Methoxylation of Acyl Fluorides with Tris(2,4,6-trimethoxyphenyl)phosphine via C-OMe Bond Cleavage under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.0c00640

Acyl fluorides are subjected to methoxylation with tris(2,4,6-trimethoxyphenyl)phosphine (TMPP) to afford the corresponding methyl esters in good to excellent yields. This transformation is featured by C(sp2)-OMe bond cleavage under metal-free conditions. Unprecedented utilization of TMPP as a methoxylating agent realized the installation of an OMe group into the desired products.

Full text of DOI:10.1021/acs.joc.0c00640

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Note
Methoxylation of Acyl Fluorides with Tris(2,4,6-trimethoxyphenyl)phosphine
via C–OMe Bond Cleavage under Metal-Free Conditions
Xiu Wang, Zhenhua Wang, Takumi Ishida, and Yasushi Nishihara
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Apr 2020
Downloaded from pubs.acs.org on May 2, 2020
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Methoxylation of Acyl Fluorides with Tris(2,4,6-trimethoxyphenyl)phosphine
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via C–OMe Bond Cleavage under Metal-Free Conditions
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Xiu Wang,‡ Zhenhua Wang,‡ Takumi Ishida,‡ and Yasushi Nishihara*,†
‡Graduate School of Natural Science and Technology, Okayama University,
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
†Research Institute for Interdisciplinary Science, Okayama University,
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required)
Reproduced in part with permission from the Journal of Organic Chemistry, submitted for publication.
Unpublished work copyright 2020 American Chemical Society.
Abstract: Acyl fluorides are subjected to methoxylation with tris(2,4,6-trimethoxyphenyl)phosphine
(TMPP) to afford the corresponding methyl esters in good to excellent yields. This transformation is
featured by C(sp2)–OMe bond cleavage under metal-free conditions. Unprecedented utilization of TMPP
as a methoxylating agent realized the installation of an OMe group into the desired products.
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Ether cleavage as a fundamental transformation in organic synthesis has been extensively studied.1
Preparation and degradation of ethers have often been utilized as an efficient synthetic strategy of
protection/deprotection of hydroxyl groups. With respect to unsymmetrical ethers consisting of C(sp2)–O–
C(sp3) scaffolds, numerous studies on demethylation in aryl methyl ethers have been explored, where bond
dissociation energies for C(aryl)–O and O–Me bonds are 100 kcal/mol and 65 kcal/mol, respectively.2
Although the methyl group eliminated by O–Me bond cleavage have little been installed into the products,
only two transition-metal catalyzed reactions donating a methyl group to the products have been reported.
The RhH(CO)(PPh3)3/DPPE catalytic system could activate the O–Me bond in aryl methyl ethers, in which
thioesters served as electrophiles to give an array of aromatic esters.3 In addition, Rh2(OAc)4-catalyzed
methylation of aromatic carboxylic acids with tris(o-methoxyphenyl)phosphine via O–Me bond cleavage
afforded the corresponding aryl esters.4
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Although the cleavage pattern can be affected by the reagents used, selective C(aryl)–OMe cleavage in
anisole derivatives is relatively rare. Conventionally, reductive C(aryl)–OMe cleavage by potassium metal5
and LiAlH4/KOtBu6 have been reported (Scheme 1a). In the past decade, phenol derivatives have been
utilized as cheap and sustained alternatives to conventional organic halides in transition-metal catalyzed
cross-coupling reactions.7 Among them, extensive researches of simple and commercially available aryl
methyl ethers as the coupling partners have been well documented (Scheme 1b).8-11 Recently,
transformation of aryl methyl ethers via C(aryl)–OMe cleavage under metal-free conditions has attracted
considerable attention.12 In these reactions, however, an OMe group are utilized as a leaving group, and
protocols where the eliminated OMe group was installed into the products are quite rare.
