Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid

Article abstract of DOI:10.1021/acs.joc.5b01077

The oxidative coupling of alkylboronic acids with oxygen nucleophiles offers a strategy for replacing toxic, electrophilic alkylating reagents. Although the Chan-Lam reaction has been widely applied in the arylation of heteroatom nucleophiles, O-alkylation with boronic acids is rare. We report a Cu-catalyzed nondecarboxylative methylation of carboxylic acids with methylboronic acid that proceeds in air with no additional oxidant. An isotope-labeling study supports an oxidative cross-coupling mechanism, in analogy to that proposed for Chan-Lam arylation.

Full text of DOI:10.1021/acs.joc.5b01077

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Note
Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid
Clare E Jacobson, Noelia Martinez-Munoz, and David J. Gorin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01077 • Publication Date (Web): 26 Jun 2015
Downloaded from http://pubs.acs.org on July 2, 2015
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Aerobic CopperꢀCatalyzed OꢀMethylation with Methylboronic Acid
Clare E. Jacobson, Noelia MartinezꢀMuñoz, and David J. Gorin*
Department of Chemistry, Smith College, Northampton, MA 01063
dgorin@smith.edu
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Abstract:
O
O
cat. CuCO3—Cu(OH)2
H3C B(OH)2
H
+
CH3
py, DMC, 90 oC
"open flask"
R
O
R
O
20 examples
60-91% yield
R = aromatic, aliphatic, alkenyl
The oxidative coupling of alkylboronic acids with oxygen nucleophiles offers a strategy for replacing toxic,
electrophilic alkylating reagents. Although the ChanꢀLam reaction is widely applied in the arylation of
heteroatom nucleophiles, Oꢀalkylation with boronic acids is rare. We report a Cuꢀcatalyzed
nondecarboxylative methylation of carboxylic acids with methylboronic acid that proceeds under air with
no additional oxidant. An isotopeꢀlabeling study supports an oxidative crossꢀcoupling mechanism, in
analogy to that proposed for ChanꢀLam arylation.
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The methylation of oxygen nucleophiles is ubiquitous in contemporary academic and industrial organic
synthesis.1 Typical methods use electrophilic reagents such as methyl iodide, dimethyl sulfate, and
diazomethane.2 While effective, these reagents are generally unstable and/or hazardous.3 which has
motivated chemists to seek safer alternatives. as in the use of trimethylsilyl diazomethane rather than
diazomethane.4 Unfortunately, trimethylsilyl diazomethane exposure is implicated in two recent
laboratoryꢀrelated deaths,5 demonstrating the unmet need for safe, effective methylating reagents.
Therefore, we are pursuing alternate strategies and reagents for Oꢀalkylation.6 The use of a nucleophilic
methyl source to replace typical reagents would avoid the intrinsic toxicity associated with electrophiles,
offering a practical advantage.7 Additionally, the selective oxidative crossꢀcoupling of an alkylmetal(loid)
reagent and an oxygen nucleophile might enable reaction selectivity and functional group compatibility
that complement traditional methods.8
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The Cuꢀcatalyzed oxidative coupling of heteroatom nucleophiles with arylboronic acids, known as the
ChanꢀLam reaction, is widelyꢀapplied for Nꢀ and Oꢀarylation.9 In some cases, oxygen present under "open
flask" conditions enables catalyst turnover, offering practical and green oxidative conditions.10 Despite the
success of ChanꢀLam arylation, the first couplings of alkylboronic acids with heteroatom nucleophiles
have emerged only recently.11 Although stoichiometric Cu is often required,11bꢀd,g the alkylation of phenols,
anilines, and amides proceeds with catalytic Cu using an organic peroxide as the terminal oxidant.11e,f To
the best of our knowledge, Tsuritani's Nꢀcyclopropylation of indoles is the sole ChanꢀLam alkylation that
proceeds with catalytic Cu and air as the only added oxidant.11a
Methylboronic acid (1) and related compounds, especially trimethylboroxine and methyltrifluoroborate
salts, have been previously employed as methylating reagents.12 Methyl transfer from 1 to canonical
nucleophiles is rare; Cruces used stoichiometric Cu to mediate the Nꢀmethylation of anilines,11c but this
has not yet been extended to any oxygen nucleophile.
