Palladium-Catalyzed Ortho-Alkoxylation of N-Benzoyl α-Amino Acid Derivatives at Room Temperature

Article abstract of DOI:10.1021/acs.joc.6b02257

An efficient palladium-catalyzed ortho-alkoxylation of N-benzoyl α-amino acid derivatives at room temperature has been explored. This novel transformation, using amino acids as directing groups, Pd(OAc)₂ as catalyst, alcohols as the alkoxylation reagents, and PhI(OAc)₂ as the oxidant, showed wide generality, good functional tolerance, and high monoselectivity and regioselectivity.

Full text of DOI:10.1021/acs.joc.6b02257

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Article
Palladium-catalyzed ortho-alkoxylation of N-
benzoyl #-amino acid derivatives at room temperature
Shuangjie Li, Wei Zhu, Feng Gao, Chunpu Li, Jiang Wang, and H. Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02257 • Publication Date (Web): 21 Nov 2016
Downloaded from http://pubs.acs.org on November 21, 2016
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Palladium-catalyzed ortho-alkoxylation of
N-benzoyl α-amino acid derivatives at room
temperature
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Shuangjie Li,† Wei Zhu,‡ Feng Gao,‡ Chunpu Li,‡ Jiang Wang,‡ and Hong Liu*‡
†School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009, P. R. China
‡Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
hliu@simm.ac.cn (Hong Liu)
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Graphic Abstract
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Abstract
An efficient palladiumꢀcatalyzed orthoꢀalkoxylation of Nꢀbenzoyl αꢀamino acid derivatives under
room temperature has been explored. This novel transformation, using amino acids as directing
groups, Pd(OAc)2 as catalyst, alcohols as the alkoxylation reagents and PhI(OAc)2 as the oxidant,
showed wide generality, good functional tolerance, high monoꢀselectivity and regioselectivity.
Introduction
Functionalized amino acid derivatives representing as important class of privilege structures have
been widely found in numerous biologically active compounds and natural products (Fig. 1).1
Among them, orthoꢀalkoxyl substituted Nꢀbenzoyl αꢀamino acid derivatives serve as useful
intermediates in drug discovery and medicinal chemistry.2 The construction of such scaffolds is
mainly achieved by Ullmann reaction, while the traditional methods often suffer from harsh reaction
conditions, preꢀfunctionalization of substrates and limited generality.3 Thus, there remains the need
to develop efficient and economical methodologies for elaborating amino acid derivatives under
mild condition.
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Figure 1. Bioactive orthoꢀalkoxyl substituted derivatives.
In past decades, selective C–H functionalization, assisted by directingꢀgroup has drawn
considerable attention and emerged as a powerful tool to construct CꢀC or CꢀX bonds.4 Very recently,
environmentally friendly and inexpensive amino acid moieties have been employed as novel
directing groups in CꢀH activation for the modification of amino acid derivatives (Scheme 1A).5 The
special structure of amino acid made itself as a feasible directing group without the necessary of
being removed and the products are very useful building blocks for making bioactive molecules.
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Scheme 1. Palladium-catalyzed C-H activation of amino acid derivatives.
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Despite the great progress of Pdꢀcatalyzed direct orthoꢀalkoxylation of the C(sp2)−H bonds has
been achieved,6 huge challenges still remain in the development of environmentally friendly and
efficient transformation systems for the selective monoꢀalkoxylation of C−H bonds under mild
conditions. Given the importance of αꢀamino acid derivatives, we herein report the
palladiumꢀcatalyzed alkoxylation of Nꢀbenzoyl αꢀamino acid derivatives under room temperature
(Scheme 1B).
Results and Discussion
To verify the hypothesis, we initiated our investigation of the direct orthoꢀmethoxylation of
Nꢀbenzoyl αꢀamino acid 1a. After extensive attempts, 2ꢀ(2ꢀmethoxybenzamido)ꢀ2ꢀmethylpropanoic
acid 2a was afforded in 29% yield with Pd(OAc)2 as catalyst and DMP as oxidant under room
temperature (Table 1, entry 1). As shown in Table 1, various oxidants, palladium catalysts and
solvents were screened for the best reaction condition. The oxidant had a remarkable impact on the
reaction yield, and the PhI(OAc)2 gave the best yield (Table 1, entry 4). The effect of different
solvents on the transformation was subsequently investigated. Among them, the mixed solvent of
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toluene led to slightly increase in yields, while other mixed solvents resulted in decrease in yields
(entries 5ꢀ9). Meanwhile, choosing toluene as coꢀsolvent is due to solubility. The yield was slightly
decreased with the presence of oxygen, which was consistent with earlier findings (entries 10−11).7
Compared with PdCl2, Pd(OAc)2 was proved to be the better catalyst (entry 12).
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Table 1. Optimization of reaction conditionsa
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O
O
[Pd-cat] (10mol%)
Oxdant
OH
OH
N
N
H
H
O
O
MeOH, solvent, r.t.
H
1a
OMe
2a
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Entry
Pdꢀcat
Oxidant
Solvent
Yield (%)
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NR b
NR b
83
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1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
DMP
MeOH
MeOH
MeOH
MeOH
2
NaIO3
3
Na2S2O8
4
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
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DCE/MeOH(1:1)
85
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CH3CN/MeOH(1:1) 78
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DMF/MeOH(1:1)
THF/MeOH(1:1)
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NR b
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PhMe/MeOH(1:1) 87
10 c
11 d
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PhMe/MeOH(1:1)
PhMe/MeOH(1:1)
PhMe/MeOH(1:1)
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a Unless otherwise specified, all the reactions were carried out with 0.2 mmol of 1a, 0.02 mmol of
Pdꢀcat and 0.3 mmol of oxidant under argon atmosphere at room temperature for 12 h. All listed
b
c
yields are isolated ones. NR = no reaction. The reaction were carried out under O2 atmosphere.
dThe reaction were carried out under Air.
With the optimal condition in hands, the substrates scope of Nꢀbenzoyl αꢀamino acid derivatives
was investigated (Table 2). Generally, various substituents both on the aromatic ring and αꢀamino
acid moieties were well tolerated in this direct alkoxylation reaction, and afforded the corresponding
monoꢀmethoxyl products in moderate to high yields (Table 2).
