Br?nsted Acid-Catalyzed Reactions of Trifluoroborate Salts with Benzhydryl Alcohols

Article abstract of DOI:10.1021/acs.joc.5b02273

Br?nsted acid-catalyzed carbon-carbon bond forming methodology using potassium alkynyl- and alkenyltrifluoroborate salts has been developed. Organotrifluoroborates react with benzhydryl alcohols to afford a broad range of alkynes and alkenes in good to excellent yields. This protocol features good atom economy because organotrifluoroborate salts and alcohols react in a 1:1 ratio. Furthermore, a variety of unprotected functional groups were tolerated under the developed conditions, including amide, aldehyde, free hydroxyl, and carboxylic acid.

Full text of DOI:10.1021/acs.joc.5b02273

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Note
Brønsted Acid-Catalyzed Reactions of
Trifluoroborate Salts with Benzhydryl Alcohols
Kayla M. Fisher, and Yuri Bolshan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02273 • Publication Date (Web): 20 Nov 2015
Downloaded from http://pubs.acs.org on November 23, 2015
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Brønsted Acid-Catalyzed Reactions of Trifluoroborate Salts with
Benzhydryl Alcohols
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Kayla M. Fisher and Yuri Bolshan*
University of Ontario Institute of Technology (UOIT) 2000 Simcoe Street North, Oshawa,
Ontario, Canada L1H 7K4.
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E-mail: yuri.bolshan@uoit.ca
Abstract: Brønsted acid-catalyzed carbon-carbon bond forming methodology using
potassium alkynyl- and alkenyltrifluoroborate salts has been developed.
Organotrifluoroborates react with benzhydryl alcohols to afford a broad range of alkynes
and alkenes in good to excellent yields. This protocol features good atom economy since
organotrifluoroborate salts and alcohols react in 1:1 ratio. Furthermore, a variety of
unprotected functional groups were tolerated under the developed conditions including
amide, aldehyde, free hydroxyl, and carboxylic acid.
Internal alkynes are important building blocks in organic chemistry and are a common structural
unit in a vast array of pharmaceuticals, bioactive compounds and natural products1. They are
traditionally synthesized via harsh reaction conditions through substitution2 or elimination3
reactions. Metal catalysis emerged as an alternative to the classic approaches.4 In addition,
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reactions of trichloroacetimidates in the presence of AuCl/AgOTf5 as well as secondary halides6
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and N-Tosylhydrazones7 using Pd catalysts have been reported. Furthermore, a direct C-H
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functionalization of benzylic position using DDQ and either CuOTf8 or Fe(OTf)2 is also known.
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Moreover, FeCl3-catalyzed direct nucleophilic substitutions of ethers using carbon nucleophiles10
and the cross-coupling of N-benzylic sulfonamides with terminal alkynes in the presence of
catalytic amounts of Bi(OTf)3 and (Tf)2NH11 have been reported. More recently, a direct metal-
catalyzed dehydrative coupling of diarylmethanols to synthesize bis-benzylic secondary
alkylacetylenes has gained attention due to its atom economy.12 Numerous diarylmethanol
derivatives are commercially available and can be easily prepared. Metal-catalyzed alkenylation
of benzhydryl alcohols is also known.13 Recently, Gandon and co-workers reported that Ca(NTf2)2
catalyzed the alkenylation of alcohols using two equivalents of vinylboronic acids.14 Common
disadvantages of metal-catalyzed approach include the employment of oftentimes expensive and
sensitive metal catalysts, which results in low functional group tolerance. Kabalka and co-workers
described a metal-free methodology for the substitution of hydroxyl groups of benzylic alcohols
with preformed alkenyl- and alkynylboron dihalides.15 The same group reported dialkynylation of
aldehydes using preformed dialkynylboron chlorides.16 Other metal-free alkenylation reactions of
benzhydryl alcohols have also been described in the literature.17 Furthermore, Schaus and co-
workers illustrated that the enantioselective alkenylation of benzhydryl alcohols and ethers
proceeded in the presence of alkenylboronates and chiral biphenols.18 More recently, acid-
catalyzed propargylation of phenols has been developed.19 The limitations of these protocols
include the exposure of both starting materials to n-BuLi, the necessity to preform unstable
haloborane intermediates and narrow substrate scope.
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Our research is focused on metal-free reactions of trifluoroborate salts. In general,
organotrifluoroborates are attractive reagents due to their shelf-stability, straightforward
preparation, and relative non-toxic nature.20 They have been shown to act as boronic acid
equivalents in the palladium-catalyzed Suzuki-Miyaura couplings.21 Recently, our group23g,h and
others reported metal-free transformations of organotrifluoroborates.22,23 Generally, these
reactions rely on in situ generation of boron dihalide species using strong Lewis acids. These
approaches, however, suffer from low functional group tolerance due to the instability of boron
dihalide intermediates.
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Recently, we developed a Brønsted acid-catalyzed methodology for the preparation of propargylic
ethers from acetals and alkynyltrifluoroborates.24 Here, we report a Brønsted acid-catalyzed
reaction between trifluoroborate salts and benzhydryl alcohols. At the outset, we envisaged that
the employment of the appropriate acid would address the deficiencies associated with previously
reported Lewis acid- and metal-catalyzed protocols. Nucleophilic boron-ate complexes are known
to react with pre-formed stabilized carbocations.25 However, examples of their generation in situ
using a Brønsted acid in the presence of trifluoroborates under metal-free conditions are scarce. In
addition to the recently published manuscript from this laboratory,24 literature survey indicated
that organotrifluoroborates have been shown to participate in reactions whereby Brønsted acids
are present.26 In these cases, however, either HF or KHF2 have been used as additives. Both
reagents are known to serve as sources of fluoride for the conversion of boronic acids or boronate
esters to trifluoroborates.,27 Allylation-like addition of trifluoroborates to aldehydes has been
reported in the presence of trifluoromethanesulfonic acid.28 This protocol, however, was
mechanistically similar to Lewis acid-catalyzed transformations due to the formation of boron
dihalide intermediate. After careful consideration, we decided to utilize tetrafluoroboric acid
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(HBF4) as a catalyst. It has a pKa = 0.5 in water,29 which is strong enough to promote the formation
of benzhydrylium carbocations from diarylmethanols.30 Therefore, our initial efforts were focused
on the preparation of secondary alkylacetylene 1a from diphenylmethanol and potassium
phenylacetylenetrifluoroborate salt S1 (Table 1).
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A screen of solvents revealed that acetonitrile (CH3CN) was well suited for the reaction (Table 1,
entries 1-4). Conducting a reaction in the presence of substoichiometric amount of HBF4 resulted
in the formation of the inseparable mixture of product 1a and undesired dibenzhydryl ether by-
product 4a (Table 1, entry 3). By gradually increasing the amount of HBF4 we discovered that the
optimal acid loading was 1.6 equivalents (Table 1, entry 6). These results were consistent with the
findings that increasing the amount of HBF4 suppressed the formation of undesired dimer 4a.
Efforts to use alternative acids such as HCl and HSbF6·6H2O only resulted in trace amounts of
product formation (Table 1, entries 7, 8). Interestingly, the yield decreased from 41% to 34% when
the reaction was conducted under anhydrous conditions (Table 1, entry 9). Further attempts to
optimize the reaction temperature and relative equivalents of alcohol or trifluoroborate salts were
fruitless.
TABLE 1. Optimization of Conditions for the Preparation of Secondary Alkylacetylene 1a
Entry
Acid
Acid
(eq.)
1.0
Solvent
yield
1a (%)
trace
Ratio
1a : 4a
1
2
3a
4a
5a
6
HBF4·OEt2
HBF4·OEt2
HBF4·OEt2
HBF4·OEt2
HBF4·OEt2
HBF4·OEt2
DCM
1.6
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
trace
0.5
1 : 1
1 : 0
25:1
1 : 0
1.0
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37
41
1.2
1.6
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9b
4.0 M HCl
HSbF6·6H2O
HBF4·OEt2
1.6
1.5
1.6
CH3CN
CH3CN
CH3CN
trace
trace
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1 : 0
aThe ratio has been determined by NMR analysis of crude reaction mixtures. bAnhydrous conditions.
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The investigation on the substituent effects revealed that electron-donating substituents result in
higher yields (Figure 1). For instance, the presence of 4-methyl substituent increased the yield of
1b to 67% compared to 41% for the unsubstituted product 1a. The reaction exhibited mild
sensitivity to the steric hindrance. The yield of the 2-methyl substituted substrate 1c was 51%.
Electron-rich substrates afforded the desired products 1d and 1e in excellent yields. Notably, a
scale-up reaction afforded 0.20 g of 1d with 10% yield erosion. Starting material bearing 4-chloro
substituent resulted in the formation the corresponding product 1f only in 19%. Electron-
withdrawing substituents destabilize the carbocation intermediate, thus, resulting in the formation
of unidentified by-products. Efforts to decrease the reaction temperature to -40oC led to the
competing formation of the dimer 4a. This issue, however, can be alleviated by the introduction of
an electron-donating functionality to offset the destabilizing effect. Product 1g with 4-chloro-4’-
methoxy substituents was isolated in 84% yield. Next, we decided to expand the scope to
unprotected protic functional groups. Free phenol and amide containing substrates afforded
products 1h and 1i in 66% and 61% yield respectively. Modest 42% yield of 1j was observed when
carboxylic acid functional group was present. The yield increased to 62% when the amount of
HBF4 was decreased to 1.3 equivalents.
