Synthesis of Functionalized 1H-Indenes and Benzofulvenes through Iodocyclization of o-(Alkynyl)styrenes

Article abstract of DOI:10.1021/acs.joc.6b02788

A convenient method for the preparation of synthetically useful 3-iodoindene derivatives has been developed. This protocol, based on the 5-endo iodocyclization reaction of o-(alkynyl)styrenes, represents one of the scarce examples of halocyclizations using olefins as nucleophilic counterparts and allows the synthesis of both 3-iodo-1H-indenes (from β-alkyl-β-alkyl/aryl-o-(alkynyl)styrenes) and 3-iodobenzofulvenes (from β,β-diaryl-o-(alkynyl)styrenes) in good yields under mild reaction conditions. In addition, related alkoxyiodocyclization processes are described, which are particularly interesting in their intramolecular version because they allow the synthesis of heteropolycyclic structures containing the indene core. Finally, the usefulness of the prepared 3-iodoindenes has been demonstrated by the synthesis of several polysubstituted indene derivatives through conventional palladium-catalyzed cross-coupling reactions and iodine-lithium exchange processes.

Full text of DOI:10.1021/acs.joc.6b02788

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Article
Synthesis of Functionalized 1H-Indenes and Benzofulvenes
through Iodocyclization of ortho-(Alkynyl)styrenes
Patricia García-García, Ana M. Sanjuán, Muhammad A. Rashid, Alberto Martínez-
Cuezva, Manuel Angel Fernandez-Rodriguez, Félix Rodríguez, and Roberto Sanz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02788 • Publication Date (Web): 19 Dec 2016
Downloaded from http://pubs.acs.org on December 24, 2016
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Page 1 of 33
The Journal of Organic Chemistry
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Synthesis of Functionalized 1HꢀIndenes and
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Benzofulvenes through Iodocyclization of orthoꢀ
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(Alkynyl)styrenes
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,a
,b
Patricia García-García,*† Ana M. Sanjuán,‡ Muhammad A. Rashid,‡ Alberto Martínez-Cuezva,‡
Manuel A. Fernández-Rodríguez,‡ Félix Rodríguez,§ and Roberto Sanz*‡
† Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871-Alcalá de
Henares, Madrid (Spain)
‡ Área de Química Orgánica, Departamento de Química, Facultad de Ciencias, Universidad de
Burgos, Pza. Misael Bañuelos s/n, 09001-Burgos (Spain)
§ Instituto Universitario de Química Organometálica “Enrique Moles”, Universidad de Oviedo,
C/Julián Clavería, 8, 33006-Oviedo (Spain)
a Current address: Department of Chemistry, University of Agriculture, Faisalabad (Pakistan)
b Current address: Departmento de Química Orgánica, Facultad de Química; Regional Campus of
International Excellence “Campus Mare Nostrum”; Universidad de Murcia, 30100-Murcia (Spain)
patricia.garciagarci@uah.es
rsd@ubu.es
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ABSTRACT:
A convenient method for the preparation of synthetically useful 3ꢀiodoindene derivatives has been
developed. This protocol, based on the 5ꢀendo iodocyclization reaction of oꢀ(alkynyl)styrenes,
represents one of the scarce examples of halocyclizations using olefins as nucleophilic counterparts,
and allows the synthesis of both 3ꢀiodoꢀ1Hꢀindenes (from βꢀalkylꢀβꢀalkyl/aryl oꢀ(alkynyl)styrenes)
and 3ꢀiodobenzofulvenes (from β,βꢀdiaryl oꢀ(alkynyl)styrenes) in good yields under mild reaction
conditions. Besides, related alkoxyiodocyclization processes are described, which are particularly
interesting in their intramolecular version because they allow the synthesis of heteropolycyclic
structures containing the indene core. Finally, the usefulness of the prepared 3ꢀiodoindenes has been
demonstrated by the synthesis of several polysubstituted indene derivatives through conventional
palladium−catalyzed crossꢀcoupling reactions and iodine−lithium exchange processes.
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The Journal of Organic Chemistry
INTRODUCTION
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Indene derivatives, including methyleneindenes (benzofulvenes), are privileged scaffolds in organic
chemistry. These molecules are present in the structure of many biologically active compounds1ꢀ4 and
they have also found application in material chemistry5ꢀ9 and as ligands in metal catalysis.10ꢀ11
Therefore, several approaches for the synthesis of 1Hꢀindenes and benzofulvenes have been
described.12 In particular, haloindenes are highly attractive building blocks, as they provide
opportunity for subsequent functionalization. Therefore, the search for new simple, efficient, and
general methods for the synthesis of haloindenes is an active field in organic chemistry.13
On the course of our studies on goldꢀcatalyzed cyclizations of 1,3ꢀdienꢀ5ꢀynes,14ꢀ19 we have reported
practical methods for the synthesis of 1Hꢀindenes17ꢀ19 and benzofulvenes16 by cycloisomerization of
appropriately substituted oꢀ(alkynyl)styrenes (Scheme 1a). The reaction is in both cases based on the
nucleophilic attack of the olefin unit to the goldꢀcoordinated triple bond. Taking into account these
results and considering the known ability of iodonium species to activate alkynes,20,21 we thought that
the 5ꢀendo iodocyclization of oꢀ(alkynyl)styrenes could provide a useful method for the synthesis of
3ꢀiodoꢀ1Hꢀindenes and 3ꢀiodobenzofulvenes (Scheme 1b).22
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SCHEME 1. Reported gold-catalyzed cycloisomerizations of o-(alkynyl)styrenes, and proposed
synthesis of 3-iodo-1H-indenes and 3-iodobenzofulvenes.
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Although it is well known that iodocyclizations involving alkynes are valuable transformations for
the synthesis of a variety of functionalized cyclic structures,20,21 it should be noted that iodocyclization
processes involving the addition of carbonꢀcentered nucleophiles to alkynes are an underdeveloped
area.23 Particularly, the iodocyclization of enyne derivatives (and related compounds such as oꢀ
(alkynyl)styrenes) has received very little attention. The work of S. F. Kirsch and coꢀworkers on the 6ꢀ
endo iodocyclization of 1,5ꢀenynes24ꢀ27 and 5ꢀ and 6ꢀexo iodocyclization of 1,6ꢀenynes26,28 should be
remarked upon at this point. In this context, we have recently reported pioneering preliminary results
regarding the 5ꢀendo iodocyclization reaction proposed in Scheme 1b for the synthesis of 1Hꢀ
indenes.29,30 Herein we provide a detailed investigation on this area, including its application for the
preparation of benzofulvenes.31
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RESULTS AND DISCUSSION
Initial results:
At the beginning of the project we thought that the best way to get the desired 5ꢀendo iodocyclization
reaction could be the use of β,βꢀdisubstituted oꢀ(alkynyl)styrenes, because upon the intramolecular
addition of the alkene to the activated alkyne a relatively stable tertiary carbocation would be formed
(Scheme 1b). With this idea in mind, we initially selected β,βꢀdimethyl oꢀ(alkynyl)styrene 1a as
model substrate to check the viability of our proposal. Gratifyingly, 1a cleanly afforded the
iodoindene 2a (71% yield) when stirred with Nꢀiodosuccinimide (NIS) in dichloromethane at room
temperature for 24 h (Scheme 2, conditions a). The yield could be improved (85%) and the reaction
time reduced (3 h) by performing the process at reflux (Scheme 2, conditions b). Interestingly, we also
observed that the reaction could be done with molecular iodine in the presence of a base (K3PO4)
instead of NIS (Scheme 2, conditions c). However, under these conditions compound 2a was isolated
in slightly lower yield (74%). These results demonstrated the feasibility of our proposed synthesis of
3ꢀiodoꢀ1Hꢀindenes through a 5ꢀendo halocyclization reaction of enyne derivatives.
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SCHEME 2. Proof of concept and initial experiments.
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Synthesis of 3-iodo-1H-indenes 2 by iodocyclization of o-(alkynyl)styrenes 1:
Once the potential of oꢀ(alkynyl)styrenes as precursors of 3ꢀiodoꢀ1Hꢀindenes had been demonstrated,
we explored the scope and limitations of this transformation. We initially tested the iodocyclization of
diverse β,βꢀdimethyl oꢀ(alkynyl)styrenes 1 with NIS as the iodinating agent (Table 1). Gratifyingly, 3ꢀ
iodoꢀ1Hꢀindenes with various substituents at the aromatic ring, including electronꢀwithdrawing
(entries 2−3) or electronꢀdonating groups (entry 4) could be efficiently synthesized. Moreover, 3ꢀiodoꢀ
1Hꢀindenes with aromatic (entries 1−5), heteroaromatic (entry 6), aliphatic (entries 7−9), and
heteroatomic (entry 10) groups at Cꢀ2 could be easily obtained by using as substrate the oꢀ
(alkynyl)styrene appropriately substituted at the terminal position of the alkyne. Nevertheless,
decomposition was observed for an oꢀ(alkynyl)styrene having an iodine at this position, whereas the
corresponding terminal or TMSꢀsubstituted alkynes were not reactive in the presence of NIS. The
iodocyclization of β,βꢀdimethyl oꢀ(alkynyl)styrenes 1 is also possible using as halogen source
molecular iodine in the presence of a base, as previously shown for 1a and further illustrated in entries
4 and 5.
TABLE 1. Synthesis of 3-iodo-1H-indenes 2 by iodocyclization of o-(alkynyl)styrenes 1.[a]
entry
R1
H
F
R2
H
R3
Ph
Ph
t (h) yield [%][b]
1
2
56
57
58
59
60
1
2
3
85(74)[c]
1a
1b
2a
2b
H
17
79
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3
Br
H
Ph
Ph
7
1
84
78(67)[c]
92(71)[c]
87
1c
2c
2d
2e
2f
1
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4
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4
1d −OCH2O−
5
H
H
H
Br
H
H
H
H
H
H
H
H
4ꢀMeOC6H4
3ꢀTh[c]
nꢀBu
1
1e
1f
6
2.5
2
7
81
1g
1h
1i
2g
2h
2i
8
nꢀBu
16
15
1
82
9
9
(CH2)3CN
SPh
71
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1j
2j
[a] Reactions conducted using 0.5 mmol of oꢀ(alkynyl)styrene
derivative 1 and 1.5 mmol of NIS in CH2Cl2 (2 mL) at reflux. These
reactions can also be performed at RT although with prolonged
reaction times and slightly lower yields. [b] Yield of product based
on starting material 1. [c] Performed with I2/K3PO4 (3 equiv.) as
electrophilic source at RT. [d] 3ꢀThienyl.
