Br?nsted Acid Catalyzed Peterson Olefinations

Article abstract of DOI:10.1021/acs.joc.9b02489

A mild and facile Peterson olefination has been developed employing low catalyst loading of the Br?nsted acid HNTf₂. The reactions are typically performed at room temperature, with the reaction tolerant to a range of useful functionalities. Furthermore, we have extended this methodology to the synthesis of enynes.

Full text of DOI:10.1021/acs.joc.9b02489

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Brønsted Acid Catalyzed Peterson Olefinations
Thomas Kenton Britten, and Mark Gerard McLaughlin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02489 • Publication Date (Web): 27 Nov 2019
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The Journal of Organic Chemistry
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Brønsted Acid Catalyzed Peterson Olefinations.
Thomas K. Britten and Mark G. McLaughlin*
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Department of Natural Sciences, Manchester Metropolitan University, Chester Street, Manchester, United Kingdom,
M15GD.
Supporting Information Placeholder
resulted in several alternatives being reported. Of these, triflimide
HNTf2, has shown promise.13 Not only is it easier to handle (solid
vs viscous oil) but it’s pKa is a fold lower than TfOH (-12.3 vs -
11.4 in DCE),14 allowing for potentially milder activation
conditions. We therefore envisaged that we could take advantage
of this increased acidity, and develop a general catalytic Peterson
olefination employing low catalyst loading.
ABSTRACT: A mild and facile Peterson olefination has been
developed employing low catalyst loading of the Brønsted acid
HNTf2. The reactions are typically performed at room temperature,
with the reaction tolerant to a range of useful functionalities.
Furthermore, we have extended this methodology to the synthesis
of enynes.
Scheme 2. Previously Reported Catalytic Peterson’s
He (2016)
Introduction
Ar
TMS
O
N
The Peterson olefination has enjoyed sustained interest from the
synthetic community since its discovery in the late 1960’s (Scheme
1).1 This is unsurprising, given the large numbers of bioactive
natural products that contain alkene functional groups.2 In its
simplest guise, the Peterson olefination, or silyl-Wittig, is the
elimination of -silyl alcohols, promoted by the -silicon effect.3.
N
Ar
OTMS
H
R
H
CO2Et
R
Ar = 2,6-(iPr)2C6H3
OEt
O'Shea (2015)
R1 R2
TMS
S
TMS
S
O
TMSOK/Bu4NCl (10 mol%)
S
S
Scheme 1. General Peterson Olefination
R1 R2
R1
Leadbetter (2014)
O
HO
R1
SiR3
Acid or base
R2
RF
R1 R2
RF
XMg
SiR3
TMSOTf (10-30 mol%)
HNTf2 (0.1-1 mol%)
HO
R2
TMS
R
R
This work
TMS
TMS
One key characteristic of the Peterson is that it can afford both E
and Z isomers depending on the conditions employed.4 Routinely
employing super-stoichiometric quantities of strong acids or bases
results in a facile elimination reaction, however due to the necessity
of large quantities of reagents, functional group tolerance and
utility in complex target synthesis remains an issue. Recent
advances in rendering the Peterson olefination catalytic have
resulted in a small number of strategies (Scheme 2),5 however this
area remains underexplored.
R2
R2
or
HO
R1
R
HO
TMS
or
R1
TMS
R1
Results and Discussion
We began our investigation using crude 2a, readily formed by
the addition of TMSCH2MgCl to benzophenone (1a) followed by
simple DCM workup, and 10 mol% HNTf2 in refluxing DCM. To
our delight, the reaction was complete within 15 minutes, affording
the 1,1-disubstituted alkene in 90% yield. Reducing the catalyst
loading to 1 mol% had little effect on the reaction, nor did running
the reaction at room temperature. Further reducing the catalyst
loading to 0.1 mol% produced 3a in 89% yield after 15 minutes.
Further attempts to increase the yield through varying the solvent
were unsuccessful (Table 1). We also performed the reaction on 5.5
mmol scale, which resulted in effectively the same yield as the
small scale reaction.
