Boronic acid/Br?nsted acid co-catalyst systems for the synthesis of 2: H -chromenes from phenols and α,β-unsaturated carbonyls

Article abstract of DOI:10.1039/c6ob01026a

Protocols for the synthesis of substituted 2H-chromenes from α,β-unsaturated carbonyls and phenols are described. Optimal combinations of arylboronic acids and Br?nsted acids have been identified, such that both can be employed in catalytic quantities to accelerate these condensations. The method has been used to synthesize a variety of substituted 2H-chromenes, as well as photochromic naphthopyrans. The use of pentafluorophenylboronic acid and diphenylphosphinic acid enabled an expansion of the electrophile scope to include α,β-unsaturated ketones. Hall's 'phase-switching' of boronic acids has been exploited to achieve the separation of the two co-catalysts from unpurified reaction mixtures by a simple liquid-liquid extraction.

Full text of DOI:10.1039/c6ob01026a

Organic &
Biomolecular Chemistry
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Boronic acid/Brønsted acid co-catalyst systems for
the synthesis of 2H-chromenes from phenols and
α,β-unsaturated carbonyls†
Cite this: DOI: 10.1039/c6ob01026a
Victoria Dimakos, Tishaan Singh and Mark S. Taylor*
Protocols for the synthesis of substituted 2H-chromenes from α,β-unsaturated carbonyls and phenols are
described. Optimal combinations of arylboronic acids and Brønsted acids have been identified, such that
both can be employed in catalytic quantities to accelerate these condensations. The method has been
used to synthesize a variety of substituted 2H-chromenes, as well as photochromic naphthopyrans. The
use of pentafluorophenylboronic acid and diphenylphosphinic acid enabled an expansion of the electro-
phile scope to include α,β-unsaturated ketones. Hall’s ‘phase-switching’ of boronic acids has been
exploited to achieve the separation of the two co-catalysts from unpurified reaction mixtures by a simple
liquid–liquid extraction.
Received 11th May 2016,
Accepted 7th June 2016
DOI: 10.1039/c6ob01026a
www.rsc.org/obc
Introduction
The 2H-chromene ring system is a core structure of numerous
biologically active natural products,1 and its annelated conge-
ners (naphthopyrans and related structures) display useful
photochromic properties.2 Several methods exist for the syn-
thesis of 2H-chromenes, enabling access to a variety of substi-
tution patterns.3 Transition metal-catalyzed transformations
that have been exploited for 2H-chromene synthesis include
alkyne hydroarylation,4 allylic substitution5 and olefin meta-
thesis.6 Approaches based on Brønsted or Lewis acid-catalyzed
condensations7–9 or cyclizations10 have also been reported.
Boronic acid-promoted condensations of phenols with
α,β-unsaturated carbonyl compounds provide access to 2H-
chromenes from readily available starting materials
(Scheme 1). This mode of reactivity was initially reported by
scientists at Merck,11 and was further developed into a general
method for 2H-chromene synthesis by Snieckus and co-
workers.12 The likely reaction pathway involves formation of
a benzodioxaborinine intermediate by Nagata alkylation,13 fol-
lowed by fragmentation to an ortho-quinone methide and elec-
trocyclic ring closure. Over the years, boronic acid-mediated
condensations of this type have been applied to the synthesis
of several classes of benzopyran-based natural products.14–16
The protocol for boronic acid-promoted 2H-chromene syn-
thesis has changed relatively little since Dufresne’s initial
Scheme 1 Phenylboronic acid-mediated condensations of phenols and
α,β-unsaturated aldehydes. A proposed pathway is shown below the
reaction equation.
report more than two decades ago. This described the use of
1.6 equivalents of phenylboronic acid (PhB(OH)2) and 30 mol%
of propionic acid relative to phenol, with removal of water
by azeotropic reflux in toluene using a Dean–Stark trap.11
Snieckus and co-workers reported similar conditions, employ-
ing 1 equivalent of PhB(OH)2 and an excess (>85 equiv.) of
acetic acid, also in toluene with a Dean–Stark apparatus.12
A survey of Brønsted acids (including carboxylic acids, sulfonic
acids and H2SO4) was carried out in 2007, revealing that pro-
pionic acid (110 equiv.) provided best results for the coupling
of umbelliferone and 3-methyl-2-butenal (1 equiv. of PhB(OH)2
in toluene at reflux). Each of these studies points towards the
combination of stoichiometric phenylboronic acid and a
carboxylic acid promoter.
Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
E-mail: mtaylor@chem.utoronto.ca
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all new compounds. See DOI: 10.1039/c6ob01026a
Although the thermolysis of the benzodioxaborinine inter-
mediate provides a pathway for catalyst turnover, examples of
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protocols that employ substoichiometric quantities of aryl-
boronic acid are scarce. Wilson and co-workers showed that
25 mol% of PhB(OH)2 was able to promote the condensation
of phloroglucinol with 3-methyl-2-butenal, yielding a mixture
of bis- and tris-annulated products (39% and 55% yields,
respectively, for a total of >9 turnovers).17 As part of the syn-
thesis of a series of pyranocarbazole alkaloids, Knölker’s group
found that condensations of citral with a hydroxycarbazole
could be achieved in 75% yield using 20 mol% of PhB(OH)2 in
toluene at reflux.15 Another relevant study by McCubbin
showed that pentafluorophenylboronic acid (10 mol%) was
able to catalyse condensations of 2-naphthol with propargylic
alcohols, generating substituted naphthopyran products.18
These same conditions were used to effect Friedel–Crafts
propargylations of other electron-rich aromatics, and it is not
clear whether there is a direct mechanistic connection to the
above-mentioned phenol–enal annulations. In any case, it
appeared to us that evaluating a range of organoboron acid
and Brønsted acid catalysts might be an opportunity to
improve the efficiency or expand the scope of such conden-
sations, especially given the impressive progress that has been
achieved in the development of ‘designer’ boronic acids for
use in catalysis in recent years.19,20
Table 1 Catalyst optimization for the synthesis of 2H-chromene 4a
Entry
Organoboron acid
Brønsted acid HX
Yielda
1
2
Ph2BOH
1a
—
—
<5%
5%
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph2BOH
1a
PhB(OH)2
1b
1c
1d
1e
PhB(OH)2
PhB(OH)2
1c
1c
1c
1e
1e
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
CH3CH2CO2H
Ph2PO2H
CH3CH2CO2H
Ph2PO2H
CSA
15%
30%
20%
30%
40%
45%
45%
10%
60%
60%
70%
<5%
15%
70%
CH3CH2CO2H
Ph2PO2H
Here, we describe a systematic evaluation of organoboron
acid/Brønsted acid combinations for the synthesis of 2H-
chromenes from phenols and α,β-unsaturated carbonyl com-
pounds. By variation of the two promoters, we have developed
efficient and operationally simple protocols in which both are
employed in catalytic quantities. These conditions have been
a Determined by 1H NMR spectroscopy of the crude reaction mixture
using 1,3,5-trimethoxybenzene as an internal standard. Reactions were
carried out under inert atmosphere.
applied to a range of reaction partners, including α,β-unsatu- 10–16). Diphenylphosphinic acid provided superior results to
rated ketones as well as aldehydes.
propionic and benzoic acid, whereas the use of the stronger
acid camphorsulfonic acid (CSA) resulted in decomposition.
