A study of palladium catalyzed intra/intermolecular cascade cross coupling/cyclizations involving bicyclopropylidene

Article abstract of DOI:10.3390/molecules19056058

The compounds [3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert- butyldimethylsilane 3, [4-(2-bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert- butyldimethylsilane 5 and dimethyl 2-(2-bromocyclohex-2-enyl)-2-(3-(tert- butyldimethylsilanyl)prop-2-ynyl)malona

Full text of DOI:10.3390/molecules19056058

Molecules 2014, 19, 6058-6069; doi:10.3390/molecules19056058
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Study of Palladium Catalyzed Intra/Intermolecular Cascade
Cross Coupling/Cyclizations Involving Bicyclopropylidene
Aydin Demircan
Department of Chemistry, Faculty of Arts &Science, Nigde University, Nigde 51240, Turkey;
E-Mail: ademircan@gmail.com; Tel.: +90-532-609-27-80; Fax: +90-388-225-01-80
Received: 13 February 2014; in revised form: 6 May 2014 / Accepted: 7 May 2014 /
Published: 13 May 2014
Abstract: The compounds [3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert-butyl-
dimethylsilane 3, [4-(2-bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert-butyldimethylsilane
5 and dimethyl 2-(2-bromocyclohex-2-enyl)-2-(3-(tert-butyldimethylsilanyl)prop-2-
ynyl)malonate 9 were prepared and subjected to palladium-catalyzed intra-intermolecular
cascade cross couplings incorporating bicyclopropylidene 10 under two types of
conditions. In the presence of Pd(OAc)2, PPh3 and K2CO3 in acetonitrile at 80 °C, the
products were indene analogues, cross-conjugated tetraenes 11, 12 and 13, respectively.
The corresponding spirocyclopropanated tricycle 16 in dimethylformamide at 110 °C was
obtained, albeit in low yield (24%), and observed as an equimolar mixture of
diastereomers, whereas 14, 15 were not fully isolated.
Keywords: cascade reactions; cross-coupling; palladium; cyclopropanes; electrocyclization
1. Introduction
Intra- as well as intermolecular so-called domino or cascade reactions is particularly
efficient in terms of increasing the molecular complexity in a minimum number of steps [1–12].
Especially, palladium-catalyzed carbon-carbon bond forming reactions that involve carbopalladations
of carbon-carbon double bonds can favorably be combined in all-intra-, intra-inter- and intermolecular
cascade reactions [5–12]. The so-called Mizoroki-Heck reaction, i.e., the palladium-catalyzed arylation
or alkenylation of alkenes has been applied in a variety of new concepts [5–26]. In view of the
steadily growing number of oligocyclic compounds with cyclopropyl moieties that show interesting
biological activities [27–29], it is noteworthy and helpful that the highly reactive building block
bicyclopropylidene 10 [30,31] can participate in various palladium-catalyzed cascade reactions to

Molecules 2014, 19
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furnish complex skeletons containing cyclopropyl groups [17–20] A particularly high increase in
molecular complexity can be achieved with sequential reactions starting with an intramolecular
carbopalladation (the first step of a Heck reaction) of a 2-bromo-1-ene-6-yne and trapping of the
formed reactive vinylpalladium halide intermediate by bicyclopropylidene 10 and subsequent
transformations [32]. We have been working on synthesis of fused ring systems, for indene [33,34]
utilizing the intramolecular addition of alkenyl radicals to furans, for benzofuran and benzothiophene [35]
towards indene also utilizing the thermal intramolecular Diels Alder cycloadduct. As this cascade
reaction principle appeared to deserve further development, we embarked on a project to prepare a few
more 2-bromo-1-ene-6-ynes and employ them in palladium-catalyzed cocyclizations involving
bicyclopropylidene 10.
2. Results and Discussion
Two major routes for the synthesis of 2-bromo-1,6-enynes as precursors for palladium-catalyzed
cascade cyclizations have previously been developed [32]. Employing experimental procedures from
both of these routes; three new 2-bromo-1,6-enynes with a 2-bromocyclohexene moiety for application in
palladium-catalyzed cascade cyclizations with incorporation of bicyclopropylidene 10 [32] were prepared.
Toward the first one, 2-bromocyclohexen-3-ol 1 [36] was deprotonated with sodium hydride and
then treated with propargyl bromide to give the ether 2 (73% yield). The latter was deprotonated with
n-butyllithium, and the resulting acetylide was trapped with paraformaldehyde to furnish the propargyl
alcohol 4 (75% yield). The latter, in the presence of N,N-dimethylaminopyridine and imidazole, was
treated with tert-butyldimethylsilyl chloride to yield bromoenyne 5 (75%). A second new cocyclization
precursor, the silylated bromoenyne 3, was obtained in 69% yield by trapping the acetylide from 2
with tert-butyldimethylsilyl chloride (Scheme 1).