Brønsted acid catalysts have become a mainstay of modern
synthetic chemistry, and have been successfully used in a wide
range of applications.6 BINOL-derived phosphoric acids and
amides have shown great utility in the synthesis of complex
scaffolds via numerous transformations,7 as have urea8 and thiourea
derivatives.9 These Brønsted acids have been shown to activate
carbonyls, imines as well as olefins to form the corresponding salts
or carbocations.10 Furthermore, Brønsted acids have been shown to
activate hydroxyl groups, but typically require much higher catalyst
loadings.11
A potential solution is to use more acidic Brønsted acids, such as
the readily available triflic acid, TfOH.12 Although useful, its
toxicity and difficulty in handling renders its use problematic.
Nevertheless, the synthetic utility of super Brønsted acids has
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We then turned our attention to the use of readily available
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propargylic ketones to provide enynes following the Peterson
olefination. As shown, the reaction proceeded smoothly, affording
the desired enyne products in moderate to high yields (Scheme 4).
This is one of very few examples of using the Peterson to produce
these high value compounds,15 and is, to the best of our knowledge,
the only catalytic version of the Peterson to achieve this.
Table 1. Optimization Studies
OH
cat. HNTf2
Ph
O
Me3SiCH2MgCl
THF, rt, 12 h
SiMe3
Ph
Ph
Solvent
Temperature
Ph
Ph
Ph
1a
3a
2a
Temp (oC) Yield (%)a
Scheme 4. Synthesis of Enynes
Entry Cat. loading (mol %) Solvent
1
2
3
4
5
6
7
8
10
1
1
0.1
0.1
0.1
0.1
-
DCM
DCM
DCM
40
40
rt
rt
rt
rt
rt
rt
90
87
85
TMS
TMS
1) TMSCH2MgCl, THF
9
DCM
88
89 (88)b
88
1,2-DCE
MeCN
Acetone
1,2-DCE
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2) HNTf2 (0.1 mol%)
DCE, r.t, 15 minutes
R1
60
n.r
R
O
4
5
TMS
a Isolated Yields, b 5.5 mmol scale (starting from 1.0 g of 1a)
TMS
With these conditions in hand, we probed the functional group
tolerance of the reaction. We initially focused on the use of
aldehydes and ketones to provide the corresponding styrenes. As
shown, the reaction is tolerant to a range of both aromatic and alkyl
substituents, providing the desired olefins in good yield after 15
minutes. Benzophenone derived products all reacted well (3a-3d),
as did fluorenone (3e) and propionphenone (3f). Products derived
from aldehydes were also synthesized via this methodology, with
electron withdrawing groups such as bromide (3g) trifluromethyl
(3h) and cyano (3i) providing the styrene in good yields. Electron
donating groups also proved successful, giving the desired products
(3j-3l) efficiently and in good yields. Heterocyclic groups are also
well tolerated, with the corresponding thiophene and furan (3m and
3n) derivatives being produced. Finally, this methodology can
extend to cyclic alkyl (3o) and heteroalkyl (3p and 3q) groups,
providing the desired olefins in synthetically useful yields. Of
particular note is the compatibility with carbamate protecting
groups, which are well known to cause issues in traditional
Peterson olefinations.
Ph
a
5a
5b
, 72%
, 87%
TMS
TMS
S
Br
a
a
5c
5d
, 86%
, 51%
a
Reaction performed in CDCl3 and the yield was determined
through 1H NMR spectroscopy of the reaction mixture using 1,3,5-
trimethoxybenzene as an internal standard
A proposed mechanism is shown below (Figure 1). Owing to the
pKa differential between the catalyst and the alcohol, we envisage
that a facile deprotonation event occurs. This results in intermediate
I, which then undergoes elimination to form the desired product.
The silylenium cation16 is then trapped out with water to produce
silanol, and the resultant proton generated via this process
regenerates the catalyst.