Although further mechanistic study is needed to make a
definitive conclusion on this point, we speculate that increas-
ing the acidity of both the boronic acid and Brønsted acid
Results and discussion
3-Methoxyphenol (2a) and enone 3a were chosen as the sub- components (relative to the original PhB(OH)2/carboxylic acid
strates for evaluation of organoboron acid and Brønsted acid system) accelerates the addition of the phenol to the rather
co-catalysts (Table 1). Previous reports of boronic acid- poorly electrophilic enone. It should be noted that the yields
promoted 2H-chromene synthesis describe couplings of reported in Table 1 are for reactions carried out under an inert
α,β-unsaturated aldehydes, but not ketones, and so we antici- argon atmosphere. Inferior results were obtained when air was
pated that screening against this substrate combination might not excluded. However, azeotropic removal of water using a
be useful for identifying particularly active catalysts.
Dean-Stark apparatus was not required under this protocol.
Having identified the combination of pentafluorophenyl-
We began by testing diarylborinic acids R2BOH: these are
more Lewis acidic than the corresponding boronic acids RB boronic acid and diphenylphosphinic acid (20 mol% each) as
(OH)2, and are useful catalysts for several types of transform- being optimal, we investigated the scope of this process
ations, including carbon–carbon21 and carbon–heteroatom (Scheme 2). Enones 3a–3e were successfully coupled with
bond-forming reactions,22 dehydrations23 and oxidations.24 3-methoxyphenol and 1-naphthol, yielding 2,4-disubstituted
However, both Ph2BOH and oxaboraanthracene-derived and 2,2,4-trisubstituted 2H-chromene products. These were
borinic acid 1a showed only modest activity: yields of 4a were obtained in high levels of purity after column chromatography
low (≤5%) in the absence of a Brønsted acid (entries 1 and 2), on silica gel, with the exception of products 4f and 4g, which
and were not significantly different from that obtained with were isolated along with small amounts (<10%) of the corres-
PhB(OH)2 when benzoic acid was employed as a co-catalyst ponding 4-methylenechromane regioisomers.
(entries 3–5). On the other hand, an improvement in yield was
Condensations of α,β-unsaturated aldehydes with phenols
achieved using more Lewis acidic arylboronic acids 1c–1e were also investigated under boronic acid/Brønsted acid co-
(entries 7–9). Several Brønsted acids, including carboxylic, catalysis (Scheme 3). Unlike the aforementioned reactions with
phosphinic and sulfonic acids, were then surveyed (entries enones, syntheses of 2H-chromenes from α,β-unsaturated alde-
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Scheme 2 Condensations of α,β-unsaturated ketones with phenol
derivatives. Reaction conditions: phenol (0.2 mmol), enone (0.4 mmol),
1e (20 mol%), Ph2PO2H (20 mol%) in heptane (1 mL) at 100 °C for 3 h
under argon. Isolated yields after purification by chromatography on
silica gel are listed. Products 4f and 4g were obtained as mixtures of
endocyclic and exocyclic olefin isomers.
hydes did not require an argon atmosphere, and benzoic acid
(rather than Ph2PO2H) was found to be the most suitable
Brønsted acid catalyst. Variation in the identity of the optimal
boronic acid was also observed. The parent PhB(OH)2 was able
to promote condensations of activated phenols, and provided
superior results in cases where electron-deficient 1c promoted
decomposition of the phenol (2a) or aldehyde (5b) component.
On the other hand, 1c displayed higher activity than Ph2BOH
for condensations of less nucleophilic phenols (2b and 2g–2i).
When unsubstituted phenol was subjected to these conditions,
little to no product was observed.
Scheme 3 Condensations of α,β-unsaturated aldehydes with phenol
derivatives. Reaction conditions: phenol (0.5 mmol), aldehyde
(1.0 mmol), ArB(OH)2 (5–20 mol%), PhCO2H (20 mol%), in heptane
(2.5 mL) at 60–100 °C for 17 h. For details, see the Experimental section.
Isolated yields after purification by chromatography on silica gel are
listed. a PhB(OH)2 was used as the catalyst. b 1c was used as the catalyst.
c The reaction was carried out using 6.0 equiv. of 5a. d Ph2PO2H
(10 mol%) was used as the Brønsted acid co-catalyst.
acidification and extraction of the aqueous sorbitol solution
(Scheme 4). The recovered catalyst mixture was re-used without
To establish the preparative utility of this method, we
undertook the synthesis of naphthopyran 6g on gram scale
(5 mmol). For this larger-scale experiment, we took advantage
of the ‘phase-switching’ protocol developed by Hall and co-
workers.25 This technique uses simple liquid–liquid extrac-
tions to separate boronic acids from other organic compounds,
based on the pH-switchable solubility of boronic acids in
aqueous sorbitol solution (increased solubility at high pH due
to formation of a tetracoordinate boronate ester). In the
present case, working up the reaction mixture by extraction
with basic aqueous sorbitol solution resulted in a straight-
forward separation of the product (organic phase) from the
arylboronic acid and carboxylic acid components (aqueous
phase). The product was purified by elution through a short
further purification in
affording 6g in 70% yield.
a second gram scale synthesis,
Scheme 4 Separation of co-catalysts from naphthopyran product by
plug of silica gel, while the catalyst mixture was recovered after phase-switching.
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Hall’s ‘phase-switching’ protocol has been used to achieve a
convenient separation of both catalyst components from
unpurified reaction mixtures by
extraction.
a simple liquid–liquid
Experimental
Scheme 5 Synthesis of naphthopyrans from propargylic alcohols.
General methods
Reactions were carried out without effort to exclude air or
moisture, unless otherwise indicated. Stainless steel needles
and syringes were used to transfer air- and moisture-sensitive
liquids. Flash chromatography was carried out using neutral
silica gel (60 Å, 230–400 mesh, Silicycle). Analytical thin layer
chromatography was carried out using aluminum-backed
silica gel 60 F254 plates (EMD), and compounds were visualized
through the use of UV light or basic KMnO4 stain. HPLC grade
THF was dried and purified using a solvent purification
system equipped with columns of activated alumina, under
nitrogen (Innovative Technology, Inc.). Anhydrous heptane was
purchased from Sigma Aldrich. Distilled water was obtained
from an in-house supply. All other solvents and reagents were
purchased from Sigma Aldrich or Alfa Aesar and used without
further purification. Screw cap test tubes were purchased from
Pyrex® (13 mm × 100 mm, mfr. no. = Corning, 9825-13).