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FIGURE 1. Reactions of Phenylacetylenetrifluoroborate Salt with Benzhydryl Alcohols
a1.3 equiv. of HBF4 was used.
Next, we investigated the scope of potassium alkynyltrifluoroborate salts. Their reactivity was
examined under the optimized conditions (Figure 2). Good to excellent yields were observed with
a wide range of salts such as trifluoromethyl-, chloro-, and fluorophenylacetylenetrifluoroborates.
Unsubstituted biphenyl- and naphthylacetylenetrifluoroborates afforded the products in good
yields (2g-2i). We further examined the effect of substituents on diarylmethanol starting material.
The substrate scope was expanded to benzhydryl alcohols that contained amine functional group.
Modest 53% yield of 2f was observed when dimethylamine functionality was present. The ability
of basic amine functionality to undergo protonation in the presence of acid prompted us to increase
acid to substrate ratio. We observed that the yield of 2f improved to 61% when the amount of
HBF4 was increased from 1.6 to 2.6 equivalents. Applying these conditions to Boc-protected amine
bearing substrate resulted in 51% yield of the deprotected product 2j. In addition to
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phenylacetylenetrifluoroborates, hexynyltrifluoroborate salt was a good coupling partner. The
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desired product 2k was formed in a 73% yield.
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FIGURE 2. Reactions of Various Alkynyltrifluoroborates with Benzhydryl Alcohols
a2.6 equiv. of HBF4 was used. (Note about 2j: Boc-protected amine was used as a starting
material.)
Lastly, the scope of styryltrifluoroborate salts was explored (Figure 3). To our delight, alkenyl
trifluoroborates such as potassium styryl- and 2-(3-fluorophenyl)vinyltrifluoroborate salts
provided the desired products in good to excellent yields (3a-3e). Once again, increasing the
amount of the added acid for the amine bearing substrate improved the yield of 3d to 84%. Only
modest yield increase of 3e was noted when 1.3 equivalents of HBF4 were used. Expanding the
scope to alkenyltrifluoroborate salts further increases the utility of the developed methodology.
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FIGURE 3. Reactions of Styryltrifluoroborates with Benzhydryl Alcohols
a2.6 equiv. of HBF4 was used. b1.3 equiv. of HBF4 was used.
A plausible reaction mechanism includes the formation of benzhydrilum ion as a reaction
intermediate. Subsequently, nucleophilic trifluoroborate salts react with the electrophilic centre to
afford the final product.
Finally, the developed methodology was applied to the synthesis of benzofuran 7 (Scheme 1).
Benzhydryl alcohol 5 reacted with alkynyltrifluoroborate in the presence of HBF4 to afford alkyne
6. Demethylation31 and cyclization proceeded under the reported conditions.
SCHEME 1. Application of the Developed Methodology to the Synthesis of Benzofuran
In conclusion, we have developed a novel method for the preparation of internal alkynes and
alkenes from benzhydryl alcohols and potassium trifluoroborate salts. This transformation
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proceeds rapidly in the presence of a Brønsted acid without exclusion of air or moisture. The
developed protocol features good atom economy since organotrifluoroborate salts and alcohols
reacted in 1:1 ratio. Furthermore, this methodology demonstrates functional group tolerance
superior to that of Lewis acid- and metal-catalyzed approaches.
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Experimental Section
General: All reactions were set up in 2 ml glass vials at room temperature under atmosphere.
Unless otherwise noted, all other reagents and materials were obtained from commercial suppliers
and used without further purification. Potassium trifluoroborate salts were synthesized according
to published procedures.1 Reaction progress was monitored via thin layer chromatography (TLC)
on silica gel (60 Å) with visualization using ultraviolet light (254 nm) and by staining with
potassium permanganate (KMnO4). NMR characterization data was collected at 25 oC as solutions
in deuterated solvents (CDCl3, acetone-d6 and DMSO-d6). 1H and 19F-NMR spectra were collected
at 400 MHz and 376 MHz respectively while 13C {1H} and 11B NMR spectra were collected at 100
MHz and 128 MHz respectively. Chemical shifts are expressed in ppm values. IR spectra were
recorded on a FTIR spectrometer using a platinum ATR with a diamond ATR crystal. Spectra are
reported in terms of frequency of absorption (cm-1) and only partial data is provided. Melting points
were measured with a melting point apparatus and are uncorrected. High resolution mass spectra
(HRMS) were recorded using electrospray ionization (ESI), electron impact ionization (EI), direct
analysis in real time (DART) ion source and time-of-flight (TOF) mass analysis. Column
chromatography was carried out on silica gel (60 Å, low acidity) and reagent grade solvents.
Preparation of Alkynyl Potassium Organotrifluoroborate Salts:
General Procedure 1
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o
To a solution of the indicated terminal alkyne (1.0 equiv.) in dry THF at -70 C under argon
atmosphere, n-BuLi (1.0 equiv.) was added dropwise and the solution was stirred for 1 h at this
temperature. Trimethylborate (1.5 equiv.) was added dropwise at -60 oC. The solution was stirred
at this temperature for 2 h. A saturated aqueous solution of potassium hydrogen difluoride (6.0
equiv.) was added at -20 oC. The mixture was allowed to stir for 1 h at -20 oC and for 1 h at room
temperature. The solvent was removed under reduced pressure, and the resulting solid was placed
under vacuum overnight to remove remaining water. The solid was washed several times with hot
acetone (4 x 10 mL), which was collected and concentrated to a volume of ~5 mL. The product
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was precipitated with diethyl ether (30 mL) and cooled to 4 C to complete precipitation. The
crystalline trifluoroborate salt was collected by gravity filtration.
General Procedure 2
o
To a solution of the indicated terminal alkyne (1.0 equiv.) in dry THF at -78 C under argon
atmosphere, t-BuLi (1.0 equiv.) was added dropwise and the solution was stirred for 2 h at this
temperature. Trimethylborate (1.5 equiv.) was added dropwise at -65 oC. The solution was stirred
at this temperature for 1 h 40 min. A saturated aqueous solution of potassium hydrogen difluoride
(6.0 equiv.) was added at -30 oC. The mixture was allowed to stir for 1 h at -30 oC and for 1 h at
room temperature. The solvent was removed under reduced pressure, and the resulting solid was
placed under vacuum overnight to remove remaining water. The solid was washed several times
with hot acetone (4 x 10 mL), which was collected and concentrated to a volume of ~5 mL. The
product was precipitated with diethyl ether (30 mL) and cooled to 4 oC to complete precipitation.
The crystalline trifluoroborate salt was collected by gravity filtration.
Potassium trifluoro(phenylethynyl)borate (S1)23: Phenylacetylene (2.45 g, 24.0 mmol, 1.0
equiv.), n-BuLi (1.54 g, 24.0 mmol, 1.0 equiv.), B(OMe)3 (3.75 g, 36.1 mmol, 1.5 equiv.), and
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aqueous KHF2 (11.26 g, 144.2 mmol, 6.0 equiv.) in 50 mL of THF following Procedure 1,
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1
afforded S1 (1.190 g, 24% yield) as a white crystalline solid. H NMR (DMSO) δ 7.28-7.30 (m,
7
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9
4H), 7.21-7.26 (m, 1H); 13C {1H} NMR (DMSO) δ 130.9, 128.2, 126.7, 125.5; 19F NMR (DMSO)
δ -131.71 (s, 3F).
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Potassium
trifluoro((2-(tluoromethyl)phenyl)ethynyl)borate
(S2)24:
1-ethynyl-2-
trifluoromethylbenzene (1.00 g, 5.70 mmol, 1.0 equiv.), n-BuLi (0.365 g, 5.70 mmol, 1.0 equiv.),
B(OMe)3 (0.89 g, 8.55 mmol, 1.5 equiv.) and aqueous KHF2 (2.67 g, 34.2 mmol, 6.0 equiv.) in
17.0 mL THF following Procedure 1, afforded S2 (0.879 g, 56% yield) as a white crystalline
solid. 1H NMR (DMSO) δ 7.65 (d, J = 7.4 Hz, 1H), 7.51-7.58 (m, 2H), 7.39-7.44 (m, 1H).
Potassium trifluoro((3,5-bis(trifluoromethyl)phenyl)ethynyl)borate (S3)24: 1-ethynyl-3,5-
bis(trifluoromethyl)benzene (1.00 g, 4.07 mmol, 1.0 equiv.), n-BuLi (0.261 g, 4.07 mmol, 1.0
equiv.), B(OMe)3 (0.63 g, 6.11 mmol, 1.5 equiv.) and aqueous KHF2 (1.90 g, 24.4 mmol, 6.0
equiv.) in 12.2 mL THF following Procedure 1, afforded S3 (0.444 g, 32% yield) as a white
crystalline solid. 1H NMR (DMSO) δ 7.92-7.93 (m, 3H).