Scheme 3. Substrate Scope
OH
R2
HNTf2 (0.1 mol%)
TMS
R1
R1
R2
DCE, r.t, 15 minutes
Ph
2
3
Ph
Ph
Figure 1. Proposed Catalytic Cycle
F3C
H
N
Me
F
F3CO2S
SO2CF3
OH
R
3b
3f,
3c
3d
3e
, 66%
Et
, 74%
, 81%
, 76%
TMSOH
TMS
NTf2
R
F3C
3h
Br
NC
a
a,b
b
NTf2
89%
3g
, 67%
3i
, 68%
, 75%
S
MeO
OMe
, 89%
OH
3k
a
c
OH2
R2
3m,
3j
3l
60%
O
, 88%
, 83%
TMS
H2O TMS
R1
O
I
N
Boc
a
a,d
a
3n,
3o,
3p,
3q,
64%
75%
64%
40%
a
Reaction performed in CDCl3 and the yield was determined
through 1H NMR spectroscopy of the reaction mixture using 1,3,5-
trimethoxybenzene as an internal standard; b 1 mol% HNTf2 used;
c Reaction performed in MeCN; d 0.5 mol% HNTf2 used
R1 R2
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The Journal of Organic Chemistry
In summary, we have developed a highly efficient, one pot
DCE (0.01 M, 0.1-1.0 mol%) was added in one portion to a stirred
solution of the crude product in CDCl3 (0.5 M) at room
temperature, then stirred for 15 minutes. An aliquot of the reaction
mixture was removed (0.6 mL, 0.3 mmol of substrate), combined
with 1,3,5-trimethoxybenzene and analyzed by 1H NMR
spectroscopy. The amount of alkene present was quantified using
the following equation: nA = nIS x rA/IS, where nA = mmol of analyte,
nIS = mmol of internal standard and rA/IS = ratio of analyte to
internal standard (see supporting information for example
calculation).
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catalytic Peterson olefination employing 0.1 mol% bistriflimide as
catalyst. As shown, the reaction is tolerant of a range of functional
groups, including groups unsuited to the traditional Peterson
reaction (3i, 3k and 3p). We have also investigated the use of
propargylic ketones in the reaction, affording a small library of
enynes. Investigations towards its applicability in complex natural
product synthesis is currently underway.
EXPERIMENTAL SECTION
9
Solvents and reagents
1,1'-(ethene-1,1-diyl)dibenzene (3a). Using general procedure A,
benzophenone (182 mg, 1.00 mmol) and HNTf2 (0.1 mL, 0.1
mol%) provided alkene 3a (161 mg, 0.89 mmol, 89%) as a colorless
oil after purification by flash column chromatography (eluent:
hexane).
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All solvents were purchased from commercial sources and used
without purification (HPLC or analytical grade). Anhydrous
solvent was obtained from a Pure Solv™ Solvent Purification
System. Standard vacuum line techniques were used and glassware
was oven dried prior to use. Organic solvents were dried during
workup using anhydrous Na2SO4. All calcium catalyzed reactions
where done without the need for anhydrous or air free conditions.
Purification and chromatography
Thin Layer Chromatography (TLC) was carried out using
aluminum plates coated with 60 F254 silica gel. Plates were
visualized using UV light (254 or 365 nm) or staining with 1% aq.
KMnO4. Normal-phase silica gel chromatography was carried out
using either a Biotage Isolera One flash column chromatography
system (LPLC) or traditional flash column chromatography using
Geduran® Silica gel 60, 40–63 microns RE.
Rf (hexane) = 0.38
1H NMR (400 MHz, CDCl3);  7.36–7.32 (m, 5H), 5.47 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3);  150.2, 141.6, 128.4, 128.3,
127.9, 114.5.
Spectral data in accordance to previously published data.18
1-Methyl-4-(1-phenylethenyl)benzene (3b). Using general
procedure A, 4-methylbenzophenone (196 mg, 1.00 mmol) and
HNTf2 (0.1 mL, 0.1 mol%) provided alkene 3b (133 mg, 0.68
mmol, 68%) as a colorless oil after purification by flash column
chromatography (eluent: hexane).
