α,α-Diarylethylene Glycols as Valuable Precursor for Synthesis of 1,1-Diarylethenes and α,α-Diaryl Acetaldehydes

Article abstract of DOI:10.1002/ejoc.201700467

Towards assembling of diarylmethine unit present in biologically important molecules, we have developed a new Weinreb Amide (WA) based building block derived from glycolic acid. The WA functionality present in this building block permits the sequential addition of various arylmagnesium bromide reagents in a controlled manner that enables assembly of a diarylmethine unit. The developed synthetic route provides easy access to important diarylethenes and α,α-diarylethylene glycols. The synthesized α,α-diarylethylene glycols provide access to synthetically important symmetrical and unsymmetrical α,α-diaryl acetaldehydes as valuable intermediates.

Full text of DOI:10.1002/ejoc.201700467

DOI: 10.1002/ejoc.201700467
Full Paper
Weinreb-Amide-Based Building Block
α,α-Diarylethylene Glycols as Valuable Precursor for Synthesis
of 1,1-Diarylethenes and α,α-Diaryl Acetaldehydes
Praveen Kumar Tiwari,[a] Balasubramaniam Sivaraman,[a] and Indrapal Singh Aidhen*[a]
Abstract: Towards assembling of diarylmethine unit present in methine unit. The developed synthetic route provides easy ac-
biologically important molecules, we have developed a new cess to important diarylethenes and α,α-diarylethylene glycols.
Weinreb Amide (WA) based building block derived from glycolic The synthesized α,α-diarylethylene glycols provide access to
acid. The WA functionality present in this building block permits synthetically important symmetrical and unsymmetrical α,α-di-
the sequential addition of various arylmagnesium bromide rea- aryl acetaldehydes as valuable intermediates.
gents in a controlled manner that enables assembly of a diaryl-
Introduction
The diarylmethine unit is a common framework present in vari-
ous biologically important molecules illustrated by sertraline
1,[1a] peperomin-E 2[1b,1e] and (R)-tolterodine 3,[1c,1d] isochro-
mans derivatives 4,[2a] and potent antidepressant agent 5.[2c] In
a similar context, compounds 6, 7, and 8 that contain a 1,1-
diarylethene unit display important biological activities.[2] Com-
pound 6 is a new analogue of tiagabine 7 for γ-aminobutyric
acid uptake inhibition studies,[2b] whereas compound 8a,
known as isocombretastatin A-4, has emerged as a promising
anti-mitotic agent[3] with biological activity comparable to that
of natural product combretastatin A-4,[4] which acts on the col-
chicine binding site. The essentiality of aryl ring A for bioactivity
is evident from studies (Figure 1).
Although access to biologically active molecules with a
diarylmethine structural unit, represented by the synthesis of
isochromans 4,[2a] 5,[2c] and 6,[2b] has invoked use of α,α-diaryl
acetaldehydes 9 as valuable intermediates. Their low stability
and propensity to undergo oxidative degradation to ket-
ones[5a,6] has restricted the use of aldehydes 9 as valuable start-
ing compounds for synthetic endeavors. Preparative procedures
for the synthesis of aldehydes 9 with identical or different aryl
residues at the α-position are mainly based on α-arylation of 2-
arylacetaldehyde,[5] Wittig olefination of diaryl ketones,[7] and
rearrangements of suitable aryl-substituted epoxides.[8] All
these approaches rely on the use of starting materials either
Figure 1. Important biologically active molecules with diarylmethine and di-
arylethene units.
with one aryl or two aryl groups. Vinyl ethers, with a coordinat-
ing auxiliary, are the only two carbon building blocks available
in the literature to assemble two different aryl units onto
Our success with ring-B glycosylated analogues of phenstatin
8b[9] coupled with the growing importance of isocombreta-
statin A-4 8a, we envisaged the use of α,α-diarylethylene
glycols 10 as valuable starting compounds. There are limited
methods to synthesize unsymmetrical α,α-diaryl acetaldehydes
9, so substrates 10 would additionally serve as stable and
storable precursors for reactive α,α-diaryl acetaldehydes 9 for
use in any synthetic endeavor. With this premise, Weinreb
alkenic carbon and provide access to aldehydes 9 after aqueous
acidic work up.[5c]
[a] Department of Chemistry, Indian Institute of Technology Madras,
Chennai 600036, India
E-mail: isingh@iitm.ac.in
http://chem.iitm.ac.in/professordetails/profsingh/index.htm
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201700467.
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amide (WA)[10,11] based building block 11 derived from glycolic were obtained in satisfactory yields 60–84 %. These ketones
acid 12 was conceived for the synthesis of ethylene glycols 10. were further reacted with another arylmagnesium bromide un-
Building block 11 enabled consecutive addition of different aryl der similar reaction conditions to obtain corresponding diaryl-
residues onto the carbonyl carbon through arylmagnesium substituted and pivaloyl-protected glycols 15a–15z in 58–87 %
bromides and paved the way for convenient access to unsym- yield (26 examples, Table 1). Pivalate ester deprotection in com-
metrical α,α-diaryl acetaldehydes 9, 1,1-diarylethenes 13, iso- pounds 15 with aqueous KOH in ethanol furnished desired α,α-
combretastatin A-4 8a, and several analogues of isocombreta- diarylethylene glycol 10 in 65–94 % yield. In substrates with
statin (Figure 2). The efforts of this synthetic endeavor and suc- base-sensitive functionalities, such as 15r, that contain silyl
cessful results obtained are described herein.
ether protection pivalate ester deprotection was achieved un-
der reductive conditions by using solution of LiBH4 [2
hydrofuran (THF)] in CH2Cl2 at 0 °C (Scheme 2).
M in tetra-
Figure 2. Retrosynthetic analysis for 13 and 9.
Scheme 2. Synthesis of α,α-diarylethylene glycol 10 from building block 11.
The successful synthesis of α,α-diarylethylene glycols 10
(Table 1) enabled synthesis of 1,1-diarylethene 13 (Table 2). To-
wards this, diol compound 11a was treated with 1,1-thio-
carbonyl diimidazole in dry THF or toluene. Expected cyclic
thionocarbonate 16a was formed in 5 h and the product was
obtained in excellent yield (83 %) after purification by silica gel
column chromatography. Formation of cyclic thionocarbonate
16a was confirmed through the observation of a signal at δ =
190.9 ppm (C=S) in the 13C NMR spectrum (Scheme 3). Addi-
tional support for elemental composition of product 16a came
from HRMS data, C17H16O2SNa [M + Na]+ observed 307.0780;
calculated 307.0769. Compound 16a was reacted with trimeth-
ylphosphite in accordance with a literature procedure[12], and
was heated to reflux temperatures in trimethylphosphite for
20–24 h under a nitrogen atmosphere to furnish targeted mol-
ecule 13a in 73 % yield (60 % over two steps, Scheme 3). The
Results and Discussion
The synthesis of requisite building block 11 on a multi-gram
scale was achieved by one-pot reaction of glycolic acid 12 with
pivaloyl chloride and triethylamine (TEA) at 0 °C followed
by addition of N,O-dimethylhydroxylamine hydrochloride
(DMHA·HCl) and TEA to afford compound 11 as a light yellow
liquid in 78 % yield (Scheme 1). The structure of product 11
was evident from the presence of expected four singlet a t
δ ppm = 1.27 (tert-butyl), 3.19 (NCH3), 3.74 (NOCH3) and 4.18
1
(CH2O) in the H NMR spectrum and seven carbon signals a t
δ ppm = 27.2 (CH3)3, 32.3 (NCH3), 38.8 (C), 60.9 (CH2O), 61.5
(NOCH3), 168.2 (amide carbonyl) and 178.4 (carbonyl for ester)
in the 13C NMR spectrum. The high-resolution mass spectrum
further confirmed the molecular constitution, C9H18NO4 with
observed [M + H]+ peak at 204.1233, (calculated: 204.1236).
1
formation of product 13a was evident from the H NMR spec-
trum as the alkenic protons were observed at δH = 5.37 ppm
(s, 2 H, =CH2). The corresponding methylene carbon signal was
observed at δC = 113.0 ppm (=CH2) in the 13C NMR spectrum.
Scheme 1. Synthesis of building block 11.
Towards the stated objectives, addition reactions of arylmag-
nesium bromide were tried under different reaction conditions
and addition at –45 °C was found to be the most suitable tem-
perature for selective nucleophilic addition over WA functional-
ity. As an illustration, the formation of aryl ketone 14a from 11a
was confirmed by the presence of characteristic peaks in the
aromatic region of the 1H NMR spectrum with δ = 7.74–
7.19 ppm (4 H, ArH) along with a new peak at δ = 192.2 ppm
(C=O, ketone) and disappearance of the peak at δ = 168.2 ppm
(C=O, amide) from compound 11 as detected by 13C NMR spec-
troscopy. Pivaloyl-protected α-hydroxy arylketones 14a–14e
Scheme 3. Synthesis of 1,1-diarylethene 13 from α,α-diarylethylene glycol
10.
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Table 1. Synthesis of aryl ketone 14, alcohol 15, and α,α-diarylethylene glycol 10 from building block 11.
[a] Isolated yield.
Table 2. Synthesis of 1,1-diarylethene 13.
[a] Isolated yields. [b] For 13m over three steps.
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Table 3. Synthesis of isocombretastatin A-4 8a and analogues 8s–8z.
[a] Isolated yields. [b] For 8a yield over three step.
The optimized reaction conditions for conversion of glycol rings, the reactions were extremely slow, particularly with sub-
11a into 1,1-diarylethene 13a were used to illustrate the sim- strates 10f and 10g. Reflux temperature conditions afforded
plicity of this process through the synthesis of 1,1-diarylethenes 17f–17g as the main product accompanied by traces of desired
13f–13m and 13p (Table 2) and several analogues of iso- aldehyde 9f–9g. This is presumably a result of the high reactiv-
combretastatin 8s–8z as a specific application (Table 3).