Although an array of oxygen nucleophiles participate in ChanꢀLam coupling, most examples use phenols
or aliphatic alcohols and carboxylic acids are rarely employed. The use of carboxylic acids is complicated
by the potential for decarboxylation, which occurs under an array of conditions.13 Nonꢀdecarboxylative
arylations and alkenylations of carboxylic acids with boronic acids are reported, but the analogous
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alkylation has not been demonstrated.14 We therefore chose to investigate the synthesis of methyl esters
by crossꢀcoupling of 1 and carboxylic acids.15
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We report herein an aerobic, Cuꢀcatalyzed methylation of carboxylic acids with 1. The basic reaction
conditions complement those of Fisher esterification and the reaction proceeds open to air without any
additional oxidant. Mechanistic studies support a ChanꢀLamꢀtype mechanism where the methyl group is
transferred from the boronic acid to the substrate.
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Table 1. Optimization of CuꢀCatalyzed Esterification
The reaction of 4ꢀfluorobenzoic acid (2a) was chosen for preliminary study so that conversion to 3a could
be quantitatively determined by 19F NMR. Initial screening conditions were adopted from close literature
precedent, with the added constraint that only 0.2 equiv of the Cu catalyst was used. The reaction of 2a
and 1 under Cheng's conditions for the arylation of carboxylic acids14c yielded no product (Table 1, entry
1). In contrast, 3a was formed in 54% yield using modified conditions from Cruces' methylation of anilines
(entry 2).11c Surprisingly, this initial result demonstrated catalyst turnover under "open flask" conditions.
Other solvents were screened and found to be effective, including chlorobenzene and diethyl carbonate
(DEC) (entries 3ꢀ4). Dialkyl carbonates have emerged as nonꢀtoxic, green solvents, and therefore DEC
was chosen for further optimization studies.16
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Since carboxylic acids are substrates in this chemistry, we sought a catalyst precursor without
carboxylate ligands. Although CuBr2 was ineffective, Cu complexes with oxyanionic ligands of varying
basicities, including Cu(OTf)2 and Cu(acac)2, catalyzed formation of 3a (entries 4ꢀ8). Ultimately, cupric
carbonate [CuCO3—Cu(OH)2] emerged as the optimal Cu source (entry 8).17
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Pyridine is essential for the reaction. When Cs2CO3 replaced pyridine, no 3a was observed (entry 9). Low
yields also resulted with triethylamine or urea (entries 10ꢀ11). In the final, optimized conditions, dimethyl
carbonate (DMC) replaced higherꢀboiling DEC to ease solvent removal, and 3a was isolated in 76% yield
(entry 12).
Table 2. Methylation of Aromatic Carboxylic Acids
O
O
0.1 equiv CuCO3—Cu(OH)2
CH3
H
Ar
O
Ar
O
2.5 equiv 1, py, DMC
air, 90 oC, 24 h
3bꢀl
2bꢀl
substrate
yield (%)
entry
X = 4ꢀtBu 2b
91
85
88
66
79
74
68
78
1
2
3
4
5
6
7
8
O
4ꢀBr 2c
3ꢀCl 2d
4ꢀAc 2e
4ꢀCN 2f
3,4ꢀ(ꢀOCH2Oꢀ) 2g
2ꢀCH3 2h
X
H
O
2ꢀOMe 2i
O
H
O
2j
73
9
O
H
O
Y = H 2k
CH3 2l
0
10
11
N
67
Y
An array of aromatic carboxylic acids undergo Cuꢀcatalyzed oxidative methylation. Alkylꢀsubstituted 2b
provided ester 3b in 91% yield. Despite the potential for Cuꢀmediated reactions of aryl halides,18
brominated and chlorinated benzoic acid derivatives were smoothly transformed (entries 2ꢀ3). However,
no methyl ester was observed in the reaction with 4ꢀiodobenzoic acid.
