One-Pot Enol Silane Formation-Alkylation of Ketones with Propargyl Carboxylates Promoted by Trimethylsilyl Trifluoromethanesulfonate

Article abstract of DOI:10.1021/acs.joc.8b01997

Ketones readily undergo conversion to enol silanes in the presence of a trialkylamine base and trimethylsilyl trifluoromethanesulfonate (TMSOTf) and add to propargyl cations to yield β-alkynyl ketones. The propargyl cations are generated in the same react

Full text of DOI:10.1021/acs.joc.8b01997

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Note
One-Pot Enol Silane Formation-Alkylation of Ketones with Propargyl
Carboxylates Promoted by Trimethylsilyl Trifluoromethanesulfonate
C. Wade Downey, Danielle N. Confair, Yiqi Liu, and Elizabeth D. Heafner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01997 • Publication Date (Web): 24 Sep 2018
Downloaded from http://pubs.acs.org on September 30, 2018
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One-Pot Enol Silane Formation-Alkylation of Ketones with
Propargyl Carboxylates Promoted by Trimethylsilyl
Trifluoromethanesulfonate
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C. Wade Downey,* Danielle N. Confair, Yiqi Liu, and Elizabeth D. Heafner
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University of Richmond
Gottwald Center for the Sciences
28 Westhampton Way
Richmond, VA 23173
wdowney@richmond.edu
ABSTRACT
Ketones readily undergo conversion to enol silanes in the presence of trialkylamine base
and trimethylsilyl trifluoromethanesulfonate (TMSOTf) and add to propargyl cations to
yield βꢀalkynyl ketones. The propargyl cations are generated in the same reaction flask
through the TMSOTfꢀpromoted ionization of propargyl acetates or propargyl propionates.
A range of enol silane precursors and propargyl carboxylates reacts efficiently (20
examples, up to 99% yield). Cyclization of a representative product in the presence of
TMSOTf provided 61% yield of the trisubstituted furan.
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Ketone alkylation is a powerful and established tool for organic synthesis, drawing
interest from researchers for decades and continuing to inspire new advances.1 Although
αꢀalkylation of ketones typically occurs under highly basic conditions, the alkylation of
enols and enol silanes also has been shown to proceed under Lewis acidic conditions
where the alkylating agent first undergoes ionization to produce a carbocationic
intermediate.2 For example, the ionization of propargyl acetates under metal catalysis
allows for reaction with enol silanes to yield βꢀalkynyl ketones, 3 which have been
demonstrated to be useful intermediates in several total syntheses, including (+)ꢀ
cortistatin,4 (+)ꢀryanodol,5 and morphine.6 Further synthetic utility for these building
blocks derives from their facile conversion to trisubstituted furans.3bꢀc,7 Catalysis of a
closely related reaction by trimethylsilyl trifluoromethanesulfonate (TMSOTf) provides a
route to allenes and enynes when αꢀsubstituted enol silanes are employed.2c To our
knowledge, however, the efficient use of TMSOTf to carry out both the ionization of a
propargyl carboxylate8 and the formation of an enol silane nucleophile in a single
reaction sequence has not been reported. In the course of our investigation of oneꢀpot
enol silane formationꢀαꢀsubstitution reactions,9 we reported that paraꢀmethoxybenzyl
methyl ether acts as a convenient alkylating agent for aryl methyl ketones in the presence
of TMSOTf and a trialkylamine base. We now report that secondary propargyl acetates
are readily ionized by TMSOTf and act as efficient alkylation agents for in situꢀformed
enol silanes to yield βꢀalkynyl ketones as exemplified by eq 1.
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The study began with the attempted activation of propargyl alcohol 1 in the presence of
TMSOTf and Et3SiH. Recovery of the deoxygenated alkyne as the major product
demonstrated that TMSOTfꢀpromoted ionization of the propargyl position was viable (eq
2).10 When the Et3SiH nucleophile was replaced with enol silane 2, however, the
expected ketone product was not observed. Instead, formation of bispropargyl ether 3
was observed as a mixture of diastereomers (eq 3).11
In order to prevent alcohol 1 from acting as a competing nucleophile, it was protected as
its acetate ester. When enol silane 2 was reacted with propargyl acetate 4a in the
presence of 0.5 equiv TMSOTf at –78 °C in CH2Cl2, 12% conversion to the desired βꢀ
alkynyl ketone was observed after 1 h (eq 4), with the remainder of the mixture
consisting of unreacted starting materials. Based upon this lead, a survey of reaction
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conditions was conducted to determine the optimal conditions for the oneꢀpot enol silane
formationꢀαꢀalkylation reaction of acetophenone with propargyl acetate 4a. The optimal
conditions are illustrated in eq 5.12 Several trialkylamine bases promoted the reaction at ꢀ
78 °C, most notably triethylamine and Nꢀmethylmorpholine. When the triethylamine
reaction was conducted at 0 °C, 95% conversion to the desired product was observed.
Further study optimized stoichiometry of the reaction to achieve up to 99% conversion.
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A proposed mechanistic scheme for this reaction is presented in Figure 1. In situ
formation of enol silane with Et3N and TMSOTf provides the active nucleophile and an
ammonium salt. Residual TMSOTf activates the propargyl acetate to provide the
propargyl cation. Attack of the enol silane on the carbocation forms the new carbonꢀ
carbon bond, and desilylation affords a silyl cation capable of activating more of the
propargyl acetate. Generation of allenyl products is also possible, either via attack at the
γ carbon of the cation or through an SN2’ reaction.
Figure 1. Proposed Mechanistic Scheme
Some experimental evidence supports this mechanism. As described in eq 4 above, it has
been observed that enol silane 2 reacts with propargyl acetate 4a at –78 °C, albeit in
lower conversion than under our oneꢀpot reaction conditions. In order to test whether or
not the presence of residual Et3N helps or hinders the carbonꢀcarbon bondꢀforming
reaction, a series of experiments at 0 °C, the optimal reaction temperature, was
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conducted. First, enol silane 2 and propargyl acetate 4a were simply mixed with 0.3
equiv TMSOTf and 0.2 equiv Et3N, the approximate amounts of these reagents that
would be present if 100% conversion of the ketone to the enol silane were to occur.
Under these conditions, 91% conversion to the desired product was observed (eq 6).
When only Et3N was present, however, the same attempted reaction provided no product,
which demonstrates that TMSOTf must be present to activate the acetate group (eq 7).
Finally, when only catalytic TMSOTf was present, enol silane 2 and propargyl acetate 4a
reacted in 94% conversion at 0 °C (eq 8). Together, these results indicate that the
presence of Et3N has no significant impact on the progression of the carbonꢀcarbon bondꢀ
forming step, but TMSOTf is catalytically active for the transformation.
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Once the optimal reaction conditions were determined, the scope of the oneꢀpot reaction
was examined. First, propargyl acetate 4a was reacted with a series of ketones, as
described in Table 1. Most aryl methyl ketones reacted with propargyl acetate 4a in high
yield,13 as shown in entries 1ꢀ3 and 6. The more sterically hindered 1ꢀacetonaphthone
and the electronꢀrich 4ꢀmethoxyacetophenone, however, provided relatively
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disappointing results (typically 70ꢀ80% conversion). Preliminary H NMR experiments
suggested that enol silane formation was slower for these ketones than for the other aryl
methyl ketones examined, which would allow decomposition of the propargyl cation to
compete with the desired reaction. Moreover, formation of the trimethylsilyl acetate
leaving group appears to be a thermodynamic sink, permanently removing TMSOTf from
the reaction mixture and reducing the likelihood of further enol silane formation.
Table 1. Nucleophile scope
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aReaction conditions: enol silane precursor (1.0 mmol), propargyl carboxylate (1.1
mmol), TMSOTf (1.3 mmol), Et3N (1.2 mmol), CH2Cl2 (5.0 mL), 0 °C, 2 h. bIsolated
yield after chromatography. cYield includes trace amount of allene byproduct. dYield
includes 4% allene byproduct.