The utility of α,α-diarylethylene glycols 10 as useful precur-
sors for ready access to sensitive α,α-diaryl acetaldehydes 9 was
now explored and demonstrated. With this objective, com-
pound 10a was subjected to rearrangement under acidic condi-
tions with the use of p-toluenesulfonic acid (pTsA) in CH2Cl2 at
room temperature. Complete consumption of starting com-
pound 10a took place within 2–3 h to give a non-polar 2,4-
dinitrophenylhydrazine active spot as monitored by TLC. Purifi-
cation by silica gel column chromatography afforded aldehyde
9a in 86 %. To further substantiate the efficacy of α,α-diaryleth-
ylene glycols 10 as stable and storable precursors, α,α-diaryl
acetaldehydes glycols 10e, 10h, 10p, and 10q were subjected
to the same reaction conditions to obtain corresponding alde-
hydes 9e, 9h, 9p, and 9q, respectively, in good yields
(Scheme 4).
ity of the formed aldehyde and reaction conditions that enables
acetalization with the starting reactant itself as the requisite
diol. To circumvent this undesired product formation, and ac-
centuate exclusive formation of aldehyde pivalate-protected
α,α-diarylethylene glycol substrates 15 were used. Pivalate-pro-
tected compound 15f, in lieu of corresponding 10f, was heated
to reflux with pTsA in dry CH2Cl2 or treated with Eaton's reagent
Scheme 4. Synthesis of aldehyde 9 from α,α-diarylethylene glycol 10.
Although the reaction conditions were suitable for α,α-di-
arylethylene glycol substrates 10 with electron-rich aromatic
Scheme 5. Synthesis of α,α-diaryl acetaldehyde 9 from compound 15.
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(1:8 ratio of P2O5 and MeSO3H)[13] in CH2Cl2 at room tempera-
In this context, two carbon-chain elongations were per-
ture for dehydration. The reaction afforded desired O-pivaloyl formed with aldehyde 9 by using a Wittig-olefination proce-
enol ester 18f in 78 % yield. Subsequent removal of the pivaloyl dure. The reaction of crude aldehyde 9g under reflux conditions
group in compound 18f with NaOMe in dry ether, followed with Wittig reagent 20 in dry CH2Cl2 yielded a olefin product,
by acidic workup with aqueous HCl (10 %) furnished desired which upon subsequent reduction with H2-Pd/C in ethyl acet-
aldehyde 9f as the exclusive product (Scheme 5). This modifica- ate, furnished homologated saturated ester 21g in 90 % yield.
tion was successfully used for access to O-pivaloyl enol esters In addition, ester deprotection of compound 21g was accom-
18d, 18g, 18i, 18k–18l, and 18n–18p that resulted in corre- plished by using aqueous KOH solution in ethanol. 4,4′-Diaryl
sponding aldehydes 9d, 9g, 9i, 9k–9l, and 9n–9p.
butanoic acid 22g was obtained in 70 % yield. Intramolecular
acylation with Eaton's reagent furnished desired 4-aryltetralone
19g in 83 % yield. Similarly, aldehydes 9 synthesized as shown
in Scheme 5 were also equally reactive under these optimized
conditions and afforded various 4-aryltetralones 19a, 19d, 19f,
19i, and 19k–19l in good yields (Scheme 6).
To demonstrate the significance of the route developed for
ready access to α,α-diaryl acetaldehydes 9 and to obviate the
difficulties associated with their isolation and degradation pro-
pensities,[14,15] direct use of these aldehydes were made for two
synthetic endeavors. Given the fact that 4-aryltetralone 19g
serves as valuable building block for synthesis of sertraline 1, a
We chose synthesis of 1,2,2-triarylethanone 24 as another
clinically used anti-depressant drug that contains a diaryl- demonstration of the usefulness and ready accessibility of
methine unit, we targeted synthesis of 4-aryltetralone 19.
α,α-diaryl acetaldehydes 9 through our developed route. These
Scheme 6. Synthesis of 4-aryltetralone 19 from α,α-diaryl acetaldehyde 9.
Scheme 7. Synthesis of 1,2,2-triarylethanone 24 from α,α-diaryl acetaldehyde 9.
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ketones[16] were prepared by palladium-catalyzed arylation of
acetophenone for two identical aryl units on the α-carbon or
arylation on deoxybenzoins for non-identical aryl unit's α-
carbon. The aforementioned ready access to α,α-diaryl acet-
aldehydes with different aryl-units enabled synthesis of 1,2,2-
triarylethanone 24, with different aryl units on α-carbon, merely
through addition of arylmagnesium bromides on aldehydes 9.
As an illustration and for demonstrating the simplicity of con-
cept, aldehyde 9h obtained through Scheme 4 was first treated
Synthesis of WA-Based Building Block (11): To a solution of
glycolic acid (4.9 g, 64.3 mmol) and TEA (19.7 mL, 141.4 mmol) in
dry CH2Cl2 (150 mL), pivaloyl chloride (17.3 mL, 141.4 mmol) was
added at 0 °C under nitrogen and stirred for 3 h at room temp.
After this, solid DMHA·HCl (7.5 g, 77.1 mmol) was added, which
followed a slow addition of TEA (19.7 mL, 141.4 mmol) at 0 °C
and the reaction mixture was stirred for 15 h at room temp. After
completion of the reaction, CH2Cl2 (70 mL) was added and the or-
ganic layer was washed with water (4 × 60 mL) and then brine
(50 mL). The organic layer was dried with anhydrous Na2SO4 and
with phenylmagnesium bromide at 0 °C. The reaction afforded the solvent was evaporated under reduced pressure. Finally, the
crude mixture was purified by silica gel column chromatography
(EtOAc/hexanes, 1:4) to afford compound 11 as light yellow liquid
10.2 g (78 %). Rf = 0.35 (hexanes/EtOAc, 8:2). 1H NMR (400 MHz,
CDCl3): δ = 4.81 (s, 2 H, CH2O), 3.74 (s, 3 H, NOCH3), 3.19 (s, 3 H,
NCH3), 1.27 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ =
178.4 (CO, ester), 168.2 (CO, amide), 61.5 (OCH3), 60.9 (CH2O), 38.8
triaryl alcohol 23a as a mixture of diastereomers (≈ 1:1) in 62 %
yield over 2 steps (Scheme 7).
Oxidation of triaryl alcohol 23a by pyridinium chloro-
chromate (PCC) in CH2Cl2 solvent at room temperature fur-
nished expected 1,2,2-triarylethanone 24a in 87 % yield within
7–8 h. By using the optimized procedure, several other 1,2,2-
triarylethanones 24b–24d, 24e, 24f, and 24h were synthesized
from aldehydes 9h, 9b, 9c, and 9p, respectively, obtained from
corresponding diol compounds 10h, 10b, 10c, and 10p, respec-
tively. In a similar way, 1,2,2-triarylethanone 24g, 24i–24j, 24k–
24l and 24m–24n were obtained from aldehydes 9o, 9d, 9g,
and 9n, respectively, but they were obtained from correspond-
ing O-pivaloyl enol esters 18o, 18d, 18g, and 18n (Scheme 7).
[C(CH3)3], 32.3 (NCH3), 27.2 [(CH3)3C] ppm. IR (CHCl3): νmax = 1740,
˜
1684, 1481, 1461, 1420, 1397, 1366, 1285, 1150, 1116 cm–1. HRMS
(ESI): m/z calcd. for C9H17NO4 [M + H]+ 204.1236; found 204.1233.
Preparation of Grignard Reagent and Synthesis of Aryl Ketones
14a–14d: Grignard reagent was prepared from 4-bromotoluene
(3.6 mL, 29.6 mmol) and magnesium (0.71 g, 29.6 mmol, activated
with iodine) in anhydrous THF (30 mL) at room temperature. Initia-
tion of Grignard reagent was observed within 5–10 min. After com-
plete consumption of magnesium within 50–60 min, the resulting
solution was slowly added to a solution of compound 11 (2.0 g,
9.85 mmol) in THF (10 mL) at –45 °C and the mixture was stirred for
a further 4–5 h. After completion of the reaction, saturated aqueous
solution of NH4Cl was added cautiously at 0 °C, and the organic
layer was separated. The aqueous layer was further extracted with
EtOAc (3 × 15 mL). The combined organic layers were dried with
anhydrous Na2SO4, concentrated, and purified by silica gel column
chromatography (EtOAc/hexanes, 0.5:9.5) to afford ketone 14a as a
colorless crystalline solid 1.7 g (73 %). Rf = 0.53 (hexanes/EtOAc,
9:1). M.p. 42–44 °C. 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz,
2 H, ArH), 7.20 (d, J = 8.8 Hz, 2 H, ArH), 5.22 (s, 2 H, COCH2), 2.34 (s,
3 H, ArCH3), 1.23 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz, CDCl3):
δ = 192.2 (CO, ketone), 178.2 (CO, ester), 144.8 (ArC), 131.9 (ArC),
129.6 (ArCH), 127.9 (ArCH), 65.9 (COCH2), 38.9 [C(CH3)3], 27.3
Conclusions
In conclusion, new WA-based building block 11 has been devel-
oped from a two carbon containing glycolic acid as starting
material. The building block has enabled assembly of a diaryl-
methine unit in several valuable compounds, such as α,α-diaryl
acetaldehydes 9, 4-aryltetralone 19, and 1,2,2-triarylethanone
24, through the intermediacy of α,α-diarylethylene glycols 10.
Synthesis of biologically important isocombretastatin A-4 8a
along with fluorinated and non-fluorinated analogues 8s–8z
have been achieved through the same building block.
[(CH3)3C], 21.8 (ArCH3) ppm. IR (CHCl3): νmax = 3032, 2978, 2931,
˜
1734, 1700, 1607, 1475, 1416, 1368, 1287, 1234 cm–1. HRMS (ESI):
m/z calcd. for C14H18O3 [M + H]+ 235.1334; found 235.1344.
Experimental Section
2-Oxo-2-phenylethyl Pivalate (14b): Colorless crystalline solid.
Yield: (1.82 g, 84 %). Rf = 0.6 (hexanes/EtOAc, 9:1). M.p. 58–60 °C.