Electronꢀdeficient substrates with ketone and nitrile substituents formed the corresponding methyl esters
3e and 3f in 66% and 79% yield, respectively (entries 4ꢀ5). Electronꢀdonating substituents are similarly
tolerated (entries 1, 6ꢀ8). For example, piperonylic acid (2g) was methylated in 74% yield (entry 6).
The methylation of 2ꢀsubstituted benzoic acid derivatives proceeded despite the increased steric
demands of the substrates (entries 7ꢀ9). Notably, Pdꢀcatalyzed carboxylateꢀdirected CꢀH methylation of
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2h and similar compounds with 1 has been reported.12b This demonstrates that the chemoselectivity of
the methylation event may be controlled by the choice of catalyst and reaction conditions.
Given the importance of aromatic heterocycles, the reaction of indoleꢀ2ꢀcarboxylic acid (2k) was
investigated. Although no product was observed with the NꢀH indole, Nꢀmethyl derivative 2l was
transformed into 3l in 67% yield.
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The oxidative methylation was applied to aliphatic carboxylic acids to further probe reaction scope.
Hydrocinnamic acid (2m) was methylated in 80% yield (Table 3, entry 1). Neopentylic ester 3n was also
formed, albeit in reduced yield (entry 2). αꢀOxygenated 2o, which might be susceptible to elimination
under the basic reaction conditions, provided 3o in 78% yield (entry 3). Substrates with alkene
functionality are methylated in moderate yields, including cinnamic acid derivatives (entries 4ꢀ6) and
primary olefin 2s (entry 7).
Table 3. Esterification of Aliphatic and Alkenyl Substrates
O
O
—
0.1 equiv CuCO3 Cu(OH)2
CH3
H
R
O
3mꢀu
R
O
2mꢀu
1
2.5 equiv , py, DMC
air, 90 oC, 24 h
substrate
O
yield (%)
entry
H
2m
1
2
80
Ph
Ph
O
O
H
2n
65
78
O
O
O
H
2o
3
Ph
O
O
4
5
6
Ar = Ph
2p
66
67
67
H
O
4ꢀOMeꢀPh 2q
4ꢀClꢀPh
2r
Ar
O
H
2s
7
60
73
78
O
O
8
O
H
O
2t
8
9
N(Boc)
EtO
H
2u
O
O
As demonstrated by the transformation of acidꢀsensitive NꢀBocꢀproline (2t), this Oꢀmethylation is
complementary to Fisher esterification. Ester 2u was methylated to see if the ethyl ester would endure.
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Mixed diester 3u was exclusively observed, demonstrating that transesterification does not occur under
the basic reaction conditions.
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The coupling of 1 with a carboxylic acid requires an oxidation event and we next investigated the terminal
oxidant. Since the catalytic reaction proceeds under "open flask" conditions, we propose that molecular
oxygen from air serves as the ultimate electron acceptor. To test this, oxygen was excluded from the
reaction, which resulted in only trace formation of 3a (Table 4, entry 1). To exclude the possibility that the
combination of atmospheric water and methylboronic acid is the oxidant,19 water was added to the
reaction. Low product yield was observed, suggesting that oxygen is necessary (entry 2).
Other oxidants were also screened. While use of HOOtBu and PhI(OAc)2 resulted in low yields,
tBuOOtBu provided 3a in yield comparable to the "openꢀflask" reaction. A control experiment in which 1
was omitted resulted in no product formation, suggesting that the peroxide is not the methyl source under
these conditions (See SI, eq S1).20 While practically the use of air is advantageous, it is noteworthy that
the successful reaction observed with tBuOOtBu parallels previous nonꢀaerobic Cuꢀcatalyzed ChanꢀLam
alkylations.11e,f
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Table 4. Terminal Oxidant Screen
We next considered possible reaction mechanisms. The Oꢀmethylation may proceed similarly to Chanꢀ
Lam Oꢀarylation, which has recently been studied (Scheme 1, path A).21 In accord with Stahl's studies,
intermediate 4 may be formed by ligand exchange with the carboxylic acid and transmetallation with 1.
