Ring-Closing Enyne Metathesis of Terminal Alkynes with Propargylic Hindrance

Article abstract of DOI:10.1021/acs.joc.5b00659

The ring closing enyne metathesis of substrates with propargylic hindrance was investigated, revealing the successful combination of the Stewart-Grubbs catalysts and microwave heating sometimes up to 170 C for oxacycles. Medium-sized rings were obtained from terminal alkynes previously reputed as reluctant substrates. This unmatched combination was applied to the synthesis of carbocycles and oxacycles. In addition, this is the first report on the use of the Stewart Grubbs catalyst in ring closing enyne metatheses. (Figure Presented).

Full text of DOI:10.1021/acs.joc.5b00659

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Ring-closing enyne metathesis of terminal alkynes with propargylic hindrance
Benjamin Laroche, Morgane Detraz, Alain Blond, Lionel Dubost, Patrick Mailliet, and Bastien Nay
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00659 • Publication Date (Web): 20 Apr 2015
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Ring-closing enyne metathesis of terminal alkynes with propargylic hindrance
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Benjamin Laroche,a Morgane Detraz,a Alain Blond,a Lionel Dubost,a Patrick Mailliet,b Bastien
Naya,*
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a
Unité Molécules de Communication et Adaptation des Microꢀorganismes, Sorbonne
Universités, Muséum National d'Histoire Naturelle, Centre National de la Recherche Scientifique
(CNRS UMR 7245), 57 rue Cuvier (CP 54), 75005 Paris, France
b
Unité Structure et instabilité des génomes, Sorbonne Universités, Muséum National d'Histoire
Naturelle, Centre National de la Recherche Scientifique (CNRS UMR 7196), Institut National de
la Santé et de la Recherche Médicale (INSERM U 1154), 57 rue Cuvier (CP 26), 75005 Paris,
France
* Corresponding author: bnay@mnhn.fr (Dr. Bastien Nay)
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Abstract
The ring closing enyne metathesis of substrates with propargylic hindrance was investigated,
revealing the successful combination of the StewartꢀGrubbs catalysts and microwave heating
sometimes up to 170 °C for oxacycles. Mediumꢀsized rings were obtained from terminal alkynes
previously reputed as reluctant substrates. This unmatched combination was applied to the
synthesis of carbocycles and oxacycles. In addition this is the first report on the use of the
Stewart Grubbs catalyst in ring closing enyne metatheses.
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Ringꢀclosing enyne metathesis (RCEYM) is a powerful synthetic tool compatible with a wide
range of substrates for the preparation of ringꢀembedded 1,3ꢀdienes and highly functionalized
chemical entities.1 To perform such transformations, the first and second generations Grubbs (1,
2) and HoveydaꢀGrubbs (3, 4) catalysts have been routinely used (Figure 1). Yet in some cases,
the efficiency of these nowadays classical catalysts can be limited, particularly when hindered
substrates are implemented.2 This may discourage the use of this methodology in synthetic
strategies where hindered alkynes are required.
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Figure 1. Structure of some ruthenium-based metathesis catalysts used in this study (in
total, fourteen catalysts were tested, the structures of which are provided in Figure S1).
With olefin metatheses, this problem has been solved by the use of less hindered ruthenium
catalysts compatible with sterically crowded olefins, either for ringꢀclosing or cross metathesis.
Grubbs and coꢀworkers developed an oꢀtolyl substituted catalyst (6) and reported its efficiency
towards the formation of tetrasubstituted olefins by RCM.3 They also highlighted cross
metathesis improvement when this catalyst was used for the formation of disubstituted olefins
containing one or more allylic substituents.4 The drawbacks associated to the RCEYM of
alkynes with hindered propargylic positions2 compelled us to test catalyst 6 in this
transformation. Curiously the use of 6 in RCEYM has never been reported in the literature even
if it was previously found effective, along with other catalysts drawn in Figure 1, in enyne crossꢀ
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metathesis with strained geminallyꢀsubstituted alkenes.5 Herein, we report the efficacy of the oꢀ
tolyl substituted StewartꢀGrubbs catalyst 6 when combined to microwave heating for the
RCEYM of substrates hindered at the propargylic position, leading to the synthesis of
carbocyclic and oxacyclic 1,3ꢀdienes.