1H NMR (500 MHz, CDCl3): δ = 7.91–7.89 (m, 2 H, ArH), 7.61–7.58
(m, 1 H, ArH), 7.49–7.46 (m, 2 H, ArH), 5.31 (s, 2 H, COCH2), 1.27 [s,
9 H, (CH3)3C] ppm. 13C NMR (125 MHz, CDCl3): δ = 192.6 (CO, ket-
one), 178.1 (CO, ester), 134.5 (ArC), 133.9 (ArCH), 128.9 (ArCH), 127.8
(ArCH), 65.9 (COCH2), 38.9 [C(CH3)3], 27.3 [(CH3)3C] ppm. IR (CHCl3):
General Information: All reactions were carried out in oven-dried
glassware. Solvents used for column chromatography were labora-
tory reagent grade. Thin layer chromatography was performed on
aluminum plates coated with silica gel 60. Visualization was ob-
served by U.V. light or by dipping into a solution of cerium(IV) sulf-
ate (2.5 g) and ammonium molybdate (6.25 g) in 10 % sulfuric acid
(250 mL) followed by charring on a hot plate. Melting points were
determined in capillaries. 1H NMR (400 MHz, 500 MHz) and 13C NMR
(100 MHz, 125 MHz) spectra were recorded in [D]chloroform (CDCl3)
and [D6]DMSO. 1H NMR spectra were referenced to CDCl3 (δ =
7.26 ppm) and central line of [D6]DMSO (δ =2.5 ppm), whereas
13C NMR spectra were referenced to the central line of CDCl3 (δ =
77.16 ppm) and [D6]DMSO (δ =39.5 ppm). Multiplicities are given
as, s = singlet, d = doublet, t = triplet, dd = doublet of doublet,
m = multiplet, and br. s = broad singlet. IR spectra was recorded
with a JASCO-FT/IR-4100 Spectrometer with a NaCl cell. Elemental
analyses was determined with Perkin–Elmer Instruments series II
νmax = 3034, 2978, 2934, 1735, 1706, 1474, 1456, 1369, 1283, 1234,
˜
1225 cm–1. HRMS (ESI): m/z calcd. for C13H16O3 [M + Na]+ 243.0997;
found 243.0998.
2-(4-Fluorophenyl)-2-oxoethyl Pivalate (14c): Colorless crystalline
solid. Yield: (0.96 g, 66 %). Rf = 0.32 (hexanes/EtOAc, 9.5:0.5). M.p.
46–48 °C. 1H NMR (400 MHz, CDCl3): δ = 7.97–7.92 (m, 2 H, ArH),
7.19–7.14 (m, 2 H, ArH), 5.27 (s, 2 H, COCH2), 1.30 [s, 9 H,
(CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 191.1 (CO, ketone),
178.0 (CO, ester), 166.1 (d, J = 254.3 Hz, ArCF), 130.9 (d, J = 3.1 Hz,
ArC), 130.5 (d, J = 9.4 Hz, ArCH), 116.1 (d, J = 21.9 Hz, ArCH), 65.7
CHNS/O analyzer. HRMS were recorded with a MICRO-QTOF mass (COCH2), 38.9 [C(CH3)3], 27.2 [(CH3)3C] ppm. IR (CHCl3): νmax = 2977,
˜
spectrometer by using the ESI technique at 10 eV.
2934, 1736, 1706, 1600, 1513, 1479, 1418, 1368, 1286, 1149, 971,
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631 cm–1. HRMS (ESI): m/z calcd. for C13H15O3F [M + Na]+ 261.0903; 2-(Benzo[d][1,3]dioxol-5-yl)-2-hydroxy-2-(p-tolyl)ethyl Pivalate
found 261.0896.
(15b): Colorless solid. Yield: (0.87 g, 78 %). Rf = 0.28 (EtOAc/hexanes,
1:9). M.p. 84–86 °C. 1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 8.4 Hz,
2 H, ArH), 7.12 (d, J = 8.0 Hz, 2 H, ArH), 6.89 (d, J = 1.6 Hz, 1 H, ArH),
6.84 (dd, J = 8.0, 2.0 Hz, 1 H, ArH), 6.73 (d, J = 8 Hz, 1 H, ArH), 5.91
(s, 2 H, OCH2O), 4.58 (AB quartet, J = 11.6 Hz, 2 H, OCH2), 2.93 (br.
s, 1 H, OH), 2.32 (s, 3 H, ArCH3), 1.08 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δ = 178.3 (CO, ester), 147.7 (ArC), 146.9 (ArC),
140.7 (ArC), 137.9 (ArC), 137.3 (ArC), 129.0 (ArCH), 126.3 (ArCH),
119.8 (ArCH), 107.8 (ArCH), 107.6 (ArCH), 101.1 (OCH2O), 77.6 (C-
OH), 70.1 (CH2O), 38.9 [C(CH3)3], 27.1 [C(CH3)3], 21.1 (ArCH3) ppm. IR
2-(4-Methoxyphenyl)-2-oxoethyl Pivalate (14d):[17] Colorless
crystalline solid. Yield: (2.0 g, 82 %). Rf = 0.43 (hexanes/EtOAc, 9:1).
M.p. 44–46 °C. 1H NMR (500 MHz, CDCl3): δ = 7.90–7.87 (m, 2 H,
ArH), 6.95–6.92 (m, 2 H, ArH), 5.26 (s, 2 H, COCH2), 3.86 (s, 3 H,
ArOCH3), 1.30 [s, 9 H, (CH3)3C] ppm. 13C NMR (125 MHz, CDCl3): δ =
191.0 (CO, ketone), 178.2 (CO, ester), 164.0 (ArC), 130.1 (ArCH), 127.5
(ArC), 114.1 (ArCH), 65.7 (COCH2), 55.6 (ArOCH3), 38.9 [C(CH3)3], 27.3
[(CH3)3C] ppm. IR (CHCl3): νmax = 3033, 2974, 2936, 1733, 1694, 1602,
˜
1512, 1471, 1423, 1368 cm–1
.
(CHCl3): νmax = 3435, 2976, 2903, 1726, 1610, 1505, 14841459,
˜
1436 cm–1. HRMS (ESI): m/z calcd. for C21H24O5 [M + Na]+ 379.1521;
Preparation of Grignard Reagent and Synthesis of Aryl Ketones
(14e): A solution of azeotropically dried (toluene, 3 × 5 mL) 1-
bromo-3,4,5-trimethoxybenzene (1.83 g, 7.38 mmol) in anhydrous
THF (14 mL) was added to magnesium turnings (213 mg,
8.86 mmol, activated with iodine), followed by the addition of MeI
(catalytic, 0.1 mL) under nitrogen and the reaction mixture was kept
at 55 °C. Initiation of Grignard reagent was observed within 5–
10 min and, after initiation, the reaction mixture was allowed to stir
at room temp. After consumption of magnesium within 50–60 min,
the resulting off white solution was slowly added to a solution of
compound 11 (0.5 g, 2.46 mmol) in dry THF (4 mL) at –45 °C and the
resulting mixture was stirred for a further 4–5 h. After completion
of reaction, a saturated aqueous solution of NH4Cl was added cau-
tiously and the organic layer was separated. The aqueous layer was
extracted with EtOAc (3 × 5 mL). The combined organic layers were
dried with anhydrous Na2SO4, concentrated, and purified by silica
gel column chromatography (EtOAc/hexanes, 1:4) to afford aryl ket-
one 14e as a colorless crystalline solid 0.45 g (60 %). Rf = 0.5 (hex-
anes/EtOAc, 8:2). M.p. 82–84 °C. 1H NMR (400 MHz, CDCl3): δ = 7.15
(s, 2 H, ArH), 5.27 (s, 2 H, COCH2), 3.91 (s, 3 H, ArOCH3), 3.98 (s, 6 H,
2 × ArOCH3), 1.29 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz, CDCl3):
δ = 191.5 (CO, ketone), 178.1 (CO, ester), 153.4 (ArC), 143.3 (ArC),
129.6 (ArC), 105.4 (ArCH), 65.7 (COCH2), 61.1 (ArOCH3), 56.4
found 379.1506.
2-Hydroxy-2-(4-methoxyphenyl)-2-(p-tolyl)ethyl Pivalate (15c):
Colorless solid. Yield: (0.83 g, 81 %). Rf = 0.32 (EtOAc/hexanes, 1:9).
M.p. 58–60 °C. 1H NMR (400 MHz, CDCl3): δ = 7.30–7.25 (m, 4 H,
ArH), 7.11 (d, J = 8.0 Hz, 2 H, ArH), 6.84–6.81 (m, 2 H, ArH), 4.60 (s,
2 H, OCH2), 3.76 (3 H, ArOCH3), 2.96 (br. s, 1 H, OH), 2.31 (s, 3 H,
ArCH3), 1.07 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ =
178.3 (CO, ester), 158.9 (ArC), 140.9 (ArC), 137.1 (ArC), 136.0 (ArC),
128.9 (ArCH), 127.8 (ArCH), 126.4 (ArCH), 113.5 (ArCH), 77.4 (C-OH),
70.2 (CH2O), 55.3 (ArOCH3), 38.9 [C(CH3)3], 27.1 [C(CH3)3], 21.1
(ArCH3) ppm. IR (CHCl3): νmax = 3489, 2973, 2936, 2873, 1725, 1609,
˜
1584, 1511, 1479, 1461 cm–1. HRMS (ESI): m/z calcd. for C21H26O4
[M + Na]+ 365.1729; found 365.1709.
2-(3-Chlorophenyl)-2-hydroxy-2-(p-tolyl)ethyl Pivalate (15d):
Colorless solid. Yield: (1.29 g, 79 %). Rf = 0.36 (EtOAc/hexanes,
0.5:9.5). M.p. 70–72 °C. 1H NMR (400 MHz, CDCl3): δ = 7.45–7.44 (m,
1 H, ArH), 7.27–7.21 (m, 5 H, ArH), 7.16–7.12 (m, 2 H, ArH), 4.62 (s,
2 H, OCH2), 3.00 (s, 1 H, OH), 2.32 (s, 3 H, ArCH3), 1.08 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 178.4 (CO, ester),
145.9 (ArC), 140.0 (ArC), 137.7 (ArC), 134.3 (ArC), 129.5 (ArCH), 129.2
(ArCH), 127.7 (ArCH), 129.9 (ArCH), 126.3 (ArCH), 124.7 (ArCH), 77.5
(C-OH), 69.9 (CH2O), 39.0 [C(CH3)3], 27.1 [C(CH3)3], 21.6 (ArCH3) ppm.