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Table 2. Scope of N-benzoyl α-amino acid derivativesa
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2b, 75%
2e, 73%
2c, 73%
2f, 75%
2i, 62%
2d, 92%
2g, 90%
2j, 67%
2h, 89% (ee% >99%)
2k, 72%
2n, 55%
2q, 88%
2l, 55%
2o, 62%
2m, 64%
2p, 57%
2s, 49%
2r, 60% (90%)b
aUnless otherwise specified, all the reactions were carried out with 0.2 mmol of 1,
0.02 mmol of Pd(OAc)2, 0.3 mmol of PhI(OAc)2, MeOH/toluene (1:1) as solvent
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under argon atmosphere at room temperature for 12 h. All listed yields are isolated
ones. bThe reaction was performed at 80 oC.cNR = no reaction.
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Cyclic amino acid derivatives worked well under standard conditions with high yields (2b-2d);
αꢀmonoꢀsubstituted amino acids derivatives proceeded smoothly with moderate to high yields
(2e-2h), while glycine derivative gave slightly lower yield (2i). Notably, the chirality of the amino
acids substrate was not influenced under this mild transformation condition (2h, ee > 99%),
guaranteeing further applications.
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The influence of different substituents at aromatic ring was evaluated. To our delight, both
electronꢀrich and electronꢀpoor amino acids derivatives were well tolerated without diꢀmethoxyl
products dectected. The protocol was found to be broadly applicable for this type of derivatives
bearing electronꢀdonating or withdrawing substituents on the phenyl ring (2jꢀ2l). Moreover,
halogens, such as F, Cl, Br, were well tolerated under the standard reaction conditions (2mꢀ2o). The
broad functional group tolerance highlights the potential utility of this reaction in the lateꢀstage
modification of complex molecules as well as in the total synthesis of natural products. The cleavage
of CꢀH bonds in metaꢀsubstituted substrates occurred predominantly at lessꢀhindered sites to give
moderate to good yields and excellent regioꢀselectivity, irrespective of the electronic nature of the
substituents (2q and 2r). The thiophene substrate also provided the desired products in moderate
yields (2s). However, substrate 2ꢀ(2ꢀmethoxybenzamido)ꢀ2ꢀmethylpropanoic acid did not afford
corresponding product. The alkoxylation reaction didn’t proceed when amino acid is protected
higher chain length analogues like phenyl acetyl. Importantly, we also carried it out on a gram scale
without any additives to afford 2a in 87% yield (Scheme 2).
Scheme 2. Gram-scale reaction.
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Next, we investigated a variety of linear and branched alcohols as coupling partners, which
demonstrated wide generality and moderate to high yields. Generally, the primary alcohols, such as
ethanol, propanol, 3ꢀtrifluoroꢀ1ꢀpropanol and phenylethanol could be transformed into the
corresponding ethers in excellent yields (3a-3d). The increased steric hindrance of benzyl alcohol
and branched alcohols led to decrease in yields, while the corresponding products could be afforded
in good yields under elevated temperature (3eꢀ3i). Unfortunately, the tertꢀbutoxy substituted product
could not be achieved under these reaction conditions, which indicated the important influence of the
steric effect.
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Table 3. Scope of various alcoholsa
3a, 95%
3b, 94%
3c, 83%
3d, 76%
3e, 46% (70%)b
3f, 72%
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O
O
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OH
N
H
O
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3g, 49%(82%)b
3h, 35% (85%)b
3i, 50%
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aUnless otherwise specified, all the reactions were carried out with 0.2 mmol of 1,
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0.02 mmol of Pd(OAc)2, 0.3 mmol of PhI(OAc)2, ROH/toluene (1:1) under argon
b
atmosphere at room temperature for 12 h. All listed yields are isolated ones. The
reaction was performed at 80 oC.
To obtain more insight into the mechanism, some controlled experiments were performed. The
addition of 2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl (TEMPO) as a radical quencher slightly inhibited
the reaction (Scheme 3, eq 1), suggesting that the reaction doesn’t involve a radical pathway. As
shown in Scheme 3, the KIE was observed to be 4.0 (Scheme 3, eq 2), indicating that the C−H bond
cleavage at the orthoꢀposition of Nꢀbenzoyl αꢀamino acid is most likely involved with the
rateꢀlimiting step. The carboxyl group of substrate was crucial to the reaction based on the fact that
substrate 1t or 1u was not transformed into corresponding products under the standard reaction
conditions (Scheme 3, eq 3). On the basis of previous literatures,6c, 7b, 8 a plausible mechanism was
proposed in Scheme 4. First, the coordination of nitrogen atom and oxygen atom to the Pd Catalyst
generates a palladium intermediate (I) followed by concerted metalation deprotonation (CMD)
process to produce the palladacycle complexes (II). Cyclopalladated intermediate (II) is then
oxidized to a highꢀvalent Pd intermediate (III) by PhI(OAc)2. In the presence of alcohol solvent, the
OAc ligands of (III) could be exchanged to form intermediate (IV), which could undergo C−OR RE
to give alkoxylated products.
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Scheme 3. Control Experiments
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Scheme 4. Plausible reaction mechanism.
O
O
O
H
N
H
OMe
2a
O
OH
N
H
Pd(OAc)2
OH
HOAc
1a
O
OMe
O
L
H
N
O
Pd
H
N
L
(IV)
O
O
Pd
O
OMe
L
(I)
MeOH
O
OAc
HOAc
O
H
N
O
Pd
H
N
L
O
L=OAc
O
Pd
O
OAc
PhI(OAc)2
L
(II)
(III)
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Conclusion
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In conclusion, we have successfully developed an efficient and environmentally friendly
palladiumꢀcatalyzed alkoxylation of C(sp2)−H bonds in αꢀamino acid derivatives under room
temperature. This reaction features broad substrate scopes, good tolerance, high monoꢀselectivity
and regioselectivity. This mild procedure will be of importance to medicinal chemists.
Experimental Section
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General Information. Unless otherwise noted, the reagents (chemicals) were purchased from
commercial sources, and used without further purification. Water was deionized before used.
Analytical thin layer chromatography (TLC) was HSGF 254 (0.15ꢀ0.2 mm thickness). Compound
spots were visualized by UV light (254 nm). Column chromatography was performed on silica gel
FCP 200ꢀ300. NMR spectra were run on 400 or 500 MHz instrument. Chemical shifts were reported
in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns are
described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Lowꢀ and
highꢀresolution mass spectra (LRMS and HRMS) were measured on spectrometer.
General procedure for the synthesis of substrates (1a-1s).
2ꢀAminoꢀ2ꢀmethylpropionic acid (2 g, 19.4 mmol) was dissolved in 1M NaOH aqueous solution (20
mL). The mixture was cooled to 0 °C, then benzoyl chloride (2.30 mL, 19.4 mmol) and 1M NaOH
aqueous solution (20 mL) were added dropwise simultaneously. The resulting mixture was stirred for
5 hours at room temperature. Then 1M HCl (60 mL) was added to the reaction mixture and stirred
for 10 minutes. The resulting solid was collected by filtration, washed with water and Et2O. The
desired product 1a was obtained as a white solid (3.02 g, 72%). Compounds 1b-1s were prepared in
a similar manner with different yields (45%ꢀ70%).