On the other hand, utilization of acyl fluorides in transition-metal-catalyzed reactions has been attracted
much attention,13 due to a good balance between stability and reactivity, and transmetalation activity as
well as controllable selectivity.14 As a part of our continuing studies in transformations of acyl halides,15
we herein report an unprecedented methoxylation through C(aryl)–OMe bond cleavage of tris(2,4,6-
trimethoxyphenyl)phosphine (TMPP, 2a)16 under transition-metal-free conditions, in which a diverse of
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acyl fluorides were subjected to methoxylation to give the corresponding aromatic esters in high yields
(Scheme 1c). In the previous studies, highly basic TMPP acts as an excellent hemilabile ligand for
stabilizing metal complexes by ligating with ortho-oxygen atoms,17 and as a nucleophile for ring-opening
of epoxides.18 To the best our knowledge, however, utilization of TMPP as a methoxylating agent via
C(aryl)–OMe bond cleavage has not been reported.19
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Scheme 1. Patterns of C(aryl)–O Bond Cleavage
During the course of our studies on various palladium-catalyzed transformations of benzoyl fluoride (1a),
we screened various phosphine ligands. To our surprise, when TMPP (2a) was employed as the ligand, the
formation of methyl benzoate (3a) was observed, presumably due to unexpected aryl C(sp2)–OMe bond
cleavage, in 60% NMR yield, based on the added TMPP (Scheme S1). We thus turned our attention to the
reactions of 1a with 2a with other transition metals (Tables 1 and S1). After extensive screening of the
reaction conditions, we found that this methoxylation occurred without any transition metal catalysts
(entries 1-3). As shown in entries 3-5, the addition of 0.11 mmol (F:OMe = 1:5) of 2a was found to be
effective for this transformation, affording 3a in 92% NMR yield. Even when the reaction was performed
in air, 80% yield of 3a was obtained. Decreasing the reaction temperature to 100 °C had a deleterious
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effect on reactivity (entry 6). Interestingly, when a viable surrogate of 1a, benzoyl chloride was employed,
3a was obtained only in 43% yield (Scheme 2). These results indicated that benzoyl fluoride (1a) showed
specific reactivity in the present reaction.
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Table 1. Optimization of Reaction Conditionsa
entry
catalyst
Ni(cod)2
Pd(dba)2
none
2a (mmol)
0.2
yield (%)b
63 (60)
45
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6c
0.2
0.2
95
0.11
0.06
0.11
92 (89)
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aBenzoyl fluoride (1a) (0.2 mmol), toluene (0.5 mL) at 130 ºC for 24 h
under Ar. bNMR yields. Isolated yields are shown in parentheses. cAt 100
ºC.
Scheme 2. Methoxylation of Benzoyl Chloride with 2a
We next evaluated the reactions of benzoyl fluoride (1a) with various OMe-substituted triarylphosphines
2 (Scheme 3). Compared to TMPP (2a), triarylphosphines 2b-2e afforded no trace of 3a. Considering the
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reported properties of triarylphosphines, these results can be explained by unusual basicity (pKa = 11.02)
and nucleophilicity of 2a caused by additional methoxy groups in 2,6-positions.20
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Scheme 3. Scope of Phosphines 2a,b
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aReaction conditions: 1a (0.20 mmol), 2 [2a (0.11 mmol), 2b (0.33 mmol), 2c (0.33 mmol),
2d (0.495 mmol), 2e (0.99 mmol)], toluene (0.5 mL), 130 ºC, 24 h. Isolated yields. n.r.: not
reported.
b
With the optimized conditions in hand, we surveyed the scope of acyl fluorides 1. As shown in Scheme
4, regardless of the electronic and steric nature of the substituents in 1, the corresponding methyl benzoates
3 were formed in good to excellent yields. Acyl fluorides bearing electron-rich methyl, n-butyl, phenyl in
para- or ortho-position proved to be very effective, affording 3b-3e in 90-96% yields. Even the highly
sterically congested acyl fluoride 1f gave 3f in 81% yield. Particularly, ethereal substrates can also be
tolerated under the optimized conditions, affording 3g-3i in 68-91% yields. Notably, acyl fluorides bearing
halogen groups were also compatible to afford 3j-3m in moderate to high yields. In particular, bromide and
iodide are highly reactive for oxidative addition to transition metals and the corresponding products can be
subjected to further transformations. The introduction of an electron-withdrawing group onto acyl fluorides
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led to a slight decrease in yield of the products 3n-3p. Moreover, acyl fluorides substituted by
methoxycarbonyl and benzoyl groups were also good reaction partners to form the corresponding products
3q and 3r in 99% and 89% yields, respectively. In order to elucidate an electronic effect of the substituents
in acyl fluorides 1, we conducted a series of competitive reactions (see, ESI). Acyl fluorides 1o or 1p with
electron-withdrawing groups gave higher yield than 1g with an electron-donating OMe group to some
extents, indicating that electronically poor acyl fluorides can render oxidation addition to Pd(0) more easier,
leading to the higher yields of 3. The generality of the reaction was further extended by varying acyl
fluorides with fused ring, affording the 3s-3u in 69-92% yields. Oxygen- and sulfur-containing
heterocycles could be compatible to afford the products 3v-3x in 70-86% yields. Alkenoyl fluoride as well
as primary and tertiary aliphatic acyl fluorides could furnish 3y-3aa in moderate yields.
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Scheme 4. Scope of Acyl Fluoridesa,b
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aReaction conditions: 1 (0.20 mmol), 2a (0.11 mmol), toluene (0.5 mL), 130 ºC, 24 h.
bIsolated yields.
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To shed light on the mechanism of the present methoxylation, the reactions of benzoyl fluoride (1a) with
TMPP (2a) in the presence of various radical scavengers were examined (Table 2). Different radical
scavengers including 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 2,6-bis(1,1-dimethylethyl)-4-
methylphenol (BHT), and galvinoxyl resulted in the decreased yields of 3a, which could rule out the radical
pathway of this transformation. The possibility of light-induced methoxylation was also examined by
performing the reaction of 1a with 2a in dark under the standard reaction conditions. As a result, 3a was
obtained in 97% NMR yield, which further excluded the light induction.
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Table 2. Methoxylation of Benzoyl Fluoride (1a) in the presence of Radical Scavengersa
entry
radical scavenger
TEMPO
yield (%)b
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BHT
Gulvinoxyl
aBenzoyl fluoride (1a) (0.2 mmol), 2a (0.11 mmol), radical scavenger (0.2
b
mmol) in toluene (0.5 mL) at 130 ºC for 24 h under Ar. NMR yields.
A proposed reaction mechanism is outlined in Scheme 5. The highly basic TMPP attacks at a carbonyl
carbon in 1 to afford phosphonium fluoride 4.21 Then an outer fluoride ion attacks at the relatively
electrophilic OMe group in the 4-position to generate Meisenheimar intermediate 5 found in aromatic
nucleophilic substitution.22 Subsequently, intermolecular and/or intramolecular nucleophilic attack of an
OMe group to give the corresponding esters 3. When the reaction of benzoyl fluoride (1a) with phosphine
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oxide, TMPP=O, instead of TMPP was also tested, no desired product 3a was observed, suggesting that
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TMPP=O cannot participate in the reaction due to a poor nucleophilic ability.
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Scheme 5. Proposed Mechanism
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Conclusions
In conclusion, we have developed an unprecedented C-O bond cleavage and its utilization for
methoxylation of acyl fluorides with tris(2,4,6-trimethoxyphenyl)phosphine. Although there have been
numerous synthetic options to access such motifs, as well as several similar transformations to synthesize
methyl benzoates, this transformation provides a new concept of carbon-oxygen bond activation strategy.
Experimental Section
General. For thin layer chromatography (TLC) analyses throughout this work, Merck precoated TLC
plates (silica gel 60 GF254, 0.25 mm) were used. Silica gel column chromatography was carried out using
Silica gel 60 N (spherical, neutral, 40-100 m) from Kanto Chemicals Co. Ltd. NMR spectra (1H, 13C{1H},
31P{1H} and 19F{1H}) were recorded on Varian INOVA-600 (600 MHz) or Mercury-400 (400 MHz)
spectrometers. Chemical shifts (δ) are in parts per million related to CDCl3 at 7.26 ppm for 1H and at 77.16
13
ppm for C{1H} NMR measurements. The GC yields were determined using n-dodecane as an internal
1
standard. The NMR yields were determined by H NMR spectra using dibromomethane as an internal
standard. Chemicals. Unless otherwise noted, materials obtained from commercial suppliers were used
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without further purification. Benzoyl fluoride (1a) (purity > 98%) and dibromomethane (purity > 99%)
were purchased from Tokyo Chemical Industry Co. Ltd. Bis(1,5-cycloctadiene)nickel and tris(2,4,6-
trimethoxyphenyl)phosphine (2a) were purchased from Sigma-Aldrich Co. Ltd (12,000 JPY/5 g).
A Typical Procedure for the Synthesis of Acyl Fluorides from Acyl Chlorides23
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To a 20 mL of Schlenk tube with a magnetic stirrer bar, were successively added acyl chlorides 1-Cl (2.0
mmol), 18-crown-6 (26.4 mg, 0.1 mmol, 5 mol %), KF (1.16 g, 20 mmol, 10 equiv), and THF (10 mL)
under Ar. After the reaction was stirred at 40 ºC (in a heating block) for 24 h, the insoluble inorganic solid
(KF or KCl) was filtered, and the volatiles were removed using a rotary evaporator. The crude product was
purified by bulb-to-bulb distillation to afford the corresponding acyl fluorides 1 in 30-72% yields.
A Typical Procedure for Methoxylation of Acyl Fluorides 1 with 2a
To
a
20 mL Schlenk tube were added acyl fluorides (1, 0.20 mmol), tris(2,4,6-
trimethoxyphenyl)phosphine (2a, 61.5 mg, 0.11 mmol), and toluene (0.5 mL) at room temperature under
argon atmosphere. After being stirred at 130 ºC in a heating block for 24 h, the reaction mixture was
quenched with 1 M HCl aq solution, extracted with diethyl ether, and dried over MgSO4. After the
volatiles were removed under vacuum, the crude product was purified by column chromatography on silica
gel or bulb-to-bulb distillation to afford the products 3.
Characterization of Compounds.
Methyl benzoate (3a)24
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1
Purification: bulb-to-bulb distillation (60 ºC/5 mmHg). Colorless oil. Yield: 89% (24.2 mg). H NMR
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(400 MHz, CDCl3): δ 3.91 (s, 3H), 7.41-7.45 (m, 2H), 7.53-7.57 (m, 1H), 8.03-8.06 (m, 2H).
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Methyl 4-methylbenzoate (3b)24
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Purification: bulb-to-bulb distillation (80 ºC/5 mmHg). Colorless oil. Yield: 95% (28.5 mg). H NMR
(400 MHz, CDCl3): δ 2.41 (s, 3H), 3.90 (s, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H).
Methyl 2-methylbenzoate (3c)25
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Purification: bulb-to-bulb distillation (85 ºC/5 mmHg). Colorless oil. Yield: 90% (27 mg). 1H NMR (400
MHz, CDCl3): δ 2.60 (s, 3H), 3.89 (s, 3H), 7.22-7.26 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz,
1H).
Methyl 4-butylbenzoate (3d)26
Purification: column chromatography (n-Hexane/Et2O = 20:1, Rf = 0.67). Colorless oil. Yield: 90% (34.6
mg). 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J = 7.6 Hz, 3H), 1.35 (sext, J = 8.0 Hz, 2H), 1.57-1.65 (m, 2H),
2.66 (t, J = 7.6 Hz, 2H), 3.90 (s, 3H), 4.01 (s, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 8.0 Hz, 2H).
Methyl [1,1'-biphenyl]-4-carboxylate (3e)27
Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.67). White solid. Yield: 96% (40.8
mg). 1H NMR (400 MHz, CDCl3): δ 3.95 (s, 3H), 7.40 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.63 (d,
J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 8.11 (d, J = 8.0 Hz, 2H).
Methyl 2,4,6-trimethylbenzoate (3f)28
Purification: column chromatography (n-Hexane/Et2O = 20:1, Rf = 0.50). White solid. Yield: 81% (28.8
mg). 1H NMR (400 MHz, CDCl3): δ 2.28 (s, 9H), 3.89 (s, 3H), 6.85 (s, 2H).
Methyl 4-methoxybenzoate (3g)24
Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.55). Colorless oil. Yield: 90% (29.9
mg). 1H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H), 3.88 (s, 3H), 6.91 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.0 Hz,
2H).
Methyl 4-(benzyloxy)benzoate (3h)29
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Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.56). White solid. Yield: 91% (44.1
mg). 1H NMR (600 MHz, CDCl3) δ 3.89 (s, 3H), 5.11 (s, 2H), 7.00 (t, J = 6.0 Hz, 1H), 7.01 (t, J = 6.0 Hz,
1H), 7.34-7.37 (m, 1H), 7.39-7.45 (m, 2H), 8.01 (t, J = 6.0 Hz, 1H), 8.02 (t, J = 6.0 Hz, 1H).
Methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (3i)30
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Purification: column chromatography (n-Hexane/Et2O = 50:1, Rf = 0.50). Colorless oil. Yield: 68% (26.4
mg). 1H NMR (400 MHz, CDCl3): δ 3.87 (s, 3H), 4.26-4.28 (m, 2H), 4.29-4.32 (m, 2H), 6.87-6.89 (m, 1H),
7.54-7.56 (m, 2H).
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Methyl 4-fluorobenzoate (3j)31
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Purification: bulb-to-bulb distillation (60 ºC/20 mmHg). Colorless oil. Yield: 76% (23.4 mg). H NMR
(600 MHz, CDCl3) δ 3.91 (s, 3H), 7.09-7.12 (m, 2H), 8.04-8.07 (m, 2H).
Methyl 4-chlorobenzoate (3k)31
Purification: column chromatography (n-Hexane/Et2O = 20:1, Rf = 0.57). White solid. Yield: 85% (15.8
mg). 1H NMR (400 MHz, CDCl3): δ 3.92 (s, 3H), 7.42 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H).
Methyl 4-bromobenzoate (3l)31
Purification: column chromatography (n-Hexane/Et2O = 20:1, Rf = 0.50). White solid. Yield: 72% (31.0
mg). 1H NMR (600 MHz, CDCl3) δ 3.91 (s, 3H), 7.58 (d, J = 6.0 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H).
Methyl 4-iodobenzoate (3m)31
Purification: column chromatography (n-Hexane/Et2O = 20:1, Rf = 0.56). White solid. Yield: 63% (33.0
mg). 1H NMR (600 MHz, Chloroform-d) δ 3.91 (s, 3H), 7.75 (m, 2H), 7.80 (m, 2H).
Methyl 4-(trifluoromethyl)benzoate (3n)24
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Purification: bulb-to-bulb distillation (65 ºC/5 mmHg). Colorless oil. Yield: 76% (31.0 mg). H NMR
(400 MHz, CDCl3): δ 3.96 (s, 3H), 7.71 (d, J = 8.0 Hz, 2H), 8.15 (d, J = 8.0 Hz, 2H).
Methyl 4-nitrobenzoate (3o)32
Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.53). White solid. Yield: 89% (32.1
mg). 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 3H), 8.20-8.23 (m, 2H), 8.28-8.31 (m, 2H).
Methyl 4-cyanobenzoate (3p)33
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Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.43). White solid. Yield: 75% (24.2
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mg). 1H NMR (400 MHz, CDCl3): δ 3.96 (s, 3H), 7.75 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.0 Hz, 2H).
Dimethyl terephthalate (3q)32
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Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.53). White solid. Yield: 99% (39.2
mg). 1H NMR (400 MHz, CDCl3): δ 3.94 (s, 6H), 8.10 (s, 4H).
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Methyl 4-benzoylbenzoate (3r)34
Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.50). White solid. Yield: 89% (42.8
mg). 1H NMR (600 MHz, CDCl3) δ 3.96 (s, 3H), 7.47-7.51 (m, 2H), 7.58-7.64 (m, 1H), 7.75-7.86 (m, 4H),
8.12-8.17 (m, 2H).
Methyl 1-naphthoate (3s)25
Purification: column chromatography (n-Hexane/Et2O = 20:1, Rf = 0.50). White solid. Yield: 75% (27.9
mg). 1H NMR (400 MHz, CDCl3): δ 4.01 (s, 3H), 7.48-7.56 (m, 2H), 7.62 (dt, J = 8.0, 1.6 Hz, 1H), 7.89 (d,
J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.19 (dd, J = 8.0, 1.2 Hz, 1H), 8.91 (d, J = 8.0 Hz, 1H).
Methyl 2-naphthoate (3t)35
Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.72). White solid. Yield: 92% (34.3
mg). 1H NMR (400 MHz, CDCl3): δ 3.99 (s, 3H), 7.54-7.62 (m, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.96 (d, J =
8.0 Hz, 1H), 8.07 (dd, J = 8.0, 2.0 Hz, 1H), 8.62 (s, 1H).
Methyl anthracene-9-carboxylate (3u)35
Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.57). Yellow solid. Yield: 69% (32.6
mg). 1H NMR (400 MHz, CDCl3): δ 4.19 (s, 3H), 7.48-7.57 (m, 4H), 8.02-8.05 (m, 4H), 8.54 (s, 1H).
