Radical-Mediated Activation of Esters with a Copper/Selectfluor System: Synthesis of Bulky Amides and Peptides

Article abstract of DOI:10.1021/acs.joc.1c00188

Herein, we describe a new approach for the activation of esters via a radical-mediated process enabled by a copper/Selectfluor system. A variety of para-methoxybenzyl esters derived from bulky carboxylic acids and amino acids can be easily converted into the corresponding acyl fluorides, directly used in the one-pot synthesis of amides and peptides. As a proof of concept, this method was applied to the iterative formation of sterically hindered amide bonds.

Full text of DOI:10.1021/acs.joc.1c00188

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Radical-Mediated Activation of Esters with a Copper/Selectfluor
System: Synthesis of Bulky Amides and Peptides
Akira Matsumoto,* Zhe Wang, and Keiji Maruoka*
Cite This: J. Org. Chem. 2021, 86, 5401−5411
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ABSTRACT: Herein, we describe a new approach for the
activation of esters via a radical-mediated process enabled by a
copper/Selectfluor system. A variety of para-methoxybenzyl esters
derived from bulky carboxylic acids and amino acids can be easily
converted into the corresponding acyl fluorides, directly used in the
one-pot synthesis of amides and peptides. As a proof of concept,
this method was applied to the iterative formation of sterically
hindered amide bonds.
wing to the ubiquity and significance of amide
compounds in many scientific fields, the formation of
species into its active form for further transformation can be
expected to be particularly useful for the iterative synthesis of
repeated structures from modular building blocks without extra
deprotection steps.8 As part of our continuing research on the
selective hydrogen atom abstraction from specific C−H
bonds,9 we envisaged that the activation of benzylic esters
triggered by a suitable hydrogen atom abstractor would
provide a new opportunity for transformations other than
simple debenzylations.10 Thus, we chose a copper/Selectfluor
(1) system, which efficiently generates the nitrogen-centered
radical cation I as the electrophilic hydrogen atom abstractor
(Scheme 1a).11 Then, I can induce hydrogen atom abstraction
(HAA) from a benzylic C−H bond of the substrate ester 2 to
form the corresponding benzyl radical II (Scheme 1b). The
subsequent single-electron oxidation of II by a copper species
affords the transient acyl oxonium species III. This
intermediate is highly susceptible to nucleophilic addition at
the carbonyl carbon by a fluoride ion derived from 1. Thus, the
desired acyl fluoride 3 is obtained and can be used in a further
amidation step.
O
amide bonds constitutes one of the most fundamental class of
chemical transformations. It has been frequently used for the
synthesis of natural products, functional materials, and
pharmaceuticals.1 Accordingly, numerous approaches for the
synthesis of amides have been developed.2 Most of these
methods employ carboxylic acid derivatives as acyl coupling
partners, each of which shows unique reactivity when coupled
with an amine nucleophile. Thus, a judicious choice of acyl
coupling partner, depending on the structure of the targeted
amide, is crucial for the successful formation of the amide
bond. Acyl fluorides have been recognized as suitable
intermediates for the construction of sterically hindered
amides and peptides.3 The relatively small steric demand of
the fluorine atom as a leaving group makes it possible for bulky
nucleophiles to approach the carbonyl carbon. In addition,
their improved stability, compared to the more commonly
employed acyl chlorides, can avoid undesired intramolecular
pathways.4 Indeed, the use of acyl fluorides has enabled the
formation of sterically demanding peptide bonds derived from
α,α-dialkyl amino acids and/or N-alkylated amino acids, which
are encountered in biologically active peptides.4,5 However,
most methods for the preparation of acyl fluorides depend on
the deoxyfluorination of carboxylic acids and employ highly
reactive fluorination reagents, most of which are toxic and
thermally unstable.6 These drawbacks have driven organic
chemists to develop various methods and reagents to access
acyl fluorides in a more practical manner.7 In this context, we
wish to report a novel method for the synthesis of amides and
peptides via acyl fluoride intermediates generated from
carboxylic acid esters.
To validate our hypothesis, we initially conducted the
reaction of para-methoxybenzyl ester 2a with 1 in the presence
of various copper sources (Table 1). We found that the use of
a catalytic amount of CuBr2 (10 mol %) and MeCN as the
solvent at 80 °C was optimal, furnishing the desired acyl
fluoride 3a in a satisfactory 19F NMR yield (Table 1, entry 1).
By adding benzylamine to the reaction mixture, 3a could be
used directly in a one-pot amidation that afforded the
Received: January 24, 2021
Published: March 15, 2021
While most methods for the preparation of acyl fluorides use
free carboxylic acids as the starting material, we focused on the
direct activation of esters as the protected form of carboxylic
acids. Such a method for the direct conversion of a protected
https://dx.doi.org/10.1021/acs.joc.1c00188
© 2021 American Chemical Society
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Note
Scheme 1. Synthesis of Acyl Fluorides from Benzylic Esters by the Copper/Selectfluor System
a
Table 1. Optimization of the Reaction Conditions
the formation of 3a. This result suggests that the reaction
mechanism involves radical species (entry 10).
Apart from para-methoxybenzyl ester 2a, we also examined
several other esters and a free carboxylic acid as substrates for
this reaction (Scheme 2). The use of simple benzyl ester A and
Scheme 2. Screening of Ester Substrates
conversion
yield of 3a
b
c
entry
deviation from standard conditions
none
open to air
(%)
(%)
1
2
3
4
5
6
7
8
9
>99
>99
>99
>99
>99
>99
96
89 (97)
82
43
71
59
74
29
41
trace
without CuBr2
CuBr instead of CuBr2
Cu(OAc)2 instead of CuBr2
d
with bpy
AgNO3 instead of CuBr2
e
NFSI instead of 1
>99
53
N-fluoropyridinium tetrafluoroborate
instead of 1
f
10
TEMPO (2.0 equiv)
>99
4
a
Unless otherwise noted, reactions were conducted using 2a (0.20
mmol), 1 (0.40 mmol), CuBr2 (0.020 mmol, 10 mol % of Cu), and
b
MeCN (2.0 mL) at 80 °C for 1 h. Conversions were determined by
1H NMR of the crude reaction mixture using 1,1,2,2-tetrachloro-
c
ethane as an internal standard. Yields of 3a were determined by 19F
ortho-methoxybenzyl ester B resulted in the formation of 3a in
reduced yields. These results indicate that the presence of a
methoxy substituent at the para-position of the benzyl group is
crucial. This remarkable substituent effect could potentially be
derived from a favorable polar transition state that includes an
electron-rich benzylic C−H bond and electrophilic radical
cation I.13 However, the introduction of additional sub-
stituents, such as a methyl group (C) and another para-
methoxyphenyl group (D), at the benzylic position lowered
the product yield, probably due to increased steric hindrance
around the benzylic C−H bond. The nonbenzylic ester E
contains a relatively weak acetal C−H bond and was not
compatible with the reaction conditions, affording only a small
amount of 3a. The use of free carboxylic acid F did not
generate any 3a at all.
With the optimized reaction conditions in hand, we
investigated the scope of applicable substrates (Table 2).
The efficiency of this transformation was evaluated by 19F
NMR of the obtained acyl fluoride 3 and/or the isolated yields
of the corresponding benzylamide 4 after a one-pot amidation
with benzylamine. We found that various para-methoxybenzyl
esters 2 derived from primary, secondary, or tertiary carboxylic
acids are applicable, and in most cases, the corresponding acyl
fluorides 3 and benzylamides 4 could be obtained in high
yields. Notably, bulky tertiary acid esters could be successfully
converted using our method, affording the desired acyl
fluorides (3c−g) and benzylamides (4b−g) in good to high
yields. Several oxygen-containing functional groups such as a
NMR of the crude reaction mixture using benzotrifluoride as an
internal standard. The isolated yield of the one-pot amidation
product, N-benzyl-2-methyl-2-phenylpropanamide (4a), is shown in
d
e
parentheses. 10 mol % of 2,2′-bipyridine (bpy) was used. N-
f
Fluorobenzenesulfonimide (NFSI). 2,2,6,6-Tetramethylpiperidine 1-
oxyl (TEMPO).
corresponding benzylamide 4a in a near quantitative yield (see
the Supporting Information for details). The reaction even
proceeded under conditions where the reaction was exposed to
air, albeit that the yield of 3a decreased slightly (entry 2).
Although the formation of 3a was observed in the absence of
any copper source, we confirmed a significant improvement of
the reaction efficiency upon the addition of CuBr2 (entry 3).
Other copper species such as CuBr, Cu(OAc)2 and a Cu/2,2′-
bipyridine (bpy) complex gave lower yields than when CuBr2
was used (entries 4−6). In addition, the use of a silver species,
another candidate for mediating the generation of active
radical species I from 1,12 was found to be less effective than
CuBr2 (entry 7). We also examined the use of fluorination
reagents other than 1, i.e., N-fluorobenzenesulfonimide (NFSI)
and N-fluoropyridinium tetrafluoroborate (entries 8 and 9).