This problem was solved by the replacement of the acetate group with a propionate
group, which provides two advantages. First, for steric reasons, coordination of the
TMSOTf with the carbonyl of the propionate is likely to be slower than coordination to
the acetate; ionization of the propionate is consequently slowed but the rate of enol silane
formation is not affected. In this situation, the higher concentration of the enol silane
would lead to a faster alkylation, which would be competitive with decomposition.
Second, previous work in our group has shown that trimethylsilyl acetate, which is the
byproduct of the ionization of propargyl acetate 4a, can be readily converted to the highly
nucleophilic bisꢀtrimethylsilyl ketene acetal in the presence of TMSOTf and an amine
base.9c Trimethylsilyl propionate, while still active under those conditions, reacts
considerably more slowly and is less likely to compete with our desired nucleophiles.
As shown in entries 4 and 5 of Table 1, propargyl propionate 4b reacted in good yield
when paired with 4ꢀmethoxyacetophenone and 1ꢀacetonaphthone. Because of the
advantages of the propionate ester described above, all subsequent reactions in this study
were examined with propargyl propionates rather than acetates. Indeed, the less active
ketone pinacolone was an effective reaction partner when paired with propargyl
propionate 4b, despite its steric hindrance and relatively high pKa in comparison to aryl
methyl ketones (entry 7). 14 A typical thioester also performed well (entry 8), but
attempted reactions with amide and ester pronucleophiles resulted only in the
decomposition of the electrophile.
With the nucleophile scope firmly established, an investigation into the scope of the
propargyl propionate reaction partner commenced. As illustrated in Table 2, a series of
propargyl propionates reacted in moderate to high yield when coupled with
acetophenone. Entries 1ꢀ5 describe substitution at the alkynyl position, demonstrating
that a range of aromatic groups as well as an alkyl group are all well tolerated. Only the
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triethylsilylꢀsubstituted substrate reacted in poor yield, with the remainder of the reaction
mixture consisting of decomposition products. Aryl substitution at the 1ꢀposition (R2) of
the propargyl propionate also led to good results (entries 6ꢀ11), but some relatively
electronꢀrich substrates did require a modification of the reaction conditions to achieve
high yield. Both the 4ꢀmethylphenyl substrate (entry 9) and the 4ꢀmethoxyphenyl
substrate (entry 10) reacted in poor yield when triethylamine was used as the base, but
performed well with the somewhat less basic Nꢀmethylmorpholine. In general, the
propargyl propionates represented in Table 2 were less reactive than standard propargyl
propionate 4b, and required additional TMSOTf in order to reach full conversion. The
amount of extra TMSOTf necessary varied by substrate, ranging from 0.1ꢀ0.55 equiv.
For best results, the propargyl propionate and the extra TMSOTf were added sequentially
after an incubation period of about 15 min. Not all substrates were entirely successful,
however, even under these modified conditions (entries 12ꢀ15). Substitution at the 1ꢀ
position with heteroaromatic groups (2ꢀfuryl, 2ꢀthiophenyl) or secondary alkyl groups
(cyclohexyl) led only to decomposition of the electrophile, and when the 1ꢀposition was
occupied by an ethyl group, no ionization was observed even at reflux (40 °C).15
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Table 2. Electrophile scope
aReaction conditions: 1. acetophenone (1.0 mmol), propargyl propionate (1.1 mmol),
Et3N (1.2 mmol), TMSOTf (1.3 mmol), CH2Cl2 (5.0 mL). 2. TMSOTf (0.1 – 0.55
b
equiv); see Experimental Section for details. Isolated yield after chromatography. cYield
includes 4% allene byproduct. dReaction performed at room temperature. eNꢀ
methylmorpholine used instead of Et3N.
Given the success with methyl ketones, extension to propiophenone was briefly
examined. Successful substitution of the propionate group of the electrophile 4b with
propiophenone generated product 5x as a 1:1 mixture of diastereomers in 97% yield (eq
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9). In order to achieve full conversion with this more sterically demanding nucleophile,
additional TMSOTf was added after cannula transfer of the in situꢀformed enol silane
into a solution of the propionate.
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The cyclization of βꢀalkynyl ketones analogous to products 5a-t to yield 2,3,5ꢀ
trisubstituted furans is well precedented in the literature,7 and has been achieved under
both basic and acidic conditions. Based on these precedents, and because TMSOTfꢀ
promoted cyclization would be a convenient addition to our oneꢀpot method, a brief
investigation into its feasibility was undertaken. Subjection of βꢀalkynyl ketone 5a to
TMSOTf in a variety of solvents provided little to no cyclization at room temperature,
but significant cyclization was observed in both toluene and cyclopentyl methyl ether
when those reactions were heated to reflux. In both cases, however, competing
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generation of a sparingly soluble yellow byproduct was observed. Analysis of the H
NMR spectrum of this byproduct showed it to be consistent with previous reports of the
2,4,6ꢀtriphenylpyrylium ion (7), illustrated in Figure 2. 16 This ion is known to be
generated in the presence of trifluoromethanesulfonic acid from dione 8,16a a byproduct
resulting from alkyne hydration that was also observed during the cyclization reaction of
substrate 5a. Despite these side reactions, a 61% yield of furan 6 was obtained via
TMSOTfꢀpromoted cyclization (eq 10). Attempts to incorporate the cyclization into the
oneꢀpot sequence failed, however. When direct cyclization reaction was attempted in one
pot starting from acetophenone and propargyl propionate 4b, addition product 5a was
observed; nonetheless, only trace cyclization occurred even when additional TMSOTf
and toluene were added and the reaction mixture was heated to reflux. This lack of
reactivity may attributable to the presence of the amine base and its derivatives in the
reaction mixture.17
Figure 2. Byproducts of cyclization reaction
In conclusion, a TMSOTfꢀpromoted oneꢀpot enol silane formationꢀαꢀalkylation reaction
with propargyl carboxylates has been realized. The TMSOTf plays two distinct roles in
the reaction, both in the formation of the enol silane and in the ionization of the propargyl
carboxylate. The reaction shows significant reaction scope with regard to the ketone
pronucleophile and the substitution pattern on the propargyl carboxylate. Cyclization to
yield the trisubstituted furan has been demonstrated.
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Experimental Section
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General. Reactions were carried out under an atmosphere of nitrogen with a septum cap
in ovenꢀdried glassware with magnetic stirring. Methylene chloride and toluene were
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purified by passage through a bed of activated alumina.
Trimethylsilyl
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trifluoromethanesulfonate (TMSOTf) was stored in a Schlenk flask under inert
atmosphere. Triethylamine was distilled from calcium hydride and stored in a Schlenk
flask under inert atmosphere. All other chemicals were used as received or prepared
according to literature precedent. Purification of reaction products was carried out by
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flash chromatography using silica gel (230ꢀ400 mesh).
Analytical thin layer
chromatography was performed on silica gel plates. Visualization was accomplished with
UV light and phosphomolybdic acid stain, followed by heating. Infrared spectra were
recorded on an FTꢀIR spectrometer. 1H NMR spectra were recorded on a 500 MHz
spectrometer or 300 MHz spectrometer, and are reported in ppm using solvent as an
internal standard (CDCl3 at 7.28 ppm). Data are reported as (ap = apparent, s = singlet, d
= doublet, t = triplet, q = quartet, sx = sextet, sp=septet, m = multiplet, b = broad;
coupling constant(s) in Hz; integration). Protonꢀdecoupled 13C NMR spectra were
recorded on a 125 MHz spectrometer or 75 MHz spectrometer, and are reported in ppm
using solvent as an internal standard (CDCl3 at 77.0 ppm). Highꢀresolution mass spectra
were obtained by electrospray ionization unless otherwise indicated. Melting points were
determined using a capillary melting point apparatus.
General Procedure A. Reactions with 1,3-diphenylprop-2-yn-1-yl acetate
To an ovenꢀdried flask under N2 atmosphere was added the 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl
acetate (1.10 mmol), methylene chloride (10 mL), ketone (1.00 mmol), and Et3N (167
ꢁL, 121 mg, 1.20 mmol). The reaction mixture was cooled to 0 °C and TMSOTf (235
ꢁL, 289 mg, 1.30 mmol) was added. The reaction mixture was stirred for 2 h. The
reaction mixture was passed through a column of silica (2 cm x 1 cm) with diethyl ether.
