether 25 in 87% yield. This was subjected to gold(I)
catalysis providing, after addition of 3.0 M MeMgBr solution in
diethyl ether to the crude reaction mixture, indenyl alcohol 26
in 62% yield over the two steps. This was hydrogenated to
furnish saturated alcohol 27 (as a 1:1 mixture of the cis
diastereomers). However, the hydrogenation was not complete
as 10% of the starting material remained in the crude reaction
mixture and could not be separated by chromatography. Thus,
to TLC carried out on 0.25 mm silica gel plates (F254) with the same
1
eluent as indicated for column chromatography. H NMR (200 or
13
4
00 MHz) and C NMR (100.4 MHz) spectra were recorded either on
Varian Inova (400 MHz) or Mercury (200 or 400 MHz) spectrometers
in the specified deuterated solvent at 25
°
C. Solvent reference lines
were set at 7.26 and 77.00 (CDCl ), 2.05 and 29.84 (acetone-d6) in
3
1
13
H and C NMR spectra, respectively. Mass spectra were carried out
either by direct inlet of a 10 ppm solution in CH OH on a LCQ
3
TM
Fleet Ion Trap LC/MS system (Thermo Fisher Scientific) with
electrospray ionization (ESI) interface in the positive or negative ion
mode or by EI at 70 eV on a Varian GC/MS Saturn 2200 instrument
equipped with a CP-sil8 Varian column. HRMS analyses were
performed under conditions of ESI-MS through direct infusion of a
1 uM 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.
2
7 was subjected to the next oxidation with the Dess-Martin
periodinane finally providing key intermediate 23 in 90% yield
over the two steps. The overall yield in this sequence was 27%
over 8 steps. Therefore, although, it requires two more steps
than the previous route, this sequence seems a more efficient
strategy for the synthesis of our target compound.
[
5]
[19]
[8]
[8]
[5]
Compounds 10, 17,
5
and 29, are known. Acetate 10 and
were prepared as reported. Bromohydrine
c is also commercially available.
[13,14]
bromohydrines 8a–c,
Eventually, we tried two routes to convert 23 into epi-
jungianol (Scheme 8). In the first one, we carried out a Wittig
olefination to generate compound 28 in 75% yield which
however was difficult to purify by chromatography. This was
8
[3-(1-Bromomethyl-4-phenylpropoxy)-but-1-ynyl]benzene (11a):
To a solution of acetate 10 (800 mg, 4.3 mmol) and bromohydrin
8a (1.95 g, 8.5 mmol) in nitromethane (17.0 mL), under nitrogen
atmosphere, anhydrous InCl3 (47 mg, 0.21 mmol, 5 mol%) was
[8b]
subjected to isomerization to known 29
according to a
procedure reported for a very similar compound (p-TsOH,
added. The resulting mixture was heated at 60
2.5 h. After cooling, water (20 mL) was added, and the product
extracted with DCM (3×20 mL). The combined organic extracts
°
C (external) for
[8a]
CH Cl ), but even after long reaction times, about 17% of the
2
2
starting material remained unreacted. Instead, by reacting 23
with methyl magnesium bromide to give tertiary alcohol 30
were dried over anhydrous Na SO . After filtration and evaporation
2 4
of the solvent, the crude residue was purified by flash chromatog-
(67%) followed by pTsOH-catalyzed elimination, compound 29
raphy (EtOAc/n-hexane, 1:30; R =0.36), affording pure 11a as a
f
could be obtained in 90% yield with only 7% of the other
Eur. J. Org. Chem. 2021, 1266–1273
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pale yellow oil (768 mg, 50%) and both starting materials. The so
recovered acetate 10 (36%) was allowed to react again with the
bromohydrin 8a under the above reported conditions and a final
1.6 Hz, 1 H), 2.10 (t, J=7.6 Hz, 2 H), 1.62 (d, J=6.8 Hz, 3 H), 1.59–
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
13
1.50 (m, 2 H), 0.94 (t, J=7.2 Hz, 3 H). C NMR (100.4 MHz, CDCl ) δ
3
(ppm): 161.3, 131.7 (2 C), 128.6, 128.2 (2 C), 122.8, 88.7, 84.7, 83.1,
1
+
67% yield (1.03 g) was eventually obtained after the two cycles. H
62.8, 37.0, 21.9, 20.5, 13.5. GCMS (EI) m/z (%): 214 ([M] , 33), 199
NMR (400 MHz, CDCl
7
6
) (1.4:1 mixture of diastereoisomers) δ (ppm):
.47–7.15 (m, 10 H), 4.63 (q, J=6.8 Hz, 1 H, major), 4.48 (q, J=
.8 Hz, 1 H, minor), 4.02–3.95 (m, 1 H, major), 3.88–3.82 (m, 1 H,
(84), 171 (100).
3
1
-(3-Methyl-3H-inden-1-yl)-4-phenylbutan-2-ol (15a): To a solu-
tion of propargyl vinyl ether 12a (120 mg, 0.43 mmol) in anhydrous
DCM (8.7 mL) and under nitrogen atmosphere was added commer-
cially available gold(I) complex IPrAu(CH CN)BF (9.2 mg, 12.9 μmol,
minor), 3.72 (dd, J=10.4, 6.4 Hz, 1 H, minor), 3.56 (dd, J=10.0,
.8 Hz, 1 H, minor), 3.50 (dq, J=10.8, 5.6 Hz, 2 H, major), 2.95–2.88
6
3
4
(m, 1 H, major), 2.84–2.66 (m, 1 H major and 2 H minor), 2.16–2.07
3
mol%) and the reaction mixture was stirred at 25°C. After
(m, 1 H, minor), 2.04–1.95 (m, 1 H minor and 2 H major), 1.60 (d, J=
1
3
complete consumption of starting material (TLC monitoring; 4.5 h),
the mixture was diluted with MeOH (17.4 mL) and NaBH (16 mg,
6
.4 Hz, 3 H, major), 1.56 (d, J=6.8 Hz, 3 H, minor). C NMR
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
4
(
1
1
100.4 MHz, CDCl ) (mixture of diastereoisomers) δ (ppm): 141.8 and
41.5, 131.6 (2 C), 128.5, 128.43 and 128.39 (2 C), 128.31 (2 C),
28.27 (2 C), 125.9 and 125.8, 122.5 and 122.4, 89.3 and 89.0, 85.2
3
0
.43 mmol) was immediately added. After 20 min, the reduction
was completed. The solvent was then evaporated, water was added
to the residue (10 mL), and the product extracted with DCM (3×
10 mL). The combined organic extracts were dried over anhydrous
and 85.0, 77.5 and 75.3, 65.8 and 64.4, 35.5 and 35.2, 34.8 and 34.5,
+
31.5 and 31.2, 22.6 and 22.5. MS (ESI) m/z (%): 381 ([M+Na] , 100)
+
Na SO . After filtration and evaporation of the solvent, the oily
2 4
and 379 ([M+Na] , 96).