Scheme 1. Preparation of oxygen-containing 2-bromo-1,6-enynes.
OH
H
O
O
Br
H
H
ii
i
Br
SiMe2tBu
Br
1
2
3
iii
O
O
H
H
iv
Br
Br
OH
OSiMe2tBu
4
5
Reagents and Conditions: i. NaH, propargyl bromide, THF, 0 °C, 73%; ii. n-BuLi, TBDMSCl,
THF, −78 °C, 69%; iii. n-BuLi, (CH2O)n, THF, −78 °C, 75%; iv. DMAP, imidazole, TBDMSCl,
DCM, 0 °C, 75%.

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Alkylation of the sodium enolate of dimethyl malonate generated by deprotonation with sodium
hydride, with 2,3-dibromocyclohexene 6 [37] provided the bromocyclohexenylbutyne 8 (82% yield),
which was deprotonated at the acetylene terminus with n-butyllithium and the acetylide was silylated
with tert-butyldimethylsilyl chloride to furnish 9 (58% yield) as a third cyclization precursor
(Scheme 2).
Scheme 2. Preparation of carbon-containing 2-bromo-1,6-enynes.
Reagents and Conditions: i. NaH, dimethyl malonate, DME, 0 °C, 82%; ii. NaH, propargyl
bromide, DME, 0 °C, 74%; iii. n-BuLi, TBDMSCl, THF, −78 °C, 58%, E = CO2Me.
Under cross-coupling conditions as previously employed for palladium-catalyzed cascade
co-cyclizations of 2-bromo-1-en-6-ynes and bicyclopropylidene [Pd(OAc)2, PPh3, K2CO3, MeCN, 80 °C,
5–8 h] were performed [32]. All three substrates 3, 5 and 9 furnished cross-conjugated tetraenes with
bicyclic skeletons, i.e., 11, 12 and 13, respectively, in 61%, 42% and 73% yield (Scheme 3).
Scheme 3. Formation of cross-conjugated tetraenes from 2-bromoenynes and bicyclopropylidene 10.
O
t
SiMe2 Bu
H
O
i
H
t
Br
SiMe2 Bu
+
61%
3
10
10
11
12
O
t
H
OSiMe2 Bu
O
H
i
Br
+
t
42%
OSiMe2 Bu
5
E
E
E
E
t
SiMe2 Bu
H
i
H
t
Br
SiMe Bu
+
2
73%
9
10
13
Reagents and Conditions: i. Pd(OAc)2 (10 mol %), PPh3 (30 mol %), K2CO3, MeCN, 80 °C,
12–14 h, E = CO2Me.

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Mechanistically the reactions can be explained by the following sequences; initial oxidative
addition of the bromo-ene onto a palladium(0) species, followed by the intramolecular
carbopalladation of the triple bond to give vinyl palladium moiety, then cabopalladation of
bicyclopropylidene furnish a (cyclopropylcarbynyl)palladium moiety at the intermediate which
directly undergoes a cyclopropylmethyl-to-homoallyl rearrangement to bring palladium species to
subsequent syn-β-hydride elimination stage which generates the conjugated tetraene. This corresponds
to the previous observation in that the expected 6π-electrocyclizations of such initially formed
tetraenes do not occur at 80 °C [32]. In the current case the tetraenes 11, 12 and 13 did not undergo
6π-electrocyclization to the corresponding skeletons even upon heating at 100 °C for four days in a
sealed tube.
The development of the yields in series 11, 12 and 13 corresponds to that previously observed for
another series with a similar substitution pattern [32]. The highest yield obtained for compound 13
obviously is due to the Thorpe-Ingold gem-disubstitution effect [38]. Precursors with heteroatoms in
the chain consistently give lower yields than their all-carbon atoms. Presumably, heteroatoms in the
chain may coordinate to the active metal catalyst and there by disturb the course or even alter mode of
the reaction. When treated with palladium acetate in the presence of triphenylphosphane and potassium
carbonate in N,N-dimethylformamide at 110 °C (instead of 80 °C), the bromoenynes 3, 5, 9 and
bicyclopropylidene 10 underwent the desired intra-intermolecular cascade cross-coupling with
subsequent 6π-electrocyclization to furnish the spirocyclopropanated tricycles for 16, albeit in low
yields (24%) as 1:1 mixtures of diastereomers regarding to NMR data, on the other hand of 14 and 15
were not obtained and observed clearly only trace besides not cyclized 11 and 12. (Scheme 4).