The solvent was removed in vacuo. Column chromatography of the residue (0 – 5%
EtOAc/hexanes) provided the product.
General Procedure B. Reactions with propargyl propionates
To an ovenꢀdried (flask 1) under N2 atmosphere was added the propargyl carboxylate
(1.10 mmol). To a separate ovenꢀdried flask under N2 atmosphere was added methylene
chloride (2.5 mL), ketone (1.00 mmol), Et3N (167 ꢁL, 121 mg, 1.20 mmol), and
TMSOTf (235 ꢁL, 289 mg, 1.30 mmol). Both flasks were cooled to 0 °C. After 15 min,
the contents of flask 2 were transferred via cannula into flask 1. Flask 2 was rinsed with
2.5 mL methylene chloride, then the rinse was transferred via cannula into flask 1.
Additional TMSOTf was added, and the reaction mixture was stirred for 2 h. The
reaction mixture was passed through a column of silica (2 cm x 1 cm) with diethyl ether.
The solvent was removed in vacuo. Column chromatography of the residue (0 – 5%
EtOAc/hexanes) provided the product.
1,3,5-Triphenylpent-4-yn-1-one (5a) The title compound3c was prepared according to
General Procedure A, using acetophenone (117 ꢀL, 120 mg, 1.00 mmol) and 1,3ꢀ
diphenylpropꢀ2ꢀynꢀ1yl acetate (250 mg, 1.00 mmol). The product was isolated as a white
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solid (267 mg, 86% yield): mp: 77ꢀ78 °C; IR 3084, 3063, 3029, 2903, 1680, 1488, 1361,
1206, 748, 686 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.05 – 7.99 (m, 2H), 7.63 – 7.56 (m,
3H), 7.53 – 7.46 (m, 2H), 7.45 – 7.38 (m, 4H), 7.34 – 7.29 (m, 4H), 4.72 (dd, J = 7.9, 6.2
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Hz, 1H), 3.72 (dd, J = 16.6, 7.9 Hz, 1H), 3.47 (dd, J = 16.6, 6.2 Hz, 1H); C NMR (125
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MHz, CDCl3) δ 197.1, 141.3, 136.9, 133.2, 131.7, 128.8, 128.7, 128.3, 128.2, 127.9,
127.7, 127.2, 123.5, 90.8, 83.4, 47.3, 33.8; HRMS (ESI, TOF): Exact mass calcd for
C23H18ONa [M+Na]+, 333.1250; found, 333.1262.
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1-(4-Fluorophenyl)-3,5-diphenylpent-4-yn-1-one (5b) The title compound 19 was
prepared according to General Procedure A, using 4ꢀfluoroacetophenone (121 ꢀL, 138
mg, 1.00 mmol) and 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl acetate (275 mg, 1.10 mmol). The
product was isolated as a white solid (271 mg, 83% yield): mp: 36ꢀ37 °C; IR 3089,
3036, 2933, 1666, 1592, 1506, 1488, 1322, 1258, 1234, 1159, 1026, 831, 756, 692 cmꢀ1;
1H NMR (500 MHz, CDCl3) δ 8.08 – 7.99 (m, 2H), 7.62 – 7.56 (m, 2H), 7.47 – 7.39 (m,
4H), 7.36 – 7.29 (m, 4H), 7.20 – 7.12 (m, 2H), 4.71 (dd, J = 7.9, 6.2 Hz, 1H), 3.69 (dd, J
= 16.6, 7.9 Hz, 1H), 3.43 (dd, J = 16.6, 6.2 Hz, 1H).13C NMR (125 MHz, CDCl3) δ
195.5, 165.9 (J = 255.0 Hz), 141.2, 133.4 (J = 3.0 Hz), 131.7, 130.9 (J = 9.3 Hz), 128.8,
128.2, 128.0, 127.6, 127.2, 123.4, 115.7 (J = 21.8 Hz), 90.7, 83.5, 47.2, 33.9.; HRMS
(ESI, TOF): Exact mass calcd for C23H17OFNa [M+Na]+, 351.1156; found, 351.1147.
1-(4-Bromophenyl)-3,5-diphenylpent-4-yn-1-one (5c) The title compound19 was
prepared according to General Procedure A, using 4ꢀbromoacetophenone (200 mg, 1.00
mmol) and 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl acetate (275 mg, 1.10 mmol). The product was
isolated as an offꢀwhite solid (351 mg, 90% yield): mp: 95ꢀ98 °C; IR 3089, 3060, 3032,
2917, 2897, 2856, 1679, 1584, 1488, 1397, 1202, 1068, 996, 819, 756, 724, 693 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 7.92 – 7.78 (m, 2H), 7.65 – 7.59 (m, 2H), 7.59 – 7.53 (m,
2H), 7.44 – 7.36 (m, 4H), 7.35 – 7.25 (m, 4H), 4.67 (dd, J = 7.9, 6.2 Hz, 1H), 3.66 (dd, J
= 16.6, 7.9 Hz, 1H), 3.41 (dd, J = 16.6, 6.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
196.1, 141.1, 135.6, 132.0, 131.7, 129.8, 128.8, 128.5, 128.2, 128.0, 127.6, 127.2, 123.3,
90.6, 83.6, 47.2, 33.8; HRMS (ESI, TOF): Exact mass calcd for C23H17OBrNa [M+Na]+,
411.0355; found, 411.0345.
1-(4-Methoxyphenyl)-3,5-diphenylpent-4-yn-1-one (5d) The title compound19 was
prepared according to General Procedure B, using 4ꢀmethoxyacetophenone (200 mg, 1.00
mmol) and 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl propionate (290 mg, 1.10 mmol). No additional
TMSOTf was added following the transfer via cannula. The product was isolated as a
pale yellow solid (252 mg, 74% yield): mp: 62ꢀ65 °C; IR 3080, 3055, 3023, 3009, 2963,
1
2935, 2896, 2840, 1673, 1597, 1486, 1257, 1168, 1024, 978, 827, 759, 693 cmꢀ1; H
NMR (500 MHz, CDCl3) δ 8.06 – 7.97 (m, 2H), 7.66 – 7.59 (m, 2H), 7.50 – 7.39 (m,
4H), 7.38 – 7.25 (m, 4H), 7.02 – 6.90 (m, 2H), 4.76 (dd, J = 7.8, 6.2 Hz, 1H), 3.85 (s,
3H), 3.69 (dd, J = 16.4, 7.8 Hz, 1H), 3.43 (dd, J = 16.4, 6.3 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 195.6, 163.7, 141.5, 131.7, 130.6, 130.1, 128.8, 128.3, 128.0, 127.7,
127.2, 123.6, 113.9, 91.2, 83.4, 55.5, 47.0, 34.0; HRMS (ESI, TOF): Exact mass calcd
for C24H20O2Na [M+Na]+, 363.1356; found, 363.1369.
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1-(Naphthalen-1-yl)-3,5-diphenylpent-4-yn-1-one (5e) The title compound19 was
prepared according to General Procedure B, using 1ꢀacetonaphthone (152 ꢀL, 200 mg,
1.00 mmol) and 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl propionate (291 mg, 1.10 mmol). No
additional TMSOTf was added following the transfer via cannula. The product was
isolated as a yellow oil (320 mg, 89% yield). Yield is corrected for 2 mol% 1ꢀ
1
acetonaphthone visible in H NMR spectrum: IR 3062, 2978, 2918, 2863, 2244, 1677,
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1597, 1490, 1442, 1242, 1103, 911, 802, 755, 690 cmꢀ1; H NMR (500 MHz, CDCl3) δ
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8.58 – 8.52 (m, 1H), 8.02 – 7.97 (m, 1H), 7.92 – 7.87 (m, 1H), 7.86 – 7.81 (m, 1H), 7.59
– 7.52 (m, 3H), 7.52 – 7.47 (m, 1H), 7.41 – 7.33 (m, 3H), 7.32 – 7.22 (m, 6H), 4.73 (dd, J
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= 8.4, 6.2 Hz, 1H), 3.72 (dd, J = 16.1, 8.4 Hz, 1H), 3.51 (dd, 1H); C NMR (126 MHz,
CDCl3) δ 201.5, 141.0, 136.2, 133.9, 132.6, 131.6, 130.1, 128.7, 128.4, 128.1, 127.9,
127.6, 127.4, 127.2, 126.5, 125.8, 124.3, 123.3, 90.5, 83.7, 50.8, 34.5; HRMS (ESI,
TOF): Exact mass calcd for C27H20ONa [M+Na]+, 383.1406; found, 383.1392.