Next, we explored the halocyclization of several oꢀ(alkynyl)styrenes 3 possessing different aliphatic
and aromatic groups at the olefin (Scheme 3). Thus, substrates 3a and 3b having a cycloalkane as
R1−R2 substituent provided the corresponding iodoindenes with high yields in short reaction times
(2−3 h). oꢀ(Alkynyl)styrenes 3c and 3d, which have two different alkyl groups in the alkene, furnished
iodoindenes 4c,d in high yields as mixtures of isomers that differ in the position of the external double
bond (1:1.5 for 4c, 4:1 for 4d). The formation of isomeric products can be explained from a common
carbocationic intermediate that experiences proton elimination from either of the two different
aliphatic groups. Conversely, in the halocyclization of 3e to give 4e, only the indene coming from the
elimination of the proton from the methyl group was observed (the cyclohexyl group remained
unaffected). Moreover, substrates 3fꢀh, having both an aliphatic and an aromatic substituent at the
olefin, efficiently provided the corresponding 3ꢀiodoꢀ1Hꢀindenes 4fꢀh. oꢀ(Alkynyl)styrenes with an
aliphatic substituent at the alkyne and two different groups at the olefin, either alkyl/alkyl (3i) or
alkyl/aryl (3j), were also useful starting materials for the synthesis of iodoindenes via iodocyclization
in the presence of NIS. In the case of 4i a 2:1 mixture of olefin isomers was obtained. On the other
hand, an oꢀ(alkynyl)styrene lacking substituents at the double bond (R1=R2=H) turned out to be
unreactive, whereas oꢀ(alkynyl)styrene derivatives monosubstituted at the terminal position of the
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alkene (βꢀmethyl or βꢀphenyl oꢀ(alkynyl)styrenes) decomposed under the optimal reaction conditions.
These results demonstrate the requirement of a starting material with a β,βꢀdisubstituted olefin as a
prerequisite for an efficient iodocyclization that leads to 3ꢀiodoindenes.
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SCHEME 3. Iodocyclization of o-(alkynyl)styrenes 3 bearing different substituents at the olefin.
Synthesis of 3-iodobenzofulvenes 6 from o-(alkynyl)styrenes 5:
Next, we studied the reaction with starting materials where the olefin was substituted with aryl
groups. Considering the cationic intermediate of this process (see Scheme 1), it should be noted that in
these cases the final elimination process would involve the hydrogen at C1 of the indene. Thus, these
reactions should deliver fulvene derivatives instead of the previously observed indenes. In fact, when
oꢀ(alkynyl)styrene 5a having two phenyl groups as substituents of the olefin was used as starting
material under the previous optimal conditions, 3ꢀiodobenzofulvene 6a was obtained as only product
in good yield (Scheme 4).
SCHEME 4. Synthesis of 3-iodobenzofulvenes: proof of concept.
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The structure of 6a was confirmed by Xꢀray diffraction analysis (Scheme 4).32 A significant twist of
the three aryl substituents with respect to the benzofulvene plane is observed, with the phenyl in Cꢀ2
and one of the phenyls linked to the external olefin adopting an almost faceꢀtoꢀface arrangement,
which suggests that πꢀπꢀinteractions are established between both rings. These observations are in full
agreement with those previously reported for related arylꢀsubstituted benzofulvenes.33
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To further assess the usefulness of our methodology, the scope of the iodocyclization of β,βꢀdiaryl
oꢀ(alkynyl)styrenes 5 was analyzed (Table 2). Gratifyingly, a variety of 3ꢀiodobenzofulvenes with
substituents of different nature at Cꢀ2 could be obtained in good to excellent yields, as either aromatic,
heteroaromatic, alkenyl, alkyl, and heteroatomic groups were well tolerated as substituents of the
triple bond in the starting material (entries 1−8). Moreover, variability in the aromatic rings of the
double bond was also possible, including phenyl rings with either electronꢀdonating (entries 9−12) or
electronꢀwithdrawing (entry 14) substituents and also heteroaromatic rings (entry 13). When an oꢀ
(alkynyl)styrene with two different aryl rings in the olefin was used as starting material (entries
11−14), the corresponding 3ꢀiodobenzofulvene was obtained as a ~1:1 mixture of E/Z isomers,
regardless of the E/Z ratio of the starting material.
TABLE 2. Synthesis of 3-iodobenzofulvenes 6 by iodocyclization of β,β-diaryl-substituted o-
(alkynyl)styrenes 5.[a]
entry
Ar1
Ph
Ph
Ph
Ph
Ar2
Ph
Ph
Ph
Ph
R1
yield [%][b]
5
6
1
2
3
4
Ph
89
90
91
92
5a
5b
5c
5d
6a
6b
6c
6d
4ꢀMeC6H4
4ꢀMeOC6H4
3ꢀFC6H4
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5
Ph
Ph
Ph
Ph
3ꢀTh[c]
84
69
5e
5f
6e
6f
1
2
3
4
5
6
7
8
[d]
6
cꢀC6H9
nꢀBu
7
Ph
Ph
59
5g
5h
5i
6g
6h
6i
8
Ph
Ph
SPh
95
9
4ꢀMeC6H4
4ꢀMeC6H4
Ph
4ꢀMeC6H4
4ꢀMeC6H4
3,4,5ꢀMeOC6H4
4ꢀMeOC6H4
2ꢀTh[c]
4ꢀMeC6H4
nꢀBu
90
10
11
12
13
14
70
5j
6j
9
nꢀBu
54[e]
75[e]
59[e]
72[e]
5k
5l
6k
6l
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Ph
nꢀBu
Ph
nꢀBu
5m
5n
6m
6n
4ꢀFC6H4
4ꢀMeOC6H4
nꢀBu
[a] Reactions conducted using 0.2 mmol of oꢀ(alkynyl)styrene derivative 5 and 0.6 mmol
of NIS in CH2Cl2 (0.8 mL) at reflux. [b] Yield of product based on starting material 5. [c]
3ꢀThienyl. [d] Cyclohexenyl. [e] Obtained as a ~1:1 mixture of geometrical isomers.
Synthesis of oxygen-functionalized 3-iodo-1H-indenes:
Considering the carbocationic nature of the intermediate proposed in the halocyclization mechanism
(see Scheme 1b), we decided to explore the possibility of trapping this intermediate with a nucleophile
before the proton elimination occurred.34 In this way, indenes having additional functionalization at
the Cꢀ1 substituent could be easily obtained. First assays were performed with oꢀ(alkynyl)styrene 1a
and methanol as nucleophile in the presence of NIS as iodinating agent. We were glad to observe the
formation of the corresponding new indene derivative 7a, incorporating the methoxy group in the C1ꢀ
substituent, when performing the reaction in a 2:1 mixture of dichloromethane and methanol at room
temperature.35 The scope of the methoxyiodocyclization of oꢀ(alkynyl)styrenes 1, 3, and 5 was then
evaluated (Table 3). Different groups in the triple bond were tolerated including phenyl (entries 1−3,
6, 8−10), functionalized aryl (entry 4) as well as heteroatomic groups (entry 5). In the case of oꢀ
(alkynyl)styrenes having two different substituents in the olefin, the corresponding
alkoxyiodocyclization products 7 were obtained as mixtures of diastereoisomers, ranging from 1:1 to
3:1 (entries 6, 8 and 9). Finally, β,βꢀdiphenyl oꢀ(alkynyl)styrene 5a efficiently led to indene 7i under
the optimized methoxyiodocyclization conditions.
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It should be noted that along with the alkoxyiodocyclization products 7 we detected in most of the
cases the formation of small amounts of the corresponding products 2, 4, or 6, derived from the
competitive elimination process. In this sense, we observed that the amount of the corresponding
elimination product was increased when the olefin of the starting material was substituted with
sterically hindered groups. A limit situation was found when the alkoxyiodocyclization reaction was
attempted with oꢀ(alkynyl)styrene 3d having a bulky isopropyl group. In this particular case, we only
observed the formation of the elimination product 4d (entry 7).
1
2
3
4
5
6
7
8
9
10
11
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13
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15
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17
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TABLE 3. Synthesis of oxygen-functionalized 3-iodo-1H-indenes 7.[a]
entry
R1 R2 R3
R4
yield [%][b]
66(58)[c]
1,3,5
1a
1b
1c
7
1
2
Me Me
Me Me
H
F
Ph
7a
7b
7c
7d
7e
7f
−
Ph
78
3
Me Me Br
Ph
72
4
Me Me
Me Me
Me Et
Me iꢀPr
Me Ph
Et Ph
Ph Ph
H
H
H
H
H
H
H
4ꢀMeOC6H4
70
1e
5
SPh
Ph
Ph
Ph
Ph
Ph
58
45[d]
1j
6
3c
[e]
7
3d
3f
−
8
81[d]
60[d]
66
7g
7h
7i
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3g
5a
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[a] Reactions conducted using 0.5 mmol of oꢀ(alkynyl)styrene
derivative 1, 3, or 5, and 1.5 mmol of NIS in a mixture of MeOH (1
mL) and CH2Cl2 (2 mL) at RT. [b] Yield of product based on
starting material 1, 3 or 5. [c] Performed with I2/K3PO4 (3 equiv.) as
electrophilic source. [d] Obtained as a mixture of diasteroisomers:
3:1 (entry 6), 2:1 (entry 8), 1:1 (entry 9). [e] Only 4d is formed, no
incorporation of MeOH is observed.
With the aim of accessing polycyclic compounds, the alkoxyiodocyclization reaction was also tried
in an intramolecular fashion. Thus, several oꢀ(alkynyl)styrenes 8 with a pendant hydroxyl group were
prepared and their reactivity tested under the standard conditions (Scheme 5). Pleasantly, iodoindenes
fused to 5ꢀ, 6ꢀ and 7ꢀmembered oxygen−containing heterocyclic rings could be obtained in this way.36
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However, the corresponding iodoindene fused to an 8ꢀmembered heterocycle could not be synthesized
1
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following this methodology since indene 2m was the only product observed in the reaction of 8d with
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NIS.
7
8
SCHEME 5. Synthesis of polycyclic compounds 9 by intramolecular alkoxyiodocyclization of o-
9
(alkynyl)styrenes 8.
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Derivatization of 3-iodoindenes:
An appealing issue of the reported method for the synthesis of indenes and benzofulvenes from oꢀ
(alkynyl)styrenes is that it provides indene derivatives containing a carbon−iodine bond. The rich
reactivity of this bond can be exploited to get indenes and benzofulvenes with a variety of substituents
at Cꢀ3. For example, palladium−catalyzed Suzuki crossꢀcoupling of indenes 2a and 2e with
phenylboronic acid afforded 3ꢀphenylindenes in excellent yields (Scheme 6, eq 1). Indenes 7 were
also suitable partners for this coupling, as illustrated in the reaction of 7d with phenylboronic acid
(Scheme 6, eq 2).
3ꢀPhenylbenzofulvene 13a could also be easily obtained by Suzuki coupling of the corresponding 3ꢀ
iodobenzofulvene 6a, (Scheme 6, eq 3). Moreover, the synthesis of 3ꢀalkynylbenzofulvenes 14a and
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14b was efficiently achieved by means of a Sonogashira reaction between the corresponding
iodobenzofulvene 6 and phenylacetylene (Scheme 6, eq 4).
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SCHEME 6. Palladium-catalyzed cross-coupling reactions of 3-iodo-1H-indenes 2 and 7, and 3-
iodobenzofulvenes 6.
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Besides these typical palladium−catalyzed crossꢀcoupling reactions that allow the introduction of
aryl and alkynyl groups at Cꢀ3 we also tried other type of reactions. Thus, iodoꢀ1Hꢀindenes 2 and
iodobenzofulvenes 6 could be alternatively functionalized by iodine−lithium exchange followed by
treatment with selected electrophiles (Scheme 7). Accordingly, treatment of 2a in Et2O with 1
equivalent of butyllithium at −78 ºC followed by addition of MeOD quantitatively led to deuterated
derivative 15a, thus confirming that the halogen−lithium exchange had efficiently occurred. We were
glad to find that other electrophiles, such as disulfides, chlorostannanes, aldehydes, and
chloroformates, also reacted with the in situ formed organolithium compound. Moreover, 3ꢀ
iodobenzofulvenes 7 bearing substituents of varied nature at Cꢀ2 were also efficiently functionalized
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at Cꢀ3 position following an analogous iodine−lithium exchange protocol. Therefore, a variety of 1Hꢀ
indenes and benzofulvenes with either heteroatom or carbon substituents in Cꢀ3, complementary to the
ones obtained by palladium−catalyzed crossꢀcoupling reactions, were synthesized in good to excellent
yields.
