Modular Synthesis of Arylacetic Acid Esters, Thioesters, and Amides from Aryl Ethers via Rh(II)-Catalyzed Diazo Arylation

Article abstract of DOI:10.1021/acs.joc.6b01426

One-pot formation of arylacetic acid esters, thioesters, and amides via Rh(II)-catalyzed arylation of a Meldrum's acid-derived diazo reagent with electron-rich arenes is described. The methodology was used to efficiently synthesize an anticancer compound.

Full text of DOI:10.1021/acs.joc.6b01426

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Article
Modular synthesis of arylacetic acid esters, thioesters and
amides from aryl ethers via Rh(II)-catalyzed diazo arylation
Daniel Best, Mickael Jean, and Pierre van de Weghe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01426 • Publication Date (Web): 28 Jul 2016
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Modular synthesis of arylacetic acid esters, thioesters and amides from aryl
ethers via Rh(II)-catalyzed diazo arylation
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Daniel Best,* Mickaël Jean, Pierre van de Weghe
Université de Rennes 1, UMR CNRS 6226, Institut des Sciences Chimiques de Rennes, Equipe
PNSCM, UFR des Sciences, Biologiques et Pharmaceutiques, 2 Avenue du Prof Leon Bernard,
Rennes Fꢀ35043 Cedex, France.
daniel.best@univꢀrennes1.fr
ABSTRACT: Oneꢀpot formation of arylacetic acid esters, thioesters and amides via Rh(II)ꢀ
catalyzed arylation of a Meldrum’s acidꢀderived diazo reagent with electronꢀrich arenes is
described. The methodology was used to efficiently synthesize an anticancer compound.
INTRODUCTION
Diaryl ethers are privileged structures in medicinal chemistry,1 and there are many examples of
biologically active aryloxyphenylacetic acid derivatives, which contain this motif (e.g. Figure
1).2 Several methods have been established for the synthesis of diaryl ethers,3ꢀ7 but only SNAr
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reactions, which are limited to electronꢀpoor arenes, have shown general efficiency in delivering
aryloxyphenylacetic acid derivatives directly;2c,8 phenylacetic acid derivatives generally perform
poorly in Cuꢀcatalyzed phenolic Oꢀarylation reactions9,10 unless aryliodonium reagents are
used.7c,11 αꢀArylation of acetic acid derivatives is wellꢀdeveloped,12 but requires reactive
handles13,14 or orthoꢀdirectors15,16 on the arene and is thus rarely applied to diaryl ether systems.17
Direct functionalization of commercially or readily available diaryl ethers would provide a
convenient alternative route to medicinallyꢀrelevant aryloxyphenylacetic acid derivatives. A few
methods for direct formation of ethyl arylacetates via arylation of ethyl diazoacetate are known,18
but these methods usually also form cycloheptatriene (Büchner addition) side products (Scheme
1A). A strategy that avoids this complication and provides a wider range of arylacetic acid
derivatives would be advantageous for library synthesis and drug discovery. paraꢀSelective
functionalization of arenes with diazo compounds is wellꢀdeveloped for αꢀaryldiazoesters,19 but
relatively uncommon for diazoꢀ1,3ꢀdicarbonyls.20 Rh(II)ꢀcatalyzed functionalization of arenes
(including diaryl ethers) was recently demonstrated with diazobarbiturates.21 A similar insertion
reaction of the benchꢀstable, crystalline diazo reagent 1 with arenes 2 would give products 3,
which are highly susceptible to hydrolysis/alcoholysis through ketene formation via
cyclorevertive extrusion of acetone (Scheme 1B).22 We postulated that products 3 could serve as
latent ketenes23 for the decarboxylative construction of arylacetic acid derivatives 5.16,24 Herein
we describe a oneꢀpot procedure for the modular construction of arylacetic esters, thioesters and
amides via Rh2(esp)2ꢀcatalyzed (0.1ꢀ0.25 mol%) arylation of diazo 1 with electronꢀrich arenes 2
and its application to the concise synthesis of an anticancer compound.
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Figure 1. Biologically active aryloxyphenylacetic acid derivatives.
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CO2H
H
N
O
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O
O
Anticancer [Ref 2a]
Me
O
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OH
Me
HN
Me
O
O
O
O
O
O
HN
OMe
O
S
O
OH
Anti-allergenic
Cl
Anticancer
[Ref 2b]
O
[Ref 2c]
HO
Cl
Scheme 1. Synthesis of arylacetic acid derivatives via Rh(II) catalysis.
RESULTS AND DISCUSSION
In a preliminary experiment, 1 was stirred with Rh2(esp)2 in toluene at RT overnight, resulting in
>95% conversion and formation of intermediate 3a in 65% NMR yield (Scheme 2).25 No other
byproducts were detected by H or 13C{1H} NMR, suggesting competitive decomposition of
1
diazo 1 into volatile products, which has been documented under photolytic conditions.26 More
nucleophilic anisole underwent a similar reaction in >95% NMR yield. Heating 3a with EtOH
resulted in quantitative conversion to halfꢀester 6a, which rapidly and quantitatively
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decarboxylated on addition of NEt3 to provide inseparable esters 7a and 7aa in a 9:1 ratio
(Scheme 2), isolated in 60% yield in a repeat experiment (Table 1).
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Scheme 2. Functionalization of toluene monitored by 1H NMR.25
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Table 1. Synthesis of ethyl arylacetates 7.a
a Reactions were conducted on 1.0 mmol scale (ca 1 M with respect to 1), DCE coꢀsolvent was sometimes added in step 2, see
experimental section. Regioisomeric ratios (rr) were determined by H NMR analysis of the crude reaction mixtures and were
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b
>19:1 unless otherwise specified in parentheses; rr remained unchanged after purification. Reaction conducted in neat toluene
(9.5 equiv.). c From TMSOPh. d Reaction conducted using 5.0 equiv. diphenyl ether. e Reaction conducted on 0.50 mmol scale.
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4ꢀChlorobenzotrifluoride (CBTF) was identified as an affordable solvent that did not react with
in situꢀgenerated Rhꢀcarbenoids, allowing engagement of solid or expensive arenes in this
transformation.28 Inclusion of Na2SO4 and a dry atmosphere suppressed hydrolysis of 3, which
was occasionally observed if atmospheric humidity was high or when undried reagents were
used. Reaction of 1 with anisole (2 equiv) in CBTF followed by ethanolysis and decarboxylation
provided 7b in 86% yield as a single isomer (Table 1). In the case of toluene, reducing the molar
excess of the arene from 9.5 equiv to 2 equiv reduced the yield of 7a and 7aa from 60% to 38%
(9:1 rr), and less electronꢀrich fluorobenzene or bromobenzene were not synthetically useful
(<10%). While reaction of phenol produced a complex mixture from which 7c was isolated in
only 28% yield, similar treatment of (trimethylsilyl)oxybenzene gave the free phenol product 7c
in good yield (71%). As observed previously,21 catalyst poisoning resulted in no conversion of
N,Nꢀdimethylaniline or decomposition of 1 in the arylation step. Introduction of a Boc group to
the aniline system nullified this poisoning effect and led to the formation of 7d in low yield
(40%). The observation of similar yields of 7a from toluene and 7d from NꢀBocꢀaniline
correlates with the similar Hammett σP constants of alkyl and carbamate substituents.29 Diaryl
ethers reacted well; various electronꢀdonating and ꢀwithdrawing groups were tolerated at the 4ꢀ
position of the nonꢀreacting benzene ring (products 7e-h), and regioselectivity was >19:1 in all
cases. In the case of 7f, 5.0 equiv diphenyl ether was used to avoid reaction at both phenyl rings.
Electronꢀwithdrawing substituents were similarly tolerated at the 3ꢀposition of the nonꢀreacting
ring (7i-j), but substitution at the 2ꢀposition led to moderate regioselectivity, with the minor
isomer arising from reaction at the more substituted ring (7k-l).30 Note that transesterification of
the methyl ester in 7l was not observed. 2ꢀ And 3ꢀphenoxyanisole both produced inseparable
mixtures of 3 regioisomers in moderate yield with poor selectivity,31 indicating substantial
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reactivity of electronꢀrich disubstituted benzene rings. When 2ꢀ(4ꢀfluorophenoxy)anisole was
engaged in the reaction sequence, 7m was formed in 83% yield (5:1 rr) with preferential reaction
para to the methoxy group. 3ꢀ(4ꢀFluorophenoxy)anisole led primarily to 7n (5:2 rr) via reaction
at the least hindered electronꢀrich centre. Electron rich naphthalenes were also competent
reaction partners; 1ꢀmethoxynaphthalene reacted exclusively at the 4ꢀposition (7o) whereas 2ꢀ
methoxynaphthalene gave 7p in good yield but with low regioselectivity.30
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Table 2. Synthesis of esters, acetanilides and thioesters 8.a
a Reactions were conducted on 0.50 mmol scale (ca 1 M with respect to 1), DCE coꢀsolvent was sometimes added in step 2, see
1
experimental section. Regioisomeric ratios (rr) were determined by H NMR analysis of the crude reaction mixtures and were
b
>19:1 in all cases. 5 equiv. diphenyl ether and 1.5 equiv. cholesterol were used. c Decarboxylation (step 3) was performed at
100 °C for 30 min.
