Synthesis of Sterically Hindered β-Diketones via Condensation of Acid Chlorides with Enolates

Article abstract of DOI:10.1021/acs.joc.9b00433

Bulky β-diketones have rarely exceeded dipivaloylmethane (DPM) in steric demand, largely due to synthetic limitations of the Claisen condensation. This work demonstrates hindered acid chlorides to be selective electrophiles in noncoordinating solvents for condensations with enolates. An improved synthesis of DPM is described (90% yield), and crowded β-diketones featuring bulky o-biphenyl or m-terphenyl fragments were prepared in good to excellent yields. These compounds are anticipated to have a steric profile far greater than that of DPM. General reaction conditions and mechanistic considerations are included.

Full text of DOI:10.1021/acs.joc.9b00433

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Note
Synthesis of Sterically Hindered #-Diketones via
Condensation of Acid Chlorides with Enolates
Aaron S. Crossman, Alec T. Larson, Jake X. Shi, Sebastian
Matthew Krajewski, Eser S. Akturk, and Michael P. Marshak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00433 • Publication Date (Web): 09 May 2019
Downloaded from http://pubs.acs.org on May 11, 2019
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The Journal of Organic Chemistry
Synthesis of Sterically Hindered β-Diketones via Condensation of Acid
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Chlorides with Enolates
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Aaron S. Crossman, Alec T. Larson, Jake X. Shi, Sebastian M. Krajewski, Eser S. Akturk, Michael P.
Marshak*
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Department of Chemistry, University of Colorado at Boulder, Boulder, CO 80303.
Supporting Information Placeholder
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ABSTRACT: Bulky β-diketones have rarely exceeded dipivaloylmethane (DPM) in steric demand, largely due to
synthetic limitations of the Claisen condensation. This work demonstrates hindered acid chlorides to be selective
electrophiles in non-coordinating solvents for condensations with enolates. An improved synthesis of DPM is de-
scribed (90% yield), and crowded β-diketones featuring bulky o-biphenyl or m-terphenyl fragments were prepared
in good to excellent yields. These compounds are anticipated to have a steric profile far greater than that of DPM.
General reaction conditions and mechanistic considerations are included.
Over the last fifty years, acetylacetonate (acac)-supported catalysts have proven capable of forming C–C
bonds (via iron,1–4 cobalt,5 nickel,6,7 and copper8–10), C–N bonds (via iron,11 cobalt,12 nickel,13 and copper14), and C–
O bonds (via iron,15 cobalt,16,17 nickel,18 and copper19) to highlight select metals. These examples illustrate the gen-
erality of late, first-row metal catalysis using β-diketonates in carbon bond-forming reactions, which have devel-
oped in parallel to the second- and third-row transition metal catalysis. However, there is a renewed interest in these
“base metal” catalysts due to sustainability, scalability, and other concerns of the “precious metal” catalysts.20–22 In
some cases, the larger dipivaloylmethane (DPM, 1) offered a significant improvement in catalytic performance over
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acac, and even choice reactivity over other ligand classes.23–25 Unfortunately, synthetic challenges have limited
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exploration of sterically hindered β-diketonates.
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The synthesis of β-diketones is usually accomplished in good yields via the Claisen condensation.26 Ad-
vancements have been made in increasing the efficiency of the coupling using soft enolization techniques of acti-
vated esters and methyl ketones.27–29 Although these procedures are particularly robust and chemoselective,28 the
reactions are under thermodynamic control and specifically fail in preparing sterically hindered products.27,30 Efforts
to improve the yield of DPM syntheses often focus on changing the base or the ester substituent with modest im-
provement.31–34 An efficient synthesis is highly desirable given this compound has applications in catalysis, metal
refining, atomic layer deposition, precursor to heterocycles, and is notable for being the common “hindered β-
diketone” of choice.35–39 Other known methods for the synthesis of sterically hindered β-diketones include a double
Friedel-Crafts acylation of malonyl dichloride,40–42 the reaction of β,δ-triketones with pyrylium salts,43 and treat-
ment of acid chlorides with stoichiometric methyllithium.44 In the last example, treating pivaloyl chloride 2 with
methyllithium only produces DPM in 10% yield, instead providing 84% of the tertiary alcohol.
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Other examples in the literature where acid chlorides are employed as electrophiles in condensations are
rare.44–46 Obtaining C-acylated products preferentially over the kinetically favored O-acylated products is a chal-
lenge.47,48 This can be suppressed using excess enolate, which reduces the atom economy.49 Nonetheless, the in-
creased reactivity of acid chlorides can enable the construction of more crowded, decorated β-diketones, albeit in
poor yields and with difficult separations.50,51 Acid chlorides derived from meta-terphenyls show a remarkably
slowed reactivity.52 This very encumbering moiety has stabilized extremely reactive, low-coordinate metal com-
plexes.53–56 We have previously shown that a m-terphenyl appended to a β-diketone enables steric control of a
metal’s coordination sphere,57 a historically difficult challenge for acac-type ligands.58–60 Here we describe the prep-
aration and synthetic considerations of a range of sterically hindered β-diketones.
Using DPM as a model compound, the reactivity of pivaloyl chloride 2 and methyl pivalate 3 with sodium
pinacolonate 4 was investigated to shed light on their relative behavior in crowded environments (Table 1). Due to
the sensitivity of acid chlorides to even weakly nucleophilic bases, it was advantageous to synthesize and isolate
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the enolates free of residual solvents or conjugate acids. Treating pinacolone with an excess of sodium amide (1.5
equiv.) followed by filtration of residual base and removal of solvent in vacuo results in an isolation of 4 in 94%
yield to produce 91 g of the tetrahydrofuran-adduct 4. Two equivalents of the enolate 4 were treated with electro-
philes 2 or 3 (1 M) at 0°C before warming, while varying the solvent, temperature, and reaction duration. DPM was
conveniently isolated by subjecting the reaction mixture to aqueous work-up to remove residual pivalic acid fol-
lowed by vacuum to remove pinacolone. The products were assayed by 1H NMR to determine the purity. Reported
crude yields have been corrected using the determined purity by mass.
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Table 1. Comparative study of esters and acid chlorides in the preparation of dipivaloylmethane.