Scheme 4. One pot domino-Heck co-cyclizations and thermal 6π –electrocyclization
attemts of acyclic 2-bromo-1,6-enynes and bicyclopropylidene 10 under different contions.
Reagents and Conditions: Pd(OAc)2 (10 mol %), PPh3 (30 mol%), K2CO3, DMF, 110 °C, 12−18 h.
Presumably, molecular structural features behave main role like angular torsion-difficulty, structural
rigidity obstruct the 6π electrocyclization sequence or probably make reversible whereas scissor
(Thorpe-Ingold) effect, with TBDMS group on compound 16 case possibly force tetraenes towards the
6π electrocyclization progress under thermal condition in a polar solvent system [33,34].

Molecules 2014, 19
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3. Experimental
General Information
1H-NMR spectra were obtained with a Bruker 300 MHz DPX 300 spectrometer. Chemical shifts are
quoted as δ values in ppm downfield from tetramethylsilane. Infrared (IR) spectra were recorded on
thin films with a Perkin-Elmer 1720 spectrophotometer; Elemental analyses were carried out by
TUBITAK (The Scientific and Research Council of Turkey) Marmara Research Centre on a Thermo
Finnigan Flash EA 1112, (C, H, N). Electron impact (EI, 70 eV) ionization mass spectra were recorded
on a Finnigan MAT 95 mass spectrometer. All reagents were used as purchased from commercial
suppliers without further purification. All reactions in non-aqueous solvents were carried out using
standard Schlenk techniques under a dry nitrogen atmosphere. Solvents were purified and dried
according to conventional methods prior to use; tetrahydrofuran (THF), diethyl ether, dimethoxyethane
(DME) were distilled from sodium/benzophenone; dichloromethane was distilled from calcium hydride.
Acetonitrile and dimethylformamide were initially stirred over potassium carbonate (1 day), then over
phosphorus pentoxide (1 day) and distilled (DMF was distilled under reduced pressure) onto 3Å
molecular sieves. Reactions were monitored by thin layer chromatography (TLC) using pre-coated
silica plates (Macherey Nagel SIL G UV254). Compounds were visualized using a UV lamp, alkaline
potassium permanganate or acidic cerium(IV) sulfate solutions. Column chromatography was carried
out on Macherey Nagel Kieselgel 60 (230−240 mesh).
1-Bromo-6-prop-2-ynyloxy cyclohexene (2): 2-Bromocyclohexen-3-ol (1) [38] (2.58 g, 16 mmol) in THF
(10 mL) was added dropwise to the suspension of sodium hydride (60% in mineral oil, 0.75 g, 18 mmol)
in THF (50 mL) kept at 0 °C. The mixture was stirred at room temperature for 30 min. Subsequently,
propargyl bromide (2, 1.9 g, 16 mmol) was added dropwise at 0 °C. The mixture was stirred at room
temperature overnight. The reaction was quenched by careful addition of brine (50 mL). The aqueous
phase was extracted with diethyl ether (2 × 50 mL), the organic extracts were dried with MgSO4 and
concentrated under reduced pressure. The residue was purified by column chromatography, eluting
with pentane/diethyl ether 4:1 (Rf = 0.81), to afford 2 (2.50 g, 73%) as a pale yellow oil. IR (film):
1
3294 (CH), 2942 (CH), 2238 (CC), 1653 (C=C), 1083 and 1066 (C–O), 668 cm−1 (C-Br). H-NMR
(CDCl3): 6.20 (t, J = 3.4 Hz, 1 H), 4.25 (m, 2 H), 4.0 (m, 1 H), 2.40 (t, 1 H, J = 2.3 Hz), 2.1–1.85 (m,
13
3 H), 1.8–1.4 (m, 3 H). C-NMR (CDCl3): 134.1, 121.9 (Cquat), 79.9 (Cquat), 76.3, 74.4, 57.1, 29.3,
+
27.7, 16.8. MS (DCI, NH3): m/z (%) = 232 (M+NH4 , 100), 186 (18), 168.1 (38). C9H11BrO (215.1),
calcd. C 50.26, H 5.15; found C 50.32, H 5.10.