Next, we examined the scope of the alcoholysis step using various aryl ethers (some of which
differ from those used in Table 1). Benzyl and allyl alcohols led to esters 8a-b in high yields
(note preservation of the ethyl ester in 8a) (Table2). tertꢀAmyl alcohol (8c) and cholesterol (8e)
both reacted efficiently despite their steric bulk, which may be explained by the formation and
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interception of unhindered ketene intermediates 4. Nucleophilic trapping with phenol led to
phenyl ester 8d in good yield. The scope of the reaction was further extended by replacing the
alcohol with anilines or thiols under otherwise similar conditions. Primary, secondary and
sterically hindered acetanilides 8f-h formed efficiently; the third stage of the oneꢀpot sequence
was carried out at 100 °C to compensate for the slower rate of decarboxylation in these cases.
Thioesters from an aliphatic thiol (8i) and thiophenol (8j) could also be accessed, which is of
synthetic interest given the straightforward conversion of thioesters to aryl ketones (Liebeskindꢀ
Srogl coupling)32 or aldehydes (Fukuyama reduction).33 It should also be noted that allyl esters,
aryl esters, thioesters and secondary amides have limited compatibility with existing phenol Oꢀ
arylation and carbonyl αꢀarylation methods.
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Deprotonation of 3 interfered with its direct aminolysis by aliphatic amines, but we addressed
this problem by using 1Hꢀbenzotriazole (BtH) as a synthetic auxiliary.34 Following arylation of
1, introduction of BtH followed by the amine coupling partner of choice led cleanly to the
corresponding amide (Table 3). Secondary (9a, 9c-d), tertiary (9b, 9e) and bulky (9d) amides
were readily synthesized; Morpholine amide 9e and Weinreb amide 9f have wellꢀestablished
synthetic utility as aldehyde or ketone precursors. Note that aminolysis of the ethyl ester in 9c-d
was not observed.
Table 3. Synthesis of arylacetamides 9.a
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a Reactions were conducted on 0.50 mmol scale (ca 1 M with respect to 1). Regioisomeric ratios (rr) were >19:1 in all cases. b
equiv. diphenyl ether was used. NEt3 was also added in step 3. DMF was used as a coꢀsolvent in step 3. N,Oꢀ
dimethylhydroxylamine hydrochloride was used in step 3.
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d
e
Finally, we applied our methodology to the synthesis of known cytotoxic anticancer agent 1335
(LC50 = 48 nM vs L929 murine fibrosarcoma cells)2a via diaryl ether 11 (prepared by alkylation
of 4ꢀphenoxyphenol 10, Scheme 3). Diazo 1 was arylated with ether 11 (2 mmol scale) in the
presence of 0.1 mol% Rh2(esp2), followed by aminolysis with ethyl 2ꢀaminobenzoate and
decarboxylation in the same pot to give product 12 in 87% yield. Alkaline hydrolysis of ethyl
ester 12 provided cytotoxic agent 13 in an overall yield of 70% from 10. Compound 13 was
previously prepared from 4ꢀ(benzyloxy)phenol via Ullman coupling in 5% yield over 6 steps.2a
Scheme 3. Synthesis of cytotoxic anticancer agent 13.
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In conclusion, we have developed a oneꢀpot, modular synthesis of arylacetic acid derivatives
involving Rh(II)ꢀcatalyzed arylation of diazo reagent 1 with nonꢀprefunctionalized, aryl ethers,
followed by nucleophilic lysis and decarboxylation. The procedure utilizes a low loading of a
commercially available catalyst (down to 0.1 mol%) and exhibits high functional group tolerance
with respect to the lysing nucleophile. Esters, thioesters and amides (several of which have
limited compatibility with existing arylation methods) are easily prepared. This method is
particularly well suited to the functionalization of simple diaryl ethers and can streamline access
to products of pharmaceutical value that are otherwise laborious to prepare.
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EXPERIMENTAL SECTION
General information
Commercially available reagents and solvents were used as received. All reactions were
performed under an Ar or N2 atmosphere. Pet. ether refers to 40–60 °C petroleum ether. Thin
layer chromatography (TLC) was performed on TLC silica gel 60 F254 aluminium plates.
Compounds were visualized by exposure to UV light or by dipping the plates into potassium
permanganate or phosphomolybdic acid solution followed by heating. Flash column
chromatography was carried out using silica gel (particle size 40–63 µm) with step gradient
elution as indicated. Melting points were recorded on a Kofler bench. Infraꢀred (IR) spectra were
recorded on the neat compound using an instrument with a UATR single reflection diamond,
only the characteristic peaks are reported. NMR spectra were acquired on 300 MHz or 500 MHz
spectrometers and were referenced to the residual protonated solvent (1H NMR, 7.26 ppm for
CDCl3, 7.16 ppm for C6D6), the solvent itself (13C{1H} NMR, 77.00 ppm for CDCl3, 128.06 for
C6D6), or CFCl3 as an external standard at 0.00 ppm (19F{1H} NMR). All chemical shifts are
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reported in parts per million (ppm). Abbreviations used in the description of resonances are: s
(singlet), d (doublet), t (triplet), q (quartet), sept (septet), a (apparent), br (broad), m (multiplet).
Coupling constants (J) are quoted to the nearest 0.1 Hz. Assignments in 13C{1H} NMR were
made on the basis of JMOD and HSQC spectra. Highꢀresolution mass (HRMS) spectra were
recorded on QꢀTOF or TOFꢀQ instruments using electrospray ionization (ESI) techniques.
Optical rotation (10ꢀ1·deg·cm2·gꢀ1) was measured on a polarimeter with a path length of 10 cm,
concentration (c) is quoted in 10ꢀ2·g·cmꢀ3.
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NMR-monitored synthesis of 7a and 7aa
A mixture of diazo 1 (85 mg, 0.50 mmol) and Rh2(esp)2 (1.0 mg, 1.3 µmol) was stirred in
toluene (0.50 mL, 4.7 mmol) at RT for 18 h. The volatiles were removed in vacuo at <30 °C and
1,3,5ꢀtrimethoxybenzene (16.0 mg, 0.0952 mmol) was added. The mixture was completely
dissolved in CDCl3, and an aliquot was withdrawn for NMR analysis. The remaining bulk
solution was concentrated in vacuo and resuspended in toluene (0.50 mL). EtOH (60 µL, 1.0
mmol) was added and the reaction mixture was heated to 80 °C for 2 h and cooled to RT. An
1
aliquot of the homogeneous reaction mixture was withdrawn, concentrated and analysed by H
NMR. To the remaining bulk solution was added NEt3 (70 µL, 0.50 mmol) and the reaction was
heated at 80 °C for 15 min, concentrated and analyzed by 1H NMR. The crude 1H NMR spectra
(see Supporting Information) indicated that the arylation step proceeded in 65% yield, and the
subsequent alcoholysis and decarboxylation steps were quantitative.
Synthesis of starting materials 1 and 2
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5-Diazo-2,2-dimethyl-1,3-dioxane-4,6-dione 136
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To a solution of Meldrum’s acid (7.20 g, 50.0 mmol) and pꢀacetamidobenzenesulfonyl azide
(12.0 g, 50.0 mmol) in anhydrous MeCN (200 mL) at 0 °C was added NEt3 (7.0 mL, 50 mmol).
The reaction mixture was stirred at RT for 2 h, diluted with Et2O (200 mL), filtered and
concentrated in vacuo. The residue was resuspended in 1:1 CH2Cl2/pet. ether (100 mL), stirred
for 10 min at RT, filtered and concentrated in vacuo. Purification by flash column
chromatography (5→40% EtOAc/pet. ether) provided the diazo 1 as a white crystalline solid
(6.95 g, 82%). NMR data were in accordance with the literature.36 1H NMR (300 MHz, CDCl3) δ
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1.73 (6H, s); C{1H} NMR (75 MHz, CDCl3, C=N2 not resolved) δ 158.2 (2 × C), 106.9 (C),
26.6 (2 × CH3).