Characterization
Rf (hexane-EtOAc, 7:1) = 0.59
Infrared spectroscopy was carried out with a Nicolet® 380 FT/IR
– Fourier Transform Infrared Spectrometer. Only the most
significant frequencies have been considered during the
characterization and selected absorption maxima (max) recorded
in wavenumbers (cm-1). NMR spectra were recorded using a
JEOL® ECS-400 MHz spectrometer using the deuterated solvent
stated. Chemical shifts (δ) quoted in parts per million (ppm) and
referenced to the residual solvent peak. Multiplicities are denoted
as s- singlet, d- doublet, t- triplet, q- quartet and quin- quintet and
derivatives thereof (br denotes a broad resonance peak). Coupling
constants recorded as Hz and round to the nearest 0.1 Hz. High
Resolution Mass Spectrometry (HRMS) was recorded using an
Agilent Technologies® 6540 Ultra-High-Definition (UHD)
AccurateMass equipped with a time of flight (Q-TOF) analyzer and
the samples were ionized by ESI techniques and introduced through
a high pressure oil chromatography (HPLC) model Agilent
Technologies® 1260 Infinity Quaternary LC system.
1H NMR (400 MHz, CDCl3);  7.36–7.31 (m, 5H), 7.25 (d, J = 8.1
Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 5.44 (d, J = 1.2 Hz, 1H), 5.42 (d,
J = 1.2 Hz, 1H), 2.38 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3);  150.0, 141.8, 138.7, 137.7,
129.0, 128.4, 128.29, 128.26, 127.8, 21.3.
Spectral data in accordance to previously published data.19
1-Fluoro-2-(1-phenylethenyl)benzene (3c). Using general
procedure A, 2-fluorobenzophenone (168 µL, 1.00 mmol) and
HNTf2 (0.1 mL, 0.1 mol%) provided alkene 3c (147 mg, 0.74
mmol, 74%) as a colorless oil after purification by flash column
chromatography (eluent: hexane).
Rf (hexane) = 0.26
1H NMR (400 MHz, CDCl3);  7.36–7.27 (m, 7H), 7.17–7.05 (m,
2H), 5.76 (d, J = 1.1 Hz, 1H), 5.43 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3);  160.3 (d, JF = 248.5 Hz),
144.3, 140.7, 131.7 (d, JF = 3.4 Hz), 129.5 (d, JF = 7.9 Hz), 129.3,
128.4, 127.9, 126.9, 124.1 (d, JF = 3.6 Hz), 117.2 (d, JF = 1.7 Hz),
115.9 (d, JF = 22.2 Hz).
Propargyl ketones 4a-d were synthesized according to previously
published procedures.17
General
Procedure
A:
Synthesis
of
Alkenes.
19F (376 MHz, CDCl3)  -113.1
(Trimethylsilylmethyl)magnesium chloride (1.3 M solution in
THF, 3.0 equiv.) was added dropwise to a stirred solution of
aldehyde/ketone (1.0 equiv.) in THF (0.2 M) at 0 ºC under argon
and then stirred at room temperature overnight. The reaction
mixture was cooled to 0 ºC and quenched with a saturated aqueous
solution of NH4Cl (5 mL). The aqueous phase was extracted with
CH2Cl2 (3 x 5 mL), dried (Na2SO4) and evaporated under reduced
pressure to give the crude product, which was used without further
purification. A stock solution of HNTf2 in 1,2-DCE (0.01 M, 0.1-
1.0 mol%) was added in one portion to a stirred solution of the
crude product in 1,2-DCE (0.5 M) at room temperature, then stirred
for 15 minutes. The solvent was removed under reduced pressure
and the crude product was purified by flash column
chromatography using an appropriate solvent system, as described
for each individual procedure. Note: stock solutions of
trifluoromethanesulfonimide in 1,2-DCE were stored in the fridge
to avoid decomposition.
Spectral data in accordance to previously published data.20
1-(1-Phenylethenyl)-3-(trifluoromethyl)benzene
(3d).