Potassium trifluoro((3-chlorophenyl)ethynyl)borate (S4)24: 3-chloro-1-ethynylbenzene (0.44
g, 3.25 mmol, 1.0 equiv.), t-BuLi (0.21 g, 3.25 mmol, 1.0 equiv.), B(OMe)3 (0.51 g, 4.87 mmol,
1.5 equiv.) and aqueous KHF2 (1.52 g, 19.5 mmol, 6.0 equiv.) in 10.0 mL of THF following
Procedure 2, afforded S4 (0.460 g, 59 % yield) as a white crystalline solid. 1H NMR (DMSO) δ
7.30-7.32 (m, 3H), 7.24-7.28 (m, 1H).
Potassium trifluoro((3-fluorophenyl)ethynyl)borate (S5)24: 1-ethynyl-3-fluorobenzene (0.67 g,
5.44 mmol, 1.0 equiv.), n-BuLi (0.349 g, 5.44 mmol, 1.0 equiv.), B(OMe)3 (0.85 g, 8.16 mmol,
1.5 equiv.) and aqueous KHF2 (2.55 g, 32.7 mmol, 6.0 equiv.) in 17.0 mL THF following
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Procedure 1, afforded S5 (1.038 g, 84 % yield) as a white crystalline solid. 1H NMR (DMSO) δ
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7.30-7.35 (m, 1H), 7.07-7.14 (m, 3H).
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Potassium
trifluoro((3,4-dichlorophenyl)ethynyl)borate
(S6)24:
3,4-dichloro-1-
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ethynylbenzene (0.894 g, 5.22 mmol, 1.0 equiv.), n-BuLi (0.335 g, 5.22 mmol, 1.0 equiv.),
B(OMe)3 (0.81 g, 7.84 mmol, 1.5 equiv.) and aqueous KHF2 (2.45 g, 31.3 mmol, 6.0 equiv.) in
17.5 mL THF following Procedure 1, afforded S6 (0.618 g, 43% yield) as an off white crystalline
solid. 1H NMR (DMSO) δ 7.51-7.54 (m, 2H), 7.26 (dd, J = 2.0, 8.2 Hz, 1H).
Potassium trifluoro([1,1’-biphenyl]-4-ylethynyl)borate (S7)24: 4-ethynylbiphenyl (1.00 g, 5.44
mmol, 1.0 equiv.), n-BuLi (0.349 g, 5.44 mmol, 1.0 equiv.), B(OMe)3 (0.85 g, 8.16 mmol, 1.5
equiv.) and aqueous KHF2 (2.55 g, 32.7 mmol, 6.0 equiv.) in 17.0 mL THF following Procedure
1
1, afforded S7 (0.201 g, 13% yield) as an off white crystalline solid. H NMR (DMSO) δ 7.65-
7.67 (d, J = 7.03 Hz, 2H), 7.58-7.61 (d, J = 8.6 Hz, 2H), 7.44-7.47 (m, 2H), 7.33-7.39 (m, 3H).
Potassium trifluoro(naphthalen-1-ylethynyl)borate (S8)24: 1-ethynylnaphthalene (0.854 g,
5.44 mmol, 1.0 equiv.), n-BuLi (0.349 g, 5.44 mmol, 1.0 equiv.), B(OMe)3 (0.85 g, 8.16 mmol,
1.5 equiv.) and aqueous KHF2 (2.55 g, 32.7 mmol, 6.0 equiv.) in 17.0 mL THF following
1
Procedure 1, afforded S8 (0.876 g, 62% yield) as a slightly pink crystalline solid. H NMR
(DMSO) δ 8.33 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.51-7.61
(m, 3H), 7.42-7.45 (m, 1H).
Potassium trifluoro(hex-1-yn-1-yl)borate (S9)23: 1-hexyne (2.0 g, 23.6 mmol, 1.0 equiv.), n-
BuLi (1.51 g, 23.6 mmol, 1.0 equiv.), B(OMe)3 (3.68 g, 35.4 mmol, 1.5 equiv.), and aqueous KHF2
(11.06 g, 142 mmol, 6.0 equiv.) in 25 mL THF following Procedure 1, afforded S9 (1.659 g, 36%
yield) as a white crystalline solid. 1H NMR (DMSO) δ 1.98 (m, 2H) 1.33 (m, 4H), 0.85 (m, 3H);
13C {1H} NMR (DMSO) δ 31.1, 21.4, 18.5, 13.5; 19F NMR (DMSO) δ -131.01 (s, 3F).
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Preparation of Benzhydryl Alcohols (General Procedure 3)
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A solution of the indicated para substituted benzaldehyde (1.0 equiv.) in dry THF was treated with
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the indicated phenylmagnesium bromide solution (1.1 - 4.0 equiv.) at 0 C. After addition was
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complete, the mixture was allowed to stir at room temperature for 30 - 120 minutes. The reaction
was quenched with aqueous 1 M HCl solution and extracted with 50 mL of EtOAc. The organic
layer was washed with water (3 x 30 mL) followed by brine (1 x 25 mL). The organic layer was
dried with MgSO4 and concentrated. The product was purified by flash chromatography with
hexanes/ethyl acetate.
4-(Hydroxy(phenyl)methyl)phenol (S10)32: Derived from 4-hydroxybenzaldehyde (0.153 g,
1.25 mmol, 1.0 equiv.) and phenylmagnesium bromide (0.453 g, 2.50 mmol, 2.0 equiv.) in 5.0 mL
of anhydrous THF following Procedure 3. Purification by automated flash column
chromatography on silica gel using hexanes/EtOAc (3:1) afforded product S10 (0.196 g, 79%
1
yield) as a white solid. H NMR (DMSO) δ 9.22 (s, 1H), 7.26-7.34 (m, 4H), 7.12-7.19 (m, 3H),
6.67 (d, J = 8.6 Hz, 2H), 5.67 (d, J = 3.9 Hz, 1H), 5.59 (d, J = 3.9 Hz, 1H).
Bis(4-methoxyphenyl)methanol (S11)33: Derived from 4-methoxybenzaldehyde (0.139 g, 1.02
mmol, 1.0 equiv.) and 4-methoxyphenylmagnesium bromide (0.649 g, 3.07 mmol, 3.0 equiv.) in
3.0 mL of anhydrous THF following Procedure 3. Purification by silica gel column
chromatography using hexanes/EtOAc (5:1) afforded the product S11 (0.248 g, 99% yield) as a
yellow solid. 1H NMR (CDCl3) δ 7.26 (d, J = 8.2 Hz, 4H), 6.86 (d, J = 9.0 Hz, 4H), 5.75 (s, 1H),
3.78 (s, 6H), 2.18 (s, 1H).
(4-Chlorophenyl)(4-methoxyphenyl)methanol (S12)34: Derived from 4-chlorobenzaldehyde
(0.1413 g, 1.01 mmol, 1.0 equiv.) and 4-methoxyphenylmagnesium bromide (0.850 g, 4.02 mmol,
4.0 equiv.) in 3.0 mL of anhydrous THF following Procedure 3. Purification by silica gel
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chromatography using hexanes/EtOAc (5:1) afforded product S12 (0.203 g, 81% yield) as an off
white solid. 1H NMR (CDCl3) δ 7.30 (s, 4H), 7.24 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),
5.77 (d, J = 3.1 Hz, 1H), 3.79 (s, 3H), 2.20 (d, J = 3.5 Hz, 1H).
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(4-(dimethylamino)phenyl)(4-methoxyphenyl)methanol
(S13)35:
Derived
from
4-
(dimethylamino)benzaldehyde (0.174 g, 1.17 mmol, 1.0 equiv.) and 4-methoxyphenylmagnesium
bromide (0.271 g, 1.28 mmol, 1.1 equiv.) in 3.0 mL of anhydrous THF following Procedure 3.