However, neither reagent showed promise, demonstrating that
1 does not only act as a fluorinating reagent but also as a
precursor for an efficient hydrogen atom abstractor. Finally, the
addition of the radical scavenger 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO) in the reaction system significantly inhibited
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Note
a
Table 2. Substrate Scope
a
Unless otherwise noted, reactions were conducted using 2 (0.20 mmol), 1 (0.40 mmol), CuBr2 (0.020 mmol, 10 mol % of Cu), and MeCN (2.0
mL) at 80 °C for 1 h. Yields of 3 were determined by 19F NMR of the crude reaction mixture using benzotrifluoride as an internal standard. For 4,
the isolated yields following the one-pot amidation from 2 are shown.
benzoyloxy moiety (3f and 4f), a cyclic ether (4k), and acetoxy
groups (3o and 4o) were well-tolerated. In addition to
aliphatic acid esters, substrates derived from α,β-unsaturated
acids as well as aryl carboxylic acids also furnished the desired
products (3l−n and 4l−n) in good to high yields. Moreover,
biologically relevant molecules such as deoxycholic acid and
ibuprofen (3o−p and 4o−p) could be used under this
protocol. To probe the applicability of this method to amino
acid derivatives, several para-methoxybenzyl esters derived
from N-protected amino acids were employed. Unfortunately,
frequently used N-protecting groups such as tert-butoxycar-
bonyl and benzyloxycarbonyl groups did not tolerate the
oxidative conditions. However, more strongly electron-with-
drawing N-protecting groups such as phthaloyl, 2,2,2-
trifluoroacetyl, and para-toluenesulfonyl moieties tolerate the
conditions. Thus, various amino acid fluorides (3q−w) and
one-pot amidation products (4q−w) were formed. It should be
noted here that substrates derived from sterically hindered α,α-
dialkylamino acids reacted more efficiently than those derived
from α-unsubstituted or α-monosubstituted amino acids,
probably due to the absence of potentially reactive α-hydrogen
atoms (3s−t and 4s−t). We also confirmed that the reaction of
proline ester 3u proceeded without detectable racemization
(see the Supporting Information for details). In addition to α-
amino acid derivatives, β-aminobutyric acid ester and
isonipecotic acid ester could also be used as substrates,
affording the corresponding products (3v−w and 4v−w) in
moderate to high yields.
We also explored the potential of our method for the
formation of sterically hindered peptide bonds, a challenging
topic in peptide synthesis. Aminoisobutyric acid ester 2s was
treated under the standard conditions followed by the addition
of L-phenylalanine methyl ester hydrochloride in the presence
of triethylamine as a base, which furnished dipeptide 5 in a
high yield (Scheme 3a). Moreover, the use of aminoisobutyric
acid or L-proline instead of L-phenylalanine with a prolonged
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Note
Scheme 3. One-Pot Synthesis of Bulky Peptides
Scheme 4. Iterative Formation of Bulky Amide Bonds
reaction time furnished the sterically more demanding
dipeptides 6 and 7 in a high yield (Scheme 3b,c).
synthesis of sterically hindered peptides have been shown.
Notably, the preliminary demonstration of the iterative
formation of amide bonds (Scheme 4) represents a novel
strategy for the iterative synthesis of bulky peptides. This
elongation in the N → C direction is complementary to the
conventional methods that rely on N-terminal ligation.14
Further studies to expand the reaction scope of this
methodology and its application to the synthesis of more
diverse peptide structures are currently in progress in our
laboratory.
To demonstrate the synthetic utility of our method, we
conducted the iterative formation of amide bonds, where the
extra deprotection steps after the formation of each amide
bond is not necessary (Scheme 4). Thus, in the steps shown as
[Activation], the amino acid para-methoxybenzyl ester was
converted into the corresponding acyl fluoride. This was then
passed through a short silica gel pad to remove any residues
derived from 1 and the copper species. The obtained crude
product was then treated with another amino acid ester (8 or
10), which are the steps shown as [Coupling]. These two
simple operations allowed for the formation of a bulky amide
bond, and the desired product 11 could be obtained by
repeating this protocol. Although there is still room for
improvement in terms of yield and amino acid scope, this
strategy represents a novel approach to the construction of
bulky peptide structures.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under an
argon atmosphere with dehydrated solvents under anhydrous
conditions. Dehydrated solvents were purchased and used as received:
tetrahydrofuran (THF), dichloromethane (CH2Cl2), dimethylforma-
mide (DMF), diethyl ether (Et2O), and acetonitrile (MeCN) were
purchased as “super dehydrated” grade from FUJIFILM Wako Pure
Chemical Co., Inc. 1,2-Dichloroethane (DCE) was purchased as
“dehydrated” grade from Kanto Chemical Co., Inc. Commercially
available reagents were purchased from FUJIFILM Wako, Sigma-
Aldrich, Nacalai Tesque, BLDpharm, and TCI and used as received
for the reactions without any purification. 1H NMR spectra were
In conclusion, we have developed a novel approach for the
synthesis of acyl fluorides from para-methoxybenzyl esters
using a CuBr2/Selectfluor system. This method is particularly
useful for obtaining bulky amides, and its applications to the
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1
recorded on a JEOL JNM-AL400 (400 MHz) spectrometer. Data for
1H NMR are reported as follows: chemical shifts in ppm relative to
zyl alcohol: yellow oil, 55% yield (644 mg);. H NMR (400 MHz,
CDCl3) δ 7.28−7.21 (m, 5H), 7.04−7.02 (d, J = 8.4 Hz, 4H), 6.78−
6.75 (d, J = 8.8 Hz, 4H), 6.74 (s, 1H), 3.75 (s, 6H), 1.60 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ175.5, 159.0, 144.4, 132.6,
128.23, 128.15, 126.5, 125.8, 113.6, 76.4, 55.2, 46.6, 26.2; HRMS
(ESI) m/z [M + Na]+ calcd for C17H18O2Na 277.1199, found
277.1200.
tetramethylsilane (0.00 ppm) as an internal standard in CDCl3,
integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad), coupling constants (Hz), and
assignment. 13C{1H} NMR spectra were recorded on a JEOL JNM-
AL400 (100 MHz) spectrometer with complete proton decoupling
(13C{1H}). Chemical shifts for 13C{1H} NMR were reported in ppm
relative to CDCl3 (77.16 ppm) as an internal standard. High-
resolution mass spectra (HRMS) were performed on a Shimadzu
LCMS-IT-TOF mass spectrometer or Thermo Exactive plus
(Supporting Information, quadrupole) spectrometer. Enantiomeric
excesses (ee) were determined by analysis on Shimadzu HPLC with
Daicel chiral columns. For thin-layer chromatography (TLC), Merck
precoated glass TLC plates (Merck, TLC silica gel 60 F254) were used,
and compounds were visualized with a UV light at 254 nm. Further
visualization was achieved by basic aqueous KMnO4 solution stain or
phosphomolybdic acid stain. The products were purified by flash
column chromatography on neutral silica gel 60 (Kanto Chemical Co.
Inc., silica gel 60 N, spherical, neutral, 40−50 μm). Further
purification by preparative thin-layer chromatography was performed
using Merck silica gel (Merck, PLC silica gel 60 F254, 0.5 mm) if
necessary.
General Procedure for the Synthesis of Substrates.
Procedure A. To a mixture of para-methoxybenzyl alcohol (447 μL,
3.6 mmol), 4-dimethylaminopyridine (367 mg, 3.0 mmol), and
triethylamine (839 μL, 6.0 mmol) in CH2Cl2 (10 mL) was added acid
chloride (3.0 mmol) dropwise at 0 °C, and the reaction solution was
allowed to warm to an ambient temperature and stirred for 10 h under
an argon atmosphere. The reaction was quenched with saturated
NaHCO3 aq, and the mixture was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The obtained crude product was
purified by flash silica gel column chromatography using hexane/
EtOAc (v/v = 20:1 to 3:1) as an eluent to afford the corresponding
para-methoxybenzyl esters.
Procedure B. To a mixture of carboxylic acid (3.0 mmol) and
potassium carbonate (621 mg, 4.5 mmol) in MeCN (20 mL) was
added para-methoxybenzyl bromide (724 mg, 4.5 mmol) at room
temperature, and the reaction solution was stirred at 80 °C in an oil
bath for 3 h under an argon atmosphere. The reaction was quenched
with H2O (20 mL), and the mixture was extracted with EtOAc (3 ×
20 mL). The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The obtained crude product
was purified by flash silica gel column chromatography using hexane/
EtOAc (v/v = 20:1 to 3:1) as an eluent to afford the corresponding
para-methoxybenzyl esters.