Using
general procedure A, 3-(trifluoromethyl)benzophenone (249 mg,
1.00 mmol) and HNTf2 (0.1 mL, 0.1 mol%) provided alkene 3d
(199 mg, 0.80 mmol, 81%) as a colorless oil after purification by
flash column chromatography (eluent: hexane).
Rf (hexane) = 0.29
1H NMR (400 MHz, CDCl3);  7.62–7.43 (m, 4H), 7.38–7.30 (m,
5H), 5.55 (d, J = 0.6 Hz, 1H), 5.50 (d, J = 0.6 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3);  149.0, 142.4, 140.7, 131.7,
130.8 (q, JF = 31.9 Hz), 128.8, 128.5, 128.3, 125.6, 125.1 (q, JF =
3.5 Hz), 124.6 (q, JF = 3.6 Hz), 122.9, 115.8.
19F (376 MHz, CDCl3)  -62.5
Spectral data in accordance to previously published data.21
General Procedure B: NMR Reactions in the Synthesis of
Alkenes. A stock solution of trifluoromethanesulfonimide in 1,2-
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9-Methylidene-9H-fluorene (3e). Using general procedure A, 9-
(eluent: hexane:Et2O, 4:1). Note: the second step (HNTf2 reaction)
was performed in MeCN rather than 1,2-DCE due to solubility
issues.
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fluorenone (181 mg, 1.00 mmol) and HNTf2 (0.1 mL, 0.1 mol%)
provided alkene 3e (135 mg, 0.76 mmol, 76%) as a white solid after
purification by flash column chromatography (eluent: hexane).
Rf (hexane) = 0.33
1H NMR (400 MHz, CDCl3);  7.76–7.10 (m, 4H), 7.41–7.30 (m,
4H), 6.09 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3);  143.5, 140.3, 138.2, 128.9,
127.2, 121.1, 119.9, 108.0.
Rf (hexane-Et2O, 4:1) = 0.19
1H NMR (400 MHz, CDCl3);  7.21 (t, J = 7.9 Hz, 1H), 7.01–6.98
(m, 1H), 6.91–6.90 (m, 1H), 6.76–6.73 (m, 1H), 6.67 (dd, J = 17.4,
11.0 Hz, 1H), 5.73 (d, J = 17.4 Hz, 1H), 5.26 (d, J = 11.0 Hz, 1H),
5.06 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3);  155.8, 139.4, 136.6, 129.9,
119.3, 115.0, 114.5, 112.9.
Spectral data in accordance to previously published data.20
(But-1-en-2-yl)benzene (3f). Using general procedure B,
propiophenone (130 µL, 0.98 mmol), HNTf2 (0.1 mL, 0.1 mol%)
and 1,3,5-trimethoxybenzene (3.0 mg, 0.018 mmol) provided
alkene 3f (89% NMR yield).
Spectral data in accordance to previously published data.25
2-Ethenylnaphthalene (3l). Using general procedure A, 2-
naphthaldehyde (157 mg, 1.01 mmol) and HNTf2 (0.1 mL, 0.1
mol%) provided alkene 3l (129 mg, 0.84 mmol, 83%) as a white
solid after purification by flash column chromatography (eluent:
hexane).
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1-Bromo-4-ethenylbenzene (3g). Using general procedure A, 4-
bromobenzaldehyde (187 mg, 1.01 mmol) and HNTf2 (1.0 mL, 1.0
mol%) provided alkene 3g (126 mg, 0.69 mmol, 68%) as a colorless
oil after purification by flash column chromatography (eluent:
hexane).
Rf (hexane) = 0.42
1H NMR (400 MHz, CDCl3);  7.86–7.81 (m, 4H), 7.78 (s, 1H),
7.67 (dd, J = 8.6, 1.6 Hz, 1H), 7.51–7.44 (m, 2H), 6.91 (dd, J =
17.6, 10.9 Hz, 1H), 5.90 (d, J = 17.6 Hz, 1H), 5.37 (d, J = 10.9 Hz,
1H).