Entry Solvent Group X Temperature (°C) Time (hrs) Crude Yield (%) Purity (%)
1
2
Cl
Cl
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60
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0.08
1
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90
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Cl
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OMe
Cl
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Cl
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Cl
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OMe
OMe
Cl
Cl
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Cl
OMe
OMe
After five minutes, DPM 4 was obtained from the acid chloride 1 in in 65% yield (Entry 1). Toluene, THF,
and DCM each gave similar yields for the reaction with 1 after one hour (Entries 2, 7, 12), although toluene proved
most effective when allowed to react overnight (Entry 3). In all solvents, the acid chloride condensations showed a
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decreased yield when heated (Entries 4, 9, 14). Conversely, reactions with the ester 2 resulted in poor conversions
at room temperature (Entries 5, 10, 15), which did improve upon heating (Entries 6, 11, 16). The best yield obtained
is 90% for this reaction, using acid chloride 1 as the electrophile and toluene as the solvent. The method was proven
on multi-gram scales, with an 88% yield obtained. While the O-acylation byproduct was observed in <1% in the
preparation of DPM, this problematic impurity is more frequently observed with more sterically hindered acid chlo-
rides and nucleophiles.
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Table 2. Lewis acid screen for a hindered reaction.
Entry Lewis acid Conversion (%) C:O ratio (100:X)
1
2
3
4
5
LiCl
n/a (Na)
MgSO4
CuCl2
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2
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100
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ZnBr2
100
As steric bulk increases, the separation of large molecules which only differ by the transposition of oxygen
and methylene linkages becomes increasingly intractable, requiring a two-step metalation/demetalation sequence
or more preferably the inhibition of this by-product forming at all. The condensation of 2,6-dimesitylbenzoyl chlo-
ride 5 with the sodium enolate derived from trimethylacetophenone 6, resulted in significant formation of the O-
acylated product. Transmetalation with various Lewis acids was observed to improve the C/O acylation product
ratio (Table 2). Zinc bromide resulted in the highest selectivity for the β-diketone product, and these conditions
were employed to prepare 7 in >99% selectivity on multi-gram scales. In addition, the C/O-acylation selectivity is
sensitive to the coordinating ability of the solvent.
For example, the preparation of 8 (Table 3) proceeds with high C-selectivity in toluene using zinc bromide
with 3, but same reaction and Lewis acid resulted in significant O-acylated product when performed in THF. In
contrast, no solvent dependence was observed (PhMe, DCM, THF, Et2O, hexanes) when sodium was employed as
a Lewis acid in the high yielding synthesis of 8. The condensations can be scaled up with no decrease in yields,
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The Journal of Organic Chemistry
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allowing the synthesis of 8 in over 40 grams. Furthermore, the reaction can be performed without the isolation of
the enolate, obviating the need for a glovebox. This can be accomplished by swapping the ethereal solvent for a
non-coordinating one after enolization prior to introducing the electrophile—affording 8 in typical yield and over
10-gram scale.
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Table 3. m-Terphenyl β-diketones prepared using acid chlorides and enolate salts.
Entry Aryl group (Ar) Enolate group (R) Lewis acid (M) Isolated yield (%)
1 (7)
2 (8)
Mes
Mes
Mes
Mes
TMP
Trip
Trip
Mes
tBu
Zn
Na
Na
Na
Na
Na
Na
70
92
73
65
54
75
25
3 (9)
3’,5’-tBu2Ph2
3’,4’,5’-(OMe)3Ph
tBu
4 (10)
6 (11)
7 (12)
8 (13)
tBu
3’,5’-tBu2Ph2
While steric bulk disfavors multiple acylation reactions to form triketones, as the size of each fragment
increases the reaction favors C–O bond formation. The decreased steric hindrance of the lone pairs on oxygen
relative to methylene of the enolate induce a steric preference (Figure 1a). In addition, the greater electronegativity
of oxygen makes it the kinetically favored nucleophile. A Lewis acid bound to the oxygen of the enolate attenuates
its nucleophilicity and increases its steric demand, improving both steric and electronic factors to increase the se-
lectivity for C–C bond formation (Figure 1b). The Lewis acid pre-organizes the transition state by coordinating the
oxygen of the enolate and the acyl chloride (Figure 1c). This weak interaction can be disrupted by the presence of
coordinating solvents, thus rationalizing the observed solvent effect (Figure 1b). This effect has been demonstrated
previously using strongly coordinating additives such as TMEDA to generate un-complexed enolate anions, result-
ing in the highly selective formation of O-acylation products (Figure 1d).61 Therefore, control of the C/O-acylation
selectivity seems determined by the promotion or interference of the metal-enolate complexes in solution.
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An additional complication in preparing especially hindered
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β-diketones is the competing aldol condensation of the enolate nucle-
ophile with the methyl ketone regenerated by deprotonation of the β-
diketone product.62,63 This reaction was most problematic in the prep-
aration of 13. In examples using 2,6-bis(2,4,6-triisopropylphenyl)ben-
zoyl chloride as electrophile, the methyl ketones regenerated proved
to be better electrophiles than the acid chloride. Lewis acids such as
zinc and cadmium have been shown to prevent aldol condensation
products.64 Although in the case of 13, no improvement was afforded
by transmetalation to zinc. It is possible that either the zinc-enolate
interaction shows diminished chemo-selectivity at the elevated tem-
peratures required for the reaction or that sodium enolates transiently
form which are capable of aldol condensation. Nevertheless, 13 can
be isolated in 25% yield after purification by chromatography.
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Figure 1. Factors which affect the C/O-
acylation selectivity in acid chlo-
ride/enolate condensations.
To better understand the crowding about the β-diketone moi-
ety, single crystals of 9, 12, and 13 were grown and analyzed by X-ray diffraction. The structure of the most steri-
cally hindered derivative, 13, is presented below (Figure 2). 13 represents the most hindered β-diketone ever re-
ported. Despite these results, accessing increasingly hindered β-diketone products is difficult because steric de-
mands require higher temperatures and Lewis acids that can maintain their coor-
dination in the extreme conditions. More reactive electrophiles are currently be-
ing investigated. Additionally, the condensation of secondary enolates have re-
sulted in mixtures of C/O-acylation products, which is being probed with more
effective Lewis acids.
In summary, acid chlorides were found to be more effective electrophiles
than corresponding esters in congested steric regimes. Reaction optimization for
Figure 2. Crystal structure of
the hindered β-diketone, 13.
DPM has resulted in excellent yield and purity, which represents an improvement
Thermal ellipsoids drawn at
the 50% probability level.
over the state of the art (90% vs. 65%). Application of this insight permitted the
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preparation of sterically hindered examples which have proven to be synthetically challenging to date. The reactions
of m-terphenyl acid chlorides require elevated temperatures (60–140°C) and increased times (4–96 hrs), standing
in sharp contrast to typical acid chloride reaction conditions.47 The reactions selectivity is sensitive to the identity
of the Lewis acid and solvent. As a heuristic, it is preferable to employ the larger fragment as the electrophile to
maximize the selectivity control, and similarly a smaller enolate seems a more competent nucleophile.