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General procedure for the alkoxylation of substrates
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Substrate 1 (0.2 mmol), PhI(OAc)2 (97 mg, 0.3 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), alcohol (1
mL) and toluene (1 mL) were added in a 25 mL tube under argon. The tube was sealed and the
mixture was stirred at room temperature for 12 h. After completion of the reaction, the solution was
concentrated by vacuum. The residue was purified by silica gel column using
(DCM/MeOH/HAc=100:5:1) as eluent to give the corresponding pure products.
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Determination of Intermolecular Kinetic Isotope Effect
Substrate benzoylalanine (1h) (0.2 mmol, 19 mg), (benzoylꢀ2,3,4,5,6ꢀd5)alanine (d5-1h) (0.2 mmol,
20 mg ), PhI(OAc)2 (97 mg, 0.3 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), methanol (1 mL) and
toluene (1 mL) were added in a 25 mL tube under argon. The mixture was stirred at room
temperature for 4 h, The solution was concentrated by vacuum. The residue was purified by silica
gel column using（DCM/MeOH/HAc=100:5:1）as eluent to give the corresponding pure product. The
ratio of 2h/ d4-2h was determined to be 8.00/2.00 (KIE = 4.0) by 1H NMR spectroscopy.
Chiral HPLC analysis of products
Sample A [racꢀ2ꢀbenzamidopropanoic acid (were prepared under epimerizationꢀfree condition from
racꢀ2ꢀaminopropanoic acid)], Sample B [Dꢀ2ꢀbenzamidopropanoic acid (were prepared under
epimerizationꢀfree condition from Dꢀ2ꢀaminopropanoic acid), Sample C synthesized from Sample A
(which is the product of direct CꢀH alkoxylation of racꢀ2ꢀbenzamidopropanoic acid under standard
protocol)] and Sample D synthesized from Sample B (which is the product of direct CꢀH
alkoxylation of Dꢀ2ꢀbenzamidopropanoic acid under standard protocol)] were separated by Chiral
HPLC using a ChiralcelꢀIC column (25% iꢀPrOH and 0.5% CF3COOH in hexanes, flow rate 0.3
mL/min, UV lamp 215 or 254 nm). In the HPLC profile of Sample A, the two peaks correspond to 1:
1 mixture of Dꢀ2ꢀbenzamidopropanoic acid (tR = 17.3 min) and Lꢀ2ꢀbenzamidopropanoic acid (tR =
20.1 min). In the HPLC profile of Sample B, the peak corresponds to Dꢀ2ꢀbenzamidopropanoic acid
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(tR = 17.3 min). In the HPLC profile of Sample C, peak corresponds to 1: 1 mixture of
Dꢀ2ꢀ(2ꢀmethoxybenzamido)propanoicacid (tR = 39.1 min) and Lꢀ2ꢀ(2ꢀmethoxybenzamido)propanoic
acid (tR = 48.6 min). In the HPLC profile of Sample D, peak corresponds to
Dꢀ2ꢀ(2ꢀmethoxybenzamido)propanoic acid, which indicates that no diastereomer of product was
observed.
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Analytical Characterization Data of Products.
2-(2-methoxybenzamido)-2-methylpropanoic acid (1a): This compound is known.9a 1H NMR
(400 MHz, MeODꢀd4) δ 8.46 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.46 (t, J =
7.7 Hz, 2H), 1.61 (s, 6H).
1-benzamidocyclopropane-1-carboxylic acid (1b): This compound is known.9a Compound 1b was
prepared in a similar manner as described for compound 1a. 1H NMR (400 MHz, DMSOꢀd6) δ 12.36
(s, 1H), 8.95 (s, 1H), 7.86 – 7.82 (m, 2H), 7.52 (d, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 1.40 (dd,
J = 7.7, 4.4 Hz, 2H), 1.09 (dd, J = 7.7, 4.4 Hz, 2H).
1-benzamidocyclopentane-1-carboxylic acid (1c): This compound is known.9b Compound 1c was
prepared in a similar manner as described for compound 1a. 1H NMR (400 MHz, DMSOꢀd6) δ 12.13
(s, 1H), 8.50 (s, 1H), 7.86 – 7.81 (m, 2H), 7.55 – 7.50 (m, 1H), 7.46 (t, J = 7.5 Hz, 2H), 2.13 (m, 2H),
2.09 – 2.00 (m, 2H), 1.75 – 1.61 (m, 4H).
1-benzamidocyclohexane-1-carboxylic acid (1d): This compound is known.9c Compound 1d was
prepared in a similar manner as described for compound 1a. 1H NMR (400 MHz, DMSOꢀd6) δ 12.18
(s, 1H), 8.26 (s, 1H), 7.87 (d, J = 7.3 Hz, 2H), 7.56 (d, J = 6.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 2.16
(m, 2H), 1.83 – 1.70 (m, 2H), 1.57 (m, 5H), 1.32 (m, 1H).
2-benzamido-2-phenylacetic acid (1e): This compound is known.9d Compound 1e was prepared in
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a similar manner as described for compound 1a. H NMR (400 MHz, DMSOꢀd6) δ 12.93 (s, 1H),
9.06 (d, J = 7.4 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 7.50 (m, 5H), 7.37 (m, 3H), 5.61 (d, J = 7.4 Hz,
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1H).
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Benzoylvaline (1f): This compound is known.9e Compound 1f was prepared in a similar manner as
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described for compound 1a. H NMR (400 MHz, DMSOꢀd6) δ 12.60 (s, 1H), 8.42 (d, J = 8.2 Hz,
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1H), 7.88 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 4.28 (dd, J = 8.0,
6.0 Hz, 1H), 2.19 (m, 1H), 0.97 (m, 6H).
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2-benzamidobutanoic acid (1g): This compound is known.9e White Compound 1g was prepared in
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a similar manner as described for compound 1a. H NMR (400 MHz, DMSOꢀd6) δ 12.56 (s, 1H),
8.55 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.3 Hz, 2H), 7.57 – 7.51 (m, 1H), 7.47(m, 2H), 4.30 (ddd, J =
9.2, 7.8, 5.1 Hz, 1H), 1.92 – 1.81 (m, 1H), 1.81 – 1.73 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H).
benzoyl-L-alanine (1h): This compound is known.9e White Compound 1h was prepared in a similar
manner as described for compound 1a. 1H NMR (400 MHz, DMSOꢀd6) δ 12.53 (s, 1H), 8.65 (d, J =
7.2 Hz, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.47 (m, 2H), 4.44 – 4.40 (m, 1H),
1.39 (d, J = 7.4 Hz, 3H).