Rf (hexane) = 0.49
1H NMR (400 MHz, CDCl3);  7.48–7.43 (m, 2H), 7.30–7.27 (m,
2H), 6.67 (dd, J = 17.6, 11.0 Hz, 1H), 5.78–5.73 (m, 1H), 5.29 (d,
J = 11.0 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3);  137.1, 135.1, 133.7, 133.3,
128.3, 128.2, 127.8, 126.5, 126.4, 126.0, 123.3, 114.3.
Spectral data in accordance to previously published data.22
13C{1H} NMR (100 MHz, CDCl3);  136.6, 135.9, 131.8, 127.9,
121.7, 114.8.
2-Ethenylthiophene (3m). Using general procedure B, 2-
thiophenecarboxaldehyde (93 µL, 1.00 mmol), HNTf2 (0.1 mL, 0.1
mol%) and 1,3,5-trimethoxybenzene (3.3 mg, 0.020 mmol)
provided alkene 3m (60% NMR yield).
Spectral data in accordance to previously published data.22
1-Ethenyl-4-(trifluoromethyl)benzene (3h). Using general
procedure B, 4-(trifluoromethyl)benzaldehyde (140 µL,1.03
mmol), HNTf2 (1.0 mL, 1.0 mol%) and 1,3,5-trimethoxybenzene
(4.0 mg, 0.024 mmol) provided alkene 3h (67% NMR yield).
1H NMR (400 MHz, CDCl3);  7.57 (d, J = 8.4 Hz, 2H), 7.49 (d, J
= 8.4 Hz, 2H), 6.73 (dd, J = 17.6, 10.9 Hz, 1H), 5.84 (d, J = 17.6
Hz, 1H), 5.37 (d, J = 10.9 Hz, 1H).
2-Ethenylfuran (3n). Using general procedure B, furfural (83 µL,
1.00 mmol), HNTf2 (0.1 mL, 0.1 mol%) and 1,3,5-
trimethoxybenzene (3.0 mg, 0.018 mmol) provided alkene 3n (75%
NMR yield).
1H NMR (400 MHz, CDCl3);  7.37–7.33 (m, 1H), 6.51 (dd, J =
17.6, 11.3 z, 1H), 6.37 (dd, J = 3.3, 1.8 Hz, 1H), 6.26 (d, J = 3.3
Hz, 1H), 5.66 (dd, J = 17.6, 1.2 Hz, 1H), 5.16 (dd, J = 11.3, 1.2 Hz,
1H).
4-Ethenylbenzonitrile (3i). Using general procedure A, 4-
cyanobenzaldehyde (131 mg, 1.00 mmol) and HNTf2 (1.0 mL, 1.0
mol%) provided alkene 3i (90 mg, 0.75 mmol, 75%) as a colorless
oil after purification by flash column chromatography (eluent:
hexane:Et2O, 4:1).
Ethenylcyclohexane (3o). Using general procedure B,
cyclohexanecarboxaldehyde (120 µL, 0.99 mmol), HNTf2 (0.5 mL,
0.5 mol%) and 1,3,5-trimethoxybenzene (3.1 mg, 0.018 mmol)
provided alkene 3o (64% NMR yield).
Rf (hexane) = 0.13
1H NMR (400 MHz, CDCl3);  7.62–7.50 (m, 2H), 7.49–7.47 (m,
2H), 6.73 (dd, J = 17.6, 10.9 Hz, 1H), 5.88 (d, J = 17.6 Hz, 1H),
5.45 (d, J = 10.9 Hz, 1H).
tert-Butyl 4-methylidenepiperidine-1-carboxylate (3p). Using
general procedure A, N-Boc-4-piperidone (298 mg, 1.50 mmol)
and HNTf2 (0.1 mL, 0.1 mol%) provided alkene 3p (117 mg, 0.59
mmol, 40%) as a colorless oil after purification by flash column
chromatography (eluent: hexane:EtOAc, 14:1).