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RCEYMs toward sevenꢀmembered rings (9aꢀc) were first investigated in the course of a natural
product synthesis.6 After having synthesized the 1,8ꢀenyne substrates 8aꢀc (Scheme 1) in two
steps from 4ꢀpentenal,7 RCEYMs were attempted in a wide range of conditions, including the
use of an ethylene atmosphere (Mori’s conditions)8 which only resulted in the formation of
acyclic dienes (10). Most of the fourteen commercially available catalysts which were screened
in this preliminary study (see the Supporting information for a complete list, Figure S1) proved
unsuccessful with the exception of a few of them. This initial screening was performed with a 5
mol% catalyst loading and resulted in the selection of the five catalysts 2, 4, 5, 6 and 7 (Figure
1), respectively providing 8, 6, 38, 38 and 4% of partial conversion9 of enyne substrate 8c (R =
TBS) into cycloheptene 9c, when running the reaction in toluene at 80°C during 48 h with
complete exo regioselectivity. With 6, increasing catalyst loading to 10 mol% only resulted in a
slightly better conversion rate of 42% for 9c. Under similar conditions at 5 mol% catalyst, the
tertiary alcohol 8a was unreactive and the acetate 8b only poorly reactive, giving 9b in 7, 10 and
5% yields with catalysts 5, 6 and 7, respectively (2 and 4 did not induce any reaction with 8a and
8b), and showing at this stage a slight superiority of the oꢀtolyl substituted StewartꢀGrubbs
catalysts with this propargylic acetate.
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conditions
(see text)
OR
5
OR
OR
6
10
when running the reaction in
an ethylene atmosphere
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8a: R = H
8b: R = Ac
8c: R = TBS
9a: R = H
9b: R = Ac
9c: R = TBS
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Scheme 1. RCEYM toward vinylcycloheptenes 9a-c from enynes substrates 8a-c.
Less bulky NHCꢀsubstituants like L3 (Figure 1) have demonstrated their utility to improve
catalyst reactivity towards hindered substrates in olefin metathesis.3,4 In fact, structural studies on
catalyst 6 showed that the Nꢀaryl rings are bearing both methyl substituents on the more
sterically accessible face. The methyls are squeezed out, thus opening the space near the
ruthenium center and enhancing the reactivity of the catalyst toward sterically demanding
substrates.10 With compound 8c, this would favor the coordination of ruthenium by the hindered
alkyne (AꢀA', yneꢀfirst mechanism, Scheme 2) or ring closing after alkylidene formation with
the alkene (BꢀB', eneꢀfirst mechanism), which would not be possible with an Nꢀmesityl NHC
ligand on ruthenium (A'', B'').
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Scheme 2. A steric model to explain the reactivity of 6 with hindered enynes (grey arrows
figure out methyls drawn aside).
Yet, dealing with the yield obstacle, the use of microwave irradiation, constituting an attractive
alternative to conventional heating,11,12 was rapidly envisaged in this study. In many cases,
microwaves have been shown to dramatically reduce reaction times, increase product yields and
purity by preventing side reactions. The outstanding benefit provided with microwaves for olefin
metathesis has been well reviewed,13 while examples of microwaveꢀassisted enyne metathesis
also demonstrated their indisputable effect in RCEYM.14,15 The TBSꢀprotected substrate 8c was
therefore gambled into microwave irradiations. Gratifyingly, performing the reaction in toluene
at 120 °C under microwave (850 W) for 1h in presence of 10 mol% of the selected catalysts 2, 4,
6, 5 and 7 dramatically enhanced the reaction yields and reaction times (Table 1). It is worth
noting that the best yields were still obtained with the oꢀtolyl substituted catalysts 5 and 6
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(entries 3 and 4), confirming our previous observations, with the StewartꢀGrubbs catalyst 6 being
the most efficient, affording diene 9c in 88% isolated yield (entry 4). Comparatively, the second
generation Grubbs (2 and 4) and Zhanꢀ1B (7) catalysts only provided low yields between 13 and
24% (entries 1, 2 and 5). In addition, the more challenging acetate substrate 8b could also be
converted into diene 9b in a reasonable 55% yield, yet in the presence of 15 mol% of the
StewartꢀGrubbs catalyst 6 (entry 10). This successful combination of a microwave facility and oꢀ
tolyl substituted ruthenium catalysts (5 and 6) on the RCEYM of challenging substrates would
thus allow the swift access to highly functionalized dienes in excellent yields and purity. To
extend the scope of these conditions, the methodology was applied to the synthesis of small to
mediumꢀsized rings in the carbo– and oxacycle series.