Nuclear magnetic resonance (NMR) solvents were purchased
from Cambridge Isotope Laboratories or from Sigma Aldrich.
1H and 13C NMR spectra were recorded in CDCl3 or C6D6 using
either a Bruker Avance III 400 MHz, Varian Mercury 400 MHz
or Agilent 500 MHz spectrometer. 1H NMR are reported in
parts per million (ppm) relative to tetramethylsilane and refer-
enced to residual protium in the solvent. Spectral features are
tabulated in the following order: chemical shift (δ, ppm);
multiplicity (s-singlet, d-doublet, t-triplet, q-quartet,
m-complex multiplet); number of protons; coupling constant
(s) (J, Hz). High-resolution mass spectra (HRMS) were obtained
on a JEOL AccuTOF JMS-T1000LC mass spectrometer equipped
with a DART (direct analysis in real time) ion source, and are
not corrected for the mass of the electron. Infrared (IR) spectra
were obtained on a Perkin-Elmer Spectrum 100 instrument
equipped with a single-bounce diamond/ZnSe ATR accessory
as solids or thin films, as indicated. Spectral features are
tabulated as follows: wavenumber (cm−1); intensity (s-strong,
m-medium, w-weak).
Hall and co-workers have shown that electron-deficient
boronic acids catalyze the Meyer–Schuster rearrangement of
propargylic alcohols to α,β-unsaturated compounds.26 We envi-
sioned that an in situ rearrangement of this type could enable
the synthesis of 2H-chromene derivatives from propargylic
alcohols under our optimized reaction conditions. To test this
idea, we investigated condensations of 2-naphthol with readily
available 1,1-diarylpropyn-1-ol derivatives as a way to access
gem-diaryl-substituted naphthopyran products (Scheme 5). The
latter have been studied extensively for applications in
ophthalmic lenses due to their useful photochromic pro-
perties.2 Using 20 mol% each of 1c and benzoic acid, naphtho-
pyran 6l was generated from 2-naphthol and propargylic
alcohol 7a. The yield of this process was comparable to that
obtained from enal 5d (Scheme 3), and the isomerization of 7a
to 5d was evident upon monitoring the condensation reaction
by thin layer chromatography. In a similar way, the photochro-
mic and solvatochromic naphthopyran 6m was synthesized
from 7b.27 As mentioned in the introduction, McCubbin and
co-workers have also developed condensations of 2-naphthol
with propargylic alcohols, using pentafluorophenylboronic
acid and 4 Å molecular sieves in dichloromethane at room
temperature. Propargylic alcohols having a (trimethylsilyl)
alkynyl or phenylalkynyl group, rather than a terminal alkynyl
group, were employed. The proposed mechanism involved
Friedel–Crafts allenylation followed by cyclization through
addition of the phenol group across the terminal carbon–
carbon double bond. Subjecting compound 7a and 2-naphthol
to these conditions resulted in appreciable consumption of 7a
(approximately 55% conversion), but only
a 10% yield
of naphthopyran 6l (conversion and yield were determined by
1H NMR with an internal standard). Thus, these superficially
similar protocols appear to differ in scope, and may proceed
by different mechanisms.
General procedure A: condensations of phenols and
naphthols with α,β-unsaturated ketones. An oven-dried 25 mL
Schlenk tube equipped with a teflon-coated magnetic stir bar
was evacuated and purged with argon. The phenol (0.2 mmol),
Conclusions
Through variation of the arylboronic acid and Brønsted acid pentafluorophenylboronic acid (8.5 mg, 0.04 mmol, 20 mol%),
components, we have identified combinations that show diphenylphoshinic acid (8.7 mg, 0.04 mmol, 20 mol%), α,β-un-
optimal catalytic activity for 2H-chromene synthesis via con- saturated ketone (0.4 mmol) and heptane (1 mL) were added
densations of phenols and α,β-unsaturated carbonyls. The use to the tube under argon. The tube was evacuated and back-
of an electron-deficient boronic acid (C6F5B(OH)2 or 3,5-(CF3)2- filled three times with argon after addition of the solid
C6H3B(OH)2), in concert with diphenylphosphinic acid, is par- reagents and prior to the addition of the liquid reagents. The
ticularly effective for condensations of less reactive substrates tube was capped, sealed and stirred at 100 °C for three hours.
such as α,β-unsaturated ketones or non-activated phenols. The tube was then cooled to room temperature and the
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mixture was concentrated in vacuo. The resulting crude (126 MHz, C6D6): δ 161.7, 156.0, 141.4, 139.0, 137.1, 129.1,
material was purified by flash chromatography on silica gel. 128.8, 128.7, 128.5, 127.6, 127.2, 121.0, 116.4, 107.7, 102.6,
General procedure B: condensations of phenols and 77.6, 54.8, 30.3. IR (neat, cm−1): 3059 (w), 3030 (w), 3000 (w),
naphthols with α,β-unsaturated aldehydes. To a screw cap test 2926 (w), 2851 (w), 2835 (w), 1609 (m), 1567 (m), 1501 (m),
tube equipped with a teflon-coated magnetic stir bar were 1443 (m), 1351 (m), 1308 (m), 1268 (m), 1247 (m), 1193 (m),
added phenol (0.5 mmol), arylboronic acid (5–20 mol%), 1155 (s), 1111 (m), 1031 (m), 979 (m), 760 (m), 696 (s). HRMS
Brønsted acid (20 mol%), α,β-unsaturated aldehyde (1.0 mmol) (DART-TOF+, m/z): Calculated for C22H19O2 [(M
+
H)+]:
and heptane (2.5 mL). The tube was capped in ambient atmo- 315.1385. Found: 315.1390.
sphere and stirred at 60–100 °C. The catalyst loading and reac-
2,4-Diphenyl-2H-naphtho[1,2-b]pyran
(4d).
