One-Pot Access to 1,7a-Dihydro-1,3a-ethano-indene and 1,8a-Dihydro-1,3a-ethano-azulene Skeletons by a Sequential Gold(I)-Catalyzed Propargyl Claisen Rearrangement/Nazarov Cyclization/[4+2] Cycloaddition Reaction

Article abstract of DOI:10.1021/acs.joc.0c00088

An efficient synthetic approach to the tricyclic 1,7a-dihydro-1,3a-ethano-indene and 1,8a-dihydro-1,3a-ethano-azulene skeletons from suitable propargyl vinyl ethers is based on a one-pot, multistep process entailing a gold(I)-catalyzed propargyl Claisen rearrangement/Nazarov cyclization, a [4+2] cycloaddition of the formed six-or seven-membered ring-fused cyclopentadiene system, and a final protection step for the easy isolation and purification of the products by chromatography.

Full text of DOI:10.1021/acs.joc.0c00088

Subscriber access provided by EDINBURGH UNIVERSITY LIBRARY | @ http://www.lib.ed.ac.uk
Note
One-pot Access to the 1,7a-Dihydro-1,3a-ethano-indene and
1,8a-Dihydro-1,3a-ethano-azulene Skeletons by Sequential
Gold(I)-catalyzed Propargyl Claisen Rearrangement/
Nazarov Cyclization/[4+2] Cycloaddition Reaction
Antonia Rinaldi, Vittoria Langé, Dina Scarpi, and Ernesto Giovanni Occhiato
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00088 • Publication Date (Web): 20 Mar 2020
Downloaded from pubs.acs.org on March 20, 2020
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One-pot Access to the 1,7a-Dihydro-1,3a-ethano-indene and 1,8a-Dihydro-1,3a-ethano-azulene
Skeletons by Sequential Gold(I)-catalyzed Propargyl Claisen Rearrangement/Nazarov
Cyclization/[4+2] Cycloaddition Reaction
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Antonia Rinaldi, Vittoria Langé, Dina Scarpi,* Ernesto G. Occhiato*
Dipartimento di Chimica “U. Schiff”, Università degli Studi di Firenze, Via della Lastruccia 13, 50019,
Sesto Fiorentino (FI), Italy.
dina.scarpi@unifi.it, ernesto.occhiato@unifi.it
TOC/Abstract Graphic:
EWG
EWG
R
H
LAuX,
EWG
EWG
( )n
DCM, 25 °C
( )n
then 1,2-ethandiol,
p-TsOH
O
O
O
n = 1,2
R
All in one pot
14 examples, 56-99 %
propargyl Claisen
rearrangement
aldehyde
protection
R
Nazarov
reaction
R
[4 + 2]
cycloaddition
R
H
( )n
EWG
( )n
( )n
•
EWG
+
AuL
EWG
CHO
EWG
CHO
CHO
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Abstract.
An efficient synthetic approach to the tricyclic 1,7a-dihydro-1,3a-ethano-indene and 1,8a-dihydro-1,3a-
ethano-azulene skeletons from suitable propargyl vinyl ethers is based on a one-pot, multi-step process
entailing a gold(I)-catalyzed propargyl Claisen rearrangement/Nazarov cyclization, a [4 + 2] cycloaddition of
the formed six- or seven-membered ring-fused cyclopentadiene system, and a final protection step for the
easy isolation and purification of the products by chromatography.
The 1,7a-dihydro-1,3a-ethano-indene is an unusual tricyclic skeleton found in some natural products with up
to three contiguous quaternary carbon atoms. Sesquiterpenes -neoclovene,1 -neoclovene,1,2 junicedranol,3
and myltaylenol,4 as well as the tetracyclic diterpene coronopifoliol,5 are among the few examples of known
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natural products with the 1,7a-dihydro-1,3a-ethano-indene skeleton (Figure 1). Guanacastapene K6 and the
dimeric guaianolides,7,8 e.g. caruifolins B7 and absinthin7, are examples of the more numerous 1,8a-dihydro-
1,3a-ethano-azulene-containing natural products (Figure 1). The latter in particular possess remarkable
pharmacological activities, which include anti-HIV-1 protease activity, inhibition of cyclooxygenase-2,
cytotoxic activity, inhibition of LPS-induced HF-B activation and NO production, as well as selective
inhibition of farnesyl protein transferase (FTPase).8
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1
1
8a
3a
7a
3a
1,8a-Dihydro-1,3a-ethano-azulene
1,7a-Dihydro-1,3a-ethano-indene
OH
Junicedranol
-Neoclovene
OH
-Neoclovene
OAc
OH
H
Br
H
OH
O
O
O
HO
guanacastepene K
coronopifoliol
(-)-myltaylenol
HO
O
HO
O
HO
HO
H
H
H
O
O
O
O
O
O
O
absinthin
caruifolin B
Figure 1. Some natural compounds embodying the 1,7a-dihydro-1,3a-ethano-indene and 1,8a-dihydro-1,3a-
ethano-azulene skeletons
Either because these unique tricyclic structures represent a synthetic challenge or because their uncommon
occurrence in nature, only a handful of approaches have been described for the construction of the 1,3a-
ethano-indene skeleton, of which the most explored is based on the [4 + 2] cycloaddition reaction between
suitable dienophiles and 4,5,6,7-tetrahydro-3aH-indene derivatives.9,10,11 Despite their potential in medicinal
chemistry, no examples of cycloadditions or alternative synthetic methods leading to 1,8a-dihydro-1,3a-
ethano-azulene compounds have instead been reported, the only exception being the biomimetic dimerization
of a guaiane-type precursor for the synthesis of absinthin.12
We have recently reported that suitably substituted enynyl vinyl ethers 1 undergo a propargyl Claisen
rearrangement/Nazarov cyclization cascade process, when subjected to gold(I)-catalysis, to efficiently
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provide functionalized cyclopentadienes fused with six- and seven-membered carbocycles (2) (Scheme 1).13
The gold-allene complex (I) generated by the metal-catalyzed [3,3]-rearrangement of 1 immediately
undergoes a 4-electrocyclization via the corresponding pentadienyl cation (II). This cascade process
provides cyclopentadiene 2 bearing, on one side chain, an aldehyde group which we have shown can be
easily subjected to further in situ elaboration for incrementing the structural diversity of the products.13,14
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Scheme 1. The cascade process leading to the target compounds 3
R 1
EWG
( )n
( )n
LAuX
EWG
2 EWG
3a
O
CHO
EWG
1
3
EWG
n = 1,2
R
[4 + 2]
cycloaddition
propargyl Claisen
rearrangement
EWG
R
Nazarov
reaction ( )n
R
R
3a
3
( )n
( )n
+
•
+
AuL
1
AuL
CHO
CHO
CHO
2
I
II
In order to establish a quick access to functionalized 1,7a-dihydro-1,3a-ethano-indene and 1,8a-dihydro-1,3a-
ethano-azulene skeletons 3, we decided to evaluate whether the diene system of aldehyde 2, once generated
through the rearrangement/cyclization step, could be trapped by a dienophile present in situ via a [4+2]
cycloaddition process (Scheme 1).15 This approach, which entails three steps in one pot, would also have the
advantage of avoiding the isolation and purification of dienes of type 2, which are in general susceptible of
double bond isomerization and degradation during chromatography and thus very difficult to be isolated as
such. In this Note we show that it is possible to perform such a multi-step process allowing for the rapid
access to a variety of new products embodying the 1,7a-dihydro-1,3a-ethano-indene and 1,8a-dihydro-1,3a-
ethano-azulene skeletons which could be useful in biological studies or as synthetic intermediates. Moreover,
since no synthetic methods to 1,8a-dihydro-1,3a-ethano-azulenes have been reported so far, this would
represent the first general approach to such a class of compounds.
Enynyl vinyl ether 1a, prepared as reported,13 was used for some preliminary experiments using

[IPrAu]+SbF6 (3 mol %) as the catalyst prepared by mixing IPrAuCl and AgSbF6 in CH2Cl2 (0.05 M in
1a).13 The first experiment (Scheme 2) was carried out by adding 2 equiv of N-methylmaleimide to the above
solution after the rearrangement/cyclization step was complete (10 min) and leaving at room temperature.
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We were glad to observe that the cyclopentadiene system generated by the former process was quickly
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6
1
consumed (in less than 15 min), giving rise with high diastereoselectivity (dr = 24:1 by integration of H
7
8
NMR signals of 2-H) to a cycloadduct possessing the ,-unsaturated aldehyde moiety of 4.16
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Scheme 2. Preliminary experiment leading to aldehyde 5
a) 3 mol % IPrAuCl,
3 mol % AgSbF6
CH2Cl2, 25 °C
O
H
N
Me
b) N-Methylmaleimide
O
O
(2 equiv)
CHO
1a
4
O
dr = 24:1
H
N
Me
SiO2
chromatography
O
CHO
5 (53%)
Chromatography of 4 on silica gel caused the expected migration of the double bond to the exocyclic
position, providing ,-unsaturated aldehyde 5 in 53% yield.17 We then carried out a second experiment
(Scheme 3) by adding a solution of 1a and N-methylmaleimide (1 equiv.) in CH2Cl2 to a solution of the
1
preformed catalyst. After 20 min the reaction was complete and the H NMR analysis of a small fraction of
the crude reaction mixture revealed the exclusive formation of aldehyde 4. The rest of the solution was
diluted with MeOH and treated with NaBH4 to reduce the aldehyde to alcohol 7, so to avoid isomerization of
the double bond during chromatography.13 Although vinyl allenes are known to readily react with
dienophiles,18 in fact no traces of products deriving from the reaction of the maleimide with the vinyl allene
from I (Scheme 1) were detected, consistent with the fast ring closure step of the latter to give diene 2a (R =
Me, n = 1). While allene intermediates can be isolated in the tandem Claisen rearrangement/hydroarylation
reaction of 3-arylsubstituted vinyl allenes,14 with substrates of type 1 only the Nazarov product intermediate
2 can be observed while monitoring the reaction by 1H NMR.