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(benzoyl-2,3,4,5,6-d5)alanine (d5-1h): H NMR (400 MHz, MeODꢀd4) 1H NMR (400 MHz,
MeODꢀd4) δ 4.62 (q, J = 7.3 Hz, 1H), 1.54 (d, J = 7.3 Hz, 3H).
benzoylglycine(1i): This compound is known.9e Compound 1i was prepared in a similar manner as
described for compound 1a. 1H NMR (400 MHz, MeODꢀd4) δ 7.90 – 7.79 (d, J = 8.4 Hz, 2H), 7.52
(d, J = 7.4 Hz, 1H), 7.49 – 7.37 (m, 2H), 4.09 (s, 2H).
2-methyl-2-(4-methylbenzamido)propanoic acid (1j): This compound is known.9f Compound 1j
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was prepared in a similar manner as described for compound 1a. H NMR (400 MHz, DMSOꢀd6) δ
12.19 (s, 1H), 8.36 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H), 1.45 (s,
6H).
2-(4-methoxybenzamido)-2-methylpropanoic acid (1k): This compound is known.9f Compound
1k was prepared in a similar manner as described for compound 1a. 1H NMR (400 MHz, DMSOꢀd6)
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δ 12.12 (s, 1H), 8.28 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 1.43 (s,
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2-([1,1'-biphenyl]-4-carboxamido)-2-methylpropanoic acid (1l): Compound 1l was prepared in a
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similar manner as described for compound 1a. White solid, 2.3 g, 56% yield. Mp: 156ꢀ158 °C. H
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NMR (400 MHz, DMSOꢀd6) δ 12.28 (s, 1H), 8.52 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.2
Hz, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 7.4 Hz, 1H), 1.47 (s, 6H). 13C
{1H} NMR (125 MHz, DMSOꢀd6) δ 176.0, 165.9, 143.1, 139.6, 129.5, 128.6, 127.3, 126.8, 55.9,
25.5. LRMS (ESI) [MꢀH]+ m/z found: 282.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C17H16NO3
282.1136, found 282.1132.
2-(4-fluorobenzamido)-2-methylpropanoic acid (1m): Compound 1m was prepared in a similar
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manner as described for compound 1a. White solid, 1.6 g, 46% yield. Mp: 167ꢀ169 °C. H NMR
(400 MHz, DMSOꢀd6) δ 12.22 (s, 1H), 8.49 (s, 1H), 7.93 (dd, J = 12.3, 5.3 Hz, 2H), 7.29 (dd, J =
12.3, 5.3 Hz, 2H), 1.45 (s, 6H). 13C {1H} NMR (125 MHz, DMSOꢀd6) δ 176.0, 165.2, 165.1, 163.5,
131.2, 131.1, 130.7, 130.6, 115.5, 115.4, 55.9, 25.4. LRMS (ESI) [MꢀH]+ m/z found: 224.0. HRMS
(ESIꢀTOF) [MꢀH]+ m/z calcd for C11H11FNO3 224.0728, found 224.0724.
2-(4-chlorobenzamido)-2-methylpropanoic acid (1n): Compound 1n was prepared in a similar
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manner as described for compound 1a. White solid, 2.5 g, 56% yield. Mp: 185ꢀ187 °C. H NMR
(400 MHz, DMSOꢀd6) δ 8.56 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H, 7.53 (d, J = 8.5 Hz, 2H), 1.45 (s, 6H).
13C {1H} NMR (125 MHz, DMSOꢀd6) δ 175.96, 165.31, 136.54, 133.41, 129.90, 128.71, 56.00,
25.40. LRMS (ESI) [MꢀH]+ m/z found: 240.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for
C11H11ClNO3 240.0433, found 240.0429.
2-(4-bromobenzamido)-2-methylpropanoic acid (1o): Compound 1o was prepared in a similar
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manner as described for compound 1a. White solid, 1.3 g, 55% yield. Mp: 162ꢀ165 °C. H NMR
(400 MHz, DMSOꢀd6) δ 12.23 (s, 1H), 8.55 (s, 1H), 7.80 (dd, J = 8.8, 2.0 Hz, 2H), 7.68(dd, J = 8.8,
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2.0 Hz, 2H), 1.45 (s, 6H). 13C {1H} NMR (125 MHz, DMSOꢀd6) δ 175.9, 165.3, 133.7, 131.6, 130.1,
125.4, 55.9, 25.4. LRMS (ESI) [MꢀH]+ m/z found: 283.9. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for
C11H11BrNO3 283.9928, found 283.9924.
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2-methyl-2-(4-(trifluoromethyl)benzamido)propanoic acid (1p): Compound 1p was prepared in a
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similar manner as described for compound 1a. White solid, 3.1 g, 60% yield. Mp: 134ꢀ136 °C. H
NMR (400 MHz, DMSOꢀd6) δ 12.30 (s, 1H), 8.73 (s, 1H), 8.05 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.2
Hz, 2H), 1.47 (s, 6H). C {1H} NMR (125 MHz, DMSOꢀd6) δ 175.8, 165.2, 138.5, 131.6, 131.4,
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128.8, 125.7, 125.6, 125.3, 123.5, 56.1, 25.3. LRMS (ESI) [MꢀH]+ m/z found: 274.0. HRMS
(ESIꢀTOF) [MꢀH]+ m/z calcd for C12H11F3NO3 274.0697, found 274.0690.
2-methyl-2-(3-methylbenzamido)propanoic acid (1q): Compound 1q was prepared in a similar
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manner as described for compound 1a. White solid, 2.4 g, 44% yield. Mp: 165ꢀ167 °C. H NMR
(400 MHz, MeODꢀd4) δ 7.67 (s, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.41 – 7.32 (m, 2H), 2.43 (s, 3H),
1.62 (s, 6H). 13C {1H} NMR (125 MHz, DMSOꢀd6) δ 176.1, 166.1, 141.5, 131.9, 129.1, 127.9, 55.8,
25.5, 21.4. LRMS (ESI) [MꢀH]+ m/z found: 220.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for
C12H14NO3 220.0979, found 220.0975.
2-methyl-2-(3-(trifluoromethyl)benzamido)propanoic acid (1r): Compound 1r was prepared in a
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similar manner as described for compound 1a. White solid, 2.1 g, 34% yield. Mp: 145ꢀ147 °C. H
NMR (400 MHz, MeODꢀd4) δ 8.71 (s, 1H), 8.11 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.9
Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 1.57 (s, 6H). 13C {1H} NMR (125 MHz, DMSOꢀd6) δ 175.8, 164.8,
135.4, 132.1, 130.0, 129.5, 129.3, 128.3, 125.4, 124.5, 124.4, 123.5, 56.1, 25.3. LRMS (ESI) [MꢀH]+
m/z found: 274.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C12H11F3NO3 274.0697, found 274.0693.
2-methyl-2-(thiophene-2-carboxamido)propanoic acid (1s): Compound 1s was prepared in a
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similar manner as described for compound 1a. White solid, 2.3 g, 56% yield. Mp: 134ꢀ136 °C. H
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NMR (400 MHz, MeODꢀd4) δ 8.40 (s, 1H), 7.76 (d, J = 3.7 Hz, 1H), 7.64 (d, J = 5.0 Hz, 1H), 7.12
(dd, J = 4.9, 3.8 Hz, 1H), 1.58 (s, 6H). 13C {1H} NMR (125 MHz, DMSOꢀd6) δ 175.9, 161.1, 140.3,
131.3, 129.0, 128.3, 55.9, 25.5. LRMS (ESI) [MꢀH]+ m/z found: 212.0. HRMS (ESIꢀTOF) [MꢀH]+
m/z calcd for C9H10NO3S 212.0387, found 212.0381.
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2-(2-methoxybenzamido)-2-methylpropanoic acid (2a): This compound is known.9g White solid,
41 mg, 87% yield. Mp: 142ꢀ144 °C. 1H NMR (400 MHz, MeODꢀd4) δ 8.99 (s, 1H), 7.91 (dd, J = 7.8,
1.7 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.04 (t, J = 8.1 Hz, 1H), 3.99 (s,
3H), 1.63 (s, 6H). 13C {1H} NMR (125 MHz, MeODꢀd4) δ 178.5, 167.3, 159.7, 134.8, 132.5, 123.3,
122.5, 113.5, 58.2, 57.1, 25.6. LRMS (ESI) [MꢀH]+ m/z found: 236.0. LRMS (ESI) [MꢀH]+ m/z
found: 236.0. HRMS (ESIꢀTOF) [MꢀH ] + m/z calcd for C12H14NO4 236.0923, found 236.0919.
1-(2-methoxybenzamido)cyclopropane-1-carboxylic acid (2b)； Compound 2b was prepared in a
similar manner as described for compound 2a. White solid, 35 mg, 75% yield. Mp: 108ꢀ110 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 7.93 – 7.82 (m, 3H), 7.48 (dd, J = 8.8, 2.2 Hz, 1H), 7.16 – 7.11 (m,
1H), 7.04 (t, J = 7.5 Hz, 1H), 3.95 (s, 3H), 1.61 – 1.54 (m, 2H), 1.21 – 1.26 (m, 2H). 13C {1H} NMR
(125 MHz, MeODꢀd4) δ 169.8, 159.7, 134.7, 132.6, 123.5, 122.3, 113.4, 57.0, 18.4. LRMS (ESI)
[MꢀH]+ m/z found: 234.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C12H12NO4 234.0766, found
234.0760.
1-(2-methoxybenzamido)cyclopentane-1-carboxylic acid (2c): Compound 2c was prepared in a
similar manner as described for compound 2a. White solid, 38 mg, 73% yield. Mp: 106ꢀ108 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 7.87 (dd, J = 7.7, 1.6 Hz, 1H), 7.52 – 7.44 (m, 1H), 7.14 (d, J = 8.5
Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 3.98 (s, 3H), 2.25 – 2.34 (m, 2H), 2.14 – 2.07 (m, 2H), 1.80 – 1.89
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(m, 4H). C {1H} NMR (125 MHz, MeODꢀd4) δ 178.3, 167.9, 159.6, 134.7, 132.43, 123.4, 122.5,
113.5, 67.8, 57.1, 38.7, 26.2. LRMS (ESI) [MꢀH]+ m/z found: 262.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z
calcd for C14H16NO4 262.1079, found 262.1073.
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1-(2-methoxybenzamido)cyclohexane-1-carboxylic acid (2d): This compound is known.9d
Compound 2d was prepared in a similar manner as described for compound 2a. White solid, 51 mg,
92% yield. Mp: 103ꢀ105 °C. 1H NMR (400 MHz, MeODꢀd4) δ 8.50 (s, 1H), 7.93 – 7.78 (m, 1H),
7.50 (ddd, J = 11.0, 8.9, 2.3 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 4.02 (s, 3H),
2.13 – 2.24 (m, 2H), 1.81 – 1.90 (m, 2H), 1.64 – 1.76 (m, 4H), 1.47 – 1.61 (m, 2H). 13C {1H} NMR
(125 MHz, MeODꢀd4) δ 182.3, 171.2, 163.6, 138.8, 136.5, 126.5, 119.3, 117.5, 64.5, 61.2, 37.7,
30.8, 27.1. LRMS (ESI) [MꢀH]+ m/z found: 276.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for
C15H18NO4 276.1236, found 276.1228.
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2-(2-methoxybenzamido)-2-phenylacetic acid (2e): Compound 2e was prepared in a similar
manner as described for compound 2a. White solid, 42 mg, 73% yield. Mp: 173ꢀ175 °C. 1H NMR
(400 MHz, MeODꢀd4) δ 7.97 (dd, J = 7.8, 1.6 Hz, 1H), 7.52 – 7.55 (m, 1H), 7.49 – 7.51 (m, 2H),
7.35 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H),
5.53 (s, 1H), 4.06 (s, 3H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 172.4, 164.6, 157.6, 137.7, 132.7,
130.4, 127.7, 127.0, 126.3, 120.2, 120.0, 111.2, 57.4, 54.0. LRMS (ESI) [MꢀH]+ m/z found: 284.0.
HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C16H14NO4 284.0923, found 284.0915.
(2-methoxybenzoyl)valine (2f): Compound 2f was prepared in a similar manner as described for
compound 2a. White solid, 37 mg, 75% yield. Mp: 133ꢀ135 °C. 1H NMR (400 MHz, MeODꢀd4) δ
8.00 – 7.89 (m, 1H), 7.56 – 7.48 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 4.59 (d,
J = 4.6 Hz, 1H), 4.02 (s, 3H), 2.38 – 2.23 (m, 1H), 1.03 (dd, J = 6.8, 1.4 Hz, 6H).13C {1H} NMR
(125 MHz, MeODꢀd4) δ 175.6, 167.9, 159.8, 135.0, 132.9, 122.7, 122.6, 113.6, 59.9, 57.3, 32.8, 20.1,
18.7. LRMS (ESI) [MꢀH]+ m/z found: 250.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C13H16NO4
250.1079 found 250.1075.
2-(2-methoxybenzamido)butanoic acid (2g): Compound 2g was prepared in a similar manner as
described for compound 2a. White solid, 43 mg, 90% yield. Mp: 126ꢀ128 °C. 1H NMR (400 MHz,
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MeODꢀd4) δ 8.00 – 7.88 (m, 1H), 7.52 (ddd, J = 8.9, 8.0, 2.3 Hz, 1H), 7.19 (dd, J = 8.6, 3.2 Hz, 1H),
7.08 (t, J = 7.6 Hz, 1H), 4.67 – 4.51 (m, 1H), 4.02 (s, 3H), 2.09 – 1.97 (m, 1H), 1.83 – 1.94(m, 1H),
1.00 (td, J = 7.4, 3.1 Hz, 3H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 176.0, 167.8, 159.8, 135.0,
132.7, 127.6, 122.5, 113.6, 57.2, 55.9, 26.7, 10.3. LRMS (ESI) [MꢀH]+ m/z found: 236.0. HRMS
(ESIꢀTOF) [MꢀH]+ m/z calcd for C12H14NO4 236.0923, found 236.0924.
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(2-methoxybenzoyl)-L-alanine (2h): Compound 2h was prepared in a similar manner as described
for compound 2a. White solid, 40 mg, 89% yield. Mp: 120ꢀ122 °C. 1H NMR (400 MHz, MeODꢀd4)
δ 8.00 – 7.88 (m, 1H), 7.51 (ddd, J = 10.2, 8.7, 2.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 7.6
Hz, 1H), 4.68 – 4.52 (m, 1H), 4.01 (d, J = 1.7 Hz, 3H), 1.52 (d, J = 7.1 Hz, 3H).13C {1H} NMR (125
MHz, MeODꢀd4) δ 167.6, 159.9, 135.0, 132.7, 122.7, 122.5, 113.5, 57.1, 19.1. LRMS (ESI) [MꢀH]+
m/z found: 222.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C11H12NO4 222.0766, found 222.0760.
(2-methoxybenzoyl)glycine (2i): This compound is known.9i Compound 2i was prepared in a
similar manner as described for compound 2a. White solid, 26 mg, 62% yield. Mp: 117ꢀ119 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 8.00 (dd, J = 7.8, 1.8 Hz, 1H), 7.51 (ddd, J = 8.4, 7.3, 1.9 Hz, 1H),
7.14 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 4.14 (s, 2H), 3.99 (s, 3H).13C {1H} NMR (101
MHz, MeODꢀd4) δ 173.6, 168.3, 159.9, 135.0, 132.8, 122.4, 113.4, 57.0, 43.1. LRMS (ESI) [MꢀH]+
m/z found: 208.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C10H10NO4 208.0610, found 208.0607.
2-(2-methoxy-4-methylbenzamido)-2-methylpropanoic acid (2j): Compound 2j was prepared in a
similar manner as described for compound 2a. White solid, 34 mg, 67% yield. Mp: 98ꢀ100 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 8.90 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 6.89 (d, J = 8.0
Hz, 1H), 4.00 (s, 3H), 2.40 (s, 3H), 1.65 (s, 6H).13C {1H} NMR (150 MHz, MeODꢀd4) δ 165.3,
157.8, 144.1, 130.7, 121.4, 118.5, 114.4, 112.2, 61.2, 55.1, 23.7, 20.3. LRMS (ESI) [MꢀH]+ m/z
found: 250.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C13H16NO4 250.1079, found 250.1029.
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2-(2,4-dimethoxybenzamido)-2-methylpropanoic acid (2k): Compound 2k was prepared in a
similar manner as described for compound 2a. White solid, 38 mg, 72% yield. Mp: 112ꢀ114 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 7.91 (d, J = 8.9, 1H), 6.63 (m, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 1.64 (s,
6H).13C {1H} NMR (100 MHz, MeODꢀd4) δ 178.6, 166.9, 165.9, 161.2, 134.3, 115.6, 107.3, 99.9,
57.12, 56.5, 25.7. LRMS (ESI) [MꢀH]+ m/z found: 266.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for
C13H16NO5 266.1028, found 266.1024.
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2-(3-methoxy-[1,1'-biphenyl]-4-carboxamido)-2-methylpropanoic acid (2l): Compound 2l was
prepared in a similar manner as described for compound 2a. White solid, 34 mg, 55% yield. Mp:
156ꢀ158 °C. 1H NMR (400 MHz, MeODꢀd4) δ 9.01 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.68 (dd, J =
8.3, 1.3 Hz, 2H), 7.48 – 7.44 (m, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.32 (dd, J
= 8.1, 1.6 Hz, 1H), 4.08 (s, 3H), 1.66 (s, 6H).13C {1H} NMR (100 MHz, MeODꢀd4) δ 166.9, 160.07,
148.0, 141.7, 133.2, 130.5, 129.7, 128.7, 122.1, 122.0, 121.0, 111.9, 58.5, 57.2, 25.6. LRMS (ESI)
[MꢀH]+ m/z found: 312.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C18H18NO4 312.1236, found
312.1234.
2-(4-fluoro-2-methoxybenzamido)-2-methylpropanoic acid (2m): Compound 2m was prepared in
a similar manner as described for compound 2a. White solid, 33 mg, 64% yield. Mp: 86ꢀ88 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 8.81 (s, 1H), 7.97 (dd, J = 8.6, 7.1 Hz, 1H), 6.97 (dd, J = 11.0, 2.3 Hz,
1H), 6.82 (td, J = 8.3, 2.3 Hz, 1H), 4.02 (s, 3H), 1.65 (s, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ
174.7, 163.5, 157.3, 130.6, 115.9, 105.1, 97.5, 54.3, 53.6, 21.6. LRMS (ESI) [MꢀH]+ m/z found:
254.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C12H13NO4F 254.0829, found 254.0829.
2-(4-chloro-2-methoxybenzamido)-2-methylpropanoic acid (2n): Compound 2n was prepared in
a similar manner as described for compound 2a. White solid, 30 mg, 55% yield. Mp: 112ꢀ114 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 8.91 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.09
(dd, J = 8.4, 1.8 Hz, 1H), 4.03 (s, 3H), 1.65 (s, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 165.0,
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159.0, 138.9, 132.6, 121.4, 121.3, 112.9, 56.4, 24.3. LRMS (ESI) [MꢀH]+ m/z found: 270.0. HRMS
(ESIꢀTOF) [MꢀH]+ m/z calcd for C12H13NO4Cl 270.0533, found 270.0531.
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2-(4-bromo-2-methoxybenzamido)-2-methylpropanoic acid (2o): Compound 2o was prepared in
a similar manner as described for compound 2a. White solid, 39 mg, 62% yield. Mp: 116ꢀ118 °C.
1H NMR (400 MHz, MeODꢀd4) δ 8.90 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.23 (dd, J =
8.3, 1.4 Hz, 1H), 4.02 (s, 3H), 1.65 (s, 6H).13C {1H} NMR (100 MHz, MeODꢀd4) δ 166.3, 160.0,
133.9, 128.3, 125.7, 122.8, 117.0, 58.6, 57.6, 25.5. LRMS (ESI) [MꢀH]+ m/z found: 314.0. HRMS
(ESIꢀTOF) [MꢀH]+ m/z calcd for C12H13BrNO4 314.0028, found 314.0019, 316.003.
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2-(2-methoxy-4-(trifluoromethyl)benzamido)-2-methylpropanoic acid (2p): Compound 2p was
prepared in a similar manner as described for compound 2a. White solid, 35 mg, 57% yield. Mp:
160ꢀ162 °C.1H NMR (400 MHz, MeODꢀd4) δ 8.99 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H),
7.37 (d, J = 8.3 Hz, 1H), 4.07 (s, 3H), 1.66 (s, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 177.7,
164.9, 158.4, 134.52, 132.0, 126.6, 124.2, 117.7, 109.23,57.5, 56.4, 24.3. LRMS (ESI) [MꢀH]+ m/z
found: 304.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C13H13NO4F3 304.0797, found 304.0793.
2-(2-methoxy-5-methylbenzamido)-2-methylpropanoic acid (2q): Compound 2q was prepared in
a similar manner as described for compound 2a. White solid, 44 mg, 88% yield. Mp: 142ꢀ144 °C. 1H
NMR (400 MHz, MeODꢀd4) δ 8.93 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.4, 2.2 Hz, 1H),
7.04 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 1.65 (s, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 178.8,
167.31, 157.6, 135.1, 132.7, 131.9, 122.8, 113.5, 58.3, 57.1, 25.6, 20.9. LRMS (ESI) [MꢀH]+ m/z
found: 250.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C13H16NO4 250.1079, found 250.1074.
2-(2-methoxy-5-(trifluoromethyl)benzamido)-2-methylpropanoic acid (2r): Compound 2r was
prepared in a similar manner as described for compound 2a. White solid, 37 mg, 60% yield. Mp:
177ꢀ179 °C. 1H NMR (400 MHz, MeODꢀd4) δ 8.19 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 8.7, 2.1 Hz,
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1H), 7.34 (d, J = 8.7 Hz, 1H), 4.09 (s, 3H), 1.66 (s, 6H). C {1H} NMR (125 MHz, MeODꢀd4) δ
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178.6, 165.8, 162.0, 131.4, 129.4, 126.1, 124.4, 124.4, 114.2, 58.5, 57.6, 25.5. LRMS (ESI) [MꢀH]+
m/z found: 304.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C13H13NO4F3 304.0797, found 304.0790.
2-(3-methoxythiophene-2-carboxamido)-2-methylpropanoic acid (2s): Compound 2s was
prepared in a similar manner as described for compound 2a. White solid, 24 mg, 49% yield. Mp:
137ꢀ139 °C. 1H NMR (400 MHz, MeODꢀd4) δ 8.13 (s, 2H), 7.61 (d, J = 5.5 Hz, 1H), 7.08 (d, J = 5.5
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Hz, 1H), 4.08 (s, 3H), 1.65 (s, 6H). C {1H} NMR (125 MHz, MeODꢀd4) δ 178.5, 163.6, 159.4,
131.1, 117.6, 117.2, 60.3, 58.1, 25.7. LRMS (ESI) [MꢀH]+ m/z found: 242.0. HRMS (ESIꢀTOF)
[MꢀH]+ m/z calcd for C10H12NO4S 242.0487, found 242.0482.
2-(2-ethoxybenzamido)-2-methylpropanoic acid(3a): Compound 3a was prepared in a similar
manner as described for compound 2a. White solid, 49 mg, 95% yield. Mp: 137ꢀ139 °C. 1H NMR
(400 MHz, MeODꢀd4) δ 9.02 (s, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.5 Hz 2H), 7.14 (d, J =
8.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 4.26 (q, J = 6.9 Hz, 2H), 1.66 (s, 6H), 1.56 (t, J = 7.0 Hz,
3H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 167.2, 159.1, 134.7, 132.5, 123.2, 122.4, 114.40, 66.6,
25.7, 15.6. LRMS (ESI) [MꢀH]+ m/z found: 250.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for
C13H16NO4 250.1079, found 250.1078.
2-methyl-2-(2-propoxybenzamido)propanoic acid (3b): Compound 3b was prepared in a similar
manner as described for compound 2a. White solid, 50 mg, 94% yield. Mp: 167ꢀ169 °C. 1H NMR
(400 MHz, MeODꢀd4) δ 8.86 (s, 1H), 7.92 (dd, J = 7.8, 1.7 Hz, 1H), 7.55 – 7.33 (m, 1H), 7.12 (d, J =
8.3 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 1.99 – 1.88 (m, 2H), 1.63 (s, 6H), 1.10
(t, J = 7.4 Hz, 3H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 178.5, 167.3, 159.1, 134.8, 132.5, 123.2,
122.3, 114.3, 72.5, 58.2, 25.9, 24.0, 11.6. LRMS (ESI) [MꢀH]+ m/z found: 264.0. HRMS (ESIꢀTOF)
[MꢀH]+ m/z calcd for C14H18NO4 264.1236, found 264.1240.
2-methyl-2-(2-(3,3,3-trifluoropropoxy)benzamido)propanoic acid (3c): Compound 3c was
prepared in a similar manner as described for compound 2a. White solid, 53 mg, 83% yield. Mp:
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175ꢀ177 °C.1H NMR (400 MHz, MeODꢀd4) δ 8.74 (s, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.56 –
7.43 (m, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 4.41 (t, J = 5.9 Hz, 2H), 2.96 – 2.80
(m, 1H), 1.64 (s, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 178.8, 167.0, 158.1, 134.7, 132.7,
123.9, 123.0, 114.0, 63.9, 58.5, 34.9, 25.4. LRMS (ESI) [MꢀH]+ m/z found: 318.0. HRMS (ESIꢀTOF)
[MꢀH]+ m/z calcd for C14H15NO4F3 318.0953, found 318.0945.