Purification by automated flash column chromatography on silica gel using hexanes/EtOAc (5:1)
afforded product S13 (0.174, 58% yield) as an off white solid. 1H NMR (CDCl3) δ 7.29 (d, J = 8.6
Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 5.73 (d, J =
3.5 Hz, 1H), 3.78 (s, 3H), 2.92 (s, 6H), 2.07 (d, J = 3.9 Hz, 1H).
N-(4-(hydroxy(p-tolyl)methyl)phenyl)acetamide
(S14):
Derived
from
4-
acetamidobenzaldehyde (0.192 g, 1.18 mmol, 1.0 equiv.) and 4-methylphenylmagnesium bromide
(0.459 g, 2.35 mmol, 2.0 equiv.) in 3.0 mL of anhydrous THF following Procedure 3. Purification
by automated flash column chromatography on silica gel using hexanes/EtOAc (1:1) afforded
o
product S14 (0.199 g, 66% yield) as a yellow solid, mp 139-142 C. IR (Diamond-ATR) ν 3309,
1657, 1601, 1535, 1412, 1318, 1268, 1012, 819, 758, 552, 477 cm-1; 1H NMR (DMSO) δ 9.85 (s,
1H), 7.48 (d, J = 8.6 Hz, 2H), 7.21-7.25 (m, 4H), 7.09 (d, J = 7.8 Hz, 2H), 5.72 (d, J = 4.3 Hz,
1H), 5.60 (d, J = 3.9 Hz, 1H), 2.25 (s, 3H), 2.01 (s, 1H); 13C {1H} NMR (DMSO) δ 168.0, 142.8,
140.5, 137.8, 135.5, 128.5, 126.5, 126.1, 118.7, 73.7, 23.9, 20.6; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C16H18NO2 256.1332; Found 256.1329.
tert-butyl (4-(hydroxy(p-tolyl)methyl)phenyl)carbamate (S15): Derived from 4-(Boc-
amino)benzaldehyde (0.100 g, 0.45 mmol, 1.0 equiv.) and 4-methoxyphenylmagnesium bromide
(0.239 g, 1.13 mmol, 2.5 equiv.) in 3.0 mL of anhydrous THF following Procedure 3. Purification
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by silica gel chromatography using hexanes/EtOAc (3:1) afforded product S15 (0.111 g, 74%
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yield) as a yellow solid, mp 106-109 C. IR (Diamond-ATR) ν 3367, 1696, 1507, 1235, 1157,
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1035, 824, 574 cm-1; 1H NMR (CDCl3) δ 7.24-7.32 (m, 6H), 6.85 (d, J = 8.6 Hz, 2H), 6.47 (s, 1H),
5.75 (s, 1H), 3.78 (s, 3H), 2.16 (s, 1H), 1.50 (s, 9H); 13C {1H} NMR (CDCl3) δ 159.0, 152.7, 138.7,
137.6, 136.2, 127.8, 127.1, 118.5, 113.8, 80.5, 75.4, 55.3, 28.3; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C19H23NO4Na 352.1519; Found 352.1520.
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4-(Hydroxy(4-methoxyphenyl)methyl)benzoic acid (S16): Derived from 4-formylbenzoic acid
(0.174 g, 1.16 mmol, 1.0 equiv.) and 4-methoxyphenylmagnesium bromide (0.737 g, 3.48 mmol,
3.0 equiv.) in 5.0 mL of anhydrous THF following Procedure 3. Purification by silica gel
chromatography using hexanes/EtOAc/AcOH (1.5:1:0.01% v/v) afforded product S16 (0.208 g,
69% yield) as a white solid, mp 158-160 oC. IR (Diamond-ATR) ν 3468, 2920, 1675, 1607, 1508,
1423, 1293, 1228, 1169, 1025, 742, 551 cm-1; 1H NMR (DMSO) δ 12.80 (s, 1H), 7.87 (d, J = 8.6
Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.92 (s, 1H),
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5.71 (s, 1H), 3.71 (s, 3H); C {1H} NMR (DMSO) δ 167.2, 158.2, 150.9, 137.2, 129.2, 129.1,
127.5, 126.1, 113.5, 73.4, 55.0; HRMS (ESI-TOF) m/z: [M-H]- Calcd for C15H13O4 257.0819;
Found 257.0817.
4-(Hydroxy(4-methoxyphenyl)methyl)benzaldehyde (S17): Derived from 4-(diethoxymethyl)
benzaldehyde (0.258 g, 1.24 mmol, 1.0 equiv.) and 4-methoxyphenylmagnesium bromide (0.419
g, 1.98 mmol, 1.6 equiv.) in 3.0 mL of anhydrous THF following Procedure 3. Purification by
silica gel chromatography using hexanes/EtOAc (3:1) afforded product S17 (66.0 mg, 22% yield)
as a yellow oil. IR (Diamond-ATR) ν 3421, 1690, 1605, 1509, 1244, 1169, 1027, 818, 785, 554
cm-1; 1H NMR (CDCl3) δ 9.98 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.26 (d,
J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.86 (s, 1H), 3.79 (s, 3H), 2.34 (s, 1H); 13C {1H} NMR
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(CDCl3) δ 191.9, 159.4, 150.6, 135.5, 135.4, 129.9, 128.1, 126.8, 114.2, 75.5, 55.3; HRMS (EI)
m/z: [M+] Calcd for C15H14O3 242.0943; Found 242.0944.
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(2-methoxyphenyl)(p-tolyl)methanol (5)36: Derived from 2-methoxybenzaldehyde (0.298 g,
2.19 mmol, 1.0 equiv.) and p-tolylmagnesium bromide (0.642 g, 3.29 mmol, 1.5 equiv.) in 5.0 mL
of anhydrous THF following Procedure 3. Purification by automated flash column
chromatography on silica gel using hexanes/EtOAc (gradient: 49:1 ‰ 12:1) afforded product 5
(0.396 g, 79% yield) as a white solid. 1H NMR (CDCl3) δ 7.26-7.20 (m, 4H), 7.10 (d, J = 7.8 Hz,
2H), 6.92 (t of d, J = 0.8, 7.4 Hz, 1H), 6.85 (d of d, J = 0.8, 8.6 Hz, 1H), 6.00 (s, 1H), 3.76 (s,
3H), 3.05 (s, 1H), 2.31 (s, 3H).
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Synthesis of Internal Alkenes and Alkynes (General Procedure 4):
In a 2 mL vial containing a stir bar, the indicated benzhydrol alcohol (1.0 equiv.) and potassium
trifluoroborate salt (1.0 equiv.) were added followed by addition of anhydrous acetonitrile (0.3
mL). HBF4·OEt2 (1.3-2.6 equiv.) was added dropwise and the reaction was allowed to stir at room
temperature for 15 min. The reaction was quenched with water and extracted in 20 mL of ethyl
acetate. The organic layer was washed with water (3 x 15 mL) followed by brine (1 x 10 mL). The
organic layer was dried with MgSO4 and concentrated. Purification procedures varied based on
the product synthesized. For specific details, see below. In the cases where a CH3CN/hexanes
extraction was required, the product was solubilized in 5 mL of anhydrous acetonitrile in a 20 mL
vial. Then, 1 mL of hexanes was added forming a bilayer. The two layers were thoroughly mixed
and then allowed to settle. The bottom acetonitrile layer was then removed and concentrated. In
the cases where a pentane wash was required, in a minimum of chloroform, the product was
washed with 5 mL of pentane on a pipette column and eluted with diethyl ether to afford the
product.
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prop-2-yne-1,1,3-triyltribenzene (1a)15: Derived from diphenylmethanol (13.3 mg, 0.072 mmol,
1.0 equiv.), potassium trifluoro(phenylethynyl)borate (S1) (15.0 mg, 0.072 mmol, 1.0 equiv.) and
HBF4·OEt2 (18.7 mg, 0.12 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification by automated flash column chromatography on silica gel using hexanes and
subsequent CH3CN/hexanes extraction afforded product 1a (7.8 mg, 41% yield) as a yellow oil.
1H NMR (CDCl3) δ 7.43-7.49 (m, 6H), 7.29-7.34 (m, 7H), 7.21-7.25 (m, 2H), 5.21 (s, 1H).
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(3-(p-tolyl)prop-1-yne-1,3-diyl)dibenzene (1b)7: Derived from phenyl(p-tolyl)methanol (21.1
mg, 0.11 mmol, 1.0 equiv.), potassium trifluoro(phenylethynyl)borate (S1) (22.1 mg, 0.11 mmol,
1.0 equiv.) and HBF4·OEt2 (27.5 mg, 0.17 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following
Procedure 4. Purification by silica gel column chromatography using hexanes afforded product
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1b (20.2 mg, 67% yield) as a yellow oil. H NMR (CDCl3) δ 7.42-7.48 (m, 4H), 7.28-7.33 (m,
7H), 7.20-7.24 (m, 1H), 7.13 (d, J = 7.8 Hz, 2H), 5.17 (s, 1H), 2.31 (s, 3H).
(3-(o-toyl)prop-1-yne-1,3-diyl)dibenzene (1c)37: Derived from phenyl(o-toyl)methanol (21.1
mg, 0.11 mmol, 1.0 equiv.), potassium trifluoro(phenylethynyl)borate (S1) (22.1 mg, 0.11 mmol,
1.0 equiv.) and HBF4·OEt2 (27.5 mg, 0.17 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following
Procedure 4. Purification by silica gel column chromatography using hexanes afforded product
1c (15.2 mg, 51% yield) as a yellow oil. 1H NMR (CDCl3) δ 7.50 (dd, J = 1.6, 7.03 Hz, 1H), 7.44-
7.46 (m, 2H), 7.37-7.39 (m, 2H), 7.27-7.32 (m, 5H), 7.14-7.25 (m, 4H), 5.38 (s, 1H), 2.33 (s, 3H).
(3-(4-Methoxyphenyl)prop-1-yne-1,3-diyl)dibenzene
(1d)38:
Derived
from
(4-
methoxyphenyl)(phenyl)methanol (21.5 mg, 0.10 mmol, 1.0 equiv.), potassium
trifluoro(phenylethynyl)borate (S1) (20.9 mg, 0.10 mmol, 1.0 equiv.) and HBF4·OEt2 (26.0 mg,
0.16 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by silica gel
column chromatography using hexanes/diethyl ether (40:1) afforded product 1d (26.2 mg, 87%
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yield) as a yellow oil. H NMR (CDCl3) δ 7.41-7.48 (m, 4H), 7.28-7.36 (m, 7H), 7.20-7.24 (m,
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1H), 6.85 (d, J = 9.0 Hz, 2H), 5.16 (s, 1H), 3.77 (s, 3H).