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In a more specific context, the method described herein has been used to prepare a family of sterically
hindered β-diketones that can function as ancillary ligands for transition metal catalysis. Work continues in our
laboratory probing the novel coordination and catalytic chemistry of bulky acac-type metal complexes, especially
of the first-row transition metals, a critical need identified in recent reports.65,66
EXPERIMENTAL SECTION
General Considerations
Syntheses were performed in a nitrogen-filled glovebox or in a fume hood using standard air-free Schlenk techniques. Organic reagents were
purchased from Alfa Aesar, TCI Chemical, or Sigma Aldrich and used as received, except as noted below. Deuterated solvents were pur-
chased from Cambridge Isotope Labs and stored over 4Å molecular sieves. All other solvents were purchased in anhydrous form from Sigma
Aldrich and further dried with and stored over 4Å molecular sieves. 2,6-bis(2,4,6-trimethylphenyl)benzoyl chloride was prepared according
to literature procedures.67 Enolizations can be monitored by disappearance of ammonia emission upon N2 sparging. Condensations may be
monitored by withdrawing a 0.25 mL aliquot, shaking with ethyl acetate/1 M hydrochloric acid (1 mL each), removing the aqueous layer,
concentrating the organics, and subjecting the residue to 1H NMR analysis, using the 1H triplet at approximately 7.5 ppm as a diagnostic
peak. NMR spectra were recorded on a Bruker Avance-III 300 NMR spectrometer (300 MHz) or 400 NMR spectrometer (400 MHz). IR
were spectra recorded on an Agilent Cary 630 FTIR with ATR attachment. UV-Vis spectra were recorded on an Agilent Cary 5000 UV-Vis-
NIR spectrophotometer. High-Resolution Mass Spectrometry (HRMS) data were recorded at the University of Colorado Central Analytical
Laboratory on a Waters Synapt G2 (ESI) by Dr. Danijel Djukavic or Mr. Duk Yi. X-ray crystal structures were recorded using a Bruker D8
Quest Eco three circle goniometer platform equipped with a Bruker APEX-II CCD detector, a graphite monochromator was employed for
wavelength selection of the Mo Kα radiation (λ = 0.71073 A), and the data were processed using APEX III software provided by Bruker.
Except as noted below, structures were solved by intrinsic phasing in SHELXT68 and refined by standard difference Fourier techniques with
SHELXL69 within the OLEX270 software package. Hydrogen atoms were placed in calculated positions using the standard riding model and
refined isotropically except as noted below.
Dipivaloylmethane (1)
To a 250 mL oven-dried one-neck round bottom flask equipped with a stirbar and septum is charged sodium 1-tert-butylethenolate (9.70 g,
50 mmol) and toluene (50 mL). The contents are cooled in an icebath to 0°C, and then pivaloyl chloride (3.05 mL, 25 mmol) is added in a
single portion rapidly—dropwise addition results in ~60% yield. The contents are allowed to warmed to ambient over 16 hours. The vial is
opened and 1 M hydrochloric acid (5 mL) is added. The color transitions from clear red-orange to yellow. The contents are stirred vigorously
for about 15 minutes, allowed to settle, and the aqueous layer removed using a pipette. The organics are dried over sodium sulfate and
concentrated to a pale-yellow oil, which is further dried in vacuo (4.05 g, 88%). Crude material may be purified by distillation or isolation
as the copper(II) salt.71 Spectroscopic data matches the previously reported (AIST, SDBS No.: 8580).
Sodium 1-tert-butylethenolate, THF adduct (4)
To an oven-dried 1000 mL one-neck round bottom flask equipped with a stirbar, addition funnel, and septum is charged sodium amide (24.4
g, 625 mmol) and tetrahydrofuran (250 mL). The flask is attached to a nitrogen manifold with adequate ventilation and heated to 40°C in an
oil bath. Pinacolone (50.1 g, 500 mmol) is added dropwise over 2 hours. The contents are then allowed to react for 10 hours, and then allowed
to cool to room temperature. Under an inert atmosphere, the grey suspension is diluted with diethyl ether (100 mL) and filtered through an
oven-dried, medium-porosity frit, and the solvent is removed in vacuo to afford a white powder, which is further dried overnight (77.7 g,
80%). The product may develop a yellow patina after several months under nitrogen, with little to no loss of potency. 1H NMR (400 MHz,
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Benzene-d6) δ 3.74 (s, 1H), 3.73 – 3.67 (m, 4H), 3.47 (s, 1H), 1.45 – 1.40 (m, 4H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, C6D6) δ 181.3,
1
128.3, 128.1, 127.8, 69.5, 68.4, 38.0, 30.1, 25.6.
2
3
Sodium 1-(2,4,6-trimethylphenyl)ethenolate, THF adduct (6)
4
5
6
7
8
9
To an oven-dried 250 mL one-neck round bottom flask equipped with a stirbar, addition funnel, and septum is charged sodium amide (3.9
g, 100 mmol) and tetrahydrofuran (100 mL). The flask is attached to a nitrogen manifold with adequate ventilation and heated to 60 °C in
an oil bath. A solution of 2’,4’,6’-trimethylacetophenone (8.11 g, 50 mmol) is added dropwise over 1 hour. The contents are then heated to
60°C for 12 hours, and then allowed to cool to ambient. Large parallelepiped crystals form in the flask after reaching ambient temperature.
Under an inert atmosphere, the grey suspension is diluted with diethyl ether (100 mL) and filtered through an oven-dried, medium-porosity
frit, and the solvent is removed in vacuo to afford off-white microcrystalline material, which is further dried overnight (8.308 g, 65%). 1H
NMR (400 MHz, Benzene-d6) δ 6.84 (s, 2H), 4.10 (d, J = 1.1 Hz, 1H), 3.69 (d, J = 1.1 Hz, 1H), 3.52 – 3.35 (m, 4H), 2.57 (s, 6H), 2.20 (s,
3H), 1.44 – 1.29 (m, 4H). 13C{1H} NMR (101 MHz, C6D6) δ 170.4, 145.0, 134.4, 134.2, 128.3, 128.1, 128.1, 127.8, 78.0, 68.1, 25.6, 21.1,
20.5.