1-(Naphthalen-2-yl)-3,5-diphenylpent-4-yn-1-one (5f) The title compound3e was
prepared according to General Procedure A, using 2ꢀacetonaphthone (171 mg, 1.00
mmol) and 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl acetate (275 mg, 1.10 mmol). The product was
isolated as an offꢀwhite solid (352 mg, 98% yield): mp: 99ꢀ100 °C; IR 3089, 3056, 3036,
1
2905, 1676, 1626, 1597, 1490, 1174, 1129, 819, 753, 699 cmꢀ1; H NMR (500 MHz,
CDCl3) δ 8.54 – 8.47 (m, 1H), 8.11 – 8.05 (m, 1H), 8.00 – 7.94 (m, 1H), 7.94 – 7.86 (m,
2H), 7.67 – 7.50 (m, 4H), 7.44 – 7.34 (m, 4H), 7.33 – 7.22 (m, 4H), 4.75 (dd, J = 7.8, 6.2
Hz, 1H), 3.84 (dd, J = 16.5, 7.9 Hz, 1H), 3.58 (dd, J = 16.5, 6.2 Hz, 1H). 13C NMR (126
MHz, CDCl3) δ 197.0, 141.3, 135.7, 134.3, 132.5, 131.7, 130.0, 129.6, 128.7, 128.6,
128.5, 128.1, 127.9, 127.8, 127.7, 127.1, 126.8, 123.9, 123.4, 90.8, 83.4, 47.4, 33.9;
HRMS (ESI, TOF): Exact mass calcd for C27H20ONa [M+Na]+, 383.1406; found,
383.1411.
2,2-Dimethyl-5,7-diphenylhept-6-yn-3-one (5g) The title compound7b was prepared
according to General Procedure B, using pinacolone (125 ꢀL, 100 mg, 1.00 mmol) and
1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl propionate (291 mg, 1.10 mmol). No additional TMSOTf was
added following the transfer via cannula. The product was isolated as a pale yellow solid
(273 mg, 94% yield): mp: 66ꢀ71 °C; IR 3078, 3058, 3030, 2970, 2938, 2907, 2867, 2232,
1704, 1597, 1498, 1362, 1087, 971, 763, 690 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.54 –
7.48 (m, 2H), 7.47 – 7.42 (m, 2H), 7.41 – 7.35 (m, 2H), 7.34 – 7.26 (m, 4H), 4.57 (dd, J
= 7.8, 6.4 Hz, 1H), 3.22 (dd, J = 16.8, 7.9 Hz, 1H), 2.93 (dd, J = 16.8, 6.4 Hz, 1H), 1.13
13
(s, 9H); C NMR (126 MHz, CDCl3) δ 212.2, 141.4, 131.6, 128.6, 128.2, 127.9, 127.6,
127.0, 123.5, 91.0, 82.9, 45.8, 44.1, 33.6, 25.9; HRMS (ESI, TOF): Exact mass calcd for
C21H22ONa [M+Na]+, 313.1563; found, 313.1551.
S-Phenyl 3,5-diphenylpent-4-ynethioate (5h) The title compound19 was prepared
according to a variation of General Procedure B, using Sꢀphenyl thioacetate (135 ꢀL, 152
mg, 1.00 mmol), 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl propionate (291 mg, 1.10 mmol) and a
different amount of TMSOTf (272 ꢀL, 333 mg, 1.50 mmol). Additional TMSOTf (10
ꢀL, 12 mg, 0.05 mmol) was added immediately after the contents of the flasks were
combined. The product was isolated as a yellow oil (260 mg, 76% yield): IR 3062, 3026,
1
1701, 1597, 1489, 1441, 1042, 1024, 961, 745, 689 cmꢀ1; H NMR (500 MHz, CDCl3) δ
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7.53 – 7.45 (m, 4H), 7.45 – 7.36 (m, 7H), 7.35 – 7.29 (m, 4H), 4.49 (dd, J = 8.3, 6.7 Hz,
1H), 3.25 (dd, J = 14.8, 8.3 Hz, 1H), 3.13 (dd, J = 14.8, 6.7 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 194.7, 140.0, 134.4, 131.7, 129.5, 129.2, 128.8, 128.2, 128.1, 127.6,
127.5, 127.4, 123.2, 89.3, 84.2, 51.6, 35.2; HRMS (ESI, TOF): Exact mass calcd for
C23H18OSNa [M+Na]+, 365.0971; found, 365.0962.
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5-(4-Chlorophenyl)-1,3-diphenylpent-4-yn-1-one (5i) The title compound19 was
prepared according to a variation of General Procedure B, using acetophenone (117 ꢀL,
120 mg, 1.00 mmol), 3ꢀ(4ꢀchlorophenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl propionate (328 mg,
1.10 mmol) and a different amount of triethylamine (209 ꢀL, 152 mg, 1.50 mmol).
Additional TMSOTf (100 ꢀL, 123 mg, 0.55 mmol) was added immediately after the
contents of the flasks were combined. The product was isolated as a white solid (290 mg,
84% yield): mp: 71ꢀ73 °C; IR 3062, 3031, 2911, 2844, 1684, 1600, 1489, 1449, 1088,
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1013, 833, 742, 699 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.04 – 7.98 (m, 2H), 7.62 –
7.58 (m, 1H), 7.58 – 7.54 (m, 2H), 7.52 – 7.47 (m, 2H), 7.43 – 7.38 (m, 2H), 7.34 – 7.29
(m, 3H), 7.29 – 7.25 (m, 2H), 4.69 (dd, J = 8.0, 6.0 Hz, 1H), 3.71 (dd, J = 16.7, 8.1 Hz,
1H), 3.46 (dd, J = 16.8, 6.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 197.0, 141.0, 136.8,
133.9, 133.3, 132.9, 128.8, 128.7, 128.5, 128.2, 127.6, 127.2, 121.9, 91.9, 82.2, 47.2,
33.8; HRMS (ESI, TOF): Exact mass calcd for C23H17OClNa [M+Na]+, 367.0860;
found, 367.0870.
5-(4-Pentylphenyl)-1,3-diphenylpent-4-yn-1-one (5j)
The title compound3c was
prepared according to a variation of General Procedure B, using acetophenone (117 ꢀL,
120 mg, 1.00 mmol) and 3ꢀ(4ꢀpentylphenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl propionate (368 mg,
1.10 mmol). Additional TMSOTf (20 ꢀL, 25 mg, 0.11 mmol) was added immediately
after the contents of the flasks were combined. The product was isolated as a yellow oil
(357 mg, 92% yield): IR 3026, 2958, 2930, 2851, 1685, 1609, 1448, 1354, 1261, 1205,
1
838, 747, 699 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.01 – 7.96 (m, 2H), 7.58 (ddt, J =
8.0, 6.9, 1.3 Hz, 1H), 7.56 – 7.53 (m, 2H), 7.50 – 7.45 (m, 2H), 7.39 – 7.34 (m, 2H), 7.31
– 7.25 (m, 3H), 7.11 – 7.07 (m, 2H), 4.66 (dd, J = 7.8, 6.3 Hz, 1H), 3.68 (dd, J = 16.6, 7.8
Hz, 1H), 3.43 (dd, J = 16.6, 6.3 Hz, 1H), 2.64 – 2.54 (m, 2H), 1.65 – 1.56 (m, 2H), 1.39 –
1.26 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 197.1, 143.0,
141.5, 137.0, 133.2, 131.6, 128.7, 128.6, 128.32, 128.26, 127.7, 127.1, 120.6, 90.1, 83.6,
47.4, 35.9, 33.9, 31.5, 31.0, 22.6, 14.1; HRMS (ESI, TOF): Exact mass calcd for
C28H28ONa [M+Na]+, 403.2032; found, 403.2035.