residue was purified by flash chromatography (EtOAc/n-hexane,
[
3-(1-Bromomethylbutoxy)-but-1-ynyl]benzene (11b): Prepared as
1:8; R =0.24) to give the corresponding indene 15a as a colourless
f
1
reported for 11a, starting from acetate 10 (500 mg, 2.7 mmol) and
bromohydrine 8b (887 mg, 5.3 mmol). Purification of the crude was
oil (99 mg, 83% over two steps). H NMR (400 MHz, CDCl ) δ (ppm):
3
7.42 (d, J=7.2 Hz, 1 H), 7.32–7.27 (m, 4 H), 7.25–7.18 (m, 4 H), 6.28
(s, 1 H), 4.05–3.95 (m, 1 H), 3.48 (q, J=7.6 Hz, 1 H), 2.93–2.85 (m, 1
H), 2.83–2.71 (m, 2 H), 2.70–2.63 (m, 1 H), 1.95–1.88 (m, 2 H), 1.76 (d,
accomplished by flash chromatography (EtOAc/n-hexane, 1:30; R =
f
0
.28) to afford the target compound 11b (431 mg, 55%) as a pale
1
3
yellow oil. Recovered starting material 10 (30%) was used to carry
J=2.8 Hz, 1 H, OH), 1.31 (d, J=7.6 Hz, 3 H). C NMR (100.4 MHz,
out the reaction again, affording eventually 11b in the total yield of
CDCl ) (1:1 mixture of diastereoisomers) δ (ppm): 149.9 and 149.8,
3
1
7
0% (550 mg) after the two cycles. H NMR (400 MHz, CDCl ) (1.3:1
144.0 and 143.9, 142.0, 139.00 and 138.99, 138.2 and 138.1, 128.43
and 128.42 (2 C), 128.4 (2 C), 126.3, 125.8, 125.1, 122.8 and 122.7,
119.2 and 119.1, 69.2 and 69.1, 43.9, 38.7, 36.1 and 36.0, 32.1, 16.3
3
mixture of diastereoisomers) δ (ppm): 7.45–7.40 (m, 2 H), 7.32–7.30
(m, 3 H), 4.60 (q, J=6.8 Hz, 1 H, major), 4.48 (q, J=6.4 Hz, 1 H,
minor), 3.95–3.89 (m, 1 H, major), 3.85–3.78 (m, 1 H, minor), 3.64
+
and 16.2. MS (ESI) m/z (%): 301 ([M+Na] , 100). HRMS (ESI/TOF) m/
+
(
dd, J=10.4, 4.4 Hz, 1 H, minor), 3.49 (dd, J=10.0, 6.4 Hz, 1 H,
minor), 3.50–3.42 (m, 2 H, major), 1.74–1.60 (m, 2 H), 1.54 (d, J=
.8 Hz, 3 H, major), 1.53 (d, J=6.4 Hz, 3 H, minor), 1.50–1.34 (m, 2
z: [M+Na] calcd for C H ONa: 301.1563. Found: 301.1554.
2
0
22
1-(3-Methyl-3H-inden-1-yl)-pentan-2-ol (15b): Prepared as re-
ported for 15a, starting from 12b (120 mg, 0.56 mmol). The
6
13
H), 0.96 (t, J=7.6 Hz, 3 H, minor), 0.95 (t, J=7.2 Hz, 3 H, major).
C
purification by flash chromatography (EtOAc/n-hexane, 1:15; R =
f
NMR (100.4 MHz, CDCl ) (mixture of diatereoisomers) δ (ppm):
3
0
.24) afforded pure 15b as a colourless oil (88 mg, 73% over two
131.64 and 131.58, 128.4 and 128.3 (2 C), 128.28 and 128.27 (2 C),
1
steps). H NMR (400 MHz, CDCl ) δ (ppm): 7.42 (d, J=7.2 Hz, 1 H),
3
1
22.7 and 122.6, 89.5 and 89.2, 84.9 and 84.8, 77.9 and 76.0, 65.6
7
.35–7.21 (m, 3 H), 6.29 (s, 1 H), 4.01–3.92 (m, 1 H), 3.48 (q, J=
and 64.5, 36.0, 35.5 and 35.0, 22.6 and 22.5, 18.6 and 18.4, 14.1 and
+
7.6 Hz, 1 H), 2.80–2.74 (m, 1 H), 2.65–2.59 (m, 1 H), 1.71 (d, J=
3.2 Hz, 1 H, OH), 1.61–1.52 (m, 3 H), 1.51–1.39 (m, 1 H), 1.32 (d, J=
7.6 Hz, 3 H), 0.97 (t, J=7.2 Hz, 3 H). C NMR (100.4 MHz, CDCl ) (1:1
14.0. GCMS (EI) m/z (%): 215 ([M - Br] , 49), 129 (100).
1
3
[
3-(1-Methylene-3-phenylpropoxy)-but-1-ynyl]benzene (12a): To
3
a solution of 11a (572 mg, 1.6 mmol) and 18-crown-6 (21 mg,
mixture of diastereoisomers) δ (ppm): 149.94 and 149.92, 144.1 and
144.0, 139.30 and 139.28, 138.0 and 137.9, 126.3, 125.0, 122.73 and
122.70, 119.17 and 119.13, 69.7 and 69.6, 43.9, 39.3, 36.1 and 36.0,
0.08 mmol, 5 mol%) in anhydrous toluene (2.4 mL) under nitrogen
atmosphere, solid t-BuOK (215 mg, 1.92 mmol) was added in one
portion, and the mixture was left at room temperature under
vigorous stirring for 5 h. Water (5 mL) was then added and the
product extracted with n-hexane (3×5 mL). The combined organic
extracts were dried over anhydrous K CO . After filtration and
+
19.0, 16.3 and 16.2, 14.1. MS (ESI) m/z (%): 239 ([M+Na] , 100).