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1-[2,6-Bis(2,4,6-trimethylphenyl)phenyl]-3-(2,4,6-trimethylphenyl)-propan-1,3-dione (7)
To an oven-dried 250 mL one-neck round bottom flask equipped with a stirbar and septum is charged sodium 1-(2,4,6-trime-
thylphenyl)ethenolate (4.8 g, 18.8 mmol), zinc bromide (6.32 g, 28.1 mmol), and toluene (50 mL). The flask is stirred and heated to 60°C in
an oil bath for 30 minutes, and then 2,6-bis(2,4,6-trimethylphenyl)-benzoyl chloride (2.35 g, 6.3 mmol) is added in one portion. The contents
are stirred for an additional 8 hours at 60°C, and then allowed to cool to room temperature. The flask is opened, 1 M hydrochloric acid (25
mL) is slowly added, followed by 5 M hydrochloric acid (25 mL), and the mixture is allowed to stir for 30 minutes. The color transitions
from clear red-orange to opaque yellow. The mixture is then transferred to a separatory funnel, allowed to settle, and separated. The organics
are concentrated to a thick, orange-colored oil and diluted with methanol (50 mL) is added, inducing precipitation of a fine powder. The
suspension is stored in an icebath for 1 hour, filtered, and dried in vacuo. The crude material is purified by column chromatography (1.5%
EtOAc/hexane isocratic) and obtained as a white, microcrystalline powder (2.2 g, 70%). m.p.: 215.7–216.8°C. 1H NMR (400 MHz, Chloro-
form-d) δ 15.49 (s, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.01 (s, 4H), 6.88 (s, 2H), 5.40 (s, 1H), 2.42 (s, 6H), 2.36 (s, 3H),
2.18 (s, 11H), 1.97 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 191.6, 187.9, 139.2, 138.5, 137.3, 137.0, 136.8, 136.1, 134.5, 134.5, 129.7,
128.8, 128.1, 128.0, 103.8, 77.5, 77.2, 76.8, 21.2, 21.1, 20.9, 18.6. IR (ν, cm−1): 2947, 2918, 2858, 1618, 1577, 1454, 1380, 1275, 1041, 929,
854, 817, 791, 769, 743, 679, 590, 568, 538. UV-Vis (λmax): 296 nm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C36H39O2 503.2950;
Found: 503.2965
1-[2,6-Bis(2,4,6-trimethylphenyl)phenyl]-4,4-dimethylpentan-1,3-dione (8)
To an oven-dried 500 mL one-neck round bottom flask equipped with a stirbar and septum is charged sodium 1-tert-butylethenolate (30.9 g,
159.2 mmol), 2,6-bis(2,4,6-trimethylphenyl)-benzoyl chloride (20 g, 53.1 mmol), and toluene (150 mL). The flask is stirred and heated to
60°C in an oil bath for 4 hours, and then allowed to cool to room temperature. The flask is opened, 1 M hydrochloric acid (150 mL) is slowly
added, and the mixture is allowed to stir for 30 minutes. The color transitions from clear red-orange to yellow. The mixture is then transferred
to a separatory funnel, allowed to settle and separated, and the aqueous layer is washed with ethyl acetate (100 mL). The combined organics
are concentrated to a thick, orange-colored oil. 95:5 methanol/water (100 mL) is added and the mixture is triturated at 60°C for 15 minutes,
inducing precipitation of a fine powder. The suspension is then stored in an icebath for 1 hour. The resultant colorless crystals are filtered,
and dried in vacuo (21.63 g, 92%). Spectroscopic data matches the previously reported.67
1-[2,6-Bis(2,4,6-trimethylphenyl)phenyl]-3-[2-(3,5-di-tert-butylphenyl)phenyl]-propan-1,3-dione (9)
To an oven-dried 250 mL one-neck round bottom flask equipped with a stirbar and septum is charged sodium 1-[2-(3,5-di-tert-bu-
tylphenyl)phenyl]ethenolate (9.2 g, 21.07 mmol), 2,6-bis(2,4,6-trimethylphenyl)-benzoyl chloride (3.60 g, 9.58 mmol), and toluene (125
mL). The flask is stirred and heated to 60 °C in an oil bath for 16 hours, and then allowed to cool to room temperature. The flask is opened,
1 M hydrochloric acid (100 mL) is slowly added, and the mixture is allowed to stir for 30 minutes. The color transitions from clear red-
orange to opaque yellow. The mixture is then transferred to a separatory funnel, allowed to settle and separated, and the aqueous is washed
with toluene (50 mL). The combined organics are concentrated to a thick, orange-colored oil. 98:2 methanol/water (100 mL) is added and
the mixture is triturate at 60 °C for 15 minutes, inducing precipitation of a fine powder. The suspension is then stored in an ice bath for 1
hour, filtered, and recrystallized from minimal 1:1 diethyl ether/ethanol and dried in vacuo (4.5 g, 73%). m.p.: 205.0–206.5°C. 1H NMR (300
MHz, Chloroform-d) δ 14.76 (s, 1H), 7.50 (dd, J = 7.9, 7.3 Hz, 1H), 7.40 (td, J = 7.5, 1.3 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.21 (td, J = 7.5, 1.4
Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 7.00 (d, J = 1.8 Hz, 2H), 6.87 (s, 4H), 6.66 (dd, J = 7.8, 1.3 Hz, 1H), 5.42 (s, 1H), 2.30 (s, 6H), 2.01 (s,
12H), 1.25 (s, 18H). 13C{1H} NMR (75 MHz, CDCl3) δ 188.3, 187.5, 150.2, 142.4, 140.2, 140.0, 137.6, 136.5, 136.4, 136.1, 135.9, 130.8,
130.3, 129.9, 129.4, 129.2, 128.0, 126.3, 123.0, 120.7, 103.1, 34.7, 31.5, 21.1, 20.6. IR (ν, cm−1): 2959, 2921, 2865, 1596, 1581, 1451, 1428,
1365, 1271, 1245, 1212, 1037, 880, 854, 821, 776, 743, 720, 642, 571, 545. UV-Vis (λmax): 325 nm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C47H53O2 649.4045; Found: 649.4047
1-[2,6-Bis(2,4,6-trimethylphenyl)phenyl]-3-(3,4,5-trimethoxyphenyl)-propan-1,3-dione (10)
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To an oven-dried 20 mL vial equipped with a stirbar and cap is charged sodium 1-(3,4,5-trimethoxyphenyl)ethenolate (1.35 g, 4.44 mmol),
2,6-bis(2,4,6-trimethylphenyl)-benzoyl chloride (0.55 g, 1.46 mmol), and toluene (5 mL). The vial is stirred and heated to 60°C in an oil
bath for 16 hours, and then allowed to cool to room temperature. The flask is opened, 5 M hydrochloric acid (2 mL) is slowly added, and the
mixture is allowed to stir for 30 minutes. The color transitions from clear red-orange to opaque yellow over 2 minutes. The mixture is then