5-(4-Methoxyphenyl)-1,3-diphenylpent-4-yn-1-one (5k) The title compound19 was
prepared according to a variation of General Procedure B, using acetophenone (117 ꢀL,
120 mg, 1.00 mmol), 3ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl propionate (324 mg,
1.10 mmol) and a different amount of triethylamine (209 ꢀL, 152 mg, 1.50 mmol).
Additional TMSOTf (100 ꢀL, 123 mg, 0.55 mmol) was added immediately after the
contents of the flasks were combined. The product was isolated as an offꢀwhite solid
(205 mg, 60% yield): mp: 68ꢀ71 °C; IR 2967, 2931, 2852, 1682, 1510, 1290, 1249, 1172,
1
1025, 825, 757, 694 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.05 – 7.99 (m, 2H), 7.63 –
7.56 (m, 3H), 7.54 – 7.46 (m, 2H), 7.44 – 7.38 (m, 2H), 7.38 – 7.34 (m, 2H), 7.34 – 7.29
(m, 1H), 6.88 – 6.80 (m, 2H), 4.70 (dd, J = 7.9, 6.2 Hz, 1H), 3.81 (s, 3H), 3.71 (dd, J =
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16.6, 7.9 Hz, 1H), 3.46 (dd, J = 16.7, 6.2 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 197.2,
159.3, 141.5, 136.9, 133.3, 133.1, 128.75, 128.67, 128.3, 127.7, 127.1, 115.6, 113.8, 89.3,
83.2, 55.3, 47.4, 33.8; HRMS (ESI, TOF): Exact mass calcd for C24H20O2Na [M+Na]+,
363.1356; found, 363.1355.
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1,3-Diphenylnon-4-yn-1-one (5l)
The title compound3c was prepared according to a
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variation of General Procedure B, using acetophenone (117 ꢀL, 120 mg, 1.00 mmol), 1ꢀ
phenylheptꢀ2ꢀynꢀ1ꢀyl propionate (268 mg, 1.10 mmol). No additional TMSOTf was
added after the contents of the flasks were combined. The product was isolated as a
yellow oil (273 mg, 94% yield): IR 3072, 2957, 2931, 2867, 1686, 1598, 1494, 1448,
1
1254, 1206, 1002, 747, 697 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.00 – 7.94 (m, 2H),
7.61 – 7.55 (m, 1H), 7.52 – 7.44 (m, 4H), 7.39 – 7.33 (m, 2H), 7.30 – 7.24 (m, 1H), 4.44
(ddt, J = 8.3, 6.0, 2.3 Hz, 1H), 3.57 (dd, J = 16.4, 8.2 Hz, 1H), 3.30 (dd, J = 16.4, 6.0 Hz,
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1H), 2.20 (td, J = 7.0, 2.3 Hz, 2H), 1.51 – 1.34 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); C
NMR (126 MHz, CDCl3) δ 197.5, 142.0, 137.1, 133.1, 128.6, 128.5, 128.2, 127.5, 126.9,
83.6, 81.0, 47.7, 33.4, 31.0, 21.9, 18.5, 13.6; HRMS (ESI, TOF): Exact mass calcd for
C21H22ONa [M+Na]+, 313.1563; found, 313.1574.
1,3-Diphenyl-5-(triethylsilyl)pent-4-yn-1-one (5m) The title compound19 was prepared
according to a variation of General Procedure B, using acetophenone (117 ꢀL, 120 mg,
1.00 mmol), 1ꢀphenylꢀ3ꢀ(triethylsilyl)propꢀ2ꢀynꢀ1ꢀyl propionate (333 mg, 1.10 mmol)
and, instead of triethylamine, diisopropyl(ethyl)amine (261 ꢀL, 194 mg, 1.50 mmol).
Additional TMSOTf (20 ꢀL, 25 mg, 0.11 mmol) was added after the contents of the
flasks were combined. The product was isolated as a yellow oil (130 mg, 39% yield).
Yield is not corrected for the presence of significant unknown impurities evident in the
NMR spectra, roughly estimated at 25 mol%: IR 2954, 2910, 2874, 2177, 1688, 1494,
1
1449, 1255, 1017, 724, 689 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.00 – 7.95 (m, 2H),
7.60 – 7.56 (m, 1H), 7.55 – 7.51 (m, 2H), 7.50 – 7.45 (m, 2H), 7.39 – 7.35 (m, 2H), 7.31
– 7.25 (m, 1H), 4.55 (dd, J = 7.7, 6.4 Hz, 1H), 3.62 (dd, J = 16.4, 7.8 Hz, 1H), 3.34 (dd, J
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= 16.3, 6.4 Hz, 1H), 1.01 (t, J = 7.9 Hz, 9H), 0.61 (q, J = 7.7 Hz, 6H); C NMR (126
MHz, CDCl3) δ 197.2, 141.1, 137.1, 133.1, 128.61, 128.57, 128.2, 127.6, 127.0, 108.6,
84.9, 47.6, 34.4, 7.5, 4.5; HRMS (ESI, TOF): Exact mass calcd for C23H28OSiNa
[M+Na]+, 371.1802; found, 371.1796.
1,5-Diphenyl-3-(4-(trifluoromethyl)phenyl)pent-4-yn-1-one
(5n)
The
title
compound19 was prepared according to a variation of General Procedure B at room
temperature, using acetophenone (117 ꢀL, 120 mg, 1.00 mmol) and 3ꢀphenylꢀ1ꢀ(4ꢀ
(trifluoromethyl)phenyl)propꢀ2ꢀynꢀ1ꢀyl propionate (365 mg, 1.10 mmol). Additional
TMSOTf (100 ꢀL, 123 mg, 0.55 mmol) was added after the contents of the flasks were
combined. The product was isolated as a pale yellow solid (268 mg, 71% yield): mp: 82ꢀ
86 °C; IR 3087, 2908, 2851, 1679, 1328, 1161, 1126, 1108, 1069, 1019, 845, 759, 687
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cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.03 – 7.94 (m, 2H), 7.72 – 7.57 (m, 5H), 7.53 –
7.45 (m, 2H), 7.43 – 7.37 (m, 2H), 7.33 – 7.26 (m, 3H), 4.75 (ap t, J = 6.9 Hz, 1H), 3.71
(dd, J = 16.9, 7.1 Hz, 1H), 3.48 (dd, J = 16.9, 6.8 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ 196.4, 145.4, 136.9, 133.2, 131.6, 129.6 (d, J = 32.4 Hz), 128.6, 128.15, 128.12, 128.0
(double peak), 125.6 (q, J = 3.8 Hz), 123.1, 124.1 (d, J = 271.8 Hz), 89.8, 84.0, 46.9,
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33.6; HRMS (ESI, TOF): Exact mass calcd for C24H17OF3Na [M+Na]+, 401.1124;
found, 401.1122.
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3-(4-Fluorophenyl)-1,5-diphenylpent-4-yn-1-one (5o) The title compound19 was
prepared according to a variation of General Procedure B, using acetophenone (117 ꢀL,
120 mg, 1.00 mmol), 1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl propionate (310 mg,
1.10 mmol), and a different amount of triethylamine (209 ꢀL, 152 mg, 1.50 mmol).
Additional TMSOTf (100 ꢀL, 123 mg, 0.55 mmol) was added after the contents of the
flasks were combined. The product was isolated as a white solid (282 mg, 86% yield):
mp: 51ꢀ59 °C; IR 3082, 2930, 2905, 1679, 1595, 1508, 1489, 1413, 1228, 1206, 1184,
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1001, 838, 758, 687 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.05 – 7.98 (m, 2H), 7.65 –
7.58 (m, 1H), 7.57 – 7.52 (m, 2H), 7.52 – 7.47 (m, 2H), 7.46 – 7.40 (m, 2H), 7.36 – 7.29
(m, 3H), 7.12 – 7.04 (m, 2H), 4.71 (ap t, J = 7.0 Hz, 1H), 3.70 (dd, J = 16.8, 7.4 Hz, 1H),
3.46 (dd, J = 16.7, 6.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 196.9, 161.9 (d, J = 245.4
Hz), 137.1 (d, J = 3.2 Hz), 136.8, 133.3, 131.7, 129.3 (d, J = 8.0 Hz), 128.7, 128.24,
128.22, 128.1, 123.3, 115.5 (d, J = 21.5 Hz), 90.7, 83.5, 47.3, 33.0; HRMS (ESI, TOF):
Exact mass calcd for C23H17OFNa [M+Na]+, 351.1156; found, 351.1139.