Anal. Calcd for C H O: C, 83.28; H, 9.32. Found: C, 83.00; H, 9.56.
1
5
20
1
-(3-Methylindan-1-yl)-4-phenylbutan-2-one (16a): To a solution
2
3
of propargyl vinyl ether 12a (80 mg, 0.28 mmol) in anhydrous DCM
evaporation of the solvent, the purification of the crude residue by
(5.6 mL) and under nitrogen atmosphere was added commercially
flash chromatography on alumina (n-hexane; R =0.87) afforded
f
available gold(I) complex IPrAu(CH CN)BF (6.2 mg, 8.6 μmol) and
3 4
pure 12a as a pale yellow oil (221 mg, 50%). Compound 12a was
the reaction mixture was stirred at 25°C. After complete con-
stored as a solution in n-hexane, concentrated and dried under
1
sumption of the starting material (TLC monitoring), a few drops of
vacuum just prior use. H NMR (400 MHz, CDCl ) δ (ppm): 7.49–7.45
3
Et N were added and the solvent evaporated. The so obtained
3
(
1
m, 2 H), 7.36–7.18 (m, 8 H), 4.85 (q, J=6.4 Hz, 1 H), 4.20 (d, J=
crude 4a was used for the next step without further purifications.
.6 Hz, 1 H), 4.05 (d, J=1.6 Hz, 1 H), 2.88 (t, J=7.2 Hz, 2 H), 2.46 (t,
1
13
H NMR (200 MHz, CDCl ) δ (ppm): 7.49–7.10 (m, 9 H), 6.27 (s, 1 H),
3
J=7.2 Hz, 2 H), 1.67 (d, J=6.4 Hz, 3 H). C NMR (100.4 MHz, CDCl3)
δ (ppm): 160.5, 141.7, 131.7 (2 C), 128.6, 128.5 (2 C), 128.3 (2 C),
3.61 (s, 2 H), 3.48 (q, J=14.8 Hz, 1 H), 2.95–2.78 (m, 4 H), 1.30 (d, J=
14.8 Hz, 3 H). Crude 4a was dissolved in THF (1.6 mL) and added to
a suspension of the activated 10% Pd/C (48 mg, 45 μmol, 16 mol%)
and NaHCO3 (62 mg, 0.74 mmol) in THF (7 mL). The reaction
mixture was vigorously stirred at room temperature under hydro-
gen atmosphere (balloon). After completion (1 h), the reaction
mixture was filtered over a celite pad and the solvent removed
under reduced pressure. The resulting crude oil was purified by
1
28.2 (2 C), 125.7, 122.7, 88.6, 84.9, 83.7, 62.9, 37.0, 33.7, 22.0. GCMS
+
(EI) m/z (%): 276 ([M] , 14), 262 (100).
[
3-(1-Methylenebutoxy)-but-1-ynyl]benzene (12b): Prepared as
reported for 12a, starting from 11b (390 mg, 1.3 mmol) and
obtaining, after purification of the crude by flash chromatography
on alumina (n-hexane; R =0.88), pure 12b as a pale yellow oil
f
(
144 mg, 51%). Compound 12b was stored as a solution in n-
flash chromatography (EtOAc/n-hexane, 1:40; R =0.20) affording
f
1
hexane, concentrated and dried under vacuum just prior use. H
pure cis-indane 16a (65 mg, 83% over two steps) as colourless oil.
1
NMR (400 MHz, CDCl ) δ (ppm): 7.44–7.41 (m, 2 H), 7.36–7.27 (m, 3
H NMR (400 MHz, CDCl ) δ (ppm): 7.32–7.27 (m, 2 H), 7.22–7.13 (m,
3
3
H), 4.81 (q, J=6.8 Hz, 1 H), 4.16 (d, J=1.6 Hz, 1 H), 4.04 (d, J=
6 H), 7.03 (d, J=7.6 Hz, 1 H), 3.57–3.49 (m, 1 H), 3.16–3.06 (m, 1 H),
Eur. J. Org. Chem. 2021, 1266–1273
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3
.02–2.91 (m, 3 H), 2.89–2.75 (m, 2 H), 2.60–2.50 (m, 2 H), 1.30 (d,
72.8, 64.7 and 64.2, 60.5 and 60.4, 37.0 and 36.3, 22.6 and 22.4, 20.2
and 18.3, 16.0. MS (ESI) m/z (%): 333 ([M+Na] , 100).
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
13
+
J=6.8 Hz, 3 H), 1.10 (q, J=10.4 Hz, 1 H). C NMR (100.4 MHz, CDCl3)
δ (ppm): 209.3, 148.4, 145.8, 141.0, 128.5 (2 C), 128.4 (2 C), 126.7,
126.3, 126.1, 123.1, 122.8, 48.8, 44.8, 42.9, 38.8, 38.0, 29.8, 19.4. MS
(ESI) m/z (%): 301 ([M+Na] , 100). HRMS (ESI/TOF) m/z: [M+H]
calcd for C H O: 279.1743. Found: 279.1746.
1
-(3-Isopropenyloxybut-1-ynyl)-2-methoxy-3-methylbenzene (21):
Compound 21 was prepared as reported for 12a, starting from 20
225 mg, 0.72 mmol). Purification of the crude residue by flash
+
+
(
20
22
chromatography on alumina (n-hexane; R =0.90) afforded pure 21
f
1
4-(2-Methoxy-3-methylphenyl)-but-3-yn-2-ol (18): To a solution of
bromide 17 (2.27 g, 11.3 mmol) in pyrrolidine (22.6 mL), under
nitrogen atmosphere, were added 3-butyn-2-ol (1.78 mL,
(81 mg, 49%) as a colourless oil. H NMR (400 MHz, acetone-d6) δ
(ppm): 7.23–7.18 (m, 2 H), 6.97 (t, J=7.6 Hz, 1 H), 4.91 (q, J=6.8 Hz,
1 H), 4.17 (d, J=2.0 Hz, 1 H), 4.04–4.03 (m, 1 H), 3.86 (s, 3 H), 2.23 (s,
1
3
2
2.6 mmol),
CuI
(215 mg,
1.1 mmol)
and
tetrakis
3 H), 1.79 (d, J=1.0 Hz, 3 H), 1.59 (d, J=6.8 Hz, 3 H). C NMR
(100.4 MHz, acetone-d6) δ (ppm): 160.6, 158.5, 132.4, 132.2, 132.1,
124.3, 116.9, 93.5, 84.2, 82.1, 63.6, 60.7, 22.4, 21.2, 16.1. MS/MS (ESI)
(triphenylphosphine)palladium (653 mg, 0.6 mmol). The reaction
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
mixture was heated at 70°C (external) and stirred overnight. The
mixture was cooled to room temperature and water (25 mL) was
added. The product was extracted with DCM (3×20 mL) and the
combined organic extracts were dried over anhydrous Na
3
+
+
[M+Na] m/z (%): 253 ([M+Na] , 10), 195 (100). Anal. Calcd for
C H O : C, 78.23; H, 7.88. Found: C, 77.98; H, 7.96.