transferred to a separatory funnel, allowed to settle, and separated, and the aqueous layer is washed with EtOAc (10 mL). The organics are
concentrated to a thick, orange-colored oil and diluted with methanol (50 mL) is added, inducing precipitation of a fine powder from a deep
red filtrate. The suspension is stored in an icebath for 1 hour, filtered, and dried in vacuo. The crude material is purified by trituation in
acetone and obtained as an off-white powder (0.52 g, 65%). m.p.: 220.5–222.6°C. 1H NMR (400 MHz, Chloroform-d) δ 15.62 (s, 1H), 7.54
(t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 2H), 6.88 (s, 4H), 6.72 (s, 2H), 5.69 (s, 1H), 3.90 – 3.85 (m, 9H), 2.27 (s, 6H), 2.08 (s, 12H). 13C{1H}
NMR (101 MHz, CDCl3) δ 189.0, 183.4, 153.1, 141.6, 140.1, 137.6, 136.9, 136.7, 136.0, 131.0, 130.2, 129.4, 128.1, 104.3, 98.5, 77.5, 77.2,
76.8, 61.1, 56.3, 21.2, 20.9. IR (ν, cm−1): 3000, 2940, 2921, 1581, 1503, 1462, 1413, 1380, 1335, 1238, 1186, 1171, 1130, 1000, 950, 855,
821, 791, 773, 736. UV-Vis (λmax): 351 nm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C36H38O5Na 573.2617; Found: 573.2617
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1-[2,6-Bis(2,4,5-trimethylphenyl)phenyl]-4,4-dimethylpentan-1,3-dione (11)
To an oven-dried 20 mL vial equipped with a stirbar and vial-cap is charged sodium 1-tert-butylethenolate (1.94 g, 10 mmol), 2,6-bis(2,4,5-
trimethylphenyl)-benzoyl chloride (1.13 g, 3 mmol), and toluene (7.5 mL). The flask is stirred and heated to 60°C in an oil bath for 8 hours,
and then allowed to cool to room temperature. The flask is opened, 1 M hydrochloric acid (2 mL) is slowly added, followed by 5 M hydro-
chloric acid (2 mL), and the mixture is allowed to stir for 30 minutes. The color transitions from clear red-orange to yellow. The mixture is
then transferred to a separatory funnel, allowed to settle, and separated. The organics are concentrated to a thick, orange-colored oil and
diluted with 98:2 methanol/water (2 mL) is added, inducing precipitation of a fine powder. The suspension is then stored in an icebath for 1
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hour, filtered, and dried in vacuo. A second crop is obtained from the filtrates (716 mg, 54%). m.p.: 98.5–100.2°C. H NMR (400 MHz,
Chloroform-d) δ 14.93 (d, J = 8.7 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 2H), 6.99 (s, 2H), 6.96 (s, 2H), 5.23 (s, 1H), 2.25 (s,
6H), 2.21 (s, 6H), 2.13 (s, 3H), 2.11 (s, 3H), 0.86 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 198.5, 189.7, 189.5, 140.5, 138.2, 137.4,
135.6, 133.1, 131.2, 131.2, 130.9, 129.2, 128.6, 128.5, 100.2, 100.0, 77.5, 77.2, 76.8, 38.8, 26.9, 19.7, 19.5, 19.5, 19.2. IR (ν, cm−1): 2970,
2921, 2869, 1584, 1506, 1450, 1365, 1286, 1234, 1130, 1104, 1022, 880, 858, 832, 810, 784, 702, 676, 478. UV-Vis (λmax): 282 nm. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C31H37O2 441.2794; Found: 441.2797
1-[2,6-Bis(2,4,6-tri-iso-propylphenyl)phenyl]-4,4-dimethylpentan-1,3-dione (12)
To an oven-dried 100 mL one-neck round bottom flask equipped with a stirbar and septum is charged sodium 1-tert-butylethenolate (3.89 g,
20.1 mmol), 2,6-bis(2,4,6-tri-iso-propylphenyl)-benzoyl chloride (2.73 g, 5 mmol), and toluene (30 mL). The flask is stirred and heated to
60 C in an oil bath for 72 hours, and then allowed to cool to room temperature. The flask is opened, 1 M hydrochloric acid (50 mL) is slowly
charged, and the mixture is allowed to stir for 30 minutes. The color transitions from clear red-orange to yellow. The mixture is then trans-
ferred to a separatory funnel, allowed to settle and separated, and the aqueous layer is washed with diethyl ether (50 mL). The combined
organics are concentrated to a thick, orange-colored oil. 98:2 methanol/water (50 mL)is added and the mixture is triturated at 60 °C for 15
minutes, inducing precipitation of a fine powder. The suspension is then stored in an ice bath for 1 hour, filtered, and dried in vacuo. The
crude material is purified by column chromatography (gradient 0–0.5% Et2O/hexanes), and obtained as a white, microcrystalline powder
(2.3 g, 75%). m.p.: 144.6–146.9°C. 1H NMR (400 MHz, Chloroform-d) δ 15.46 (s, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H),
6.97 (s, 4H), 5.12 (s, 1H), 2.89 (hept, J = 6.9 Hz, 2H), 2.64 (hept, J = 6.8 Hz, 4H), 1.27 (d, J = 7.0 Hz, 12H), 1.12 (d, J = 6.9 Hz, 12H), 1.07
(d, J = 6.8 Hz, 16H), 0.76 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 203.6, 184.1, 148.0, 146.4, 139.8, 136.4, 135.6, 130.1, 128.4, 120.7,
99.7, 77.5, 77.2, 76.8, 40.0, 34.4, 30.8, 27.1, 25.6, 24.2, 23.2. IR (ν, cm−1): 2959, 2929, 2869, 1607, 1584, 1461, 1432, 1383, 1365, 1324,
1286, 1234, 1126, 1104, 1055, 944, 880, 854, 813, 769, 653, 478. UV-Vis (λmax): 282 nm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C43H61O2 609.4672; Found: 609.4663.
1-[2,6-Bis(2,4,5-tri-iso-propylphenyl)phenyl]-3-[2-(3,5-di-tert-butylphenyl)phenyl]-propan-1,3-dione (13)
To an oven-dried 20 mL vial equipped with a stirbar and a vial-cap is charged sodium 1-[2-(3,5-di-tert-butylphenyl)phenyl]ethenolate (2.47
g, 7.47 mmol), 2,6-bis(2,4,6-tri-iso-propylphenyl)-benzoyl chloride (1 g, 1.87 mmol), and toluene (5 mL). The vial stirred and heated to
100°C in an oil bath for 72 hours, and then allowed to cool to ambient. The vial is opened and transferred to a separatory funnel. The mixture
is quenched with 1 M hydrochloric acid (30 mL) and diluted with 20 mL of ethyl acetate. The color transitions from clear red-orange to
opaque yellow when shaken. The aqueous is washed with ethyl acetate (10 mL). The combined organics are concentrated to a thick, orange-
colored oil. 95:5 methanol/water (30 mL) is added and the mixture triturated at 60 °C for 15 minutes, inducing precipitation of a fine powder.