13C{1H} NMR (100 MHz, CDCl3);  142.0, 135.5, 132.5, 126.9,
119.1, 117.9, 111.2.
Spectral data in accordance to previously published data.23
Rf (hexane-EtOAc, 2:1) = 0.61
4-Ethenyl-1,2-dimethoxybenzene (3j). Using general procedure A,
3,4-dimethoxybenzaldehyde (168 mg, 1.01 mmol) and HNTf2 (0.1
mL, 0.1 mol%) provided alkene 3j (147 mg, 0.90 mmol, 89%) as a
colorless oil after purification by flash column chromatography
(eluent: hexane:Et2O, 4:1).
1H NMR (400 MHz, CDCl3);  4.74 (s, 2H), 3.43–3.39 (m, 4H),
2.19–2.16 (m, 4H), 1.46 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3);  154.9, 145.6, 109.2, 79.7,
45.5, 34.7, 28.6.
Rf (hexane-Et2O, 4:1) = 0.26
Spectral data in accordance to previously published data.26
1H NMR (400 MHz, CDCl3);  6.98–6.93 (m, 2H), 6.83 (d, J = 8.2
Hz, 1H), 6.66 (dd, J = 17.5, 11.0 Hz, 1H), 5.64–5.59 (m, 1H), 5.15
(dd, J = 11.0, 0.7 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3);  149.10, 149.08, 136.6, 130.8,
119.6, 112.0, 111.1, 108.6, 56.1, 55.9.
4-Methylideneoxane (3q). Using general procedure B, 4-
oxotetrahydropyran (92 µL, 1.00 mmol), HNTf2 (1.0 mL, 1.0
mol%) and 1,3,5-trimethoxybenzene (3.8 mg, 0.023 mmol)
provided alkene 3q (64% NMR yield).
Spectral data in accordance to previously published data.24
3-Ethenylphenol (3k). Using general procedure A, 3-
hydroxybenzaldehyde (123 mg, 1.01 mmol) and HNTf2 (0.1 mL,
0.1 mol%) provided alkene 3k (108 mg, 0.89 mmol, 88%) as a
colorless oil after purification by flash column chromatography
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Hegde, S. G.; Hubbard, R. D.; Zhang, L.,
1
2
3
4
5
6
7
8
Trimethyl(3-phenylbut-3-en-1-yn-1-yl)silane (5a). Using general
procedure A, ketone 4a (67 mg, 0.33 mmol) and HNTf2 (33 µL, 0.1
mol%) provided enyne 5a (47 mg, 0.24 mmol, 72%) as a pale
yellow oil after purification by flash column chromatography
(eluent: hexane). Note: crude and isolated samples of enynes 5
degraded regardless of storage temperature (See supporting
information).
Total Synthesis of (−)-Laulimalide. J.
Am. Chem. Soc. 2002, 124, 4956; (c)
Stathakis, C. I.; Yioti, E. G.; Gallos, J. K.,
Total Syntheses of (–)-α-Kainic Acid.
Eur. J. Org. Chem. 2012, 2012, 4661.
Lambert, J. B.; Wang, G. T.; Finzel, R.
B.; Teramura, D. H., Stabilization of
positive charge by .beta.-silicon. J. Am.
Chem. Soc. 1987, 109, 7838.
Rf (hexane-EtOAc, 2:1) = 0.63
3.
1H NMR (400 MHz, CDCl3);  7.66–7.63 (m, 2H), 7.38–7.31 (m,
3H), 5.94 (d, J = 0.8 Hz, 1H), 5.71 (s, 1H), 0.26 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3);  137.0, 130.7, 128.50, 128.45,
126.2, 121.6, 104.2, 96.0, 0.09.
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Spectral data in accordance to previously published data.27
4.
Das, M.; O’Shea, D. F., Z-Stereoselective
Aza-Peterson Olefinations with
Trimethyl[3-(naphthalen-2-yl)but-3-en-1-yn-1-yl]silane
(5b).