General Procedure A37
A mixture of CuI, N,Nꢀdimethylglycine, phenol (7.5 mmol), aryl halide (5.0 mmol) and Cs2CO3
(3.26 g, 10.0 mmol) in anhydrous 1,4ꢀdioxane (10 mL) was stirred at 90 °C under Ar for 18 h.
The reaction mixture was cooled to RT, poured into 1 M NaOH(aq) (50 mL) and stirred with pet.
ether (50 mL) for 5 min. The aqueous layer was discarded and the organic was washed with
water (50 mL) and brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo.
Purification by flash column chromatography (Et2O/pet. ether) provided the pure diaryl ether.
4-Phenoxyanisole 2a38
The title compound was prepared according to General Procedure A using 4ꢀmethoxyphenol
(930 mg, 7.50 mmol), iodobenzene (0.56 mL, 5.0 mmol), CuI (50 mg, 0.26 mmol) and N,Nꢀ
dimethylglycine (80 mg, 0.78 mmol). Chromatographic purification (2→8% Et2O/pet. ether)
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provided the title ether (827 mg, 83%) as a colourless oil. NMR data were in accordance with the
literature.38 1H NMR (300 MHz, CDCl3) δ 7.36–7.27 (2H, m, ArH), 7.09–7.02 (1H, m, ArH),
7.02–6.93 (4H, m, ArH), 6.93–6.86 (2H, m, ArH), 3.82 (3H, s, OCH3); 13C{1H} NMR (75 MHz,
CDCl3) δ 158.5 (C), 155.9 (C), 150.1 (C), 129.6 (2 × CH), 122.4 (CH), 120.8 (2 × CH), 117.5 (2
× CH), 114.8 (2 × CH), 55.6 (CH3).
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4-Phenoxytoluene 2b38
The title compound was prepared according to General Procedure A using phenol (705 mg, 7.50
mmol), 4ꢀiodotoluene (1.09 g, 5.00 mmol), CuI (50 mg, 0.26 mmol) and N,Nꢀdimethylglycine
(80 mg, 0.78 mmol). Chromatographic purification (1→4% Et2O/pet. ether) provided the title
ether (385 mg, 42%) as a pale yellow oil. NMR data were in accordance with the literature.38 1H
NMR (300 MHz, CDCl3) δ 7.38–7.30 (2H, m, ArH), 7.20–7.13 (2H, m, ArH), 7.12–7.06 (1H, m,
13
ArH), 7.04–6.98 (2H, m, ArH), 6.98–6.92 (2H, m, ArH), 2.37 (3H, s, ArCH3); C{1H} NMR
(75 MHz, CDCl3) δ 157.8 (C), 154.7 (C), 132.9 (C), 130.2 (2 × CH), 129.6 (2 × CH), 122.8
(CH), 119.1 (2 × CH), 118.3 (2 × CH), 20.7 (CH3).
1-Fluoro-4-phenoxybenzene 2c38
The title compound was prepared according to General Procedure A using 4ꢀfluorophenol (840
mg, 7.50 mmol), iodobenzene (0.56 mL, 5.0 mmol), CuI (50 mg, 0.26 mmol) and N,Nꢀ
dimethylglycine (80 mg, 0.78 mmol). Chromatographic purification (1→4% Et2O/pet. ether)
provided the title ether (777 mg, 83%) as a colourless oil. NMR data were in accordance with the
literature.38 1H NMR (300 MHz, CDCl3) δ 7.39–7.30 (2H, m, ArH), 7.15–7.07 (1H, m, ArH),
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7.09–6.96 (6H, m, ArH); C{1H} NMR (75 MHz, CDCl3) δ 158.8 (d, J = 241.6 Hz, C), 157.7
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(C), 152.8 (d, J = 2.5 Hz, C), 129.8 (2 × CH), 123.1 (CH), 120.5 (d, J = 8.3 Hz, 2 × CH), 118.2
(2 × CH), 116.3 (d, J = 23.3 Hz, 2 × CH).
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1-Chloro-3-phenoxybenzene 2d38
The title compound was prepared according to General Procedure A using phenol (705 mg, 7.50
mmol), 1ꢀbromoꢀ2ꢀfluorobenzene (0.55 mL, 5.0 mmol), CuI (200 mg, 1.05 mmol) and N,Nꢀ
dimethylglycine (320 mg, 3.11 mmol). Chromatographic purification (1→4% Et2O/pet. ether)
provided the title ether (654 mg, 64%) as a colourless oil. NMR data were in accordance with the
literature.38 1H NMR (300 MHz, CDCl3) δ 7.42–7.33 (2H, m, ArH), 7.25 (1H, t, J = 8.1, ArH),
7.20–7.12 (1H, m, ArH), 7.10–6.98 (4H, m, ArH), 6.93–6.87 (1H, m, ArH); C{1H} NMR (75
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MHz, CDCl3) δ 158.3 (C), 156.3 (C), 135.0 (C), 130.5 (CH), 129.9 (2 × CH), 124.0 (CH), 123.2
(CH), 119.4 (2 × CH), 118.8 (CH), 116.7 (CH).
1-Fluoro-2-phenoxybenzene 2e39
The title compound was prepared according to General Procedure A using 4ꢀmethoxyphenol
(930 mg, 7.50 mmol), iodobenzene (0.56 mL, 5.0 mmol), CuI (50 mg, 0.26 mmol) and N,Nꢀ
dimethylglycine (80 mg, 0.78 mmol). Chromatographic purification (2→8% Et2O/pet. ether)
provided the title ether (199 mg, 21%) as a colourless oil. NMR data were in accordance with the
literature.39 1H NMR (300 MHz, CDCl3) δ 7.39–7.29 (2H, m, ArH), 7.25–7.04 (5H, m, ArH),
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7.04–6.96 (2H, m, ArH); C{1H} NMR (75 MHz, CDCl3) δ 157.4 (C), 154.4 (d, J = 248.7 Hz,
C), 143.8 (d, J = 11.4 Hz, C), 129.7 (2 × CH), 124.74 (d, J = 6.9 Hz, CH), 124.64 (d, J = 3.9 Hz,
CH), 123.1 (CH), 121.9 (d, J = 1.2 Hz, CH), 117.3 (2 × CH), 117.1 (d, J = 18.2 Hz, CH).
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2-(4-Fluorophenoxy)anisole 2f
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The title compound was prepared according to General Procedure A using 2ꢀmethoxyphenol
(930 mg, 7.50 mmol), 1ꢀfluoroꢀ4ꢀiodobenzene (0.58 mL, 5.0 mmol), CuI (200 mg, 1.05 mmol)
and N,Nꢀdimethylglycine (320 mg, 3.11 mmol). Chromatographic purification (2→8% Et2O/pet.
ether) provided the title ether (395 mg, 36%) as a pale yellow oil. Rf = 0.55 (10% Et2O/pet. ether,
1H NMR (300 MHz, CDCl3) δ 7.12 (1H, ddd, J = 8.2, 5.9, 3.1 Hz, ArH), 7.04–6.87 (7H, m,
ArH), 3.85 (3H, s, OCH3); 13C{1H} NMR (75 MHz, CDCl3) δ 158.3 (d, J = 240.4 Hz, C), 153.7
(d, J = 2.4 Hz, C), 151.2 (C), 145.5 (C), 124.7 (CH), 121.1 (CH), 120.4 (CH), 118.66 (d, J = 8.2
Hz, 2 × CH), 116.0 (d, J = 23.3 Hz, 2 × CH); 112.8 (CH), 55.9 (CH3); 19F{1H} NMR (282 MHz,
CDCl3) δ ꢀ121.54; HRMS (ESI +ve) exact mass calculated for C13H11O2FNa+ [M+Na]+:
241.0635, found: 241.0635.
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3-(4-Fluorophenoxy)anisole 2g40
The title compound was prepared according to General Procedure A using 3ꢀmethoxyphenol
(930 mg, 7.50 mmol), 1ꢀfluoroꢀ4ꢀiodobenzene (0.58 mL, 5.0 mmol), CuI (200 mg, 1.05 mmol)
and N,Nꢀdimethylglycine (320 mg, 3.11 mmol). Chromatographic purification (1→4% Et2O/pet.
ether) provided the title ether (496 mg, 46%) as a pale yellow oil. NMR data was in accordance
with the literature.40 1H NMR (300 MHz, CDCl3) δ 7.25–7.18 (1H, m, ArH), 7.08–6.95 (4H, m,
ArH), 6.64 (1H, ddd, J = 8.3, 2.3, 1.0 Hz, ArH), 6.57–6.51 (2H, m, ArH), 3.78 (3H, s, OCH3);
13C{1H} NMR (75 MHz, CDCl3) δ 161.0 (C), 158.93 (C), 158.89 (d, J = 241.8 Hz, C), 152.6 (d,
J = 2.6 Hz, C), 130.2 (CH), 120.7 (d, J = 8.3 Hz, 2 × CH), 116.26 (d, J = 23.3 Hz, 2 × CH),
110.3 (CH), 108.7 (CH), 104.3 (CH), 55.3 (CH3).