The suspension is then stored in an ice bath for 1 hour, filtered, and recrystallized out of boiling methanol, filtered again, and washed with
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cold methanol, then dried in vacuo to yield a white, microcrystalline powder (380 mg, 25%). m.p.: 229.5–231.1 °C. H NMR (400 MHz,
Chloroform-d) δ 15.08 (s, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.36 (td, J = 7.5, 1.3 Hz, 1H), 7.29 – 7.24 (m, 2H), 7.19 (d, J = 7.6 Hz, 2H), 7.14
(td, J = 7.6, 1.3 Hz, 1H), 7.02 (s, 4H), 6.99 (d, J = 1.8 Hz, 2H), 6.50 (dd, J = 7.8, 1.4 Hz, 1H), 5.56 (s, 1H), 2.93 (hept, J = 6.9 Hz, 2H), 2.66
(hept, J = 6.7 Hz, 4H), 1.31 (d, J = 6.9 Hz, 12H), 1.21 (s, 18H), 1.09 (dd, J = 9.6, 6.8 Hz, 24H). 13C{1H} NMR (101 MHz, CDCl3) δ 189.1,
186.5, 150.1, 147.9, 146.5, 142.4, 140.0, 140.0, 136.7, 135.9, 135.6, 131.5, 130.5, 130.1, 129.9, 128.5, 126.4, 123.5, 120.8, 120.6, 104.3,
77.5, 77.2, 76.8, 34.9, 34.3, 31.6, 31.0, 25.7, 24.2, 23.4. IR (ν, cm−1): 2959, 2933, 2869, 1599, 1566, 1465, 1387, 1365, 1320, 1242, 1108,
880, 772, 720, 642, 493. UV-Vis (λmax): 305 nm, 320 nm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C59H77O2 817.5923; Found: 817.5920
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Bis[2-(3,5-di-tert-butylphenyl)benzoyl]methane (14)
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To an oven-dried 20 mL vial equipped with a stirbar and septum is charged sodium amide (0.082 g, 2.00 mmol) and toluene (3 mL). The
vial and septum are affixed using copper wire and the vial is attached to a nitrogen manifold with adequate ventilation, and a solution of 2’-
(3,5-di-tert-butylphenyl)-acetophenone (0.339 g, 1.10 mmol) in toluene (1.1 mL) is added dropwise over 5 minutes. The contents are then
heated to 80 °C stirred for an additional 10 minutes, after which a solution of methyl 2-(3,5-di-tert-butylphenyl)-benzoate (0.292 g, 0.90
mmol) in toluene (0.9 mL) is added dropwise over 5 minutes. The vial stirred at 80 °C for 16 hours, and then cooled to ambient. The mixture
is quenched with 1 M hydrochloric acid (5 mL) and diluted with ethyl acetate (2 mL). The contents are allowed to stir for 30 minutes and
then transferred to a separatory funnel and the aqueous layer washed with ethyl acetate (2 × 2 mL). The combined organics are dried over
sodium sulfate and concentrated to a yellow powder. The crude material is purified by column chromatography (isocratic 2.5% EtOAc/hex-
anes) and obtained as a white powder (0.218 g, 36%). A similar yield is obtained when the reaction is carried out with the isolated enolate.
m.p.: 170.3–171.6°C. 1H NMR (400 MHz, Chloroform-d) δ 15.23 (s, 1H), 7.49 – 7.42 (m, 6H), 7.28 (ddd, J = 7.7, 6.7, 2.0 Hz, 2H), 7.20 (d,
J = 1.8 Hz, 4H), 7.05 (ddd, J = 7.8, 1.3, 0.6 Hz, 2H), 5.41 (s, 1H), 1.32 (s, 36H). 13C{1H} NMR (101 MHz, CDCl3) δ 188.6, 150.9, 142.2,
139.9, 136.7, 130.6, 130.4, 128.9, 127.0, 123.7, 121.4, 104.7, 77.5, 77.2, 76.8, 35.1, 31.6. IR (ν, cm−1): 2962, 2903, 2865, 1596, 1469, 1428,
1365, 1249, 1208, 1063, 1033, 951, 903, 884, 810, 772, 717, 612, 553. UV-Vis (λmax): 295 nm, 335 nm. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C43H53O2 601.4045; Found: 601.4045
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2,6-Bis(2,4,5-trimethylphenyl)benzoyl chloride (15)
To an oven-dried 500 mL one-neck round bottom flask equipped with a stirbar, condenser, addition funnel, and septum is charged magnesium
turnings (6.1 g, 250 mmol), tetrahydrofuran (200 mL), and 1,2-dibromoethane (0.5 mL, 5.7 mmol). The contents are heated to 60°C in an
oil bath and stirred for at least 3 hours, at which point 1 mL of a solution of 2,4,5-trimethylbromobenzene (25.0 g, 125 mmol) in tetrahydro-
furan (50 mL) is added through the addition funnel. After initiation of reaction, the heating is stopped, and the remainder of the solution is
added dropwise at a rate which maintains reflux of flask contents. The solution is then reheated to 60 °C for 12 hours, and then cooled to
ambient. The flask is capped with a fresh septum and stored until ready for use. To an oven-dried 500 mL two-neck round bottom flask
equipped with a stirbar, addition funnel, and septum is charged 1,3-dichlorobenzene (5.71 mL, 20 mmol) and tetrahydrofuran (100 mL). The
contents are cooled to −78 °C and n-butyllithium, 2.5 M in hexanes (20 mL, 50 mmol) is added dropwise over 30 minutes, forming a bright
yellow solution which turns into a white suspension. The contents are stirred an additional 30 minutes before adding the pre-formed Grignard
solution dropwise over several hours. Then the flask is allowed to warm to ambient, the addition funnel is replaced with a condenser, and
the contents are heated to 60 °C for at least 12 hours. The now red solution is sparged with carbon dioxide gas for several days, during which
it turns brown. After completion of the reaction (determined by 1H NMR assay), the contents are cooled to ambient, slowly quenched using
1 M hydrochloric acid (100 mL) and 5 M hydrochloric acid (100 mL), and stirred vigorously for 30 minutes. The aqueous layer is separated
and washed with diethyl ether (50 mL), and the combined organics are concentrated to an oil and passed through a silica plug using 10%
ethyl acetate/hexane. The crude product is concentrated and dried in vacuo to remove traces of ethanol. To an oven-dried 250 mL one-neck
round bottom flask equipped with a stirbar, condenser, and septum is charged the crude product, dichloromethane (100 mL), thionyl chloride
(7.25 mL, 100 mmol), and pyridine (0.1 mL, 1.2 mmol). The contents are stirred and heated to reflux for at least 4 hours, cooled to ambient,
and washed with deionized water (50 mL). The organics are diluted with hexane, concentrated to remove dichloromethane, and cooled to 0
°C for at least 1 hour. The product is filtered, washed with hexanes, and dried in vacuo to yield an off-white powder (10.5 g, 56%). m.p.:
145–148°C (decomp. at 125 °C). 1H NMR (400 MHz, Chloroform-d) δ 7.50 (q, J = 7.5 Hz, 1H), 7.26 (d, J = 7.7 Hz, 2H), 7.08 (s, 1H), 7.06