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Table 1. RCEYM of enynes 8b and 8c into cycloheptenes 9b and 9c under microwave
conditions (see Scheme 1).
Entry
Catalysta
Substrateb
Conditions
Yields (%)
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2
3
4
5
6
7
8
9
8c (R = TBS)
8c (R = TBS)
8c (R = TBS)
8c (R = TBS)
8c (R = TBS)
8c (R = TBS)
8c (R = TBS)
8b (R = Ac)
8b (R = Ac)
120 °C, MW, 1h
120 °C, MW, 1h
120 °C, MW, 1h
120 °C, MW, 1h
120 °C, MW, 1h
80 °C (oil bath), 2d
13
24
79
88
17
33
2
4
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6
7
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6
2
4
120 °C (sealed tube), 1h 48
120 °C, MW, 1h
120 °C, MW, 1h
<1
<1
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8b (R = Ac)
120 °C, MW, 1h
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a Catalyst loading: 10 mol% except Entry 10: 15 mol%; b Concentration: 0.03 M in toluene.
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As depicted in Table 2, the synthesis of various carbocycles was achieved and allowed
comparing the reactivity of catalysts 2 and 4 with the lessꢀhindered one 6 under our optimized
conditions. The reactions ran through in every case with these three catalysts. For terminal
alkynes 8c, 11 and 12 (entries 1ꢀ3), the best yields were observed for 5ꢀ (14) and 7ꢀmembered
(9c) carbocycles with the StewartꢀGrubbs catalyst 6, again showing its versatility. With the
propynyl derivative 13 (R = Me, entry 4), 6 did not bring a real advantage compared to 2 and 4,
as expected from the existing literature on the reactivity of propynyl substrates, especially in the
oxacycle series.16 The scope of this RCEYM was extended to oxacycles 21ꢀ24 with
monosubstituted alkynes 17ꢀ20, showing again the advantage of 6 when a propargylic hindrance
is present (Table 3). In addition to providing good to excellent yields, the combination of catalyst
6 and microwave heating at 170 °C allowed for the first time the access to a eightꢀmembered
oxacyclic diene (23) by RCEYM from a terminal alkyne17 with a yield of 63% (entry 3, n = 4)
strikingly contrasting with the results obtained with 2 and 4. Even though these results could not
be transposed to the formation of a nineꢀmembered ring like 24 (entry 4, n = 5), this tremendous
reactivity confirmed the efficacy of the StewartꢀGrubbs catalyst 6 for the microwaveꢀassisted
RCEYM of hindered substrates in the oxacycle series.
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Table 2. Synthesis of various carbocycles through RCEYM involving catalysts 2, 4 and 6.
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Entry
n
R
Product
Yield per cat. (%)
2
4
6
1
2
3
4
1 (11)
2 (12)
3 (8c)
3 (13)
H
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68
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9c
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H
H
Me
Table 3. Synthesis of various oxacycles through RCEYM involving catalysts 2, 4 and 6.
Entry
n
Product
T (°C)
Yield per catalyst (%)a
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4
6
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4
1 (17)
3 (18)
4 (19)
5 (20)
120
170
170
170
42
55
28
n.r.
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64
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n.r.
95
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63
n.r.
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a n.r.: no reaction.
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In summary, we have investigated the application of RCEYM to alkyne substrates with steric
hindrance at the propargylic position. The conversion into the corresponding vinyl cycloalkenes
was achieved with exclusive exo selectivity by combining the attractive reactivity of the Stewartꢀ
Grubbs catalyst 6 with microwave irradiations. This method was extended to the synthesis of
carbocycles and oxacycles and in most cases demonstrated its superiority by comparison with
other available catalysts, while in the worst case, the catalyst showed equivalent efficacy as 2
and 4. Consequently, we suggest that these conditions could be generalized as firstꢀtoꢀuse with
such hindered alkynes.