[3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert-butyldimethylsilane (3): n-Butyllithium (2.0 M in
hexane, 2.5 mL, 5.1 mmol) was added dropwise to a solution of 2 (1.1 g, 5 mmol) in THF (25 mL)
kept at −78 °C. The mixture was stirred at this temperature for 30 min, then tert-butyldimethylsilyl
chloride (TBDMSCl, 0.74 g, 5.07 mmol) in THF (5 mL) was added, and the mixture was stirred at
room temperature for 4 h. The reaction mixture was poured into water (30 mL), the mixture extracted
with diethyl ether (3 × 50 mL), the organic extracts were washed with brine (50 mL), dried over
MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography,
eluting with pentane/diethyl ether 9:1 (Rf = 0.73), to afford 3 (1.15 g, 69%) as a light yellow oil. IR

Molecules 2014, 19
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1
(film): 2952 (CH), 2857 (CH), 2173 (CC), 1645 (C=C), 1083 (C–O), 684 cm−1 (CBr). H-NMR
(CDCl3): 6.2 (t, 1 H, J = 3.4 Hz), 4.25 (d, 2 H J = 4.7 Hz), 4.05 (t, 1 H, J = 3.2 Hz), 2.1 (m, 3 H), 1.8–1.5
(m, 3 H), 0.9 (s, 9 H), 0.0 (s, 6 H). 13C-NMR (CDCl3): 133.9, 121.2 (Cquat), 102.4 (Cquat), 89.7 (Cquat),
75.9, 57.3, 29.3 (3×C), 27.8, 26.0, 16.8, 16.5, −4.7 (2×C). MS (DCI, NH3): m/z (%) = 348.3 (M+NH+,
+
100), 346 (M+NH4 , 98), 282.4 (15), 162.1 (25). C15H25BrOSi (329.3): calcd. C 54.70, H 7.65; found
C 54.72, H 7.75.
4-(2-Bromocyclohex-2-enyloxy)but-2-yn-1-ol (4): n-Butyllithium (1.8 M in hexane, 3.9 mL, 6.98 mmol)
was added dropwise to a solution of 1-bromo-6-prop-2-ynyloxy-cyclohexene (2, 1.5 g, 6.98 mmol)
in THF (50 mL) kept at −78 °C. The mixture was stirred at this temperature for 30 min, then
paraformaldehyde (1.03 g, 32.3 mmol) in THF (10 mL) was added, and the mixture was stirred at
room temperature for 4 h. The reaction mixture was poured into water (30 mL), the mixture extracted
with diethyl ether (3 × 75 mL). The organic extracts were washed with brine (75 mL), dried over
MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography,
eluting with pentane/diethyl ether 4:1 (Rf = 0.24), to afford 4 (1.33 g, 75.0%) as a light yellow oil. IR
(film): 3402 (O–H), 2936 (CH), 2856 (CH), 2239 (CC), 1669 (C=C), 1024 (C–O), 668 cm−1 (CBr).
1H-NMR (CDCl3): 6.2 (t, J = 3.4 Hz, 1 H), 4.3 (m, 4 H), 4.0 (t, J= 3.2 Hz, 1 H), 2.1–2.0 (m,
13
3 H), 1.8–1.5 (m, 4 H). C-NMR (CDCl3): 134.1, 121.5 (Cquat), 114.8, 84.5 (Cquat), 82.1 (Cquat), 57.4,
+
+
51.2, 29.3, 27.2, 16.8. MS (DCI, NH3): m/z (%) = 264.2 (M+NH4 , 98), 262.2 (M+NH4 , 100), 180.2
(60%). C10H13BrO2 (245.1): calcd. C 49.00, H 5.35; found C 49.08, H 5.30.
[4-(2-Bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert-butyldimethylsilane (5): N,N-Dimethyl-
aminopyridine (0.18 g, 1.5 mmol) and imidazole (0.52 g, 7.5 mmol) were added to a stirred solution of
4 (1.2 g, 5 mmol) in CH2Cl2 (25 mL) kept at 0 °C, and the mixture was stirred for 15 min.
tert-Butyldimethylsilyl chloride (1.13 g, 7.6 mmol) was added in small portions, and the mixture was
stirred at room temperature for 12 h. The reaction mixture was poured into water (50 mL) and the
aqueous mixture extracted with diethyl ether (3 × 50 mL). The organic extracts were dried over
Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography,
eluting with pentane/diethyl ether 4:1 (Rf = 0.73), to afford 5 (1.33 g, 75%) as a colorless oil. IR (film):
1
2951 (CH), 2857 (CH), 2246 (CC), 1653 (C=C), 1086 and 1063 (C–O), 668 cm−1 (C-Br). H-NMR
(CDCl3): 6.2 (t, J = 3.4 Hz, 1 H), 4.3 (m, 4 H), 4.0 (t, J = 3.3 Hz, 1 H), 2.1–2.0 (m, 3 H), 1.8–1.4 (m,
3 H), 0.9 (s, 9 H), 0.1 (s, 6 H). 13C-NMR (CDCl3): 133.9, 129.4, 122.2 (Cquat), 114.8, 84.9 (Cquat), 80.9
(Cquat), 71.4, 56.0, 51.7, 29.3 (3×C), 18.3 (Cquat), −5.6 (2×C). MS (DCI, NH3): m/z (%) = 378
+
+
(M+NH4 , 100), 376 (M+NH4 , 98), 262.2 (20). C16H27BrO2Si (359.4): calcd. C 53.47, H 7.57; found
C 53.41, H 7.61.