1
5
18
2
SO for
2
4
1
2
-(7-Methoxy-3,6-dimethylindan-1-yl)-propan-2-one (23): From
1. Indane 23 was prepared as reported for 16a, starting from
0 min. After filtration and evaporation of the solvent, the crude
reaction mixture was purified by flash column chromatography (n-
hexane/EtOAc, 4:1; R =0.37), affording pure propargyl alcohol 18
propargyl vinyl ether 21 (69 mg, 0.3 mmol) and obtaining inter-
mediate 22 (reaction time: 50 minutes), which was used in the next
f
1
(
(
1.58 g, 74%) as a yellow oil. H NMR (400 MHz, CDCl ) δ (ppm): 7.22
d, J=8.0 Hz, 1 H), 7.12 (d, J=7.6 Hz, 1 H), 6.93 (t, J=7.6 Hz, 1 H),
3
1
step without purification. H NMR (200 MHz, acetone-d6) δ (ppm):
7.11–6.99 (m, 2 H), 6.20 (s, 1 H), 3.79–3.76 (m, 1 H), 3.75 (s, 2 H), 3.70
4.82–4.75 (m, 1 H), 3.89 (s, 3 H), 2.67–2.56 (m, 1 H, OH), 2.26 (s, 3 H),
1
13
(s, 3 H), 2.27 (s, 3 H), 2.15 (s, 3 H), 1.24 (d, J=14.8 Hz, 3 H).
Hydrogenation of 22 was performed as reported for 16a.
.56 (d, J=6.4 Hz, 3 H). C NMR (100.4 MHz, CDCl ) δ (ppm): 159.3,
3
1
31.5, 131.2, 131.1, 123.5, 116.1, 95.0, 80.4, 60.4, 58.8, 24.2, 16.0. MS
+
Purification by flash chromatography (EtOAc/n-hexane, 1:20; R =
f
(ESI) m/z (%): 213 ([M+Na] , 100). Anal. Calcd for C H O : C, 75.76;
12
14
2
0.10) afforded indane 23 (50 mg, 72% over 2 steps) as a pale yellow
solid. From 26. Accordingly to the above reported hydrogenation
procedure for compound 22, compound 26 (79 mg, 0.34 mmol)
was used to furnish the product 27 (72 mg, 90%) as a colourless oil,
after purification by flash chromatography (EtOAc/n-hexane, 1:4;
H, 7.42. Found: C, 75.51; H, 7.68.
3
-(2-Methoxy-3-methylphenyl)-1-methylprop-2-ynyl acetate (19):
A solution of intermediate 18 (826 mg, 4.3 mmol) in anhydrous
DCM (43 mL) under nitrogen atmosphere was cooled to 0°C (ice
1
bath); Et N (1.8 mL, 12.9 mmol) and 4-dimethylaminopyridine
R =0.22). H NMR (400 MHz, CDCl ) (1:1 mixture of diastereoisom-
3
f
3
(
26 mg, 0.22 mmol) were then added, followed by dropwise
ers) δ (ppm): 7.04 (d, J=7.6 Hz, 1 H), 7.03 (d, J=7.6 Hz, 1 H), 6.87 (t,
J=7.6 Hz, 2 H), 4.01–3.87 (m, 2 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.51–
3.47 (m, 1 H), 3.34–3.26 (m, 1 H), 3.13–3.04 (m, 2 H), 2.65–2.51 (m, 2
H), 2.49–2.42 (m, 1 H), 2.31–2.20 (m, 1 H), 2.28 (s, 3 H), 2.27 (s, 3 H),
1.77–1.69 (m, 2 H), 1.49–1.35 (m, 2 H), 1.31 (d, J=6.8 Hz, 3 H), 1.30
(d, J=7.2 Hz, 3 H), 1.27 (d, J=6.0 Hz, 3 H), 1.26 (d, J=6.0 Hz, 3 H).
addition of Ac O (1.1 mL, 8.6 mmol). After 10 min, the ice bath was
2
removed, and the resulting mixture was stirred at room temper-
ature for 3 h. A satd solution of NaHCO (40 mL) was added and the
mixture left under vigorous stirring for 5 min; after separation of
the phases, the product was extracted with DCM (2×20 mL) and
the combined organic extracts were dried over anhydrous K CO .
3
+
MS (ESI) m/z (%): 257 ([M+Na] , 100). Dess-Martin periodinane
2
3
After filtration and evaporation of the solvent, the crude acetate
was purified by flash chromatography (n-hexane/EtOAc, 7:1; R
.35), affording pure acetate 19 (998 mg, quantitative) as a pale
(145 mg, 0.34 mmol) was added to an ice-bath cooled solution of
alcohol 27 (72 mg, 0.31 mmol) in DCM (1.5 mL). The reaction
=
f
0
mixture was stirred at room temperature for 2 h. Et O (0.8 mL) was
2
1
yellow oil. H NMR (400 MHz, CDCl ) δ (ppm): 7.24 (d, J=8.0 Hz, 1
added followed by an aqueous satd solution of NaHCO containing
3
3
H), 7.13 (d, J=7.6 Hz, 1 H), 6.92 (t, J=7.6 Hz, 1 H), 5.70 (q, J=6.8 Hz,
25% w/w Na S O (1.5 mL) and the mixture was vigorously stirred
2
2
3
1
H), 3.89 (s, 3 H), 2.25 (s, 3 H), 2.09 (s, 3 H), 1.59 (d, J=6.8 Hz, 3 H).