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4,4’-(3-Phenylprop-2-yne-1,1-diyl)bis(methoxybenzene) (1e)15: Derived from bis(4-
methoxyphenyl)methanol (S11) (22.3 mg, 0.091 mmol, 1.0 equiv.), potassium
trifluoro(phenylethynyl)borate (S1) (19.0 mg, 0.091 mmol, 1.0 equiv.) and HBF4·OEt2 (23.7 mg,
0.14 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Aqueous work-up afforded
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product 1e (27.2 mg, 91% yield) as a yellow/orange oil. H NMR (CDCl3) δ 7.48-7.51 (m, 2H),
7.36 (d, J = 8.2 Hz, 4H), 7.31-7.33 (m, 3H), 6.88 (d, J = 8.6 Hz, 4H), 5.15 (s, 1H), 3.81 (s, 6H).
(3-(4-Chlorophenyl)prop-1-yne-1,3-diyl)dibenzene
(1f)15:
Derived
from
(4-
chlorophenyl)(phenyl)methanol (21.7 mg, 0.10 mmol, 1.0 equiv.) potassium
trifluoro(phenylethynyl)borate (S1) (20.6 mg, 0.10 mmol, 1.0 equiv.) and HBF4·OEt2 (25.7 mg,
0.16 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by automated
flash column chromatography on silica gel using hexanes and subsequent CH3CN/hexanes
extraction afforded product 1f (5.7 mg, 19% yield) as a yellow oil. 1H NMR (CDCl3) δ 7.46-7.48
(m, 2H), 7.35-7.42 (m, 5H), 7.29-7.33 (m, 6H), 7.24-7.27 (m, 1H), 5.18 (s, 1H).
1-Chloro-4-(1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl)benzene (1g)39: Derived from (4-
chlorophenyl)(4-methoxyphenyl)methanol (S12) (22.4 mg, 0.090 mmol, 1.0 equiv), potassium
trifluoro(phenylethynyl)borate (S1) (18.7 mg, 0.090 mmol, 1.0 equiv.) and HBF4·OEt2 (23.4 mg,
0.14 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by silica gel
column chromatography using hexanes/EtOAc (10:1) afforded product 1g (25.3 mg, 84% yield)
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as a yellow oil. H NMR (CDCl3) δ 7.45-7.47 (m, 2H), 7.27-7.36 (m, 9H), 6.86 (d, J = 8.6 Hz,
2H), 5.13 (s, 1H), 3.78 (s, 3H).
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4-(1,3-Diphenylprop-2-yn-1-yl)phenol (1h)38: Derived from 4-(hydroxy(phenyl)methyl)phenol
(S10) (21.1 mg, 0.11 mmol, 1.0 equiv.), potassium trifluoro(phenylethynyl)borate (S1) (21.9 mg,
0.11 mmol, 1.0 equiv.) and HBF4·OEt2 (27.3 mg, 0.17 mmol, 1.6 equiv.) in 0.3 mL of CH3CN
following Procedure 4. Purification was conducted by automated flash column chromatography
on silica gel using hexanes/EtOAc (5:1) and subsequent CH3CN/hexanes extraction afforded
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product 1h (19.9 mg, 66% yield) as a burgundy/brown oil. H NMR (CDCl3) 7.41-7.48 (m, 4H),
7.28-7.33 (m, 7H), 7.22-7.24 (m, 1H), 6.77-6.79 (m, 2H), 5.14 (s, 1H).
N-(4-(3-phenyl-1-(p-tolyl)prop-2-yn-1-yl)phenyl)acetamide (1i): Derived from N-(4-
hydroxy(p-tolyl)methyl)phenyl)acetamide (S14) (22.6 mg, 0.088 mmol, 1.0 equiv.), potassium
trifluoro(phenylethynyl)borate (S1) (18.4 mg, 0.088 mmol, 1.0 equiv.) and HBF4·OEt2 (22.9 mg,
0.141 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification was conducted
by silica gel column chromatography using hexanes/EtOAc (1:2) and subsequent CH3CN/hexanes
extraction afforded product 1i (18.3 mg, 61% yield) as a yellow oil. IR (Diamond-ATR) ν 3301,
2922, 1662, 1599, 1508, 1407, 1314, 754, 689 cm-1; 1H NMR (CDCl3) 7.45-7.49 (m, 4H), 7.38-
7.40 (m, 3H), 7.30-7.33 (m, 4H), 7.14 (d, J = 7.8 Hz, 2H), 5.15 (s, 1H), 2.34 (s, 3H), 2.15 (s, 3H);
13C {1H} NMR (CDCl3) δ 168.3, 138.7, 137.9, 136.6, 136.5, 131.6, 129.3, 128.4, 128.2, 127.9,
127.7, 123.5, 120.1, 90.3, 84.7, 42.8, 24.5, 21.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C24H22NO 340.1696; Found 340.1693.
4-(1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl)benzoic acid (1j): Derived from 4-
(hydroxy(4-methoxyphenyl)methyl)benzoic acid (S16) (13.8 mg, 0.053 mmol, 1.0 equiv.),
potassium trifluoro(phenylethynyl)borate (S1) (11.1 mg, 0.053 mmol, 1.0 equiv.) and HBF4·OEt2
(11.2 mg, 0.069 mmol, 1.3 equiv.) in 0.2 mL of CH3CN following Procedure 4. Purification was
conducted by silica gel column chromatography using hexanes/EtOAc/AcOH (2:1:0.01% v/v) and
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subsequent CH3CN/hexanes extraction afforded product 1j (11.3 mg, 62% yield) as a yellow oil.
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IR (Diamond-ATR) ν 2919, 1691, 1607, 1508, 1297, 1246, 1173, 758, 740, 691, 554 cm-1; H
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NMR (acetone-d6) 8.02 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.50-7.53 (m, 2H), 7.44 (d,
J = 8.6 Hz, 2H), 7.37-7.38 (m, 3H), 6.92 (d, J = 8.6 Hz, 2H), 5.41 (s, 1H), 3.77 (s, 3H); 13C {1H}
NMR (acetone-d6) δ 159.9, 148.3, 134.5, 132.5, 131.0, 129.8, 129.4, 129.2, 128.7, 124.3, 115.0,
91.0, 85.8, 55.6, 43.3 (the carbonyl carbon and one aromatic carbon were not resolved in this
spectrum); HRMS (ESI-TOF) m/z: [M-H]- Calcd for C23H17O3 341.1183; Found 341.1186.
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1-(3-(4-Methoxyphenyl)-3-phenylprop-1-yn-1-yl)-2-(trifluoromethyl)benzene (2a): Derived
from (4-methoxyphenyl)(phenyl)methanol (17.6 mg, 0.082 mmol, 1.0 equiv), potassium
trifluoro((2-(trifluoromethyl)phenyl)ethynyl)borate (S2) (22.6 mg, 0.082 mmol, 1.0 equiv.) and
HBF4·OEt2 (21.2 mg, 0.13 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification by silica gel column chromatography using hexanes/EtOAc (15:1) afforded product
2a (26.8 mg, 89% yield) as a yellow/orange oil. IR (Diamond-ATR) ν 2929, 1601, 1508, 1314,
1249, 1167, 1127, 1031, 764, 697 cm-1; 1H NMR (CDCl3) δ 7.64 (d, J = 7.4 Hz, 1H), 7.58 (d, J =
7.4 Hz, 1H), 7.42-7.47 (m, 3H), 7.30-7.38 (m, 5H), 7.21-7.24 (m, 1H), 6.85 (d, J = 8.6 Hz, 2H),
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5.20 (s, 1H), 3.77 (s, 3H); C {1H} NMR (CDCl3) δ 158.5, 141.6, 134.1, 133.5, 131.6, 131.3,
128.9, 128.6, 127.8, 127.6, 126.9, 125.7 (q, J = 5.4 Hz), 123.6 (q, J = 273.7 Hz), 121.8, 114.0,
96.4, 80.7, 55.2, 43.2; 19F NMR (CDCl3) δ -62.17 (s, 3F); HRMS (EI) m/z: [M+] Calcd for
C23H17F3O 366.1232; Found 366.1231.