Dimethyl 2-(2-Bromocyclohex-2-enyl)malonate (7) [35]: Dimethyl malonate (5.3 g, 40.3 mmol) was
added to a suspension of sodium hydride (0.9 g, 37 mmol) in freshly distilled DME (100 mL) kept at 0 °C.
The mixture was stirred for an additional 15 min after the gas evolution had ceased.
2,3-Dibromocyclohexene (6) [11a] (8.8 g, 36.7 mmol) was added dropwise, and the mixture was
stirred at room temperature for 4 h. The reaction mixture was slowly poured into water (250 mL), the
aqueous mixture extracted with diethyl ether (3 × 150 mL). The organic extracts were dried over

Molecules 2014, 19
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MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography,
eluting with pentane/diethyl ether 9:1 (Rf = 0.27), to afford 7 (8.70 g, 82%) as a colorless oil. IR (film):
2952 (CH), 2856 (CH), 1636 (C=C), 1210 and 1024 cm−1 (C–O). 1H-NMR (CDCl3): 6.2 (td, J = 3.4 Hz,
J = 1.7 Hz, 1 H), 4.0 (d, J = 5.4 Hz, 1 H), 3.7 (s, 6 H), 3.2 (m, 1 H), 2.1 (m, 4 H), 1.6 (m, 2 H). 13C-NMR
(CDCl3): 169.0 (Cquat), 168.3 (Cquat), 133, 123.3 (Cquat), 54.0, 52.6, 52.3, 42.3, 27.5, 26.6, 19.9. MS
+
+
+
(DCI, NH3): m/z (%) = 600.5, (2M+NH4 , 5), 310.3 (M(81Br)+NH4 , 100), 308 (M(79Br)+NH4 , 98),
244.3 (20), 211.3 (10%). C11H15BrO4 (291.1): calcd. C 45.38; H 5.19; found C. 45.42, H 5.07.
Dimethyl-2-(2-Bromocyclohex-2-enyl)-2-prop-2-ynyl-malonate (8): A solution of compound 7,
(4.0 g, 13.75 mmol) in DME (10 mL) was added dropwise to a suspension of sodium hydride (60% in
mineral oil, 0.4 g, 16.6 mmol) in DME (50 mL) at 0 °C. The mixture was stirred at room temperature
for 30 min. Subsequently, propargyl bromide (1.66 g, 14 mmol) was added dropwise at 0 °C. The
reaction mixture was stirred at room temperature overnight, then it was poured into brine (75 mL) and
the aqueous mixture extracted with diethyl ether (3 × 75 mL). The organic extracts were dried over
MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography,
eluting with pentane/diethyl ether 4:1 (Rf = 0.24), to afford 8 (3.34 g, 74.0%) as a colorless oil. IR
(film): 2953 (CH), 2930 (CH), 2857 (CH), 2179 (CC), 1739 (C=O), 1635 (C=C), 1206 (C–O), 682 cm−1
1
(C-Br). H-NMR (CDCl3): 6.2 (dt, J = 1.7 Hz, J = 3.4 Hz, 1 H), 3.8 (s, 6 H, OMe), 3.6 (m, 1 H), 3.1
(dd, J = 2.7 Hz, J = 17.0 Hz, 1 H), 2.9 (dd, J = 2.7 Hz, J = 17.0 Hz, 1 H), 2.1 (m, 3 H), 1.9 (m, 2 H),
1.7–1.6 (m, 2 H). 13C-NMR (CDCl3): 169.9 (Cquat), 169.5 (Cquat), 135.3, 121.8 (Cquat), 80.5 (Cquat),
+
70.8, 60.4, 52.8, 52.7, 45.8, 27.5, 27.2, 23.1, 20.7. MS (DCI, NH3): m/z (%) = 348.3 (M+NH4 , 100),
+
346 (M+NH4 , 98), 331.2 (M+H+, 15), 329 (M+H+, 14). C14H17BrO4 (329.2): calcd. C 51.08, H 5.21;
found C 51.16, H 5.20.
Dimethyl-2-(2-Bromocyclohex-2-enyl)-2-[3-(t-butyldimethylsilanyl)prop-2-ynyl]malonate (9) n-Butyl-
lithium (2.5 M in hexane, 1.36 mL, 3.4 mmol) was added dropwise to a solution of 8 (1.12 g,
3.46 mmol) in THF (30 mL) kept at −78 °C. The mixture was stirred at this temperature for 30 min,
then tert-butyldimethylsilyl chloride (0.53 g, 3.4 mmol) in THF (5 mL) was added, and the mixture
was stirred at room temperature for 4 h. The reaction mixture was poured into water (75 mL), the
aqueous mixture was extracted with diethyl ether (3 × 50 mL) and washed with 50 mL brine. The
organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was
purified by column chromatography, eluting with pentane/diethyl ether 4:1 (Rf = 0.44), to afford 9
(0.90 g, 58.0%) as a light yellow oil. IR (film): 2952 (CH), 2858 (CH), 2179 (CC), 1736 (C=O), 1679
1
(CC), 1093 (C–O), 659 cm−1 (CBr). H-NMR (CDCl3): 6.2 (t, J = 3.4 Hz, 1 H), 3.8 (s, 6 H), 3.6 (m,
1H), 3.2 (d, J = 17 Hz, 1 H), 2.8 (d, J = 17 Hz, 1 H), 2.0 (m, 4 H), 1.6 (m, 2 H), 0.9 (s, 9 H), 0.0 (s,
13
6 H). C-NMR (CDCl3): 170.1 (Cquat), 169.8 (Cquat), 135.1, 122.0 (Cquat), 103.4 (Cquat), 85.7 (Cquat),
52.7 (Cquat), 52.6, 45.9, 27.5, 27.3 (3xC), 25.9, 24.5, 22.3, 20.5, 16.5, –4.6 (2xC). MS (DCI, NH3): m/z
+
+
(%) = 904.7 (2M+NH4 , 100), 460.4 (M+NH4 , 10), 445.3 (M (81Br) + H+, 98), 443.3 (M(79Br)+H+,
96), 363.4 (90). C20H31BrO4Si (443.4): calcd. C 54.17, H 7.05; found C 54.44, H 7.06.
GP1: General Procedure for the Palladium-Catalyzed Cocyclization of 2-Bromo-1,6-enynes and
Bicyclopropylidene (10) to Yield Tetraenes: Palladium acetate (11.2 mg, 49.9 µmol, 10 mol %),

Molecules 2014, 19
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triphenylphosphane (39.3 mg, 150 µmol, 30 mol %) and potassium carbonate (138 mg, 998 µmol)
were suspended in anhydrous acetonitrile (5 mL) in a screw-cap Pyrex bottle. The respective
bromoenyne (0.5 mmol) was added and argon gas was bubbled through the mixture for 5 min. Then
bicyclopropylidene 10 (80 mg, 1 mmol) was added, the bottle was tightly closed, and the mixture
heated in a preheated oil bath at 80 °C for the given period of time. After cooling down to room
temperature, the reaction mixture was taken up in diethyl ether (10 mL), the mixture filtered through a
pad of Celite (5 cm) and the solvent evaporated in vacuo to leave about 1 mL. The crude product was
purified by flash column chromatography on silica gel, eluting with pentane/diethyl ether.
GP2: General Procedure for the Palladium-Catalyzed Cocyclization of 2-Bromo-1,6-enynes and
Bicyclopropylidene (10) with Subsequent 6π-Electrocyclization: Palladium acetate (11.2 mg,
49.9 µmol, 10 mol %), triphenylphosphane (39.3 mg, 150 µmol, 30 mol %) and potassium carbonate
(138 mg, 998 µmol) were suspended in anhydrous DMF (5 mL) in a screw-cap Pyrex bottle. The
respective bromoenyne (0.5 mmol) was added and argon gas was bubbled through the mixture
for 5 min. Then bicyclopropylidene 10 (80 mg, 1 mmol) was added, the bottle was tightly closed, and
the mixture was heated at 110 °C in a preheated oil bath for the given period of time. After cooling
down to room temperature, the reaction mixture was directly added onto a pre-packed column of silica
gel and the column eluted with pentane/diethyl ether.
tert-Butyl-[2-cyclopropylidene-1-(5,6,7,7a-tetrahydrobenzofuran-3-ylidene)but-3-enyl]dimethylsilane (11):
Treatment of compound 3, (165 mg, 0.5 mmol) and bicyclopropylidene (10, 80 mg, 1 mmol) according
to GP1 for 12 h gave 11. Purification by column chromatography, eluting with pentane/diethyl ether
9:1 (Rf = 0.43), gave a compound 11 (100 mg, 61%) as a yellow oil. IR (film): 3055 (CH), 2954 (CH),
1
2931 (CH), 2858 (CH), 1653 (C=C), 1036 cm−1 (C–O). H-NMR (CDCl3): 6.5 (dd, J = 17.8 Hz,
J = 10.5 Hz 1 H), 5.8 (t, J = 3.5 Hz, 1 H), 5.0 (dd, J = 1.9 Hz, J = 11.5 Hz 1 H), 4.9 (dd, J = 1.9 Hz,
J = 11.5 Hz 1 H), 4.6 (dd, 1 H), 4.4 (dd, J = 2.4 Hz, J = 12.9 Hz, 1 H), 4.0 (m, 1 H), 2.15 (m, 2 H), 2.8
(m,1 H), 1.4–1.0 (m, 6 H, Cpr + 2 H), 0.9 (s, 9 H), 0.0 (s, 6 H). 13C-NMR (CDCl3): 148.2 (Cquat), 138.6
(Cquat), 136.4, 132.7 (Cquat), 128.3 (Cquat), 123.6 (Cquat), 123.3, 113.6, 78.2, 72.6, 28.4, 27.8 (3xC), 26.3,
+
20.0, 18.7 (Cquat), 4.21, 2.76, −3.4 (2xC). MS (DCI, NH3): m/z (%) = 674.7 (2M+NH4 , 15), 346.4
(M+NH4+, 25), 329.4 (M+H+, 60), 251.3 (100). C21H32OSi (328.6): calcd. C 76.77, H 9.82; found
76.61, H 9.86.
tert-Butyl-[3-cyclopropylidene-2-(5,6,7,7a-tetrahydrobenzofuran-3-ylidene)pent-4-enyloxy]dimethylsilane
(12): Treatment of compound 5, (179 mg, 0.5 mmol) and bicyclopropylidene (10, 80 mg, 1 mmol)
according to GP1 for 12 h gave 12. Purification by column chromatography, eluting with a
pentane/diethyl ether 10:1 (Rf = 0.51) gave the title compound 12 (64 mg, 42%) as a yellow oil. IR
(Film): 2952 (CH), 2856 (CH), 1686 (C=C), 1018 cm−1 (C–O). 1H-NMR (CDCl3): 6.5 (dd, J = 17.8 Hz
J = 10.5 Hz, 1 H), 6.1 (m, 1 H), 5.0 (m, 2 H), 4.4 (m, 2 H), 4.0 (m, 2 H), 2.2 (m, 2 H), 2.0–1.8 (m, 2 H),
13
1.6–1.4 (m, 4 H, Cpr), 1.2 (m, 2 H), 0.9 (s, 9 H), 0.0 (s, 6 H). C-NMR (CDCl3): 140 (Cquat), 138.7
(Cquat), 136.6 (Cquat), 128.1, 124.5, 122.2 (Cquat), 115.3, 70.1 (Cquat), 66.4, 46.0, 30.1, 29.7, 27.2 (3xC),
22.1, 20.8, 18.7 (Cquat), 10.1, 8.3, −4.0 (2xC). MS (DCI, NH3): m/z (%) = 298.4 (100), 227.2 (25), 149.2
(55). C22H34O2Si (326.6): calcd. C 73.69, H 9.56; found C 73.73, H 9.58.

Molecules 2014, 19
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Dimethyl 3-[1-(tert-Butyldimethylsilyl)-2-cyclopropylidenebut-3-en-1-ylidene]-2,3,5,6,7,7a-hexahydro-1H-
indene-1,1-dicarboxylate (13): Treatment of compound 9 (222 mg, 0.5 mmol) and bicyclopropylidene
(10, 80 mg, 1 mmol) according to GP1 for 14 h, after purification by column chromatography, eluting
with pentane/diethyl ether 9:1 (Rf = 0.36) gave 13 (162 mg, 73%) as a yellow oil. IR (film): 3054
1
(CH), 2953 (CH), 2857 (CH), 2739, 2708, 1734 (C=O), 1653 (C=C), 1093 cm−1 (C–O). H-NMR
(CDCl3): 6.5 (dd, J = 17.8 Hz, J = 10.5 Hz 1 H), 6.0 (t, J = 3.4 Hz, 1 H), 5.10 (dd, J = 1.9 Hz, J = 11.5 Hz,
1 H), 5.0 (dd, J = 1.9 Hz, J = 11.5 Hz, 1H ), 3.8 (s, 6 H, OCH3), 3.2 (t, J = 6.2 Hz, 1 H), 3.0 (m,
1 H), 2.8 (d, J = 16.2 Hz, 1 H), 2.0 (m, 2H), 1.6 (m, 2 H), 1.4 (m, 2 H), 1.2–1.0 (m, 4 H, Cpr), 0.9 (s,
13
9 H), 0.0 (s, 6 H). C-NMR (CDCl3): 172.2 (Cquat), 170.7 (Cquat), 147.6 (Cquat), 138.7 (Cquat), 137.8
(Cquat), 133.4 (Cquat), 131.3 (Cquat), 125.5, 124.9 (Cquat), 113, 6, 60.8, 52.5, 51.8, 47.2, 42.4, 28.1 (3xC),
+
26.4, 25.9, 21.8, 18.9 (Cquat), 4.09, −3.1 (2xC), 2.5. MS (DCI, NH3): m/z (%) = 905 (2M+NH4 , 18),
+
460.5 (M+NH4 , 100), 443.5 (M+H+, 60%), 347.4 (68), 327.2 (18), 300.2 (20). C26H38O4Si (442.7):
calcd. C 70.55, H 8.65; found C 70.48, H 8.72.
Dimethyl
3-(tert-Butyldimethylsilyl)-4-ethenyl-6,7,8,8a-tetrahydro-1H-spiro[acenaphthylene-5,1'
cyclopropane]-1,1-(2H,5aH)dicarboxylate (16): Treatment of compound 9 (222 mg, 0,5 mmol) and
bicyclopropylidene 10 (80 mg, 1 mmol) according to GP2 for 12 h, after purification by column
chromatography, eluting with pentane/diethyl ether 10:1 (Rf = 0.32) gave 16 (53 mg, 24%) as pale
yellow oil. IR (film): 2952 (CH), 2856 (CH), 1734 (C=O), 1654 (C=C), 1251, 1055 cm−1 (C–O).
1H-NMR (CDCl3): 6.1 (dd, J = 17.8 Hz, J = 11.5 Hz, 1 H), 5.8 (dd, J = 2.0 Hz, J = 11.5 Hz, 1 H), 4.8
(dd, J = 2.0 Hz, J = 11.5 Hz, 1 H), 3.8 (m, 1 H), 3.7 (s, 6 H), 3.0 (d, J = 2.6 Hz, 1 H), 2.82 (d,
J = 2.6 Hz, 1 H), 2.1 (brm, 1 H), 1.8 (m, 2 H), 1.6 (m, 2 H), 1.2 (m, 2 H), 0.9 (s, 9 H), 0.6–0.3 (m, 4 H,
13
Cpr), 0.0 (s, 6 H). C-NMR (CDCl3): 172.7 (Cquat), 170.7 (Cquat), 152.0 (Cquat), 139.2 (Cquat), 136.0,
128.2 (Cquat), 125.8 (Cquat), 119.1, 61.8 (Cquat), 52.6, 52.2, 45.5, 43.2, 34.1, 30.5, 27.8, 27.5 (3xC), 26.8,
+
21.4 (Cquat), 19.2 (Cquat), 16.3, 14.5,
̶
4.0 (2xC). MS (DCI, NH3): m/z (%) = 460.5 (M+NH4 , 82),
459.5 (M-H+NH4 , 100), 443.5 (M+H+, 60), 365.4 (85), 177.2 (85). C26H38O4Si (442.7): calcd. C
+
70.55, H 8.65; found C 70.54, H 8.65.
4. Conclusions
The new 2-bromo-2-en-6-ynes 3, 5 and 9 each containing a bromocyclohexene initiator, like
the previously investigated completely acyclic analogues, [32] undergo palladium-catalyzed
intra-intermolecular cascade cross coupling reactions in the presence of bicyclopropylidene 10 to give
indene analogues, conjugated tetraenes, 11, 12, 13 (in MeCN at 80 °C). The reaction, under different
conditions (in dimethylformamide at 110 °C) the desired spirocyclopropanated tricycle 16 was
obtained albeit in low yield (24%) and observed as an equimolar mixture of diastereomers, whereas
others 14, 15 were not fully isolated. Although the yield of spirocyclopropanated tricycle 16 was rather
disappointing, the concept of the 6π-electrocyclizations proved to be feasible on less strained
compounds. Additionally, an alternative palladium-mediated process rather than its free radical version
we studied before [33–35] give indene skeletons with higher yield.

Molecules 2014, 19
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Acknowledgments
Author would like to thank to Armin de Meijere all for his support and proofreading. This work was
also supported by The Scientific and Technological Research Council of Turkey (TUBITAK-2219).
A. D. is indebted to TUBITAK for a travel grant and research fellowship to perform some experimental
work in the laboratory of Armin de Meijere at the Georg-August-Universität Göttingen, Germany.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds data are available from the authors.
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