Reductive elimination, likely from a Cu(III) species, and oxidation with O2 would yield the product and
regenerate the Cu(II) catalyst.
Given the single prior report of aerobic Cuꢀcatalyzed ChanꢀLam alkylation,11a alternate mechanistic
pathways were considered. Oxidation of arylꢀ or alkylꢀboronic acids to the corresponding phenols and
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alcohols occurs under a variety of conditions,22 and methanol formed in situ might react with the
carboxylic acid to form the product (Scheme 1, path B).23
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Scheme 1. Possible Mechanistic Pathways
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An isotopeꢀlabeling experiment was used to differentiate between the mechanistic proposals. The
reaction of 18Oꢀlabeled benzoic acid ([18O]2ꢀ2v) resulted in the formation of ester [18O]2ꢀ3v with both
labeled atoms retained (eq 1). This is inconsistent with a carbonyl substitution mechanism (path B).
Additionally, no product was observed upon substitution of methanol for 1 (see SI, eq S2). Taken
together, these experiments suggest that Cuꢀcatalyzed Oꢀmethylation proceeds via a crossꢀcoupling
mechanism analogous to that proposed for ChanꢀLam arylation (path A).21
In conclusion, a Cuꢀcatalyzed ChanꢀLam methylation of carboxylic acids has been developed. The
esterification of aryl, aliphatic, and alkenyl carboxylic acids with 1 proceeds under air without any
additional oxidant. The basic reaction conditions complement those of Fisher esterification, and
mechanistic studies support a methyl transfer mechanism from 1 to the substrate. This reaction expands
the scope of ChanꢀLam coupling to include nondecarboxylative alkylation of carboxylic acids and
demonstrates a strategy to replace toxic electophilic reagents in Oꢀalkylation.
Experimental Section.
General Information. Unless otherwise noted, all reagents were obtained commercially and used without
further purification. Basic cupric carbonate (CuCO3—Cu(OH)2, CAS: 12069ꢀ69ꢀ1) was obtained from Fisher
Scientific. TLC analysis of reaction mixtures was performed on silica gel 60 F254 TLC plates using
KMnO4 stain and UV light to visualize the reaction components. Column chromatography was carried out
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on 60 Å, 40ꢀ63 ꢁm silica gel using mixtures of ethyl acetate and hexanes as eluent. 1H NMR spectra were
1
referenced to chloroform and obtained at a frequency of 300 MHz or 500 MHz, as noted. Hꢀdecoupled
6
19F NMR spectra were referenced to 4ꢀmethoxyꢀ3ꢀnitroꢀbenzotrifluoride and obtained at 470 MHz. GCMS
analysis was performed using a J&W DB5ꢀms GC capillary column (0.25 mm x 30 m, 0.25 ꢁM film
thickness).
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General procedure for optimizing the methylation of 2a
To a 2 dram screwꢀtop vial equipped with a magnetic stir bar was added 2a (31 mg, 0.22 mmol), 4ꢀ
methoxyꢀ3ꢀnitroꢀbenzotrifluoride (internal standard, 16 mg, 0.07 mmol), and the appropriate solvent (1.1
mL). The appropriate amine was added (3.5 equiv, 0.77 mmol). An aliquot (100 uL) was removed and
used as the T = 0 sample for quantifying reaction progress. To the remaining solution was added the
copper complex (0.2 equiv, 0.04 mmol) and methylboronic acid (1) (30 mg, 0.5 mmol). (For the reactions
with CuCO3—Cu(OH)2, 0.1 equiv of the copper complex was used.) A rubber septa with a vent needle was
placed over the top of the screw top vial and the reaction mixture was heated to 90 oC. After stirring for 24
hours, the reaction was cooled and a second aliquot was removed. The T=0 and T=24 hour aliquots were
each diluted in CDCl3 and analyzed by 1Hꢀdecoupled 19F NMR.