Methyl furan-2-carboxylate (3v)36
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Purification: bulb-to-bulb distillation (70 ºC/20 mmHg). Colorless oil. Yield: 70% (17.7 mg). H NMR
(400 MHz, CDCl3): δ 3.86 (s, 3H), 6.47 (dd, J = 3.6, 1.6 Hz, 1H), 7.14 (dd, J = 3.6, 0.8 Hz, 1H), 7.54 (dd, J
= 1.6, 0.8 Hz, 1H).
Methyl benzofuran-2-carboxylate (3w)37
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Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.60). White solid. Yield: 86% (30.3
mg). 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 3H), 7.31 (td, J = 8.0, 0.8 Hz, 1H), 7.43-7.48 (m, 1H), 7.54 (s,
1H), 7.59 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 8.0, 0.8 Hz, 1H).
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Methyl thiophene-2-carboxylate (3x)25
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Purification: bulb-to-bulb distillation (65 ºC/5 mmHg). Colorless oil. Yield: 80% (22.7 mg). H NMR
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(400 MHz, CDCl3): δ 3.89 (s, 3H), 7.10 (dd, J = 4.8, 3.6 Hz, 1H), 7.55 (dd, J = 4.8, 1.6 Hz, 1H), 7.80 (dd, J
= 3.6, 1.6 Hz, 1H).
Methyl cinnamate (3y)32
Purification: column chromatography (n-Hexane/Et2O = 10:1, Rf = 0.47). White solid. Yield: 85% (27.6
mg). 1H NMR (400 MHz, CDCl3): δ 3.81 (s, 3H), 6.45 (d, J = 16.0 Hz, 1H), 7.38-7.40 (m, 3H), 7.52-7.54
(m, 2H), 7.70 (d, J = 16.0 Hz, 1H).
Methyl dodecanoate (3z)38
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Purification: bulb-to-bulb distillation (100 ºC/5 mmHg). Colorless oil. Yield: 86% (36.6 mg). H NMR
(400 MHz, CDCl3) δ 0.85-0.90 (m, 3H), 1.23-1.30 (m, 16H), 1.62 (td, J = 7.1, 3.0 Hz, 2H), 2.27-2.32 (m,
2H), 3.66 (s, 3H).
Methyl (3r,5r,7r)-adamantane-1-carboxylate (3aa)39
1
Purification: bulb-to-bulb distillation (100 ºC/5 mmHg). White solid. Yield: 70% (27.4 mg). H NMR
(600 MHz, CDCl3) δ 1.68-1.73 (m, 6H), 1.88-1.89 (m, 6H), 1.99-2.02 (m, 3H), 3.64 (s, 3H).
A Typical Procedure for the Large-Scale Synthesis of 3e
To a 20 mL Schlenk tube were added 4-phenylbenzoyl fluoride (1e, 1 mmol, 200.2 mg), tris(2,4,6-
trimethoxyphenyl)phosphine (2a, 0.55 mmol, 293 mg), and toluene (2.5 mL) at room temperature under
argon. After being heated at 130 ºC in a heating block for 24 h, the reaction mixture was quenched with 1
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M HCl aq solution, extracted with diethyl ether, and dried over MgSO4. After the volatiles were removed
under vacuum, the crude product was purified by column chromatography on silica gel (n-hexane/Et2O =
10:1, Rf = 0.67) to afford the desired product 3e as white solid in 78% yield (165.2 mg).
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Supporting Information Available.
The Supporting Information is available free of charge on the ACS Publications website. More detailed
results of esterification and 1H, 13C{1H}, and 19F{1H} NMR spectra of the representative products (PDF)
Author Information
Corresponding Author.
*E-mail: ynishiha@okayama-u.ac.jp.
ORCID
Yasushi Nishihara: 0000-0001-5409-4207
Notes.
The authors declare no competing financial interest.
Acknowledgements
This study was partly supported by Marubun Research Promotion Foundation. We gratefully thank the
SC-NMR Laboratory (Okayama University) for the NMR spectral measurements.
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(14) (a) Zhang, Y. D.; Rovis, T. A Unique Catalyst Effects the Rapid Room-Temperature Cross-Coupling
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