(2 × ArOCH3), 38.9 [C(CH3)3], 27.3 [(CH3)3C] ppm. IR (CHCl3): νmax
=
˜
2972, 1734, 1698, 1586, 1505, 1461, 1417, 1368, 1328, 1284,
1140 cm–1. HRMS (ESI): m/z calcd. for C16H22O6 [M + H]+ 311.1495;
found 311.1491.
IR (CHCl3): νmax = 3489, 2975, 2933, 1725, 1595, 1573, 1512,
˜
1479 cm–1. HRMS (ESI): m/z calcd. for C20H23O3Cl [M + Na]+
369.1233; found 369.1258.
Procedure for Synthesis of Diaryl Alcohol (15a–15l), (15o–15q),
and (15s–15z): Grignard reagent was prepared from 4-bromo-
toluene (0.82 mL, 6.67 mmol) and magnesium (160 mg, 6.67 mmol,
activated with iodine) in anhydrous THF (7 mL) under an inert at-
mosphere at room temperature. Initiation of the Grignard reagent
was observed within 5–10 min and, after complete consumption of
magnesium within 50–60 min, the resulting solution was slowly
added to a solution of compound 14a (0.52 g, 2.23 mmol) in THF
(3 mL) at – 45 °C and the overall mixture was stirred for 4 h. After
completion of the reaction, a saturated aqueous solution of NH4Cl
was added cautiously at 0 °C, and the organic layer was separated.
The aqueous layer was further extracted with EtOAc (3 × 5 mL).
The combined organic layers were dried with anhydrous Na2SO4,
concentrated, and purified by silica gel column chromatography
(EtOAc/hexanes, 1:4) to afford alcohol 15a as colorless solid 0.63 g
2-Hydroxy-2-(thiophen-2-yl)-2-(p-tolyl)ethyl Pivalate (15e): Vis-
cous liquid. Yield: (0.25 g, 61 %). Rf = 0.46 (EtOAc/hexanes, 0.5:9.5).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.34 (m, 2 H, ArH), 7.25–7.23
(m, 1 H, ArH), 7.16–7.14 (m, 2 H, ArH), 6.97–6.92 (m, 1 H, ArH), 6.90
(dd, J = 3.2, 1.2 Hz, 1 H, ArH), 4.66 (d, J = 11.6 Hz, 1 H, OCHaHb),
4.58 (d, J = 11.6 Hz, 1 H, OCHaHb), 3.21 (br. s, 1 H, OH), 2.33 (s, 3 H,
ArCH3), 1.08 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ =
178.3 (CO, ester), 148.6 (ArC), 139.7 (ArC), 137.7 (ArC), 129.0 (ArCH),
126.7 (ArCH), 126.0 (ArCH), 125.5 (ArCH), 124.9 (ArCH), 76.7 (C-OH),
70.9 (CH2O), 38.9 [C(CH3)3], 27.1 [C(CH3)3], 21.1 (ArCH3) ppm. IR
(CHCl3): νmax = 3436, 2976, 2934, 2873, 1728, 1512, 1480, 1459,
˜
1399, 1367 cm–1. HRMS (ESI): m/z calcd. for C18H22O3S [M + Na]+
341.1187; found 341.1195.
2-Hydroxy-2,2-diphenylethyl Pivalate (15f): Colorless solid. Yield:
1
(85 %). Rf = 0.4 (hexanes/EtOAc, 9:1). M.p. 80–82 °C. 1H NMR (0.93 g, 86 %). Rf = 0.33 (hexanes/EtOAc, 9.5:0.5). M.p. 86–88 °C. H
(400 MHz, CDCl3): δ = 7.19 (d, J = 8.4 Hz, 4 H, ArH), 7.04 (d, J = 8 Hz,
4 H, ArH), 4.54 (s, 2 H, CH2O), 2.24 (s, 3 H, ArCH3), 1.00 [s, 9 H,
(CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 178.3 (CO, ester),
140.8 (ArC), 137.2 (ArC), 129.0 (ArCH), 126.4 (ArCH), 77.6 (C-OH), 70.1
(CH2O), 38.9 [C(CH3)3], 27.1 [(CH3)3C], 21.1 (ArCH3) ppm. IR (CHCl3):
NMR (400 MHz, CDCl3): δ = 7.42–7.39 (m, 4 H, ArH), 7.34–7.30 (m, 4
H, ArH), 7.28–7.24 (m, 2 H, ArH), 4.67 (s, 2 H, CH2O), 3.02 (br. s, 1 H,
OH), 1.06 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 178.4
(CO, ester), 143.5 (ArC), 128.3 (ArCH), 127.6 (ArCH), 126.5 (ArCH), 77.9
(C-OH), 70.1 (CH2O), 38.9 [C(CH3)3], 27.1 [(CH3)3C] ppm. IR (CHCl3):
νmax = 3034, 2978, 2934, 1735, 1706, 1474, 1456, 1369, 1283, 1234 νmax = 3035, 2979, 1728, 1486, 1454, 1282, 1227, 1151, 782, 768,
˜
˜
cm–1. HRMS (ESI): m/z calcd. for C21H26O3 [M + Na]+ 349.1780; found
759 cm–1. HRMS (ESI): m/z calcd. for C19H22O3 [M + K]+ 337.1206;
349.1801.
found 337.1209.
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2-(3,4-Dichlorophenyl)-2-hydroxy-2-phenylethyl Pivalate (15g): (ArC), 139.6 (ArC), 136.4 (ArC), 128.4 (d, J = 8.1 Hz, ArCH), 127.7
Colorless solid. Yield: (1.26 g, 86 %). Rf = 0.64 (hexanes/EtOAc, 8:2).
(ArCH), 116.3 (ArCH), 115.0 (d, J = 21.1 Hz, ArCH), 96.5 (OCHO), 96.4
M.p. 76–78 °C. H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 2.0 Hz, 1 (OCHO), 77.4 (C-OH), 70.2 (CH2O), 62.2 (CH2O), 38.9 [C(CH3)3], 30.4
H, ArH), 7.39–7.31 (m, 5 H, ArH), 7.30–7.26 (m, 1 H, ArH), 7.21 (dd, (CH2), 27.1 [(CH3)3C], 25.3 (CH2), 18.9 (CH2) ppm. IR (CHCl3): νmax
1
=
˜
J = 8.4, 2.4 Hz, 1 H, ArH), 4.65 (d, J = 11.6 Hz, 1 H, HaCHbO), 4.60 (d,
J = 11.6 Hz, 1 H, HbCHaO), 3.08 (s, 1 H, CH2OH), 1.08 [s, 9 H,
(CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 178.4 (CO, ester),
144.0 (ArC), 142.6 (ArC), 132.6 (ArC), 131.8 (ArC), 130.2 (ArCH), 128.9
(ArCH), 128.6 (ArCH), 128.1 (ArCH), 126.3 (ArCH), 126.1 (ArCH), 77.4
(C-OH), 69.7 (CH2O), 39.0 [C(CH3)3], 27.1 [(CH3)3C] ppm. IR (CHCl3):
3595, 3014, 2953, 2353, 1726, 1606, 1509, 1483, 1394, 1363, 1282,
1236, 1225 cm–1
.
2-[4-(Benzyloxy)phenyl]-2-(4-fluorophenyl)-2-hydroxyethyl
Pivalate (15n): Yellowish solid. Yield: (0.47 g, 66 %). Rf = 0.14
1
(EtOAc/hexanes, 0.5:9.5). M.p. 76–78 °C. H NMR (400 MHz, CDCl3):
δ = 7.42–7.31 (m, 7 H, ArH), 7.30–7.24 (m, 2 H, ArH), 7.02–6.97 (m,
2 H, ArH), 6.94–6.90 (m, 2 H, ArH), 5.03 (s, 2 H, OCH2Ph), 4.59 (s, 2
H, OCH2), 2.98 (br. s, 1 H, OH), 1.07 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δ = 178.3 (CO, ester), 162.1 (d, J = 245.0 Hz, ArCF),
νmax = 3594, 2975, 1728, 1473, 1380, 1282, 1148, 1033, 823, 759,
˜
746, 703 cm–1. C19H20Cl2O3 (367.27): calcd. C 62.14, H 5.49; found C
62.58, H 5.62.
2-Hydroxy-2-(4-methoxyphenyl)-2-phenylethyl Pivalate (15h): 158.3 (ArC), 139.6 (d, J = 3.0 Hz, ArC), 136.9 (ArC), 135.8 (ArC), 128.7
Colorless solid. Yield: (1.02 g, 80 %). Rf = 0.35 (hexanes/EtOAc, (ArCH), 128.4 (ArCH), 128.3 (ArCH), 128.1 (ArCH), 127.8 (ArCH), 127.5
9.5:0.5). M.p. 84–86 °C. 1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = (ArCH), 115.2 (ArCH), 114.9 (ArCH), 114.7 (ArCH), 77.4 (C-OH), 70.2
8.0 Hz, 2 H, ArH), 7.33–7.28 (m, 4 H, ArH), 7.25 (t, J = 6.8 Hz, 1 H,
ArH), 6.84 (d, J = 8.4 Hz, 2 H, ArH), 4.65 (d, J = 11.6 Hz, 1 H, HaCHbO),
4.61 (d, J = 11.6 Hz, 1 H, HbCHaO), 3.78 (s, 3 H, ArOCH3), 1.07 [s, 9
H, (CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 178.3 (CO, ester),
159.0 (ArC), 143.7 (ArC), 135.8 (ArC), 128.3 (ArCH), 127.8 (ArCH),
127.5 (ArCH), 126.5 (ArCH), 113.6 (ArCH), 77.6 (C-OH), 70.2 (CH2O),
(OCH2Ph), 70.1 (CH2O), 38.9 [C(CH3)3], 27.1 [C(CH3)3] ppm. IR (CHCl3):
νmax = 3467, 2975, 2936, 2873, 1725, 1606, 1509, 1479, 1458,
˜
1371 cm–1. HRMS (ESI): m/z calcd. for C26H27O4F [M + Na]+ 445.1791;
found 445.1792.