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General procedure B
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Phenoxybenzoic acid (1.07 g, 5.0 mmol) was dissolved in EtOH/AcCl (9:1, 10 mL) and heated at
reflux. The reaction mixture was cooled to RT, diluted with pet. ether (50 mL) and washed with
NaHCO3(aq) (3 × 50 mL) and brine (25 mL). The organic fraction was dried over MgSO4,
concentrated in vacuo and used without further purification.
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Ethyl 3-phenoxybenzoate 2h41
Ester 2h was obtained from 3ꢀphenoxybenzoic acid as a colourless oil (1.19 g, 98%) according to
General Procedure B, the reaction time was 2 h. NMR data were in accordance with the
literature.41 1H NMR (300 MHz, CDCl3) δ 7.79 (1H, ddd, J = 7.7, 1.5, 1.1 Hz, ArH), 7.68 (1H,
dd, J = 2.3, 1.7 Hz, ArH), 7.40 (1H, t, J = 7.9 Hz, ArH), 7.39–7.31 (2H, m, ArH), 7.20 (1H, ddd,
J = 8.2, 2.6, 1.1 Hz, ArH), 7.17–7.10 (1H, m, ArH), 7.05–6.98 (2H, m, ArH), 4.36 (2H, q, J =
7.1 Hz, OCH2CH3), 1.38 (3H, t, J = 7.1 Hz, OCH2CH3); 13C{1H} NMR (75 MHz, CDCl3) δ
166.0 (C), 157.3 (C), 156.8 (C), 132.3 (C), 129.9 (2 × CH), 129.7 (CH), 124.3 (CH), 123.6 (CH),
123.2 (CH), 119.7 (CH), 119.0 (2 × CH), 61.1 (CH2), 14.3 (CH3).
Ethyl 4-phenoxybenzoate 2i38
Ester 2i was obtained from 4ꢀphenoxybenzoic acid as a colourless oil (1.16 g, 96%) according to
General Procedure B, the reaction time was 3 h. NMR data were in accordance with the
literature.38 1H NMR (300 MHz, CDCl3) δ 8.07–7.95 (2H, m, ArH), 7.44–7.34 (2H, m, ArH),
7.23–7.14 (1H, m, ArH), 7.10–7.03 (2H, m, ArH), 7.03–6.95 (2H, m, ArH), 4.36 (2H, q, J = 7.1
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Hz, OCH2CH3), 1.39 (3H, t, J = 7.1 Hz, OCH2CH3); C{1H} NMR (75 MHz, CDCl3) δ 166.1
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(C), 161.7 (C), 155.7 (C), 131.6 (2 × CH), 130.0 (2 × CH), 124.8 (C), 124.4 (CH), 120.0 (2 ×
CH), 117.3 (2 × CH), 60.8 (CH2), 14.3 (CH3).
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Synthesis of 7 and 8
General Procedure C
A mixture of diazo 1 (170 mg, 1.00 mmol), arene 2 (2.0 mmol), Rh2(esp)2 (1.9 mg, 2.5 µmol)
and Na2SO4 (200 mg) in 4ꢀchlorobenzotrifluoride (CBTF) was stirred at RT for 18 h. Ethanol
(0.12 mL, 2.0 mmol) and DCE (if indicated) were added and the reaction mixture was stirred at
80 °C for 2.5 h, then cooled to RT. NEt3 (0.15 mL, 1.1 mmol) was added and the reaction
mixture was stirred at 80 °C for 15 min (evolution of CO2 ceased). The reaction mixture was
loaded directly onto a silica column and purified by flash chromatography using the eluent
specified.
General Procedure D
A mixture of diazo 1 (85 mg, 0.50 mmol), arene 2 (1.0 mmol), Rh2(esp)2 (1.0 mg, 1.3 µmol) and
Na2SO4 (100 mg) in 4ꢀchlorobenzotrifluoride (CBTF) was stirred at RT for 18 h. Alcohol,
aniline or thiol (1.0 mmol) and DCE (if indicated) were added and the reaction mixture was
stirred at 80 °C for 2.5 h, then cooled to RT. NEt3 (0.07 mL, 0.5 mmol) was added and the
reaction mixture was stirred at 80 °C for 15 min (evolution of CO2 ceased). The reaction mixture
was loaded directly onto a silica column and purified by flash chromatography using the eluent
specified.
Ethyl 2-(4-methylphenyl)acetate 7a14d and ethyl 2-(2-methylphenyl)acetate 7aa14d
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Method A: A mixture of diazo 1 (170 mg, 1.00 mmol), Rh2(esp)2 (1.9 mg, 2.5 µmol) and Na2SO4
(200 mg) in toluene (1.0 mL, 9.5 mmol) was stirred at RT for 18 h. Ethanol (0.12 mL, 2.0 mmol)
was added and the reaction mixture was stirred at 80 °C for 2.5 h, then cooled to RT. NEt3 (0.15
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mL, 1.1 mmol) was added and the reaction mixture was stirred at 80 °C for 15 min (evolution of
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CO2 ceased). H NMR analysis of an aliquot of the crude mixture indicated a 9:1 mixture of
regioisomers. The reaction mixture was loaded directly onto a silica column and purified by flash
chromatography (2→10% Et2O/pet. ether) to provide the title compounds 7a and 7aa in a 9:1
ratio (106 mg, 60%) as a colourless oil. NMR data were in accordance with the literature (for
both isomers).14d
Method B: The title ester was prepared according to General Procedure C using toluene (0.21
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mL, 2.0 mmol) and CBTF (0.80 mL). H NMR analysis of the crude indicated a 9:1 mixture of
regioisomers. Chromatographic purification (2→10% Et2O/pet. ether) provided a mixture of the
title esters 7a and 7aa in a 9:1 ratio (67 mg, 38%) as a colourless oil. NMR data were in
accordance with the literature (for both isomers).14d 1H NMR (300 MHz, CDCl3, isomer 7a) δ
7.23–7.08 (4H, m, ArH), 4.15 (2H, q, J = 7.1 Hz, OCH2CH3), 3.58 (2H, s, CH2CO2), 2.34 (3H,
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s, ArCH3), 1.26 (3H, t, J = 7.1 Hz, OCH2CH3); C{1H} NMR (75 MHz, CDCl3, isomer 7a) δ
171.8 (C), 136.6 (C), 131.1 (C), 129.2 (2 × CH), 129.1 (2 × CH), 60.8 (CH2) , 41.0 (CH2), 21.1
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(CH3), 14.2 (CH3); H NMR (300 MHz, CDCl3, isomer 7aa) δ 7.23–7.08 (4H, m, ArH), 4.16
(2H, q, J = 7.1 Hz, OCH2CH3), 3.63 (2H, s,), 2.33 (3H, s, ArCH3), 1.26 (3H, t, J = 7.1 Hz,
OCH2CH3); 13C{1H} NMR (75 MHz, CDCl3, isomer 7aa) δ 171.5 (C), 136.8 (C), 132.9 (C),
130.3 (CH), 130.1 (CH), 127.3 (CH), 126.1 (CH), 60.8* (CH2), 39.3 (CH2), 19.6 (CH3), 14.2*
(CH3) [*coincident with major isomer].
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Ethyl 2-(4-methoxyphenyl)acetate 7b14d
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The title ester was prepared according to General Procedure C using anisole (0.22 mL, 2.0
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mmol) and CBTF (0.80 mL). H NMR analysis of the crude indicated a single regioisomer.
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Chromatographic purification (2→10% Et2O/pet. ether) provided the title ester 7b (163 mg,
86%) as a colourless oil. NMR data were in accordance with the literature.14d 1H NMR (300
MHz, CDCl3) δ 7.25–7.16 (2H, m, ArH), 6.90–6.83 (2H, m, ArH), 4.14 (2H, q, J = 7.1 Hz,
OCH2CH3), 3.79 (3H, s, OCH3), 3.55 (2H, s, CH2CO2), 1.25 (3H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CDCl3) δ 171.9 (C), 158.6 (C), 130.2 (2 × CH), 126.2 (C), 113.9 (2 ×
CH), 60.7 (CH2), 55.2 (CH3), 40.5 (CH2), 14.2 (CH3).