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EXPERIMENTAL SECTION
General information
All reactions were carried out in ovenꢀdried reaction vessels under an atmosphere of argon and in
anhydrous solvents. Reactions under microwave conditions were carried out in an Anton Paar
Microwave 300 apparatus (850) equipped with an infrared external temperature sensor and a
stirrer. Reactions and purifications were monitored by TLC on silica gel 60 F254 aluminum,
using UV absorption then vanillin–H2SO4 (1% vanillin in ethanol + 2% H2SO4) as staining
system. The products were purified by flash chromatography on silica gel Si 60, 40–63 ꢁm.
NMR spectra were recorded on 400 MHz and 600 MHz spectrometers. Chemical shifts (δ) are
quoted in ppm with internal calibration from the residual solvent peak (CHCl3: 7.27, 77.0 ppm
for 1H and 13C NMR, respectively). All coupling constants (J) are quoted in Hertz. The following
abbreviations are used to designate multiplicities: s = singlet, d = doublet, t = triplet, q =
quadruplet, m = multiplet, br = broad. High resolution mass spectra (HRMS) of synthesized
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compounds were measured on a QqꢀToF spectrometer using electrospray ionization (ESI).
Infrared spectra were recorded on a FTIR spectrometer. The following compounds used in this
study where prepared according to the literature: tertꢀbutyldimethyl[(4ꢀmethyldecaꢀ9ꢀenꢀ2ꢀynꢀ4ꢀ
yl)oxy]silane (13),20 heptꢀ6ꢀenꢀ2ꢀone,21 3ꢀphenylbutꢀ1ꢀynꢀ3ꢀol,22 [3ꢀ(allyloxy)butꢀ1ꢀynꢀ3ꢀ
yl]benzene (17),23 [3ꢀ(pentꢀ4ꢀenꢀ1ꢀyloxy)butꢀ1ꢀynꢀ3ꢀyl]benzene (18),22 [3ꢀ(hexꢀ5ꢀenꢀ1ꢀ
yloxy)butꢀ1ꢀynꢀ3ꢀyl]benzene (19).22
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3-Methylnon-8-en-1-yn-3-ol (8a). To a solution of octꢀ7ꢀenꢀ2ꢀone18,19 (114.8 mg, 0.91 mmol) in
THF (10 mL) was added sodium acetylide (18% slurry in xylene, 0.56 mL, 1.82 mmol) and the
mixture was stirred at room temperature for 16h. The reaction mixture was slowly quenched
using a saturated aqueous solution of NH4Cl (8 mL), extracted with Et2O (3x10 mL), washed
with brine (10 mL) and concentrated under reduced pressure. The crude material was purified by
chromatography on silica gel (pentane/ether 8:2), to afford 8a as a pale yellow liquid (123.6 mg,
1
89%). H NMR (400 MHz, CDCl3): δ 1.39–1.59 (m, 7H), 1.64–1.71 (m, 2H), 1.84 (brs, 1H),
2.05–2.13 (m, 2H), 2.43 (s, 1H), 4.91–5.06 (m, 2H), 5.75–5.88 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 24.1, 29.0, 29.7, 33.7, 43.3, 68.1, 71.3, 87.7, 114.5, 138.8. IR (NaCl): ν = 3391, 3078,
2978, 2936, 2858, 2110, 1643, 1373, 1265, 910, 741 cm–1. HRMS (ESI+) m/z calc. for C10H15
[M–OH–]+ 135.1168; found: 135.1164.
3-Methylnon-8-en-1-yn-3-yl acetate (8b). To a solution of octꢀ7ꢀenꢀ2ꢀone18,19 (1 g, 7.92 mmol) in
THF (79 mL) was added sodium acetylide (18% slurry in xylene, 7.33 mL, 23.8 mmol) and the
mixture was stirred at room temperature for 16h. The reaction mixture was quenched using
acetic anhydride (2.25 mL, 15.85 mmol) while the mixture turned from yellow to white and was
stirred 30 min at room temperature until complete conversion. Water (50 mL) was then added
and the mixture was extracted with Et2O (3x50 mL), washed with brine (50 mL), dried over
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MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel
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chromatography (pentane/ether 95:5), to afford 8b as a colorless liquid (1.34 g, 87%). H NMR
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8
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(400 MHz, CDCl3): δ 1.37–1.57 (m, 4H), 1.67 (s, 3H), 1.76–2.00 (m, 2H), 2.03 (s, 3H), 2.04–
2.12 (m, 2H), 2.54 (s, 1H), 4.92–5.06 (m, 2H), 5.75–5.87 (m, 1H). 13C NMR (75 MHz, CDCl3):
δ 22.0, 23.5, 26.4, 28.7, 33.6, 41.1, 68.1, 73.3, 75.0, 114.5, 138.7, 169.4. IR (NaCl): ν = 3296,
3077, 2978, 2935, 2857, 2118, 1740, 1639, 1368, 1240 cm–1. HRMS (ESI+) m/z calc. for
C12H18NaO2 [M+Na]+ 217.1199; found: 217.1190.