The same sequence was repeated by using N-phenylmaleimide as the dienophile (10 min for completion of
the rearrangement/cycloaddition steps), which provided cycloadduct 8 in quantitative yield (99%) and with
even higher facial selectivity (dr = 32:1). We also found that it was possible to protect the aldehyde
functionality in the final product by adding, once the sequential process was complete, ethylene glycol (2
equiv.) and p-TsOH·H2O (5 mol %), so that protected aldehyde 9 could be obtained in 79% yield after
chromatography (Scheme 3).
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Scheme 3. Preliminary experiments and synthesis of compounds 7-9
O
3 mol % IPrAuCl,
3 mol % AgSbF6
CH2Cl2, 25 °C
H
N
R
7
8
9
O
O
O
CHO
N
R
1a
4 R = Me
6 R = Ph
R = Me, Ph
(1 equiv)
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O
OH
(2 equiv)
5 mol % pTsOH
O
HO
NaBH4,
MeOH
O
H
H
N
Me
N
R
O
O
7 R = Me (89%)
dr = 24:1
O
9 (79%)
dr = 24:1
8 R = Ph (99%)
OH
O
dr = 32:1
To prove that the metal cations present in the reaction mixture (Au+ and residual Ag+) have no role in the
cycloaddition process, we prepared and purified by chromatography cyclopentadiene 10 (Scheme 4) obtained
by reduction with NaBH4 of intermediate 2a.13 Compound 10 was dissolved in CH2Cl2 in the presence of a
slight excess of N-methylmaleimide (1.2 equiv) and, also under these conditions, the cycloaddition
quantitatively provided alcohol 7 in 10 min in an 24:1 diastereomeric ratio.
Scheme 4. Cycloaddition reaction of the isolated diene 10
O
N-Methylmaleimide
(1.2 equiv)
H
N Me
CH2Cl2, 25 °C
O
7 (100%)
dr = 24:1
OH
10
OH
Compound 9 and ,-unsaturated aldehyde 5 were fully characterized (Supporting Information) and used for
NOE studies (Figure 2) after unambiguous assignment of all 1H NMR signals.
H
H
H
9
O
H
H
9
O
O
H
8
H
H
7
H
7
H
9
8
7a
H
N
N
Me
8
2
N
H 4
7a
7a
2
4
H
H
4
O
O
O
CHO
H
H
H
H
O
CHO
5
9
O
H
10
H
10
O
O
H
9
H
9
H
H
N
Me
N
Me
8a
8a
4
4
O
O
H
H
O
O
O
O
19
20
Figure 2. NOE studies on some the polycyclic compounds prepared
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In compound 5 NOE cross-peaks between protons at position 9 (2.93 ppm) and 8 (3.2 ppm) with the
bridgehead proton at position 7a (at about 1.6 ppm) and the axial 4a-H (at about 1.6 ppm), respectively, were
diagnostic of the endo approach of the dienophile to the less hindered face of the diene 2. The other NOE
enhancements found in 5 were consistent with this stereochemical attribution, in particular the one between
the endo proton on C2 (2.59 ppm) with axial proton on C7 (0.91 ppm) and that between the 1-methyl (1.37
ppm) with 9-H. Finally, two NOE cross-peaks, one between the CHO proton with exo 2-H (2.59 ppm) and
the other between the double bond proton at 5.85 ppm with the equatorial 4-H (2.39 ppm), allowed us to
establish the geometry of the double bond itself, as eventually confirmed by X-ray analysis of compound 5
(Supporting Information).19 In compound 9, NOE cross-peaks between 9-H and 8-H (isochronous at 2.91
ppm) with 7a-H (1.40 ppm) and 4-Hax (1.48 ppm) were in accordance with the proposed structure. As
expected, the approach of the dienophile to our 4,5,6,7-tetrahydro-3aH-indene intermediate is not different
from that reported in literature for isolated six-membered ring-fused cyclopentadienes such as the
Winterfeldt’s cyclopentadiene (possessing a bridgehead methyl group at position 7a and a 4-methoxyphenyl
group at C1), which undergoes an endo attack by dienophiles on the  face (i.e. on that containing the
bridgehead methyl group at position 7a).9c-d,f,h,j
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A series of dienophiles were then used to explore the scope of this sequential process with both six- and
seven-membered ring carbocycles bearing a differently substituted propargyl vinyl ether moiety (compounds
1a-f). The reactions were carried out in the presence of 1-1.5 equiv. of the dienophile and the aldehyde
functionality was in most cases protected as dioxolane before work-up. As confirmed by NOE studies, with
cyclohexene derivatives 1a-c (Scheme 5) the reaction proceeded with an endo approach of the dienophile to
the less hindered face (the  face) of the cyclopentadiene intermediate and the products – with a single
exception – were obtained in good to excellent yield (57-95%) after chromatography and with high facial
selectivity (d.r. from 20:1 to >100:1). Irrespective of the dienophile, the facial selectivity was very high with
the isopropyl substituent at position 3 of the intermediate diene (compounds 13-16). The time required for
the cycloadditions varied from 5 min to 70 min, depending on the dienophile and its relative amount. In
particular, with tetracyanoethylene it was not possible to perform the reaction by mixing the substrate and the
dienophile as the latter underwent a nucleophilic attack by the vinyl moiety of the substrate. Thus
tetracyanoethylene, in this case, was added after formation of the diene to form 16.
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Scheme 5. Synthesis of 1,7a-dihydro-1,3a-ethano-indene derivatives 9-18
a) 3 mol % [IPrAu]SbF6,
R
EWG
EWG
H
( )n
EWG
EWG (1-1.5 equiv)
7
8
9
CH2Cl2, 25 °C
b) ethylene glycol (2 equiv)
5 mol % p-TsOH
CH2Cl2, 25 °C
O
O
1a R = Me
1b R = iPr
1c R = nBu
R
9-18
O
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
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O
O
O
Me
R
R
H
R
N
O
H
H
O
O
O
O
O
O
O
O
O
11 R = Me (95%)a
12 R = Me (94%)a
dr = 33:1
15 R = iPr (88%)c
9 R = Me (79%)a
dr = 23:1
dr = 24:1
14 R = iPr (64%)c
dr > 100:1
13 R = iPr (90%)b
dr > 100:1
dr = 80:1
O
O
CN
CN
Ph
N
H
H
H
CN
CN
O
O
O
O
O
O
O
O
18 (82%)b
16 (92%)b,d
17 (57%)b
dr = 20:1
dr = 22:1
dr > 100:1
aWith 1.0 equiv of dienophile; bwith 1.2 equiv of dienophile; cwith 1.5 equiv of
dienophile;ddienophile added after the rearrangement/cyclization was complete
Double bond isomerization is a particularly serious issue when attempting to isolate aldehydes of type 2 in
which the cyclopentadiene moiety is fused to a seven-membered ring.13 Such isomerization even starts to
take place during the gold(I)-catalyzed reaction of the enynyl vinyl ethers, so we were very glad to see that
dienophiles present in situ quickly reacted (10 min) with the 3a,4,5,6,7,8-hexahydroazulenes once generated
from 1d-f (Scheme 6). However, the facial selectivity in the cycloaddition was somewhat lower than with the
previous substrates. For example, n-butyl substituted compound 19 was obtained as a 9:1 mixture of
diastereomers in 69% yield by using 2 mol % [IPrAu]SbF6 as the catalyst.20 The relative stereochemistry of
major isomer 19, consistent with an endo attack to the  face of the diene, was assigned by NOE studies
(Figure 2). Changing the n-butyl group with a methyl group in the enynyl vinyl ether, the facial selectivity in
the cycloaddition step increased and compound 20 (see Figure 2 for NOE correlations and Supporting
Information) was obtained as a 15:1 mixture of diastereomers and in 73% yield when using 1.5 mol %
[IPrAu]SbF6 as the catalysts. The same facial selectivity was obtained reacting 1e with 0.8 equiv. of N-
phenylmaleimide under the same conditions (compound 21).