2-Methoxybenzyl 2-Methyl-2-phenylpropanoate (B). The com-
pound was prepared in a similar fashion to general procedure A using
ortho-methoxybenzyl alcohol instead of para-methoxybenzyl alcohol:
colorless oil, quantitative yield (853 mg); 1H NMR (400 MHz,
CDCl3) δ 7.34−7.20 (m, 6H), 7.11 (m, 1H), 6.88−6.82 (m, 2H),
5.15 (s, 2H), 3.75 (s, 3H), 1.61 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 176.6, 157.3, 144.8, 129.2, 128.9, 128.4, 126.6, 125.8, 124.7,
120.3, 110.3, 62.2, 55.4, 46.7, 26.6; HRMS (ESI) m/z [M + Na]+
calcd for C18H20O3Na 307.1305, found 307.1306.
Methoxymethyl 2-Methyl-2-phenylpropanoate (E). The com-
pound was prepared in a similar fashion to general procedure B using
chloro(methoxy)methane instead of para-methoxybenzyl bromide
and N,N-diisopropylethylamine instead of K2CO3: colorless oil,
1
quantitative yield (625 mg); H NMR (400 MHz, CDCl3) δ 7.38−
7.31 (m, 4H), 7.24 (m, 1H), 5.19 (s, 2H), 3.28 (s, 3H), 1.61 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 144.4, 128.5, 126.9,
125.8, 90.6, 57.4, 46.8, 26.4; HRMS (ESI) m/z [M + Na]+ calcd for
C12H16O3Na 231.0992, found 231.0993.
4-Methoxybenzyl 2,2-Diphenylpropanoate (2c). The compound
was prepared following general procedure A: colorless oil, 93% yield
(967 mg); 1H NMR (400 MHz, CDCl3) δ 7.32−7.12 (m, 12H), 6.82
(d, J = 8.4 Hz, 2H), 5.11 (s, 2H), 3.79 (s, 3H), 1.92 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 175.0, 159.6, 144.5, 129.9, 128.23,
128.15, 126.9, 113.9, 66.9, 56.7, 55.4, 27.2 (one aromatic carbon is
overlapping); HRMS (ESI) m/z [M + Na]+ calcd for C23H22O3Na
369.1461, found 369.1462.
4-Methoxybenzyl 2,2,2-Triphenylacetate (2d). The compound
was prepared following general procedure B: white solid, 97% yield
(1.19 g); 1H NMR (400 MHz, CDCl3) δ 7.28−7.20 (m, 9H), 7.18−
7.12 (m, 6H), 7.09 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 5.18
(s, 2H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.5,
159.6, 143.0, 130.5, 130.1, 127.8, 127.0, 113.8, 67.7, 67.2, 55.4 (one
aromatic carbon is overlapping); HRMS (ESI) m/z [M + Na]+ calcd
for C28H24O3Na 431.1618, found 431.1625.
4-Methoxybenzyl 1-Phenylcyclopropane-1-carboxylate (2e). The
compound was prepared following general procedure B: colorless oil,
98% yield (830 mg); H NMR (400 MHz, CDCl3) δ 7.38−7.22 (m,
5H), 7.15 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H),
3.78 (s, 3H), 1.60 (dd, J = 7.2, 4.0 Hz, 2H), 1.19 (dd, J = 7.2, 4.0 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.5, 159.5, 139.6, 130.6,
129.4, 128.5, 128.2, 127.3, 113.9, 66.4, 55.4, 29.4, 16.6; HRMS (ESI)
m/z [M + Na]+ calcd for C18H18O3Na 305.1148, found 305.1150.
3-((4-Methoxybenzyl)oxy)-2,2-dimethyl-3-oxopropyl Benzoate
(2f). The compound was prepared following general procedure B:
1
1
colorless oil, 98% yield (674 mg); H NMR (400 MHz, CDCl3) δ
7.89 (dd, J = 8.4, 1.2 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.8
Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 5.09 (s,
2H), 4.34 (s, 2H), 3.74 (s, 3H), 1.31 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 175.6, 166.3, 159.6, 133.1, 130.03, 129.99, 129.7,
128.5, 128.3, 114.0, 70.8, 66.5, 55.3, 43.0, 22.5; HRMS (ESI) m/z [M
+ Na]+ calcd for C20H22O5Na 365.1359, found 365.1355.
4-Methoxybenzyl 2,4,6-Trimethylbenzoate (2n). The compound
was prepared following general procedure B: white solid, 98% yield
(835 mg); H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.8 Hz, 2H),
6.89 (d, J = 8.8 Hz, 2H), 6.81 (s, 2H), 5.28 (s, 2H), 3.80 (s, 3H), 2.25
(s, 3H), 2.23 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.2,
159.8, 139.4, 135.3, 131.0, 130.6, 128.5, 128.1, 114.0, 66.6, 55.4, 21.2,
19.8; HRMS (ESI) m/z [M + Na]+ calcd for C18H20O3Na 307.1305,
found 307.1299.
4-Methoxybenzyl (S)-2-(1,3-Dioxoisoindolin-2-yl)propanoate
(2r). The compound was prepared following general procedure B:
white solid, quantitative yield (1.02 g); 1H NMR (400 MHz, CDCl3)
δ 7.85 (dd, J = 5.6, 3.2 Hz, 2H), 7.73 (dd, J = 5.6, 3.4 Hz, 2H), 7.23
(d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.14 (d, J = 12.0 Hz,
1H), 5.10 (d, J = 12.0 Hz, 1H), 4.99 (q, J = 7.3 Hz, 1H), 3.79 (s, 3H),
1.71 (d, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.8,
167.6, 159.8, 134.3, 132.1, 130.1, 127.6, 123.6, 114.0, 67.5, 55.4, 47.9,
15.4; HRMS (ESI) m/z [M + Na]+ calcd for C19H17NO5Na
362.0999, found 362.0970.
1
1-(4-Methoxyphenyl)ethyl 2-Methyl-2-phenylpropanoate (C).
The compound was prepared in a similar fashion to general
procedure A using 1-(4-methoxyphenyl)ethan-1-ol instead of para-
1
methoxybenzyl alcohol: colorless oil, 47% yield (421 mg); H NMR
(400 MHz, CDCl3) δ 7.29−7.28 (m, 4H), 7.22 (m, 1H), 7.11−7.09
(d, J = 8.8 Hz, 2H), 6.81−6.78 (d, J = 8.4 Hz, 2H), 5.81 (q, J = 6.4
Hz, 1H), 3.77 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H), 1.41 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.9, 159.2, 144.8, 134.0,
128.4, 127.4, 126.6, 125.8, 113.8, 72.4, 55.3, 46.6, 26.5, 22.1; HRMS
(ESI) m/z [M + Na]+ calcd for C19H22O3Na 321.1461, found
321.1464.
Bis(4-methoxyphenyl)methyl 2-Methyl-2-phenylpropanoate (D).
The compound was prepared in a similar fashion to general procedure
A using bis(4-methoxyphenyl)methanol instead of para-methoxyben-
4-Methoxybenzyl 2-(1,3-Dioxoisoindolin-2-yl)-2-methylpropa-
noate (2s). The compound was prepared following general procedure
1
B: white solid, 98% yield (1.04 g); H NMR (400 MHz, CDCl3) δ
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Note
7.80 (dd, J = 5.6, 3.2 Hz, 2H), 7.70 (dd, J = 5.6, 2.8 Hz, 2H), 7.25 (d,
J = 7.2 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.13 (s, 2H), 3.79 (s, 3H),
1.82 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 168.4,
159.7, 134.2, 132.0, 127.9, 123.2, 114.0, 67.4, 10.5, 55.4, 24.5 (one
aromatic carbon is overlapping); HRMS (ESI) m/z [M + Na]+ calcd
for C20H19NO5Na 376.1155, found 376.1155.
31.4, 31.0, 27.5, 27.0, 26.8, 26.0, 25.8, 23.6, 23.2, 21.6, 21.5, 17.6,
12.5; HRMS (ESI) m/z [M + Na]+ calcd for C36H52O7Na 619.3605,
found 619.3612.
General Procedure for the One-Pot Synthesis of Benzyla-
mide 4. CuBr2 (4.5 mg, 0.20 mmol, 10 mol % of Cu), 1 (142 mg,
0.40 mmol), and para-methoxybenzyl ester 2 (0.20 mmol) were
placed in an oven-dried 10 mL glass tube capped with a rubber
septum. The tube was evacuated and then refilled with argon gas for 5
cycles. MeCN (2.0 mL) was added successively, and the reaction
solution was stirred at 80 °C in an oil bath for 1 h under an argon
atmosphere. The mixture was cooled down to room temperature, and
subsequently benzylamine (43.7 μL, 0.40 mmol) and triethylamine
(55.4 μL, 0.40 mmol) were added. The mixture was stirred at room
temperature for 3 h under an argon atmosphere and passed through a
short pad of silica gel with EtOAc as an eluent. The filtrate was
concentrated in vacuo, and the obtained crude product was purified
by flash silica gel column chromatography using hexane/EtOAc as an
eluent to afford the corresponding benzylamide 4. For each reaction,
the yield of the corresponding acyl fluorides 3 was monitored by 19F
NMR using benzotrifluoride as an internal standard.