2-{3-[(tert-Butyldimethylsilyl)oxy]-4-methoxyphenyl}-2-
hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl Pivalate (15r): A solu-
tion of (5-bromo-2-methoxyphenoxy)-tert-butyldimethyl-silane
(0.8 g, 2.52 mmol) in anhydrous THF (4 mL) was added to magne-
sium turnings (60 mg, 2.52 mmol, activated with iodine) under
nitrogen and heated to reflux temperatures with an oil bath. Initia-
55.3 (ArOCH3), 38.9 [C(CH3)3], 27.1 [(CH3)3C] ppm. IR (CHCl3): νmax
=
˜
3593, 2974, 2935, 2907, 2873, 2839, 1725, 1609, 1513, 1474, 1457,
1398 cm–1. HRMS (ESI): m/z calcd. for C20H24O4 [M + Na]+ 351.1572;
found 351.1594.
2-(3,5-Difluorophenyl)-2-hydroxy-2-phenylethyl Pivalate (15i): tion of the Grignard reagent was observed within 5–10 min, and
Colorless solid. Yield: (0.48 g, 79 %). Rf = 0.58 (hexanes/EtOAc, 8:2).
consumption of magnesium took place within 60–70 min. The re-
sulting solution was cooled to room temp. and then slowly added
M.p. 86–88 °C. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H,
ArH), 6.99–6.94 (m, 2 H, ArH), 6.73–6.67 (m, 1 H, ArH), 4.67 (d, J = to a solution of compound 14e (0.25 g, 0.84 mmol) in dry THF
11.6 Hz, 1 H, HaCHbO), 4.59 (d, J = 11.6 Hz, 1 H, HbCHaO), 3.12 (s, 1 (4 mL) at –45 °C and stirring was continued for 4–5 h. After comple-
H, OH), 1.08 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ =
178.4 (CO, ester), 163.0 (d, J = 247.0 Hz, ArCF), 162.9 (d, J = 246.8 Hz,
tion of reaction, saturated aqueous NH4Cl solution was added cau-
tiously and organic layer was separated. The aqueous layer was
ArCF), 147.8 (ArC), 142.4 (ArC), 128.6 (ArCH), 128.2 (ArCH), 126.2 extracted with EtOAc (3 × 5 mL). The combined organic layers were
(ArCH), 109.7 (dd, J = 19.1, 7.3 Hz, ArCH), 103.0 (t, J = 25.3 Hz, ArCH), dried with anhydrous Na2SO4, concentrated, and purified by silica
77.5 (C-OH), 69.7 (CH2O), 38.9 [C(CH3)3], 27.1 [(CH3)3C] ppm. IR gel column chromatography (EtOAc/hexanes, 1:4) to afford com-
(CHCl3): νmax = 3593, 3033, 2977, 1728, 1624, 1599, 1454, 1397, pound 15r as a colorless viscous liquid 0.34 g (75 %). Rf = 0.18
˜
1369, 1283, 1234, 1156, 1035 cm–1. HRMS (ESI): m/z calcd. for (hexanes/EtOAc, 8:2). 1H NMR (400 MHz, CDCl3): δ = 6.93 (dd, J =
C
19H20O3F2 [M + Na]+ 357.1278; found 357.1269.
8.4, 2.4 Hz, 1 H, ArH), 6.86 (d, J = 2.4 Hz, 1 H, ArH), 6.79 (d, J =
8.4 Hz, 1 H, ArH), 6.60 (s, 2 H, ArH), 4.66 (d, J = 11.6 Hz, 1 H, HaCHbO),
4.52 (d, J = 11.6 Hz, 1 H, HbCHaO), 3.81 (s, 3 H, ArOCH3), 3.78 (s, 9
H, 3 × ArOCH3), 2.90 (s, 1 H, OH), 1.07 [s, 9 H, (CH3)3C], 0.94 [s, 9 H,
(CH3)3C], 0.10 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 178.3 (CO, ester), 152.9 (ArC), 144.7 (ArC),
139.3 (ArC), 137.2 (ArC), 135.8 (ArC), 119.8 (ArCH), 119.6 (ArCH),
111.6 (ArCH), 103.9 (ArCH), 77.8 (C-OH), 70.0 (CH2O), 60.9 (ArOCH3),
56.1 (2 × ArOCH3), 55.5 (ArOCH3), 38.9 [C(CH3)3], 27.1 [(CH3)3C], 25.8
[(CH3)3C], 18.5 [C(CH3)3], –4.4 (SiCH3), –4.5 (SiCH3) ppm. IR (CHCl3):
Synthesis of Diaryl Alcohol (15m–15n): A solution of 4-tetra-
hydropyranyloxy bromobenzene (1.9 g, 7.37 mmol) in anhydrous
THF (7 mL) was added to magnesium turnings (214 mg, 8.11 mmol,
activated with iodine), and followed by the addition of MeI (cata-
lytic, 0.1 mL) under nitrogen. The reaction mixture was heated to
55 °C. Initiation of Grignard reagent was observed within 10–20 min
and, after initiation, the reaction mixture was allowed to stir at room
temp. until consumption of magnesium was complete (1–2 h). Fi-
nally, the resulting off white solution was slowly added to a solution
of compound 14c (0.59 g, 2.46 mmol) in dry THF (4 mL) at –45 °C
and the resulting solution was stirred for 4–5 h. After completion
of the reaction, a saturated aqueous NH4Cl solution was added cau-
tiously and the organic layer was separated. The aqueous layer was
νmax = 3592, 3008, 2960, 2936, 2858, 1725, 1590, 1509, 1461, 1417,
˜
1366, 1328 cm–1. HRMS (ESI): m/z calcd. for C29H44OSi [M + H]+
437.3240; found 437.3227.
Synthesis of α,α-diarylethylene Glycol (10) by aqueous KOH So-
extracted with EtOAc (3 × 5 mL). The combined organic layers were lution: To a solution of alcohol 15a (0.65 g, 2.0 mmol) in ethanol
dried with anhydrous Na2SO4, concentrated, and purified by silica (10 mL), aqueous KOH solution (0.46 g, 6.0 mmol, 4 mL, ≈ 10 %)
gel column chromatography (EtOAc/hexanes, 1:4) to afford aryl ket- was added at room temp. and stirred for 2–3 h. After complete
one 15m as a colorless solid 0.83 g (85 %). Rf = 0.28 (hexanes/ consumption of the starting material, the solvent was evaporated
EtOAc, 8:2). H NMR (400 MHz, CDCl3): δ = 7.38–7.34 (m, 2 H, ArH), under reduced pressure to remove the majority of the solvent and
1
7.27 (d, J = 8.8 Hz, 2 H, ArH), 7.02–6.98 (m, 4 H, ArH), 5.39 (s, 1 H,
OCHO), 4.63–4.57 (m, 2 H, CH2O), 3.91–3.85 (m, 1 H), 3.61–3.56 (m,
1 H), 2.93 (s, 1 H, OH), 2.04–1.94 (m, 1 H), 1.86–1.82 (m, 2 H, CH2),
then aqueous layer was extracted with CH2Cl2 (2 × 10 mL). Later,
all organic layers were collected, dried with anhydrous Na2SO4, con-
centrated under reduced pressure, and the crude compound was
1.69–1.59 (m, 3 H), 1.07 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz, purified with silica gel column chromatography (EtOAc/hexanes,
CDCl3): δ = 178.3 (CO, ester), 162.1 (d, J = 244.6 Hz, ArCF), 156.6
1:4) to furnish compound 10a as a colorless solid 0.43 g (89 %). Rf =
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0.21 (hexanes/EtOAc, 9:1). M.p. 110–112 °C. 1H NMR (500 MHz,
the organic layer was separated, dried with Na2SO4, concentrated,
CDCl3): δ = 7.32–7.29 (m, 4 H, ArH), 7.14 (d, J = 8 Hz, 4 H, ArH), 4.12 and purified with silica gel column chromatography (EtOAc/hex-
(s, 2 H, CH2OH), 3.09 (br. s, 1 H, OH), 2.32 (s, 6 H, ArCH3), 1.87 (br. s, anes, 3:7) to furnish compound 10u as a colorless solid 112 mg
1 H, OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 141.1 (ArC), 137.2 (85 %). Rf = 0.2 (hexanes/EtOAc, 6:4). M.p. 110–102 °C. 1H NMR
(ArC), 129.2 (ArCH), 126.4 (ArCH), 78.5 (C-OH), 69.6 (CH2O), 21.1 (400 MHz, CDCl3): δ = 7.32 (d, J = 8.4 Hz, 2 H, ArH), 7.15 (d, J =
(ArCH3) ppm. IR (CHCl3): νmax = 3596, 2926, 2401, 2352, 1605, 1516, 8.0 Hz, 2 H, ArH), 6.66 (s, 2 H, ArH), 4.10 (s, 2 H, CH2OH), 3.81–3.80
˜
1479, 1428, 1216, 1080, 1046, 929, 790 cm–1. HRMS (ESI): m/z calcd. (two singlets, 9 H, ArOCH3), 3.20 (br. s, 1 H, -OH), 2.33 (s, 3 H, ArCH3),
for C16H18O2 [M + H]+ 243.1385; found 243.1383.
2.01 (br. s, 1 H, -OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.2
(2 × ArC), 140.8 (ArC), 139.7 (ArC), 137.4 (ArC), 129.2 (ArCH), 126.3
(ArCH), 104.0 (ArCH), 78.6 (C-OH), 69.6 (CH2OH), 60.9 (ArOCH3), 56.3
1-(Benzo[d][1,3]dioxol-5-yl)-1-(p-tolyl)ethane-1,2-diol (10b):
Gummy solid. Yield: (0.68 g, 87 %). Rf = 0.17 (EtOAc/hexanes, 2:8).
1H NMR (400 MHz, CDCl3): δ = 7.29–7.27 (m, 2 H, ArH), 7.13 (d, J =
8.0 Hz, 2 H, ArH), 6.90 (d, J = 1.6 Hz, 1 H, ArH), 6.85 (dd, J = 8.0,
2.0 Hz, 1 H, ArH), 6.74 (d, J = 8.0 Hz, 1 H, ArH), 5.91 (s, 2 H, OCH2O),
4.04 (AB quartet, J = 11.2 Hz, 2 H, CH2OH), 2.32 (s, 3 H, ArCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 147.8 (ArC), 146.8 (ArC), 141.0 (ArC),
138.2 (ArC), 137.3 (ArCH), 129.2 (ArCH), 126.3 (ArCH), 119.7 (ArCH),
108.0 (ArCH), 107.6 (ArCH), 101.1 (OCH2O), 78.4 (C-OH), 69.5
(2 × ArOCH3), 21.1 (ArCH3) ppm. IR (CHCl3): νmax = 3585, 1507, 1459,
˜
1231, 1199, 1132, 1042, 854, 818, 768 cm–1. HRMS (ESI): m/z calcd.
for C18H22O5 [M + Na]+ 341.1365; found 341.1350.