for 5 min. After separation of the phases, the organic one was firstly
dried over anhydrous Na SO and then filtered and concentrated
13
C NMR (100.4 MHz, CDCl ) δ (ppm): 169.9, 159.7, 131.7, 131.4,
3
2
4
131.2, 123.3, 115.6, 91.3, 81.2, 60.9, 60.4, 21.3, 21.0, 16.0. MS (ESI) m/
z (%): 487 ([2 M+Na] , 47), 255 ([M+Na] , 100). Anal. Calcd for
C H O : C, 72.39; H, 6.94. Found: C, 72.19; H, 7.15.
under vacuum. The crude was purified by flash chromatography (n-
hexane/EtOAc, 20:1; R =0.10) affording pure ketone 23 (72 mg,
+
+
f
1
quantitative) as a pale yellow solid. M.p.=55.6–57.1°C. H NMR
1
4
16
3
(
400 MHz, CDCl ) δ (ppm): 7.04 (d, J=7.6 Hz, 1 H), 6.86 (d, J=7.6 Hz,
3
1-[3-(2-Bromo-1-methylethoxy)-but-1-ynyl]-2-methoxy-3-meth-
ylbenzene (20): Prepared as reported for 11a, starting from acetate
1
1
3
9
H), 3.76–3.68 (m, 1 H), 3.66 (s, 3 H), 3.46 (dd, J=17.2, 4.0 Hz, 1 H),
.13–3.04 (m, 1 H), 2.66 (dt, J=12.8, 7.6 Hz, 1 H), 2.49 (dd, J=17.2,
9 (630 mg, 2.7 mmol) and 1-bromopropan-2-ol (8c, 754 mg,
.4 mmol). The crude was purified by flash chromatography (n-
.2 Hz, 1 H), 2.26 (s, 3 H), 2.20 (s, 3 H), 1.28 (d, J=6.8 Hz, 3 H), 1.16
(dt, J=12.8, 8.4 Hz, 1 H). C NMR (100.4 MHz, CDCl ) δ (ppm): 208.4,
5
13
3
hexane/EtOAc, 40:1; R =0.34) and pure 20 (336 mg, 40%) was
f
1
3
55.1, 148.7, 136.7, 130.2, 128.7, 118.9, 59.6, 49.1, 42.5, 38.0, 37.6,
0.5, 20.5, 15.6. MS (ESI) m/z (%): 255 ([M+Na] , 100). Anal. Calcd
obtained as pale yellow oil. By repeating the reaction on the
recovered starting acetate 19, compound 20 was obtained in the
total amount of 523 mg and in 62% overall yield. H NMR
(400 MHz, CDCl
+
for C H O : C, 77.55; H, 8.68. Found: C, 77.42; H, 8.99.
1
15 20
2
) (1.1:1 mixture of diastereoisomers) δ (ppm): 7.25–
.22 (m, 2 H), 7.16–7.12 (m, 2 H), 6.95 (t, J=7.6 Hz, 2 H), 4.62 (q, J=
.4 Hz, 1 H, major), 4.57 (q, J=6.4 Hz, 1 H, minor), 4.13–4.05 (m, 2
1-[3-(2-Bromoethoxy)but-1-ynyl]-2-methoxy-3-methylbenzene
(24): Prepared as reported for 11a, starting from acetate 19
(232 mg, 1.0 mmol) and 2-bromoethanol (213 μL, 3.0 mmol) but
heating at 50°C. The crude was purified by flash chromatography
3
7
6
H), 3.90 (s, 3 H, minor), 3.89 (s, 3 H, major), 3.58 (dd, J=10.4, 4.8 Hz,
H, major), 3.47–3.42 (m, 2 H, minor), 3.40 (dd, J=10.4, 6.4 Hz, 1 H,
1
(n-hexane/EtOAc, 20:1; R =0.29) and pure 24 (226 mg, 76%) was
f
1
major), 2.27 (s, 6 H), 1.56 (d, J=2.8 Hz, 3 H, major), 1.55 (d, J=
3.6 Hz, 3 H, minor), 1.38 (d, J=6.4 Hz, 3 H, major), 1.32 (d, J=6.4 Hz,
obtained as pale yellow oil. H NMR (400 MHz, CDCl ) δ (ppm): 7.25
3
(dd, J=7.6, 1.2 Hz, 1 H), 7.14 (dd, J=7.6 Hz, 0.8 Hz, 1 H), 6.95 (t, J=
7.6 Hz, 1 H), 4.52 (q, J=6.8 Hz, 1 H), 4.12 (dt, J=10.8, 6.4 Hz, 1 H),
3.90 (s, 3 H), 3.84 (dt, J=10.4, 6.4 Hz, 1 H), 3.58–3.49 (m, 1 H), 2.27
13
3
H, minor). C NMR (100.4 MHz, CDCl ) (1.1:1 mixture of
3
diastereoisomers) δ (ppm): 159.5, 131.6 and 131.5, 131.4, 131.34
1
3
and 131.32, 123.53, 116.13, 93.0 and 92.9, 81.6 and 81.5, 73.0 and
(s, 3 H), 1.57 (d, J=6.8 Hz, 3 H). C NMR (100.4 MHz, CDCl ) δ
3
(ppm): 159.5, 131.6, 131.34, 131.33, 123.5, 116.0, 92.4, 82.0, 68.5,
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+
6
3
6.2, 60.5, 30.4, 22.1, 16.0. MS (ESI) m/z (%): 321 ([M+Na] , 93) and
combined organic extracts were dried over anhydrous Na SO . After
2 4
filtration and evaporation of the solvent, the oily residue was
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
+
19 ([M+Na] , 100). Anal. Calcd for C H BrO : C, 56.58; H, 5.77.
14
17
2
Found: C, 56.23; H, 5.51.
purified by flash chromatography (n-hexane; R =0.20) affording 28
f
1
(35 mg, 75%) as a colourless oil. H NMR (400 MHz, CDCl ) δ (ppm):
3
2
-Methoxy-1-methyl-3-(3-vinyloxybut-1-ynyl)benzene (25): Pre-
pared as reported for 12a, starting from compound 24 (193 mg,
.65 mmol) and leaving the reaction under stirring for 16 h at room
7.05 (d, J=7.6 Hz, 1 H), 6.87 (d, J=7.6 Hz, 1 H), 4.80 (s, 1 H), 4.75 (s,
1
H), 3.76 (s, 3 H), 3.48–3.40 (m, 1 H), 3.15–3.04 (m, 2 H), 2.43 (dt, J=
0
1
2.8, 8.0 Hz, 1 H), 2.28 (s, 3 H), 1.99 (dd, J=14.0, 11.6 Hz, 1 H), 1.82
temperature. The crude reaction mixture was filtered over a thin
silica gel layer (165 mg) and the filter cake washed with n-hexane/
EtOAc 20:1 (3 mL). After filtration and evaporation of the solvent,
the so obtained crude was purified by flash column chromatog-
raphy (n-hexane/EtOAc, 30:1+1% Et N; R =0.14) to give pure 25
13
(
s, 3 H), 1.34 (dt, J=13.2, 8.0 Hz, 1 H), 1.30 (d, J=6.8 Hz, 3 H).