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SCHEME 7. Derivatization of 3-iodoindenes 2 and 6 via I−Li exchange.
CONCLUSIONS
Polysubstituted indene derivatives can be conveniently prepared from easily available oꢀ
(alkynyl)styrene derivatives by a 5ꢀendo iodocyclization process. The presence of a new C−I bond in
the final products allows for subsequent functionalization through conventional palladium−catalyzed
crossꢀcoupling processes and iodine−lithium exchange reactions followed by coupling with
appropriate electrophiles.
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It was found that the reaction of β,βꢀdialkyl or βꢀalkyl,βꢀaryl oꢀ(alkynyl)styrenes with a source of
1
2
electrophilic iodine efficiently leads to 3ꢀiodoꢀ1Hꢀindenes, whereas the reaction of β,βꢀdiaryl oꢀ
(alkynyl)styrenes gives rise to 3ꢀiodobenzofulvenes in high yields. Moreover, alkoxyiodocyclizations
are achieved when the reactions are performed in the presence of an alcohol. These reactions allow the
introduction of an oxygenated functionality at Cꢀ1 of the indene. Particularly interesting is the
intramolecular version of these alkoxyiodocyclization reactions as complex polycyclic compounds
containing the indene core are easily available.
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Overall, the current methodology provides an appealing alternative for the synthesis of
polysubstitued indene derivatives.
EXPERIMENTAL SECTION
General Experimental Methods: All reactions involving airꢀsensitive compounds were carried out under a
N2 atmosphere in ovenꢀdried glassware with magnetic stirring. Temperatures are reported as bath temperatures.
Solvents used in extraction and purification were distilled prior to use. TLC was performed on aluminaꢀbacked
plates coated with silica gel 60 with F254 indicator; the chromatograms were visualized by UV light (254 nm)
and/or by staining with a Ce/Mo reagent solution and subsequent heating. Rf values refer to silica gel. Flash
column chromatography was carried out on silica gel 60, 230ꢀ400 mesh. 1H NMR spectra were recorded at 300
or 500 MHz. Chemical shifts are reported in ppm with the residual solvent resonance as the internal standard
(CHCl3: δ 7.26). Data are reported as follows: chemical shift, multiplicity (s: singlet, bs: broad singlet, d:
doublet, dd: doublet of doublets, ddd: doublet of doublet of doublets, td: triplet of doublets, t: triplet, dq:
doublet of quartets, sex: sextet, sep: septet, m: multiplet), coupling constants (J in Hz) and integration. 13C
NMR spectra were recorded at 75.4 or 100 MHz using broadband proton decoupling. Chemical shifts are
reported in ppm with the solvent resonance as internal standard (CDCl3: δ 77.16). Carbon multiplicities were
assigned by DEPT techniques. Gas chromatography–mass spectra (GCꢀMS) were recorded on an instrument
equipped with a 30 m × 0.25 mm capillary apolar column (stationary phase: 5% diphenyldimethylpolysiloxane
film, 0.25 ꢀm). Lowꢀresolution electron impact mass spectra (EIꢀLRMS) were obtained at 70 eV and only the
molecular ions and/or base peaks as well as significant peaks in MS are given. Highꢀresolution mass spectra
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(HRMS) were recorded on an instrument equipped with a magnetic sector ion analyzer using EI at 70 eV or on
an instrument equipped with a QTOF analyzer using ESI (+). Melting points were measured on a microscopic
apparatus using open capillary tubes and are uncorrected. All commercially available reagents were used
without purification unless otherwise indicated and were purchased from standard chemical suppliers. oꢀ
(Alkynyl)styrenes 1, 3, 5, 8 have been previously reported and were prepared following two step protocols that
involve an olefination reaction of a carbonyl derivative and a Sonogashira coupling.29, 16ꢀ19
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Synthesis of 3-iodo-1H-indenes 2 and 4 by iodocyclization of o-(alkynyl)styrenes 1 and 3:
Method A: NꢀIodosuccinimide (338 mg, 1.5 mmol) was added to a solution of the corresponding starting oꢀ
(alkynyl)styrene 1 or 3 (0.5 mmol) in CH2Cl2 (2 mL). The reaction vial was sealed and protected from light.
The resulting mixture was heated at reflux until complete consumption of the starting material as determined by
TLC or GCꢀMS (1ꢀ48 h). The mixture was quenched by addition of saturated aq Na2S2O3 (10 mL). The layers
were separated and the aqueous one was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were
dried (Na2SO4) and the solvents were removed under reduced pressure. The residue was purified by flash
column chromatography on silica gel using mixtures of hexane and EtOAc as eluents to obtain the
corresponding 3ꢀiodoꢀ1Hꢀindenes 2 or 4 in the yields reported in Table 1 and Scheme 3.
Method B: Iodine (381 mg, 1.5 mmol) was added to a solution of the corresponding starting oꢀ(alkynyl)styrene
1 (0.5 mmol) and K3PO4 (318 mg, 1.5 mmol) in CH2Cl2 (2 mL). The reaction vial was sealed and protected
from light. The resulting mixture was stirred at RT until complete consumption of the starting material as
determined by TLC (1ꢀ3 h). The mixture was quenched by addition of saturated aq Na2S2O3 (10 mL). The
layers were separated and the aqueous one was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were dried (Na2SO4) and the solvents were removed under reduced pressure. The residue was purified by flash
column chromatography on silica gel using mixtures of hexane and EtOAc as eluents to obtain the
corresponding 3ꢀiodoꢀ1Hꢀindenes 2 in the yields reported in Table 1.
The characterization data of 2aꢀj and 4a,b,f,j have been previously reported.29
The characterization data of novel compounds obtained by method A are reported below:
3-Iodo-1-[(E)-1-methyl-1-propenyl]-2-phenyl-1H-indene and 1-(1-ethylvinyl)-3-iodo-2-phenyl-1H-indene (4c).
Pale yellow oil; Rf = 0.51 (hexane); 76% yield (141 mg); Obtained as a 1.5:1 mixture: major isomer (maj) 3ꢀ
iodoꢀ1ꢀ[(E)ꢀ1ꢀmethylꢀ1ꢀpropenyl]ꢀ2ꢀphenylꢀ1Hꢀindene; minor isomer (min) 1ꢀ(1ꢀethylvinyl)ꢀ3ꢀiodoꢀ2ꢀphenylꢀ
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1Hꢀindene; 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.73 (t, J = 7.4 Hz, 3H, min), 0.99 (s, 3H, maj), 1.30–1.62
(m, 2H, min), 1.60 (d, J = 6.7 Hz, 3H, maj), 4.48 (s, 1 H, maj), 4.65 (s, 1H, min), 4.98 (m, 1H, min), 5.24 (bs,
1H, min), 5.73 (m, 1H, maj), 7.21–7.49 (m, 14H), 7.54–7.65 (m, 4H) ppm; 13C{1H}NMR (75 MHz, CDCl3, 25
ºC): δ = 11.1 (CH3), 11.9 (CH3), 13.8 (CH3), 22.9 (CH2), 62.3 (CH), 63.5 (CH), 94.4 (C), 94.7 (C), 113.4 (CH2),
122.8 (CH), 122.9 (CH), 123.08 (CH), 123. 10 (CH), 124.9 (CH), 126.5 (CH), 126.6 (CH), 127.6 (CH), 127.7
(CH), 127.9 (CH), 128.0 (CH), 128.1 (2 x CH), 128.2 (2 x CH), 129.0 (4 x CH), 133.1 (C), 135.9 (C), 136.0
(C), 144.3 (C), 145.5 (C), 146.1 (C), 146.0 (C), 148.5 (C), 152.3 (C), 152.7 (C) ppm; HRMS (EI): calcd for
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C19H17I+: 372.0369, found: 372.0374
.
3-Iodo-1-(1-isopropylvinyl)-2-phenyl-1H-indene (4d). Colourless oil; Rf = 0.44 (hexane); 66% yield (127 mg).
1
Isolated from a ca. 4:1 crude mixture of isomers; H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.60 (t, J = 6.8 Hz,
3H), 0.67 (t, J = 6.8 Hz, 3H), 1.52 (sep, J = 6.8 Hz, 1H), 4.62 (s, 1H), 5.01 (s, 1H), 5.17 (s, 1H), 7.24–7.45 (m,
13
7H), 7.59–7.64 (m, 2H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 23.1 (CH3), 24.7 (CH3), 29.7 (CH),
62.3 (CH), 94.8 (C), 113.2 (CH2), 123.0 (CH), 123.5 (CH), 126.5 (CH), 127.7 (CH), 128.0 (CH), 128.1 (2 x
CH), 129.2 (2 x CH), 136.0 (C), 144.5 (C), 146.1 (C), 152.4 (C), 153.8 (C) ppm; LRMS (EI): m/z (%): 386 (M+,
26), 259 (86), 217 (100), 202 (71); HRMS (EI): calcd for C20H19I+: 386.0526; found: 386.0533.
1-(1-Cyclohexylvinyl)-3-iodo-2-phenyl-1H-indene (4e). Pale yellow oil. Rf = 0.53 (hexane). 72% yield (153
mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.84–1.29 (m, 7H), 1.41–1.55 (m, 4H), 4.60 (s, 1H), 4.98 (s, 1H),
13
5.16 (s, 1H), 7.25–7.45 (m, 7H), 7.55–7.63 (m, 2H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 26.2
(CH2), 26.7 (CH2), 26.8 (CH2), 33.5 (CH2), 35.2 (CH2), 40.4 (CH), 62.2 (CH), 94.7 (C), 113.6 (CH2), 123.0
(CH), 123.5 (CH), 126.4 (CH), 127.7 (CH), 128.0 (CH), 128.07 (CH), 128.11 (2 x CH), 129.2 (2 x CH), 136.1
(C), 144.5 (C), 146.0 (C), 152.5 (C), 152.7 (C) ppm; LRMS (EI): m/z (%): 426 (M+, 6), 300 (31), 217 (100),
202 (35); HRMS (EI): calcd for C23H23I+: 426.0839; found: 426.0846.
3-Iodo-2-phenyl-1-(1-phenyl-1-propenyl)-1H-indene (4g). Pale yellow solid; Rf = 0.47 (hexane:CH2Cl2 20:1).