Synthesized
tion temperature for each substrate combination are provided according to general procedure A, from 1-naphthol (29.1 mg,
below. After 17 hours, the mixture was concentrated in vacuo 0.20 mmol) and trans-chalcone (83.6 mg, 0.40 mmol). Isolated
and the resulting crude material was purified by flash chrom- as a pale yellow solid after flash chromatography on silica gel,
atography on silica gel.
eluting with 2–3% diethyl ether/hexanes (50.6 mg, 75%). 1H
7-Methoxy-4-methyl-2-propyl-2H-chromene (4a). Synthesized NMR (500 MHz, C6D6): δ 8.49–8.43 (m, 1H), 7.56–7.53 (m, 1H),
according to general procedure A, from 3-methoxyphenol 7.47–7.44 (m, 2H), 7.33–7.29 (m, 3H), 7.27–7.17 (m, 5H),
(24.7 mg, 0.20 mmol) and 3-hepten-2-one (47.6 mg, 7.14–7.10 (m, 2H), 7.08–7.04 (m, 1H), 5.88 (d, J = 3.7 Hz, 1H),
0.42 mmol). Isolated as a pale yellow oil after flash chromato- 5.65 (d, J = 3.7 Hz, 1H). 13C NMR (126 MHz, C6D6): δ 150.2,
graphy on silica gel, eluting with 2% diethyl ether/hexanes 141.4, 138.9, 137.8, 135.2, 129.2, 128.9, 128.7, 128.5, 128.1,
(47.6 mg, 70%). 1H NMR (500 MHz, C6D6): δ 6.95 (d, J = 8.4 Hz, 128.0, 127.3, 127.0, 126.0, 125.5, 123.8, 122.9, 122.3, 120.7,
1H), 6.65 (d, J = 2.6 Hz, 1H), 6.49 (dd, J = 8.4, 2.6 Hz, 1H), 5.10 117.6, 77.6. IR (neat, cm−1): 3057 (w), 2922 (w), 2851 (w), 1638
(dq, J = 3.0, 1.4 Hz, 1H), 4.72 (dddq, J = 7.9, 4.9, 3.3, 1.7 Hz, (w), 1615 (w), 1599 (w), 1562 (w), 1494 (w), 1454 (w), 1385 (m),
1H), 3.28 (s, 3H), 1.80 (dd, J = 1.6, 1.6 Hz, 3H), 1.77–1.69 (m, 1345 (m), 1298 (m), 1257 (m), 1209 (m) 1096 (m), 953 (m), 808
1H), 1.59–1.32 (m, 4H), 0.84 (dd, J = 7.3, 7.2 Hz, 3H). 13C NMR (s), 748 (s), 695 (s). HRMS (DART-TOF+, m/z): Calculated for
(126 MHz, C6D6): δ 161.4, 155.9, 129.7, 124.6, 120.1, 117.5, C25H19O1 [(M + H)+]: 335.1436. Found: 335.1438.
107.1, 102.2, 75.4, 54.8, 38.1, 18.6, 18.6, 18.1, 14.2, 14.2.
4-Methyl-2,2-diphenyl-2H-naphtho[1,2-b]pyran (4e). Syn-
IR (neat, cm−1): 2957(m), 2932 (m), 2872 (w), 2836 (w), 1652 thesized according to general procedure A, from 1-naphthol
(w), 1612 (s), 1570 (m), 1504 (s), 1443 (m), 1379 (m), 1311 (m), (28.7 mg, 0.20 mmol) and 4,4-diphenylbut-3-en-2-one
1275 (m), 1194 (m), 1159 (s), 1145 (s), 1132 (s), 1067 (m), 1031 (89.1 mg, 0.40 mmol). Isolated as a pale yellow solid after flash
(s), 809 (m). HRMS (DART-TOF+, m/z): Calculated for C14H19O2 chromatography on silica gel, eluting with 2% diethyl ether/
[(M + H)+]: 219.1385. Found: 219.1383.
hexanes (50.1 mg, 72%). 1H NMR (500 MHz, C6D6): δ 8.56–8.51
7-Methoxy-4-methyl-2-propyl-2H-chromene (4b). Synthesized (m, 1H), 7.62–7.57 (m, 4H), 7.57–7.53 (m, 1H), 7.28 (ddd, J =
according to general procedure A, from 3-methoxyphenol 8.3, 6.8, 1.3 Hz, 1H), 7.25–7.17 (m, 2H), 7.13 (d, J = 8.5 Hz, 2H),
(24.8 mg, 0.2 mmol) and benzylideneacetone (58.9 mg, 7.10–7.05 (m, 4H), 7.02–6.95 (m, 2H), 5.83 (q, J = 1.5 Hz, 1H),
0.4 mmol). Isolated as a pale yellow oil after flash chromato- 1.88 (d, J = 1.5 Hz, 3H). 13C NMR (126 MHz, C6D6): δ 148.3,
graphy on silica gel, eluting with 2% diethyl ether/hexanes 146.1, 135.1, 130.0, 128.4, 128.0, 127.7, 127.4, 126.6, 126.0,
(40.7 mg, 81%).1H NMR (500 MHz, CDCl3): δ 7.46–7.41 (m, 125.4, 124.8, 122.8, 121.8, 120.7, 117.8, 83.6, 18.4. IR (neat,
2H), 7.39–7.34 (m, 2H), 7.34–7.29 (m, 1H), 7.10 (d, J = 8.5 Hz, cm−1): 3049 (w), 2968 (w), 2918 (w), 2854 (w), 1653 (w), 1618
1H), 6.47 (dd, J = 8.4, 2.6 Hz, 1H), 6.42 (d, J = 2.6 Hz, 1H), 5.84 (w), 1563 (w), 1491 (w), 1465 (w), 1445 (m), 1372 (m), 1264 (m),
(dq, J = 3.5, 1.8 Hz, 1H), 5.48 (dq, J = 3.3, 1.7 Hz, 1H), 3.76 (s, 1206 (m), 1074 (m), 972 (m), 819 (m), 748 (s), 686 (s), 684 (m).
3H), 2.06 (dd, J = 1.7, 1.7 Hz, 3H). 13C NMR (126 MHz, CDCl3): HRMS (DART-TOF+, m/z): Calculated for C26H21O1 [(M + H)+]:
δ 160.9, 154.7, 141.5, 129.7, 128.7, 128.3, 127.1, 124.4, 119.1, 349.1592. Found: 349.1600.
116.7, 106.9, 101.8, 77.6, 55.5, 18.2. IR (neat, cm−1): 3061 (w),
4-Methyl-2-phenyl-2H-naphtho[1,2-b]pyran (4f). Synthesized
3031 (w), 2999 (w), 2917 (w), 2835 (w), 1648 (w), 1612 (s), 1504 according to general procedure A, from 1-naphthol (28.8,
(s), 1442 (m), 1310 (m), 1274 (s), 1193 (s), 1193 (s), 1159 (s), 0.20 mmol) and benzylideneacetone (58.5 mg, 0.40 mmol).