1-{3-[(tert-Butyldimethylsilyl)oxy]-4-methoxyphenyl}-1-(3,4,5-
trimethoxyphenyl)ethane-1,2-diol (10r): Colorless viscous liquid.
Yield: (0.33 g, 73 %). Rf = 0.28 (hexanes/EtOAc, 6:4). 1H NMR
(400 MHz, [D6]DMSO): δ = 6.98 (dd, J = 8.4, 2.0 Hz, 1 H, ArH), 6.86
(d, J = 8.4 Hz, 1 H, ArH), 6.83 (d, J = 2.0 Hz, 1 H, ArH), 6.68 (s, 2 H,
ArH), 5.34 (s, 1 H, OH), 4.76 (t, J = 6 Hz, 1 H, OH), 3.89 (dd, J = 11.2,
5.6 Hz, 1 H, HaCHbO), 3.83 (dd, J = 11.2, 5.6 Hz, 1 H, HbCHaO), 3.70
(s, 3 H, ArOCH3), 3.69 (s, 6 H, 2 × ArOCH3), 3.61 (s, 3 H, ArOCH3), 0.90
[s, (CH3)3CSi], 0.06 (s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 152.0 (ArC), 148.9 (ArC), 143.2 (ArC), 142.0
(ArC), 138.6 (ArC), 135.9 (ArC), 119.7 (ArCH), 119.3 (ArCH), 111.5
(ArCH), 104.1 (ArCH), 77.2 (C-OH), 68.3 (CH2O), 59.8 (ArOCH3), 55.7
(2 × ArOCH3), 55.3 (ArOCH3), 25.5 [(CH3)3C], 18.1 [C(CH3)3], –4.65
(CH2OH), 21.1 (ArCH3) ppm. IR (CHCl3): νmax = 3426, 2974, 2928,
˜
2889, 1610, 1505, 1485, 1460, 1436 cm–1. HRMS (ESI): m/z calcd. for
C16H16O3 [M + K]+ 295.0737; found 295.0756.
1-(4-Methoxyphenyl)-1-(p-tolyl)ethane-1,2-diol (10c): Colorless
solid. Yield: (0.58 g, 75 %). Rf = 0.41 (EtOAc/hexanes, 2:8). M.p. 94–
1
96 °C. H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m, 4 H, ArH), 7.15–
7.12 (m, 2 H, ArH), 6.87–6.83 (m, 2 H, ArH), 4.09 (s, 2 H, CH2OH), 3.77
(s, 3 H, ArOCH3), 3.11 (br. s, 1 H, OH), 2.32 (s, 3 H, ArCH3), 1.97 (br.
s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.9 (ArC), 141.2
(ArC), 137.2 (ArC), 136.2 (ArC), 129.2 (ArCH), 127.8 (ArCH), 126.4
(ArCH), 113.8 (ArCH), 78.3 (C-OH), 69.7 (CH2OH), 55.3 (ArOCH3), 21.1
(SiCH3), –4.69 (SiCH3) ppm. IR (CHCl3): νmax = 3585, 2360, 2340, 1591,
˜
1509, 1460, 1417, 1217, 1130, 840, 786 cm–1. HRMS (ESI): m/z calcd.
for C24H36O7Si [M + Na]+ 487.2128; found 487.2132.
(ArCH3) ppm. IR (CHCl3): νmax = 3423, 2956, 2936, 2838, 1610, 1583,
˜
1511, 1462, 1442 cm–1. HRMS (ESI): m/z calcd. for C16H18O3 [M +
1-(4-Methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)ethane-1,2-
diol (10s): Colorless gummy solid. Yield: (0.22 g, 88 %). Rf = 0.13
(hexanes/EtOAc, 6:4). 1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J =
8.4 Hz, 2 H, ArH), 6.87 (d, J = 6.8 Hz, 2 H, ArH), 6.65 (s, 2 H, ArH),
4.09 (s, 1 H, CH2OH), 3.82 (s, 3 H, ArOCH3), 3.80 (s, 6 H, 2 × ArOCH3),
3.79 (s, 3 H, ArOCH3), 3.25 (br. s, 1 H, -OH), 2.10 (br. s, 1 H, -OH) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.9 (ArC), 153.0 (2 × ArC), 139.7
(ArC), 137.1 (ArC), 135.7 (ArC), 127.6 (ArCH), 113.7 (ArCH), 103.8
(ArCH), 78.4 (C-OH), 69.5 (CH2OH), 60.7 (ArOCH3), 56.1 (2 × ArOCH3),
Na]+ 281.1154; found 281.1159.
1-(3-Chlorophenyl)-1-(p-tolyl)ethane-1,2-diol (10d): Colorless
solid. Yield: (0.17 g, 72 %). Rf = 0.26 (EtOAc/hexanes, 2:8). M.p. 92–
1
94 °C. H NMR (400 MHz, CDCl3): δ = 7.45–7.44 (m, 1 H, ArH), 7.29–
7.26 (m, 3 H, ArH), 7.25–7.21 (m, 2 H, ArH), 7.15 (d, J = 8.0 Hz, 2 H,
ArH), 4.12 (d, J = 11.2 Hz, 1 H, CHaHbOH), 4.04 (d, J = 11.6 Hz, 1 H,
CHaHbOH), 3.25 (br. s, 1 H, OH), 2.32 (s, 3 H, ArCH3), 2.04 (br. s, 1 H,
OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.3 (ArC), 140.3 (ArC),
137.6 (ArC), 134.5 (ArC), 129.7 (ArCH), 129.4 (ArCH), 127.6 (ArCH),
126.8 (ArCH), 126.3 (ArCH), 124.6 (ArCH), 78.2 (C-OH), 69.3 (CH2OH),
21.1 (ArCH3) ppm. HRMS (ESI): m/z calcd. for C15H15O2Cl [M + K]+
301.0398; found 301.0390.
55.2 (ArOCH3) ppm. IR (CHCl3): νmax = 3493, 3016, 2939, 2838, 1590,
˜
1509, 1460, 1415, 1332, 1247, 1177, 1129 cm–1. HRMS (ESI): m/z
calcd. for C18H22O6 [M + Na]+ 357.1314; found 357.1309.
1-Phenyl-1-(3,4,5-trimethoxyphenyl)ethane-1,2-diol (10t): Col-
orless viscous liquid. Yield: (0.19 g, 94 %). Rf = 0.16 (hexanes/EtOAc,
6:4). 1H NMR (500 MHz, CDCl3): δ = 7.45–7.43 (m, 2 H, ArH), 7.36–
7.33 (m, 2 H, ArH), 7.29–7.26 (m, 1 H, ArH), 6.66 (s, 2 H, ArH), 4.13
(s, 2 H, CH2OH), 3.81 (s, 3 H, ArOCH3), 3.80 (s, 6 H, 2 × ArOCH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 153.1 (2 × ArC), 143.7 (ArC), 139.6
(ArC), 137.2 (ArC), 128.5 (ArCH), 127.7 (ArCH), 126.4 (ArCH), 103.9
(ArCH), 78.7 (C-OH), 69.5 (CH2 OH), 60.9 (ArOCH3 ), 56.2
1-(Thiophen-2-yl)-1-(p-tolyl)ethane-1,2-diol (10e): Brownish
semi solid. Yield: (0.13 g, 70 %). Rf = 0.26 (EtOAc/hexanes, 2:8). 1H
NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.0 Hz, 2 H, ArH), 7.26 (d,
J = 5.6 Hz, 1 H, ArH), 7.17 (d, J = 7.6 Hz, 2 H, ArH), 6.97–6.92 (m, 2
H, ArH), 4.12 (d, J = 11.6 Hz, 1 H, CHaHbOH), 4.04 (d, J = 11.6 Hz, 1
H, CHaHbOH), 3.40 (br. s, 1 H, OH), 2.34 (s, 3 H, ArCH3), 2.03 (br. s, 1
H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.0 (ArC), 140.1 (ArC),
137.4 (ArC), 129.1 (ArCH), 126.7 (ArCH), 125.9 (ArCH), 125.4 (ArCH),
124.8 (ArCH), 77.4 (C-OH), 70.3 (CH2OH), 21.1 (ArCH3) ppm. IR
(2 × ArOCH3) ppm. IR (CHCl3): νmax = 3516, 2940, 2837, 1650, 1586,
˜
1504, 1459, 1415, 1335, 1233, 1223, 1182 cm–1. HRMS (ESI): m/z
calcd. for C17H20O5 [M + Na]+ 327.1208; found 327.1211.
(CHCl3): νmax = 3454, 2975, 1631, 1607, 1513, 1479, 1415 cm–1
.
˜
Synthesis of 1,1-Diarylethenes (13): A solution of α,α-diarylethyl-
ene glycol 10a (100 mg, 0.413 mmol) in dry THF/toluene (3 mL)
was heated to reflux temperatures with 1,1-thiocarbonyldiimidazole
(81 mg, 0.454 mmol) under nitrogen for 4–5 h. After complete con-
sumption of the starting material, the product was purified by flash
chromatography (EtOAc/hexanes, 1:9) to afford yellow semi-solid
intermediate compound 16a, which was immediately used in the
next step and heated to reflux with P(OMe)3 (3.0 mL) under nitro-
gen for 20–24 h. Finally, the reaction was quenched by stirring with
HRMS (ESI): m/z calcd. for C13H14O2S [M + Na]+ 257.0612; found
257.0618.