3-(4-Bromophenyl)-1,5-diphenylpent-4-yn-1-one (5p) The title compound7a was
prepared according to a variation of General Procedure B, using acetophenone (117 ꢀL,
120 mg, 1.00 mmol) and 1ꢀ(4ꢀbromophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl propionate (378
mg, 1.10 mmol), and a different amount of triethylamine (209 ꢀL, 152 mg, 1.50 mmol).
Additional TMSOTf (20 ꢀL, 25 mg, 0.22 mmol) was added after the contents of the
flasks were combined. The product was isolated as an offꢀwhite solid (292 mg, 75%
yield): mp: 62ꢀ68 °C; IR 3062, 2975, 2927, 2896, 1670, 1489, 1304, 1259, 1010, 828,
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752, 688 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.06 – 7.95 (m, 2H), 7.60 (ddt, J = 8.6,
6.9, 1.3 Hz, 1H), 7.53 – 7.44 (m, 6H), 7.44 – 7.39 (m, 2H), 7.35 – 7.29 (m, 3H), 4.68 (ap
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t, J = 7.0 Hz, 1H), 3.69 (dd, J = 16.8, 7.3 Hz, 1H), 3.46 (dd, J = 16.8, 6.7 Hz, 1H); C
NMR (126 MHz, CDCl3) δ 196.7, 140.4, 136.7, 133.4, 131.8, 131.7, 129.5, 128.7, 128.3,
128.2, 128.1, 123.2, 121.0, 90.3, 83.6, 47.0, 33.2; HRMS (ESI, TOF): Exact mass calcd
for C23H17OBrNa [M+Na]+, 411.0355; found, 411.0371.
1,5-Diphenyl-3-(p-tolyl)pent-4-yn-1-one (5q) The title compound7a was prepared
according to a variation of General Procedure B, using acetophenone (117 ꢀL, 120 mg,
1.00 mmol) and 3ꢀphenylꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀynꢀ1ꢀyl propionate (334 mg, 1.20 mmol). In
the place of triethylamine, dicyclohexyl(methyl)amine was used (138 ꢀL, 127 mg, 1.25
mmol). Additional TMSOTf (100 ꢀL, 123 mg, 0.55 mmol) was added after the contents
of the flasks were combined. The product was isolated as a pale orange solid (266 mg,
82% yield): mp: 79ꢀ83 °C; IR 3087, 3032, 2963, 2908, 2854, 1679, 1329, 1206, 1109,
1069, 760, 693 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.02 – 7.96 (m, 2H), 7.58 (ddt, J =
8.5, 6.9, 1.3 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.45 – 7.40 (m, 2H), 7.40 – 7.34 (m, 2H), 7.29
– 7.25 (m, 3H), 7.21 – 7.15 (m, 2H), 4.63 (dd, J = 7.8, 6.3 Hz, 1H), 3.66 (dd, J = 16.5, 7.8
13
Hz, 1H), 3.42 (dd, J = 16.5, 6.3 Hz, 1H), 2.36 (s, 3H); C NMR (126 MHz, CDCl3) δ
197.1, 158.8, 137.3, 133.4, 132.9, 131.6, 128.5, 128.5, 128.2, 128.0, 127.7, 123.6, 114.2,
91.2, 83.3, 55.3, 47.4, 33.2; HRMS (ESI, TOF): Exact mass calcd for C24H20ONa
[M+Na]+, 347.1406; found, 347.1409.
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3-(4-Methoxyphenyl)-1,5-diphenylpent-4-yn-1-one (5r)
The title compound7a was
prepared according to a variation of General Procedure B, using acetophenone (117 ꢀL,
120 mg, 1.00 mmol) and 1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl propionate (353
mg, 1.20 mmol). In the place of triethylamine, dicyclohexyl(methyl)amine was used
(138 ꢀL, 127 mg, 1.25 mmol). Additional TMSOTf (100 ꢀL, 123 mg, 0.55 mmol) was
added after the contents of the flasks were combined. The product was isolated as a
white solid (271 mg, 84% yield): mp: 98ꢀ100 °C; IR 3087, 3058, 3035, 2949, 2931, 2900,
1679, 1512, 1245, 1205, 1027, 832, 727, 692 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.01 –
7.96 (m, 2H), 7.61 – 7.55 (m, 1H), 7.50 – 7.42 (m, 4H), 7.39 – 7.35 (m, 2H), 7.30 – 7.25
(m, 3H), 6.94 – 6.88 (m, 2H), 4.62 (dd, J = 7.6, 6.6 Hz, 1H), 3.82 (s, 3H), 3.65 (dd, J =
16.4, 7.6 Hz, 1H), 3.41 (dd, J = 16.5, 6.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 197.1,
158.8, 137.3, 133.4, 132.9, 131.6, 128.53, 128.51, 128.2, 128.0, 127.7, 123.6, 114.2, 91.2,
83.3, 55.3, 47.4, 33.2; HRMS (ESI, TOF): Exact mass calcd for C24H20O2Na [M+Na]+,
363.1356; found, 363.1348.
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3-(Naphthalen-2-yl)-1,5-diphenylpent-4-yn-1-one (5s) The title compound19 was
prepared according to a variation of General Procedure B on a 0.5 mmol scale, using
acetophenone (59 ꢀL, 61 mg, 0.51 mmol), 1ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl
propionate (175 mg, 0.56 mmol), triethylamine (85 ꢀL, 62 mg, 0.61 mmol), TMSOTf
(119 ꢀL, 146 mg, 0.66 mmol), and methylene chloride (6 mL). Additional TMSOTf (40
mL, 49 mg, 0.22 mmol) was added after the contents of the flasks were combined. The
product was isolated as a white solid (148 mg, 80% yield): mp: 93ꢀ98 °C; IR 3057, 3023,
1
2881, 1681, 1606, 1489, 1262, 1208, 979, 824, 756, 688 cmꢀ1; H NMR (500 MHz,
CDCl3) δ 8.05 – 7.97 (m 3H), 7.94 – 7.80 (m, 3H), 7.68 (d, J = 8.4 Hz, 1H), 7.58 (t, J =
7.4 Hz, 1H), 7.55 – 7.35 (m, 6H), 7.36 – 7.19 (m, 3H), 4.86 (ap t, J = 7.1 Hz, 1H), 3.78
(dd, J = 16.7, 7.8 Hz, 1H), 3.55 (dd, J = 16.7, 6.3 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ 197.0, 138.6, 136.9, 133.5, 133.2, 132.6, 131.7, 128.6, 128.5, 128.17, 128.23, 127.93,
127.88, 127.6, 126.3, 126.2, 125.83, 125.80, 123.4, 90.8, 83.6, 47.1, 33.9; HRMS (ESI,
TOF): Exact mass calcd for C27H20ONa [M+Na]+, 383.1406; found, 383.1402.
2-Methyl-1,3,5-triphenylpent-4-yn-1-one (5x) The title compound19 was prepared
according to General Procedure B, using propiophenone (133 ꢀL, 134 mg, 1.00 mmol)
and 1,3ꢀdiphenylpropꢀ2ꢀynꢀ1yl acetate (291 mg, 1.10 mmol). Additional TMSOTf (100
ꢀL, 123 mg, 0.55 mmol) was added after the contents of the flasks were combined. The
product was isolated as a pale yellow oil consisting of a 1:1 mixture of diastereomers,
including 5% allene (314 mg, 97% yield): IR 3066, 3027, 2971, 2935, 2876, 1680, 1596,
1447, 1239, 1207, 966, 908, 756, 730, 690 cmꢀ1; HRMS (ESI, TOF): Exact mass calcd
for C24H20ONa [M+Na]+, 347.1406; found, 347.1399.