1141 (s), 1126 (s), 1066 (s), 1028 (s), 810 (m), 745 (m), 696 (s). Isolated as a light green oil after flash chromatography on
HRMS (DART-TOF+, m/z): Calculated for C17H17O2 [(M + H)+]: silica gel, eluting with 2% diethyl ether/hexanes. The title com-
253.1229. Found: 253.1229.
7-Methoxy-2,4-diphenyl-2H-chromene
pound was isolated as an inseparable mixture of regioisomers
Synthesized (11 : 1, H NMR) (47.8 mg, 88%). H NMR (500 MHz, C6D6): δ
1
1
(4c).
according to general procedure A, from 3-methoxyphenol 8.45–8.41 (m, 1H), 7.63–7.58 (m, 1H), 7.43–7.39 (m, 2H), 7.31
(24.8 mg, 0.20 mmol) and trans-chalcone (83.4 mg, (d, J = 8.5 Hz, 1H), 7.26–7.17 (m, 4H), 7.15–7.07 (m, 3H),
0.40 mmol). Isolated as a yellow oil after flash chromatography 7.08–7.03 (m, 1H), 5.86 (dq, J = 3.6, 1.8 Hz, 1H), 5.32 (dq, J =
on silica gel, eluting with 2% diethyl ether/hexanes (39.1 mg, 3.2, 1.5 Hz, 1H), 1.83 (dd, J = 1.7, 1.7 Hz, 3H). 13C NMR
57%). 1H NMR (400 MHz, C6D6): δ 7.48–7.42 (m, 2H), (126 MHz, C6D6): δ 149.4, 142.2, 135.1, 130.3, 128.8, 128.2,
7.34–7.29 (m, 2H), 7.20–7.12 (m, 5H), 7.11–7.05 (m, 2H), 6.68 127.9, 127.0, 126.7, 125.9, 125.2, 122.9, 121.8, 120.6, 120.6,
(d, J = 2.5 Hz, 1H), 6.39 (dd, J = 8.6, 2.6 Hz, 1H), 5.79 (d, J = 117.9, 77.8, 18.3. IR (neat, cm−1): 3059 (w), 3030 (w), 2970 (w),
3.7 Hz, 1H), 5.53 (d, J = 3.7 Hz, 1H), 3.20 (s, 3H). 13C NMR 2915 (w), 2854 (w), 1653 (w), 1620 (w), 1564 (m), 1465 (w), 1453
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(w), 1389 (m), 1377 (m), 1259 (m), 1205 (m), 1092 (m), 1074 lenedioxy)phenol (68.7 mg, 0.5 mmol) and 3-methyl-2-butenal
(m), 947 (m), 811 (s), 739 (s), 695 (s), 678 (m). HRMS (100 μL, 1.0 mmol) using phenylboronic acid (20 mol%) and
(DART-TOF+, m/z): Calculated for C20H17O1 [(M
+
H)+]: benzoic acid (20 mol%) at 100 °C. Isolated as a pale yellow oil
273.1279. Found: 273.1276. Selected NMR data for the minor after flash chromatography on silica gel, eluting with 0.5–1%
1
regioisomer: H NMR (500 MHz, C6D6): δ 5.51 (d, J = 2.1 Hz, EtOAc/pentane (91.3 mg, 90% yield). Spectral data were in
1H), 4.96 (dd, J = 11.5, 2.7 Hz, 1H), 4.76 (ddd, J = 2.1, 0.8, 0.7 agreement with previous reports.12 1H NMR (400 MHz, CDCl3):
Hz, 1H), 2.71 (dddd, J = 14.8, 11.5, 2.1, 2.1 Hz, 1H), 2.52 (ddd, δ 6.47 (s, 1H), 6.38 (s, 1H), 6.19 (d, J = 9.7 Hz, 1H), 5.87 (s, 2H),
J = 14.8, 2.7, 1.0 Hz, 1H).
5.47 (d, J = 9.7 Hz, 1H), 1.39 (s, 6H). 13C NMR (100 MHz,
2,2,4-Trimethyl-2H-naphtho[1,2-b]pyran (4g). Synthesized CDCl3): δ 148.4, 147.7, 141.5, 128.3, 122.4, 114.4, 105.8, 101.0,
according to general procedure A, from 1-naphthol (28.8 mg, 99.2, 76.2, 27.6.
0.20 mmol) and mesityl oxide (39.3 mg, 0.40 mmol). Isolated
5,7-Dimethoxy-2,2-dimethyl-2H-chromene (6d). Synthesized
as a pale yellow oil after flash chromatography on silica gel, according to general procedure B, from 3,5-dimethoxyphenol
eluting with 2% diethyl ether/hexanes. The title compound (78.6 mg, 0.51 mmol) and 3-methyl-2-butenal (100 μL,
was isolated as an inseparable mixture of regioisomers (14 : 1, 1.0 mmol) using phenylboronic acid (5 mol%) and benzoic
1H NMR) (21.4 mg, 48%). 1H NMR (500 MHz, C6D6): acid (20 mol%) at 100 °C. Isolated as a pale yellow oil after
δ 8.51–8.49 (m, 1H), 7.66–7.63 (m, 1H), 7.34–7.29 (m, 2H), 7.26 flash chromatography on silica gel, eluting with 1–2% EtOAc/
(ddd, J = 8.1, 6.8, 1.4 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.12 (q, pentane (109.4 mg, 97%). Spectral data were in agreement
J = 1.5 Hz, 1H), 1.84 (d, J = 1.5 Hz, 3H), 1.35 (s, 6H). 13C NMR with previous reports.28 1H NMR (500 MHz, CDCl3): δ 6.58 (dd,
(126 MHz, C6D6): δ 148.9, 135.0, 128.6, 127.9, 126.5, 126.0, J = 9.9, 0.7 Hz, 1H), 6.03 (dd, J = 2.3, 0.7 Hz, 1H), 6.01 (d, J =
125.8, 125.6, 122.9, 121.8, 120.0, 117.4, 76.6, 28.0, 18.3. IR 2.3 Hz, 1H), 5.42 (d, J = 9.9 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H),
(neat, cm−1): 3056 (w), 2973 (w), 2923 (w), 2855 (w), 1657 (w), 1.41 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 161.1, 156.3, 154.8,
1619 (w), 1565 (w), 1508 (w), 1459 (w), 1377 (s), 1358 (m), 1279 126.0, 116.8, 104.3, 94.1, 91.6, 76.4, 55.7, 55.5, 27.9.