1-(3-(4-Methoxyphenyl)-3-phenylprop-1-yn-1-yl)-3,5-bis(trifluoromethyl)benzene
(2b):
Derived from (4-methoxyphenyl)(phenyl)methanol (14.8 mg, 0.069 mmol, 1.0 equiv), potassium
trifluoro((3,5-bis(trifluoromethyl)phenyl)ethynyl)borate (S3) (23.8 mg, 0.069 mmol, 1.0 equiv.)
and HBF4·OEt2 (17.9 mg, 0.11 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
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Purification by silica gel column chromatography using hexanes/EtOAc (14:1) afforded product
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2b (25.6 mg, 85% yield) as a yellow/orange oil. IR (Diamond-ATR) ν 2928, 1600, 1509, 1381,
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1275, 1171, 1129, 697, 681 cm-1; H NMR (CDCl3) δ 7.88 (s, 2H), 7.78 (s, 1H), 7.25-7.41 (m,
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7H), 6.88 (d, J = 9.0 , 2H), 5.20 (s, 1H), 3.79 (s, 3H); C {1H} NMR (CDCl3) δ 158.8, 141.1,
132.9, 131.8 (q, J = 33.7 Hz), 131.6 (q, J = 4.6 Hz), 128.9, 128.8, 127.8, 127.2, 125.8, 123.0 (q, J
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= 273.0 Hz), 121.3 (q, J = 3.8 Hz), 114.2, 94.5, 81.8, 55.3, 42.9; F NMR (CDCl3) δ -63.13 (s,
6F); HRMS (EI) m/z: [M+] Calcd for C24H16F6O 434.1105; Found 434.1100.
1-Chloro-3-(3-(4-methoxyphenyl)-3-phenylprop-1-yn-1-yl)benzene (2c): Derived from (4-
methoxyphenyl)(phenyl)methanol (19.3 mg, 0.090 mmol, 1.0 equiv), potassium trifluoro((3-
chlorophenyl)ethynyl)borate (S4) (21.9 mg, 0.090 mmol, 1.0 equiv.) and HBF4·OEt2 (23.4 mg,
0.14 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by silica gel
column chromatography using hexanes/EtOAc (14:1) afforded product 2c (29.7 mg, 99% yield)
as a yellow/orange oil. IR (Diamond-ATR) ν 2930, 1592, 1507, 1247, 1173, 1030, 780, 696, 680
cm-1; 1H NMR (CDCl3) δ 7.45-7.46 (m, 1H), 7.39-7.41 (m, 2H), 7.30-7.35 (m, 5H), 7.19-7.28 (m,
3H), 6.86 (d, J = 9.0 Hz, 2H), 5.16 (s, 1H), 3.77 (s, 3H); 13C {1H} NMR (CDCl3) δ 158.6, 141.7,
134.0, 133.5, 131.6, 129.8, 129.4, 128.9, 128.6, 128.2, 127.8, 126.9, 125.2, 114.0, 91.9, 83.3, 55.3,
42.9; HRMS (EI) m/z: [M+] Calcd for C22H17ClO 332.0968; Found 332.0962.
1,2-Dichloro-4-(3-(4-chlorophenyl)-3-(4-methoxyphenyl)prop-1-yn-1-yl)benzene
(2d):
Derived from (4-chlorophenyl)(4-methoxyphenyl)methanol (S12) (18.6 mg, 0.075 mmol, 1.0
equiv.), potassium trifluoro((3,4-dichlorophenyl)ethynyl)borate (S6) (20.7 mg, 0.075 mmol, 1.0
equiv.) and HBF4·OEt2 (19.3 mg, 0.12 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following
Procedure 4. Purification by silica gel column chromatography using hexanes/EtOAc (20:1)
afforded product 2d (25.0 mg, 83% yield) as a yellow oil. IR (Diamond-ATR) ν 2926, 1508, 1487,
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1461, 1173, 1089, 1031, 817 cm-1; H NMR (CDCl3) δ 7.54 (d, J = 2.0 Hz, 1H), 7.35-7.37 (m,
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6
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1H), 7.25-7.33 (m, 7H), 6.87 (d, J = 9.0 Hz, 2H), 5.12 (s, 1H), 3.79 (s, 3H); C {1H} NMR
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(CDCl3) δ 158.8, 140.0, 133.3, 132.9, 132.8, 132.48, 132.45, 130.8, 130.3, 129.1, 128.80, 128.79,
123.2, 114.2, 92.1, 82.8, 55.3, 42.3; HRMS (EI) m/z: [M+] Calcd for C22H15Cl3O 400.0188; Found
400.0186.
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4-(3-(3-Fluorophenyl)-1-(4-methoxyphenyl)prop-2-yn-1-yl)benzaldehyde (2e): Derived from
4-(hydroxy(4-methoxyphenyl)methyl)benzaldehyde (S17) (21.1 mg, 0.087 mmol, 1.0 equiv.),
potassium trifluoro((3-fluorophenyl)ethynyl)borate (S5) (19.7 mg, 0.087 mmol, 1.0 equiv.) and
HBF4·OEt2 (22.6 mg, 0.14 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification by silica gel column chromatography using hexanes/EtOAc (6:1) afforded product 2g
(24.6 mg, 82% yield) as a yellow oil. IR (Diamond-ATR) ν 2926, 1697, 1603, 1578, 1508, 1246,
1148, 1032, 783, 681 cm-1; 1H NMR (CDCl3) δ 9.99 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.58 (d, J =
8.2 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.25-7.28 (m, 2H), 7.15-7.18 (m, 1H), 7.00-7.05 (m, 1H),
6.88 (d, J = 9.0 Hz, 2H), 5.23 (s, 1H), 3.79 (s, 3H); 13C {1H} NMR (CDCl3) δ 191.7, 162.3 (d, J =
246.14 Hz), 158.9, 148.5, 135.2, 132.4, 130.1, 129.8 (d, J = 6.2 Hz), 128.9, 128.4, 127.5 (d, J =
19
3.1 Hz), 124.9, 118.5 (d, J = 23.0 Hz), 115.6 (d, J = 21.5 Hz), 114.3, 90.3, 84.3, 55.3, 43.0; F
NMR (CDCl3) δ -112.97 (s, 1F); HRMS (EI) m/z: [M+] Calcd for C23H17FO2 344.1213; Found
344.1217.
4-(3-(3-Chlorophenyl)-1-(4-methoxyphenyl)prop-2-yn-1-yl)-N,N-dimethylaniline
(2f):
Derived from (4-(dimethylamino)phenyl)(4-methoxyphenyl)methanol (S13) (20.5 mg, 0.080
mmol, 1.0 equiv.), potassium trifluoro((3-chlorophenyl)ethynyl)borate (S4) (19.4 mg, 0.080
mmol, 1.0 equiv.) and HBF4·OEt2 (33.6 mg, 0.21 mmol, 2.6 equiv.) in 0.3 mL of CH3CN following
Procedure 4. Purification by automated flash column chromatography on silica gel using
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hexanes/EtOAc (3:1) afforded product 2h (18.4 mg, 61% yield) as a brown oil. IR (Diamond-
ATR) ν 2926, 1607, 1507, 1246, 1172, 1033, 782, 680, 555 cm-1; 1H NMR (CDCl3) δ 7.44-7.45
(m, 1H), 7.31-7.33 (m, 3H), 7.18-7.26 (m, 4H), 6.85 (d, J = 8.6 Hz, 2h), 6.69 (d, J = 9.0 Hz, 2H),
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5.08 (s, 1H), 3.78 (s, 3H), 2.91 (s, 6H); C {1H} NMR (CDCl3) δ 158.4, 149.6, 134.3, 134.0,
131.5, 129.8, 129.6, 129.4, 128.8, 128.4, 128.0, 125.5, 113.9, 112.7, 92.7, 82.8, 55.3, 41.9, 40.6;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H23ClNO 376.1463; Found 376.1458.
4-(3-([1,1’-Biphenyl]-4-yl)-1-phenylprop-2-yn-1-yl)phenol
(2g):
Derived
from
4-
(hydroxy(phenyl)methyl)phenol (S10) (16.7 mg, 0.083 mmol, 1.0 equiv.), potassium
trifluoro([1,1’-biphenyl]-4-ylethynyl)borate (S7) (23.6 mg, 0.083 mmol, 1.0 equiv.) and
HBF4·OEt2 (21.6 mg, 0.13 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification by automated flash column chromatography on silica gel using hexanes/EtOAc (5:1)
afforded product 2i (21.3 mg, 71% yield) as an orange/pink oil. IR (Diamond-ATR) ν 3331, 2922,
1597, 1508, 1485, 1447, 1170, 840, 761, 692, 560 cm-1; H NMR (CDCl3) δ 7.57-7.59 (m, 2H),
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7.53 (s, 4H), 7.41-7.45 (m, 4H), 7.29-7.36 (m, 5H), 7.21-7.25 (m, 1H), 6.78 (d, J = 8.6 Hz, 2H),
5.17 (s, 1H), 4.84 (s, 1H); C {1H} NMR (CDCl3) δ 154.4, 142.0, 140.7, 140.4, 134.1, 132.1,
13
129.1, 128.8, 128.6, 127.8, 127.5, 127.0, 126.9, 126.8, 122.4, 115.4, 91.1, 84.6, 43.0; HRMS (EI)
m/z: [M+] Calcd for C27H20O 360.1514; Found 360.1509.