Ethyl 2-(4-hydroxyphenyl)acetate 7c42
Method A: The title ester was prepared according to a modification of General Procedure C (4
equivs of EtOH were added and an aqueous workup was performed) using phenol (188 mg, 2.0
mmol) and CBTF (0.80 mL). Following addition of ethanol (0.25 mL, 4.3 mmol), DCE (1.50
mL) was added for solubility. 1H NMR analysis of the crude indicated a single regioisomer. The
reaction mixture was diluted with EtOAc (10 mL), washed with 1 M HCl (2 × 10 mL) and brine
(10 mL), dried over MgSO4, filtered and concentrated in vacuo. Chromatographic purification
(4→24% acetone/pet. ether) provided title ester 7c (50 mg, 28%) as a colourless oil. NMR data
were in accordance with the literature.42
Method B: The title ester was prepared according to a modification of General Procedure C (4
equivs of EtOH were added and an aqueous workup was performed) using
(trimethylsilyloxy)benzene (332 mg, 2.0 mmol) and CBTF (0.60 mL). Following addition of
ethanol (0.25 mL, 4.3 mmol), DCE (0.50 mL) was added for solubility. 1H NMR analysis of the
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crude indicated a single regioisomer. The reaction mixture was diluted with EtOAc (10 mL),
washed with 1 M HCl (2 × 10 mL) and brine (10 mL), dried over MgSO4, filtered and
concentrated in vacuo. Chromatographic purification (4→24% acetone/pet. ether) provided title
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ester 7c (128 mg, 71%) as a colourless oil. NMR data were in accordance with the literature.42 1
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NMR (300 MHz, CDCl3) δ 7.14–7.06 (2H, m, ArH), 6.76–6.69 (2H, m, ArH), 5.93 (1H, s,
ArOH), 4.16 (2H, q, J = 7.1 Hz, OCH2CH3), 3.54 (2H, s, CH2CO2), 1.26 (3H, t, J = 7.1 Hz,
OCH2CH3); 13C{1H} NMR (75 MHz, CDCl3) δ 172.8 (C), 154.9 (C), 130.4 (2 × CH), 125.7 (C),
115.5 (2 × CH), 61.1 (CH2), 40.5 (CH2), 14.1 (CH3).
Ethyl 2-((4-(tert-butoxycarbonyl)amino)phenyl)acetate 7d43
The title ester was prepared according to a modification of General Procedure C (DMF was also
added in the second step) using Nꢀbocꢀaniline (286 mg, 2.0 mmol) and CBTF (2.0 mL).
Following addition of ethanol (0.12 mL, 2.0 mmol), DCE (2.0 mL) and DMF (0.20 mL) were
added for solubility. 1H NMR analysis of the crude indicated a single regioisomer.
Chromatographic purification (6→30% Et2O/pet. ether) provided title ester 7d (112 mg, 40%) as
a white crystalline solid. NMR data were in accordance with the literature.43 1H NMR (300 MHz,
CDCl3) δ 7.31 (2H, d, J = 8.5 Hz, ArH), 7.19 (2H, d, J = 8.6 Hz, ArH), 6.53 (1H, brꢀs, NH), 4.13
(2H, q, J = 7.1 Hz, OCH2CH3), 3.54 (2H, s, CH2CO2), 1.51 (9H, s, C(CH3)3), 1.23 (2H, t, J = 7.1
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Hz, OCH2CH3); C{1H} NMR (75 MHz, CDCl3) δ 171.7 (C), 152.7 (C), 137.3 (C), 129.7 (2 ×
CH), 128.6 (C), 118.6 (2 × CH), 80.4 (C), 60.8 (CH2), 40.7 (CH2), 28.3 (3 × CH3), 14.1 (CH3).
Ethyl 2-(4-(4-methoxyphenoxy)phenyl)acetate 7e
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The title compound was prepared according to General Procedure C using 1ꢀmethoxyꢀ4ꢀ
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regioisomer. Chromatographic purification (2→14% EtOAc/pet. ether) provided the title ester 7e
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(237 mg, 83%) as a colourless oil. Rf = 0.30 (10% EtOAc/pet. ether); IR: 1731 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 7.25–7.19 (2H, m, ArH), 7.02–6.96 (2H, m, ArH), 6.94–6.86 (4H, m,
ArH), 4.16 (2H, q, J = 7.1 Hz, OCH2CH3), 3.81 (3H, s, OCH3), 3.58 (2H, s, CH2CO2), 1.27 (3H,
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t, J = 7.1 Hz, OCH2CH3); C{1H} NMR (75 MHz, CDCl3) δ 171.7 (C), 157.6 (C), 155.9 (C),
150.0 (C), 130.4 (2 × CH), 128.1 (C), 120.8 (2 × CH), 117.6 (2 × CH), 114.8 (2 × CH), 60.8
(CH2), 55.6 (CH3), 40.5 (CH2), 14.2 (CH3); HRMS (ESI +ve) exact mass calculated for
C17H18O4Na+ [M+Na]+: 309.1097, found: 309.1099.
Ethyl 2-(4-phenoxyphenyl)acetate 7f
The title compound was prepared according to a modification of General Procedure C (5 equiv.
of arene were used) using diphenyl ether (850 mg, 5.00 mmol) and CBTF (0.20 mL). 1H NMR
analysis of the crude indicated a single regioisomer. Chromatographic purification (2→10%
Et2O/pet. ether) provided the title ester 7f (231 mg, 90%) as a colourless oil. Rf = 0.45 (10%
EtOAc/pet. ether); IR: 1731 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.37–7.29 (2H, m, ArH), 7.28–
7.22 (2H, m, ArH), 7.13–7.06 (1H, m, ArH), 7.04–6.99 (2H, m, ArH), 6.99–6.93 (2H, m, ArH),
4.17 (2H, q, J = 7.1 Hz, OCH2CH3), 3.59 (2H, s, CH2CO2), 1.27 (3H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CDCl3) δ 171.7 (C), 157.1 (C), 156.3 (C), 130.6 (2 × CH), 129.7 (2 ×
CH), 128.9 (C), 123.2 (CH), 118.9 (4 × CH), 60.9 (CH2), 40.6 (CH2), 14.9 (CH3); HRMS (ESI
+ve) exact mass calculated for C16H16O3Na+ [M+Na]+: 279.0992, found: 279.0995.
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Ethyl 2-(4-(4-bromophenoxy)phenyl)acetate 7g
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phenoxybenzene (0.35 mL, 2.0 mmol) and CBTF (0.65 mL). Following addition of ethanol,
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DCE (2.0 mL) was added for solubility. H NMR analysis of the crude indicated a single
regioisomer. Chromatographic purification (2→10% Et2O/pet. ether) provided the title ester 7g
(283 mg, 84%) as a colourless oil. Rf = 0.40 (10% EtOAc/pet. ether); IR: 1731 cmꢀ1; H (300
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MHz, CDCl3) δ 7.46–7.38 (2H, m, ArH), 7.29–7.22 (2H, m, ArH), 6.99–6.92 (2H, m, ArH),
6.92–6.84 (2H, m, ArH), 4.16 (2H, q, J = 7.1 Hz, OCH2CH3), (2H, s, CH2CO2), 1.27 (3H, t, J =
7.1 Hz, OCH2CH3); 13C{1H} NMR (75 MHz, CDCl3) δ 171.6 (C), 156.5 (C), 155.7 (C), 132.6 (2
× CH), 130.7 (2 × CH), 129.5 (C), 120.4 (2 × CH), 119.0 (2 × CH), 115.6 (C), 60.9 (CH2), 40.6
(CH2), 14.8 (CH3); HRMS (ESI +ve) exact mass calculated for C16H15O3 BrNa+ [M+Na]+:
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357.0097, found: 357.0097.