(s, 1H), 7.04 (s, 1H), 7.00 (s, 1H), 2.29 (s, 6H), 2.27 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
169.0, 138.7, 138.5, 138.4, 136.7, 136.0, 135.9, 133.7, 133.6, 133.5, 131.6, 131.6, 131.2, 129.8, 129.5, 129.2, 77.5, 77.2, 76.8, 19.8, 19.6,
19.3. IR (ν, cm−1): 3007, 2921, 2862, 1797, 1581, 1510, 1450, 1391, 1193, 1022, 1003, 884, 854, 769, 683, 616, 594, 475. UV-Vis (λmax):
275 nm. HRMS (ESI-TOF) m/z: [M – Cl]+ Calcd for C25H25O 341.1900; Found: 349.1909
2,6-Bis(2,4,6-tri-iso-propylphenyl)benzoyl chloride (16)
To an oven-dried 500 mL one-neck round bottom flask equipped with a stirbar, condenser, addition funnel, and septum is charged magnesium
turnings (4.8 g, 200 mmol), tetrahydrofuran (200 mL), and 1,2-dibromoethane (0.5 mL, 5.7 mmol). The contents are heated to 60°C in an
oil bath and stirred for at least 3 hours, at which point 1 mL of a solution of 2,4,6-tri-iso-propylbromobenzene (28.3 g, 100 mmol) in tetra-
hydrofuran (10 mL) is added through the addition funnel. After initiation of reaction, the heating is stopped, and the remainder of the solution
is added dropwise at a rate which maintains reflux of flask contents. The solution is then reheated to 60°C for 48 hours, and then cooled to
ambient. The flask is capped with a fresh septum and stored until ready for use. To an oven-dried 500 mL two-neck round bottom flask
equipped with a stirbar, addition funnel, and septum is charged 2,6-dichloroiodobenzene (10.24 g, 37.5 mmol) and ethyl magnesium bromide,
0.9 M in tetrahydrofuran (42 mL). The contents are stirred for 1 hour before adding the pre-formed Grignard solution. The flask is allowed
to stir at ambient for at least 12 hours, the addition funnel is replaced with a condenser, and the contents are heated to 60 °C for at least 2
days. The now red solution is sparged with CO2 gas for several days, during which it turns brown. After completion of the reaction (deter-
mined by 1H NMR assay), the contents are cooled to ambient, diluted with diethyl ether (100 mL), slowly quenched using 1 M hydrochloric
acid (50 mL) and 5 M hydrochloric acid (50 mL), and stirred vigorously for 15 minutes. The aqueous layer is separated and washed with
diethyl ether (50 mL), and the combined organics are concentrated to a powder, triturated with ethanol, 95% (100 mL), and cooled to 0 °C
for at least 1 hour. The crude product is filtered and washed with ethanol, 95% and hexanes, and dried in vacuo to remove traces of ethanol.
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To an oven-dried 250 mL one-neck round bottom flask equipped with a stirbar, condenser, and septum is charged the crude product, di-
chloromethane (75 mL), thionyl chloride (3 mL, 41.3 mmol), and pyridine (0.1 mL, 1.2 mmol). The contents are stirred and heated to reflux
for at least 4 hours, cooled to ambient, and washed with DI water (50 mL). The organics are diluted with hexane, concentrated to remove
dichloromethane, and cooled to 0 °C for at least 1 hour. The product is filtered, washed with hexanes, and dried in vacuo to yield a white
powder (9.59 g, 47%). m.p.: 205–210 °C (decomp. at 190 °C). 1H NMR (400 MHz, Chloroform-d) δ 7.49 (t, J = 7.7 Hz, 1H), 7.25 (d, J =
7.7 Hz, 2H), 7.04 (s, 4H), 2.93 (hept, J = 6.9 Hz, 2H), 2.59 (hept, J = 6.8 Hz, 4H), 1.30 (d, J = 6.9 Hz, 12H), 1.23 (d, J = 6.8 Hz, 12H), 1.07
(d, J = 6.8 Hz, 12H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.7, 149.2, 147.1, 146.6, 138.5, 137.1, 132.6, 129.8, 129.3, 128.0, 120.9, 120.6,
120.4, 77.5, 77.2, 76.8, 34.4, 31.1, 31.1, 30.5, 26.0, 24.4, 24.3, 24.2, 24.2, 22.7. IR (ν, cm−1): 2959, 2933, 2869, 1793, 1610, 1573, 1461,
1383, 1365, 1190, 1175, 1108, 880, 858, 810, 772, 691, 653, 612, 497, 467. UV-Vis (λmax): 280 nm. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C37H49ClO 567.3370; Found: 567.3369
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2’-(3,5-Di-tert-butylphenyl)acetophenone (17)
Under an inert atmosphere, to an oven-dried 500 mL one-neck round bottom flask equipped with a stirbar and septum is charged potassium
carbonate (9.85 g, 71.24 mmol), bis(triphenylphosphino)palladium dichloride (0.250 g, 0.35 mmol, 1 mol%), and 3,5-di-tert-butylphenyl-
boronic acid72. 3:1 tetrahydrofuran/water (90 mL) which has been sparged with nitrogen for 30 minutes is cannulated into the flask. The
contents are stirred for 15 minutes, while the formed solution transitions from yellow through red to dark brown. 2’-Bromoacetophenone
(4.80 mL, 35.6 mmol) is added via syringe, and the solution is heated to 60°C in an oil bath for 72 hours. The reaction progress may be
followed by TLC on silica plates (10% EtOAc/hexanes). The solution is then cooled to room temperature and poured into a separatory funnel
with 1 M hydrochloric acid (50 mL), and then washed with ethyl acetate (2 × 50 mL). The combined organics are dried over sodium sulfate,
and concentrated to a brown oil containing trace palladium black. The crude material is purified by column chromatography (isocratic 2.5%
EtOAc/hexanes) to yield a colorless to pale-yellow oil (9.2 g, 84%). 1H NMR (400 MHz, Chloroform-d) δ 7.56 – 7.49 (m, 2H), 7.47 – 7.43
(m, 2H), 7.41 (td, J = 7.4, 1.4 Hz, 1H), 7.19 (d, J = 1.8 Hz, 2H), 1.90 (s, 3H), 1.35 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3) δ 205.7,
151.4, 141.7, 141.4, 139.8, 130.7, 130.1, 127.9, 127.3, 123.6, 121.8, 77.5, 77.2, 76.8, 35.1, 31.6, 30.4. IR (ν, cm−1): 2962, 2906, 2869, 1689,
1596, 1480, 1428, 1365, 1283, 1249, 1208, 903, 884, 761, 720, 642, 597, 571. UV-Vis (λmax): 255 nm, 293 nm. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C22H29O 309.2218; Found: 309.2218
Methyl 2’-(3,5-di-tert-butylphenyl)benzoate (18)
Under an inert atmosphere, to an oven-dried 100 mL one-neck round bottom flask equipped with a stirbar and septum is charged potassium
carbonate (5.53 g, 40 mmol), bis(triphenylphosphino)palladium dichloride (0.140 g, 0.2 mmol, 1 mol%), and 3,5-Di-tert-butylphenylboronic
acid (4.9 g, 21 mmol). 3:1 tetrahydrofuran/water (50 mL) which has been sparged with nitrogen for 30 minutes is cannulated into the flask.