(m), 1208 (m), 1158 (m), 1146 (m), 1077 (s), 951 (m), 924 (m),
2,2,6,6,10,10-Hexamethyl-2H,6H,10H-dipyrano[6,5-f,6′,5′-h]
815 (s), 799 (s), 744 (s), 685 (m). HRMS (DART-TOF+, m/z): Cal- chromene (6e). Synthesized according to general procedure B,
culated for C16H17O1 [(M + H)+]: 225.1279. Found: 225.1279. from 1,3,5-trihydroxylbenzene (60.8 mg, 0.48 mmol) and
Selected NMR data for the minor regioisomer: 1H NMR 3-methyl-2-butenal (300 μL, 3.0 mmol) using phenylboronic
(500 MHz, C6D6): δ 5.53 (dt, J = 2.3, 1.3, 1.3 Hz, 1H), 4.79 (dt, acid (20 mol%) and benzoic acid (20 mol%) at 100 °C. Isolated
J = 2.5, 1.5, 1.5 Hz, 1H), 2.24 (dd, J = 1.4, 1.4 Hz, 2H), 1.20 as a pale yellow solid after flash chromatography on silica gel,
(s, 6H).
eluting with 0.5–1% EtOAc/pentane (133.3 mg, 85%). Spectral
7-Methoxy-2,2-dimethyl-2H-chromene (6a). Synthesized data were in agreement with previous reports.17 1H NMR
according to general procedure B, from 3-methoxyphenol (400 MHz, CDCl3): δ 6.59 (d, J = 9.9 Hz, 3H), 5.42 (d, J = 9.9 Hz,
(61.6 mg, 0.5 mmol) and 3-methyl-2-butenal (100 μL, 3H), 1.41 (s, 18H). 13C NMR (100 MHz, CDCl3): δ 149.3, 126.0,
1.0 mmol) using phenylboronic acid (20 mol%) and benzoic 117.0, 103.6, 76.6, 28.1. HRMS (DART-TOF+, m/z): Calculated
acid (20 mol%) at 80 °C. Isolated as a pale yellow oil after flash for C21H25O3 [(M + H)+]: 325.1793. Found: 325.1804.
chromatography on silica gel, eluting with 0.5–1% EtOAc/
6-Methoxy-2,2-dimethyl-2H-chromene
(6f).
Synthesized
pentane (88.4 mg, 94%). Spectral data were in agreement with according to general procedure B, from 4-methoxyphenol
previous reports.12 1H NMR (500 MHz, CDCl3): δ 6.88 (dd, J = (60.2 mg, 0.5 mmol) and 3-methyl-2-butenal (100 μL,
8.2, 0.3 Hz, 1H), 6.40 (dd, J = 8.2, 2.5 Hz, 1H), 6.38–6.37 1.0 mmol) using 3,5-bis(trifluoromethyl)phenylboronic acid
(m, 1H), 6.27 (ddd, J = 9.8, 0.7, 0.3 Hz, 1H), 5.47 (dd, J = 9.8, (20 mol%) and diphenylphosphinic acid (10 mol%) at 100 °C.
0.3 Hz, 1H), 3.77 (s, 3H), 1.42 (s, 6H). 13C NMR (125 MHz, Isolated as a pale yellow oil after flash chromatography on
CDCl3): δ 160.8, 154.3, 128.0, 127.0, 122.0, 114.8, 106.8, 102.1, silica gel, eluting with 0.5–1% EtOAc/pentane (70.5 mg, 76%).
76.5, 55.4, 28.2.
Spectral data were in agreement with previous reports.12 1H
6,7-Dimethoxy-2,2-dimethyl-2H-chromene (6b). Synthesized NMR (400 MHz, CDCl3): δ 6.71 (d, J = 8.7 Hz, 1H), 6.66 (dd, J =
according to general procedure B, from 3,4-dimethoxyphenol 8.7, 2.9 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 6.28 (d, J = 9.8 Hz,
(79.2 mg, 0.51 mmol) and 3-methyl-2-butenal (100 μL, 1H), 5.64 (d, J = 9.8 Hz, 1H), 3.75 (s, 3H), 1.41 (s, 6H). 13C NMR
1.0 mmol) using phenylboronic acid (20 mol%) and benzoic (100 MHz, CDCl3): δ 153.9, 146.9, 131.9, 122.5, 122.0, 116.9,
acid (20 mol%) at 100 °C. Isolated as a pale yellow oil after 114.3, 111.6, 75.9, 55.9, 27.8.
flash chromatography on silica gel, eluting with CH2Cl2
2,2-Dimethyl-2H-naphtho[1,2-b]pyran
(6g).
Synthesized
(104.4 mg, 92%). Spectral data were in agreement with pre- according to general procedure B, from 1-naphthol (72.9 mg,
vious reports.12 1H NMR (400 MHz, CDCl3): δ 6.53 (s, 1H), 6.41 0.5 mmol) and 3-methyl-2-butenal (100 μL, 1.0 mmol) using
(s, 1H), 6.24 (d, J = 9.7 Hz, 1H), 5.48 (d, J = 9.7 Hz, 1H), 3.83 (s, 3,5-bis(trifluoromethyl)phenylboronic acid (20 mol%) and
3H), 3.82 (s, 3H), 1.41 (s, 6H). 13C NMR (100 MHz, CDCl3): benzoic acid (20 mol%) at 60 °C. Isolated as a pale yellow oil
δ 149.8, 147.4, 143.2, 128.4, 122.1, 113.2, 109.9, 101.2, 76.1, after flash chromatography on silica gel, eluting with 0.5–1%
56.7, 56.1, 27.8.
EtOAc/pentane (98.6 mg, 93%). Spectral data were in agree-
2,2-Dimethyl-6,7-methylenedioxy-2H-chromene (6c). Syn- ment with previous reports.9 1H NMR (400 MHz, CDCl3):
thesized according to general procedure A, from 3,4-(methy- δ 8.24–8.18 (m, 1H), 7.76–7.70 (m, 1H), 7.47–7.39 (m, 2H), 7.34
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(d, J = 8.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 9.7 Hz,
5,7-Dimethoxy-flav-3-ene (6j). Synthesized according to
1H), 5.64 (d, J = 9.7 Hz, 1H), 1.53 (s, 6H). 13C NMR (100 MHz, general procedure B, from 3,5-dimethoxyphenol (76.5 mg,
CDCl3): δ 148.4, 134.6, 129.4, 127.7, 126.2, 125.3, 125.2, 124.6, 0.5 mmol) and trans-cinnamaldehyde (130 μL, 1.0 mmol)
122.9, 122.1, 119.9, 115.5, 76.9, 28.1.
using phenylboronic acid (5 mol%) and benzoic acid (20 mol%)
Gram scale synthesis of 2,2-dimethyl-2H-naphtho[1,2-b] at 100 °C. Isolated as a viscous yellow oil after flash chromato-
pyran (6g). An oven-dried 100 mL round bottomed flask graphy on silica gel, eluting with 1–2% EtOAc/pentane
equipped with a teflon-coated magnetic stir bar was charged (108.6 mg, 81%). Spectral data were in agreement with pre-
with 1-naphthol (720.1 mg, 5 mmol), 3-methyl-2-butenal vious reports.29 1H NMR (400 MHz, CDCl3): δ 7.49–7.44 (m,
(0.97 mL, 10 mmol), bis(trifluoromethyl)phenylboronic acid 2H), 7.40–7.29 (m, 3H), 6.81 (ddd, J = 10.0, 1.9, 0.6 Hz, 1H),
(257.9 mg, 20 mol%), benzoic acid (121.8 mg, 20 mol%) and 6.06 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 2.3 Hz, 1H), 5.83 (dd, J =
heptane (25 mL). The reaction mixture was stirred at 60 °C for 3.4, 1.9 Hz, 1H), 5.62 (dd, J = 9.9, 3.5 Hz, 1H), 3.81 (s, 3H), 3.75
17 hours. The mixture was then cooled to room temperature, (s, 3H). HRMS (DART-TOF+, m/z): Calculated for C17H17O3
diluted with ethyl acetate (50 mL) and then transferred to a [(M + H)+]: 269.1174. Found: 269.1178.