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tert-Butyldimethyl[(3-methylnon-8-en-1-yn-3-yl)oxy]silane (8c). To a solution of octꢀ7ꢀenꢀ2ꢀ
one18,19 (106.2 mg, 0.84 mmol) in dry THF (10 mL) was added sodium acetylide (18% slurry in
xylene, 0.52 mL, 1.68 mmol) and the mixture was stirred at room temperature for 16h. The
reaction mixture was quenched using TBSOTf (0.39 mL, 1.68 mmol) while the mixture turned
from yellow/orange suspension to clear yellow solution. After stirring for 10 min a saturated
aqueous solution of NH4Cl was added (10 mL), and the two phases were separated. The aqueous
phase was extracted with Et2O (3x15 mL), the combined layers were washed with brine (15 mL),
dried over MgSO4 and concentrated under reduced pressure. The crude material was passed
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through a short silica gel pad (pentane) to afford 8c as a colorless liquid (212 mg, 95%). H
NMR (400 MHz, CDCl3): δ 0.17 (s, 6H), 0.87 (s, 9H), 1.36–1.67 (m, 9H), 2.03–2.10 (m, 2H),
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2.39 (s, 1H), 4.89–5.05 (m, 2H), 5.76–5.88 (m, 1H). C NMR (75 MHz, CDCl3): δ –3.1, –2.9,
18.0, 24.0, 25.7, 29.0, 30.9, 33.7, 45.0, 69.0, 71.7, 88.4, 114.3, 139.0. IR (NaCl): ν = 3310, 3078,
2978, 2953, 2930, 2907, 2888, 2857, 2110, 1642, 1472, 1464, 1252 cm–1. HRMS (ESI+) m/z
calc. for C16H30OSi [M+H]+.267.2139; found: 267.2153.
3-Methyloct-7-en-1-yn-3-ol (25). To a solution of heptꢀ6ꢀenꢀ2ꢀone21 (201 mg, 1.78 mmol) in
THF (18 mL) was added sodium acetylide (18% slurry in xylene, 0.66 mL, 2.15 mmol) and the
mixture was stirred at room temperature for 6h. The reaction mixture was quenched using a
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saturated aqueous solution of NH4Cl (18 mL), extracted with Et2O (3x20 mL), washed with
brine (20 mL) and concentrated under reduced pressure. The crude material was purified by
silica gel chromatography (pentane/ether 8:2), to afford the 3ꢀmethyloctꢀ7ꢀenꢀ1ꢀynꢀ3ꢀol 25 as a
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pale yellow liquid (77 mg, 31%). H NMR (400 MHz, CDCl3): δ 1.49 (s, 3H), 1.52–1.72 (m,
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4H), 1.91 (s, 1H), 2.10 (dd, J = 6.9, 13.9 Hz, 2H), 2.43 (s, 1H), 4.94–5.06 (m, 2H), 5.75–5.87 (m,
1H). 13C NMR (75 MHz, CDCl3): δ 23.8, 29.8, 33.6, 42.9, 68.0, 71.3, 87.6, 114.8, 138.4. IR
(NaCl): ν = 3391, 3306, 3078, 2978, 2943, 2866, 2843, 2110, 1643, 1492, 1443, 1373, 1157,
1119, 914 cm–1. HRMS (ESI+) m/z calc. for C9H13 [M–OH–]+ 121.1012; found: 121.1018.