Large-Scale Synthesis of 4a. CuBr2 (112 mg, 0.50 mmol, 10
mol % of Cu), 1 (3.5 g, 10.0 mmol), and 2a (1.4 g, 5.0 mmol) were
placed in an oven-dried 100 mL flask capped with a rubber septum.
The reactor was evacuated via a syringe needle and refilled with argon
gas for 5 cycles. MeCN (25 mL) was added successively, and the
reaction solution was stirred at 80 °C in an oil bath for 2 h under an
argon atmosphere. The mixture was cooled down to room
temperature, and benzylamine (1.1 mL, 10.0 mmol) and triethylamine
(1.4 mL, 10.0 mmol) were added dropwise. The mixture was stirred
at room temperature for 3 h under an argon atmosphere. The reaction
was quenched with saturated NaHCO3 aq (25 mL), and the mixture
was extracted with EtOAc (3 × 30 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The obtained crude product was purified by flash silica gel
column chromatography using hexane/EtOAc (v/v = 3:1) as an
eluent to afford the corresponding benzylamide 4a in an 87% isolated
yield (1.1 g) as a white solid.
N-Benzyl-2-methyl-2-phenylpropanamide (4a). The compound
was isolated by flash silica gel chromatography (hexane/EtOAc =
3:1): white solid, 97% yield (49.1 mg); 1H NMR (400 MHz, CDCl3)
δ 7.39−7.32 (m, 4H), 7.29−7.22 (m, 4H), 7.13−7.11 (m, 2H), 5.46
(br s, 1H), 4.37 (d, J = 6.0 Hz, 2H), 1.61 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 177.5, 145.2, 138.6, 128.8, 128.7, 127.5, 127.4,
127.2, 126.6, 47.2, 43.8, 27.2; HRMS (ESI) m/z [M + Na]+ calcd for
C17H19NONa 276.1359, found 276.1351. The formation of acyl
fluoride 3a was characterized by 19F NMR spectroscopy (δ 29.7 ppm,
CDCl3, 19F NMR yield = 89%).
N-Benzylpivalamide (4b). The compound was purified by flash
silica gel chromatography (hexane/EtOAc = 3:1): white solid, 97%
yield (37.1 mg); 1H NMR (400 MHz, CDCl3) δ 7.36−7.32 (m, 2H),
7.29−7.25 (m, 3H), 5.89 (br s, 1H), 4.44 (d, J = 6.0 Hz, 2H), 1.23 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.4, 138.8, 128.9, 127.8,
127.6, 43.8, 38.7, 27.8; HRMS (ESI) m/z [M + Na]+ calcd for
C12H17NONa 214.1202, found 214.1132.
4-Methoxybenzyl (S)-2-(1,3-Dioxoisoindolin-2-yl)-2-methylbuta-
noate (2t). The compound was prepared following general procedure
1
B: colorless oil, quantitative yield (1.10 g); H NMR (400 MHz,
CDCl3) δ 7.79 (dd, J = 5.6, 3.2 Hz, 2H), 7.70 (dd, J = 5.6, 3.2 Hz,
2H), 7.26 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.15 (d, J =
12.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 3.78 (s, 3H), 2.47 (dq, J =
14.4, 7.6 Hz, 1H), 2.16 (dq, J = 14.0, 7.2 Hz, 1H), 1.81 (s, 3H) 0.89
(t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.3,
168.7, 159.7, 134.1, 131.8, 130.2, 127.8, 123.2, 113.9, 67.2, 64.3, 56.3,
29.2, 21.6, 8.7; HRMS (ESI) m/z [M + Na]+ calcd for C21H21NO5Na
390.1312, found 390.1307.
4-Methoxybenzyl (2,2,2-Trifluoroacetyl)-L-prolinate (2u). The
compound was prepared following general procedure B: colorless
oil, quantitative yield (994 mg); 1H NMR (400 MHz, CDCl3)
observed mixture of isomers (major/minor = 81:19) δ 7.28 (d, J = 8.8
Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.14 (d, J = 11.6 Hz, 0.19H), 5.13
(d, J = 11.6 Hz, 0.81H), 5.10 (d, J = 12.0 Hz, 0.81H), 5.08 (d, J =
11.6 Hz, 0.19H), 3.88−3.62 (m, 2H), 3.82 (s, 0.57H), 3.80 (s,
2.43H), 2.32−1.83 (m, 3.81H), 1.29−1.24 (m, 0.19H); 13C{1H}
NMR (100 MHz, CDCl3) δ 171.0, 170.6, 160.0, 159.9, 156.0 (q, JCF
=
37.2 Hz), 130.4, 130.2, 127.6, 127.2, 116.3 (q, JCF = 285 Hz), 114.2,
114.1, 67.6, 67.3, 60.4, 59.5, 55.4, 48.1, 47.3, 31.7, 28.6, 25.0, 21.3;
HRMS (ESI) m/z [M + Na]+ calcd for C15H16F3NO4Na 354.0916,
found 354.0924.
4-Methoxybenzyl 3-(2,2,2-Trifluoroacetamido)butanoate (2v).
The compound was prepared following general procedure B: white
solid, 95% yield (910 mg); 1H NMR (400 MHz, CDCl3) δ 7.33 (br s,
1H), 7.28 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H),
4.37(m, 1H), 3.80 (s, 3H), 2.66−2.55 (m, 2H), 1.28 (d, J = 6.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.7, 159.8, 156.2 (q, JCF
= 37.2 Hz), 130.2, 127.2, 115.7 (q, JCF = 287 Hz), 113.9, 66.6, 55.2,
42.8, 38.9, 19.3; HRMS (ESI) m/z [M + Na]+ calcd for
C14H16F3NO4Na 342.0924, found 342.0921.
Synthesis of para-Methoxybenzyl Ester 2o. To a mixture of
deoxycholic acid (3.92 g, 10 mmol) and 4-dimethylaminopyridine
(244 mg, 2.0 mmol) in CH2Cl2 (30 mL) was added acetic anhydride
(2.83 mL, 30 mmol) dropwise at room temperature, and the reaction
solution was stirred for 2 h under an argon atmosphere. The reaction
was quenched and washed with 1 M HCl aq (2 × 20 mL). The
combined organic layers were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The resultant acetylated deoxycholic acid
was directly used for the subsequent reaction without further
purification.
To a mixture of acetylated deoxycholic acid, 4-dimethylaminopyr-
idine (610 mg, 5.0 mmol), and para-methoxybenzyl alcohol (744 μL,
6.0 mmol) in CH2Cl2 (20 mL) was added N,N′-dicyclohexylcarbo-
diimide (2.1 g, 10 mmol) at room temperature. After being stirred at
room temperature for 5 h under an argon atmosphere, the reaction
solution was filtered through a Celite pad, and the filtrate was
concentrated in vacuo. The obtained crude product was purified by
flash silica gel column chromatography using hexane/EtOAc (v/v =
5:1 to 3:1) as an eluent to afford the corresponding p-methoxybenzyl
ester 2o.
N-Benzyl-2,2-diphenylpropanamide (4c). The compound was
purified by flash silica gel chromatography (hexane/EtOAc = 3:1):
1
white solid, 90% yield (56.7 mg); H NMR (400 MHz, CDCl3) δ
7.33−7.23 (m, 13H), 7.14−7.12 (m, 2H), 5.76 (br s, 1H), 4.46 (d, J =
6.0 Hz, 2H), 2.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
175.1, 145.1, 138.4, 128.8, 128.7, 128.3, 127.52, 127.49, 127.1, 57.2,
44.0, 27.3; HRMS (ESI) m/z [M + H]+ calcd for C22H22NO
316.1696, found 316.1674. The formation of acyl fluoride 3c was
characterized by 19F NMR spectroscopy (δ 35.9 ppm, CDCl3, 19F
NMR yield = 86%).
(3R,5R,9S,10S,12S,13R,14S,17R)-17-((R)-5-((4-Methoxybenzyl)-
oxy)-5-oxopentan-2-yl)-10,13-dimethylhexadecahydro-1H-
cyclopenta[a]phenanthrene-3,12-diyl Diacetate (2o): colorless oil,
1
34% (1.0 g) from deoxycholic acid; H NMR (400 MHz, CDCl3) δ
7.27 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.09−5.02 (m,
1H), 5.04 (d, J = 12.0 Hz, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.68 (tt, J =
11.2, 4.4 Hz, 1H), 3.79 (s, 3H), 2.39−2.28 (m, 1H), 2.28−2.13 (m,
1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.96−0.93 (m, 24H), 0.89 (s, 3H),
0.77 (d, J = 6.4 Hz, 3H), 0.68 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 174.2, 170.7, 170.6, 159.8, 130.3, 128.4, 114.1, 76.0, 74.3,
66.1, 55.4, 49.6, 47.7, 45.2, 42.0, 35.8, 34.9, 34.8, 34.5, 34.2, 32.4,
N-Benzyl-2,2,2-triphenylacetamide (4d). The compound was
purified by flash silica gel chromatography (hexane/EtOAc = 3:1):
1
white solid, 70% yield (52.8 mg); H NMR (400 MHz, CDCl3) δ
7.29−7.23 (m, 18H), 7.14−7.12 (m, 2H), 6.08 (br s, 1H), 4.53 (d, J =
5.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.3, 143.5,
138.2, 130.7, 128.8, 128.1, 127.7, 127.5, 127.2, 67.9, 44.4 (one
5406
https://dx.doi.org/10.1021/acs.joc.1c00188
J. Org. Chem. 2021, 86, 5401−5411

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
aromatic carbon is overlapping); HRMS (ESI) m/z [M + H]+ calcd
for C27H24NO 378.1852, found 378.1828. The formation of acyl
fluoride 3d was characterized by 19F NMR spectroscopy (δ 45.9 ppm,
CDCl3, 19F NMR yield = 72%).