Mp = 95−97 ºC; 75% yield (163 mg); Obtained as a ~1:1 mixture of E:Z diastereoisomers; 1H NMR (400 MHz,
CDCl3, 25 ºC): δ = 1.50 (d, J = 6.8 Hz, 3H), 2.14 (d, J = 6.8 Hz, 3H), 4.80 (s, 1H), 5.31 (bs, 1H), 5.91–5.97 (m,
2H), 6.39–6.44 (m, 4H), 6.90 (t, J = 7.4 Hz, 2H), 6.97–7.01 (m, 2H), 7.04–7.08 (m, 1H), 7.25–7.50 (m, 18H)
13
ppm; C{1H}NMR (100 MHz, CDCl3, 25 ºC): δ = 14.8 (CH3), 15.0 (CH3), 54.4 (CH), 62.4 (CH), 94.0 (C),
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94.5 (C), 123.0 (CH), 123.1 (CH), 123.4 (CH), 123.5 (CH), 126.37 (2 x CH), 126.4 (CH), 126.65 (CH), 126.70
(CH), 126.72 (CH), 127.35 (CH), 127.44 (2 x CH), 127.5 (2 x CH), 127.65 (CH), 127.68 (CH), 127.80 (CH),
127.84 (CH), 127.9 (2 x CH), 128.0 (2 x CH), 128.5 (2 x CH), 128.8 (2 x CH), 129.3 (2 x CH), 136.1 (C),
136.2 (C), 137.6 (C), 138.6 (C), 138.9 (C), 141.2 (C), 144.6 (2 x C), 145.9 (C), 146.2 (C), 152.2 (C), 153.2 (C)
ppm; one aromatic CH signal is not observed probably due to overlaping with other signals. HRMS (EI):
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calcd for C24H19I+: 434.0526, found: 434.0530.
1-[Cyclohexylidene(phenyl)methyl]-3-iodo-2-phenyl-1H-indene (4h). Colourless solid; Mp = 43−45 ºC; 55%
yield (122 mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 1.32–1.48 (m, 2H), 1.62–1.70 (m, 2H), 1.80–1.91 (m,
4H), 2.77 (t, J = 6.0 Hz, 2H), 5.40 (s, 1H), 6.09 (dd, J = 8.2, 1.3 Hz, 2H), 6.84 (t, J = 7.6 Hz, 2H), 6.90–7.03
13
(m, 1H), 7.26–7.47 (m, 9H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 27.1 (CH2), 28.6 (CH2), 29.2
(CH2), 31.4 (CH2), 32.7 (CH2), 55.3 (CH), 93.5 (C), 123.0 (CH), 123.5 (CH), 126.2 (CH), 126.3 (CH), 126.9 (2
x CH), 127.4 (CH), 127.8 (CH), 127.9 (4 x CH), 129.15 (C), 129.23 (2 x CH), 136.2 (C), 138.8 (C), 140.8 (C),
144.6 (C), 146.6 (C), 152.4 (C) ppm; LRMS (EI): m/z (%): 488 (M+, 90), 406 (76), 279 (100), 215 (40); HRMS
(EI): calcd for C28H25I+: 488.0996; found: 488.1004.
2-Butyl-3-iodo-1-(1-isopropylvinyl)-1H-indene (4i). Colourless oil. Rf = 0.68 (hexane); 42% yield (77 mg);
1
Isolated along with traces of the isomer having an internal olefin from a ca. 2:1 crude mixture; H NMR (300
MHz, CDCl3, 25 ºC): δ = 0.78 (d, J = 6.8 Hz, 3H), 0.91–0.96 (m, 6H), 1.32–1.44 (m, 2H), 1.45–1.60 (m, 3H),
2.28–2.33 (m, 1H), 2.52–2.63 (m, 1H), 4.10 (s, 1H), 5.11 (s, 1H), 5.13 (s, 1H), 7.12–7.27 (m, 3H), 7.30–7.36
(m, 1H) ppm; 13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 14.1 (CH3), 22.7 (CH2), 23.6 (CH3), 24.5 (CH3), 29.9
(CH), 31.2 (CH2), 31.7 (CH2), 60.8 (CH), 94.7 (C), 112.9 (CH2), 121.7 (CH), 123.4 (CH), 125.6 (CH), 127.4
(CH), 144.8 (C), 145.8 (C), 154.1 (C), 155.8 (C) ppm; LRMS (EI): m/z (%): 366 (M+, 39), 239 (100), 197 (64);
HRMS (EI): calcd for C18H23I+: 366.0839; found: 366.0846.
Synthesis of 3-iodobenzofulvenes 6 by iodocyclization of β,β-diaryl-substituted o-(alkynyl)styrenes 5:
NꢀIodosuccinimide (338 mg, 1.5 mmol) was added to a solution of the corresponding starting oꢀ
(alkynyl)styrene 5 (0.5 mmol) in CH2Cl2 (2 mL). The reaction vial was sealed and protected from light. The
resulting mixture was heated at reflux until complete consumption of the starting material as determined by
TLC or GCꢀMS (1ꢀ6 h). The mixture was quenched by addition of saturated aq Na2S2O3 (10 mL). The layers
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were separated and the aqueous one was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were
dried (Na2SO4) and the solvents were removed under reduced pressure. The residue was purified by flash
column chromatography on silica gel using mixtures of hexane and EtOAc as eluents to obtain the
corresponding 3ꢀiodobenzofulvenes 6 in the yields reported in Table 2.
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3-Iodo-1a,1a,2-triphenylbenzofulvene (6a). Orange solid. Rf = 0.55 (hexane); Mp = 170−171 ºC; 89% yield
(215 mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 6.31 (d, J = 7.9 Hz, 1H), 6.81‒7.02 (m, 9H), 7.05‒7.10 (m,
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2H), 7.237.28 (m, 1H), 7.33‒7.54 (m, 6H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 104.3 (C), 122.7
(CH), 123.2 (CH), 126.2 (CH), 126.4 (CH), 127.1 (2 × CH), 127.2 (2 × CH), 127.5 (CH), 128.1 (CH), 128.8 (2
× CH), 129.1 (CH), 130.6 (2 × CH), 130.9 (2 × CH), 132.2 (2 × CH), 137.0 (C), 137.7 (C), 137.9 (C), 141.1
(C), 142.9 (C), 143.3 (C), 146.5 (C), 149.4 (C) ppm; LRMS (EI): m/z (%): 482 (M+, 100), 355 (38), 276 (45);
HRMS (EI): calcd for C28H19I+: 482.0526, found: 482.0537.
3-Iodo-2-(4-methylphenyl)-1a,1a-diphenylbenzofulvene (6b). Orange solid; Rf = 0.23 (hexane); Mp = 175−177
ºC; 90% yield (223 mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 2.21 (s, 3H), 6.33 (d, J = 7.8 Hz, 1H), 6.79 (d,
J = 7.8 Hz, 2H), 6.83–7.02 (m, 8H), 7.23–7.31 (m, 1H), 7.33–7.57 (m, 6H) ppm; 13C{1H}NMR (75 MHz,
CDCl3, 25 ºC): δ = 21.2 (CH3), 103.8 (C), 122.6 (CH), 123.2 (CH), 126.1 (CH) 127.1 (2 × CH), 127.4 (CH),
127.7 (CH), 127.9 (2 × CH), 128.7 (2 × CH), 129.1 (CH), 130.5 (2 × CH), 130.9 (2 × CH), 132.1 (2 × CH),
134.8 (C), 135.9 (C), 137.0 (C), 137.8 (C), 141.2 (C), 143.0 (C), 143.4 (C), 146.7 (C), 149.3 (C) ppm; LRMS
(EI): m/z (%): 496 (M+, 100), 369 (36), 354 (23); HRMS (EI): calcd for C29H21I+: 496.0683; found: 496.0669.
3-Iodo-2-(4-methoxyphenyl)-1a,1a-diphenylbenzofulvene (6c). Orange solid; Rf = 0.37 (hexane:EtOAc, 9:1);
Mp = 180−182 ºC; 91% yield (233 mg); 1H NMR (500 MHz, CDCl3, 25 ºC): δ = 3.71 (s, 3H), 6.29 (d, J = 7.8
Hz, 1H), 6.51–6.54 (m, 2H), 6.84–6.91 (m, 5H), 6.93–7.01 (m, 3H), 7.22–7.27 (m, 1H), 7.33–7.39 (m, 3H),
13
7.41–7.46 (m, 2H), 7.47–7.51 (m, 1H) ppm; C{1H}NMR (125 MHz, CDCl3, 25 ºC): δ = 55.3 (CH3), 103.9
(C), 112.9 (2 × CH), 122.6 (CH), 123.2 (CH), 126.1 (CH), 127.2 (2 × CH), 127.5 (CH), 127.9 (CH), 128.8 (2 ×
CH), 129.1 (CH), 130.3 (C), 130.9 (2 × CH), 131.8 (2 × CH), 132.1 (2 × CH), 137.0 (C), 137.8 (C), 141.2 (C),
143.0 (C), 143.4 (C), 146.3 (C), 149.3 (C), 158.0 (C) ppm; LRMS (EI): m/z (%): 512 (M+, 13), 167 (100), 105
(49); HRMS (EI): calcd for C29H21OI+: 512.0632; found: 512.0637.
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2-(3-Fluorophenyl)-3-iodo-1a,1a-diphenylbenzofulvene (6d). Orange solid; Rf = 0.25 (hexane); Mp = 179−181
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ºC; 92% yield (230 mg); 1H NMR (500 MHz, CDCl3, 25 ºC): δ = 6.37 (d, J = 7.8 Hz, 1H), 6.64–6.68 (m, 1H),
6.75 (ddd, J = 10.0, 2.5, 1.5 Hz, 1H), 6.86–7.03 (m, 8H), 7.28 (td, J = 7.5 Hz, 0.9 Hz, 1H), 7.36–7.41 (m, 3H),
7.44–7.48 (m, 2H), 7.49–7.53 (m, 1H) ppm; 13C{1H}NMR (125 MHz, CDCl3, 25 ºC): δ = 104.5 (C), 113.3 (d, J
= 21.1 Hz, CH), 117.6 (d, J = 21.9 Hz, CH), 123.0 (CH), 123.2 (CH), 126.5 (CH), 126.6 (d, J = 2.8 Hz, CH),
127.3 (2 x CH), 127.6 (CH), 128.4 (CH), 128.8 (d, J = 8.6 Hz, CH), 128.81 (2 x CH), 129.3 (CH), 130.9 (2 x
CH), 132.0 (2 x CH), 136.9 (C), 137.6 (C), 140.2 (d, J = 8.2 Hz, C), 141.2 (C), 142.6 (C), 143.1 (C), 145.2 (d, J
= 1.9 Hz, C), 149.6 (C), 161.8 (d, J = 244.9 Hz, C) ppm; LRMS (EI): m/z (%): 500 (M+, 100), 373 (28), 86
(31); HRMS (EI): calcd for C28H18IF+: 500.0432; found: 500.0427.
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3-Iodo-1a,1a-diphenyl-2-thienylbenzofulvene (6e). Orange solid; Rf = 0.24 (hexane); Mp = 161−163 ºC; 84%
yield (205 mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 6.32 (d, J = 7.8 Hz, 1H), 6.71 (dd, J = 5.0, 1.2 Hz, 1H),
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6.86 (dd, J = 5.0, 3.0 Hz, 1H), 6.89–7.11 (m, 7H), 7.24–7.31 (m, 1H), 7.33–7.56 (m, 6H) ppm; C{1H}NMR
(75 MHz, CDCl3, 25 ºC): δ = 104.2 (C), 122.8 (CH), 123.0 (CH), 123.7 (CH), 124.8 (CH), 126.2 (CH), 127.2
(2 x CH), 127.5 (CH), 128.2 (CH), 128.8 (2 x CH), 129.1 (CH), 129.5 (CH), 130.9 (2 x CH), 131.9 (2 x CH),
137.0 (C), 137.78 (C), 137.82 (C), 141.1 (C), 141.8 (C), 142.8 (C), 143.2 (C), 149.3 (C) ppm; LRMS (EI): m/z
(%): 488 (M+, 100), 361 (27), 284 (34); HRMS (ESI): calcd for C26H18IS+ [(M+H)+]: 489.0168; found:
489.0165.