General procedure for the methylation of carboxylic acids (2aꢀ2u) with 1. To a 10 mL round bottom
flask equipped with magnetic stir bar and reflux condenser was added the appropriate carboxylic acid
(2aꢀ2u, 0.6 mmol), DMC (3 mL, 0.2 M substrate concentration) and pyridine (0.17 mL, 2.1 mmol). Cupric
carbonate (CuCO3—Cu(OH)2, 13.3 mg, 0.06 mmol) was added, followed by methylboronic acid (1, 90 mg,
1.5 mmol). The heterogenous reaction mixture was left open to ambient air and heated to 90 °C. After 24
hours, the reaction was cooled to room temperature, filtered through celite, and concentrated en vacuo.
Pure methyl ester was obtained from the crude residue by flash column chromatography.
Methyl 4ꢀfluorobenzoate (3a, CAS Registry: 403-33-8). Carboxylic acid 2a (84 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3a was isolated as a clear oil (70.0 mg, 76% yield). The spectral data were
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consistent with reported values.24 1H NMR (CDCl3, 300 MHz) δ 8.06 (dd, 2 H, J = 9.0, 5.4 Hz), 7.11 (dd, 2
H, J = 8.7, 8.7 Hz), 3.91 (s, 3 H).
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Methyl 4ꢀtertꢀbutylbenzoate (3b, CAS Registry: 26537-19-9). Carboxylic acid 2b (107 mg, 0.60 mmol)
was reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl
acetate eluent), methyl ester 3b was isolated as a clear oil (104.9 mg, 91% yield). The spectral data were
consistent with reported values.25 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, 2 H, J = 8.4 Hz), 7.47 (d, 2 H, J =
8.4 Hz), 3.92 (s, 3 H), 1.36 (s, 9 H).
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Methyl 4ꢀbromobenzoate (3c, CAS Registry: 619-42-1). Carboxylic acid 2c (121 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3c was isolated as a white solid (109.7 mg, 85% yield). The spectral data were
consistent with reported values.26 1H NMR (CDCl3, 300 MHz) δ 7.88 (d, 2 H, J = 8.7 Hz), 7.56 (d, 2 H, J =
8.7 Hz), 3.90 (s, 3 H).
Methyl 3ꢀchlorobenzoate (3d, CAS Registry: 2905-65-9). Carboxylic acid 2d (94 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3d was isolated as a clear oil (89.8 mg, 88% yield). The spectral data were
consistent with reported values.27 1H NMR (CDCl3, 300 MHz) δ 8.02 (dd, 1 H, J = 1.8, 1.8 Hz), 7.92 (ddd,
1 H, J = 7.8, 1.5, 1.5 Hz), 7.53 (ddd, 1 H, J = 8.1, 2.1, 1.2 Hz), 7.38 (dd, 1 H, J = 7.8, 7.8 Hz), 3.93 (s, 3
H).
Methyl 4ꢀacetylbenzoate (3e, CAS Registry: 3609-53-8). Carboxylic acid 2e (98 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3c was isolated as a white solid (70.0 mg, 66% yield). The spectral data were
consistent with reported values.28 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, 2 H, J = 8.4 Hz), 7.99 (d, 2 H, J =
8.4 Hz), 3.94 (s, 3 H), 2.63 (s, 3 H).
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Methyl 4ꢀcyanobenzoate (3f, CAS Registry: 1129-35-7). Carboxylic acid 2f (88 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (19:1 hexanes/ethyl acetate
eluent), methyl ester 3f was isolated as a white solid (76.3 mg, 79% yield). The spectral data were
consistent with reported values.29 1H NMR (CDCl3, 300 MHz) δ 8.13 (d, 2 H, J = 8.7 Hz), 7.74 (d, 2 H, J =