tert-Butyldimethyl[(3-methyloct-7-en-1-yn-3-yl)oxy]silane (12). To a solution of 3ꢀmethyloctꢀ7ꢀ
enꢀ1ꢀynꢀ3ꢀol 25 (42.1 mg, 0.31 mmol) in CH2Cl2 (3 mL) were added 2,4,6ꢀcollidine (81 µL, 0.61
mmol) and TBSOTf (70 µL, 0.31 mmol). The reaction mixture was stirred for 1.5 h before
adding a saturated aqueous solution of NH4Cl (3 mL). The layer were separated, and the aqueous
phase was extracted with CH2Cl2 (3x10 mL). The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel
chromatography (pentane) as eluent, to afford compound 12 as a colorless liquid (61.4 mg,
80%). 1H NMR (400 MHz, CDCl3): δ 0.16 (s, 6H), 0.86 (s, 9H), 1.43 (s, 3H), 1.53–1.67 (m, 4H),
2.06 (dt, J = 6.5, 12.9 Hz, 2H), 2.39 (s, 1H), 4.90ꢀ5.07 (m, 2H), 5.75–5.88 (m, 1H). 13C NMR (75
MHz, CDCl3): δ –3.1, –2.9, 18.0, 23.7, 25.7, 31.0, 33.7, 44.6, 69.0, 71.8, 88.3, 114.4, 138.9. IR
(NaCl): ν = 3310, 3078, 2951, 2931, 2859, 2112, 1474, 1254, 1119, 1084, 837, 775 cm–1. HRMS
(ESI+) m/z calc. for C15H29OSi [M+H]+ 253.1982; found: 253.1980.
General procedure for tertiary alcohol alkylation of 3-phenylbut-1-yn-3-ol:16 To a solution
of NaH (60% in mineral oil, 1.2 equiv.) in DMF at 0 °C was slowly added a solution 3ꢀ
phenylbutꢀ1ꢀynꢀ3ꢀol22 (1 equiv.) in DMF (final concentration: 0.1 M). After 2h at the same
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temperature, the bromoalkene (1.2 equiv.) was added dropwise. The reaction mixture was then
stirred at room temperature for 13h, quenched with water and then extracted with Et2O (3 x 10
mL). Combined extracts were washed with water and brine, dried over MgSO4 and concentrated
under reduced pressure. The crude material was purified by silica gel chromatography to afford
compounds 17,23 18,22 1922 and 20.
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[3-(Hept-6-en-1-yloxy)but-1-yn-3-yl]benzene (20). Obtained as a colorless liquid (322.4 mg,
92%) from 3ꢀphenylbutꢀ1ꢀynꢀ3ꢀol (212.0 mg, 1.45 mmol). 1H NMR (400 MHz, CDCl3): δ 1.30–
1.42 (m, 4H), 1.58 (pseudoꢀquint., J = 7.1 Hz, 2H), 1.73 (s, 3H), 2.04 (m, 2H), 2.69 (s, 1H),
3.07–3.15 (m, 1H), 3.52–3.60 (m, 1H), 4.88–5.03 (m, 2H), 5.73–5.85 (m, 1H), 7.29 (m, 1H),
7.36 (m, 2H), 7.60 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 25.7, 28.7, 29.8, 32.9, 33.7, 64.9,
75.1, 75.6, 84.3, 114.2, 125.9, 127.7, 128.2, 139.0, 142.9. IR (NaCl): ν = 3302, 3063, 3028,
2990, 2932, 2862, 2112, 1447, 1223, 1096, 1072, 910, 764, 698 cm–1. HRMS (ESI+) m/z calc. for
C17H23O [M+H]+ 243.1743; found: 243.1758.
General procedure for microwave-assisted ring-closing enyne metathesis: To a microwave
tube containing the enyne (8a-c, 11-13, 16-20) in dry toluene (0.03 M) was added the catalyst
(10 mol%) under a positive pressure of argon. The resulting reaction mixture was stirred at 120
°C for 1h (or 170 °C for enyne 19) under microwave irradiations at 850 W and the solvent was
then evaporated. The crude material was purified by silica gel chromatography to afford the
corresponding vinylcycloalkene.