Ethyl 4-(4-(2-ethoxy-2-oxoethyl)phenoxy)benzoate 7h
The title compound was prepared according to General Procedure C using ethyl 4ꢀ
phenoxybenzoate 2h (484 mg, 2.0 mmol) and CBTF (0.50 mL). Following addition of ethanol,
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DCE (0.25 mL) was added for solubility. H NMR analysis of the crude indicated a single
regioisomer. Chromatographic purification (2→14% EtOAc/pet. ether) provided the title ester 7h
(263 mg, 80%) as a colourless oil. Rf = 0.30 (10% EtOAc/pet. ether); IR: 1730, 1712 cmꢀ1; H
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(300 MHz, CDCl3) δ 8.07–7.88 (2H, m, ArH), 7.33–7.26 (2H, m, ArH), 7.04–6.95 (4H, m,
ArH), 4.35 (2H, q, J = 7.1 Hz, OCH2CH3), 4.17 (2H, q, J = 7.1 Hz, OCH2CH3), 3.61 (2H, s,
CH2CO2), 1.38 (3H, t, J = 7.1 Hz, OCH2CH3), 1.27 (3H, t, J = 7.1 Hz, OCH2CH3); C{1H}
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NMR (75 MHz, CDCl3) δ 171.5 (C), 166.0 (C), 161.5 (C), 154.7 (C), 131.6 (2 × CH), 130.8 (2 ×
CH), 130.2 (C), 124.8 (C), 120.0 (2 × CH), 117.3 (2 × CH), 60.9 (CH2), 60.8 (CH2), 40.6 (CH2),
14.3 (CH3), 14.1 (CH3); HRMS (ESI +ve) exact mass calculated for C19H20O5Na+ [M+Na]+:
351.1203, found: 351.1206.
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Ethyl 2-(4-(3-chlorophenoxy)phenyl)acetate 7i
The title compound was prepared according to General Procedure C using 1ꢀchloroꢀ3ꢀ
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phenoxybenzene 2d (409 mg, 2.00 mmol) and CBTF (0.60 mL). H NMR analysis of the crude
indicated a single regioisomer. Chromatographic purification (2→10% EtOAc/pet. ether)
provided the title ester 7i (232 mg, 80%) as a colourless oil. Rf = 0.45 (10% EtOAc/pet. ether);
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IR: 1732 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.31–7.19 (3H, m, ArH), 7.06 (1H, ddd, J = 8.0,
1.9, 0.9 Hz, ArH), 7.01–6.95 (3H, m, ArH), 6.88 (1H, ddd, J = 8.2, 2.4, 0.9 Hz, ArH), 4.17 (2H,
q, J = 7.1 Hz, OCH2CH3), 3.60 (2H, s, CH2CO2), 1.27 (3H, t, J = 7.1 Hz, OCH2CH3); C{1H}
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NMR (75 MHz, CDCl3) δ 171.5 (C), 158.2 (C), 155.3 (C), 135.0 (C), 130.7 (2 × CH), 130.4
(CH), 129.7 (C), 123.2 (CH), 119.4 (2 × CH), 118.7 (CH), 116.6 (CH), 60.9 (CH2), 40.6 (CH2),
14.1 (CH3); HRMS (ESI +ve) exact mass calculated for C16H15O3 ClNa+ [M+Na]+: 313.0602,
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found: 313.0605.
Ethyl 3-(4-(2-ethoxy-2-oxoethyl)phenoxy)benzoate 7j
The title compound was prepared according to General Procedure C using ethyl 3ꢀ
phenoxybenzoate 2i (484 mg, 2.0 mmol) and CBTF (0.50 mL). Following addition of ethanol,
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DCE (1.0 mL) was added for solubility. H NMR analysis of the crude indicated a single
regioisomer. Chromatographic purification (4→20% EtOAc/pet. ether) provided the title ester 7j
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(259 mg, 79%) as a colourless oil. Rf = 0.30 (10% EtOAc/pet. ether); IR: 1718 (broad) cmꢀ1; 1H
(300 MHz, CDCl3) δ 7.78 (1H, ddd, J = 7.7, 1.6, 1.1 Hz, ArH), 7.68 (1H, dd, J = 2.2, 1.6 Hz,
ArH), 7.39 (1H, t, J = 7.9 Hz, ArH), 7.30–7.23 (2H, m, ArH), 7.19 (1H, ddd, J = 8.2, 2.2, 1.1
Hz, ArH), 7.00–6.92 (2H, m, ArH), 4.36 (2H, q, J = 7.1 Hz, OCH2CH3), 4.16 (2H, q, J = 7.1 Hz,
OCH2CH3), 3.60 (2H, s, CH2CO2), 1.37 (3H, t, J = 7.1 Hz, OCH2CH3), 1.26 (3H, t, J = 7.1 Hz,
OCH2CH3); 13C{1H} NMR (75 MHz, CDCl3) δ 171.6 (C), 166.0 (C), 157.2 (C), 155.9 (C), 132.3
(C), 130.7 (2 × CH), 129.7 (CH), 129.4 (C), 124.3 (CH), 123.2 (CH), 119.7 (CH), 118.9 (2 ×
CH), 61.1 (CH2), 60.9 (CH2), 40.6 (CH2), 14.3 (CH3), 14.2 (CH3); HRMS (ESI +ve) exact mass
calculated for C19H20O5Na+ [M+Na]+: 351.1203, found: 351.1205.
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Ethyl 2-(4-(2-fluorophenoxy)phenyl)acetate 7k and
ethyl 2-(3-fluoro-4-phenoxyphenyl)acetate 7ka
The title compounds were prepared according to General Procedure D using 1ꢀfluoroꢀ2ꢀ
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phenoxybenzene 2e (188 mg, 1.00 mmol), CBTF (0.30 mL) and ethanol (60 µL, 1.0 mmol). H
NMR analysis of the crude indicated a 3:1 mixture of regioisomers. Chromatographic
purification (2→10% EtOAc/pet. ether) provided a mixture of the title esters 7k and 7ka in a 3:1
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ratio (105 mg, 77%) as a colourless oil. Rf = 0.40 (10% EtOAc/pet. ether); IR: 1731 cmꢀ1; H
(300 MHz, CDCl3, isomer 7k) δ 7.27–7.22 (2H, m, ArH), 7.22–6.97 (4H, m, ArH), 6.97–6.91
(2H, m, ArH), 4.16 (2H, q, J = 7.1 Hz, OCH2CH3), 3.59 (2H, s, CH2CO2), 1.26 (3H, t, J = 7.1
Hz, OCH2CH3); 13C{1H} NMR (75 MHz, CDCl3, isomer 7k) δ 171.6 (C), 156.4 (C), 154.3 (d, J
= 248.7 Hz, C), 143.7 (d, J = 11.4 Hz, C), 130.5 (2 × CH), 128.8 (C), 124.8 (d, J = 6.9 Hz, CH),
124.61 (d, J = 3.9 Hz, CH), 121.9 (d, J = 1.1 Hz, CH), 117.3 (2 × CH), 117.0 (d, J = 18.2 Hz,
CH), 60.8 (CH2), 40.5 (CH2), 14.1 (CH3); 19F{1H} NMR (471 MHz, CDCl3, isomer 7k) δ ꢀ131.0;
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1H (300 MHz, CDCl3, isomer 7ka) δ 7.36–7.28 (2H, m, ArH), 7.22–6.97 (6H, m, ArH), 4.19
(2H, q, J = 7.1 Hz, OCH2CH3), 3.60 (2H, s, CH2CO2), 1.28 (3H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CDCl3, isomer 7ka) δ 171.0 (C), 157.2 (C), 154.0 (d, J = 249.0 Hz, C),
142.7 (d, J = 11.6 Hz, C), 131.0 (d, J = 6.7 Hz, C), 129.6 (2 × CH), 125.4 (d, J = 3.6 Hz, CH),
123.1 (CH), 121.7 (d, J = 1.5 Hz, CH), 117.9 (d, J = 18.9 Hz, CH), 117.3 (2 × CH), 61.0 (CH2),
40.4 (d, J = 1.3 Hz, CH2), 14.1* (CH3) [*coincident with major isomer]; 19F{1H} NMR (471
MHz, CDCl3, isomer 7ka) δ −130.6; HRMS (ESI +ve) exact mass calculated for C16H15O3FNa+
[M+Na]+: 297.0897, found: 297.0894.
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Methyl 2-(4-(2-ethoxy-2-oxoethyl)phenoxy)benzoate 7l and
methyl 5-(2-ethoxy-2-oxoethyl)-2-phenoxybenzoate 7la
The title compounds were prepared according to General Procedure C using methyl 2ꢀ
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phenoxybenzoate (456 mg, 2.00 mmol) and CBTF (0.55 mL). H NMR analysis of the crude
indicated a 4:1 mixture of regioisomers. Chromatographic purification (4→28% Et2O/pet. ether)
provided a mixture of the title esters 7l and 7la in a 4:1 ratio (219 mg, 70%) as a colourless oil.