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Scheme 6. Synthesis of 1,8a-dihydro-1,3a-ethano-azulene derivatives 19-24
R
EWG
EWG
a) 1.5-2 mol % [IPrAu]SbF6,
(1-1.2 equiv)
H
EWG
EWG
7
O
CH2Cl2, 25 °C,
8
9
R'
b) ethylene glycol (2 equiv)
5 mol % p-TsOH, CH2Cl2,
25 °C or NaBH4, MeOH
1d R = nBu
1e R = Me
1f R = iPr
R
O
19-24
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O
O
Me
Ph
N
N
Me
H
O
H
N
H
O
O
O
O
O
O
O
O
21 (95%)a,c,d dr = 15:1
19 (69%)a,b dr = 9:1 20 (73%)a,d dr = 15:1
O
O
O
Me
N
O
O
H
H
H
O
O
O
OH
24 (92%)a,d,g dr = 9:1
CHO
22 (87%)d,e,f dr = 13:1
O
O
23 (77%)d,e dr = 13:1
aWith 1.2 equiv of dienophile; bwith 2 mol % [IPrAu]SbF6;cwith 0.8 equiv. of
dienophile; dwith 1.5 mol % [IPrAu]SbF6; e1.0 equiv of dienophile; fno protection
was carried out; greduction was carried out
With maleic anhydride, finally, we stopped the sequence at the cycloaddition step and in this case isolated
cycloadduct 22 (13:1 mixture of isomers, 87% yield) with only traces of the corresponding ,-unsaturated
aldehyde after chromatography on silica gel. In any case, protected compound 23 was obtained according to
the usual one-pot procedure in 77% yield.
In contrast to the results obtained with propargyl vinyl ether 1b, the reaction of isopropyl substituted
substrate 1f in the presence of N-methylmaleimide occurred with much lower selectivity, providing alcohol
24 (after reduction instead of protection of the aldehyde group) as a 9:1 mixture of diastereomers. At the
same time, cycloaddition was slow and with 1.2 equiv. of the dienophile it reached completion in 30 min.21
From all these results it appears that with hexahydroazulenes 2 the facial selectivity decreases with the larger
groups at C3.
In conclusion we have established a quick and efficient synthetic methodology to the 1,7a-dihydro-1,3a-
ethano-indene and 1,8a-dihydro-1,3a-ethano-azulene skeletons based on a one-pot, multi-step process
entailing a gold(I)-catalyzed propargyl Claisen rearrangement/Nazarov cyclization sequence and a [4 + 2]
endo cycloaddition of the formed diene system, readily occurring at room temperature. Since no synthetic
methods to 1,8a-dihydro-1,3a-ethano-azulenes have been reported so far, this methodology represents the
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Experimental Section
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General information. 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) by using flash column techniques; Rf values refer to TLC carried out on 0.25
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mm silica gel plates (F254) with the same eluent as indicated for column chromatography. H NMR (400
MHz) and 13C 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) 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 FleetTM Ion Trap LC/MS system (Thermo Fisher Scientific) with
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. 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. 1-Cyclohexenyl trifluoromethanesulfonate is commercially available; 1-heptenyl
trifluoromethanesulfonate was prepared as reported.22 Compounds 1a, 1c and 1e are known.13
General Procedure for the Synthesis of Propargyl Vinyl Ethers 1.
A 3:1 (v/v) solution of anhydrous THF/Et3N (6.6 mL) was added to a round-bottomed flask containing either
1-cyclohexenyl or 1-cycloheptenyl trifluoromethanesulfonate (1 mmol). The alkynol (1.0-1.1 equiv.), CuI
(3.2 mol%) and (Ph3P)2PdCl2 (1.6 mol%) were then added under nitrogen atmosphere and the reaction
mixture stirred at room temperature for 3 h. Water (25 mL) was then added and the product extracted with
Et2O (3 x 20 mL). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous
K2CO3. After filtration and evaporation of the solvent, the crude reaction mixture was purified by flash
chromatography affording the intermediate enynyl alcohol which was used immediately in the next step. In a
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screw cap vial, Hg(OAc)2 (45 mol %) was added in one portion to a solution of the enynyl alcohol (1 mmol)
in ethyl vinyl ether (5 mL) under nitrogen atmosphere and the reaction mixture was heated at 50 °C (external
bath) for 1 day. The mixture was then cooled to room temperature and a solution of satd Na2CO3 (12.5 mL)
was added. The product was extracted with Et2O (3 x 10 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 1 which was stored at 4°C as a solution in the eluent
containing 1% Et3N. The solution of 1 in the eluent was concentrated and dried under vacuum just prior use.
1-(4-Methyl-3-viniloxypent-1-ynyl)cyclohexene (1b). Sonogashira coupling of 1-cyclohexenyl
trifluoromethanesulfonate (525 L, 3.0 mmol) and (±)-4-methyl-1-pentyn-3-ol (349 L, 3.3 mmol), followed
by purification by flash chromatography (n-hexane/EtOAc, 6:1 + 1% Et3N; Rf = 0.36) afforded the enynyl
alcohol intermediate which was used immediately in the next step. 1H NMR (200 MHz, CDCl3): δ 6.12–6.08
(m, 1 H), 4.30–4.25 (m, 1 H), 2.13–2.04 (m, 4 H), 1.96–1.79 (m, 1 H), 1.69–1.51 (m, 4 H), 1.01 (d, J = 6.6
Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H). Vinylation of the latter afforded 1b, which was purified by flash
chromatography (n-hexane/EtOAc, 60:1 + 1% Et3N; Rf = 0.58). Pure 1b was obtained as a yellow oil (246
mg, 46% over 2 steps from 1-cyclohexenyl trifluoromethanesulfonate). 1H NMR (400 MHz, CDCl3): δ 6.45
(dd, J = 14.0, 6.8 Hz, 1 H), 6.13–6.10 (m, 1 H), 4.40 (dd, J = 14.0, 1.6 Hz, 1 H), 4.30 (d, J = 5.6 Hz, 1 H),
4.09 (dd, J = 6.8, 1.6 Hz, 1 H), 2.14–2.05 (m, 4 H), 2.05–1.96 (m, 1 H), 1.66–1.54 (m, 4 H), 1.03 (d, J = 6.8
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Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H). C{1H} NMR (100.4 MHz, CDCl3): δ 150.1, 135.3, 120.1, 89.1, 88.9,
83.0, 74.8, 33.1, 29.2, 25.6, 22.2, 21.4, 18.4, 17.7. GCMS (CI) m/z (%): 205 ([M + 1]+, 100). Anal. Calcd for
C14H20O: C, 82.30; H, 9.87. Found: C, 82.45; H, 9.82.
1-(3-Viniloxyhept-1-ynyl)cycloheptene
(1d).
Sonogashira
coupling
of
1-cycloheptenyl
trifluoromethanesulfonate (270 mg, 1.1 mmol) and (±)-1-heptyn-3-ol (146 L, 1.1 mmol), followed by
purification of the crude by flash chromatography (n-hexane/EtOAc, 9:1 + 1% Et3N; Rf = 0.28) afforded the
1
enynyl alcohol intermediate which was used immediately in the next step. H NMR (400 MHz, CDCl3): δ
6.28 (t, J = 6.8 Hz, 1 H), 4.47 (t, J = 6.8 Hz, 1 H), 2.33–2.30 (m, 2 H), 2.20–2.15 (m, 2 H), 1.76–1.67 (m, 4
H), 1.58–1.47 (m, 4 H), 1.45–1.31 (m, 4 H), 0.92 (t, J = 7.2 Hz, 3 H). Vinylation of the latter afforded 1d,
which was purified by flash chromatography (n-hexane/EtOAc, 2:1 + 1% Et3N; Rf = 0.54). Pure 1d was
obtained as a colourless oil (187 mg, 73% over 2 steps from 1-cycloheptenyl trifluoromethanesulfonate). 1H
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NMR (400 MHz, CDCl3): δ 6.44 (dd, J = 14.0, 6.4 Hz, 1 H), 6.29 (t, J = 6.8 Hz, 1 H), 4.51 (t, J = 6.8 Hz, 1
H), 4.40 (dd, J = 14.0, 1.6 Hz, 1 H), 4.09 (dd, J = 6.4, 1.6 Hz, 1 H), 2.32–2.29 (m, 2 H), 2.19–2.15 (m, 2 H),
1.84–1.70 (m, 4 H), 1.58–1.40 (m, 6 H), 1.39–1.30 (m, 2 H), 0.91 (t, J = 7.2 Hz, 3 H). 13C{1H} NMR (100.4
MHz, CDCl3): δ 149.8, 140.5, 126.1, 89.8, 89.3, 84.2, 69.5, 35.3, 34.1, 32.0, 29.1, 27.3, 26.4, 22.3, 14.0.