8.7 Hz), 3.95 (s, 3 H).
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Methyl piperonylate (3g, CAS Registry: 326-56-7). Carboxylic acid 2g (100 mg, 0.60 mmol) was reacted
according to the general procedure. After column chromatography (19:1 hexanes/ethyl acetate eluent),
methyl ester 3g was isolated as a white solid (80.4 mg, 74% yield). The spectral data were consistent with
reported values.30 1H NMR (CDCl3, 300 MHz) δ 7.65 (dd, 1 H, J = 8.1, 1.5 Hz), 7.47 (d, 1 H, J = 1.8 Hz),
6.83 (d, 1 H, J = 8.1 Hz), 6.04 (s, 2 H), 3.88 (s, 3 H).
Methyl 2ꢀmethylbenzoate (3h, CAS Registry: 89-71-4). Carboxylic acid 2h (82 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3h was isolated as a clear oil (61.6 mg, 68% yield). The spectral data were
consistent with reported values.28 1H NMR (CDCl3, 300 MHz) δ 7.93 (dd, 1 H, J = 8.1, 1.2 Hz), 7.41 (ddd,
1 H, J = 7.5, 7.5, 1.5 Hz), 7.27 (m, 2 H), 3.91 (s, 3 H), 2.63 (s, 3 H).
Methyl 2ꢀmethyoxybenzoate (3i, CAS Registry: 606-45-1). Carboxylic acid 2i (91 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (19:1 hexanes/ethyl acetate
eluent), methyl ester 3i was isolated as a white solid (77 mg, 78% yield). The spectral data were
consistent with reported values.31 1H NMR (CDCl3, 300 MHz) δ 7.81 (d, 1 H, J = 7.9, 1.9 Hz ), 7.50 (m,
1H), 7.00 (m, 2 H), 3.90 (s, 3 H), 3.89 (s, 3 H).
Methyl 1ꢀnaphthoate (3j, CAS Registry: 2459-24-7). Carboxylic acid 2j (103 mg, 0.60 mmol) was reacted
according to the general procedure.32 After column chromatography (50:1 hexanes/ethyl acetate eluent),
methyl ester 3j was isolated as a clear oil (81.4 mg, 73% yield). The spectral data were consistent with
reported values.33 1H NMR (CDCl3, 300 MHz) δ 8.98 (d, 1 H, J = 8.7 Hz), 8.22 (dd, 1 H, J = 7.2, 1.2 Hz),
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8.04 (d, 1 H, J = 8.1 Hz), 7.91 (d, 1 H, J = 8.1 Hz), 7.69 ꢀ 7.49 (m, 3 H), 4.04 (s, 3 H). Peaks
corresponding to methyl 2ꢀnapthoate (CAS Registry: 2459-25-8)28 were also observed:32 δ 8.66 (s, 1 H),
8.11 (m, 1 H), 7.98 (m, 1 H), 7.90 (m, 2 H), 7.69 ꢀ 7.49 (m, 2 H), 4.02 (s, 3 H).
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Methyl 1ꢀmethylindoleꢀ2ꢀcarboxylate (3l, CAS Registry: 37493-34-8). Carboxylic acid 2l (105 mg, 0.60
mmol) was reacted according to the general procedure. After column chromatography (50:1
hexanes/ethyl acetate eluent), methyl ester 3l was isolated as a white solid (76.5 mg, 67% yield). The
spectral data were consistent with reported values.34 1H NMR (CDCl3, 300 MHz) δ 7.72 (d, 1 H, J = 7.8
Hz), 7.40 (m, 3 H), 7.20 (m, 1 H), 4.11 (s, 3 H), 3.96 (s, 3 H).
Methyl 3ꢀphenylpropanoate (3m, CAS Registry: 103-25-3). Carboxylic acid 2m (90 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3m was isolated as a clear oil (78.7 mg, 80% yield). The spectral data were
consistent with reported values.35 1H NMR (CDCl3, 300 MHz) δ 7.39 ꢀ 7.18 (m, 5 H), 3.71 (s, 3 H), 3.00 (t,
2 H, J = 8.1 Hz), 2.68 (t, 2 H, J = 8.1 Hz).
2ꢀMethylꢀ2ꢀphenylpropionate methyl ester (3n, CAS Registry: 57625-74-8). Carboxylic acid 2n (99 mg,
0.60 mmol) was reacted according to the general procedure. After column chromatography (100:1
hexanes/ethyl acetate eluent), methyl ester 3n was isolated as a clear oil (69.4 mg, 65% yield). The
spectral data were consistent with reported values.36 1H NMR (CDCl3, 300 MHz) δ 7.43 ꢀ 7.25 (m, 5 H),
3.69 (s, 3 H), 1.64 (s, 6 H).
Methyl 2ꢀphenoxypropanoate (3o, CAS Registry: 2065-24-9). Carboxylic acid 2o (100 mg, 0.60 mmol)
was reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl
acetate eluent), methyl ester 3o was isolated as a clear oil (84.6 mg, 78% yield). The spectral data were
consistent with reported values.37 1H NMR (CDCl3, 300 MHz) δ 7.30 (m, 2 H), 7.00 (t, 1 H, J = 7.5 Hz),
6.91 (m, 2 H), 4.80 (q, 1 H, J = 6.9 Hz), 3.77 (s, 3 H), 1.65 (d, 3 H, J = 6.9 Hz).
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Methyl cinnamate (3p, CAS Registry: 103-26-4). Carboxylic acid 2p (89 mg, 0.60 mmol) was reacted
according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate eluent),
methyl ester 3p was isolated as a white solid (64.1 mg, 66% yield). The spectral data were consistent with
reported values.28 1H NMR (CDCl3, 300 MHz) δ 7.72 (d, 1 H, J = 15.9 Hz), 7.54 (m, 2 H), 7.40 (m, 3 H),
6.47 (d, 1 H, J = 16.2 Hz), 3.83 (s, 3 H).
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Methyl 4ꢀmethoxycinnamate (3q, CAS Registry: 943-89-5). Carboxylic acid 3q (107mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3q was isolated as a white solid (76.8 mg, 67% yield). The spectral data was
consistent with reported values.38 1H NMR (CDCl3, 300 MHz) δ 7.65 (d, 1 H, J = 15.9 Hz), 7.47 (d, 2 H, J
= 8.6 Hz), 6.90 (d, 2 H, J = 8.8 Hz), 6.32 (d, 1 H, J = 15.9 Hz), 3.83 (s, 3H), 3.80 (s, 3 H).
Methyl 4ꢀchlorocinnamate (3r, CAS Registry: 7560-44-3). Carboxylic acid 2r (110 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3p was isolated as a white solid (79.6 mg, 67% yield). The spectral data were
consistent with reported values.39 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 1 H, J = 16.2 Hz), 7.44 (d, 2 H, J
= 8.4 Hz), 7.35 (d, 2 H, J = 8.7 Hz), 6.40 (d, 1 H, J = 15.9 Hz), 3.81 (s, 3 H).
Methyl 10ꢀundecenoate (3s, CAS Registry: 111-81-9). Carboxylic acid 2s (110 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (50:1 hexanes/ethyl acetate
eluent), methyl ester 3s was isolated as a clear oil (70.5 mg, 60% yield). The spectral data were
consistent with reported values.40 1H NMR (CDCl3, 300 MHz) δ 5.80 (m, 1 H), 4.95 (m, 2 H), 3.66 (s, 3 H),
2.30 (t, 2 H, J = 7.5 Hz), 2.03 (m, 2 H), 1.62 (m, 2 H), 1.29 (m, 10 H).
BocꢀProꢀOMe (3t, CAS Registry: 145681-01-2). Carboxylic acid 2t (129 mg, 0.60 mmol) was reacted
according to the general procedure. After column chromatography (10:1 hexanes/ethyl acetate eluent),
methyl ester 3t was isolated as a clear oil (100.1 mg, 73% yield). The spectral data were consistent with
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reported values and indicated the presence of conformational isomers.41 1H NMR (CDCl3, 300 MHz) δ
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4.27 ꢀ 4.15 (m, 1 H), 3.68 (s, 3 H), 3.54 ꢀ 3.30 (m, 2 H), 2.28 ꢀ 1.71 (m, 4 H), 1.43 ꢀ 1.36 (m, 9 H).
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Ethyl methyl adipate (3u, CAS Registry: 18891-13-9). Carboxylic acid 2u (105 mg, 0.60 mmol) was
reacted according to the general procedure. After column chromatography (19:1 hexanes/ethyl acetate
eluent), methyl ester 3u was isolated as a clear oil (88.8 mg, 78% yield). The spectral data were
consistent with reported values.42 1H NMR (CDCl3, 500 MHz) δ 4.08 (2 H, q, J = 7.0 Hz), 3.62 (s, 3 H),
2.28 (m, 4 H), 1.62 (m, 4 H), 1.21 (t, 3 H, J = 7.0 Hz).
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Procedure and GCMS data for the IsotopeꢀLabeling Experiment (eq 1).
[18O]2ꢀ2v was prepared from benzotrichloride (Acros) and 18Oꢀwater (97%, Cambridge Isotope) as
previously reported.43 The 1H NMR spectral data were consistent with the values observed for 2v. GCMS
m/z (% relative intensity, ion): 126.2 (81%, M), 107.2 (100%, M ꢀ (18OH)), 77.1 (94%, M ꢀ (C[18O]2H)). The
molecular ion peak corresponding to [18O]ꢀ2v was also identified: 124.1 (3.6%, M). The molecular ion
peak corresponding to unlabeled 2v was also identified: 122.1 (1.3%, M). The percentage of 18O in
synthetic [18O]2ꢀ2v was therefore calculated to be 96.5%.
[18O]2ꢀ2v was reacted with 1 according to the general methylation procedure. An aliquot was taken from
the reaction at T = 24 h and analyzed by GCMS. [18O]2ꢀ3v was identified. GCMS m/z (% relative intensity,
ion): 140.2 (28.8%, M), 107.2 (100%, M ꢀ (18OCH3)). The molecular ion peak corresponding to [18O]ꢀ3v
was also identified: 138.2 (10.2%, M). The molecular ion peak corresponding to unlabeled 3v was also
identified: 136.2 (1.2%, M). The calculated percentages of product formed are 72% [18O]2ꢀ3v, 25% [18O]ꢀ
3v, and 3% 3v. A peak for the benzoic acid ( [18O]22v) was also observed. m/z (% relative intensity, ion):
126.2 (71.8%, M), 107.2 (100%, M ꢀ (18OCH3)). The molecular ion peak corresponding to [18O]ꢀ2v was
also identified: 124.2 (28.5%, M). The molecular ion peak corresponding to unlabeled 2v was also
identified: 122.2 (12.6%, M). The calculated percentages of 2v epitopes are 64% [18O]2ꢀ2v, 25% [18O]ꢀ2v,
and 11% 2v.
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Acknowledgment We gratefully acknowledge financial support from the donors of the American
Chemical Society Petroleum Research Fund (#52706ꢀUNI1) and Smith College for a Jean Picker
Fellowship (DG) and a McKinley Fellowship (NM). We thank Dr. Charles Amass (Smith College) for
assistance with instrumentation and Dr. Craig F. Gorin (Dow) for helpful discussions.
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Supporting Information Available Control experiments with tBuOOtBu (eq S1) and MeOH (eq S2).
Copies of 1H NMR spectra for 3aꢀ3u. This material is available free of charge via the Internet at
http://pubs.acs.org.
References:
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(34) Sechi, M.; Derudas, M.; Dallocchio, R.; Dessì, A.; Bacchi, A.; Sannia, L.; Carta, F.; Palomba, M.;
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