Synthesis of α,α-Diarylethylene Glycol 10r–z by LiBH4 Solution:
To a solution of alcohol 15u (168 mg, 0.42 mmol) in dry CH2Cl2
(5 mL), a solution of LiBH4 (2
M in THF, 0.63 mL, 1.25 mmol) was
added at 0 °C and stirred for 4 h. After complete consumption of
the starting material, the reaction was quenched by slow addition
of a saturated aqueous solution of NH4Cl and cooled with an ice
bath. Then the reaction mixture was diluted with CH2Cl2 (5 mL) and
an2
M aqueous solution of NaOH (2 M , 4 mL) for 30 min, and then
Eur. J. Org. Chem. 2017, 3594–3605
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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CH2Cl2 (15 mL) was added and the mixture was stirred for a further
30 min. The organic layer was separated, dried with anhydrous
Na2SO4, concentrated, and purified by silica gel column chromatog-
raphy (hexanes) to furnish compound 13a as a colorless liquid
48 mg (73 %). Yellowish liquid. Rf = 0.83 (hexanes/EtOAc, 9.5:0.5).
1H NMR (500 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 4 H, ArH), 7.12 (d,
J = 8.0 Hz, 4 H, ArH), 5.37 (s, 2 H, =CH2), 2.35 (s, 6 H, ArCH3) ppm.
J = 1.2 Hz, 1 H, HaCHb=), 5.30 (d, J = 1.2 Hz, 1 H, HbCHa=), 3.90 (s,
3 H, ArOCH3), 3.87 (s, 3 H, ArOCH3), 3.81 (s, 6 H, 2 × ArOCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 152.9 (2 × C), 149.6 (C), 146.5 (C),
145.3 (C), 137.9 (C), 137.5 (C), 134.8 (C), 120.3 (ArCH), 114.6 (ArCH),
112.9 (=CH2), 110.3 (ArCH), 105.9 (ArCH), 61.02 (ArOCH3), 56.2
(2 × ArOCH3), 56.1 (ArOCH3) ppm. IR (CHCl3): νmax = 3545, 3017,
˜
2838, 2841, 1730, 1582, 1508, 1460, 1413, 1348, 1282, 1253 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 149.8 (C), 138.9 (C), 137.5 (C), 128.9 HRMS (ESI): m/z calcd. for C18H20O5 [M + H]+ 317.1389 found;
(ArCH), 128.3 (ArCH), 113.1 (=CH2), 21.3 (ArCH3) ppm. IR (CHCl3):
317.1382.
νmax = 1651, 1605, 1306, 1286, 929, 790, 782 cm–1. HRMS (ESI): m/z
˜
Procedure for Synthesis of Compound 8s–8z: A solution of com-
pound 10y (163 mg, 0.44 mmol) in dry THF (6 mL) was heated
to reflux temperatures with 1,1-thiocarbonyldiimidazole (195 mg,
1.09 mmol) under nitrogen for 5–6 h. After complete consumption
of the starting material, the solvent was evaporated and the prod-
uct was purified by flash chromatography (EtOAc/hexanes, 3:7),
calcd. for C16H16 [M + H]+ 209.1330; found 209.1332.
Ethene-1,1-Diyldibenzene (13f):[18] Colorless viscous liquid. Yield:
(125 mg, 88 %, over two steps). Rf = 0.25 (hexanes/EtOAc, 9:1). 1H
NMR (500 MHz, CDCl3): δ = 7.39–7.33 (m, 10 H, ArH), 5.49 (s, 2 H, =
CH2) ppm. 13C NMR (125 MHz, CDCl3): δ = 150.1 (C), 141.6 (C), 128.4
(ArCH), 128.2 (ArCH), 127.8 (ArCH), 114.4 (=CH2) ppm. IR (CHCl3): which was immediately heated to reflux temperatures with P(OMe)3
νmax = 3006, 1225, 1206, 1201, 790, 778, 765, 743, 735 cm–1
(4.0 mL) under nitrogen for 20–24 h. Finally, the reaction was
quenched by stirring with an aqueous solution of NaOH (2 , 4 mL)
.
˜
M
1,2-Dichloro-4-(1-phenylvinyl)benzene (13g): Light yellow vis-
cous liquid. Yield: (0.118 g, 79 %, over two steps). Rf = 0.35 (hexanes/
EtOAc, 9:1). H NMR (400 MHz, CDCl3): δ = 7.44 (d, J = 2.0 Hz, 1 H,
ArH), 7.40 (d, J = 8.4 Hz, 1 H, ArH), 7.37–7.34 (m, 3 H, ArH), 7.32–
7.29 (m, 2 H, ArH), 7.16 (dd, J = 8.4, 2.4 Hz, 1 H, ArH), 5.50 (s, 1 H,
HaCHb=), 5.47 (s, 1 H, HbCHa=) ppm. 13C NMR (100 MHz, CDCl3): δ =
148.1 (C), 141.6 (C), 140.5 (C), 132.4 (C), 131.8 (C), 130.2 (ArCH), 130.1
(ArCH), 128.5 (ArCH), 128.3 (ArCH), 128.2 (ArCH), 127.7 (ArCH), 115.7
for 30 min, and then CH2Cl2 (15 mL) was added and the mixture
was stirred for a further 30 min. The organic layer was separated,
dried with anhydrous Na2SO4, concentrated, and purified by silica
gel column chromatography (EtOAc/hexanes, 0.5:9.5) to furnish col-
orless semi solid compound 8y, 0.13 g (87 %, over two steps). Rf =
0.76 (hexane/EtOAc, 8:2). 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J =
8.4 Hz, 2 H, ArH), 7.46 (d, J = 8.0 Hz, 2 H, ArH), 6.51 (s, 2 H, ArH),
5.51 (s, 1 H, HaCHb=), 5.49 (s, 1 H, HbCHa=), 3.88 (s, 3 H, ArOCH3),
3.81 (s, 6 H, 2 × ArOCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.2
(2 × C), 149.1 (C), 144.9 (C), 138.3 (C), 136.5 (C), 128.6 (ArCH), 125.3
(q, J = 3.6 Hz, ArCH), 115.7 (=CH2), 105.7 (ArCH), 61.0 (ArOCH3), 56.3
1
(=CH2) ppm. IR (CHCl3): νmax = 3088, 3063, 3034, 3007, 1662, 1605,
˜
1552, 1469, 1379, 1318, 1283, 1228, 1225, 1205 cm–1. HRMS (ESI):
m/z calcd. for C14H10Cl2 [M + K]+ 286.9797; found 286.9785.
1-Methoxy-4-(1-phenylvinyl)benzene (13h): Gummy solid. Yield:
(55 mg, 45 %, over two steps). Rf = 0.83 (hexanes/EtOAc, 9.5:0.5). 1H
NMR (400 MHz, CDCl3): δ = 7.33–7.31 (m, 5 H, ArH), 7.28–7.24 (m, 2
H, ArH), 6.86 (d, J = 8.0 Hz, 2 H, ArH), 5.39 (s, 1 H, HaCHb=), 5.35 (s,
1 H, HbCHa=), 3.82 (s, 3 H, ArOCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.4 (C), 149.6 (C), 141.9 (C), 134.1 (C), 129.5 (ArCH), 128.4
(ArCH), 128.2 (ArCH), 127.7 (ArCH), 113.6 (ArCH), 113.0 (=CH2), 55.4
(2 × ArOCH3) ppm. IR (CHCl3): νmax = 3007, 2360, 1581, 1504, 1461,
˜
1412, 1348, 1325, 1267, 1238, 1172 cm–1. HRMS (ESI): m/z calcd. for
C18H17O3F3 [M + H]+ 339.1208; found 339.1222.
1,2,3-Trimethoxy-5-[1-(4-methoxyphenyl)vinyl]benzene (8s):[3b]
Colorless liquid. Yield: (78 mg, 52 %, over two steps). Rf = 0.76 (hex-
1
anes/EtOAc, 6:4). H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 8.4 Hz,
2 H, ArH), 6.87 (d, J = 8.8 Hz, 2 H, ArH), 6.55 (s, 2 H, ArH), 5.37 (s, 1
H, HaCHb=), 5.31 (s, 1 H, HbCHa=), 3.87 (s, 3 H, ArOCH3), 3.83 (s, 3 H,
ArOCH3), 3.81 (s, 6 H, 2 × ArOCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.5 (C), 152.9 (2 × C), 149.6 (C), 137.6 (C), 133.8 (C), 129.5
(ArCH), 113.6 (ArCH), 112.6 (=CH2), 105.8 (ArCH), 61.0 (ArOCH3), 56.2
(ArOCH3) ppm. IR (CHCl3): νmax = 1608, 1511, 1249, 1216, 1178,
˜
1033, 839, 784, 781, 768, 751 cm–1. HRMS (ESI): m/z calcd. for
C15H14O [M + H]+ 211.1123; found 211.1127.
Synthesis of Isocombretastatin A-4 (8a): A solution of compound
10r (205 mg, 0.44 mmol) in dry THF (5 mL) was heated to reflux
temperatures with 1,1-thiocarbonyldiimidazole (160 mg, 0.88 mmol)
under nitrogen for 5–6 h. After complete consumption of the start-
ing material, the product was purified by flash chromatography
(EtOAc/hexanes, 3:7), which was immediately used in the next step
and heated to reflux temperatures with P(OMe)3 (3.0 mL) under
nitrogen for 20–24 h. Finally, the reaction was quenched by stirring
(2 × ArOCH3), 55.4 (ArOCH3) ppm. IR (CHCl3): νmax = 3008, 2963,
˜
1719, 1648, 1600, 1583, 1509, 1463, 1433, 1414, 1335, 1245,
1171 cm–1. HRMS (ESI): m/z calcd. for C18H20O4 [M + H]+ 301.1440;
found 301.1454.