GCMS (EI) m/z (%): 232 (M+, 13), 189 (11), 175 (100), 91 (17). Anal. Calcd for C16H24O: C, 82.70; H,
10.41. Found: C, 82.55; H, 10.12.
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1-(4-Methyl-3-vinyloxypent-1-ynyl)cycloheptene (1f). Sonogashira coupling of 1-cycloheptenyl
trifluoromethanesulfonate (607 mg, 2.5 mmol) and (±)-4-methyl-1-pentyn-3-ol (263 L, 2.5 mmol),
followed by purification of the crude by flash chromatography (n-hexane/EtOAc, 5:1 + 1% Et3N; Rf = 0.54),
afforded the enynyl alcohol intermediate which was used immediately in the next step. 1H NMR (400 MHz,
CDCl3): δ 6.28 (t, J = 6.8 Hz, 1 H), 4.27 (d, J = 5.6 Hz, 1 H), 2.33–2.30 (m, 2 H), 2.20–2.16 (m, 2 H), 1.93–
1.82 (m, 1 H), 1.77–1.69 (m, 2 H), 1.59–1.47 (m, 4 H), 1.00 (t, J = 6.8 Hz, 6 H). Vinylation of the latter
afforded 1f, which was purified by flash chromatography (n-hexane + 1% Et3N; Rf = 0.214). Pure 1f was
1
obtained as a colorless oil (305 mg, 56% over 2 steps from 1-cycloheptenyl trifluoromethanesulfonate). H
NMR (400 MHz, CDCl3): δ 6.45 (dd, J = 14.4, 6.8 Hz, 1 H), 6.29 (t, J = 6.8 Hz, 1 H), 4.41 (dd, J = 14.0, 2.0
Hz, 1 H), 4.31 (d, J = 6.0 Hz, 1 H), 4.09 (dd, J = 6.8, 2.0 Hz, 1 H), 2.33–2.30 (m, 2 H), 2.20–2.14 (m, 2 H),
2.05–1.97 (m, 1 H), 1.76–1.69 (m, 2 H), 1.59–1.47 (m, 4 H), 1.03 (d, J = 6.8 Hz, 3 H), 1.01 (d, J = 6.8 Hz, 3
H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 150.2, 140.3, 126.2, 90.5, 89.1, 82.9, 74.9, 34.2, 33.1, 32.0, 29.1,
26.5, 26.4, 18.4, 17.7. GCMS (EI) m/z (%): 218 (M+, 11), 175 (100), 91 (13). Anal. Calcd for C15H22O: C,
82.52; H, 10.16. Found: C, 82.31; H, 10.29.
General Procedure for the propargyl Claisen rearrangement/Nazarov cyclization/[4+2] cycloaddition
reaction.
Gold(I) complex IPrAuSbF6 was generated in situ by mixing equimolar quantities of IPrAuCl and AgSbF6
and leaving the mixture under stirring for 5 minute at 25 °C before addition of the substrates. Gold(I)
complex IPrAuOTf was generated in situ by mixing equimolar quantities of IPrAuCl and AgOTf (0.3 M
solution in toluene) and leaving the mixture under stirring for 1 minute at 25 °C before addition of the
substrates.
The solution of propargyl vinyl ether 1a-f in n-hexane was concentrated and dried under vacuum just prior
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Method A. To a solution of gold(I) complex LAuX (3 mol%) in DCM (3 mL) stirred at 25 °C under nitrogen
atmosphere was added a solution of propargyl vinyl ether 1 (0.3 mmol) and the dienophile (0.3-0.6 mmol) in
DCM (3 mL; final concentration 0.05 M) and the reaction mixture was stirred at 25 °C until complete
consumption of aldehyde 2 (TLC monitoring).
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A.1. Isolation of the unprotected aldehyde: Water was added (6 mL) and the product extracted with DCM (2
x 5 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 afford the aldehyde in which
complete isomerization of the double bond might also have occurred during the purification.
A.2. Protection of the aldehyde as [1,3]dioxolane: Ethylene glycol (0.6 mmol) and p-toluenesulfonic acid
monohydrate (2 mg) were added and the reaction mixture stirred at 25 °C for 1 h, before quenching by
aqueous satd NaHCO3 (15 mL); the product was extracted with DCM (3 x 10 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 to afford the pure protected aldehyde.
A.3. Reduction of the aldehyde: The mixture was diluted with MeOH (12 mL) and NaBH4 (12 mg, 0.3
mmol) immediately added. After 10 minutes the reduction was completed. The solvent was then evaporated,
water added to the residue (15 mL) and the product extracted with DCM (3 x 10 mL). The combined organic
extracts were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration and evaporation
of the solvent, the crude oil was purified by flash chromatography to afford the corresponding alcohol.
Method B. To a solution of gold(I) complex LAuX (3 mol %) in DCM (3 mL) stirred at 25 °C under
nitrogen atmosphere was added a solution of propargyl vinyl ether 1 (0.3 mmol) in DCM (3 mL; final
concentration 0.05 M) and the reaction mixture was stirred at 25 °C until complete consumption of 1 (TLC
monitoring). The dienophile (0.3-0.6 mmol) was then added and the stirring continued until disappearance of
the Nazarov reaction product 2 (TLC).
The mixture was then treated as described above in Method A, in order to obtain the final cycloadduct as
either aldehyde (B.1) or [1,3]dioxolane (B.2).
Compound 5. Compound 5 was prepared following Method B.1, starting from 1a (44 mg, 0.25 mmol) and
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using IPrAuSbF6 as the catalyst. The reaction was complete in 10 minutes. Then N-methylmaleimide (56 mg,
0.50 mmol) was added and the reaction mixture stirred at 25 °C under nitrogen atmosphere for 15 minutes.
The purification by flash chromatography (EtOAc/n-hexane, 1:4; Rf = 0.26) afforded 5 (38 mg, 53%), in
which the double bond in the β,γ position with respect to the CHO functional group had completely
isomerized to the α,β position, as also confirmed by X-ray analysis (see Supporting Information).19 Colorless
crystalline solid. M.p. = 144.9 – 146.1 °C (MeOH). 1H NMR (400 MHz, CDCl3) (d.r. 24 : 1): δ 9.71 (d, J =
6.8 Hz, 1 H), 5.85 (dt, J = 6.8, 2.4 Hz, 1 H), 3.03 – 3.01 (m, 1 H), 2.94 – 2.91 (m, 1 H), 2.80 (s, 3 H), 2.65 –
2.51 (m, 2 H), 2.42 – 2.35 (m, 1 H), 1.77 – 1.70 (m, 1 H), 1.68 – 1.56 (m, 4 H), 1.37 (s, 3 H), 1.22 – 1.10 (m,
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2 H), 0.95 – 0.84 (m, 1 H). C{1H} NMR (100.4 MHz, CDCl3): δ 190.4, 177.0, 175.5, 165.8, 123.5, 59.6,
57.3, 54.7, 53.1, 47.7, 37.0, 28.4, 24.3, 24.1, 22.6, 21.4, 17.2. GCMS (CI) m/z (%): 289 ([M + 1]+, 16), 288
(M+, 100). Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.83; H, 7.51; N, 4.49.
Compound 7. Compound 7 was prepared following Method A.3, starting from 1a (34 mg, 0.19 mmol), N-
methylmaleimide (1 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 20 minutes.
After this time, the mixture was diluted with MeOH (8.4 mL), NaBH4 (8 mg, 0.21 mmol) was added and the
reaction stopped after 10 minutes. Purification by flash chromatography (EtOAc/n-hexane, 1:2; Rf = 0.36)
afforded 7 (49 mg, 89%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) (d.r. 24 : 1): δ 5.36 (s, 1 H), 3.75–
3.61 (m, 2 H), 2.94 (s, 3 H), 2.79 (s, 3 H) 2.44–2.37 (m, 1 H), 2.36–2.28 (m, 1 H), 2.13–2.05 (m, 1 H), 1.72–
1.60 (m, 2 H), 1.54–1.42 (m, 2 H), 1.43–1.32 (m, 2 H), 1.39 (s, 3 H), 1.24–1.13 (m, 1 H), 1.13–0.94 (m, 2
H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 177.8, 177.3, 144.2, 128.4, 67.6, 60.3, 59.1, 55.4, 53.9, 53.3, 30.6,
28.6, 24.1, 23.9, 23.5, 21.7, 15.3. MS (ESI) m/z (%): 312 ([M + Na]+, 100). HRMS (ESI/TOF) m/z: [M +
Na]+ calcd for C17H23NO3Na: 312.1570. Found: 312.1574.
Compound 8. Compound 8 was prepared following Method A.3, starting from 1a (25 mg, 0.14 mmol), N-
phenylmaleimide (1 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 15 minutes.
After this time, the mixture was diluted with MeOH (5.6 mL), NaBH4 (5 mg, 0.14 mmol) was added and the
reaction stopped after 10 minutes. Purification by flash chromatography (EtOAc/n-hexane, 1:4; Rf = 0.15)
afforded 8 (49 mg, 99%) as a white solid. M.p. = 100.8 – 102.2 °C. 1H NMR (400 MHz, CDCl3) (d.r. 32 : 1):
δ 7.43 – 7.39 (m, 2 H), 7.35 – 7.31 (m, 1 H), 7.17 – 7.12 (m, 2 H), 5.53 (s, 1 H), 3.82–3.67 (m, 2 H), 3.10
(AB system, JAB = 7.2 Hz, 2 H), 2.47–2.42 (m, 1 H), 2.42–2.33 (m, 1 H), 2.19–2.11 (m, 1 H), 1.75–1.64 (m,
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2 H), 1.59–1.47 (m, 2 H), 1.47–1.37 (m, 2 H), 1.45 (s, 3 H), 1.28–1.18 (m, 1 H), 1.18–1.01 (m, 2 H). 13C{1H}
NMR (100.4 MHz, CDCl3): δ 176.6, 176.1, 144.6, 131.8, 129.0 (2 C), 128.5, 128.3, 126.3 (2 C), 67.8, 60.4,
59.6, 56.0, 53.8, 53.3, 30.8, 28.6, 23.8, 23.5, 21.7, 15.4. MS (ESI) m/z (%): 374 ([M + Na]+, 100), 725 ([2M
+ Na]+, 30). HRMS (ESI/TOF) m/z: [M + H]+ calcd for C22H25NO3: 352.1907. Found: 352.1904.
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Compound 9. Compound 9 was prepared following Method A.2, starting from 1a (30 mg, 0.17 mmol), N-
methylmaleimide (1 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 20 minutes.
After protection as [1,3]dioxolane, purification of the crude by flash chromatography (EtOAc/n-hexane, 1:8;
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Rf = 0.14) afforded compound 9 as a white solid (45 mg, 79%). M.p. = 113.8 – 115.4 °C. H NMR (400
MHz, CDCl3) (d.r. 24 : 1): δ 5.46 (s, 1 H), 4.91 (t, J = 5.0 Hz, 1 H), 3.97–3.86 (m, 2 H), 3.84–3.77 (m, 2 H),
2.92 (s, 2 H), 2.79 (s, 3 H), 2.44–2.32 (m, 3 H), 2.19–2.09 (m, 1 H), 1.72–1.58 (m, 2 H), 1.54–1.44 (m, 1 H),
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1.43–1.31 (m, 2 H), 1.40 (s, 3 H), 1.13–0.92 (m, 2 H). C{1H} NMR (100.4 MHz, CDCl3): δ 177.8, 177.1,
141.6, 129.8, 102.7, 67.4, 64.8, 64.7, 59.1, 55.5, 53.8, 53.2, 32.4, 28.6, 24.2, 23.9, 23.5, 21.7, 15.3. MS (ESI)
m/z (%): 354 ([M + Na]+, 100), 685 ([2M + Na]+, 45). HRMS (ESI/TOF) m/z: [M + H]+ calcd for C19H25NO4:
332.1856. Found: 332.1866.
Compound 11. Compound 11 was prepared following Method A.2, starting from 1a (105 mg, 0.6 mmol),
maleic anhydride (1 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 30 minutes.
After protection as [1,3]dioxolane, purification of the crude by flash chromatography (EtOAc/n-hexane, 1:4;
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Rf = 0.22) afforded compound 11 as a white solid (181 mg, 95%). M.p. = 85.7 – 87.1 °C. H NMR (400
MHz, CDCl3) (d.r. 23 : 1): δ 5.75–5.72 (m, 1 H), 4.99–4.96 (m, 1 H), 4.00–3.91 (m, 2 H), 3.90–3.81 (m, 2
H), 3.23 (s, 2 H), 2.42–2.36 (m, 2 H), 2.33–2.27 (m, 1 H), 1.73–1.63 (m, 2 H), 1.53–1.45 (m, 1 H), 1.45–1.35
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(m, 2 H), 1.42 (s, 3 H), 1.29–1.22 (m, 1 H), 1.18–1.08 (m, 1 H), 1.04–0.94 (m, 1 H). C{1H} NMR (100.4
MHz, CDCl3): δ 171.3, 170.8, 142.9, 131.1, 102.7, 67.6, 65.0, 64.6, 60.5, 56.7, 54.7, 54.2, 32.2, 28.2, 23.6,
23.2, 21.7, 14.9. MS (ESI) m/z (%): 341 ([M + Na]+, 28), 373 ([M + Na + MeOH]+, 100), 723 ([2M + Na + 2
MeOH]+, 86). HRMS (ESI/TOF) m/z: [M + H]+ calcd for C18H22O5: 319.1540. Found: 319.1542.
Compound 12. Compound 12 was prepared following Method A.2, starting from 1a (45 mg, 0.26 mmol),
1,4-benzoquinone (1 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 35 minutes.
After protection as dioxolane, purification of the crude by flash chromatography (EtOAc/n-hexane, 1:5; Rf =
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0.13) afforded compound 12 as a colourless oil (80 mg, 94%). H NMR (400 MHz, CDCl3) (d.r. 33 : 1): δ
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6.49 (d, J = 1.6 Hz, 2 H), 5.48 (s, 1 H), 4.89–4.86 (m, 1 H), 3.95–3.87 (m, 2 H), 3.84–3.76 (m, 2 H), 2.89
(AB system, JAB = 8.0 Hz, 2 H), 2.34–2.24 (m, 2 H), 1.94–1.98 (m, 1 H), 1.70–1.60 (m, 2 H), 1.57–1.47 (m,
1 H), 1.38–1.28 (m, 2 H), 1.35 (s, 3 H), 1.26–1.14 (m, 1 H), 1.11–0.97 (m, 2 H). 13C{1H} NMR (100.4 MHz,
CDCl3): δ 199.1, 198.7, 142.2, 141.7, 141.4, 130.9, 102.8, 64.9, 64.8, 64.6, 63.2, 59.3, 56.9, 56.5, 32.4, 28.1,
24.1, 23.4, 21.2, 14.8. MS (ESI) m/z (%): 351 ([M + Na]+, 100), 383 ([M + Na + MeOH]+, 40). HRMS
(ESI/TOF) m/z: [M + Na]+ calcd for C20H24O4Na: 351.1567. Found: 351.1569.
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Compound 13. Compound 13 was prepared following Method A.2, starting from 1b (35 mg, 0.17 mmol), N-
methylmaleimide (1.2 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 70 minutes.
After protection as dioxolane, purification of the crude by flash chromatography (EtOAc/n-hexane, 1:6; Rf =
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0.15) afforded compound 13 as a white solid (55 mg, 90%). M.p. = 76.5 – 77.1 °C. H NMR (400 MHz,
CDCl3) (d.r. 80 : 1): δ 5.66 (s, 1 H), 4.95–4.93 (m, 1 H), 3.97–3.86 (m, 2 H), 3.86–3.78 (m, 2 H), 3.20 (d, J =
7.2 Hz, 1 H), 2.87 (d, J = 7.2 Hz, 1 H), 2.79 (s, 3 H), 2.45–2.30 (m, 3 H), 2.17–2.11 (m, 1 H), 1.69–1.54 (m,
4 H), 1.53–1.43 (m, 1 H), 1.43–1.35 (m, 1 H), 1.31–1.19 (m, 1 H), 1.12 (d, J = 6.8 Hz, 3 H), 1.01–0.96 (m, 1
H), 0.99 (d, J = 7.2 Hz, 3 H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 178.0, 177.2, 141.1, 128.2, 102.7, 64.8,
64.7, 64.4, 64.2, 58.0, 53.1, 48.7, 32.6, 28.6, 26.9, 24.3, 24.2, 23.6, 23.3, 19.0, 18.3. MS (ESI) m/z (%): 382
([M + Na]+, 100), 741 ([2M + Na]+, 14). HRMS (ESI/TOF) m/z: [M + H]+ calc. for C21H29NO4: 360.2169.
Found: 360.2170.
Compound 14. Compound 14 was prepared following Method A.2, starting from 1b (41 mg, 0.20 mmol),
maleic anhydride (1.5 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 15 minutes.
After protection as dioxolane, purification of the crude by flash chromatography (EtOAc/n-hexane, 1:6; Rf =
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0.16) afforded compound 14 as a white solid (44 mg, 64%). M.p. = 125.4 – 127.2 °C. H NMR (400 MHz,
CDCl3) (d.r. >100 : 1): δ 5.95 (s, 1 H), 5.01–4.98 (m, 1 H), 4.01–3.91 (m, 2 H), 3.90–3.81 (m, 2 H), 3.50 (d,
J = 8.0 Hz, 1 H), 3.17 (d, J = 7.6 Hz, 1 H), 2.44–2.24 (m, 4 H), 1.72–1.60 (m, 2 H), 1.60–1.54 (m, 1 H),
1.52–1.38 (m, 2 H), 1.34–1.22 (m, 1 H), 1.18–1.09 (m, 1 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.04–0.98 (m, 1 H),
1.01 (d, J = 6.8 Hz, 3 H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 171.4, 170.9, 142.4, 129.7, 102.8, 65.4,
65.0, 64.8, 64.6, 59.4, 54.1, 50.0, 32.3, 28.3, 26.8, 23.9, 23.2, 23.0, 18.7, 18.3. MS (ESI) m/z (%): 369 ([M +
Na]+, 100), 715 ([2M + Na]+, 43). HRMS (ESI/TOF) m/z: [M + H]+ calcd for C20H26O5: 347.1853. Found:
347.1855.
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Compound 15. Compound 15 was prepared following Method A.2, starting from 1b (31 mg, 0.15 mmol),
1,4-benzoquinone (1.5 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 1 h. After
protection as dioxolane, purification of the crude by flash chromatography (EtOAc/n-hexane, 1:4; Rf = 0.12)
afforded compound 10 as a colourless oil (47 mg, 88%). 1H NMR (400 MHz, CDCl3) (d.r. >100 : 1): δ 6.51–
6.44 (m, 2 H), 5.67 (s, 1 H), 4.93 (t, J = 4.8 Hz, 1 H), 3.96–3.87 (m, 2 H), 3.85–3.78 (m, 2 H), 3.15 (d, J =
8.0 Hz, 1 H), 2.86 (d, J = 8.0 Hz, 1 H), 2.45 (quintet, J = 7.2 Hz, 1 H), 2.34 (ddd, J = 17.6, 4.8, 2.4 Hz, 1 H),
2.28–2.22 (m, 1 H), 1.91 (ddd, J = 17.6, 4.8, 2.4 Hz, 1 H), 1.70–1.58 (m, 2 H), 1.55–1.44 (m, 3 H), 1.31–
1.23 (m, 1 H), 1.08–0.96 (m, 2 H), 1.05 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 7.2 Hz, 3 H). 13C{1H} NMR (100.4
MHz, CDCl3): δ 199.6, 198.9, 142.4, 141.4, 140.8, 129.7, 102.9, 68.0, 64.8, 64.6, 62.5, 61.9, 56.7, 52.3, 32.6,
28.2, 26.2, 24.6, 23.7, 23.2, 19.7, 17.4. MS (ESI) m/z (%): 379 ([M + Na]+, 100). HRMS (ESI/TOF) m/z: [M
+ Na]+ calcd for C22H28O4Na: 379.1880. Found: 379.1872.
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Compound 16. Compound 16 was prepared following Method B.2, starting from 1b (37 mg, 0.18 mmol)
and using IPrAuSbF6 as the catalyst. After 10 minutes, tetracyanoethylene (1.2 equiv.) was added and the
cycloaddition was complete in 5 minutes. After protection as dioxolane, purification of the crude mixture by
flash chromatography (EtOAc/n-hexane, 1:4; Rf = 0.20) afforded pure 16 as a white solid (62 mg, 92%).
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M.p. = 150.8 – 152.1 °C. H NMR (400 MHz, CDCl3) (d.r. >100 : 1): δ 6.32 (s, 1 H), 5.14–5.11 (m, 1 H),
4.04–3.97 (m, 2 H), 3.94–3.87 (m, 3 H), 2.70–2.65 (m, 1 H), 2.49–2.43 (m, 1 H), 2.40–2.33 (m, 1 H), 2.32–
2.25 (m, 1 H), 2.08–2.03 (m, 1 H), 1.98–1.86 (m, 2 H), 1.81–1.73 (m, 2 H), 1.35 (d, J = 7.2 Hz, 3 H), 1.33–
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1.27 (m, 1 H), 1.25 (d, J = 7.2 Hz, 3 H), 1.23–1.09 (m, 2 H). C{1H} NMR (100.4 MHz, CDCl3): δ 145.0,
131.6, 112.1, 111.7, 111.4, 110.6, 102.0, 72.4, 66.1, 65.1, 64.8, 59.0, 53.4, 50.5, 32.3, 28.5, 24.8, 24.4, 23.0,
22.1, 20.0, 19.3. MS (ESI) m/z (%): 399 ([M + Na]+, 100). HRMS (ESI/TOF) m/z: [M + Na]+ calcd for
C22H24N4O2Na: 399.1792. Found: 399.1784.
Compound 17. Compound 17 was prepared following Method A.2, starting from 1c (50 mg, 0.23 mmol),
naphtoquinone (1.2 equiv) and using IPrAuSbF6 as the catalyst. The reaction was complete in 50 minutes.
After protection as dioxolane, purification of the crude mixture by flash chromatography (Et2O/n-hexane,
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1:10; Rf = 0.25) afforded pure 17 as a pale brown oil (55 mg, 57%). H NMR (400 MHz, CDCl3) (d.r. 20 :
1): δ 7.96–7.91 (m, 2 H), 7.68–7.61 (m, 2 H), 5.26 (s, 1 H) 3.98–3.95 (m, 1 H), 3.78–3.72 (m, 1 H), 3.63–
3.56 (m, 2 H), 3.53–3.48 (m, 1 H), 3.38 (d, J = 8.0 Hz, 1 H), 3.12 (d, J = 8.0 Hz, 1 H), 2.34–2.27 (m, 1 H),
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1.02 (m, 3 H), 0.96 (t, J = 7.6 Hz, 3 H). C{1H} NMR (100.4 MHz, CDCl3): δ 197.5, 197.0, 140.8, 136.9,
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24.3, 23.6, 23.4, 21.3, 14.1. MS (ESI) m/z (%): 443 ([M + Na]+, 100), 863 ([2M + Na]+, 17). HRMS
(ESI/TOF) m/z: [M + H]+ calcd for C27H32O4: 421.2373. Found: 421.2371.
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Compound 18. Compound 18 was prepared following Method A.2, starting from 1c (51 mg, 0.24 mmol), N-
methylmaleimide (1.2 equiv.) and using IPrAuSbF6 as the catalyst. The reaction was complete in 15 minutes.
After protection as dioxolane, purification of the crude by flash chromatography (Et2O/n-hexane, 1:6; Rf =
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0.21) afforded compound 18 as a white solid (86 mg, 82%). M.p. = 121.9 – 123.2 °C. H NMR (400 MHz,
CDCl3) (d.r. 22 : 1): δ 7.43 – 7.37 (m, 2 H), 7.34 – 7.30 (m, 1 H), 7.24 – 7.20 (m, 2 H), 5.71 (s, 1 H), 4.99 (t,
J = 4.8 Hz, 1 H), 3.95 – 3.88 (m, 1 H), 3.86 – 3.72 (m, 3 H), 3.29 (d, J = 7.6 Hz, 1 H), 3.07 (d, J = 7.6 Hz, 1
H), 2.48 – 2.38 (m, 2 H), 2.28 – 2.20 (m, 1 H), 2.06 – 1.98 (m, 1 H), 1.84 – 1.76 (m, 1 H), 1.74–1.62 (m, 2
H), 1.62–1.46 (m, 3 H), 1.44–1.22 (m, 5 H), 1.22–0.97 (m, 2 H), 0.94 (t, J = 7.2 Hz, 3 H). 13C{1H} NMR
(100.4 MHz, CDCl3): δ 176.6, 176.0, 141.7, 132.0, 129.9, 128.7 (2 C), 128.1, 126.7 (2 C), 102.8, 65.8, 64.7,
64.6, 60.2, 58.9, 53.1, 50.0, 32.6, 28.8, 28.6, 26.9, 24.0, 23.4 (2 C), 22.2, 14.0. MS (ESI) m/z (%): 458 ([M +
Na]+, 44), 893 ([2M + Na]+, 100). HRMS (ESI/TOF) m/z: [M + H]+ calcd for C27H33NO4: 436.2482. Found:
436.2474.
Compound 19. Compound 19 was prepared following Method A.2, starting from 1d (38 mg, 0.16 mmol), N-
methylmaleimide (1.2 equiv.) and using IPrAuSbF6 (2 mol%) as the catalyst. After 15 minutes, the reaction
was complete. After protection as dioxolane, the crude mixture was purified by flash chromatography
(Et2O/n-hexane, 1:5; Rf = 0.18) to give pure 19 as a colorless oil (43 mg, 69%). 1H NMR (400 MHz, CDCl3)
(d.r. 9 : 1): δ 5.46 (s, 1 H), 4.87 (t, J = 5.2 Hz, 1 H), 3.95 – 3.86 (m, 2 H), 3.84 ‒ 3.77 (m, 2 H), 3.14 (d, J =
7.2 Hz, 1 H), 2.89 (d, J = 7.2 Hz, 1 H), 2.78 (s, 3 H), 2.41 (ddd, J = 17.2, 4.4, 2.0 Hz, 1 H), 2.19 ‒ 1.98 (m, 4
H), 1.80 ‒ 1.65 (m, 4 H), 1.65 ‒ 1.54 (m, 2 H), 1.50 ‒ 1.29 (m, 6 H), 1.26 ‒1.15 (m, 2 H), 0.93 (t, J = 7.2 Hz,
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3 H). C{1H} NMR (100.4 MHz, CDCl3): δ 177.9, 177.6, 142.2, 129.6, 102.8, 69.9, 64.8, 64.7, 62.3, 59.0,
51.0, 49.1, 33.1, 30.2, 29.5, 28.4, 27.5, 26.2, 24.1, 23.3, 23.2, 22.1, 14.1. MS (ESI) m/z (%): 410 ([M + Na]+,
100), 797 ([2M + Na]+, 14). HRMS (ESI/TOF) m/z: [M + H]+ calcd for C23H33NO4: 388.2482. Found:
388.2492.
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Compound 20. Compound 20 was prepared following Method A.2, starting from 1e (37 mg, 0.19 mmol), N-
methylmaleimide (1.2 equiv.) and using IPrAuSbF6 (1.5 mol%) as the catalyst. The reaction was complete in
10 minutes. After protection as dioxolane, purification of the crude by flash chromatography (Et2O/n-hexane,
1:5; Rf = 0.18) afforded compound 20 as a yellowish oil (44 mg, 73%). 1H NMR (400 MHz, CDCl3) (d.r. 15
: 1): δ 5.46 (s, 1 H), 4.87 (t, J = 5.2 Hz, 1 H), 3.94 – 3.86 (m, 2 H), 3.83 – 3.76 (m, 2 H), 2.92 (AB system,
JAB = 7.6 Hz, 1 H), 2.78 (s, 3 H), 2.41 (ddd, J = 17.6, 4.8, 2.0 Hz, 1 H), 2.19 – 2.07 (m, 2 H), 2.03 (ddd, J =
14.8, 9.6, 2.0 Hz, 1 H), 1.81 – 1.67 (m, 2 H), 1.64 – 1.53 (m, 2 H), 1.49 – 1.40 (m, 1 H), 1.38 (s, 3 H), 1.36 –
1.77 (m, 5 H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 177.8, 177.4, 142.7, 129.5, 102.8, 72.8, 64.8, 64.7,
62.9, 55.2, 53.6, 51.2, 33.1, 30.2, 29.6, 27.5, 24.1, 23.2, 22.2, 16.0. MS (ESI) m/z (%): 368 ([M + Na]+, 100).
HRMS (ESI/TOF) m/z: [M + H]+ calcd for C20H27NO4: 346.2013. Found: 346.2007.
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Compound 21. Compound 21 was prepared following Method A.2, starting from 1e (35 mg, 0.18 mmol), N-
phenylmaleimide (0.8 equiv.) and using IPrAuSbF6 (1.5 mol%) as the catalyst. The reaction was complete in
10 minutes. After protection as dioxolane, purification of the crude by flash chromatography (Et2O/n-hexane,
1:4; Rf = 0.16) afforded compound 21 as a pale yellow oil (56 mg, 95%). 1H NMR (400 MHz, CDCl3) (d.r.
15 : 1): δ 7.42 – 7.38 (m, 2 H), 7.34 – 7.30 (m, 1 H), 7.22 – 7.18 (m, 2 H), 5.68 (s, 1 H), 4.96 (t, J = 4.8 Hz, 1
H), 3.94 – 3.74 (m, 4 H), 3.10 (AB system, JAB = 7.6 Hz, 2 H), 2.47 (ddd, J = 17.6, 4.8, 2.0 Hz, 1 H), 2.28 –
2.18 (m, 2 H), 2.12 (ddd, J = 16.8, 9.2, 2.0 Hz, 1 H), 1.85 – 1.71 (m, 2 H), 1.70 – 1.57 (m, 3 H), 1.45 (s, 3
H), 1.42 – 1.22 (m, 4 H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 176.6, 176.3, 143.3, 132.0, 130.0, 128.7 (2
C), 128.1, 126.2 (2 C), 103.0, 73.2, 64.7, 64.6, 63.4, 55.9, 53.6, 51.3, 33.2, 30.2, 29.8, 27.6, 23.3, 22.0, 16.1.
MS (ESI) m/z (%): 430 ([M + Na]+, 60), 837 ([2M + Na]+, 100). HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C25H29NO4: 408.2169. Found: 408.2184.
Compound 22. Compound 22 was prepared following Method A.1, starting from 1e (62 mg, 0.33 mmol),
maleic anhydride (1.0 equiv.) and using IPrAuSbF6 (1.5 mol%) as the catalyst. The reaction was complete in
10 minutes. Purification of the crude mixture by flash chromatography (Et2O/n-hexane, 1:4; Rf = 0.16)
afforded pure 22 as a yellowish oil (82 mg, 87%). 1H NMR (400 MHz, CDCl3) (d.r. 13 : 1): δ 9.66 (t, J = 2.0
Hz, 1 H), 5.75 (s, 1 H), 3.28 (AB system, JAB = 8.0 Hz, 2 H), 3.14 (t, J = 1.6 Hz, 2 H), 2.24 – 2.15 (m, 1 H),
1.97 – 1.90 (m, 1 H), 1.85 – 1.73 (m, 2 H), 1.71 – 1.65 (m, 1 H), 1.65 – 1.55 (m, 2 H), 1.43 (s, 3 H, Me), 1.39
– 1.31 (m, 2 H), 1.31 – 1.19 (m, 2 H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 197.8, 171.1, 170.7, 140.8,
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133.8, 73.4, 64.2, 56.8, 54.4, 52.4, 42.6, 30.1, 29.2, 27.6, 23.1, 22.2, 15.5. GCMS (EI) m/z (%): 288 (M+, 5),
190 (100), 147 (5). HRMS (ESI/TOF) m/z: [M + H]+ calc. for C17H20O4: 289.1434. Found: 289.1434.
Compound 23. Compound 23 was prepared following Method A.1, starting from 1e (41 mg, 0.22 mmol),
maleic anhydride (1.0 equiv.) and using IPrAuSbF6 (1.5 mol%) as the catalyst. The reaction was complete in
10 minutes. After protection as dioxolane, purification of the crude by flash chromatography (Et2O/n-hexane,
1:4; Rf = 0.19) afforded compound 23 as a yellowish oil (56 mg, 77%). 1H NMR (400 MHz, CDCl3) (d.r. 13
: 1): δ 5.72 (s, 1 H), 4.94 (dd, J = 5.6, 4.0 Hz, 1 H), 3.99 – 3.91 (m, 2 H), 3.88 – 3.80 (m, 2 H), 3.22 (q, J =
8.0 Hz, 2 H), 2.44 – 2.41 (m, 1 H), 2.33 – 2.27 (m, 1 H), 2.12 – 2.08 (m, 2 H), 1.81 – 1.72 (m, 2 H), 1.66 –
1.55 (m, 3 H), 1.39 (s, 3 H, Me), 1.35 – 1.20 (m, 4 H). 13C{1H} NMR (100.4 MHz, CDCl3): δ 171.2, 171.1,
144.0, 131.0, 103.0, 73.0, 65.0, 64.6, 64.3, 56.4, 54.5, 52.5, 32.8, 30.0, 29.2, 27.4, 23.0, 22.1, 15.6. GCMS
(EI) m/z (%): 234 (12), 233 (65), 147 (7), 73 (100). HRMS (ESI/TOF) m/z: [M + H]+ calc. for C19H24O5:
333.1697. Found: 333.1709.
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Compound 24. Compound 24 was prepared following Method A.3, starting from 1f (50 mg, 0.23 mmol), N-
methyl maleimide (1.2 equiv.) and using IPrAuSbF6 (1.5 mol%) as the catalyst. The reaction was complete in
30 minutes. After reduction, purification of the crude by flash chromatography (EtOAc/n-hexane, 1:2; Rf =
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0.13) afforded compound 24 as a colourless oil (70 mg, 92%). H NMR (400 MHz, CDCl3) (d.r. 9 : 1): δ
5.59 (s, 1 H), 3.71 – 3.58 (m, 2 H), 3.20 (d, J = 7.2 Hz, 1 H), 2.91 (d, J = 7.2 Hz, 1 H), 2.77 (s, 3 H), 2.38 –
2.30 (m, 1 H), 2.25 – 1.96 (m, 4 H), 1.84 – 1.76 (m, 1 H), 1.76 – 1.68 (m, 2 H), 1.66 – 1.57 (m, 2 H), 1.49 –
1.39 (m, 1 H), 1.39 – 1.21 (m, 3 H), 1.19 (d, J = 7.2 Hz, 3 H), 1.21 – 1.15 (m, 1 H), 0.96 (d, J = 6.8 Hz, 3 H).
2.44–2.37 (m, 1 H), 2.36–2.28 (m, 1 H), 2.13–2.05 (m, 1 H), 1.72–1.60 (m, 2 H), 1.54–1.42 (m, 2 H), 1.43–
1.32 (m, 2 H), 1.39 (s, 3 H), 1.24–1.13 (m, 1 H), 1.13–0.94 (m, 2 H). 13C{1H} NMR (100.4 MHz, CDCl3): δ
177.6, 177.5, 144.8, 126.4, 70.4, 63.2, 61.8, 60.5, 50.8, 48.1, 31.4, 30.2, 29.0, 27.7, 26.9, 24.2, 23.0, 22.9,
18.7, 18.0. MS (ESI) m/z (%): 354 ([M + Na]+, 100). HRMS (ESI/TOF) m/z: [M + Na]+ calcd for
C20H29NO3Na: 354.2040. Found: 354.2036.
Associated contents. The Supporting Information is available free of charge:
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Copies of H and 13C NMR spectra of all new compounds; Crystal structure determination and data of
compound 5 (PDF).
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Crystallographic data of compound 5 (CIF).
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Author information
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Corresponding authors
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*E-mail: dina.scarpi@unifi.it
*E-mail: ernesto.occhiato@unifi.it
ORCID
Antonia Rinaldi: 0000-0003-4286-9946
Dina Scarpi: 0000-0001-7211-4881
Ernesto G. Occhiato: 0000-0003-2187-2409
Notes
The authors declare no competing financial interest.
Acknowledgments. Dr. Cristina Faggi is acknowledged for the X-ray analysis of compound 5. Dr
Alessandro Pratesi and Dr Carlotta Zoppi are acknowledged for HRMS analyses.
References and notes
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4) Isolated from the liverwort Mylia taylorii. Takaoka, D.; Matsuo, A.; Kuramoto, J.; Nakayama, M.;
Hayashi, S. (–)-Myltaylenol, a tricyclic sesquiterpene alcohol with a novel carbon skeleton from the
liverwort Mylia taylorii. J. Chem. Soc., Chem. Commun. 1985, 482–483.
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5) Isolated from the red algae Sphaerococcus coronopifolius. Cafieri, F.; Fattorusso, E.; Mayol, L.;
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6) Guanacastapenes were discoverd in 2000 by Clardy et al. from an unclassified endophytic fungus.
Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.; Greenstein, M.; Maiese, W. M.
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7) The dimeric guaianolides are biosynthesized through a pathway involving the dimerization of two
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9) (a) Baranovsky, A. V.; Bolibrukh, D. A.; Khripach, V. A.; Schneider, B. Diels–Alder reaction of
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transformations. Steroids 2013, 78, 282–287. (b) Carberry, P.; Viernes, D. R.; Choi, L. B.; Fegley,
M. W.; Chisholm, J. D. An unusual intramolecular Diels–Alder approach toward maoecrystal V.
Tetrahedron Lett. 2013, 54, 1734–1737. (c) Knappwost-Gieseke, C.; Nerenz, F.; Wartchow, R.;
Winterfeldt, E. High-Pressure Selectivity Studies – A Simple Route to a Homochiral Wistarin
Precursor. Chem. Eur. J. 2003, 9, 3849–3858 and references therein. (d) Trân-Huu-Dâu, M. E.;
Wartchow, R.; Winterfeldt, E.; Wong, Y.-S. New Cyclohexadienone Derivatives: Preparation and
Chiral Discrimination in High ‐ Pressure Diels–Alder Cycloadditions. Chem. Eur. J. 2001, 7,
2349–2369. (e) Wu, H.-P.; Aumann, R.; Froehlich, R.; Wibbeling, B.; Kataeva, O. Highly Selective
Formation of [4+2] and [4+3] Cycloadducts of Tetrahydroindenes Generated in Situ from a (1-
Alkynyl)carbene Tungsten Complex by the Metalla-1,3,5-hexatriene Route. Chem. Eur. J. 2001, 7,
5084–5093. (f) Gerstenberger, I.; Hansen, M.; Mauvais, A.; Wartchow, R.; Winterfeldt, E.
Regioselective and Stereoselective Transformations of Enantiopure p-Benzoquinone Equivalents.
Eur. J. Org. Chem. 1998, 643–650 and references therein. (g) Mauvais, A.; Winterfeldt, E. Dienes as
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chiral templates: easy access to pure (2S,3S,4R)-4-hydroxy-2,3-epoxycyclohex-5-en-1-one.
Tetrahedron 1993, 49, 5817–5822. (h) Röhrig, S.; Hennig, L.; Findeisen, M.; Welzel, P.; Müller, D.
Use of Winterfeldt's template to control the C-2' configuration in the synthesis of strigol-type
compounds. Tetrahedron 1998, 54, 3439–3456. (i) Bartlett, P. D.; Wu, C. Reactions of maleic
anhydride and dimethyl acetylenedicarboxylate (DMAD) with the three isodicyclopentadiene
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(j) Borm, C.; Meibom, D.; Winterfeldt, E. Chiral discrimination in cycloaddition experiments. Chem.
Commun. 1996, 887–894.
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10) Uyehara, T.; Sato, Y.; Ishizuka, H.; Sakiyama, Y.; Ueno, M; Sato, T. The first total synthesis of (±)-
junicedranol based on a novel anionic [1,3] rearrangement. Tetrahedron Lett. 2000, 41, 1939–1942.
11) (a) Doye, S.; Hotopp, T.; Wartchow, R.; Winterfeldt, E. The Enantioselective Total Synthesis of (–)-
Myltaylenol. Chem. Eur. J. 1998, 4, 1480–1488. (b) Doye, S.; Hotopp, T.; Winterfeldt, E. The
enantioselective total synthesis of (-)-myltaylenol. Chem. Commun. 1997, 1491–1492.
12) Zhang, W.; Luo,S.; Fang, F.; Chen, Q.; Hu, H.; Jia, X.; Zhai, H. Total Synthesis of Absinthin. J. Am.
Chem. Soc. 2005, 127, 18–19.
13) Rinaldi, A.; Petrović, M.; Magnolfi, S.; Scarpi, D.; Occhiato, E. G. Pentannulation Reaction by
Tandem Gold(I)-Catalyzed Propargyl Claisen Rearrangement/Nazarov Cyclization of Enynyl Vinyl
Ethers. Org. Lett. 2018, 20, 4713−4717.
14) Rinaldi, A.; Langé, V.; Gómez-Bengoa, E.; Zanella, G.; Scarpi, D.; Occhiato, E. G. Synthesis of
Indenes by Tandem Gold(I)-Catalyzed Claisen Rearrangement/Hydroarylation Reaction of
Propargyl Vinyl Ethers. J. Org. Chem. 2019, 84, 6298−6311.
15) For a review on cycloadditions initiated by gold-activation of CC triple bonds, see: (a) López, F.;
Mascareñas, J. L. Recent developments in gold-catalyzed cycloaddition reactions. Beilstein J. Org.
Chem. 2011, 7, 1075–1094. See also: (b) Gold Catalysis: An Homogeneous Approach; Michelet, V.,
Toste, F. D., Eds.; Imperial College Press: London, 2014. (c) López, F; Mascareñas, J. L. Gold(I)-
catalyzed enantioselective cycloaddition reactions. Beilstein J Org Chem. 2013, 9, 2250–2264. (d)
Huple, D. B.; Ghorpade, S.; Liu, R.-S. Recent Advances in Gold-Catalyzed N- and O-
Functionalizations of Alkynes with Nitrones, Nitroso, Nitro and Nitroxy Species. Adv. Synth. Catal.
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2016, 358, 1348–1367. Some recent examples of gold(I)-catalyzed rearrangements carried out in the
presence of an external dienophile or heterodienophile: (e) Chen, C.-N.; Liu, R.-S. Gold-catalyzed
[4+2] Annulations of Dienes with Nitrosoarenes as 4 Donors: Nitroso-Povarov Reactions. Angew.
Chem. Int. Ed. 2019, 58, 9831–9835. (f) Guo, R.; Li, K.-N.; Gong, L.-Z. Catalytic cascade
hydroalkoxylation/isomerization/[4+2] cycloaddition using enyne alcohols as latent dienes or
dienophiles. Org. Biomol. Chem. 2013, 11, 6707–6712. (g) Bolte, B.; Odabachian, Y. Gagosz, F.
Gold(I)-Catalyzed Rearrangement of Propargyl Benzyl Ethers: A Practical Method for the
Generation and in Situ Transformation of Substituted Allenes. J. Am. Chem. Soc. 2010, 132, 7294–
7296.
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16) Diagnostic H NMR signals are the dd at 9.56 ppm (J = 2.6 and 2.2 Hz) for the aldehyde proton,
which couples with 2 diastereomeric protons (CH2-CHO) resonating as dd between 3.16 and 2.88
ppm. The singlet at 5.56 ppm is assigned to the double bond proton at position 2 inside the five-
membered ring.
1
17) Diagnostic H NMR signals of the ,-unsaturated moiety are the doublet at 9.75 ppm (J = 6.5 Hz)
for the CHO proton, which couples with the double bond proton resonating at 5.85 ppm as a doublet
of triplets (J = 6.5 and 2.4 Hz) because of a long-range coupling (4J) with the diastereomeric CH2
protons of the ring (C2).
18) Lo, V. K.-Y.; Chan, Y.-M-; Zhou, D.; Toy, P. H.; Che, C.-M. Highly Enantioselective Synthesis
Using Prolinol as a Chiral Auxiliary: Silver-Mediated Synthesis of Axially Chiral Vinylallenes and
Subsequent (Hetero)-Diels–Alder Reactions. Org. Lett. 2019, 21, 7717–7721, and references therein.
19) Crystallographic data for the structure of 5 have been deposited with the Cambridge Crystallographic
Data Centre. Copies of the data can be obtained, free of charge, on application to the Director,
CCDC 1970509, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
20) In an attempt to increase the facial selectivity, generating first the diene at 25 °C and then adding the
N-methylmaleimide (1.2 equiv) to the crude solution of the diene cooled at 0, -20 or -40 °C, did not
change this ratio. Even at the lowest temperature, cycloaddition was rather fast, being complete in 3
h.
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21) A possible explanation for this result lies in the greater flexibility of the seven-membered ring in the
3a,4,5,6,7,8-hexahydroazulenes. molecular mechanics (MMFF forcefield) Montecarlo
A
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conformational search on diene 2 (Scheme 1) from 1f, showed a cluster of almost isoergonic
conformations in which the 7-membered ring is bent downward (i.e. opposite to 3a-H), with one the
methyl group of the isopropyl moiety pointing upward (and the other eclipsed to the C2-C3 bond of
the five-membered ring), a situation which increases the steric hindrance on the  face of the diene.
22) Lim, B.-Y.; Jung, B.-E.; Cho, C.-G. Ene-hydrazide from Enol Triflate for the Regioselective Fischer
Indole Synthesis. Org. Lett. 2014, 16, 4492–4495.
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