1-Methyl-2-vinylcyclohept-2-en-1-yl acetate (9b). Obtained as a yellow oil (55 mg, 55%) from
8b (106 mg, 0.55 mmol). 1H NMR (400 MHz, CDCl3): δ 1.50 (s, 3H), 1.52–1.60 (m, 1H), 1.62–
1.89 (m, 4H), 2.06–2.17 (m, 1H), 1.96 (s, 3H), 2.26–2.37 (m, 1H), 2.65–2.77 (m, 1H), 4.88 (dd, J
= 1.9, 11.0 Hz, 1H), 5.25 (dd, J = 1.9, 17.1 Hz, 1H), 5.89–5.94 (m, 1H), 6.25–6.37 (m, 1H). 13C
NMR (75 MHz, CDCl3): δ 22.1, 23.3, 25.6, 25.8, 26.8, 36.3, 85.0, 113.1, 129.6, 138.1, 144.4,
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169.7. HRMS (ESI+) m/z calc. for C12H18NaO2 [M+Na]+ 217.1199; found: 217.1205. IR (NaCl):
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ν = 2978, 2932, 2866, 1740, 1366, 1246, 1227 cm–1.
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tert-Butyldimethyl[(1-methyl-2-vinylcyclohepta-2-en-1-yl)oxy]silane (9c). Obtained as
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colorless oil (95 mg, 88%) from 8c (108 mg, 0.40 mmol). H NMR (400 MHz, CDCl3): δ 0.08
(s, 3H), 0.09 (s, 3H), 0.87 (s, 9H), 1.33 (s, 3H), 1.49–1.67 (m, 3H), 1.70–1.87 (m, 2H), 1.88–2.02
(m, 1H), 2.04–2.15 (m, 1H), 2.16–2.28 (m, 1H), 4.85 (dd, J = 10.7, 2.2 Hz, 1H), 5.21 (dd, J =
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17.1, 2.2 Hz, 1H), 5.88 (t, J = 6.6 Hz, 1H), 6.46–6.62 (m, 1H). C NMR (75 MHz, CDCl3): δ –
0.04, –0.03, 20.2, 25.2, 27.8, 27.8, 28.3, 30.1, 42.5, 80.1, 113.6, 126.6, 141.2, 150.2. IR (NaCl):
ν = 3082, 2928, 2855, 1462, 1254, 1103, 1037, 995, 837, 775, 744 cm–1. HRMS (ESI+) m/z calc.
for C16H30OSi [M+H]+ 267.2139; found: 267.2153.
tert-Butyldimethyl(1-methyl-2-vinylcyclopent-2-en-1-yloxy)silane (14). Obtained as a colorless
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oil (11 mg, 51%) from 11 (21 mg, 0.086 mmol). H NMR (400 MHz, CDCl3): δ 0.06 (s, 3H),
0.10 (s, 3H), 0.87 (s, 9H), 1.39 (s, 3H), 1.96–2.11 (m, 2H), 2.15–2.27 (m, 1H), 2.30–2.41 (m,
1H), 5.08 (d, J = 11.0 Hz, 1H), 5.60 (d, J = 17.5 Hz, 1H), 5.69 (t, J = 2.9 Hz, 1H), 6.22–6.33 (m,
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1H). C NMR (75 MHz, CDCl3): δ –2.5, –2.0, 18.4, 26.0, 27.8, 29.1, 42.2, 85.4, 115.2, 128.3,
130.9, 148.4. HRMS (ESI+) m/z calc. for C14H26NaOSi [M+Na]+ 261.1645; found: 261.1635. IR
(NaCl): ν = 2955, 2928, 2855, 1254, 1088, 1030, 837, 775, 745 cm–1.
tert-Butyldimethyl[(1-methyl-2-vinylcyclohex-2-en-1-yl)oxy]silane (15). Obtained as a colorless
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oil (13.3 mg, 74%) from 12 (18 mg, 0.072 mmol). H NMR (400 MHz, CDCl3): δ 0.06 (s, 3H),
0.09 (s, 3H), 0.86 (s, 9H), 1.34 (s, 3H), 1.48–2.17 (m, 6H), 4.96 (d, J = 11.1 Hz, 1H,), 5.36 (d, J
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= 17.9 Hz, 1H), 5.80 (t, J = 4.10 Hz, 1H), 6.33–6.45 (m, 1H). C NMR (75 MHz, CDCl3): δ –
2.1, –1.7, 18.5, 20.5, 25.9, 26.1, 29.2, 40.1, 73.3, 113.1, 123.8, 136.2, 143.0. HRMS (ESI+) m/z
calc. for C15H28NaOSi [M+Na]+ 275.1802; found: 275.1809. IR (NaCl): ν = 3082, 3013, 2932,
2893, 2859, 2835, 1250, 1126, 1103, 1034, 833, 772 cmꢀ1.