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Rf = 0.20 (10% EtOAc/pet. ether); IR: 1727 (broad) cmꢀ1; H (300 MHz, CDCl3, isomer 7l) δ
7.91 (1H, dd, J = 7.8, 1.8 Hz, ArH), 7.45 (1H, ddd, J = 8.2, 7.4, 1.8 Hz, ArH), 7.26–7.21 (2H, m,
ArH), 7.17 (1H, ddd, J = 7.8, 7.4, 1.0 Hz, ArH), 6.98 (1H, dd, J = 8.2, 1.0 Hz, ArH), 6.94–6.89
(2H, m, ArH), 4.15 (2H, q, J = 7.1 Hz, OCH2CH3), 3.80 (3H, s, OCH3), 3.57 (2H, s, CH2CO2),
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1.25 (3H, t, J = 7.1 Hz, OCH2CH3); C{1H} NMR (75 MHz, CDCl3, isomer 7l) δ 171.6 (C),
166.1 (C), 156.6 (C), 156.1 (C), 133.5 (CH), 131.8 (CH), 130.5 (2 × CH), 128.8 (C), 123.5 (CH),
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120.8 (CH), 118.2 (2 × CH), 60.8 (CH2), 52.1 (CH3), 40.6 (CH2), 14.2 (CH3); H (300 MHz,
CDCl3, isomer 7la) δ 7.83 (1H, d, J = 2.1 Hz, ArH), 7.39 (1H, dd, J = 8.5, 2.4 Hz, ArH), 7.35–
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7.27 (2H, m, ArH), 7.11–7.04 (1H, m, ArH), 6.98–6.93 (3H, m, ArH), 4.17 (2H, q, J = 7.1 Hz,
OCH2CH3), 3.80 (3H, s, OCH3), 3.62 (2H, s, CH2CO2), 1.27 (12 H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CDCl3, isomer 7la) δ 171.1 (C), 165.9 (C), 157.5 (C), 155.3 (C), 134.4
(CH), 132.6 (CH), 129.7 (2 × CH), 129.3 (C), 123.1 (CH), 121.0 (CH), 118.2* (2 × CH), 61.0
(CH2), 52.1* (CH3), 40.3 (CH2), 14.2* (CH3) [*coincident with major isomer]; HRMS (ESI +ve)
exact mass calculated for C18H18O5Na+ [M+Na]+: 337.1046, found: 337.1046.
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Ethyl 2-(3-(4-fluorophenoxy)-4-methoxyphenyl)acetate 7m and
ethyl 2-(4-(4-fluorophenoxy)-3-methoxyphenyl)acetate 7ma
The title compounds were prepared according to General Procedure D using 2ꢀ(4ꢀ
fluorophenoxy)anisole 2f (218 mg, 1.0 mmol), CBTF (0.3 mL) and ethanol (60 µL, 1.0 mmol).
1H NMR analysis of the crude indicated a 5:1 mixture of regioisomers. Chromatographic
purification (2→14% EtOAc/pet. ether) provided a mixture of the title esters 7m and 7ma in a
5:1 ratio (126 mg, 83%) as a colourless oil. Rf = 0.35 (10% EtOAc/pet. ether); IR: 1731 cmꢀ1; 1H
NMR (300 MHz, C6D6, isomer 7m ) δ 6.97 (1H, d, J = 2.1 Hz, ArH), 6.93 (1H, dd, J = 8.3, 2.2
Hz, ArH), 6.77–6.61 (4H, m, ArH), 6.55 (1H, d, J = 8.3 Hz, ArH), 3.90 (2H, q, J = 7.1 Hz,
OCH2CH3), 3.28 (2H, s, CH2CO2), 3.22 (3H, s, OCH3), 0.90 (3H, t, J = 7.1 Hz, OCH2CH3); 1H
NMR (300 MHz, CDCl3, isomer 7m ) δ 7.05–6.78 (4H, m, ArH), 4.13 (2H, q, J = 7.1 Hz,
OCH2CH3), 3.83 (3H, s, OCH3), 3.50 (2H, s, CH2CO2), 1.22 (3H, t, J = 7.1 Hz, OCH2CH3);
1H NMR (300 MHz, CDCl3, isomer 7ma ) δ 7.05–6.78 (4H, m, ArH), 4.18 (2H, q, J = 7.2 Hz,
OCH2CH3), 3.84 (3H, s, OCH3), 3.59 (2H, s, CH2CO2), 1.28 (3H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CDCl3, isomer 7m) δ 171.46 (C), 158.4 (d, J = 240.5 Hz, C), 156.78
(C), 153.5 (d, J = 2.3 Hz, C), 150.2 (C), 145.4 (C), 127.0 (C), 125.27 (CH), 121.3 (CH), 118.8
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(d, J = 8.2 Hz, 2 × CH), 115.98 (d, J = 23.3 Hz, 2 × CH), 112.8 (CH), 60.8 (CH2), 56.0 (CH3),
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40.4 (CH2), 14.1 (CH3); 19F{1H} NMR (282 MHz, CDCl3, isomer 7m) δ ꢀ121.37; 1H NMR (300
MHz, C6D6, isomer 7ma) δ 6.84 (1H, d, J = 8.1 Hz, ArH), 6.80 (1H, d, J = 2.0 Hz, ArH), 6.78–
6.60 (5H, m, ArH), 3.94 (2H, q, J = 7.1 Hz, OCH2CH3), 3.37 (2H, s, CH2CO2), 3.25 (3H, s,
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OCH3), 0.94 (3H, t, J = 7.1 Hz, OCH2CH3); H NMR (300 MHz, CDCl3, isomer 7ma ) δ 7.05–
6.78 (4H, m, ArH), 4.18 (2H, q, J = 7.1 Hz, OCH2CH3), 3.84 (3H, s, OCH3), 3.59 (2H, s,
CH2CO2), 1.28 (3H, t, J = 7.1 Hz, OCH2CH3), C{1H} NMR (75 MHz, CDCl3, isomer 7ma) δ
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171.48 (C), 158.3 (d, J = 240.5 Hz, C), 156.75 (C), 153.6 (d, J = 2.3 Hz, C), 151.0 (C), 144.6
(C), 130.7 (C), 121.8 (CH), 120.2 (CH), 118.7 (d, J = 7.7 Hz, 2 × CH), 115.94 (d, J = 23.3 Hz, 2
× CH), 113.8 (CH), 60.9 (CH2), 55.9 (CH3), 41.1 (CH2), 14.2 (CH3); F{1H} NMR (282 MHz,
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CDCl3, isomer 7ma) δ ꢀ121.46; HRMS (ESI +ve) exact mass calculated for C17H17O4FNa+
[M+Na]+: 327.1003, found: 327.1003.
Ethyl 2-(4-(4-fluorophenoxy)-2-methoxyphenyl)acetate 7n and
ethyl 2-(2-(4-fluorophenoxy)-4-methoxyphenyl)acetate 7na
The title compounds were prepared according to General Procedure D using 3ꢀ(4ꢀ
fluorophenoxy)anisole 2g (218 mg, 1.0 mmol), CBTF (0.3 mL) and ethanol (60 µL, 1.0 mmol).
1H NMR analysis of the crude indicated a 5:2 mixture of regioisomers. Chromatographic
purification (2→12% EtOAc/pet. ether) provided a mixture of the title esters 7n and 7na in a 5:2
ratio (76 mg, 50%) as a colourless oil. Rf = 0.40 (10% EtOAc/pet. ether); IR: 1732 cmꢀ1; H
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NMR (300 MHz, CDCl3, isomer 7n) δ 7.10 (1H, d, J = 8.2 Hz, ArH), 7.07–6.91 (4H, m, ArH),
6.55 (1H, d, J = 2.3 Hz, ArH), 6.46 (1H, dd, J = 8.2, 2.3 Hz, ArH), 4.16 (2H, q, J = 7.1 Hz,
OCH2CH3), 3.76 (3H, s, OCH3), 3.57 (2H, s, CH2CO2), 1.26 (3H, t, J = 7.1 Hz, OCH2CH3);
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13C{1H} NMR (75 MHz, CDCl3, isomer 7n) δ 171.8 , 158.8 (d, J = 241.7 Hz, C), 158.6 (C),
158.0 (C), 152.75 (d, J = 2.6, C), 131.3 (CH), 120.5 (d, J = 8.3 Hz, 2 × CH), 116.20 (d, J = 23.3
Hz, 2 × CH), 118.0 (CH), 109.4 (CH), 101.8 (CH), 60.6 (CH2), 55.5 (CH3), 35.3 (CH2), 14.2
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(CH3); 19F{1H} NMR (282 MHz, CDCl3, isomer 7n) δ ꢀ120.09; H NMR (300 MHz, CDCl3,
isomer 7na) δ 7.20 (1H, d, J = 8.4 Hz, ArH), 7.07–6.90 (4H, m, ArH), 6.64 (1H, dd, J = 8.4, 2.5
Hz, ArH), 6.35 (1H, d, J = 2.5 Hz, ArH), 4.09 (2H, q, J = 7.1 Hz, OCH2CH3), 3.72 (3H, s,
OCH3), 3.61 (2H, s, CH2CO2), 1.19 (3H, t, J = 7.1 Hz, OCH2CH3); C{1H} NMR (75 MHz,
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CDCl3, isomer 7na) δ 171.6 (C), 160.0 (C), 158.7 (d, J = 241.5 Hz, C), 156.3 (C), 152.80 (d, J =
2.6, C), 131.9 (CH), 120.1 (d, J = 8.2 Hz, 2 × CH), 116.16 (d, J = 23.3 Hz, 2 × CH), 117.7 (CH),
108.6 (CH), 104.5 (CH), 60.7 (CH2), 55.3 (CH3), 35.2 (CH2), 14.1 (CH3); F{1H} NMR (282
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MHz, CDCl3, isomer 7na) δ ꢀ120.34; HRMS (ESI +ve) exact mass calculated for C17H17O4FNa+
[M+Na]+: 327.1003, found: 327.1004.