C
NMR (100.4 MHz, CDCl ) δ (ppm): 155.3, 148.9, 144.7, 137.8, 129.9,
3
128.7, 118.9, 111.2, 59.5, 43.4, 40.7, 40.4, 38.0, 22.4, 21.1, 15.7. To a
solution of 28 (18 mg, 0.08 mmol) in DCM (1 mL), cooled at 0°C, a
catalytic amount of PTSA was added. After 5 minutes the ice-bath
was removed and the reaction mixture was stirred at room
temperature for 20 h. Then, water (3 mL) was added and the
product extracted with DCM (3×3 mL). The combined organic
extracts were dried over anhydrous Na SO , and, after filtration and
3
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
(
122 mg, 87%) as a pale yellow oil, which was stored at 4°C as a
1
solution in the eluent containing 1% Et N until use. H NMR
(400 MHz, CDCl ) δ (ppm): 7.26–7.23 (m, 1 H), 7.16–7.12 (m, 1 H),
3
3
6.94 (t, J=7.6 Hz, 1 H), 6.53 (dd, J=14.0, 6.8 Hz, 1 H), 4.81 (q, J=
2
4
6
.8 Hz, 1 H), 4.49 (dd, J=14.0, 1.6 Hz, 1 H), 4.17 (dd, J=6.4, 1.6 Hz, 1
evaporation of the solvent, the oily residue was purified by flash
chromatography (EtOAc/n-hexane, 1:99; R =0.20) affording 18 mg
98%) of a mixture of compound 29 (81%) and isomer 28 (17%), as
13
H), 3.89 (s, 3 H), 2.27 (s, 3 H), 1.62 (d, J=6.8 Hz, 3 H). C NMR
100.4 MHz, CDCl ) δ (ppm): 159.6, 149.7, 131.6, 131.4, 131.3, 123.4,
f
(
3
(
+
1
15.9, 91.9, 89.8, 82.3, 65.1, 60.5, 21.8, 16.00. MS/MS (ESI) [M+Na]
a colourless oil. From 30. To a solution of 30 (37 mg, 0.15 mmol) in
toluene (3 mL) was added a catalytic amount of PTSA and the
reaction mixture was refluxed under vigorous stirring. After 20 min,
the mixture was cooled, then water (5 mL) was added, and the
product extracted with DCM (2×5 mL). The combined organic
+
m/z (%): 239 ([M+Na] , 4), 195 (100). Anal. Calcd for C H O : C,
14
16
2
77.75; H, 7.46. Found: C, 77.54; H, 7.60.
1
-(7-Methoxy-3,6-dimethyl-3H-inden-1-yl)propan-2-ol (26): To a
solution of propargyl vinyl ether 25 (46 mg, 0.56 mmol) in DCM
extracts were dried over anhydrous Na SO . After filtration and
(11.2 mL) under nitrogen atmosphere was added commercially
available gold(I) complex IPrAu(CH
2 4
evaporation of the solvent, the crude was purified by flash
CN)BF
(12 mg, 16.8 μmol,
3
4
mol%) and the reaction mixture was stirred at 25°C. After
chromatography (EtOAc/n-hexane, 1:99; R =0.20) affording 35 mg
f
3
(
90%) of a mixture of compound 29 (97%) and isomer 28 (7%), as
complete consumption of 25 (TLC monitoring; 4 h), water (12 mL)
was added and, after separation of the layers, the aqueous one was
extracted with DCM (3×12 mL). The combined organic extracts
were dried over anhydrous Na SO . After filtration and evaporation
1
a colourless oil. H NMR (400 MHz, CDCl ) δ (ppm): 7.02 (d, J=
3
7.6 Hz, 1 H), 6.85 (d, J=7.6 Hz, 1 H), 5.30–5.27 (m, 1 H), 4.02 (q, J=
8.8 Hz, 1 H), 3.64 (s, 3 H), 3.11–3.01 (m, 1 H), 2.46 (dt, J=12.4,
2
4
7
3
1
.6 Hz, 1 H), 2.25 (s, 3 H), 1.79 (d, J=1.2 Hz, 3 H), 1.76 (d, J=1.2 Hz,
H), 1.36–1.27 (m, 1 H), 1.29 (d, J=6.8 Hz, 3 H). MS/MS (ESI) [M+
of the solvent, the oily residue containing the intermediate
aldehyde was used as such in the next step. H NMR (200 MHz,
acetone-d6) δ (ppm): 9.78 (t, J=1.6 Hz, 1 H), 7.14–7.02 (m, 2 H), 6.30
1
+
+
]
m/z (%): 231 ([M+1] , 14), 189 (73), 175 (100), 161 (45).
(
s, 1 H), 3.80–3.76 (m, 2 H), 3.72 (s, 3 H), 3.52–3.35 (m, 1 H), 2.29 (s, 3
1-(7-Methoxy-3,6-dimethylindan-1-yl)-2-methylpropan-2-ol (30):
A solution of key intermediate 23 (45 mg, 0.19 mmol) in anhydrous
H), 1.26 (d, J=7.4 Hz, 3 H). Crude aldehyde was dissolved in
anhydrous THF (5.6 mL) and, after cooling to À 65°C, treated with
THF (5.6 mL) was cooled to À 65°C and then treated with CH MgBr
3
CH MgBr 3.0 M in Et O (280 μL, 0.84 mmol). The reaction mixture
3
2
3
.0 M in Et O (97 μL, 0.29 mmol). The reaction mixture was allowed
2
was allowed to warm to À 20°C, and completed in 1.5 h. The
to warm at À 20°C, being completed in 1.5 h. After warming at 0°C
mixture was warmed at 0°C and quenched by addition of aqueous
a saturated aqueous solution of NH Cl (6 mL) was added and the
4
satd NH Cl (6 mL). The product was extracted with EtOAc (3×6 mL)
4
product extracted with EtOAc (3×6 mL). The combined organic
and the combined organic extracts were dried over anhydrous
Na SO . After filtration and evaporation of the solvent, the crude
extracts were dried over anhydrous Na SO . After filtration and
2
4
2
4
evaporation of the solvent, the crude was purified by flash
was purified by flash chromatography (n-hexane/EtOAc, 5:1; R =
0.19) and pure alcohol 26 (81 mg, 62% over two steps) was
obtained as a colourless oil. H NMR (400 MHz, CDCl
f
chromatography (n-hexane/EtOAc, 10:1; R =0.18) affording alcohol
f
1
3
0 (32 mg, 67%) as a colourless oil. H NMR (400 MHz, CDCl ) δ
1
3
) δ (ppm): 7.06
3
(ppm): 7.03 (d, J=7.6 Hz, 1 H), 6.87 (d, J=7.6 Hz, 1 H), 3.74 (s, 1 H),
(
(
q, J=7.6 Hz, 2 H), 6.18 (s, 1 H), 4.19–4.12 (m, 1 H), 3.80 (s, 3 H), 3.41
q, J=7.2 Hz, 1 H), 2.92 (dd, J=14.0, 4.0 Hz, 1 H), 2.74–2.68 (m, 1 H),
.47 (dd, J=21.6, 2.0 Hz, 1 H, OH), 2.34 (s, 3 H), 1.28 (d, J=6.4 Hz, 6
3.46–3.39 (m, 1 H), 3.15–3.05 (m, 1 H), 2.69 (dt, J=12.8, 8.0 Hz, 1 H),
2.52 (dd, J=14.4, 2.4 Hz, 1 H), 2.27 (s, 3 H), 1.62–1.54 (m, 1 H), 1.50–
2
13
1
.43 (m, 1 H), 1.33 (s, 6 H), 1.29 (d, J=6.8 Hz, 3 H). C NMR
13
H). C NMR (100.4 MHz, CDCl ) (mixture of diastereoisomers) δ
3
100.4 MHz, CDCl ) δ (ppm): 154.9, 148.6, 138.8, 130.0, 128.8, 119.1,
3
(
ppm): 152.4, 150.54 and 150.51, 138.8, 138.75 and 138.72, 135.61
1.2, 59.8, 49.9, 43.8, 38.8, 38.6, 30.1, 29.8, 21.7, 15.7. MS (ESI) m/z
and 135.57, 129.12 and 129.11, 128.4, 118.82 and 118.81, 66.9, 61.40
+
16 24 2
and 61.39, 43.43 and 43.41, 39.5 and 39.3, 23.04 and 23.00, 16.6 and
Found: C, 77.15; H, 10.02.
+
1
+
6.5, 15.8 and 15.7. MS (ESI) m/z (%): 487 ([2 M+Na] , 54), 255 ([M
Na] , 100). Anal. Calcd for C H O : C, 77.55; H, 8.68. Found: C,
+
[8b]
(�)-epi-Jungianol (5):
In a round bottom flask NaH (128 mg,
1
5
20
2
77.32; H, 8.99.
3.19 mmol, 60% in mineral oil) was washed three times with
anhydrous hexane, under nitrogen atmosphere. After few minutes,
anhydrous DMF (2.9 mL) was added and the suspension cooled in
an ice bath. Propanethiol (174 μL, 1.9 mmol) was then dropwise
added and, after 5 minutes, the ice bath was removed and the
mixture stirred at room temperature for 20 minutes. A solution of
substrate 29 (15 mg, 0.064 mmol) in anhydrous DMF (1 mL) was
dropwise added and the resulting mixture heated at 130°C
4
2
-Methoxy-1,5-dimethyl-3-(2-methylpropenyl)indan (29): From
3via 28. solution of commercially available meth-
A
yltriphenylphosphonium bromide (143 mg, 0.4 mmol) in anhydrous
THF (6.8 mL) was cooled to 0°C and a 1.0 M solution of t-BuOK in
THF (440 μL, 0.44 mmol) was then added dropwise. After 30
minutes, a solution of ketone 23 (47 mg, 0.20 mmol) in anhydrous
THF (4 mL) was slowly added, and the resulting mixture stirred at
(
external) for 4.5 h. After cooling to room temperature, the reaction
0
°C. After complete consumption of 23 (TLC monitoring; 2 h), the
was quenched by addition of satd NH Cl (39 mL) and the product
4
mixture was quenched by the addition of brine (20 mL) and the
product extracted by Et O (2×15 mL) and DCM (15 mL); the
extracted with Et
O (4×15 mL). The combined organic extracts
2
2
Eur. J. Org. Chem. 2021, 1266–1273
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doi.org/10.1002/ejoc.202001555
were washed once with water (39 mL) and dried over anhydrous
Na SO . After filtration and evaporation of the solvent, the crude
Scarpi, E. G. Occhiato, J. Org. Chem. 2020, 85, 5078–5086; b) A. Rinaldi,
M. Petrović, S. Magnolfi, D. Scarpi, E. G. Occhiato, Org. Lett. 2018, 20,
4713–4717.
7] F. Bohlmann, C. Zdero, Phytochemistry 1977, 16, 239–242.
8] a) D. H. Dethe, G. M. Murhade, S. Ghosh, J. Org. Chem. 2015, 80, 8367–
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
2
4
was purified by flash chromatography (n-hexane/EtOAc, 60:1; R =
f
[
[
0.17) affording (�)-epi-jungianol 5 (11 mg, 78%) as a white waxy
1
solid. H NMR (200 MHz, CDCl
) δ (ppm): 6.99 (d, J=7.4 Hz, 1 H),
3
8376; b) D. H. Dethe, G. Murhade, Org. Lett. 2013, 15, 429–431.
6
.68 (d, J=7.4 Hz, 1 H), 5.97 (s, 1 H), 5.35 (dm, J=10.2 Hz, 1 H), 4.0
[9] A. S. K. Hashmi, L. Ding, J. W. Bats, P. Fischer, W. Frey, Chem. Eur. J. 2003,
(dt, J=10.2, 7.2 Hz, 1 H), 3.16–2.97 (m, 1 H), 2.42 (dt, J=12.2, 6.8 Hz,
9, 4339–4345.
1
1
H), 2.19 (s, 3 H), 1.88 (d, J=1.4 Hz, 3 H), 1.82 (d, J=1.4 Hz, 1 H),
.35–1.23 (m, 1 H), 1.27 (d, J=4.8 Hz, 3 H). C NMR (100.4 MHz,
[10] The acid-catalyzed reaction of isopropenyl ethers with acetylenic
carbinols generates such compounds (R=Me) but they cannot be
isolated because, under the acidic reaction conditions, they immedi-
ately provide β-ketoallenes in the so called Saucy–Marbet rearrange-
ment. This approach is moreover limited by the availability of
substituted vinyl ethers. a) G. Saucy, R. Marbet, Helv. Chim. Acta 1967,
50, 1158–1167. See also: b) D. Tejedor, G. Méndez-Abt, L. Cotos, F.
García-Tellado, Chem. Soc. Rev. 2013, 42, 458–471. For a review on the
synthesis of vinyl ethers, see: c) D. J. Winternheimer, R. E. Shade, C. A.
Merlic, Synthesis 2010, 2497–2511.
13
CDCl ) δ (ppm): 151.6, 147.7, 136.0, 129.9, 127.7, 122.4, 114.6, 43.7,
3
41.1, 38.4, 25.9, 19.2, 18.2, 15.2. MS (ESI negative mode) m/z (%):
À
2
15 ([MÀ 1] , 100).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
Acknowledgements
[11] M. Lin, X.-T. Liu, Q.-Z. Chen, F. Wu, P. Yan, S.-X. Xu, X.-L. Chen, J.-J. Wen,
Z.-P. Zhan, Synlett 2011, 665–670.
[12] J.-P. Dulcère, J. Rodriguez, Synthesis 1993, 399–405.
Dr. Carlotta Zoppi is acknowledged for HRMS analyses and Dr.
Susanna Pucci for elemental analyses.
[
[
[
13] a) R. N. Nair, T. D. Bannister, J. Org. Chem. 2014, 79, 1467–1472; b) K.
Vijendhar, B. Srinivas, S. Boodid, J. Chem. Sci. 2015, 127, 2023–2028.
14] U. C. Yoon, D. U. Kim, C. W. Lee, Y. S. Choi, Y.-J. Lee, H. L. Ammon, P. S.
Mariano, J. Am. Chem. Soc. 1995, 117, 2698–2710.
15] 12a and 12b are acid sensitive compounds and decompose during
chromatography on silica gel, so purification must be carried out on
alumina. However, they could not be properly purified by chromatog-
raphy on alumina because of their very high lipophilicity, though they
could be used in the next gold(I)-catalyzed process without problems.
Instead, vinyl ethers 21 and 25 were properly purified by chromatog-
raphy on alumina and were fully characterized.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: epi-Jungianol · Gold · Homogeneous catalysis ·
Rearrangement · Total synthesis
[
16] Z.-P. Zhan, J.-L. Yu, H.-J. Liu, Y.-Y. Cui, R.-F. Yang, W.-Z. Yang, J.-P. Li, J.
Org. Chem. 2006, 71, 8298–8301.
[17] Flash chromatography (EtOAc/n-hexane, 1:25;
R
f
=0.40) provided
compound 14 as a pale yellow oil. H NMR (200 MHz, CDCl ) δ (ppm):
.45–7.14 (m, 10 H), 4.15–4.04 (m, 1 H), 3.70 (dd, J=20.0, 6.8 Hz, 1 H),
.44 (dd, J=20.0, 14.8 Hz, 1 H), 2.90–2.59 (m, 2 H), 2.25–2.07 (m, 1 H),
1
3
7
3
[
1] a) V. Michelet, F. D. Toste, Gold Catalysis: An Homogeneous Approach,
Imperial College Press, 2014; b) W. Zi, F. D. Toste, Chem. Soc. Rev. 2016,
45, 4567–4589; c) R. Dorel, A. M. Echavarren, Chem. Rev. 2015, 115,
2.04–1.88 (m, 1 H), 1.60 (s, 3 H), 1.57 (s, 3 H).
9
028–9072.
2] a) M. Marín-Luna, O. Nieto-Faza, C. Silva-López, Front. Chem. 2019,
:296.
[3] D. Pflästerer, A. S. K. Hashmi, Chem. Soc. Rev. 2016, 45, 1331–1367.
[18] We hypothesized that the antiperiplanar arrangement between the
leaving group and the proton abstracted by the base is hampered, in
the minor diastereomer, by one of the two groups on the propargyl C
atom. So, if this bears three groups (i.e., one phenylethynyl and two
methyl groups) as in 14, the antiperiplanar arrangement should be
impeded in any case and the reaction should not, as it happened,
occur.
[
7
[
4] a) D. Scarpi, C. Faggi, E. G. Occhiato, J. Nat. Prod. 2017, 80, 2384–2388;
b) D. Scarpi, M. Petrović, B. Fiser, E. Gómez-Bengoa, E. G. Occhiato, Org.
Lett. 2016, 18, 3922–3925; c) M. Petrović, D. Scarpi, B. Fiser, E. Gómez-
Bengoa, E. G. Occhiato, Eur. J. Org. Chem. 2015, 3943–3956; d) D. Scarpi,
S. Begliomini, C. Prandi, A. Oppedisano, A. Deagostino, E. Gómez-
Bengoa, B. Fiser, E. G. Occhiato, Eur. J. Org. Chem. 2015, 3251–3265; e) A.
Oppedisano, C. Prandi, P. Venturello, A. Deagostino, G. Goti, D. Scarpi,
E. G. Occhiato, J. Org. Chem. 2013, 78, 11007–11016.
[19] T. Ohmura, S. Kusaka, T. Torigoe, M. Suginome, Adv. Synth. Catal. 2019,
361, 4448–4453.
[
[
5] a) A. Rinaldi, V. Langé, E. Gómez-Bengoa, G. Zanella, D. Scarpi, E. G.
Occhiato, J. Org. Chem. 2019, 84, 6298–6311; b) for a recent review on
the synthesis of indenes, see: A. Rinaldi, D. Scarpi, E. G. Occhiato, Eur. J.
Org. Chem. 2019, 7401–7419.
6] We have also exploited this approach for cascade propargyl Claisen
rearrangement/Nazarov cyclization processes: a) A. Rinaldi, V. Langé, D.
Manuscript received: November 27, 2020
Revised manuscript received: January 20, 2021
Accepted manuscript online: January 21, 2021
Eur. J. Org. Chem. 2021, 1266–1273
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© 2021 Wiley-VCH GmbH