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tert-Butyldimethyl{[1-methyl-2-(propen-2-yl)cyclohept-2-en-1-yl]oxy}silane (16). Obtained as a
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colorless oil (14.4, 63%) from 13 (23 mg, 0.082 mmol). H NMR (400 MHz, CDCl3): δ 0.09 (s,
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6H), 0.87 (s, 9H), 1.43 (s, 3H), 1.45–1.51 (m, 2H), 1.58–1.66 (m, 2H), 1.77–1.87 (m, 2H), 1.88
(s, 3H), 2.01–2.21 (m, 2H), 4.59–4.69 (m, 2H), 5.50 (dd, J = 5.2, 8.1 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ –1.64, –1.59, 18.5, 25.4, 25.6, 26.1, 27.1, 27.6, 28.4, 42.4, 78.9, 111.5, 125.2,
150.6, 154.7. IR (NaCl): ν = 3078, 2928, 2859, 1250, 833, 775 cm–1. HRMS (ESI+) m/z calc. for
C17H32NaOSi [M+Na]+ 303.2115; found: 303.2132.
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2-Methyl-2-phenyl-3-vinyl-2,5-dihydrofuran (21). Obtained as a colorless liquid (10.7 mg, 95%)
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from 17 (11.3, 0.048 mmol). H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H,), 4.78 (brs, 2H), 5.00–
5.13 (m, 2H), 6.00 (brs, 1H), 6.17–6.29 (m, 1H), 7.24–7.28 (m, 1H), 7.31–7.35 (m, 2H), 7.42–
7.44 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 24.5, 73.3, 89.9, 117.1, 124.3, 126.2, 127.6, 128.4,
128.9, 144.6, 144.8. IR (NaCl): ν = 3095, 2986, 1420, 895, 737, 706 cm–1. HRMS (ESI+) m/z
calc. for C13H15O [M+H]+ 187.1117; found: 187.1116.
2-Methyl-2-phenyl-3-vinyl- 2,5,6,7-tetrahydrooxepine (22). Obtained as a colorless liquid (14.5
mg, 70%) from 18 (20.7 mg, 0.097 mmol). Data were consistent with those of the literature.16
(Z)-2-Methyl-2-phenyl-3-vinyl-5,6,7,8-tetrahydro-2H-oxocine (23). Obtained as a colorless
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liquid (12.7 mg, 63%) from 19 (20.1 mg, 0.088 mmol). H NMR (400 MHz, CDCl3): δ 1.42–
1.82 (m, 7H), 1.95–2.30 (m, 1H), 2.62–2.88 (m, 1H), 3.63–3.91 (m, 2H), 4.93 (dd, J = 1.9, 10.9
Hz, 1H), 5.21 (d, J = 17.1 Hz, 1H), 5.97 (t, J = 9.0 Hz, 1H), 6.25–6.37 (m, 1H), 7.20–7.25 (m,
1H), 7.29–7.32 (m, 2H), 7.50–7.53 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 25.2, 26.1, 26.7,
28.4, 64.2, 81.7, 113.9, 126.0, 126.8, 128.0, 130.0, 139.3, 143.1. IR (NaCl): ν = 3082, 3059,
2970, 2924, 2866, 1493, 1447, 1223, 1099, 1072, 1030, 910, 760, 698 cm–1. HRMS (ESI+) m/z
calc. for C16H21O [M+H]+ 229.1587; found: 229.1588.
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ASSOCIATED CONTENT
Supporting Information
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The complete list of catalysts used in this study (Figure S1) and spectral data for all new
compounds are provided. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: bnay@mnhn.fr (Bastien Nay)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the ANR (grant number ANRꢀ12ꢀBS07ꢀ0028ꢀ01, SYNBIORG).
NMR spectrometers were funded by Région IleꢀdeꢀFrance, MNHN and CNRS. We thank the
"Fondation pour le Développement de la Chimie des Substances Naturelles et ses Applications"
for granting Benjamin Laroche with a PhD fellowship.
References
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in situ quench of the resulting tertiary alcohol with an appropriate electrophile (see the
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(8)
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Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082–6083.
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(17) Terminal alkynes have been known as poor substrates for the synthesis of eightꢀ
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