7.34−7.32 (m, 2H), 7.29−7.26 (m, 3H), 7.00 (br s, 1 H), 4.50−4.40
(m, 2H), 4.42−4.39 (dd, J = 8.0, 5.6 Hz, 1H), 3.94−3,83 (m, 2H),
2.32 (m, 1H), 2.10 (m, 1H), 1.97−1.83 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 173.3, 138.2, 128.8, 127.8, 127.6, 78.6, 69.5,
43.0, 30.7, 25.6; HRMS (ESI) m/z [M + H]+ calcd for C12H16NO2
206.1176, found 206.1168.
N-Benzylcinnamamide (4l). The compound was purified by flash
silica gel chromatography (hexane/EtOAc = 3:1): white solid, 82%
yield (38.9 mg); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 16.0 Hz,
1H), 7.45−7.44 (m, 2H), 7.38−7.24 (m, 8H), 6.48−6.43 (m, 2H),
4.52 (d, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0,
141.3, 138.3, 134.9, 129.8, 128.9, 128.8, 127.94, 127.89, 127.6, 120.7,
43.9; HRMS (ESI) m/z [M + H]+ calcd for C16H16NO 238.1226,
found 238.1225. The formation of acyl fluoride 3l was characterized
by 19F NMR spectroscopy (δ 24.5 ppm, CDCl3, 19F NMR yield =
81%).
N-Benzyl-1-phenylcyclopropane-1-carboxamide (4e). The com-
pound was purified by flash silica gel chromatography (hexane/EtOAc
= 3:1): white solid, 94% yield (47.3 mg); 1H NMR (400 MHz,
CDCl3) δ 7.43−7.40 (m, 2H), 7.37−7.30 (m, 2H), 7.30−7.25 (m,
3H), 7.21 (m, 1H), 7.14−7.13 (d, J = 6.8 Hz, 2H), 5.64 (br s, 1H),
4.38 (d, J = 5.6 Hz, 2H), 1.66 (ddd, J = 4.0, 3.2, 3.2 Hz, 2H), 1.08
(ddd, J = 4.0, 3.6, 3.2, Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
173.9, 139.7, 138.5, 131.0, 129.0, 128.5, 128.0, 127.2, 127.1, 43.8,
30.5, 15.6; HRMS (ESI) m/z [M + H]+ calcd for C17H18NO
252.1383, found 252.1382. The formation of acyl fluoride 3e was
characterized by 19F NMR spectroscopy (δ 23.4 ppm, CDCl3, 19F
NMR yield = 92%).
3-(Benzylamino)-2,2-dimethyl-3-oxopropyl benzoate (4f). The
compound was purified by flash silica gel chromatography (hexane/
EtOAc = 3:1 to 2:1): white solid, 90% yield (56.0 mg); H NMR
N-Benzylbenzamide (4m). The compound was purified by flash
silica gel chromatography (hexane/EtOAc = 3:1): white solid, 78%
yield (33.0 mg); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz,
2H), 7.48 (m, 1H), 7.42−7.38 (m, 2H), 7.34−7.33 (m, 4H), 7.29 (m,
1H), 6.58 (br s, 1H), 4.62 (d, J = 5.6 Hz, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 167.5, 138.3, 134.5, 131.6, 128.9, 128.7, 128.0, 127.7,
127.1, 44.2; HRMS (ESI) m/z [M + H]+ calcd for C14H14NO
212.1070, found 212.1069. The formation of acyl fluoride 3m was
characterized by 19F NMR spectroscopy (δ 17.1 ppm, CDCl3, 19F
NMR yield = 72%).
1
(400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.2 Hz,
1H), 7.38 (t, J = 8.0 Hz, 2H), 7.28−7.23 (m, 5H), 6.25 (br s, 1H),
4,47 (d, J = 5.2 Hz, 2H), 4.38 (s, 2H), 1.32 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 175.0, 166.0, 138.3, 133.0, 129.8, 129.5, 128.6,
128.4, 127.6, 127.4, 70.9, 43.7, 42.6, 22.7; HRMS (ESI) m/z [M +
H]+ calcd for C19H22NO3 312.1594, found 312.1596. The formation
of acyl fluoride 3f was characterized by 19F NMR spectroscopy (δ
26.7 ppm, CDCl3, 19F NMR yield = 98%).
N-Benzyl-2,4,6-trimethylbenzamide (4n). The compound was
(3R,5R,7R)-N-Benzyladamantane-1-carboxamide (4g). The com-
pound was purified by flash silica gel chromatography (hexane/EtOAc
= 3:1): white solid, 81% yield (43.6 mg); 1H NMR (400 MHz,
CDCl3) δ 7.35−7.25 (m, 5H), 5.85 (br s, 1H), 4.44 (d, J = 5.6 Hz,
2H), 2.05 (s, 3H), 1.89 (d, J = 2.8 Hz, 6H), 1.77−1.68 (m, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 178.0, 138.8, 128.8, 127.8,
127.6, 43.5, 40.8, 39.5, 36.7, 28.3; HRMS (ESI) m/z [M + Na]+ calcd
for C18H23NONa 292.1672, found 292.1656. The formation of acyl
fluoride 3g was characterized by 19F NMR spectroscopy (δ 22.9 ppm,
CDCl3, 19F NMR yield = 77%).
purified by flash silica gel chromatography (hexane/EtOAc = 3:1):
white solid, 61% yield (30.9 mg); H NMR (400 MHz, CDCl3) δ
1
7.34−7.25 (m, 5H), 6.80 (s, 2H), 5.96 (br s, 1H), 4.60 (d, J = 5.6 Hz,
2H), 2.26 (s, 6H), 2.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
170.5, 138.5, 138.2, 134.8, 134.3, 128.9, 128.3, 128.2, 127.7, 43.9,
21.2, 19.3; HRMS (ESI) m/z [M + Na]+ calcd for C17H19NONa
276.1359, found 276.1348. The formation of acyl fluoride 3n was
characterized by 19F NMR spectroscopy (δ 51.5 ppm, CDCl3, 19F
NMR yield = 60%).
(3R,5R,8R,9S,10S,12S,13R,14S,17R)-17-((R)-5-(Benzylamino)-5-
oxopentan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
phenanthrene-3,12-diyl Diacetate (4o). The compound was purified
by flash silica gel chromatography (hexane/EtOAc = 3:1 to 1:1):
N-Benzyl-3-phenylpropanamide (4h). The compound was
purified by flash silica gel chromatography (hexane/EtOAc = 3:1):
1
white solid, 90% yield (43.0 mg); H NMR (400 MHz, CDCl3) δ
1
yellow solid, 90% yield (102 mg); H NMR (400 MHz, CDCl3) δ
7.30−7.24 (m, 5H), 7.21−7.16 (m, 3H), 7.13−7.11 (m, 2H), 5.86 (br
s, 1H), 4.36 (d, J = 6.0 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.49 (t, J =
7.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 140.7,
138.1, 128.6, 128.5, 128.3, 127.6, 127.3, 126.2, 43.3, 38.4, 31.6;
HRMS (ESI) m/z [M + Na]+ calcd for C16H17NONa 262.1202,
found 262.1197. The formation of acyl fluoride 3h was characterized
by 19F NMR spectroscopy (δ 44.3 ppm, CDCl3, 19F NMR yield =
82%).
N-Benzyl-2-phenylpropanamide (4i). The compound was purified
by flash silica gel chromatography (hexane/EtOAc = 3:1): white solid,
85% yield (40.7 mg); 1H NMR (400 MHz, CDCl3) δ 7.35−7.20 (m,
8H), 7.14−7.12 (m, 2H), 5.74 (br s, 1H), 4.37 (m, 2H), 3.59 (q, J =
7.2 Hz, 1H), 1.54 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 174.2, 141.4, 138.4, 129.0, 128.7, 127.8, 127.6, 127.44,
127.40, 47.3, 43.7, 18.7; HRMS (ESI) m/z [M + Na]+ calcd for
C16H17NONa 262.1202, found 262.1186. The formation of acyl
fluoride 3i was characterized by 19F NMR spectroscopy (δ 39.7 ppm,
CDCl3, 19F NMR yield = 81%).
7.36−7.26 (m, 5H), 5.68 (br s, 1H), 5.08 (m, 1H), 4.70 (tt, J = 11.6,
4.4 Hz, 1H), 4.44 (d, J = 5.2 Hz, 2H), 2.27 (m, 1H), 2.09 (s, 3H),
2.03 (s, 3H), 1.94−0.98 (m, 25H), 0.91 (s, 3H), 0.81 (d, J = 6.0 Hz,
3H), 0.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.3, 170.7,
170.6, 138.5, 128.9, 128.0, 127.7, 76.1, 74.4, 49.6, 47.9, 45.2, 43.8,
42.0, 35.8, 35.0, 34.9, 34.6, 34.2, 33.8, 32.4, 31.8, 27.6, 27.0, 26.8,
26.0, 25.8, 23.6, 23.2, 21.6, 21.5, 17.8, 12.6; HRMS (ESI) m/z [M +
Na]+ calcd for C35H51NO5Na 588.3659, found 588.3611. The
formation of acyl fluoride 3o was characterized by 19F NMR
spectroscopy (δ 44.9 ppm, CDCl3, 19F NMR yield = 91%).
N-Benzyl-2-(4-isobutylphenyl)propanamide (4p). The compound
was purified by flash silica gel chromatography (hexane/EtOAc =
3:1): white solid, 90% yield (53.2 mg); 1H NMR (400 MHz, CDCl3)
δ 7.28−7.19 (m, 5H), 7.12−7.09 (m, 4H), 5,74 (s, 1H), 4.37 (d, J =
6.0 Hz, 2H), 3.57 (q, J = 7.6 Hz, 1H), 2.44 (d, J = 7.6 Hz, 2H), 1.84
(m, 1H), 1.54 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 7.2 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 174.5, 140.9, 138.6, 138.5, 129.7, 128.7,
127.5, 127.4, 46.9, 45.1, 43.6, 30.3, 22.5, 18.6 (one aromatic carbon is
overlapping); HRMS (ESI) m/z [M + Na]+ calcd for C20H25NONa
318.1828, found 318.1825. The formation of acyl fluoride 3p was
characterized by 19F NMR spectroscopy (δ 38.3 ppm, CDCl3, 19F
NMR yield = 93%).
N-Benzylcyclohexanecarboxamide (4j). The compound was
purified by flash silica gel chromatography (hexane/EtOAc = 3:1):
1
white solid, 82% yield (35.6 mg); H NMR (400 MHz, CDCl3) δ
7.35−7.25 (m, 5H), 5,73 (br s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 2.11
(m, 1H), 1.91−1,87 (m, 2H), 1.81−1.78 (m, 2H), 1.68 (m, 1H),
1.51−1.42 (m, 2H), 1.31−1.20 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 176.0, 138.7, 128.8, 127.9, 127.6, 45.7, 43.5, 29.9, 25.9;
HRMS (ESI) m/z [M + Na]+ calcd for C14H19NONa 240.1359,
found 240.1344.
N-Benzyltetrahydrofuran-2-carboxamide (4k). The compound
was purified by flash silica gel chromatography (hexane/EtOAc =
3:1): yellow oil, 71% yield (29.1 mg); 1H NMR (400 MHz, CDCl3) δ
N-Benzyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (4q). The com-
pound was purified by flash silica gel chromatography (hexane/EtOAc
= 3:1 to 1:1): white solid, 50% yield (29.4 mg); 1H NMR (400 MHz,
CDCl3) δ 7.88−7.85 (m, 2H), 7.75−7.71 (m, 2H), 7.34−7.23 (m,
5H), 6.14 (br s, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.34 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 167.9, 166.1, 137.7, 134.4, 132.1, 128.9,
128.0, 127.8, 123.8, 44.0, 40.9; HRMS (ESI) m/z [M − H]− calcd for
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The Journal of Organic Chemistry
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Note
C17H13N2O3 293.0921, found 293.0932. The formation of acyl
fluoride 3q was characterized by 19F NMR spectroscopy (δ 31.6 ppm,
CDCl3, 19F NMR yield = 47%).
133.3, 129.8, 128.8, 127.8, 127.6, 45.6, 43.6, 42.1, 28.2, 21.6 (one
aromatic carbon is overlapping); HRMS (ESI) m/z [M − H]− calcd
for C20H23N2O3S 371.1424, found 371.1442. The formation of acyl
fluoride 3w was characterized by 19F NMR spectroscopy (δ 36.6 ppm,
CDCl3, 19F NMR yield = 86%).
(S)-N-Benzyl-2-(1,3-dioxoisoindolin-2-yl)propanamide (4r). The
compound was purified by flash silica gel chromatography (hexane/
1
EtOAc = 3:1 to 1:1): white solid, 59% yield (36.4 mg); H NMR
Procedure for One-Pot Synthesis of Bulky Peptides.
Synthesis of 5. CuBr2 (4.5 mg, 0.020 mmol, 10 mol % of Cu), 1
(85.0 mg, 0.24 mmol), and 2s (70.7 mg, 0.20 mmol) were placed in
an oven-dried 10 mL glass tube capped with a rubber septum. The
tube was evacuated and then refilled with argon gas for 5 cycles.
MeCN (2.0 mL) was added successively, and the reaction solution
was stirred at 80 °C in an oil bath for 1 h under an argon atmosphere.
The mixture was cooled down to room temperature, and subsequently
L-phenylalanine methyl ester hydrochloride (86.3 mg, 0.40 mmol)
and triethylamine (55.4 μL, 0.40 mmol) were added. The mixture was
stirred for at room temperature for 12 h under an argon atmosphere
and passed through a short pad of silica gel with EtOAc as an eluent.
The filtrate was concentrated in vacuo, and the obtained crude
product was purified by flash silica gel column chromatography using
hexane/EtOAc (v/v = 3:1) as an eluent to afford the corresponding
(400 MHz, CDCl3) δ 7.84−7.81 (m, 2H), 7.74−7.71 (m, 2H), 7.33−
7.23 (m, 5H), 6.39 (br s, 1H), 4.96 (q, J = 7.6 Hz, 1H), 4.46 (d, J =
6.0 Hz, 2H), 1.71 (d, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 169.2, 167.9, 138.0, 134.4, 132.0, 128.8, 127.8, 127.6, 123.7,
49.6, 44.0, 15.5; HRMS (ESI) m/z [M − H]− calcd for C18H15N2O3
307.1077, found 307.1088. The formation of acyl fluoride 3r was
characterized by 19F NMR spectroscopy (δ 28.2 ppm, CDCl3, 19F
NMR yield = 51%).
N-Benzyl-2-(1,3-dioxoisoindolin-2-yl)-2-methylpropanamide
(4s). The compound was purified by flash silica gel chromatography
1
(hexane/EtOAc = 3:1 to 1:1): white solid, 90% yield (58.0 mg); H
NMR (400 MHz, CDCl3) δ 7.77−7.74 (m, 2H), 7.69−7.66 (m, 2H),
7.34−7.29 (m, 4H), 7.26 (m, 1H), 6.12 (br s, 1H), 4.47 (d, J = 5.6
Hz, 2H), 1.85 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9,
168.7, 138.2, 134.2, 131.9, 128.8, 127.9, 127.6, 123.2, 61.6, 44.0, 25.0;
HRMS (ESI) m/z [M − H]− calcd for C19H17N2O3 321.1234, found
321.1245. The formation of acyl fluoride 3s was characterized by 19F
NMR spectroscopy (δ 18.3 ppm, CDCl3, 19F NMR yield = 90%).
(S)-N-Benzyl-2-(1,3-dioxoisoindolin-2-yl)-2-methylbutanamide
(4t). The compound was purified by flash silica gel chromatography
1
dipeptide 5 (80%, 63.1 mg) as a white solid: H NMR (400 MHz,
CDCl3) δ 7.81−7.79 (m, 2H), 7.72−7.70 (m, 2H), 7.21−7.19 (m,
3H), 7.14−7.12 (m, 2H), 6.14 (d, J = 7.2 Hz, 1H), 4.94 (dd, J = 13.6,
5.6 Hz, 1H), 3.72 (s, 3H), 3.17 (d, J = 5.2 Hz, 2H), 1.82 (s, 3H), 1.80
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.4, 172.0, 168.6,
135.9, 134.2, 132.0, 129.5, 128.6, 127.2, 123.3, 61.5, 53.3, 52.5, 38.0,
24.9, 24.7; HRMS (ESI) m/z [M − H]− calcd for C22H21N2O5
393.1445, found 393.1469.
1
(hexane/EtOAc = 3:1 to 1:1): white solid, 91% yield (61.1 mg); H
NMR (400 MHz, CDCl3) δ 7.81−7.77 (m, 2H), 7.72−7.69 (m, 2H),
7.36−7.29 (m, 4H), 7.27 (m, 1H), 5.97 (br s, 1H), 4.56−4.45 (m,
2H), 2.58 (m, 1H), 2.06 (m, 1H), 1.87 (s, 3H), 0.94 (t, J = 7.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 169.1, 138.2, 134.2,
131.8, 128.8, 128.0, 127.7, 123.3, 65.5, 44.1, 29.0, 22.1, 8.8; HRMS
(ESI) m/z [M − H]− calcd for C20H19N2O3 335.1390, found
335.1405. The formation of acyl fluoride 3t was characterized by 19F
NMR spectroscopy (δ 22.1 ppm, CDCl3, 19F NMR yield = 94%).
(S)-N-Benzyl-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide
(4u). The compound was purified by flash silica gel chromatography
(hexane/EtOAc = 3:1 to 1:1): white solid, 71% yield (42.6 mg),
Synthesis of 6. CuBr2 (4.5 mg, 0.020 mmol, 10 mol % of Cu), 1
(85.0 mg, 0.24 mmol), and 2s (70.7 mg, 0.20 mmol) were placed in
an oven-dried 10 mL glass tube capped with a rubber septum. The
tube was evacuated and then refilled with argon gas for 5 cycles.
MeCN (2.0 mL) was added successively, and the reaction solution
was stirred at 80 °C in an oil bath for 1 h under an argon atmosphere.
The mixture was cooled down to room temperature, and subsequently
2-aminoisobutyric acid methyl ester hydrochloride (55.8 mg, 0.40
mmol) and triethylamine (55.4 μL, 0.40 mmol) were added. The
mixture was stirred for at room temperature for 24 h under an argon
atmosphere and passed through a short pad of silica gel with EtOAc as
an eluent. The filtrate was concentrated in vacuo, and the obtained
crude product was purified by flash silica gel column chromatography
using hexane/EtOAc (v/v = 5:1 to 1:1) as an eluent to afford the
corresponding dipeptide 6 (75%, 49.9 mg) as a white solid: 1H NMR
(400 MHz, CDCl3) δ 7.81−7.79 (m, 2H), 7.71−7.69 (m, 2H), 6.45
(br s, 1H), 3.75 (s, 3H), 1.85 (s, 6H), 1.62 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 175.5, 171.9, 168.7, 134.2, 132.1, 123.3, 61.7,
57.0, 52.9, 24.9, 24.3; HRMS (ESI) m/z [M − H]− calcd for
C17H19N2O5 331.1288, found 331.1303.
Synthesis of 7. CuBr2 (4.5 mg, 0.020 mmol, 10 mol % of Cu), 1
(142 mg, 0.40 mmol), and 2s (70.7 mg, 0.20 mmol) were placed in an
oven-dried 10 mL glass tube capped with a rubber septum. The tube
was evacuated and then refilled with argon gas for 5 cycles. MeCN
(2.0 mL) was added successively, and the reaction solution was stirred
at 80 °C in an oil bath for 1 h under an argon atmosphere. The
mixture was cooled down to room temperature, and subsequently L-
proline methyl ester hydrochloride (66.2 mg, 0.40 mmol) and N,N-
diisopropylethylamine (139 μL, 0.80 mmol) were added. The mixture
was stirred at room temperature for 72 h under an argon atmosphere
and passed through a short pad of silica gel with EtOAc as an eluent.
The filtrate was concentrated in vacuo, and the obtained crude
product was purified by flash silica gel column chromatography using
hexane/EtOAc (v/v = 3:1 to 2:1) as an eluent to afford the
corresponding dipeptide 7 (85%, 58.8 mg) as a yellow solid: 1H NMR
(400 MHz, CDCl3) δ 7.87−7.83 (m, 2H), 7.78−7.74 (m, 2H), 4.57
(dd, J = 8.0, 4.0 Hz, 1H), 3.75 (s, 3H), 3.61 (m, 1H), 3.15 (m, 1H),
2.09−1.94 (m, 2H), 1.98 (s, 3H), 1.91−1.77 (m, 2H), 1.74 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 170.8, 168.1, 134.4,
131.6, 123.4, 61.0, 60.6, 52.2, 47.3, 28.0, 25.8, 25.5, 23.6; HRMS
(ESI) m/z [M + Na]+ calcd for C18H20N2O5Na 367.1264, found
367.1269.
1
>99% ee; H NMR (400 MHz, CDCl3) observed mixture of isomers
(major/minor = 88:12) δ 7.34−7.20 (m, 5H), 6.74 (br s, 0.88H),
6.32 (br s, 0.12H), 4.62 (d, J = 7.6 Hz, 0.12H), 4.53 (dd, J = 8.0, 3.6
Hz, 0.88H), 4.48−4.35 (m, 2H), 3.84−3.61 (m, 2H), 2.31−2.20 (m,
2H), 2.05−1.97 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
169.7,156.8 (q, JCF = 37.2 Hz), 138.0, 128.8, 127.8, 127.6, 116.3 (q,
JCF = 286 Hz), 61.6, 48.5, 47.6, 43.7, 32.4, 27.7, 25.3, 21.4; HRMS
(ESI) m/z [M − H]− calcd for C14H14F3N2O2: 299.1002, found
299.1011; HPLC (Daicel Chiralpak ID column, column oven: 40 °C,
eluent: hexane/2-propanol = 80:20, flow rate = 1.0 mL/min, λ = 230
nm): tminor = 7.1 min, tmajor = 11.4 min. The formation of acyl fluoride
3u was characterized by 19F NMR spectroscopy (δ 28.5 ppm, CDCl3,
19F NMR yield = 63%).
N-Benzyl-3-(2,2,2-trifluoroacetamido)butanamide (4v). The
compound was purified by flash silica gel chromatography (hexane/
1
EtOAc = 3:1 to 1:1): white solid, 99% yield (57.6 mg); H NMR
(400 MHz, CDCl3) δ 8.27 (br s, 1H), 7.38−7.26 (m, 5H), 5.94 (br s,
1H), 4.51−4.40 (m, 2H), 4.33 (m, 1H), 2,60 (dd, J = 15.2, 4.8 Hz,
1H), 2.33 (dd, J = 14.8, 4.0 Hz, 1H), 1.32 (d, J = 6.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 156.6 (q, JCF = 37.1 Hz),
137.6, 129.0, 128.0, 128.0, 116.0 (q, JCF = 286 Hz), 43.8, 43.6, 39.9,
19.4; HRMS (ESI) m/z [M − H]− calcd for C13H14F3N2O2 287.1002,
found 287.1016. The formation of acyl fluoride 3v was characterized
by 19F NMR spectroscopy (δ 49.5 ppm, CDCl3, 19F NMR yield =
99%).
N-Benzyl-1-tosylpiperidine-4-carboxamide (4w). The compound
was purified by flash silica gel chromatography (hexane/EtOAc = 3:1
to 1:1): white solid, 82% yield (61.1 mg); 1H NMR (400 MHz,
CDCl3) δ 7.61 (d, J = 8.0 Hz, 2H), 7.32−7.25 (m, 5H), 7.20 (d, J =
8.0 Hz, 2H), 5.95 (br s, 1H), 4.38 (d, J = 5,6 Hz, 2H), 3.71 (m, 2H),
2.43 (s, 3H), 2.35 (td, J = 11.6, 3.2 Hz, 2H), 2.06 (m, 1H), 1.90−1.75
(m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6, 143.7, 138.2,
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Note
General Procedure for the Synthesis of Amino Acid para-
Methoxybenzyl Ester. To a solution of amino acid (20.0 mmol)
and Na2CO3 (10.6 g, 100 mmol) in 1,4-dioxane/H2O (v/v = 1:1, 200
mL) was added 9-fluorenylmethyl chloroformate (5.7 g, 22.0 mmol)
portionwise at room temperature, and the mixture was stirred for 24
h. The reaction solution was washed with Et2O (3 × 50 mL). To the
aqueous layer was added concentrate HCl dropwise until the pH
reached 2.0. Subsequently, the solution was extracted with EtOAc (3
× 50 mL), and the combined organic layers were dried over Na2SO4
and concentrated in vacuo. The resultant Fmoc-amino acid was used
without further purification.
To a solution of Fmoc-amino acid (10.0 mmol) and potassium
carbonate (2.1 g, 15.0 mmol) in MeCN (100 mL) was added para-
methoxybenzyl bromide (1.6 mL, 11.0 mmol) at room temperature,
and the reaction solution was stirred at 80 °C in an oil bath for 3 h
under an argon atmosphere. The reaction was quenched with H2O
(100 mL), and the mixture was extracted with EtOAc (3 × 50 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The obtained crude product was
purified by flash silica gel column chromatography using hexane/
EtOAc as an eluent (v/v = 5:1 to 1:1) to afford the corresponding
Fmoc-amino acid para-methoxybenzyl ester.
To a solution of Fmoc-amino acid para-methoxybenzyl ester (5.0
mmol) in CH2Cl2 (20 mL) was added diethylamine (4.0 mL) in one
portion at 0 °C under an argon atmosphere. The mixture was allowed
to warm to room temperature and stirred for 5 h. The reaction
solution was evaporated to remove the solvent and diethylamine, and
the obtained crude mixture was purified by flash silica gel column
chromatography using CHCl3/MeOH (v/v = 20:1 to 10:1) as an
eluent to afford the corresponding amino acid para-methoxybenzyl
ester.