1,2,3-Trimethoxy-5-(1-phenylvinyl)benzene (8t): Colorless vis-
cous liquid. Yield: (118 mg, 80 %, over two steps). Rf = 0.57 (hex-
1
anes/EtOAc, 9:1). H NMR (500 MHz, CDCl3): δ = 7.38–7.31 (m, 5 H,
with an aqueous solution of NaOH (2 M, 4 mL) for 30 min, and then
ArH), 6.55 (s, 2 H, ArH), 5.44 (s, 1 H, HaCHb=), 5.42 (s, 1 H, HbCHa=),
3.87 (s, 3 H, ArOCH3), 3.81 (s, 6 H, 2 × ArOCH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 152.9 (2 × C), 150.1 (C), 141.2 (C), 137.8 (C),
137.3 (C), 128.3 (ArCH), 128.2 (ArCH), 127.9 (ArCH), 114.0 (=CH2),
105.7 (ArCH), 61.0 (ArOCH3), 56.2 (2 × ArOCH3) ppm. IR (CHCl3):
CH2Cl2 (15 mL) was added and the mixture was stirred for a further
30 min. The organic layer was separated, dried with anhydrous
Na2SO4 and concentrated. Then, the crude compound (0.27 g,
0.67 mmol) was dissolved in dry THF (4 mL) and treated with tetra-
n-butylammonium fluoride (TBAF, 1
M in THF, 0.7 mL, 0.72 mmol)
νmax = 3013, 2940, 2836, 1726, 1653, 1584, 1502, 1457, 1412, 1340,
˜
at 0 °C. After completion of the reaction (30 min), water (3 mL) was
added to the reaction mixture and the majority of the solvent was
evaporated under reduced pressure. The aqueous layer was ex-
tracted with EtOAc (3 × 3 mL). All organic layers were collectively
dried with Na2SO4, concentrated, and purified by silica gel column
chromatography (EtOAc/hexanes, 3:7) to furnish yellowish semi-
1234, 1187, 1129 cm–1. HRMS (ESI): m/z calcd. for C17H18O3 [M +
H]+ 271.1334; found 271.1346.
1,2,3-Trimethoxy-5-[1-(p-tolyl)vinyl]benzene (8u): Colorless liq-
uid. Yield: (58 mg, 67 %, over two steps). Rf = 0.66 (hexanes/EtOAc,
8:2). 1H NMR (400 MHz, CDCl3): δ = 7.26–7.24 (m, 2 H, ArH), 7.14 (d,
solid compound 8a[4] 59 mg (43 %, over three steps). Rf = 0.16 J = 8.0 Hz, 2 H, ArH), 6.55 (s, 2 H, ArH), 5.40 (d, J = 0.8 Hz, 1 H,
(hexanes/EtOAc, 8:2). 1H NMR (400 MHz, CDCl3): δ = 6.97 (d, J =
2.0 Hz, 1 H, ArH), 6.84 (dd, J = 8.4, 2.0 Hz, 1 H, ArH), 6.80 (d, J =
HaCHb=), 5.36 (d, J = 0.8 Hz, 1 H, HbCHa=), 3.87 (s, 3 H, ArOCH3),
3.80 (s, 6 H, 2 × ArOCH3), 2.37 (s, 3 H, ArCH3) ppm. 13C NMR
8.4 Hz, 1 H, ArH), 6.55 (s, 2 H, ArH), 5.62 (br. s, 1 H, ArOH), 5.37 (d, (100 MHz, CDCl3): δ = 153.0 (2 × C), 150.0 (C), 138.4 (C), 138.0 (C),
Eur. J. Org. Chem. 2017, 3594–3605
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3603 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
137.7 (C), 137.5 (C), 129.0 (ArCH), 128.2 (ArCH), 113.3 (=CH2), 105.9
(ArCH), 61.0 (ArOCH3), 56.3 (2 × ArOCH3), 21.3 (ArCH3) ppm. IR
Scheme and the ESI-MS facility under the FIST program. The
Council of Scientific & Industrial Research (CSIR) New Delhi is
acknowledged for funding of the project in 2015. P. K. T. is
thankful to the CSIR/University Grants Commission (UGC) (New
Delhi) for a Senior Research Fellowship (SRF).
(CHCl3): νmax = 3043, 1652, 1647, 1605, 1584, 1504, 1463, 1414,
˜
1334, 1236, 1189, 1180 cm–1. HRMS (ESI): m/z calcd. for C18H20O3
[M + H]+ 285.1491; found 285.1482.
5-[1-(4-Fluorophenyl)vinyl]-1,2,3-trimethoxybenzene (8v): Col-
orless viscous liquid. Yield: (90 mg, 53 %, over two steps). Rf = 0.35
(hexanes/EtOAc, 8:2). 1H NMR (400 MHz, CDCl3): δ = 7.35–7.31 (m,
2 H, ArH), 7.05–7.00 (m, 2 H, ArH), 6.52 (s, 2 H, ArH), 5.39 (s, 1 H,
HaCHb=), 5.38 (s, 1 H, HbCHa=), 3.87 (s, 3 H, ArOCH3), 3.81 (s, 6 H,
2 × ArOCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.7 (d, J =
245.6 Hz, ArCF), 153.0 (2 × C), 149.2 (C), 138.1 (C), 137.4 (C), 137.1
(C), 130.0 (d, J = 8.0 Hz, ArCH), 115.1 (d, J = 21.3 Hz, ArCH), 113.9 (=
CH2), 105.7 (ArCH), 61.0 (ArOCH3), 56.2 (2 × ArOCH3) ppm. IR (CHCl3):
Keywords: C–C coupling · Synthetic methods · Weinreb
amide · Isocombretastatin A-4 · Grignard reaction · C2 building
block
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ν
= 3007, 2940, 2837, 1656, 1589, 1506, 1459, 1412, 1339, 1228,
˜
max
1199 cm–1. HRMS (ESI): m/z calcd. for C17H17O3F [M + H]+ 289.1240;
found 289.1247.
5-[1-(2,4-Difluorophenyl)vinyl]-1,2,3-trimethoxybenzene (8w):
Colorless viscous liquid. Yield: (72 mg, 87 %, over two steps). Rf =
0.5 (hexanes/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ = 7.28–7.22
(m, 1 H, ArH), 6.90–6.81 (m, 2 H, ArH), 6.49 (s, 2 H, ArH), 5.69 (s, 1
H, HaCHb=), 5.37 (s, 1 H, HbCHa=), 3.86 (s, 3 H, ArOCH3), 3.80 (s, 6 H,
2 × ArOCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.6 (d, J =
247.6 Hz, ArCF), 160.4 (d, J = 250.0 Hz, ArCF), 153.1 (2 × C), 143.3
(C), 138.2 (C), 136.3 (C), 132.3 (dd, J = 9.3, 5.0 Hz, ArCH), 125.3 (d,
J = 14.1 Hz, ArCH), 117.0 (=CH2), 111.2 (dd, J = 20.8, 3.7 Hz, ArCH),
104.3 (t, J = 25.5 Hz, ArCH), 104.4 (ArCH), 61.0 (ArOCH3), 56.2
(2 × ArOCH3) ppm. IR (CHCl3): νmax = 3016, 1613, 1585, 1504, 1462,
˜
1416, 1344, 1269, 1238, 1183, 1131 cm–1. HRMS (ESI): m/z calcd. for
C17H16O3F2 + H+ [M + H]+ 307.1146; found 307.1144.
5-[1-(3,5-Difluorophenyl)vinyl]-1,2,3-trimethoxybenzene (8x):
Colorless semi solid. Yield: (74 mg, 77 %, over two steps). Rf = 0.66
(hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ = 6.88 (d, J =
7.2 Hz, 2 H, ArH), 6.76 (t, J = 8.8 Hz, 1 H, ArH), 6.50 (s, 2 H, ArH),
5.47 (s, 2 H, Ha CHb=), 3.88 (s, 3 H, ArOCH3 ), 3.82 (s, 6 H,
2 × ArOCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.0 (d, J =
246.7 Hz, ArCF), 162.9 (d, J = 246.4 Hz, ArCF), 153.2 (2 × ArC), 148.4
(ArC), 144.7 (t, J = 9.1 Hz, C), 138.4 (C), 136.0 (C), 115.7 (=CH2), 111.2
(dd, J = 18.5, 6.7 Hz, ArCH), 105.8 (ArCH), 103.3 (t, J = 25.1 Hz, ArCH),
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Harikrishna, R. Mukkamala, B. Hinkelmann, F. Sasse, I. S. Aidhen, Eur. J.
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bramaniam, I. S. Aidhen, Tetrahedron 2010, 66, 3723–3729.
61.0 (ArOCH3), 56.3 (2 × ArOCH3) ppm. IR (CHCl3): νmax = 2938, 2369,
˜
1622, 1588, 1505, 1461, 1436, 1415, 1354, 1337 cm–1. HRMS (ESI):
m/z calcd. for C17H16O3F2 [M + H]+ 307.1146; found 307.1137.
5-{1-[3,5-Bis(trifluoromethyl)phenyl]vinyl}-1,2,3-trimethoxy-
benzene (8z): Colorless crystalline solid. Yield: (0.15 g, 82 %, over
two steps). Rf = 0.6 (hexanes/EtOAc, 9:1). M.p. 92–94 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.84 (s, 1 H, ArH), 7.81 (s, 2 H, ArH), 6.48 (s, 2
H, ArH), 5.61 (s, 1 H, HaCHb=), 5.55 (s, 1 H, HbCHa=), 3.90 (s, 3 H,
ArOCH3), 3.81 (s, 6 H, 2 × ArOCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 153.4 (2 × C), 147.8 (C), 143.5 (C), 138.7 (C), 135.4 (C), 131.7 (q,
J = 33.5 Hz, ArC), 128.4 (ArCH), 123.4 (q, J = 271.3 Hz, ArCF3), 121.7
(q, J = 3.8 Hz, ArCH), 116.8 (=CH2), 105.6 (ArCH), 61.0 (ArOCH3), 56.3
(2 × ArOCH3) ppm. IR (CHCl3): νmax = 1582, 1505, 1461, 1413, 1385,
˜
[11] For reviews on the applications of Weinreb amides, see: a) S. Balasubra-
maniam, I. S. Aidhen, Synthesis 2008, 3707–3738; b) J. Singh, N. Satya-
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H. M. R. Hoffmann, J. Prakt. Chem. 1997, 339, 517–524.
1333, 1280, 1224, 1181, 1138 cm–1. HRMS (ESI): m/z calcd. for
C19H16O3F6 [M + H]+ 407.1082; found 407.1067.
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Acknowledgments
We thank Department of Science and Technology (DST) New
Delhi for funding towards the 400 MHz NMR spectrometer to
the Department of Chemistry, IIT-Madras under the IRPHA
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: April 4, 2017
Eur. J. Org. Chem. 2017, 3594–3605
www.eurjoc.org
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim