Catalytic methyl transfer from dimethylcarbonate to carboxylic acids

Article abstract of DOI:10.1021/jo401941v

Although methylation reactions are commonplace, currently used reagents are hazardous, toxic, and/or unstable. Dimethylcarbonate has been put forth as an inexpensive, nontoxic, and green potential methylating reagent. Herein we report a general, base-catalyzed methyl transfer from dimethylcarbonate to carboxylic acids. High selectivity for esterification is observed even in the presence of unprotected phenols, and the mild reaction conditions enable conservation of stereochemistry at epimerizable stereocenters. Isotope-labeling studies suggest a mechanism proceeding by direct methyl transfer from dimethylcarbonate to the substrate.

Full text of DOI:10.1021/jo401941v

Note
pubs.acs.org/joc
Catalytic Methyl Transfer from Dimethylcarbonate to Carboxylic
Acids
Yuan Ji, Jessica Sweeney, Jillian Zoglio, and David J. Gorin*
Department of Chemistry, Smith College, Northampton, Massachusetts 01063
S
* Supporting Information
ABSTRACT: Although methylation reactions are common-
place, currently used reagents are hazardous, toxic, and/or
unstable. Dimethylcarbonate has been put forth as an
inexpensive, nontoxic, and “green” potential methylating
reagent. Herein we report a general, base-catalyzed methyl
transfer from dimethylcarbonate to carboxylic acids. High selectivity for esterification is observed even in the presence of
unprotected phenols, and the mild reaction conditions enable conservation of stereochemistry at epimerizable stereocenters.
Isotope-labeling studies suggest a mechanism proceeding by direct methyl transfer from dimethylcarbonate to the substrate.
ethylation reactions of carboxylic acids are ubiquitously
used in chemical research, including in natural product
Herein we report a general catalytic methyl transfer from
DMC to carboxylic acid nucleophiles under basic conditions.29
Both electron-rich and electron-poor substrates are readily
esterified, and the mild reaction conditions enable conservation
of stereochemistry at epimerizable α-carbonyl stereocenters.
Mechanistic studies suggest that a direct methyl transfer from
DMC, rather than a carbonyl substitution mechanism, is
operative. The improved substrate scope and chemoselectivity
demonstrated in this work suggest that DMC should be
considered as an alternative to routinely used hazardous
methylating agents.
Our starting point for reaction development was Shieh’s
seminal report on methylation of carboxylic acids using
stoichiometric DBU to activate DMC.20,30,31 We hypothesized
that cosolvents or less basic catalysts might ameliorate the need
for stoichiometric quantities of catalyst.32 Conversion of
benzoic acid (2a) to methyl benzoate (3a) was quantified by
GC/MS. Under solvent-free conditions, catalytic quantities of
DBU mediated the formation of 3a in only 5% yield (Table 1,
entry 1). Dramatic solvent effects were observed (entries 2−4).
While increased 3a was formed in DMF, higher yield and
apparent catalyst turnover resulted from the reaction in
DMSO.33
Other catalysts were investigated in DMSO. DABCO
catalyzed formation of 3a in high yield (Table 1, entry 5).32
Surprisingly, inorganic bases such as KOH and K2CO3
catalyzed formation of 3a with similar efficiencies at 90 °C
(entries 6−7).34 Although the K2CO3-catalyzed reaction still
proceeded at lower temperature, the rate was greatly slowed;
only 20% conversion to 3a was observed at 75 °C (entry 8).
Although KHCO3 effectively catalyzed formation of 3a,
KH2PO4 did not (entries 9−10). This suggests that sufficient
basicity to deprotonate the nucleophile is necessary. The
M
synthesis,1 reaction development,2 medicinal chemistry,3 and
polymer synthesis.4 Although often effective, Fisher esterifica-
tion is incompatible with acid-sensitive substrates.5 This led to
the development of electrophilic methylating reagents that react
under mild conditions, such as diazomethane, dimethyl sulfate,
and “magic methyl”.6
Perhaps the most high-profile drawback of common
methylating reagents is their extraordinary acute toxicity.7−10
For example, trimethylsilyldiazomethane, sometimes consid-
ered a safer alternative to diazomethane due to its decreased
volatility and increased stability,11 has caused the deaths of two
chemists since 2008.7 Use of common methylating agents,
including diazomethane, trimethylsilyldiazomethane, dimethyl
sulfate, and iodomethane, is also complicated by their general
instability to light, heat, and/or moisture, along with concerns
about chronic health risks.7−11 Despite their drawbacks,
hazardous methylating reagents are regularly used in both
academic and industrial laboratories.1−4
We have therefore initiated a program to develop new
methylation methods that rely upon safe, stable reagents. While
others have sought to mitigate the hazards of current
reagents,12,13 the development of nonexplosive carbene
precursors14 and safer alternatives to hydrogen cyanide15
inspired us to pursue altogether different methylating agents.16
Increased safety and convenience will reduce the cost and risk
of an immensely useful functional group manipulation.
Dimethylcarbonate (DMC, 1) is an inexpensive, nontoxic,
and ”green” potential methylating reagent.17−19 Although
DMC has been explored in methylations of a variety of
nucleophiles, esterifications have generally been limited to
electron-rich carboxylic acids and require stoichiometric
activating agents, high (>150 °C) temperature, and/or special
reactors such as autoclaves.20−28 Perhaps due to the limited
demonstrated substrate scope and harsh reaction conditions,
methylation with DMC has not found routine application in
synthetic organic chemistry.
Received: September 2, 2013
© XXXX American Chemical Society
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The substrate scope and functional group compatibility of
the K2CO3-catalyzed methylation were investigated. Electron-
rich benzoic acid derivatives were readily esterified (Table 2,
entries 2−4). The reaction of 2-anisic acid (2c) proceeded in
excellent yield even with decreased catalyst loading (entry 3).
In contrast to previous esterification reactions that employ
DMC, electron-withdrawing groups were also well-tolerated
(Table 2, entries 5−9).20−27 Given the reported difficulties with
electron-poor substrates, the successful esterification of 2-
nitrobenzoic acid (2h, pKa = 2.2), which is far more acidic than
even 4-nitrobenzoic acid (2g, pKa = 3.4),35 is particularly
noteworthy (entry 8).
The methylation readily proceeded even with sterically
hindered substrates. Ortho-disubstituted ester 3k was synthe-
sized in high yield (Table 2, entry 11). Furthermore,
neopentylic ester 3m was formed as efficiently as unhindered
ester 3l (entries 12−13).
An array of functional groups were compatible with the
reaction conditions, including thioethers, aldehydes, and aryl
halides (Table 2, entries 4, 6, 10). The successful methylation
of acid-sensitive substrate with acetal and Boc-carbamate
moieties illustrates the complementarity of this method to
acid-mediated Fisher esterification (entries 2, 14).
The mild reaction conditions are highlighted by formation of
3o in 98% yield; no transesterification of the ethyl ester with
MeOH was observed (entry 15). To determine whether even
less basic conditions promote the reaction on useful synthetic
scale, methylation of 2p was investigated with KHCO3 (entry
16). Unsaturated ester 3p was isolated in 96% yield, confirming
that bicarbonate can effectively catalyze the esterification.
Although significant racemization has previously been
observed in DBU-mediated methylation reactions using
DMC,21 we hypothesized that epimerizable stereocenters
might be compatible with our mild, bicarbonate-catalyzed
method. R-Ibuprofen (2q), which might epimerize via an
enolate intermediate, was methylated in 87% yield with high
retention of stereochemistry (Table 3, entry 1).
Table 1. Optimization of Base-Catalyzed Esterification
a
b
c
d
entry
catalyst
solvent
-
T (°C)
yield % 3a
1
DBU
DBU
DBU
DBU
90
75
90
90
90
90
90
75
90
90
90
5
trace
20
2
CH3CN
DMF
3
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
58
5
DABCO
KOH
94
6
88
7
K2CO3
K2CO3
KHCO3
KH2PO4
Na2CO3
Cs2CO3
98
8
20
9
85
10
11
12
trace
87
DMSO
90
99
a
b
c
d
Ratio of 1:2a = 20:1. 0.2 equiv [2a] = 0.2 M. Determined by GC/
MS against an internal standard.
methylation proceeded regardless of the countercation used
(entries 11−12).
Potassium carbonate was chosen for further investigation
owing to its mild basicity, low cost, and high yield of product
formed. The conditions discovered through GC/MS screening
were readily adaptable to synthetically useful scale. Methyl
benzoate was synthesized on a 1 g scale in 93% isolated yield
(Table 2, entry 1), although increased catalyst loading (0.4
equiv) was necessary to maintain reasonable reaction time.
Unlike methylation with diazo reagents, no acidic quench was
required;3 pure 3a was obtained after simple aqueous workup
without need for further purification (see Experimental
Section).
Table 2. Scope of the Methylation
Given the importance of reactions to modify amino acids and
peptides without loss of stereochemical integrity, amino acid
substrates were also investigated.36 Methylated N-Boc-Ile (3r)
was obtained as a single observable diastereomer, while N-Boc-
Table 3. Methylation with Conservation of Stereochemistry
a
b
c
a
b
1 g scale. 0.2 equiv K2CO3 used as catalyst. 0.4 equiv KHCO3 used
as catalyst.
Enantiomeric ratio determined by polarimetry. Diastereomeric ratio
1
determined by H NMR.
B
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Phe (2s) was methylated with a 7% decrease in enantiomeric
ratio (Table 3, entries 2−3). Taken together, the syntheses of
enantioenriched 3q−3s suggest that bicarbonate-catalyzed
methylation is suitable even for epimerizable substrates.
Scheme 2. Isotope-Labeling Suggests Methyl Transfer
In previous methylations with DMC, chemoselectivity for
esterification has been difficult to achieve in substrates bearing
both carboxylic acid and phenol functional groups. Although
zeolite catalysts displayed promising selectivity,26 product
mixtures are often observed.24,37,38 Bifunctional substrate 4
was therefore investigated in reactions catalyzed by both
potassium carbonate and potassium bicarbonate (Scheme 1).
molecular excision of CO2 from 8 and intermolecular SN2-
type methyl transfer from 8 to a second molecule of 2a.40
Given the observed reactivity of 4 and 6, we initially favored
path a, but undertook further investigation.
Scheme 1. Chemoselective Esterification
To differentiate between paths a and b, an isotope-labeling
experiment was performed with doubly 18O-labeled benzoic
acid ([18O]2-2a, Scheme 2). The product mass corresponding
to doubly labeled [18O]2-3a was observed by GCMS, indicating
that both oxygen atoms originally present in [18O]2-2a are
retained in the product (see Experimental Section).
This result supports path b, a direct methyl transfer from
DMC to the substrate, and is inconsistent with path a. An SN2-
type methyl transfer from unactivated DMC (rather than 8) to
deprotonated 2a is also consistent with formation of [18O]2-2a.
To the best of our knowledge, this is the first conclusive
evidence for direct methyl transfer in esterification with DMC
absent a nucleophilic amine catalyst such as DBU. Overall, the
labeling study suggests that DMC is behaving like diazo-
methane and other electrophilic methyl transfer reagents, rather
than as a source of MeOH for a Fisher-type esterification.
In conclusion, a general base-catalyzed methylation of
carboxylic acids, including those in substrates with electron-
withdrawing groups, unprotected phenols, and epimerizable
stereocenters, has been developed. The mild reaction
conditions, formation of only MeOH and CO2 as reaction
byproducts, and use of inexpensive carbonate salts as catalysts
suggest that methyl transfer from DMC should be considered
as a viable alternative to common methods for the synthesis of
methyl esters.
Regardless of the catalyst used, esterification product 5 was
obtained in synthetically useful yield. Only trace (<5%)
1
etherification of the phenol was evident by H NMR analysis
of the crude reaction mixture, demonstrating high chemo-
selectivity for esterification.
The promising chemoselectivity observed with 4 suggested
that the reaction should be applicable to densely functionalized
substrates, such as 6 (Scheme 1). Under the standard reaction
conditions with KHCO3, only the carboxylic acid in 6 was
methylated; no reaction of the other potentially nucleophilic
moieties was observed. Methyl ester 7, which has potential
application as a component in sunscreens,39 was isolated in
92% yield, further demonstrating the compatibility of this
method with relatively complex, useful small molecules.
The mechanism of esterification with DMC in the absence of
nucleophilic amine catalysts such as DBU and DABCO is
unclear.22−27 Practical similarities between our carbonate-
catalyzed reaction and Shieh’s DBU-mediated methylation
suggest possible mechanistic parallels.20 Both proceed at 90 °C
with comparable reaction times. The DBU reaction is proposed
to proceed via a N-carbomethoxy ammonium intermediate
formed from DMC and DBU.20,30 A similarly cationic activated
intermediate is unlikely to form under the carbonate
conditions.
Based on the proposed mechanism for DBU-mediated
methylation,30 we hypothesize that DMC is activated prior to
the methylation step. Since activated covalent adducts of
catalysts such as KOH and K2CO3 with DMC are unlikely, we
propose the formation of carbonic carboxylic anhydride 8 by
reaction of the substrate (2a) with DMC (Scheme 2).40 Direct
methylation of carboxylic acids with unactivated DMC is also
possible, but is less consistent with studies of the DBU-
mediated methylation.30
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all reagents were
obtained commercially and used without further purification. 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 on 60 Å, 40−
63 μm silica gel using mixtures of ethyl acetate and hexanes as eluent.
GC/MS quantitation of reaction progress was accomplished by end-
point analysis using dimethyl pimelate as an internal standard. A GC
capillary column (0.25 mm × 30 m, 0.25 μM film thickness) was used.
1H and 13C NMR spectra were referenced to chloroform and recorded
at room temperature unless otherwise noted. Optical rotation was
determined at 589 nm. Enantiomeric ratios of both carboxylic acid
starting materials and methyl ester products were determined by
comparing observed optical rotations with previous literature reports
(see Supporting Information, Table S-1).
Methyl Benzoate (2a, CAS Registry: 93-58-3). To a 250 mL
round-bottom flask equipped with magnetic stir bar, reflux condenser,
and nitrogen inlet was added benzoic acid (2a) (1.00 g, 8.19 mmol, 1.0
equiv), DMSO (40 mL), and dimethylcarbonate (1) (13.8 mL, 160
mmol, 20.0 equiv). To the resulting solution was added potassium
carbonate (0.453 g, 3.28 mmol, 0.4 equiv). The reaction mixture was
stirred at 90 °C for 16 h and then cooled to room temperature. Ethyl
acetate (50 mL) was added, and the mixture was washed with water (2
There are two likely general mechanisms for ester formation
from 8: carbonyl substitution by MeOH liberated from DMC
(Scheme 2, path a) or direct transfer of a methyl group from
DMC to the carboxylate oxygen (Scheme 2, path b). Notably,
path b encompasses several possibilities, including intra-
C
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× 50 mL) and brine (1 × 50 mL). The organic layer was dried with
magnesium sulfate, filtered, and concentrated to yield methyl benzoate
(3a) as a clear liquid (1.043 g, 93% yield). The spectral data were
consistent with reported values.41 1H NMR (CDCl3, 300 MHz) δ 8.06
(m, 2 H), 7.57 (m, 1 H), 7.45 (m, 2 H), 3.94 (s, 3 H).
General Procedure for the Methylation of Carboxylic Acids
(2b−2s) with DMC. To a 25 mL round-bottom flask equipped with
magnetic stir bar, reflux condenser, and nitrogen inlet was added the
appropriate carboxylic acid (∼100 mg, 1 equiv), DMSO (0.2 M
substrate concentration), and DMC (20 equiv). To the resulting
solution was added potassium carbonate (0.4 equiv) in one portion.
The reaction mixture was magnetically stirred and heated to 90 °C for
16 h. After cooling to room temperature, the reaction was diluted with
ethyl acetate (15 mL), washed with water (2 × 10 mL) and brine (1 ×
10 mL), and dried with magnesium sulfate. Unless otherwise noted,
pure methyl ester was obtained upon removal of solvent.
Methyl Piperonylate (3b, CAS Registry: 326-56-7). Carboxylic
acid 2b (100 mg, 0.60 mmol) was reacted according to the general
procedure except that sodium sulfate replaced magnesium sulfate as
the drying agent. Methyl ester 3b was isolated as a white solid (106
mg, 98% yield). The spectral data were consistent with reported
values.42 1H NMR (CDCl3, 300 MHz) 7.64 (dd, 1 H, J = 8.2, 1.7 Hz),
7.47 (d, 1 H, J = 1.7 Hz), 6.85 (d, 1 H, J = 8.2 Hz), 6.03 (s, 2 H), 3.88
(s, 3 H).
Methyl 2-Methoxybenzoate (3c, CAS Registry: 606-45-1).
Carboxylic acid 2c (100 mg, 0.66 mmol) was reacted according to a
modified general procedure. A decreased catalyst loading of potassium
carbonate (18 mg, 0.13 mmol, 0.2 equiv) was used. After workup, the
crude reaction mixture was further purified by column chromatog-
raphy (9:1 hexanes/ethyl acetate eluent). Ester 3c was isolated as a
yellow oil (105 mg, 96% yield). The spectral data were consistent with
reported values.43 1H NMR (CDCl3, 300 MHz) δ 7.79 (dd, 1 H, J =
1.7, 7.9 Hz), 7.46 (m, 1 H), 6.97 (m, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H).
Methyl 4-(Methylthio)benzoate (3d, CAS Registry: 3795-79-
7). Carboxylic acid 2d (150 mg, 0.89 mmol) was reacted according to
the general procedure. Methyl ester 3d was isolated as an off-white
solid (157 mg, 97% yield). The spectral data were consistent with
reported values.44 1H NMR (CDCl3, 300 MHz) δ 7.95 (d, 2 H, J = 8.7
Hz), 7.26 (d, 2 H, J = 8.7 Hz), 3.92 (s, 3 H), 2.53 (s, 3 H).
Methyl 4-Cyanobenzoate (3e, CAS Registry: 1129-35-7).
Carboxylic acid 2e (100 mg, 0.68 mmol) was reacted according to
the general procedure except that sodium sulfate replaced magnesium
sulfate as the drying agent. Methyl ester 3e was isolated as a white
solid (102 mg, 93% yield). The spectral data were consistent with
reported values.43 1H NMR (CDCl3, 300 MHz) 8.14 (d, 2 H, J = 8.2
Hz), 7.77 (d, 2 H, J = 8.2 Hz), 3.97 (s, 3 H).
Methyl 4-Formylbenzoate (3f, CAS Registry: 1571-08-0).
Carboxylic acid 2f (101 mg, 0.67 mmol) was reacted according to
the general procedure. Methyl ester 3f was isolated as an off-white
solid (98 mg, 89% yield). The spectral data were consistent with
reported values.44 1H NMR (CDCl3, 500 MHz) δ 10.10 (s, 1 H), 8.19
(d, 2 H, J = 8.3 Hz), 7.95 (d, 2 H, J = 8.4 Hz), 3.96 (s, 3 H).
Methyl 4-Nitrobenzoate (3g, CAS Registry: 619-50-1).
Carboxylic acid 2g (100 mg, 0.60 mmol) was reacted according to
the general procedure. Methyl ester 3g was isolated as a pale-yellow
solid (93 mg, 86% yield). The spectral data were consistent with
reported values.45 1H NMR (CDCl3, 300 MHz) δ 8.3 (d, 2 H, J = 8.9
Hz), 8.2 (d, 2 H, J = 9.0 Hz), 4.0 (s, 3 H).
with reported values.41 1H NMR (CDCl3, 300 MHz) 7.81 (m, 2 H),
7.62 (m, 2 H), 3.95 (s, 3 H)
Methyl 2-Iodobenzoate (3j, CAS Registry: 610-97-9). Carbox-
ylic acid 2j (103 mg, 0.415 mmol) was reacted according to the
general procedure. Methyl ester 3j was isolated as a clear oil (96 mg,
88% yield). The spectral data were consistent with reported values.43
1H NMR (CDCl3, 300 MHz) δ 8.01 (dd, 1 H, J = 8.0, 1.0 Hz), 7.82
(dd, 1 H, J = 7.8, 1.7 Hz), 7.41 (dt, 1 H, J = 7.7, 1.2), 7.16 (dt, 1 H, J =
7.7, 1.7 Hz), 3.94 (s, 3 H).
2,3,5,6-Tetramethylbenzoic Acid Methyl Ester (3k, CAS
Registry: 22524-51-2). Carboxylic acid 2k (100 mg, 0.56 mmol)
was reacted according to the general procedure. After workup, the
crude reaction mixture was further purified by column chromatog-
raphy (50:1 hexanes/ethyl acetate eluent). Methyl ester 3k was
isolated as a white solid (97 mg, 90% yield). The spectral data were
consistent with reported values.46 1H NMR (CDCl3, 300 MHz) δ 7.02
(s, 1 H), 3.96 (s, 3 H), 2.25 (s, 6 H), 2.18 (s, 6 H).
Methyl Phenylacetate (3l, CAS Registry: 101-41-7). Carboxylic
acid 2l (112 mg, 0.82 mmol) was reacted according to the general
procedure. Methyl ester 3l was isolated as a white solid (110 mg, 89%
yield). The spectral data were consistent with reported values.47 1H
NMR (CDCl3, 300 MHz) δ 7.5−7.2 (m, 5 H), 3.73 (s, 3 H), 3.67 (s, 2
H).
2-Methyl-2-phenylpropionate Methyl Ester (3m, CAS Regis-
try: 57625-74-8). Carboxylic acid 2m (100 mg, 0.61 mmol) was
reacted according to the general procedure. Methyl ester 3m was
isolated as a white solid (99 mg, 91% yield). The spectral data were
consistent with reported values.48 1H NMR (CDCl3, 300 MHz) δ
7.5−7.2 (m, 5 H), 3.69 (s, 3 H), 1.64 (s, 6 H).
N-(tert-Butoxycarbonyl)glycine Methyl Ester (3n, CAS Regis-
try: 31954-27-5). Carboxylic acid 2n (100 mg, 0.57 mmol) was
reacted according to the general procedure. Methyl ester 3n was
isolated as a clear, colorless oil (82 mg, 76% yield). The spectral data
were consistent with reported values.45 1H NMR (CDCl3, 300 MHz) δ
5.3 (bs, 1 H), 3.9 (d, 2 H, J = 5.6 Hz), 3.74 (s, 3 H), 1.45 (s, 9 H).
Ethyl Methyl Adipate (3o, CAS Registry: 18891-13-9).
Carboxylic acid 2o (98 mg, 0.56 mmol) was reacted according to
the general procedure. After workup, the crude reaction mixture was
further purified by column chromatography (19:1 hexanes/ethyl
acetate eluent). Methyl ester 3o was isolated as a clear oil (103 mg,
98% yield). The spectral data were consistent with reported values.49
1H NMR (CDCl3, 300 MHz) δ 4.08 (2 H, q, J = 7.2 Hz), 3.62 (s, 3
H), 2.28 (m, 4 H), 1.62 (m, 4 H), 1.21 (t, 3 H, J = 7.2 Hz).
Methyl Cinnamate (3p, CAS Registry: 103-26-4). Carboxylic
acid 2p (100 mg, 0.68 mmol) was reacted according to a modified
general procedure. Potassium bicarbonate (27 mg, 0.27 mmol, 0.4
equiv) replaced potassium carbonate as the catalyst. Methyl ester 3p
was isolated as a white solid (105 mg, 96% yield). The spectral data
were consistent with reported values.45 1H NMR (CDCl3, 300 MHz) δ
7.7 (d, 1 H, J = 16.0 Hz), 7.5 (m, 2 H), 7.4 (m, 3 H), 6.5 (d, 1 H, J =
16.0 Hz), 3.8 (s, 3 H).
(S)-Ibuprofen Methyl Ester (3q, CAS Registry: 81576-55-8).
Carboxylic acid 2q (100 mg, 0.49 mmol, 91:9 er) was reacted
according to a modified general procedure. Potassium bicarbonate (19
mg, 0.19 mmol, 0.4 equiv) replaced potassium carbonate as the
catalyst. After workup, the crude reaction mixture was further purified
by column chromatography (50:1 hexanes/ethyl acetate eluent).
Methyl ester 3q was isolated as a white solid (93 mg, 87% yield, 88:12
er). 1H NMR (CDCl3, 300 MHz) δ 7.2 (d, 2 H, J = 8.0 Hz), 7.1 (d, 2
H, J = 8.0 Hz), 3.8 (q, 1 H, J = 7.2 Hz), 3.7 (s, 3 H), 2.5 (d, 2 H, J =
7.3 Hz), 1.9 (nonet, 1 H, J = 6.8 Hz), 1.5 (d, 3 H, J = 7.2 Hz), 0.9 (d, 6
H, J = 6.6 Hz). Optical rotation (see Table S-1 in Supporting
Methyl 2-Nitrobenzoate (3h, CAS Registry: 606-27-9).
Carboxylic acid 2h (134 mg, 0.80 mmol) was reacted according to
the general procedure. Methyl ester 3h was isolated as a white solid
(118 mg, 81% yield). The spectral data were consistent with reported
values.43 1H NMR (CDCl3, 300 MHz) δ 7.81 (m, 1 H), 7.8−7.6 (m, 3
H), 3.92 (s, 3 H).
Methyl 2-(Trifluoromethyl)benzoate (3i, CAS Registry: 344-
96-7). Carboxylic acid 2i (100 mg, 0.53 mmol) was reacted according
to the general procedure except that sodium sulfate replaced
magnesium sulfate as the drying agent. Methyl ester 3i was isolated
as a white solid (88 mg, 82% yield). The spectral data were consistent
Information [SI]): [α]D = +49.4 (c 1.00, CHCl3).
25
N-(tert-Butyloxycarbonyl)-L-isoleucine Methyl Ester (3r, CAS
Registry: 17901-01-8). Carboxylic acid 2r (125 mg, 0.54 mmol, >25:
1 dr) was reacted according to a modified general procedure.
Potassium bicarbonate (22 mg, 0.22 mmol, 0.4 equiv) replaced
potassium carbonate as the catalyst. Methyl ester 3r was isolated as a
clear, colorless oil (110 mg, 83% yield, >25: 1 dr). The spectral data
indicated the presence of a single diastereomer and were consistent
D
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with reported values.50 NMR data was acquired at elevated
temperature so that peaks arising from hindered rotation around the
amide bond coalesced. 1H NMR (CDCl3, 300 MHz, 47 °C) δ 5.0 (bs,
1 H), 4.2 (bs, 1 H), 3.7 (s, 3 H), 1.8 (bs, 1 H), 1.5−1.3 (m, 10 H),
1.2−1.0 (m, 1 H), 0.9−0.8 (m, 6 H).
(77%, M − (C[18O]2CH3)). The molecular ion peak corresponding to
[18O]-3a was also identified: 138.2 (3.1%, M). The molecular ion peak
corresponding to unlabeled 3a was also identified: 136.2 (0.2%, M).
The calculated percentages of product formed are 90.4% [18O]2-3a,
9.0% [18O]-3a, and 0.6% 3a.
N-(tert-Butyloxycarbonyl)-L-phenylalanine Methyl Ester (3s,
CAS Registry: 51987-73-6). Carboxylic acid 2s (100 mg, 0.377 mmol,
86:14 e.r) was reacted according to a modified general procedure.
Potassium bicarbonate (15 mg, 0.15 mmol, 0.4 equiv) replaced
potassium carbonate as the catalyst. After workup, the crude reaction
mixture was further purified by column chromatography (19:1
hexanes/ethyl acetate eluent). Methyl ester 3s was isolated as a
white solid (72 mg, 68% yield, 79:21 er). NMR data was acquired at
elevated temperature so that peaks arising from hindered rotation
ASSOCIATED CONTENT
■
S
* Supporting Information
Optical rotation data and comparison with literature data for
2q, 2s, 3q, and 3s. Copies of 1H NMR spectra for 2a−2s and 5.
1
Copies of H and 13C NMR spectra for 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
around the amide bond coalesced. H NMR (CDCl3, 300 MHz, 52
AUTHOR INFORMATION
Corresponding Author
*dgorin@smith.edu
Notes
■
°C) δ 7.2−7.3 (m, 3 H), 7.1 (m, 2 H), 5.0 (bs, 1 H), 4.6 (bs, 1 H), 3.7
(s, 3 H), 3.1 (m, 2 H), 1.4 (s, 9 H). Optical rotation (see Table S-1 in
SI): [α]D = +35.0 (c 1.00, CHCl3).
25
Methyl 3-(4-Hydroxyphenyl)propionate (5, CAS Regis-
try:5597-50-2). Carboxylic acid 4 (100 mg, 0.6 mmol) was reacted
according to the general procedure using either potassium carbonate
(33 mg, 0.24 mmol, 0.4 equiv) or potassium bicarbonate (24 mg, 0.15
mmol, 0.4 equiv) as the catalyst. After 14 h, the reactions were
subjected to the standard workup. The crude reaction mixtures were
further purified by column chromatography (9:1 hexanes/ethyl acetate
eluent). In the potassium carbonate-catalyzed case, 5 was isolated as a
clear oil (95 mg, 88% yield). In the potassium bicarbonate-catalyzed
case, 5 was isolated as a clear oil (94 mg, 86% yield). Spectral data
were consistent with reported values.51 1H NMR (CDCl3, 300 MHz) δ
7.05 (d, 2 H, J = 8.4 Hz), 6.79 (d, 2 H, J = 8.4 Hz), 6.68 (bs, 1 H),
3.70 (s, 3 H), 2.90 (t, 2 H, J = 7.5 Hz), 2.64 (t, 2 H, J = 7.5 Hz).
Methyl 2-(4-Dibutylamino-2-hydroxybenzoyl)benzoate (7,
CAS Registry: 302776-69-8). Carboxylic acid 6 (100 mg, 0.27
mmol) was reacted according to a modified general procedure.
Potassium bicarbonate (11 mg, 0.11 mmol, 0.4 equiv) replaced
potassium carbonate as the catalyst. After workup, the crude reaction
mixture was further purified by column chromatography (19:1
hexanes/ethyl acetate eluent). Methyl ester 7 was isolated as a yellow
oil (95 mg, 92% yield). Spectral data has not previously been reported
for 7. 1H NMR (CDCl3, 300 MHz) δ 12.63 (s, 1 H), 8.05 (dd, 1 H, J =
7.2, 1.2 Hz), 7.60 (td, 1 H, J = 7.2, 1.2 Hz), 7.52 (td, 1 H, J = 7.5, 1.5
Hz), 7.37 (dd, 1 H, J = 7.2, 1.2 Hz), 6.89 (d, 1 H, J = 9.0 Hz), 6.14 (d,
1 H, J = 2.4 Hz), 6.04 (dd, 1 H, J = 9.0, 2.4 Hz), 3.75 (s, 3 H,), 3.30 (t,
4 H, J = 7.5 Hz), 1.59 (m, 4 H), 1.34 (m, 4 H), 0.96 (t, 6 H, J = 7.5
Hz). 13C NMR (75 MHz) δ 198.5, 166.5, 165.3, 154.3, 140.8, 134.4,
132.1, 130.2, 129.1, 128.8, 127.9, 109.9, 103.9, 97.3, 52.3, 50.9, 29.4,
20.2, 13.9. HRMS (EI) m/z calcd for C23H29NO4 383.2097, found
383.2088.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the donors of the American
Chemical Society Petroleum Research Fund (#52706-UNI1)
for support of this research. Summer undergraduate research
fellowships were provided by the Smith College Provost’s
Office (J.S.) and Science Center (Y.J., J.Z.). We thank Dr.
Charles Amass (Smith College) for assistance with the GC/MS,
NMR spectrometers, and polarimeter. Mass spectral data were
obtained at the University of Massachusetts Mass Spectrometry
Center.
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