Using general procedure B, ketone 4b (93 mg, 0.37 mmol), HNTf2
(37 µL, 0.1 mol%) and 1,3,5-trimethoxybenzene (3.8 mg, 0.023
mmol) provided enyne 5b (87% NMR yield).
Bis(trimethylsilane) Reagents and Sulfinyl
Imines. Org. Lett. 2016, 18, 336.
(a) Hamlin, T. A.; Kelly, C. B.; Cywar, R.
M.; Leadbeater, N. E., Methylenation of
Perfluoroalkyl Ketones using a Peterson
Olefination Approach. J. Org. Chem.
2014, 79, 1145; (b) Hamlin, T. A.;
Lazarus, G. M. L.; Kelly, C. B.;
5.
[3-(4-bromophenyl)but-3-en-1-yn-1-yl](trimethyl)silane
(5c).
Using general procedure B, ketone 4c (142 mg, 0.51 mmol), HNTf2
(50 µL, 0.1 mol%) and 1,3,5-trimethoxybenzene (3.9 mg, 0.023
mmol) provided enyne 5c (86% NMR yield).
1H NMR (400 MHz, CDCl3);  7.51–7.44 (m, 4H), 5.91– 5.89 (m,
1H), 5.71– 5.70 (m, 1H), 0.24 (s, 9H).
Leadbeater, N. E., A Continuous-Flow
Approach to 3,3,3-
Trimethyl[3-(thiophen-2-yl)but-3-en-1-yn-1-yl]silane (5d). Using
general procedure B, ketone 4d (104 mg, 0.50 mmol), HNTf2 (50
µL, 0.1 mol%) and 1,3,5-trimethoxybenzene (2.1 mg, 0.013 mmol)
provided enyne 5d (51% NMR yield).ASSOCIATED CONTENT
Trifluoromethylpropenes: Bringing
Together Grignard Addition, Peterson
Elimination, Inline Extraction, and
Solvent Switching. Org, Process Res.
Dev. 2014, 18, 1253; (c) Wang, Y.; Du,
G.-F.; Gu, C.-Z.; Xing, F.; Dai, B.; He,
L., N-heterocyclic carbene-catalysed
Peterson olefination reaction.
Tetrahedron 2016, 72, 472; (d) Manvar,
A.; O'Shea, D. F., Trimethylsilyloxide-
Catalysed Peterson Olefinations with 2,2-
Bis(trimethylsilyl)-1,3-dithiane.
European Journal of Organic Chemistry
2015, 2015, 7259.
Reuping, M.; Parmer, D.; Sugiono, E.,
Asymmetric Brønsted Acid Catalysis.
Wiley-VCH2015.
(a) Merad, J.; Lalli, C.; Bernadat, G.;
Maury, J.; Masson, G., Enantioselective
Brønsted Acid Catalysis as a Tool for the
Synthesis of Natural Products and
Pharmaceuticals. Chemistry – A
European Journal 2018, 24, 3925; (b)
Uraguchi, D.; Terada, M., Chiral
Brønsted Acid-Catalyzed Direct Mannich
Reactions via Electrophilic Activation. J.
Am. Chem. Soc. 2004, 126, 5356.
Supporting Information
Copies of spectra and exemplar yield calculation.
AUTHOR INFORMATION
Corresponding Author
*E-mail: m.mclaughlin@mmu.ac.uk
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Manchester Metropolitan University (MMU) for startup
funding. TKB thanks MMU for a strategic opportunities fund
award. MML thanks MMU, Royal Society of Chemistry and
Medical Research Council for funding. We also thank Kate Jones
for synthetic assistance.
6.
REFERENCES
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Taylor, M. S.; Jacobsen, E. N.,
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27.
23.
9
Dehydration. Org. Lett. 2012, 14, 2358.
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TOC Graphic
25.
OH
17 examples
(40-89% yield)
R1
R2
R1
TMS
R2
H
O
N
O
S
S
F3C
CF3
O
O
OH
0.1 mol%
R1
R1
TMS
4 examples
(51-87% yield)
TMS
TMS
26.
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