1-(3-(4-Methoxyphenyl)-3-phenylprop-1-yn-1-yl)naphthalene (2h): Derived from (4-
methoxyphenyl)(phenyl)methanol (18.5 mg, 0.086 mmol, 1.0 equiv.), potassium
trifluoro(naphthalen-1-ylethynyl)borate (S8) (22.2 mg, 0.086 mmol, 1.0 equiv.) and HBF4·OEt2
(22.3 mg, 0.14 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by
automated flash column chromatography on silica gel using hexanes/EtOAc (20:1) afforded
product 2j (21.0 mg, 70% yield) as a yellow oil. IR (Diamond-ATR) ν 2926, 1603, 1507, 1246,
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1174, 1030, 797, 772, 696, 564 cm-1; 1H NMR (CDCl3) δ 8.33 (d, J = 7.42, Hz, 1H), 7.78-7.84
(m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 7.47-7.54 (m, 4H), 7.33-7.44 (m, 5H), 7.23-7.27 (m, 1H), 6.88
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(d, J = 8.6 Hz, 2H), 5.33 (s, 1H), 3.78 (s, 3H); C {1H} NMR (CDCl3) δ 158.6, 142.1, 134.0,
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133.5, 133.2, 130.4, 129.0, 128.7, 128.4, 128.2, 127.9, 126.9, 126.7, 126.3, 125.2, 121.2, 114.1,
95.5, 82.9, 55.3, 43.3 (one aromatic carbon was not resolved in this spectrum); HRMS (EI) m/z:
[M+] Calcd for C26H20O 348.1514; Found 348.1508.
4-(1-(4-Methoxyphenyl)-3-(naphthalen-1-yl)prop-2-yn-1-yl)benzoic acid (2i): Derived from
4-(hydroxy(4-methoxyphenyl)methyl)benzoic acid (S16) (19.7 mg, 0.076 mmol, 1.0 equiv.),
potassium trifluoro(naphthalen-1-ylethynyl)borate (S8) (19.7 mg, 0.076 mmol, 1.0 equiv.) and
HBF4·OEt2 (19.8 mg, 0.12 mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification by silica gel column chromatography using hexanes/EtOAc/AcOH (1.5:1:0.01% v/v)
afforded product 2k (19.8 mg, 66% yield) as a yellow oil. IR (Diamond-ATR) ν 2922, 1689, 1606,
1507, 1245, 1174, 1032, 771 cm-1; 1H NMR (acetone-d6) δ 8.33-8.36 (m, 1H), 8.06 (d, J = 8.2 Hz,
2H), 7.93-7.97 (m, 2H), 7.72-7.78 (m, 3H), 7.49-7.62 (m, 5H), 6.96 (d, J = 8.6 Hz, 2H), 5.61 (s,
1H), 3.79 (s, 3H); 13C {1H} NMR (acetone-d6) δ 159.9, 148.3, 134.5, 134.4, 134.3, 131.4, 131.1,
129.9, 129.6, 129.4, 128.8, 127.9, 127.5, 126.8, 126.4, 121.8, 115.1, 96.2, 83.8, 55.6, 43.7 (the
carbonyl carbon and one aromatic carbon were not resolved in this spectrum); HRMS (EI) m/z:
[M+] for C27H20O3 392.1412; Found 392.1417.
4-(1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl)aniline (2j): Derived from tert-butyl (4-
(hydroxy(p-tolyl)methyl)phenyl)carbamate (S15) (20.5 mg, 0.062 mmol, 1.0 equiv.), potassium
trifluoro((3,4-dichlorophenyl)ethynyl)borate (S6) (17.3 mg, 0.062 mmol, 1.0 equiv.) and
HBF4·OEt2 (26.2 mg, 0.16 mmol, 2.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification was conducted by silica gel column chromatography using hexanes/EtOAc (1.3:1),
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followed by a pentane wash and subsequent CH3CN/hexanes extraction afforded product 2l (15.3
mg, 51% yield) as a burgundy oil. IR (Diamond-ATR) ν 3372, 2928, 1607, 1506, 1461, 1244,
1173, 1127, 1030, 817, 729, 569 cm-1; 1H NMR (CDCl3) δ 7.53 (m, 1H), 7.34-7.36 (m, 1H), 7.24-
7.30 (m, 3H), 7.15 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 5.05
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(s, 1H), 3.78 (s, 3H); C {1H} NMR (CDCl3) δ 158.5, 145.3, 133.9, 133.3, 132.3, 132.1, 131.5,
130.8, 130.2, 128.7, 128.6, 123.7, 115.3, 114.0, 93.3, 82.0, 55.3, 42.0; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C22H18Cl2NO 382.0760; Found 382.0758.
1-Methoxy-4-(1-phenylhept-2-yn-1-yl)benzene
(2k)40:
Derived
from
(4-
methoxyphenyl)(phenyl)methanol (23.1 mg, 0.11 mmol, 1.0 equiv.), potassium trifluoro(hex-1-
yn-1-yl)borate (S9) (20.3 mg, 0.11 mmol, 1.0 equiv.) and HBF4·OEt2 (27.9 mg, 0.17 mmol, 1.6
equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by silica gel column
chromatography using hexanes/EtOAc (15:1) afforded product 2m (21.9 mg, 73% yield) as a
yellow oil. 1H NMR (CDCl3) δ 7.34-7.36 (m, 2H), 7.26-7.30 (m, 4H), 7.17-7.21 (m, 1H), 6.82 (d,
J = 9.0 Hz, 2H), 4.92 (s, 1H), 3.76 (s, 3H), 2.28 (td, J = 2.4, 7.0 Hz, 2H), 1.51-1.56 (m, 2H), 1.41-
1.46 (m, 2H), 0.92 (t, J = 7.0 Hz, 3H).
(E)-(3-(4-methoxyphenyl)prop-1-ene-1,3-diyl)dibenzene
(3a)41:
Derived
from
(4-
methoxyphenyl)(phenyl)methanol (21.4 mg, 0.100 mmol, 1.0 equiv.), potassium trifluoro(E)-2-
phenylethenylborate (21.0 mg, 0.100 mmol, 1.0 equiv.) and HBF4·OEt2 (25.9 mg, 0.16 mmol, 1.6
equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by silica gel column
chromatography using hexanes/EtOAc (15:1) afforded product 3a (29.0 mg, 97% yield) as a pale
1
yellow oil. H NMR (CDCl3) δ 7.35-7.37 (m, 2H), 7.19-7.32 (m, 8H), 7.14 (d, J = 8.6 Hz, 2H),
6.85 (d, J = 9.0 Hz, 2H), 6.65 (dd, J = 7.4, 15.6 Hz, 1H), 6.32 (d, J = 15.6 Hz, 1H), 4.84 (d, J =
7.4 Hz, 1H), 3.77 (s, 3H).
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(E)-4,4’-(3-(3-fluorophenyl)prop-2-ene-1,1-diyl)bis(methoxybenzene) (3b): Derived from
bis(4-methoxyphenyl)methanol (S11) (21.0 mg, 0.086 mmol, 1.0 equiv.), potassium trifluoro(2-
(3-fluorophenyl)vinyl) borate (19.6 mg, 0.086 mmol, 1.0 equiv.) and HBF4·OEt2 (22.3 mg, 0.14
mmol, 1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification by silica gel column
chromatography using hexanes/EtOAc (9:1) afforded product 3b (29.1 mg, 97% yield) as a pink
oil. IR (Diamond-ATR) ν 2929, 1608, 1581, 1506, 1242, 1173, 1033, 964, 825, 553 cm-1; 1H NMR
(CDCl3) δ 7.20-7.25 (m, 1H), 7.05-7.13 (m, 6H), 6.84-6.91 (m, 5H), 6.61-6.66 (m, 1H), 6.26 (d, J
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= 15.6 Hz, 1H), 4.79 (d, J = 7.4 Hz, 1H), 3.78 (s, 6H); C {1H} NMR (CDCl3) δ 163.1 (d, J =
245.4 Hz), 158.2, 139.7 (d, J = 7.7 Hz), 135.6, 134.7, 129.9 (d, J = 3.1 Hz), 129.8 (d, J = 2.3 Hz),
129.5, 122.1 (d, J = 2.3 Hz), 113.94 (d, J = 21.5 Hz), 113.87, 112.7 (d, J = 22.2 Hz), 55.2, 52.4;
19F NMR (CDCl3) δ -113.71 (s, 1F); HRMS (EI) m/z: [M+] Calcd for C23H21FO2 348.1526; Found
348.1523.
(E)-N-(4-(3-phenyl-1-(p-tolyl)allyl)phenyl)acetamide (3c): Derived from N-(4-hydroxy(p-
tolyl)methyl)phenyl)acetamide (S14) (22.4 mg, 0.088 mmol, 1.0 equiv.), potassium trifluoro(E)-
2-phenylethenylborate (18.5 mg, 0.088 mmol, 1.0 equiv.) and HBF4·OEt2 (22.8 mg, 0.14 mmol,
1.6 equiv.) in 0.3 mL of CH3CN following Procedure 4. Purification was conducted by silica gel
column chromatography using hexanes/EtOAc (1:2) and subsequent CH3CN/hexanes extraction
afforded product 3c (23.2 mg, 77% yield) as a pale white/yellow oil. IR (Diamond-ATR) ν 3294,
2922, 1662, 1599, 1509, 1407, 1369, 1315, 1262, 966, 816, 741, 691, 522 cm-1; 1H NMR (CDCl3)
δ 7.41-7.43 (m, 2H), 7.34-7.37 (m, 2H), 7.15 -7.29 (m, 5H), 7.10 (s, 4H), 6.61 (dd, J = 7.4, 16.0
Hz, 1H), 6.31 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 7.4 Hz, 1H), 2.32 (s, 3H), 2.13 (s, 3H); 13C {1H}
NMR (CDCl3) δ 168.3, 140.4, 139.7, 137.2, 136.2, 136.0, 132.6, 131.2, 129.2, 129.1, 128.5, 128.4,
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127.2, 126.3, 120.0, 53.2, 24.5, 21.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H24NO
342.1852; Found 342.1849.