Diastereomer A:
1H NMR (500 MHz, CDCl3) δ 8.14 – 8.06 (m, 2H), 7.65 – 7.59 (m, 1H), 7.55 – 7.50 (m,
2H), 7.50 – 7.44 (m, 3H), 7.43 – 7.37 (m, 2H), 7.36 – 7.30 (m, 1H), 7.24 – 7.15 (m, 2H),
7.14 – 7.10 (m, 2H), 4.17 (d, J = 9.6 Hz, 1H), 4.03 – 3.96 (m, 1H), 1.07 (d, J = 6.8 Hz,
13
3H); C NMR (126 MHz, CDCl3) δ 203.0, 139.4, 137.2, 133.1, 131.5, 128.66, 128.62,
128.57, 128.51, 127.99, 127.8, 127.4, 123.3, 90.7, 83.8, 47.7, 41.6, 16.1.
Diastereomer B:
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1H NMR (500 MHz, CDCl3) δ 7.85 – 7.78 (m, 2H), 7.55 – 7.50 (m, 1H), 7.50 – 7.44 (m,
3H), 7.43 – 7.37 (m, 2H), 7.36 – 7.30 (m, 3H), 7.28 – 7.25 (m, 2H), 7.24 – 7.15 (m, 2H),
4.42 (d, J = 8.7 Hz, 1H), 3.96 – 3.90 (m, 1H), 1.49 (d, J = 6.9 Hz, 3H); C NMR (126
MHz, CDCl3) δ 202.3, 140.4, 136.7, 133.0, 131.7, 128.72, 128.59, 128.3, 128.2, 128.1,
128.02, 127.1, 123.5, 89.6, 84.9, 48.0, 41.4, 16.4.
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2-Benzyl-3,5-diphenylfuran (6) To an ovenꢀdried flask under N2 was added compound
5a (1,3,5ꢀtriphenylpentꢀ4ꢀynꢀ1ꢀone, 311 mg, 1.0 mmol). The substrate was dissolved in
toluene (2.5 mL) and TMSOTf (180 ꢀL, 221 mg, 1.0 mmol) was added dropwise. The
flask was fitted with a reflux condenser and heated at reflux (110 °C) for 2 h. The
reaction mixture was allowed to cool to room temperature, then diluted with Et2O (150
mL) and washed with saturated NaHCO3 (50 mL). The layers were separated and the
organic layer was dried over MgSO4. The solution was filtered and the solvent was
removed in vacuo. The title compound20 was purified by column chromatography on
silica gel (0ꢀ2% EtOAc/hexanes) to yield a yellow oil contaminated with ~10% of an
unidentified impurity (189 mg, 61% yield): IR 3086, 3062, 3031, 1596, 1494, 1453,
1124, 985, 756, 727, 690 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.76 – 7.67 (m, 2H), 7.48
13
– 7.38 (m, 6H), 7.37 – 7.29 (m, 5H), 7.28 – 7.23 (m, 2H), 6.85 (s, 1H), 4.23 (s, 2H); C
NMR (126 MHz, CDCl3) δ 152.5, 149.0, 138.5, 133.8, 130.8, 128.67, 128.65, 128.61,
128.4, 127.7, 127.2, 126.8, 126.4, 124.5, 123.6, 106.6, 33.0.; HRMS (ESI, TOF): Exact
mass calcd for C23H17O [M–H]+, 309.1274; found, 309.1288.
SUPPORTING INFORMATION
Table of reaction optimization experiments and H and C NMR data for products 5aꢀs,
5x, and 6.
1
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ACKNOWLEDGMENTS
We thank the Donors of the American Chemical Society Petroleum Research Fund for
partial support of this research (55852ꢀUR1). Y.L. and E.D.H. gratefully acknowledge
the University of Richmond Department of Chemistry for summer research fellowships.
REFERENCES
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Asymmetric Alkylation of Ketones: Still Unconquered” Angew. Chem. Int. Ed. 2017, 56,
9278ꢀ9290; (b) Huang, F.; Liu, Z.; Yu, Z. “CꢀAlkylation of Ketones and Related
Compounds by Alcohols: TransitionꢀMetalꢀCatalyzed Dehydrogenation” Angew. Chem.
Int. Ed. 2016, 55, 862ꢀ875; (c) Wu, G.; Huang, M. “Organolithium Reagents in
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2 (a) Mendoza, O.; Rossey, G.; Ghosez, L. “Trialkylsilyl triflimides as easily tunable
organocatalysts for allylation and benzylation of silyl carbon nucleophiles with nonꢀ
genotoxic reagents” Tetrahedron Lett. 2010, 51, 2571ꢀ2575; (b) Brown, Adam R.; Kuo,
WenꢀHsin; Jacobsen, Eric N. “Enantioselective Catalytic αꢀAlkylation of Aldehydes via
an SN1 Pathway” J. Am. Chem. Soc. 2010, 132, 9286ꢀ9288; (c) Ishikawa, T.; Aikawa, T.;
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Mori, Y.; Saito, S. “Lewis AcidꢀCatalyzed Nucleophilic Substitutions of Propargylic and
Allylic Silyl Ethers with Enol Silyl Ethers” Org. Lett. 2003, 5, 51ꢀ54.
3 For Ir(I) catalysis, see: (a) Matsuda, I.; Komori, K.; Itoh, K. “Irꢀcatalyzed Substitution
of PropargylicꢀType Esters with Enoxysilanes” J. Am. Chem. Soc. 2002, 124, 9072ꢀ9073.
For Cu(II) catalysis, see: (b) Zhan, Z.; Wang, S.; Cai, X.; Liu, H.; Yu, J.; Cui, Y.
“Copper(II) TriflateꢀCatalyzed Nucleophilic Substitution of Propargylic Acetates with
Enoxysilanes. A Straightforward Synthetic Route to Polysubstituted Furans” Adv. Synth.
Catal. 2007, 349, 2097ꢀ2102. For Fe(III) catalysis, see: (c) Zhan, Z.; Cai, X.; Wang, S.;
Yu, J.; Liu, H.; Cui, Y. “FeCl3ꢀCatalyzed Nucleophilic Substitution of Propargylic
Acetates with Enoxysilanes” J. Org. Chem. 2007, 72, 9838ꢀ9841. For In(III) catalysis in
a related system, see: (d) Lin, M.; Hao, L.; Ma, R.; Zhan, Z. “A novel indiumꢀcatalyzed
threeꢀcomponent reaction: general and efficient oneꢀpot synthesis of substituted pyrroles”
Synlett 2010, 2345ꢀ2351. For an example with Ag(I)ꢀcatalyzed activation of a parent
propargylic alcohol, see: (e) Naveen, N.; Koppolu, S. R.; Balamurugan, R. “Silver
hexafluoroantimonateꢀcatalyzed direct αꢀalkylation of unactivated ketones” Adv. Synth.
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4 Nicolaou, K. C.; Sun, Y.ꢀP.; Peng, X.ꢀS.; Polet, D.; Chen, D. Y.ꢀK. “Total Synthesis of
(+)ꢀCortistatin A” Angew. Chem. Int. Ed. 2008, 47, 7310ꢀ7313.
5 Chuang, K. V.; Xu, C.; Reisman, S. E. “A 15ꢀStep Synthesis of (+)ꢀRyanodol” Science
2016, 353, 912ꢀ915.
6 Chu, S.; Muenster, N.; Balan, T.; Smith, M. D. “A Cascade Strategy Enables a Total
Synthesis of (±)ꢀMorphine” Angew. Chem. Int. Ed. 2016, 55, 14306ꢀ14309
7 For the cyclization of furan precursors similar to those in this report, see: (a) Campos,
C. A.; Gianino, J. B.; Ashfeld, B. L. “Bifunctional Titanocene Catalysis in
Multicomponent Couplings: A Convergent Assembly of βꢀAlkynyl Ketones” Org. Lett.
2013, 15, 2656ꢀ2659; (b) Capreti, N. M. R.; Jurberg, I. D. “Michael Addition of Soft
Carbon Nucleophiles to Alkylidene Isoxazolꢀ5ꢀones: A Divergent Entry to βꢀBranched
Carbonyl Compounds” Org. Lett. 2015, 17, 2490ꢀ2493; (c) Belting, V.; Krause, N.