The contents are stirred for 15 minutes, while the formed solution transitions from yellow through red to dark brown. Methyl 2-bromoben-
zoate (2.8 mL, 20 mmol) is charged via syringe, and the solution is heated to 65°C in an oil bath for 72 hours. The reaction progress may be
followed by TLC on silica plates (10% EtOAc/hexanes). The solution is then cooled and poured into a separatory funnel with 1 M hydro-
chloric acid (70 mL), and then washed with ethyl acetate (2 × 25 mL). The combined organics are dried over sodium sulfate and concentrated
to a brown oil with trace palladium black. The crude material is purified by column chromatography (isocratic 2.5% EtOAc/hexanes) to yield
a colorless to pale-yellow oil (5.78 g, 89%). 1H NMR (400 MHz, Chloroform-d) δ 7.77 – 7.72 (m, 1H), 7.55 – 7.50 (m, 1H), 7.46 – 7.43 (m,
1H), 7.42 – 7.37 (m, 2H), 7.18 (dd, J = 1.8, 0.6 Hz, 2H), 3.61 (d, J = 0.6 Hz, 3H), 1.36 (d, J = 0.7 Hz, 18H). 13C{1H} NMR (101 MHz,
CDCl3) δ 170.1, 150.6, 143.1, 140.3, 131.8, 131.1, 130.7, 129.4, 127.0, 122.8, 121.3, 77.5, 77.2, 76.8, 52.1, 35.0, 31.7. IR (ν, cm−1): 2955,
2906, 2869, 1726, 1599, 1480, 1432, 1365, 1294, 1271, 1249, 1193, 1126, 1100, 1070, 1044, 970, 877, 776, 761, 717, 679, 638, 575. UV-
Vis (λmax): 250 nm, 285 nm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H28O2Na 347.1987; Found: 347.1983
Sodium 1-[2-(3,5-di-tert-butylphenyl)phenyl]ethenolate, THF adduct (19)
To an oven-dried 500 mL one-neck round bottom flask equipped with a stirbar, addition funnel, and septum is charged sodium amide (2.9
g, 74.6 mmol) and tetrahydrofuran (85 mL). The flask is attached to a nitrogen manifold with adequate ventilation and heated to 50°C in an
oil bath. A solution of 2’-(3,5-di-tert-butylphenyl)-acetophenone (11.5 g, 37.3 mmol) in tetrahydrofuran (85 mL) is added dropwise over 1
hour. The contents are then reacted for 4 hours, and then allowed to cool to room temperature. Under an inert atmosphere, the yellow sus-
pension is diluted with diethyl ether (50 mL) and filtered through an oven-dried, medium-porosity frit, and the solvent is removed in
vacuo. The yellow foam is further dried overnight, and then ground into a powder (12.46 g, 83%). 1H NMR (400 MHz, Benzene-d6) δ 7.93
– 7.76 (m, 1H), 7.71 (s, 2H), 7.54 – 7.42 (m, 2H), 7.41 – 7.25 (m, 2H), 3.82 (s, 1H), 3.52 (s, 1H), 3.50 – 3.42 (m, 4H), 1.40 – 1.37 (m, 4H),
1.36 (s, 9H). 13C NMR (101 MHz, C6D6) δ 170.36, 150.65, 146.18, 143.07, 140.05, 131.19, 128.81, 128.30, 128.06, 127.82, 127.23,
126.75, 123.73, 123.49, 120.65, 81.46, 67.89, 35.27, 35.23, 35.19, 31.81, 31.75, 31.68, 25.72.
Sodium 1-(3,4,5-trimethoxyphenyl)ethenolate, bis-THF adduct (20)
To an oven-dried 100 mL one-neck round bottom flask equipped with a stirbar, addition funnel, and septum is charged sodium amide (0.8
g, 20 mmol) and tetrahydrofuran (20 mL). The flask is attached to a nitrogen manifold with adequate ventilation and heated to 60°C in an
oil bath. A solution of 3’,4’,5’-trimethoxyacetophenone (2.10 g, 10 mmol) is added dropwise over 15 minutes. The contents are stirred at
60°C for 3 hours, and then allowed to cool to ambient, transitioning from a red solution to light yellow over 30 minutes. Under an inert
atmosphere, the grey suspension is diluted with diethyl ether (100 mL) and filtered through an oven-dried, medium-porosity frit, and the
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solvent is removed in vacuo to afford peach colored powder, which is further dried overnight (2.10 g, 69%). 1H NMR (400 MHz, Methylene
Chloride-d2) δ 7.20 (s, 2H), 3.89 (s, 6H), 3.84 (s, 2H), 3.72 – 3.63 (m, 8H), 2.56 (s, 3H), 1.86 – 1.76 (m, 8H). Material insufficiently soluble
to obtain the 13C{1H} spectrum.
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ACKNOWLEDGMENT
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This work was funded by laboratory startup funds provided by the University of Colorado, Boulder, CO.
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ASSOCIATED CONTENT
Supporting Information
Full characterization data, including 1H and 13C NMR, IR, UV-Vis, HRMS, and selected crystal structure data are
provided in the Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
Accession Codes
CCDC 1892445−1892447 contain the supplementary crystallographic data for this paper. These data can be ob-
tained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
* michael.marshak@colorado.edu
Author Contributions
Experimental work was conducted by ASC, with additional work by ATL, JXS, ESA, and MPM. Crystallography
was conducted by SMK and MPM. The manuscript was prepared by ASC and MPM.
Notes
Any additional relevant notes should be placed here.
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