separatory funnel to which a 75 mL of a sorbitol : Na2CO3
7-Methoxy-2-propyl-2H-chromene (6k). Synthesized accord-
(1 M : 1 M) solution. The two layers were hand shaken for ing to general procedure B, from 3-methoxyphenol (62.2 mg,
10 minutes, separated and the organic layer was washed with 0.5 mmol) and trans-2-hexen-1-al (120 μL, 1.0 mmol) using
H2O, and then saturated aq. NaCl. The organic phase was then phenylboronic acid (20 mol%) and benzoic acid (20 mol%) at
dried with MgSO4, filtered and concentrated in vacuo to afford 100 °C. Isolated as a pale yellow oil after flash chromatography
a brown oil. This crude oil was then loaded onto a 1.5 × 1.5″ on silica gel, eluting with 0.5–1% EtOAc/pentane (83.5 mg,
silica gel column, eluted with 2.5% EtOAc/hexanes (300 mL) 82%). Spectral data were in agreement with previous reports.30
and concentrated in vacuo to give the title compound as a 1H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.2 Hz, 1H), 6.40 (dd,
yellow-orange oil (947.5 mg, 90%). Catalyst Recovery: The sorbi- J = 8.2, 2.5 Hz, 1H), 6.37 (d, J = 2.5 Hz, 1H), 6.34 (dd, J = 9.9,
tol layer was acidified with 4 M HCl (pH 2) and the catalyst 1.4 Hz, 1H), 5.54 (dd, J = 9.8, 3.3 Hz, 1H), 4.83 (dddd, J = 6.8,
mixture extracted three times with EtOAc, washed with H2O 5.0, 3.4, 1.7 Hz, 1H), 3.77 (s, 3H), 1.83–1.74 (m, 1H), 1.68–1.40
and then dried over MgSO4. The organic solution was then fil- (m, 3H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3):
tered and concentrated to afford a ∼1 : 1 mixture of boronic: δ 160.7, 155.0, 127.2, 123.6, 123.2, 115.5, 106.8, 102.0, 75.2,
benzoic acid as a light brown solid (356.5 mg, 94%). When 55.4, 37.7, 18.2, 14.1. HRMS (DART-TOF+, m/z): Calculated for
this recovered mixture was used in the same reaction described C13H17O2 [(M + H)+]: 205.1234. Found: 205.1228.
above, the titled compound was isolated in 70% yield
(728.2 mg). Workup procedure adapted from ref. 25.
3,3-Diphenyl-[3H]-naphtho-[2,1-b]pyran (6l). To a 2-dram
vial equipped with a teflon-coated magnetic stir bar was added
2,2-Dimethyl-2H-naphtho[2,1-b]pyran (6h). Synthesized 2-naphthol (28.8 mg, 0.2 mmol), β-phenylcinnamaldehyde
according to general procedure B, from 2-naphthol (71.7 mg, (83.3 mg, 0.4 mmol), 3,5-bis(trifluoromethyl)phenylboronic
0.5 mmol) and 3-methyl-2-butenal (100 μL, 1.0 mmol) using acid (20 mol%) and benzoic acid (20 mol%) and heptane
3,5-bis(trifluoromethyl)phenylboronic acid (20 mol%) and (1 mL). The reaction mixture was stirred at 80 °C for 17 hours,
benzoic acid (20 mol%) at 80 °C. Isolated as a pale yellow oil after which the mixture was cooled to room temperature and
after flash chromatography on silica gel, eluting with 0.5–1% then concentrated in vacuo. The resulting crude material was
EtOAc/pentane (97.9 mg, 94%). Spectral data were in agree- purified by silica gel chromatography (1–2% EtOAc/hexanes) to
ment with previous reports.9 1H NMR (500 MHz, CDCl3): afford the title compound in as a white solid (75%, 50 mg).
δ 7.96–7.93 (m, 1H), 7.75–7.73 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H), When 1,1-diphenylprop-2-yn-1-ol was utilized in replacement
7.47 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.33 (ddd, J = 8.1, 6.8, of β-phenylcinnamaldehyde under otherwise identical con-
1.1 Hz, 1H), 7.06 (dd, J = 8.8, 0.7 Hz, 1H), 7.03 (d, J = 9.9 Hz, ditions, the title compound was isolated as a white solid
1H), 5.72 (dd, J = 9.9, 0.3 Hz, 1H), 1.49 (s, 6H). 13C NMR (46 mg, 69%). Spectral data were in agreement with previous
(125 MHz, CDCl3): δ 151.1, 130.0, 129.5, 129.4, 129.3, 128.6, reports.8 1H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 8.5 Hz, 1H),
126.6, 123.5, 121.4, 118.6, 118.4, 113.9, 76.2, 27.7.
7.73–7.69 (m, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.52–7.42 (m, 5H),
2,2,5,7-Tetramethyl-2H-chromene (6i). Synthesized accord- 7.35–7.28 (m, 6H), 7.27–7.23 (m, 2H), 7.20 (dd, J = 8.8, 0.7 Hz,
ing to general procedure A, from 3,5-dimethylphenol (61.5 mg, 1H), 6.27 (d, J = 10.0 Hz, 1H). 13C NMR (126 MHz, CDCl3):
0.5 mmol) and 3-methyl-2-butenal (100 μL, 1.0 mmol) using δ 150.7, 145.0, 130.0, 130.0, 129.5, 128.2, 127.7, 127.2, 126.7,
3,5-bis(trifluoromethyl)phenylboronic acid (20 mol%) and 123.7, 121.5, 119.7, 118.5, 114.1, 82.7.
benzoic acid (20 mol%) at 100 °C. Isolated as a pale yellow oil
3,3-Bis[4-(N,N-dimethylamino)phenyl]-3-naphtho[2,1-b]
after flash chromatography on silica gel, eluting with 0.5–1% pyran (6m). To a 2-dram vial equipped with a teflon-coated
EtOAc/pentane (86.1 mg, 91%). Spectral data were in agree- magnetic stir bar was added 2-naphthol (21.0 mg,
ment with previous reports.12 1H NMR (500 MHz, CDCl3): 0.146 mmol), 1,1-bis(4-(dimethylamino)phenyl)prop-2-yn-1-ol
δ 6.52–6.51 (m, 1H), 6.49–6.46 (m, 2H), 5.58 (d, J = 10.0 Hz, (83.8 mg, 0.29 mmol), 3,5-bis(trifluoromethyl)phenylboronic
1H), 2.25 (s, 3H), 2.23 (s, 3H), 1.41 (s, 6H). 13C NMR (125 MHz, acid (20 mol%) and benzoic acid (20 mol%) and heptane
CDCl3): δ 153.0, 138.8, 133.8, 129.6, 123.4, 119.4, 117.3, 115.0, (0.73 mL). The reaction mixture was stirred at 80 °C for
75.4, 27.9, 21.5, 18.5.