4-Methoxybenzyl Piperidine-4-carboxylate (8). The compound
was prepared following the general procedure: yellow oil, 55% yield
for step 3 (686 mg); 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.8
Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.03 (s, 2H), 4.03 (br s, 1H), 3.78
(s, 3H), 3.13−3.10 (m, 2H), 2.69 (t, J = 10.4 Hz, 2H), 2.46 (m, 1H),
1.95−1.92 (m, 2H), 1.75−1.66 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 174.4, 159.7, 130.0, 128.2, 114.1, 66.2, 55.4, 45.1, 40.8,
28.2; HRMS (ESI) m/z [M + H]+ calcd for C14H20NO3 250.1438,
found 250.1437.
7.23 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.02 (s, 2H), 4.60−
3.60 (br s, 2H), 3.80 (s, 3H), 2.94 (t, J = 11.2 Hz, 2H), 2.47 (m, 1H),
1.90−1.85 (br s, 8H), 1.60 (br s, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 174.0, 170.2, 168.1, 159.7, 134.4, 131.7, 130.0, 128.0, 123.4,
114.1, 66.3, 60.9, 55.4, 40.9, 27.9, 25.6 (one carbon peak is not
detected); HRMS (ESI) m/z [M + Na]+ calcd for C26H28N2O6Na
487.1840, found 487.1802.
Synthesis of 11. CuBr2 (4.8 mg, 0.022 mmol, 10 mol % of Cu), 1
(114 mg, 0.32 mmol), and dipeptide 9 (100 mg, 0.22 mmol) were
placed in an oven-dried 10 mL glass tube capped with a rubber
septum. The tube was evacuated and then refilled with argon gas for 5
cycles. MeCN (2.2 mL) was added successively, and the reaction
solution was stirred at 80 °C in an oil bath for 1 h under an argon
atmosphere. The mixture was allowed to cool to room temperature,
diluted with EtOAc, and passed through a short pad of silica gel with
EtOAc as an eluent. The solution was concentrated in vacuo, and the
obtained crude mixture including the corresponding acyl fluoride was
transferred into another 10 mL glass tube attached to an argon
balloon and dissolved in MeCN (2.2 mL). To the solution were
added 10 (96.0 mg, 0.43 mmol) and triethylamine (59.6 μL, 0.43
mmol) successively. The mixture was stirred at room temperature for
12 h under an argon atmosphere and passed through a short pad of
silica gel with EtOAc as an eluent. The filtrate was concentrated in
vacuo, and the obtained crude product was purified by flash silica gel
column chromatography using hexane/EtOAc (v/v = 1:1 to 1:2) as
an eluent to afford the desired tripeptide 11 (51%, 60.5 mg) as a
1
white solid: H NMR (400 MHz, CDCl3) δ 7.84−7.82 (m, 2H),
7.74−7.72 (m, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz,
2H), 6.01 (br s, 1H), 5.06 (s, 2H), 4.60−3.70 (br s, 2H), 3.81 (s,
3H), 2.90−2.76 (m, 2H), 2.18 (m, 1H), 1.83 (s, 6H), 1.75−1.52 (m,
4H), 1.50 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.5, 173.3,
170.2, 168.2, 159.8, 134.5, 131.7, 130.1, 127.7, 123.5, 114.0, 67.3,
61.0, 56.6, 55.4, 42.9, 28.4, 26.0, 24.8 (one carbon peak is not
detected); HRMS (ESI) m/z [M + Na]+ calcd For C30H35N3O7Na
572.2367, found 572.2320.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00188.
4-Methoxybenzyl 2-Amino-2-methylpropanoate (10). The com-
pound was prepared following the general procedure: colorless oil,
1
Optimization of reaction conditions, H and 13C{1H}
1
78% yield for step 3 (870 mg); H NMR (400 MHz, CDCl3) δ 7.27
NMR spectra, and HPLC chart for 4u (PDF)
(d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.06 (s, 2H), 3.78 (s,
3H), 1.78 (br s, 2H), 1.33 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 177.8, 159.5, 129.7, 128.0, 113.8, 66.4, 55.1, 54.6, 27.6;
HRMS (ESI) m/z [M + H]+ calcd for C12H18NO3 224.1281, found
224.1278.
AUTHOR INFORMATION
■
Corresponding Authors
Procedure for Iterative Formation of Bulky Amide Bonds.
Synthesis of 9. CuBr2 (22.3 mg, 0.10 mmol, 10 mol % of Cu), 1 (425
mg, 1.2 mmol), and 2s (353 mg, 1.0 mmol) were placed in an oven-
dried 30 mL glass reaction vessel attached to an argon balloon. The
reactor was evacuated and then refilled with argon gas for 5 cycles.
MeCN (10 mL) was added successively, and the reaction solution was
stirred at 80 °C in an oil bath for 1 h under an argon atmosphere. The
mixture was allowed to cool to room temperature, diluted with
EtOAc, and passed through a short pad of silica gel with EtOAc as an
eluent. The solution was concentrated in vacuo, and the obtained
crude mixture including the corresponding acyl fluoride was
transferred into another 30 mL reactor attached to an argon balloon
and dissolved in MeCN (10 mL). To the solution were added 8 (498
mg, 2.0 mmol) and triethylamine (277 μL, 2.0 mmol) successively.
After the mixture was stirred at room temperature for 12 h under an
argon atmosphere, H2O (10 mL) was added, and the resultant
solution was extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over Na2SO4 and concentrated in vacuo.
The obtained crude product was purified by flash silica gel column
chromatography using hexane/EtOAc (v/v = 5:1 to 1:1) as an eluent
Akira Matsumoto − Graduate School of Pharmaceutical
Sciences, Kyoto University, Kyoto 606-8501, Japan;
orcid.org/0000-0002-3719-8597;
Email: matsumoto.akira.3c@kyoto-u.ac.jp
Keiji Maruoka − Graduate School of Pharmaceutical Sciences,
Kyoto University, Kyoto 606-8501, Japan; School of
Chemical Engineering and Light Industry, Guangdong
University of Technology, Guangzhou 510006, China;
orcid.org/0000-0002-0044-6411;
Email: maruoka.keiji.4w@kyoto-u.ac.jp
Author
Zhe Wang − Graduate School of Pharmaceutical Sciences,
Kyoto University, Kyoto 606-8501, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00188
1
Notes
to afford the desired dipeptide 9 (61%, 280 mg) as a white solid: H
NMR (400 MHz, CDCl3) δ 7.83−7.80 (m, 2H), 7.75−7.72 (m, 2H),
The authors declare no competing financial interest.
5409
https://dx.doi.org/10.1021/acs.joc.1c00188
J. Org. Chem. 2021, 86, 5401−5411

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Synthesis of New Immonium-Type Coupling Reagents. Eur. J. Org.
Chem. 2006, 2006, 1563−1573.
ACKNOWLEDGMENTS
■
We gratefully acknowledge partial financial support via JSPS
KAKENHI grant no. JP17H06450 (Hybrid Catalysis). We also
thank Kishida Chemical Co., Ltd. for the donation of (R)-α-
ethylalanine.
(7) For recent examples, see: (a) Gonay, M.; Batisse, C.; Paquin, J.-
F. Synthesis of Acyl Fluorides from Carboxylic Acids Using NaF-
Assisted Deoxofluorination with XtalFluor-E. J. Org. Chem. 2020, 85,
10253−10260. (b) Song, H.-X.; Tian, Z.-Y.; Xiao, J.-C.; Zhang, C.-P.
Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from Carboxylic
Acids and CF3SO2OCF3. Chem. - Eur. J. 2020, 26, 16261−16265.
(c) Yang, Z.; Chen, S.; Yang, F.; Zhang, C.; Dou, Y.; Zhou, Q.; Yan,
Y.; Tang, L. PPh3/Selectfluor-Mediated Transformation of Carboxylic
Acids into Acid Anhydrides and Acyl Fluorides and Its Application in
Amide and Ester Synthesis. Eur. J. Org. Chem. 2019, 2019, 5998−
6002. (d) Munoz, S. B.; Dang, H.; Ispizua-Rodriguez, X.; Mathew, T.;
Prakash, G. K. S. Direct Access to Acyl Fluorides from Carboxylic
Acids Using a Phosphine/Fluoride Deoxyfluorination Reagent
System. Org. Lett. 2019, 21, 1659−1663. (e) Meanwell, M.;
Lehmann, J.; Eichenberger, M.; Martin, R. E.; Britton, R. Synthesis
of acyl fluorides via photocatalytic fluorination of aldehydic C−H
bonds. Chem. Commun. 2018, 54, 9985−9988. (f) Scattolin, T.;
Deckers, K.; Schoenebeck, F. Direct Synthesis of Acyl Fluorides from
Carboxylic Acids with the Bench-Stable Solid Reagent (Me4N)SCF3.
Org. Lett. 2017, 19, 5740−5743.
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