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(E)-4-(3-(3-fluorophenyl)-1-(4-methoxyphenyl)allyl)-N,N-dimethylaniline (3d): Derived from
(4-(dimethylamino)phenyl)(4-methoxyphenyl)methanol (S13) (21.4 mg, 0.083 mmol, 1.0 equiv.),
potassium trifluoro(2-(3-fluorophenyl)vinyl) borate (18.9 mg, 0.083 mmol, 1.0 equiv.) and
HBF4·OEt2 (34.9 mg, 0.2 mmol, 2.6 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification by silica gel column chromatography using hexanes/EtOAc (6:1) afforded product 3d
(25.1 mg, 84% yield) as a pale white/yellow oil. IR (Diamond-ATR) ν 2926, 1609, 1507, 1244,
1174, 1140, 1034, 813, 774, 552 cm-1; 1H NMR (CDCl3) δ 7.19-7.25 (m, 1H), 7.04-7.15 (m, 6H),
6.83-6.90 (m, 3H), 6.62-6.71 (m, 3H), 6.27 (d, J = 16.0 Hz, 1H), 4.75 (d, J = 7.4 Hz, 1H), 3.78 (s,
3H), 2.91 (s, 6H); 13C {1H} NMR (CDCl3) δ 163.1 (d, J = 244.6 Hz), 158.1, 149.3, 140.0 (d, J =
7.7 Hz), 136.0, 135.1, 131.4, 129.9, 129.8, 129.5, 129.1, 122.1 (d, J = 3.1 Hz), 113.79, 113.78 (d,
J = 21.5 Hz), 112.74 112.65 (d, J = 22.2 Hz), 55.2, 52.3, 40.7; 19F NMR (CDCl3) δ -113.82 (s, 1F);
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H25FNO 362.1915; Found 362.1912.
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(E)-4-(3-(3-fluorophenyl)-1-(4-methoxyphenyl)allyl)benzoic acid (3e): Derived from 4-
(hydroxy(4-methoxyphenyl)methyl)benzoic acid (S16) (21.4 mg, 0.083 mmol, 1.0 equiv.),
potassium trifluoro(2-(3-fluorophenyl)vinyl) borate (18.9 mg, 0.083 mmol, 1.0 equiv.) and
HBF4·OEt2 (17.4 mg, 0.12 mmol, 1.3 equiv.) in 0.3 mL of CH3CN following Procedure 4.
Purification was conducted by silica gel column chromatography using hexanes/EtOAc/AcOH
(2:1:0.01% v/v) and subsequent CH3CN/hexanes extraction afforded product 3e (23.0 mg, 77%
yield) as a pale yellow oil. IR (Diamond-ATR) ν 2922, 1685, 1607, 1508, 1245, 1176, 1033, 963,
1
778, 683, 548 cm-1; H NMR (acetone-d6) δ 8.01 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H),
7.22-7.37 (m, 5H), 6.89-7.01 (m, 4H), 6.49 (d, J = 16.0 Hz, 1H), 5.01 (d, J = 8.2 Hz, 1H), 3.77 (s,
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3H); 13C {1H} NMR (acetone-d6) δ 164.1 (d, J = 243.1 Hz), 159.5, 150.4, 141.0 (d, J = 7.7 Hz),
136.0, 134.9, 131.3, 131.2, 131.1 (d, J = 3.1 Hz), 130.8, 130.4, 129.4, 123.52, 123.50, 114.8 (d, J
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= 20.7 Hz), 113.4 (d, J = 22.2 Hz), 55.6, 54.2; F NMR (acetone-d6) δ -115.09 (s, 1F); HRMS
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(ESI-TOF) m/z: [M+H]+ Calcd for C23H20FO3 363.1391; Found 363.1388.
1-methoxy-2-(3-phenyl-1-(p-tolyl)prop-2-yn-1-yl)benzene
(6):
Derived
from
(2-
methoxyphenyl)(p-tolyl)methanol (5) (65.8 mg, 0.288 mmol, 1.0 equiv.), potassium
trifluoro(phenylethynyl)borate (S1) (60.0 mg, 0.288 mmol, 1.0 equiv.) and HBF4·OEt2 (74.6 mg,
0.461 mmol, 1.6 equiv.) in 1.0 mL of CH3CN following Procedure 4. Purification by automated
flash column chromatography on silica gel using hexanes/diethyl ether (99:1) afforded product 6
(60.1 mg, 67% yield) as a yellow oil. IR (Diamond-ATR) ν 1597, 1488, 1460, 1243, 1103, 1026,
803, 749, 690, 560, 524 cm-1; 1H NMR (CDCl3) δ 7.60-7.62 (m, 1H), 7.44-7.47 (m, 2H), 7.35 (d,
J = 8.2 Hz, 2H), 7.25-7.29 (m, 3H), 7.19-7.23 (m, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.95 (t of d, J =
1.1, 7.4 Hz, 1H), 6.84-6.86 (m, 1H), 5.65 (s, 1H), 3.82 (s, 3H), 2.29 (s, 3H); C {1H} NMR
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(CDCl3) δ 156.1, 138.8, 136.0, 131.7, 130.5, 129.0, 128.9, 128.13, 128.05, 127.71, 127.68, 123.8,
120.9, 110.7, 91.2, 83.3, 55.5, 36.2, 21.0; HRMS (DART-TOF+) m/z: [M+H] Calcd for C23H21O
313.1592; Found 313.1600.
Demethylation Procedure (General Procedure 5):
A solution of the indicated ortho-methoxy substituted product (1.0 equiv.) in dry DCM (0.1 M)
was treated with boron tribromide solution (3.0 equiv.) at 0 oC. After addition was complete, the
mixture was allowed to stir at room temperature for 30 minutes. The reaction was quenched with
water and extracted with 20 mL of EtOAc. The organic layer was washed with water (3 x 15 mL)
followed by brine (1 x 10 mL). The organic layer was dried with MgSO4 and concentrated. The
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product was purified by flash chromatography with hexanes/ethyl acetate and concentrated.
Extraction from hexanes with acetonitrile afford the desired demethylated product.
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2-(3-phenyl-1-(p-tolyl)prop-2-yn-1-yl)phenol (S18): Derived from 1-methoxy-2-(3-phenyl-1-
(p-tolyl)prop-2-yn-1-yl)benzene (6) (60.1 mg, 0.192 mmol, 1.0 equiv.) and boron tribromide
solution [1.0 M in methylene chloride] (0.145 g, 0.577 mmol, 3.0 equiv.) in 2.0 mL of anhydrous
DCM following Procedure 5. Purification by automated flash column chromatography on silica
gel using hexanes/EtOAc (gradient: 24:1 ‰ 9:1) and subsequent CH3CN/hexanes extraction
afforded product S18 (42.0 mg, 73% yield) as a yellow oil. IR (Diamond-ATR) ν 3527, 1595,
1488, 1454, 1185, 1087, 822, 749, 689 cm-1; 1H NMR (CDCl3) δ 7.48-7.52 (m, 2H), 7.41-7.44 (m,
1H), 7.39 (d, J = 8.2 Hz, 2H), 7.31-7.35 (m, 3H), 7.19-7.22 (m, 1H), 7.17 (m, 2H), 6.96 (t of d, J
= 1.2, 7.4 Hz, 1H), 6.85 (d of d, J = 1.2, 8.2 Hz, 1H), 5.50 (s, 1H), 5.44 (s, 1H), 2.35 (s, 3H); 13C
{1H} NMR (CDCl3) δ 153.3, 137.2, 136.7, 131.7, 129.5, 129.4, 128.5, 128.23, 128.19, 127.6,
127.5, 123.0, 121.0, 116.6, 89.1, 85.3, 38.2, 21.0; HRMS (DART-TOF+) m/z: [M+H] Calcd for
C22H19O 299.1436; Found 299.1437.
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Cyclization Procedure (General Procedure 6):
The indicated ortho-hydroxy substituted product (1.0 equiv.) was dissolved in anhydrous dioxane.
Then potassium tert-butoxide (2.0 equiv.) was added and the reaction mixture was stirred at
ambient temperature for 105 minutes. The reaction solution was then diluted with DCM (10 mL)
and washed with brine (10 mL). The aqueous phase was extracted with DCM (2 x 10 mL). The
combined organic phase was washed with deionized water (3 x 15 mL) and brine (1 x 10 mL). The
organic layer was dried with MgSO4 and concentrated. The product was purified by flash
chromatography with hexanes/diethyl ether and concentrated. Extraction from hexanes with
acetonitrile afford the desired demethylated product.
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