2-(Cyclohex-1-en-1-yl)-3-iodo-1a,1a-diphenylbenzofulvene (6f). Orange solid; Rf = 0.19 (hexane); Mp =
1
117−119 ºC; 69% yield (168 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.63–0.84 (m, 1H), 1.08–1.43 (m,
3H), 1.60–2.12 (m, 4H), 5.46–5.61 (m, 1H), 6.19–6.35 (m, 1H), 6.85 (ddd, J = 7.8, 7.2, 1.4 Hz, 1H), 7.01–7.64
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(m, 12H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 21.8 (CH2), 22.2 (CH2), 25.4 (CH2), 29.5 (CH2),
102.1 (C), 122.4 (CH), 123.1 (CH), 125.7 (CH), 127.2 (bs, 2 x CH), 127.4 (CH), 128.4 (CH), 128.7 (bs, 2 x
CH), 128.9 (CH), 130.4 (bs, 2 x CH), 131.1 (bs, 2 x CH), 131.6 (CH), 135.2 (C), 136.8 (C), 137.2 (C), 141.7
(C), 142.9 (C), 143.4 (C), 148.5 (C), 149.3 (C) ppm; LRMS (EI): m/z (%): 486 (M+, 60), 359 (77), 281 (57),
252 (48); HRMS (ESI): calcd for C28H24I+ [(M+H)+]: 487.0917; found: 487.0917.
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2-Butyl-3-iodo-1a,1a-diphenyl-benzofulvene (6g). Orange oil; Rf = 0.31 (hexane); 59% yield (136 mg); H
NMR (300 MHz, CDCl3, 25 ºC): δ = 0.71 (t, J = 7.1 Hz, 3H), 0.93 (sex, J = 7.1 Hz, 2H), 1.16–1.34 (m, 2H),
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2.03–2.23 (m, 2H), 6.26 (d, J = 7.8 Hz, 1H), 6.82 (ddd, J = 7.9, 6.5, 2.2 Hz, 1H), 7.05–7.71 (m, 12H) ppm;
13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 13.9 (CH3), 22.8 (CH2), 31.5 (CH2), 32.2 (CH2), 103.1 (C), 121.6
(CH), 123.1 (CH), 125.4 (CH), 127.3 (CH), 128.1 (2 x CH), 128.6 (CH), 128.7 (2 x CH), 128.9 (CH), 130.5 (2
x CH), 130.9 (2 x CH), 137.07 (C), 137.09 (C), 142.6 (C), 143.0 (C), 143.5 (C), 146.7 (C), 147.7 (C) ppm;
LRMS (EI): m/z (%): 462 (M+, 100), 292 (95), 215 (50); HRMS (EI): calcd for C26H23I+: 462.0840; found:
462.0846.
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3-Iodo-1a,1a-diphenyl-2-phenylsulfanylbenzofulvene (6h). Orange solid; Rf = 0.50 (hexane:EtOAc, 10:1); Mp
= 71−73 ºC; 95% yield (244 mg); 1H NMR (500 MHz, CDCl3, 25 ºC): δ = 6.39 (d, J = 7.9 Hz, 1H), 6.80–6.87
(m, 2H), 6.94–6.99 (m, 1H), 7.01–7.08 (m, 3H), 7.09–7.15 (m, 2H), 7.17–7.22 (m, 2H), 7.25–7.32 (m, 3H),
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7.32–7.36 (m, 1H), 7.36–7.43 (m, 3H), 7.45–7.50 (m, 1H) ppm; C{1H}NMR (125 MHz, CDCl3, 25 ºC): δ =
117.4 (C), 123.1 (CH), 125.1 (CH), 127.0 (CH), 127.2 (2 × CH), 127.5 (CH), 127.6 (2 x CH), 128.6 (2 × CH),
128.7 (3 x CH), 128.9 (CH), 129.4 (CH), 131.0 (2 x CH), 131.9 (2 x CH), 136.4 (C), 137.3 (C), 137.5 (C),
138.1 (C), 142.1 (C), 142.5 (C), 142.9 (C), 150.7 (C) ppm; LRMS (ESI): m/z (%): 515 [(M+H)+, 73], 457 (43),
388 (100); HRMS (ESI): calcd for C28H20IS+ [(M+H)+]: 515.0325; found: 515.0324.
3-Iodo-1a,1a,2-tri-(4-methylphenyl)benzofulvene (6i). Orange solid; Rf = 0.13 (hexane); Mp = 197−199 ºC;
90% yield (236 mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 2.20 (s, 3H), 2.26 (s, 3H), 2.51 (s, 3H), 6.48 (d, J
= 7.8 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.73–6.87 (m, 4H), 6.92–6.99 (m, 3H), 7.24–7.34 (m, 5H), 7.41 (d, J =
13
7.6 Hz, 1H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 21.2 (2 x CH3), 21.6 (CH3), 102.7 (C), 122.5
(CH), 123.1 (CH), 125.9 (CH), 127.1 (CH), 127.7 (2 x CH), 127.8 (2 x CH), 129.4 (2 x CH), 130.6 (2 x CH),
131.1 (2 x CH), 132.2 (2 x CH), 135.0 (C), 135.7 (C), 137.1 (C), 137.2 (C), 138.1 (C), 138.6 (C), 139.2 (C),
140.0 (C), 143.2 (C), 146.7 (C), 149.9 (C) ppm; LRMS (EI): m/z (%): 524 (M+, 100), 382 (24), 211 (33);
HRMS (EI): calcd for C31H25I+: 524.0996; found: 524.1011.
2-Butyl-3-iodo-1a,1a-di-(4-methylphenyl)benzofulvene (6j). Orange oil; Rf = 0.29 (hexane); 70% yield (172
mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.72 (t, J = 7.3 Hz, 3H), 0.90–1.02 (m, 2H), 1.18–1.30 (m, 2H),
2.13–2.23 (m, 2H), 2.42 (s, 3H), 2.46 (s, 3H), 6.34–6.43 (m, 1H), 6.85 (ddd, J = 7.8, 6.9, 1.7 Hz ,1H), 7.13–
7.32 (m, 10H) ppm; 13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 13.9 (CH3), 21.5 (CH3), 21.6 (CH3), 22.7
(CH2), 31.5 (CH2), 32.2 (CH2), 102.2 (C), 121.5 (CH), 123.0 (CH), 125.2 (CH), 127.0 (CH), 128.7 (2 x CH),
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129.4 (2 x CH), 130.8 (2 x CH), 131.2 (2 x CH), 136.6 (C), 137.4 (C), 138.7 (C), 139.0 (C), 140.0 (C), 140.2
(C), 143.3 (C), 146.8 (C), 148.4 (C) ppm; LRMS (EI): m/z (%): 490 (M+, 100), 320 (76), 305 (47); HRMS (EI):
calcd for C28H27I+: 490.1153; found: 490.1154.
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2-Butyl-3-iodo-1a-(3,4,5-trimethoxyphenyl)-1a-phenylbenzofulvene (6k). Orange oil; Rf = 0.37 (hexane:EtOAc,
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5:1); 54% yield (149 mg); Obtained as a 1:1 mixture of E/Z isomers; H NMR (300 MHz, CDCl3, 25 ºC): δ =
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0.70 (t, J = 7.2 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H), 0.83–1.08 (m, 6H), 1.17–1.34 (m, 4H), 2.05–2.21 (m, 2H),
3.75 (s, 2 x 3H), 3.81 (s, 2 x 3H), 3.91 (s, 3H), 3.95 (s, 3H), 6.26 (dd, J = 7.8, 0.6 Hz,1H), 6.44 (dd, J = 7.8, 0.6
Hz,1H), 6.48 (s, 2H), 6.52 (s, 2H), 6.76–6.93 (m, 2H), 7.10–7.54 (m, 14H) ppm; 13C{1H}NMR (75 MHz,
CDCl3, 25 ºC): δ = 13.8 (CH3), 13.9 (CH3), 22.8 (CH2), 22.9 (CH2), 31.5 (2 x CH2), 32.2 (CH2), 32.7 (CH2),
56.3 (2 x CH3), 56.4 (2 x CH3), 61.1 (CH3), 61.2 (CH3), 102.9 (C), 103.0 (C), 107.8 (2 x CH), 108.2 (2 x CH),
121.6 (2 x CH), 123.1 (CH), 123.2 (CH), 125.4 (CH), 125.6 (CH), 127.28 (CH), 127.31 (CH), 128.0 (2 x CH),
128.7 (3 x CH), 129.1 (CH), 130.5 (2 x CH), 130.8 (2 x CH), 136.9 (2 x C), 137.0 (C), 137.1 (C), 138.0 (C),
138.1 (C), 138.7 (C), 138.9 (C), 142.3 (C), 142.5 (C), 143.3 (C), 143.5 (C), 146.6 (C), 146.7 (C), 147.5 (C),
+
147.6 (C), 152.9 (2 x C), 153.4 (2 x C) ppm; HRMS (ESI): calcd for C29H30IO3 [(M+H)+]: 553.1234; found:
553.1237.
2-Butyl-3-iodo-1a-(4-methoxyphenyl)-1a-phenylbenzofulvene (6l). Red oil; Rf = 0.29 (hexane:EtOAc, 20:1);
75% yield (185 mg); Obtained as a 1:1 mixture of E/Z isomers; 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.71 (t,
J = 7.1 Hz, 3H), 0.73 (t, J = 7.1 Hz, 3H), 0.85–1.08 (m, 4H), 1.17–1.32 (m, 4H), 2.07–2.17 (m, 2H), 2.21–2.30
(m, 2H), 3.87 (s, 3H), 3.89 (s, 3H), 6.27 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 6.79–6.96 (m, 6H), 7.14–
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7.51 (m, 18H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 13.88 (CH3), 13.94 (CH3), 22.7 (CH2), 22.8
(CH2), 31.4 (CH2), 31.5 (CH2), 32.2 (CH2), 32.3 (CH2), 55.46 (CH3), 55.50 (CH3), 102.3 (C), 102.4 (C), 113.5
(2 x CH), 114.0 (2 x CH), 121.52 (CH), 121.54 (CH), 122.9 (2 x CH), 125.2 (CH), 125.3 (CH), 126.96 (CH),
127.01 (CH), 128.0 (2 x CH), 128.6 (2 x CH), 128.7 (CH), 129.0 (CH), 131.0 (2 x CH), 131.3 (2 x CH), 132.6
(2 x CH), 132.9 (2 x CH), 135.0 (C), 135.3 (C), 136.6 (C), 136.7 (C), 137.4 (2 x C),142.9 (C), 143.2 (C), 143.3
(2 x C), 146.7 (C), 146.8 (C),147.8 (C), 147.9 (C), 160.3 (C), 160.5 (C) ppm; HRMS (EI): calcd for C27H25IO+:
492.0945; found: 492.0943.