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2-methyl-2-(2-phenethoxybenzamido)propanoic acid (3d): Compound 3d was prepared in a
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similar manner as described for compound 2a. White solid, 50 mg, 76% yield. Mp: 183ꢀ185 °C. H
NMR (400 MHz, MeODꢀd4) δ 8.73 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.0 Hz, 1H), 7.38 –
7.27 (m, 4H), 7.26 – 7.21 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 4.48 (t, J = 6.7
Hz, 2H), 3.27 (t, J = 6.7 Hz, 2H), 1.51 (s, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 167.1, 158.7,
139.7, 134.7, 132.7, 130.3, 130.3, 130.1, 128.1, 123.4, 122.5, 114.4, 70.9, 36.5, 25.6. LRMS (ESI)
[MꢀH]+ m/z found: 326.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C19H20NO4 326.1392, found
326.1393.
2-(2-(benzyloxy)benzamido)-2-methylpropanoic acid (3e): Compound 3e was prepared in a
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similar manner as described for compound 2a. White solid, 29 mg, 46% yield. Mp: 178ꢀ180 °C. H
NMR (400 MHz, MeODꢀd4) δ 8.67 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.1 Hz, 2H), 7.47 –
7.54 (m, 1H), 7.40 – 7.49 (m, 2H), 7.38 – 7.44 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 7.6 Hz,
1H), 5.27 (s, 2H), 1.38 (s, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 167.2, 158.9, 137.9, 134.7,
132.6, 130.3, 130.1, 130.1, 123.6, 122.7, 114.9, 73.0, 25.8. LRMS (ESI) [MꢀH]+ m/z found: 312.0.
HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C18H18NO4 312.1236, found 312.1230.
2-(2-isobutoxybenzamido)-2-methylpropanoic acid (3f): Compound 3f was prepared in a similar
manner as described for compound 2a. White solid, 40 mg, 72% yield. Mp: 143ꢀ145 °C.1H NMR
(400 MHz, MeODꢀd4) δ 8.77 (s, 1H), 7.92 (dd, J = 7.8, 1.7 Hz, 1H), 7.54 – 7.44 (m, 1H), 7.14 (d, J =
8.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 3.97 (d, J = 6.5 Hz, 2H), 2.18 – 2.30 (m, 1H), 1.65 (s, 6H),
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1.11 (d, J = 6.1 Hz, 6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 178.4, 167.5, 159.1, 134.7, 132.5,
123.3, 122.3, 114.2, 77.2, 58.1, 29.9, 25.9, 20.2. LRMS (ESI) [MꢀH]+ m/z found: 278.0. HRMS
(ESIꢀTOF) [MꢀH]+ m/z calcd for C15H20NO4 278.1392, found 278.1385.
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similar manner as described for compound 2a. White solid, 26 mg, 49% yield. Mp: 137ꢀ139 °C. H
NMR (400 MHz, MeODꢀd4) δ 9.00 (s, 1H), 7.94 (dd, J = 7.8, 1.7 Hz, 1H), 7.51 – 7.38 (m, 1H), 7.15
(d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.82 – 4.91 (m, 1H), 1.64 (s, 6H), 1.44 (d, J = 6.1 Hz,
6H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 176.5, 165.5, 165.4, 156.1, 132.7, 130.8, 122.3, 120.6,
114.3, 72.1, 23.8, 20.9. LRMS (ESI) [MꢀH]+ m/z found: 264.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd
for C14H18NO4 264.1236, found 264.1229.
2-(2-(cyclopropylmethoxy)benzamido)-2-methylpropanoic acid (3h): Compound 3h was
prepared in a similar manner as described for compound 2a. White solid, 19 mg, 35% yield. Mp:
146ꢀ148 °C.1H NMR (400 MHz, MeODꢀd4) δ 9.05 (s, 2H), 7.97 (dd, J = 7.8, 1.7 Hz, 1H), 7.51 –
7.43 (m, 1H), 7.13 – 6.99 (m, 2H), 4.03 (d, J = 7.2 Hz, 2H), 1.65 (s, 6H), 1.37 – 1.47 (m, 1H), 0.73 –
0.66 (m, 2H), 0.43 – 0.56 (m, 2H).13C {1H} NMR (125 MHz, MeODꢀd4) δ 178.5, 167.2, 159.2,
134.9, 132.6, 122.9, 122.4, 114.5, 75.8, 58.0, 26.0, 11.5, 4.3. LRMS (ESI) [MꢀH]+ m/z found: 276.0.
HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C15H18NO4 276.1236, found 276.1231.
2-(2-(cyclohexyloxy)benzamido)-2-methylpropanoic acid (3i): Compound 3i was prepared in a
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similar manner as described for compound 2a. White solid, 31 mg, 50% yield. Mp: 150ꢀ152 °C. H
NMR (400 MHz, MeODꢀd4) δ 8.96 (s, 1H), 7.94 – 7.88 (dd, J = 8.4, 1.2, 1H), 7.45 (t, J = 7.8 Hz,
1H), 7.16 (d, J = 8.3 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 4.59 – 4.49 (m, 1H), 2.04 – 2.14(m, 2H), 1.79
– 1.89 (m, 2H), 1.62ꢀ1.68 (m, 8H), 1.50 – 1.43 (m, 2H), 1.42 – 1.32 (m, 2H).13C {1H} NMR (100
MHz, MeODꢀd4) δ 167.5, 157.7, 134.4, 132.7, 124.6, 122.3, 116.0, 79.1, 33.4, 27.0, 25.8, 25.4.
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LRMS (ESI) [MꢀH]+ m/z found: 304.0. HRMS (ESIꢀTOF) [MꢀH]+ m/z calcd for C17H22NO4
304.1549, found 304.1545.
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Author Information
Corresponding Author
Eꢀmail: hliu@simm.ac.cn
Notes
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The authors declare no competing financial interests.
Acknowledgements
S.L., W.Z., F.G., J.W., and H.L. received funding from the National Natural Science Foundation of
China (81220108025, 21472209, and 91229204), the Major Project of Chinese National Programs
for Fundamental Research and Development (2015CB910304), the National Basic Research
Program of China (2012CB518005), and National S&T Major Projects (2013ZX09507ꢀ001, and
2014ZX09507002ꢀ001).
Associated Content
Supporting Information
Copies of 1H and 13C {1H} NMR spectra and HPLC experiments data. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
1. For selected papers, see: (a) Majmudar, J. D.; HodgesꢀLoaiza, H. B.; Hahne, K.; Donelson, J. L.;
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