17 hours, after which the mixture was cooled to room tempera-
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ture and then concentrated in vacuo. The resulting crude solution of saturated aq. NH4Cl and extracted three times with
material was purified by silica gel chromatography (20% EtOAc. The combined organic layers were washed sequentially
EtOAc/hexanes) to afford the title compound in as an off white with H2O and saturated aq. NaCl, and then dried over Na2SO4.
solid (53%, 61.4 mg), Rf = 0.4 (30% EtOAc/hexanes). Spectral The drying agent was then removed by filtration and the solu-
data were in agreement with previous reports.27 1H NMR tion was concentrated in vacuo. The title compound was
(500 MHz, CDCl3): δ 7.97–7.92 (m, 1H), 7.71–7.67 (m, 1H), 7.62 obtained by silica gel chromatography (10% EtOAc/hexanes,
(d, J = 8.8 Hz, 1H), 7.46–7.40 (m, 1H), 7.34 (d, J = 8.5 Hz, 4H), Rf = 0.3) as a white solid (90 mg, 87%). Spectral data were in
7.30–7.26 (m, 1H), 7.25 (d, J = 10.0 Hz, 1H), 7.16 (dd, J = 8.8, agreement with previous reports.34 1H NMR (400 MHz, CDCl3):
0.7 Hz, 1H), 6.67 (s, 4H), 6.21 (d, J = 9.9 Hz, 1H), 2.92 (s, 12H).
4,4-Diphenylbut-3-en-2-one (3d). Prepared according to a (s, 1H).
modified literature procedure.31 Zinc dust (<10 μm, 600 mg,
1,1-Bis[4-(N,N-dimethylamino)phenyl]prop-2-yn-1-ol
δ 7.65–7.58 (m, 4H), 7.36–7.27 (m, 6H), 2.88 (s, 1H), 2.76
(7b).
6.5, 1.3 eq.) was added to a flask containing 4 mL of 2 M HCl Prepared according to a modified literature procedure.33 To a
and stirred vigorously until the surface of the zinc became solution of trimethylsilylacetylene (0.7 mL, 5 mmol, 2 eq.) in
lustrous. The aqueous solution was decanted and the zinc THF (8 mL) at −10 °C was added a solution of nBuLi (2.5 M in
powder washed by successive decantation with H2O (4 × hexanes, 2 mL, 5 mmol, 2.0 eq.) dropwise under an atmo-
10 mL). The powder was then washed successively with MeOH sphere of argon. The resulting solution was stirred at −10 °C
(2 mL), acetone (4 mL) and dry THF (2 mL) and quickly trans- for 30 minutes after which time benzophenone (677.5 mg,
ferred to an oven dried round bottomed flask. The powder was 2.5 mmol, 1 eq.) was added. The solution was then warmed to
dried under vacuum for 20 minutes, after which the flask was room temperature and stirred for 4 hours, after which time
filled with argon. A solution of benzophenone (908 mg, KOH (1.4 g, 25 mmol, 5 eq.) in methanol was added at 0 °C
5 mmol, 1 eq.) and propargyl bromide (80 wt% in toluene, and stirred for 20 minutes. The mixture was then poured into
0.9 mL, 7.8 mmol, 1.6 eq.) in dry THF was prepared in an oven a solution of saturated aq. NH4Cl and extracted three times
dried round bottomed flask that was evacuated and backfilled with EtOAc. The combined organic layers were washed sequen-
with argon. The solution was then added to the activated zinc tially with H2O and saturated aq. NaCl, and then dried over
powder at 0 °C with vigorous stirring at room temperature. Na2SO4. The drying agent was then removed by filtration and
After three hours, the reaction mixture was poured into ice the solution was concentrated in vacuo. The crude mixture was
water and a 20 w/v% solution of aq. acetic acid was added to subjected to silica gel chromatography (30% EtOAc/hexanes,
the reaction mixture until acidic to pH paper. The mixture was Rf = 0.5) to afford a mixture of the titled compound and the
extracted twice with diethyl ether and the combined organic respective α,β-unsaturated aldehyde (337.2 mg). Half of the
layers washed successively with water, and saturated aq. mixture was recrystallized from EtOAc/hexanes to afford the
NaHCO3, and then dried over Na2SO4. Filtration and evapor- titled compound as a light green solid (85.4 mg). Spectral data
ation of the solvent afforded crude 1,1-diphenyl-but-3-yn-1-ol, were in agreement with previous reports.35 1H NMR (400 MHz,
which was subjected to a Rupe rearrangement without further C6D6): δ 7.78–7.71 (m, 4H), 6.61–6.53 (m, 4H), 2.47 (s, 12H).
purification. To a solution of the crude alcohol in concentrated
acetic acid (4 mL) was added concentrated H2SO4 (50 μL). The
reaction mixture was stirred vigorously at 70 °C for 40 minutes,
and then poured into ice water and extracted twice with
Acknowledgements
CH2Cl2. The combined organic layers were washed with H2O,
This work was supported by NSERC (Discovery Grants and
saturated aq. NaHCO3, and then dried over Na2SO4. The crude
Canada Research Chairs Programs, Graduate Fellowship to
mixture was concentrated in vacuo and then purified by silica
T. S.), the Canada Foundation for Innovation (projects #17545
gel chromatography (10–15% EtOAc/hexanes) to afford the title
and #19119), and the Ontario Research Fund.
compound as an orange oil (422 mg, 38%). Spectral data were
in agreement with previous reports.32 1H NMR (400 MHz,
CDCl3): δ 7.44–7.40 (m, 3H), 7.37–7.28 (m, 5H), 7.24–7.20
(m, 2H), 6.58 (s, 1H), 1.88 (s, 3H).
1,1-Diphenylprop-2-yn-1-ol (7a). Prepared according to a
Notes and references
modified literature procedure.33 To a solution of trimethyl-
silylacetylene (1.4 mL, 10 mmol, 2 eq.) in THF (16 mL) at
−10 °C was added a solution of nBuLi (2.5 M in hexanes,
4 mL, 10 mmol, 2.0 eq.) dropwise under an atmosphere of
argon. The resulting solution was stirred at −10 °C for
30 minutes after which time benzophenone (911 mg, 5 mmol,
1 eq.) was added. The solution was then warmed to room
temperature and stirred for 4 hours, after which time KOH
(1.4 g, 25 mmol, 5 eq.) in methanol was added at 0 °C and
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