Ethyl 2-(4-methoxynaphthalen-1-yl)acetate 7o
The title compound was prepared according to General Procedure C using 1ꢀ
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methoxynaphthalene (316 mg, 2.0 mmol) and CBTF (0.70 mL). H NMR analysis of the crude
indicated a single regioisomer. Chromatographic purification (2→10% EtOAc/pet. ether)
provided the title ester (186 mg, 76%) as a colourless oil. Rf = 0.35 (10% EtOAc/pet. ether); IR:
1728 cmꢀ1; 1H (300 MHz, CDCl3) δ 8.35–8.30 (1H, m, ArH), 7.97–7.92 (1H, m, ArH), 7.56 (1H,
ddd, J = 8.4, 6.9, 1.6 Hz, ArH), 7.50 (1H, ddd, J = 8.1, 6.9, 1.4 Hz, ArH), 7.33 (1H, d, J = 7.8
Hz, ArH), 6.78 (1H, d, J = 7.8 Hz, ArH), 4.16 (2H, q, J = 7.1 Hz, OCH2CH3), 4.00 (3H, s,
OCH3), 3.99 (2H, s, CH2CO2), 1.23 (3H, t, J = 7.1 Hz, OCH2CH3); C{1H} NMR (75 MHz,
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CDCl3) δ 172.0 (C), 155.1 (C), 132.8 (C), 127.8 (CH), 126.7 (CH), 125.9 (C), 125.0 (CH), 123.6
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(CH), 122.7 (C), 122.5 (CH), 103.3 (CH), 60.8 (CH2), 55.4 (CH3), 38.8 (CH2), 14.2 (CH3);
HRMS (ESI +ve) exact mass calculated for C15H16O3Na+ [M+Na]+: 267.0992, found: 267.0991.
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Ethyl 2-(6-methoxynaphthalen-2-yl)acetate 7p44 and
ethyl 2-(7-methoxynaphthalen-1-yl)acetate 7pa45
The title compounds were prepared according to General Procedure C using 2ꢀ
methoxynaphthalene (316 mg, 2.0 mmol) and CBTF (0.70 mL). Following addition of ethanol,
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DCE (0.50 mL) was added for solubility. H NMR analysis of the crude indicated a 2:1 mixture
of regioisomers. Chromatographic purification (2→10% EtOAc/pet. ether) provided a mixture of
the title esters 7p and 7pa in a 2:1 ratio (176 mg, 72%) as a colourless oil. NMR data were in
accordance with the literature (for both isomers).44,45 1H NMR (300 MHz, CDCl3, isomer 7p) δ
7.75–7.65 (3H, m, ArH), 7.44–7.37 (1H, m, ArH), 7.21–7.11 (2H, m, ArH), 4.18 (2H, q, J = 7.1,
OCH2CH3), 3.91 (3H, s, OCH3), 3.76 (2H, s, CH2CO2), 1.27 (3H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CDCl3, isomer 7p) δ 171.7 (C), 157.5 (C), 133.5 (C), 129.2 (C), 129.1
(CH), 128.9 (C), 127.8 (CH), 127.7 (CH), 127.0 (CH), 118.9 (CH), 105.5 (CH), 60.8 (CH2), 55.2
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(CH3), 41.3 (CH2), 14.1 (CH3); H (300 MHz, CDCl3, isomer 7pa) δ 7.77 (1H, d, J = 8.9 Hz,
ArH), 7.75–7.65 (1H, m, ArH), 7.44–7.37 (1H, m, ArH), 7.34–7.28 (2H, m, ArH), 7.21–7.11
(1H, m, ArH), 4.17 (2H, q, J = 7.1, OCH2CH3), 4.03 (2H, s, CH2CO2), 3.95 (3H, s, OCH3), 1.24
(3H, t, J = 7.1 Hz, OCH2CH3); 13C{1H} NMR (75 MHz, CDCl3, isomer 7pa) δ 171.5 (C), 157.9
(C), 133.2 (C), 130.1 (CH), 129.4 (C), 129.2 (C), 128.5 (CH), 127.6 (CH), 123.1 (CH), 118.2
(CH), 102.4 (CH), 60.9 (CH2), 55.2 (CH3), 39.7 (CH2), 14.2 (CH3).
Ethyl 4-(4-(2-(benzyloxy)-2-oxoethyl)phenoxy)benzoate 8a
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The Journal of Organic Chemistry
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The title compound was prepared according to General Procedure D using ethyl 4ꢀ
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phenoxybenzoate 2h (242 mg, 1.00 mmol), CBTF (0.25 mL) and benzyl alcohol (0.11 mL, 1.0
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mmol). H NMR analysis of the crude indicated a single regioisomer. Chromatographic
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purification (2→12% EtOAc/pet. ether) provided the title ester 8a (156 mg, 80%) as a colourless
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oil. Rf = 0.25 (10% EtOAc/pet. ether); IR: 1734, 1714 cmꢀ1; H (300 MHz, CDCl3) δ 8.06–7.98
(2H, m, ArH), 7.42–7.25 (7H, m, ArH), 7.05–6.95 (4H, m, ArH), 5.16 (2H, s, OCH2Ph), 4.37
(2H, q, J = 7.1 Hz, OCH2CH3), 3.68 (2H, s, CH2CO2), 1.39 (3H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CDCl3) δ 171.3 (C), 166.1 (C), 161.5 (C), 154.8 (C), 135.7 (C), 131.6
(2 × CH), 130.9 (2 × CH), 130.0 (C), 128.5 (2 × CH), 128.3 (CH), 128.1 (2 × CH), 124.9 (C),
120.1 (2 × CH), 117.3 (2 × CH), 66.7 (CH2), 60.8 (CH2), 40.5 (CH2), 14.3 (CH3); HRMS (ESI
+ve) exact mass calculated for C24H22O5Na+ [M+Na]+: 413.1359, found: 413.1358.
Allyl 2-(4-(4-methylphenoxy)phenyl)acetate 8b
The title compound was prepared according to General Procedure D using 4ꢀphenoxytoluene 2b
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(182 mg, 1.00 mmol), CBTF (0.30 mL) and allyl alcohol (70 µL, 1.0 mmol). H NMR analysis
of the crude indicated a single regioisomer. Chromatographic purification (2→8% EtOAc/pet.
ether) provided the title ester 8b (156 mg, 80%) as a colourless oil. Rf = 0.45 (10% EtOAc/pet.
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ether), IR: 1734 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.28–7.21 (2H, m, ArH), 7.15 (2H, d, J =
8.2 Hz, ArH), 6.98–6.90 (4H, m, ArH), 5.93 (1H, ddt, J = 17.1, 10.5, 5.7 Hz, OCH2CH=CH2),
5.30 (1H, dq, J = 17.1, 1.5 Hz, OCH2CH=CH2), 5.24 (1H, dq, J = 10.5, 1.2 Hz, OCH2CH=CH2),
4.62 (2H, dt, J = 5.7, 1.3 Hz, OCH2CH=CH2), 3.63 (2H, s, CH2CO2), 2.35 (3H, s, CH3); 13C{1H}
NMR (75 MHz, CDCl3) δ 171.3 (C), 156.9 (C), 154.6 (C), 132.9 (C), 132.0 (CH), 130.5 (2 ×
CH), 130.2 (2 × CH), 128.2 (C), 119.1 (2 × CH), 118.3 (2 × CH), 118.2 (CH2), 65.4 (CH2), 40.4
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