2-Butyl-3-iodo-1a-phenyl-1a-(2-thienyl)benzofulvene (6m). Red oil; Rf = 0.60 (hexane); 59% yield (130 mg);
Obtained as a 1:1 mixture of E/Z isomers; 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.70 (t, J = 7.2 Hz, 3H), 0.77
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(t, J = 7.3 Hz, 3H), 0.85–1.42 (m, 8H), 2.04–2.10 (m, 2H), 2.35–2.40 (m, 2H), 6.21 (d, J = 7.8 Hz, 1H), 6.69–
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6.88 (m, 3H), 6.88–7.02 (m, 2H), 7.04–7.61 (m, 18H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 13.9
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(CH3), 14.0 (CH3), 22.8 (CH2), 22.9 (CH2), 31.4 (CH2), 31.6 (CH2), 32.2 (CH2), 32.7 (CH2), 103.6 (2 x C),
121.6 (CH), 121.7 (CH), 122.8 (CH), 123.0 (CH), 125.5 (CH), 125.6 (CH), 127.1 (CH), 127.4 (CH), 127.5
(CH), 127.7 (CH), 128.1 (2 x CH), 128.7 (2 x CH), 129.2 (CH), 129.5 (CH), 129.6 (CH), 129.7 (CH), 130.7
(CH), 130.8 (2 x CH), 131.1 (2 x CH), 131.7 (CH), 137.0 (C), 137.1 (C), 138.3 (C), 138.5 (C), 139.4 (C), 139.6
(C), 142.5 (C), 142.6 (C), 143.3 (C), 143.4 (C), 144.7 (C), 145.0 (C), 146.5 (C), 146.6 (C) ppm; HRMS (EI):
calcd for C24H21IS+: 468.0403; found: 468.0395.
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2-Butyl-1a-(4-fluorophenyl)-3-iodo-1a-(4-methoxyphenyl)benzofulvene (6n). Red oil; Rf
=
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(hexane:EtOAc, 20:1); 72% yield (184 mg); Obtained as a ~1:1 mixture of E/Z isomers; H NMR (500 MHz,
CDCl3, 25 ºC): δ = 0.71 (t, J = 7.3 Hz, 3H), 0.72 (t, J = 7.4 Hz, 3H), 0.93–1.02 (m, 4H), 1.17–1.26 (m, 4H),
2.10–2.18 (m, 2H), 2.20–2.24 (m, 2H), 3.87 (s, 3H), 3.89 (s, 3H), 6.30 (d, J = 7.8 Hz, 1H), 6.44 (d, J = 7.8 Hz,
1H), 6.82–6.88 (m, 2H), 6.89–6.96 (m, 4H), 7.04–7.12 (m, 4H), 7.14–7.18 (m, 2H), 7.18–7.26 (m, 8H), 7.27–
7.31 (m, 2H) ppm; 13C{1H}NMR (125 MHz, CDCl3, 25 ºC): δ = 13.89 (CH3), 13.92 (CH3), 22.74 (CH2),
22.76(CH2), 31.5 (2 x CH2), 32.25 (CH2), 32.28 (CH2), 55.50 (CH3), 55.53 (CH3), 102.5 (C), 102.7 (C), 113.6
(2 x CH), 114.1 (2 x CH), 115.1 (d, J = 21.5 Hz, 2 x CH), 115.8 (d, J = 21.5 Hz, 2 x CH), 121.6 (CH), 121.7
(CH), 122.7 (CH), 122.8 (CH), 125.3 (CH), 125.4 (CH), 127.09 (CH), 127.11 (CH), 132.7 (2 x CH), 133.02 (d,
J = 8.2 Hz, 2 x CH), 133.03 (2 x CH), 133.3 (d, J = 8.2 Hz, 2 x CH), 134.9 (C), 135.1 (C), 136.9 (2 x C), 137.2
(C), 137.4 (C), 138.9 (d, J = 3.3 Hz, C), 139.1 (d, J = 3.4 Hz, C), 143.3 (C), 143.4 (C), 146.39 (C), 146.41 (C),
146.5 (C), 146.7 (C), 160.5 (C), 160.7 (C), 163.2 (d, J = 249.6 Hz, C), 163.4 (d, J = 249.8 Hz, C) ppm; ; HRMS
(EI): calcd for C27H24FIO+: 510.0850; found: 510.0846.
Synthesis of oxygen-functionalized 3-iodo-1H-indenes 7 by iodocyclization of o-(alkynyl)styrenes 1, 3 or
5:
NꢀIodosuccinimide (338 mg, 1.5 mmol) was added to a solution of the corresponding starting oꢀ
(alkynyl)styrene 1, 3 or 5 (0.5 mmol) in a 2/1 mixture CH2Cl2/MeOH (3 mL). The reaction vial was sealed and
protected from light. The resulting mixture was stirred at room temperature until completed consumption of the
starting material as determined by TLC (1ꢀ6 h). The mixture was quenched by addition of saturated aq Na2S2O3
(10 mL). The layers were separated and the aqueous one was extracted with CH2Cl2 (3 x 5 mL). The combined
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organic layers were dried (Na2SO4) and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography on silica gel using mixtures of hexane and EtOAc as eluents to obtain
the corresponding 1ꢀmethoxymethylꢀ3ꢀiodoꢀ1Hꢀindenes 7 in the yields reported in Table 3. The
characterization data of 7aꢀe,g have been previously reported.29
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3-Iodo-1-(2-methoxybutan-2-yl)-2-phenyl-1H-indene (7f). Yellow oil. Rf = 0.45 (hexane:CH2Cl2, 9:1). 45%
yield (91 mg). Obtained as a 3:1 mixture of isomers. Data of the major isomer from an enriched 5:1 mixture are
reported; 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.69 (t, J = 7.4 Hz, 3H), 0.78 (s, 3H), 1.12ꢀ1.34 (m, 2H), 3.30
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(s, 3H), 4.36 (s, 1H), 7.21ꢀ7.30 (m, 1H), 7.30ꢀ7.48 (m, 7H), 7.53 (d, J = 7.5 Hz, 1H) ppm; C{1H}NMR (75
MHz, CDCl3, 25 ºC): δ = 7.6 (CH3), 21.7 (CH3), 28.0 (CH2), 49.4 (CH), 59.7 (CH3), 79.6 (C), 97.9 (C), 123.0
(CH), 125.5 (CH), 126.2 (CH), 127.5 (CH), 127.7 (CH), 128.1 (2 x CH), 129.3 (2 x CH), 139.1 (C), 142.8 (C),
146.1 (C), 152.8 (C) ppm; LRMS (EI): m/z (%): 404 (M+, 1), 317 (15), 189 (45), 87(100); HRMS (EI): calcd
for C20H21IO+: 404.0632, found: 404.0629.
3-Iodo-1-(1-methoxy-1-phenylpropyl)-2-phenyl-1H-indene (7h). 60 % yield (140 mg); Obtained as a 1:1
mixture of isomers that were separated by flash column chromatography; Isomer A: Colourless oil. Rf = 0.30
1
(hexane:CH2Cl2, 9:1). 29% yield; H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.82 (t, J = 7.2 Hz, 3H), 1.60ꢀ1.77
(m, 2H), 3.21 (s, 3H), 4.52 (s, 1H), 6.73ꢀ6.84 (m, 2H), 6.94ꢀ7.12 (m, 4H), 7.20ꢀ7.34 (m, 2H), 7.36ꢀ7.52 (m,
13
5H), 7.73ꢀ7.83 (m, 1H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 7.6 (CH3), 25.9 (CH2), 49.5 (CH),
58.5 (CH3), 83.5 (C), 99.6 (C), 122.5 (CH), 125.7 (CH), 126.57 (2 x CH), 126.59 (2 x CH), 126.87 (CH),
126.90 (CH), 127.3 (CH), 127.9 (CH), 128.0 (2 x CH), 129.4 (2 x CH), 138.5 (C), 139.5 (C), 142.9 (C), 146.0
(C), 150.4 (C) ppm; LRMS (EI): m/z (%): 466 (M+, 1), 317 (18), 189 (31), 149(100); HRMS (EI): calcd for
C25H23IO+: 466.0789, found: 466.0789. Isomer B: Colourless oil; Rf = 0.40 (hexane:CH2Cl2, 9:1); 31% yield;
1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.54 (t, J = 7.4 Hz, 3H), 1.92 (dq, J = 14.9, 7.5 Hz, 1H), 2.14 (dq, J =
14.5, 7.1 Hz, 1H), 2.96 (s, 3H), 4.52 (s, 1H), 6.90 (d, J = 6.9 Hz, 2H), 6.95ꢀ7.10 (m, 5H), 7.11ꢀ7.20 (m,
13
5H),7.21ꢀ7.30 (m, 2H), 7.32ꢀ7.41 (m, 1H), 7.72 (d, J = 7.5 Hz, 1H) ppm; C{1H}NMR (75 MHz, CDCl3, 25
ºC): δ = 8.2 (CH3), 26.0 (CH2), 49.7 (CH), 61.8 (CH3), 83.6 (C), 98.3 (C), 122.8 (CH), 125.8 (CH), 126.1 (CH),
126.6 (CH), 126.88 (CH), 126.94 (2 x CH), 127.3 (2 x CH), 127.4 (2 x CH), 127.5 (CH), 129.2 (2 x CH), 138.0
(C), 142.5 (C), 143.2 (C), 146.0 (C), 152.4 (C) ppm; LRMS (EI): m/z (%): 466 (M+, <1), 317 (4), 189 (9),
149(100); HRMS (EI): calcd for C25H23IO+: 466.0789, found: 466.0799.
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3-Iodo-1-(methoxydiphenylmethyl)-2-phenyl-1H-indene (7i). Colourless solid; Mp = 163−165 ºC; Rf = 0.42
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(hexane:CH2Cl2, 9:1); 66% yield (170 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ = 2.65 (d, J = 1.1 Hz, 3H),
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5.20 (s, 1H), 6.73ꢀ6.78 (m, 3H), 6.97ꢀ7.10 (m, 3H), 7.13ꢀ7.21 (m, 2H), 7.24ꢀ7.51 (m, 9H), 7.60ꢀ7.76 (m, 2H)
ppm; 13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 51.9 (CH), 62.1 (CH3), 87.9 (C), 98.6 (C), 122.7 (CH), 125.0
(CH), 125.7 (CH), 126.4 (2 x CH), 126.9 (2 x CH), 127.0 (CH), 127.2 (CH), 127.7 (CH), 127.9 (2 x CH), 128.1
(CH), 128.4 (2 x CH), 129.7 (2 x CH), 130.1 (2 x CH), 136.0 (C), 138.5 (C), 139.0 (C), 141.3 (C), 146.9 (C),
152.4 (C) ppm; LRMS/HRMS (EI): Decomposition.
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Synthesis of polycyclic compounds 9 by intramolecular alkoxyiodocyclization of o-(alkynyl)styrenes 8: Nꢀ
Iodosuccinimide (338 mg, 1.5 mmol) was added to a solution of the corresponding starting oꢀ(alkynyl)styrene 8
(0.5 mmol) in CH2Cl2 (2 mL). The reaction vial was sealed and protected from light. The resulting mixture was
stirred at room temperature until completed consumption of the starting material as determined by TLC or GCꢀ
MS (5ꢀ12 h). The mixture was quenched by addition of saturated aq Na2S2O3 (10 mL). The layers were
separated and the aqueous one was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried
(Na2SO4) and the solvents were removed under reduced pressure. The residue was purified by flash column
chromatography on silica gel using mixtures of hexane and EtOAc as eluents to obtain the corresponding
adducts 9 in the yields depicted in Scheme 5.
8-Iodo-3,3-dimethyl-3,3a-dihydro-1H-indeno[1,2-c]furan (9a). White solid; Mp = 92−94 ºC; Rf = 0.34
1
(hexane:EtOAc 20:1); 46% yield (72 mg); H NMR (500 MHz, CDCl3, 25 ºC): δ = 0.68 (s, 3H), 1.65 (s, 3H),
3.96 (s, 1H), 4.34 (dd, J = 13.9, 1.0 Hz, 1H), 4.70 (d, J = 13.9 Hz, 1H), 7.19–7.25 (m, 2H), 7.28 (d, J = 7.1 Hz,
13
1H), 7.37 (t, J = 7.5 Hz, 1H) ppm; C{1H}NMR (125 MHz, CDCl3, 25 ºC): δ = 20.9 (CH3), 29.1 (CH3), 65.4
(CH), 67.5 (CH2), 81.4 (C), 86.8 (C), 122.4 (CH), 123.3 (CH), 126.5 (CH), 128.3 (CH), 140.8 (C), 150.2 (C),
161.0 (C) ppm; LRMS (ESI): m/z (%): 313 [(M+H)+, 100]; HRMS (ESI): calcd for C13H14IO+ [(M+H)+]:
313.0084; found: 313.0088.
11-Iodo-6,6-dimethyl-6,6a-dihydroindeno[1,2-c]chromene (9b). Yellow oil; Rf = 0.17 (hexane); 51% yield (95
mg); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.80 (s, 3H), 1.88 (s, 3H), 3.81 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H),
13
7.02 (t, J = 7.6 Hz, 1H), 7.17–7.32 (m, 2H), 7.36–7.52 (m, 3H), 8.48 (d, J = 7.6 Hz, 1H) ppm; C{1H}NMR
(75 MHz, CDCl3, 25 ºC): δ = 19.0 (CH3), 29.0 (CH3), 57.1 (CH), 81.0 (C), 87.4 (C), 117.2 (CH), 118.8 (C),
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119.8 (CH), 122.5 (CH), 123.2 (CH), 124.9 (CH), 126.1 (CH), 127.9 (CH), 130.2 (CH), 139.5 (C), 142.0 (C),
147.2 (C), 155.4 (C) ppm; LRMS (ESI): m/z (%): 375 [(M+H)+, 100]; HRMS (ESI): calcd for C18H16IO+
[(M+H)+]: 375.0240; found: 375.0230.
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12-Iodo-7,7-dimethyl-7,7a-dihydro-5H-benzo[c]indeno[2,1-e]oxepine (9c). Colourless oil; Rf = 0.40
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(hexane:CH2Cl2, 3:2); 47% yield (91 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ = 0.82 (s, 3H), 1.72 (s, 3H),
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3.96 (s, 1H), 4.46 (d, J = 14.6 Hz, 1H), 4.89 (d, J = 14.6 Hz, 1H), 7.19–7.48 (m, 7H), 7.65 (d, J = 7.4 Hz, 1H)
ppm; 13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 19.1 (CH3), 30.6 (CH3), 63.9 (CH), 66.4 (CH2), 80.4 (C), 96.6
(C), 123.4 (CH), 123.8 (CH), 126.3 (CH), 127.5 (CH), 127.7 (CH), 127.8 (CH), 128.1 (CH), 131.1 (CH), 137.4
(C), 138.8 (C), 143.5 (C), 146.7 (C), 151.3 (C) ppm; LRMS (EI): m/z (%): 388 (M+, 3), 330 (28), 203 (100),
101 (21); HRMS (EI): calcd for C19H17IO+: 388.0319; found: 388.0327.
12-Iodo-7-(iodomethyl)-7-methyl-7,7a-dihydro -5H-benzo[c]indeno[2,1-e]oxepine (10c). Colourless solid, Mp
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= 119−121 ºC, Rf = 0.50 (hexane:CH2Cl2, 3:2), 19% yield (49 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ =
0.94 (s, 3H), 3.79 (s, 2H), 4.27 (s, 1H), 4.49 (d, J = 14.6 Hz, 1H), 4.89 (d, J = 14.6 Hz, 1H), 7.18–7.49 (m, 7H),
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7.61 (d, J = 7.3 Hz, 1H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 17.3 (CH3), 20.7 (CH2), 61.6 (CH),
67.0 (CH2), 79.3 (C), 97.2 (C), 123.0 (CH), 124.1 (CH), 126.8 (CH), 127.7 (CH), 128.08 (CH), 128.12 (CH),
128.3 (CH), 131.4 (CH), 137.2 (C), 138.1 (C), 142.4 (C), 146.7 (C), 151.0 (C) ppm; LRMS (EI): m/z (%): 514
(M+, 2), 330 (49), 203 (100); HRMS (EI): calcd for C19H16I2O+: 513.9286, found: 513.9291.
2-(4-Hydroxybutyl)-3-iodo-1-(prop-1-en-2-yl)-1H-indene (2m). Colourless oil; Rf = 0.14 (hexane:EtOAc, 5:1);
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58% yield (103 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ = 1.15 (s, 3H), 1.50–1.75 (m, 4H), 2.29–2.38 (m,
1H), 2.55–2.64 (m, 1H), 3.68 (t, J = 6.1 Hz, 2H), 4.10 (s, 1H), 5.03–5.10 (m, 1H), 5.20 (bs, 1H), 7.18–7.27 (m,
13
3H), 7.31–7.37 (m, 1H) ppm; C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 16.9 (CH3), 25.2 (CH2), 30.8 (CH2),
32.4 (CH2), 60.5 (CH), 62.6 (CH2), 94.9 (C), 115.7 (CH2), 121.4 (CH), 122.7 (CH), 125.7 (CH), 127.2 (CH),
143.0 (C), 143.6 (C), 145.3 (C), 154.1 (C) ppm; HRMS (ESI): calcd for C16H19IONa+ [(M+Na)+]: 377.0373;
found: 377.0372.
Palladium-catalyzed Suzuki cross-coupling reactions of 3-iodoindenes: These reactions were conducted
following the methodology described by Wu et al.37 The corresponding 3ꢀiodoindene (0.2 mmol) was added to
a mixture of arylboronic acid (1.5 equiv., 0.3 mmol), Pd(OAc)2 (0.9 mg, 2 mol%), SꢀPhos (3.3 mg, 4 mol%)
and K3PO4 (84 mg, 2 equiv., 0.4 mmol) in toluene (1 mL) and the solution stirred at 80 ºC until full conversion
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was observed by TLC or GCꢀMS (6 h). The solvent was evaporated and the residue was purified by flash
chromatography on silica gel using mixtures of hexane and EtOAc as eluents to obtain the corresponding 2,3ꢀ
diarylꢀ1Hꢀindenes 11-12 or the 2,3ꢀdiarylbenzofulvene 13a in the yields depicted in Scheme 6. The
characterization data of 11a,b29 and 13a33 have been previously reported.
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2-(4-Methoxyphenyl)-1-(2-methoxypropan-2-yl)-3-phenyl-1H-indene (12a). White solid; Mp = 138−140 ºC; Rf
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= 0.23 (hexane:EtOAc, 20:1); 86% yield (64 mg); 1H NMR (500 MHz, CDCl3, 25 ºC): δ = 0.86 (s, 3H), 0.93 (s,
3H), 3.40 (s, 3H), 3.79 (s, 3H), 4.35 (s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.20–7.31 (m,
6H), 7.32–7.36 (m, 2H), 7.72 (d, J = 7.2 Hz, 1H) ppm; 13C{1H}NMR (125 MHz, CDCl3, 25 ºC): δ = 21.3
(CH3), 25.4 (CH3), 49.1 (CH), 55.0 (CH3), 58.4 (CH3), 113.2 (2 x CH), 119.8 (CH), 124.7 (CH), 126.0 (CH),
126.6 (CH), 126.6 (CH), 128.1 (2 x CH), 129.6 (2 x CH), 130.3 (C), 130.6 (2 x CH), 135.4 (C), 141.2 (C),
144.1 (C), 144.4 (C), 145.8 (C), 158.2 (C) ppm; LRMS (ESI): m/z (%): 393 [(M+Na)+, 100], 339 (49); HRMS
(ESI): calcd for C26H26O2Na+ [(M+Na)+]: 393.1825, found: 393.1827
.
Palladium-catalyzed Sonogashira cross-coupling reaction of 3-iodobenzofulvenes: Synthesis of 2-(aryl)-
1a,1a-diphenyl-3-(phenylethynyl)benzofulvenes 14a,b: These reactions were conducted following the
methodology described by Michelet, Toullec et al.13a The corresponding 3ꢀiodobenzofulvene 6 (0.2 mmol) was
dissolved in a 3:1 mixture of NEt3 and toluene (0.1 M) under argon. Then phenylacetylene (33 ꢀL, 0.3 mmol,
1.5 equiv.), PdCl2(PPh3)2 (8.6 mg, 6 mol %), and CuI (1.2 mg, 3 mol %) were added and the reaction mixture
was stirred at 50 ºC overnight. The resulting mixture was washed with a saturated solution of NH4Cl, the layers
were separated and the aqueous one was extracted with EtOAc (3 x 5 mL). The combined organic layers were
dried (Na2SO4) and the solvents were removed under reduced pressure. The solvent was evaporated and the
residue was purified by flash chromatography on silica gel using hexane:EtOAc (50:1) as eluent to obtain the
corresponding 2ꢀ(aryl)ꢀ1a,1aꢀdiphenylꢀ3ꢀ(phenylethynyl)benzofulvenes 14 in the yields depicted in Scheme 6.
1a,1a,2-Triphenyl-3-(phenylethynyl)benzofulvene (14a). Red solid; Mp = 173−175 ºC; Rf = 0.27
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(hexane:EtOAc, 50:1); 95% yield (87 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ = 6.45 (d, J = 7.9 Hz, 1H),
13
6.85–7.11 (m, 9H), 7.19–7.43 (m, 6H), 7.44–7.59 (m, 7H), 7.65 (d, J = 7.5 Hz, 1H) ppm; C{1H}NMR (75
MHz, CDCl3, 25 ºC): δ = 85.3 (C), 98.9 (C), 119.7 (CH), 122.9 (CH), 123.4 (C), 125.5 (CH), 125.6 (C), 125.8
(CH), 126.76 (2 x CH), 126.81 (2 x CH), 127.0 (CH), 128.0 (CH), 128.10 (3 x CH), 128.4 (2 x CH), 128.9
(CH), 129.8 (2 x CH), 131.0 (2 x CH), 131.5 (2 x CH), 132.4 (2 x CH), 136.1 (C), 137.1 (C), 137.3 (C), 141.1
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(C), 141.4 (C), 142.8 (C), 145.5 (C), 150.5 (C) ppm; LRMS (ESI): m/z (%): 457 [(M+H)+, 100]; HRMS (ESI):
calcd for C36H25+ [(M+H)+]: 457.1951; found: 457.1951.
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1a,1a-Diphenyl-3-(phenylethynyl)-2-thienylbenzofulvene (14b). Red solid; Mp = 162−164 ºC; Rf = 0.23
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(hexane:EtOAc, 50:1); 93% yield (86 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ = 6.39 (d, J = 7.8 Hz, 1H),
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6.75–6.87 (m, 2H), 6.87–7.12 (m, 6H), 7.17–7.30 (m, 2H), 7.30–7.56 (m, 10H), 7.60 (d, J = 7.4 Hz, 1H) ppm;
13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 85.3 (C), 99.6 (C), 119.7 (CH), 122.8 (CH), 122.9 (CH), 123.4 (C),
123.6 (CH), 125.2 (C), 125.5 (CH), 126.7 (2 x CH), 127.1 (CH), 128.2 (4 x CH), 128.4 (2 x CH), 128.9 (CH),
129.0 (CH), 131.0 (2 x CH), 131.5 (2 x CH), 132.3 (2 x CH), 136.3 (C), 137.0 (C), 137.5 (C), 140.2 (C), 141.0
(C), 141.3 (C), 142.7 (C), 150.4 (C) ppm; LRMS (ESI): m/z (%): 463 [(M+H)+, 100]; HRMS (ESI): calcd for
C34H23S+ [(M+H)+]: 463.1515; found: 463.1516.
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Derivatization of iodoindene 2a via I/Li exchange: Synthesis of 3-functionalized-1H-indenes 15: nꢀBuLi
(1.0 equiv., 0.5 mmol, 0.31 mL 1.6 M) was added to a solution of iodoindene 2a (1.0 equiv., 0.5 mmol, 179
mg) in Et2O (5 mL) at −78 ºC and stirred at this temperature for 30 min. Then the appropriate electrophile (1.0ꢀ
1.5 equiv., 0.5ꢀ0.75 mmol) was added and the resulting mixture stirred at −78 ºC for 30 min and then allowed to
reach room temperature. Water was added, the layers were separated and the aqueous one was extracted with
CH2Cl2 (3 x 10 mL). The combined organic layers were dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash chromatography on silica gel using mixtures of hexane and
EtOAc as eluents to obtain the corresponding 3ꢀfunctionalizedꢀ1Hꢀindenes 15 in the yields depicted in Scheme
7.
3-Deutero-1-isopropenyl-2-phenyl-1H-indene (15a). Synthesized following the general procedure using MeOD
in excess (0.25 mL/mmol, ~12 equiv.) as electrophile. White solid; Mp = 103−105 ºC; Rf = 0.43 (hexane); 99%
yield (115 mg, > 99%ꢀD at C3); 1H NMR (300 MHz, CDCl3, 25 ºC): δ = 1.19 (bs, 3H), 4.59 (s, 1H), 5.07–5.14
13
(m, 1H), 5.34–5.41 (m, 1H), 7.21–7.46 (m, 7H), 7.64–7.77 (m, 2H) ppm; C{1H}NMR (75 MHz, CDCl3, 25
ºC): δ = 17.1 (CH3), 58.8 (CH), 115.1 (CH2), 120.9 (CH), 123.3 (CH), 125.3 (CH), 126.4 (2 x CH), 127.3 (CH),
127.6 (CH), 128.6 (2 x CH), 135.7 (C), 144.3 (C), 145.1 (C), 146.4 (C), 148.6 (C) ppm. The signal
corresponding to the carbon bonded to deuterium is not observed; LRMS (EI): m/z (%): 233 (M+, 58), 218
(100), 190 (56); HRMS (EI): calcd for C18H15D+: 233.1310, found: 233.1316.
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1-Isopropenyl-3-methylsulfanyl-2-phenyl-1H-indene (15b). Synthesized following the general procedure using
dimethyl disulfide (1.5 equiv.) as electrophile. Colourless solid; Mp = 98−100 ºC; Rf = 0.45 (hexane:CH2Cl2,
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9:1); 94% yield (131 mg); H NMR (300 MHz, CDCl3, 25 ºC): δ = 1.14 (bs, 3H), 2.34 (s, 3H), 4.69 (s, 1H),
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5.01 (bs, 1H), 5.25 (bs, 1H), 7.29−7.41 (m, 2H), 7.41−7.51 (m, 4H), 7.65−7.75 (m, 3H) ppm; 13C{1H}NMR (75
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MHz, CDCl3, 25 ºC): δ = 17.0 (CH3), 17.3 (CH3), 60.9 (CH), 115.7 (CH2), 120.4 (CH), 123.3 (CH), 125.9
(CH), 127.4 (CH), 127.7 (CH), 128.1 (2 x CH), 129.3 (2 x CH), 133.7 (C), 135.3 (C), 143.9 (C), 144.4 (C),
145.0 (C), 149.7 (C) ppm; LRMS (EI): m/z (%): 278 (M+, 13), 263 (41), 215 (100), 77 (16); HRMS (EI): calcd
for C19H18S+: 278.1124, found: 278.1128.
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1-Isopropenyl-2-phenyl-3-tributylstannyl-1H-indene (15c). Synthesized following the general procedure using
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ClSnBu3 (1.0 equiv.) as electrophile. Pale yellow oil; Rf = 0.42 (hexane:CH2Cl2, 9:1); 96% yield (250 mg); H
NMR (300 MHz, CDCl3, 25 ºC): δ = 0.77−1.08 (m, 15H), 1.14 (bs, 3H), 1.18−1.55 (m, 12H), 4.57 (s, 1H), 4.93
(bs, 1H), 5.12 (bs, 1H), 7.18−7.27 (m, 1H), 7.28−7.49 (m, 8H) ppm; 13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ
= 10.8 (3 x CH2), 13.8 (3 x CH3), 17.0 (CH3), 27.7 (3 x CH2), 29.4 (3 x CH2), 63.7 (CH), 115.3 (CH2), 122.4
(CH), 123.3 (CH), 124.6 (CH), 127.1 (CH), 127.5 (CH), 128.0 (2 x CH), 128,6 (2 x CH), 139.4 (C), 142.6 (C),
144.1 (C), 146.3 (C), 151.0 (C), 161.2 (C) ppm; LRMS (EI)/HRMS (EI): Decomposition.
1-Isopropenyl-3-(1-(4-chlorophenyl)-1-hydroxylmethyl)-2-phenyl-1H-indene (15d). Synthesized following the
general procedure using pꢀchlorobenzaldehyde (1.0 equiv.) as electrophile. Colourless oil; Rf = 0.43
1
(hexane:EtOAc, 9:1); 66% yield (123 mg); Obtained as a ~1:1 mixture of diastereoisomers; H NMR (300
MHz, CDCl3, 25 ºC): δ = 1.17 (s, 6H), 4.57 (s, 1H), 4.67 (s, 1H), 4.94 (bs, 1H), 4.96 (bs, 1 H), 5.14 (bs, 1H),
5.20 (bs, 1 H), 6.10 (s, 1H), 6.12 (s, 1H), 7.14−7.55 (m, 26H) ppm; 13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ =
17.2 (CH3), 17.4 (CH3), 60.9 (CH), 61.3 (CH), 68.9 (CH), 69.4 (CH), 116.0 (2 x CH2), 121.8 (CH), 122.6 (CH),
123.5 (2 x CH), 125.55 (CH), 125.62 (CH), 127.02 (CH), 127.04 (CH), 127.2 (2 x CH), 127.89 (CH), 127.92
(CH), 128.0 (2 x CH), 128.5 (2 x CH), 128.6 (2 x CH), 128.7 (2 x CH), 128.8 (2 x CH), 128.9 (2 x CH), 129.0
(2 x CH), 132.9 (C), 133.4 (C), 135.0 (C), 135.5 (C), 139.7 (C), 140.0 (C), 140.3 (C), 140.7 (C), 142.4 (C),
142.5 (C), 143.1 (C), 143.3 (C), 145.6 (C), 145.7 (C), 147.5 (C), 148.0 (C) ppm; HRMS (EI): calcd for
C25H21ClO+: 372.1275, found: 372.1261.
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The Journal of Organic Chemistry
1-Isopropenyl-3-methoxycarbonyl-2-phenyl-1H-indene (15e). Synthesized following the general procedure
using methyl chloroformate (1.0 equiv.) as electrophile. Colourless solid; Mp= 77−79 ºC; Rf = 0.35
1
2
3
4
5
1
(hexane:CH2Cl2, 3:2); 81% yield (118 mg). Traces of the isomeric indene were detected; H NMR (300 MHz,
6
7
8
CDCl3, 25 ºC): δ = 1.13 (bs, 3H), 3.82 (s, 3H), 4.65 (s, 1H), 4.97 (bs, 1H), 5.18 (bs, 1H), 7.25−7.45 (m, 8H),
7.75−7.82 (m, 1H) ppm; 13C{1H}NMR (75 MHz, CDCl3, 25 ºC): δ = 17.3 (CH3), 51.8 (CH3), 61.9 (CH), 116.5
(CH2), 121.8 (CH), 123.4 (CH), 126.2 (CH), 127.6 (CH), 128.1 (2 x CH), 128.5 (CH), 128.9 (2 x CH), 131.2
(C), 135.0 (C), 141.8 (C), 142.8 (C), 144.6 (C), 155.9 (C), 166.1 (C) ppm; LRMS (EI): m/z (%): 290 (M+, 26),
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
230 (48), 215 (100); HRMS (EI): calcd for C20H18O2 : 290.1302, found: 290.1310.
Derivatization of iodobenzofulvenes 6 via I/Li exchange: Synthesis of 3-functionalized
benzofulvenes 16: These reactions were conducted following the same methodology described for
iodoindene 2a, although in a 0.2 mmol scale, to obtain the corresponding 3ꢀfunctionalized
benzofulvenes 16 in the yields depicted in Scheme 7.
1-(Diphenylmethylene)-3-(1-(4-chlorophenyl)-1-hydroxylmethyl)-2-(3-fluorophenyl)-1H-indene (16a)
Synthesized following the general procedure using pꢀchlorobenzaldehyde (1.0 equiv.) as electrophile. Orange
1
solid; Mp= 103−105 ºC; Rf = 0.21 (hexane:EtOAc, 20:1); 81% yield (83 mg); H NMR (500 MHz, CDCl3, 25
ºC): δ = 2.28 (bs, 1H), 5.88 (s, 1H), 6.45 (d, J = 7.9 Hz, 1H), 6.57−6.81 (m, 3H), 6.83−6.95 (m, 7H), 7.04 (td, J
= 7.5, 1.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.30−7.51 (m, 9H) ppm; 13C{1H}NMR (125 MHz, CDCl3, 25 ºC):
δ = 69.5 (CH), 113.3 (d, J = 20.7 Hz, CH), 117.3 (bs, CH), 122.0 (CH), 123.9 (CH), 125.5 (CH), 126.1 (bs,
CH), 127.0 (CH), 127.3 (2 x CH), 127.6 (bs, 2 x CH), 128.3 (CH), 128.7 (2 x CH), 128.8 (d, J = 8.5 Hz, CH),
129.1 (3 x CH), 130.8 (bs, 2 x CH), 131.0 (bs, 2 x CH), 133.1 (C), 137.9 (C), 138.0 (C), 138.6 (d, J = 7.9 Hz,
C), 139.6 (d, J = 2.0 Hz, C), 139.7 (C), 140.7 (C), 141.7 (C), 142.9 (C), 143.0 (C), 150.8 (C), 162.0 (d, J =
245.8 Hz, C) ppm; LRMS (ESI): m/z (%): 537 [(M+Na)+, 38], 497 (100); HRMS (ESI): calcd for
C35H24ClFONa+ [(M+Na)+]: 537.1392; found: 537.1397.
1-(Diphenylmethylene)-3-methoxycarbonyl-2-phenylsulfanyl-1H-indene (16b). Synthesized following the
general procedure using methyl chloroformate (1.0 equiv.) as electrophile. Red oil; Rf = 0.41 (hexane:EtOAc,
1
5:1); 76% yield (68 mg); H NMR (500 MHz, CDCl3, 25 ºC): δ = 3.62 (s, 3H), 6.44 (d, J = 7.9 Hz, 1H), 6.88
(td, J = 7.9, 1.1 Hz, 1H), 6.97−7.01 (m, 2H), 7.03−7.07 (m, 1H), 7.08−7.14 (m, 4H), 7.18 (td, J = 7.6, 0.9 Hz,
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