“Goldꢀcatalyzed cycloisomerization of alkꢀ4ꢀynꢀ1ꢀones” Org. Biomol. Chem. 2009, 7,
1221ꢀ1225; (d) Arcadi, A.; Marinelli, F.; Pini, E.; Rossi, E. “Baseꢀpromoted reactions of
4ꢀpentynones” Tetrahedron Lett. 1996, 37, 3387ꢀ3390.
8 Jacobsen et al. recently described the activation of tertiary propargyl acetates with
TMSOTf for the enantioselective alkylation of allylsilanes. See: Wendlandt, A. E.;
Vangal, P.; Jacobsen, E. N. “Quaternary Stereocentres via an Enantioconvergent
Catalytic SN1 Reaction” Nature 2018, 556, 447ꢀ451.
9 (a) Downey, C. W.; Johnson, M. W. “A Tandem Enol Silane FormationꢀMukaiyama
Aldol Reaction Mediated by TMSOTf” Tetrahedron Lett. 2007, 48, 3559ꢀ3562; (b)
Downey, C. W.; Johnson, M. W.; Tracy, K. J. “OneꢀPot Enol Silane Formationꢀ
Mukaiyama AldolꢀType Addition to Dimethyl Acetals Mediated by TMSOTf” J. Org.
Chem. 2008, 73, 3299ꢀ3302; (c) Downey, C. W.; Johnson, M. W.; Lawrence, D. H.;
Fleisher, A. S.; Tracy, K. J. “Acetic Acid Aldol Reactions in the Presence of
Trimethylsilyl Trifluoromethanesulfonate” J. Org. Chem. 2010, 75, 5351ꢀ5354; (d)
Downey, C. W.; Dombrowski, C. M.; Maxwell, E. N.; Safran, C. L.; Akomah, O. A.
“OneꢀPot Enol Silane FormationꢀMukaiyama–Mannich Addition of Ketones, Amides,
and Thioesters to Nitrones in the Presence of Trialkylsilyl Trifluoromethanesulfonates”
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Eur. J. Org. Chem. 2013, 5716ꢀ5720; (e) Downey, C. W.; Covington, S. E.; Obenschain,
D. C.; Halliday, E.; Rague, J. T.; Confair, D. N. “Silyl Trifluoromethanesulfonateꢀ
Activated paraꢀMethoxybenzyl Methyl Ether as an Alkylating Agent for Thiols and Aryl
Ketones” Tetrahedron Lett. 2014, 55, 5213ꢀ5215; (f) Downey, C. W.; Ingersoll, J. A.;
Glist, H. M.; Dombrowski, C. M.; Barnett, A. T. “OneꢀPot Silyl Ketene Acetalꢀ
Formation Mukaiyama–Mannich Additions to Imines Mediated by Trimethylsilyl
Trifluoromethanesulfonate” Eur. J. Org. Chem. 2015, 7287ꢀ7291; (g) Downey, C. W.;
Glist, H. M.; Takashima, A.; Bottum, S. R.; Dixon, G. J. “Chalcone and Cinnamate
Synthesis via OneꢀPot Enol Silane FormationꢀMukaiyama Aldol Reactions of Ketones
and Acetate Esters” Tetrahedron Lett. 2018, 59, 3080ꢀ3083.
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10 Deoxygenation of propargyl alcohols with Et3SiH under various conditions is known.
For some recent examples, see: (a) Michelet, B.; Tang, S.; Thiery, G.; Monot, J.; Li, H.;
Guillot, R.; Bour, C.; Gandon, V. “Catalytic applications of [IPr·GaX2][SbF6] and
related species” Org. Chem. Frontiers 2016, 3, 1603ꢀ1613; (b) Narayana Kumar, G. G.
K. S.; Laali, K. K. “Facile coupling of propargylic, allylic and benzylic alcohols with
allylsilane and alkynylsilane, and their deoxygenation with Et3SiH, catalyzed by
Bi(OTf)3 in [BMIM][BF4] ionic liquid (IL), with recycling and reuse of the IL” Org.
Biomol. Chem. 2012, 10, 7347ꢀ7355; (c) Meyer, V. J.; Niggemann, M. “Highly
Chemoselective CalciumꢀCatalyzed Propargylic Deoxygenation” Chem. Eur. J. 2012, 18,
4687ꢀ4691. (d) Egi, M.; Kawai, T.; Umemura, M.; Akai, S. “HeteropolyacidꢀCatalyzed
Direct Deoxygenation of Propargyl and Allyl Alcohols” J. Org. Chem. 2012, 77, 7092ꢀ
7097.
11 For a similar synthesis of this product catalyzed by Cu(OTf2), see: Huang, G.ꢀB.;
Wang, X.; Pan, Y.ꢀM.; Wang, H.ꢀS.; Yao, G.ꢀY.; Zhang, Y. “AtomꢀEconomical
Chemoselective Synthesis of 1,4ꢀEnynes from Terminal Alkenes and Propargylic
Alcohols Catalyzed by Cu(OTf)2” J. Org. Chem. 2013, 78, 2742ꢀ2745.
12 For a table that illustrates key experiments in the optimization of this reaction, see the
Supporting Information.
13 Small quantities of allenyl byproducts were observed with several substrate pairs. The
allenyl product displays a characteristic pair of doublets of doublets that appears between
3.8 ppm and 4.3 ppm in the 1H NMR spectrum. For a description of the longꢀrange
coupling that generates this splitting pattern, see: Santelli, M. “LongꢀRange Proton Spinꢀ
Spin Coupling in Allenic Compounds” Chem Commun. 1971, 938ꢀ939.
14 The pKa value for acetophenone in DMSO is 24.7. See: (a) Bordwell, F. G.
“Equilibrium Acidities in Dimethyl Sulfoxide Solution” Acc. Chem. Res. 1988, 21, 456ꢀ
463. The pKa value for pinacolone in DMSO is 27.7. See: (b) Bordwell, F. G.;
Harrelson, J. A. “Acidities and hemolytic bond dissociation energies of the α C–H bonds
in ketones in DMSO” Can. J. Chem. 1990, 1714ꢀ1718.
15 For the 1ꢀethylꢀsubstituted propargyl carboxylate, replacement of the propionyl group
with a trifluoroacetyl group provided a propargyl trifluoroacetate that was also unreactive
under the standard reaction conditions.
16 For reported spectra of this compound, see: (a) Funston, A.; Kirby, J. P.; Miller, J. R.;
Pospisil, L.; Fiedler, J.; Hromadova, M.; Gal, M.; Pecka, J.; Valasek, M.; Zawada, Z.;
Rempala, P.; Michl, J. “OneꢀElectron Reduction of an "Extended Viologen" pꢀ
Phenyleneꢀbisꢀ4,4'ꢀ(1ꢀarylꢀ2,6ꢀdiphenylpyridinium) Dication” J. Phys. Chem. A. 2005,
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109, 10862ꢀ10869; (b) Katritzky, A. R.; ElꢀMowafy, A. M.; Marzorati, L.; Patel, R. C.;
Thind, S. S. “The preparation of 2,4,6ꢀtriphenylpyrylium trifluoromethanesulfonate,
fluorosulfonate, ethoxysulfonate, naphthaleneꢀ2ꢀsulfonate, stannochloride,
trichloroacetate, and trifluoroacetate, and their reactions with primary amines” J. Chem.
Res., Synop. 1980, 310ꢀ311.
17 When pure product 5a was heated in the presence of both TMSOTf and amine base,
<5% conversion to the desired furan was observed.
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18 Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. “Safe
and Convenient Procedure for Solvent Purification” Organometallics 1996, 15, 1518ꢀ
1520.
19 This compound is unknown in the literature.
20 Kang, J. Y.; Connell, B. T. “Synthesis of Substituted Acetylenic Epoxides Followed by
IndiumꢀCatalyzed Rearrangement to 2,3,5ꢀTrisubstituted Furans” J. Org. Chem. 2011,
76, 2379ꢀ2383.
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