Highly Efficient DMSO-Promoted α-Hydrolysis of α-Halohydroxamates under Mild Conditions

Article abstract of DOI:10.1002/ejoc.202100088

A novel and efficient method for the nucleophilic α-hydrolysis of α-halohydroxamates with water under metal-free conditions is described. In this reaction, the simple and readily available dimethyl sulfoxide (DMSO) was used as a catalyst, while water serv

Full text of DOI:10.1002/ejoc.202100088

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Highly Efficient DMSO-Promoted α-Hydrolysis of
α-Halohydroxamates under Mild Conditions
Chang Yoon Lee[a] and Sung-Gon Kim*[a]
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A novel and efficient method for the nucleophilic α-hydrolysis
of α-halohydroxamates with water under metal-free conditions
is described. In this reaction, the simple and readily available
dimethyl sulfoxide (DMSO) was used as a catalyst, while water
served as the nucleophile and oxygen source. This method was
successfully employed in the synthesis of secondary α-hydroxy-
α-alkyl and α-hydroxy-α-arylhydroxamates as well as tertiary α-
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hydroxy-α-dialkylhydroxamates. Furthermore, the α-hydrolysis
of α-halo-α-dialkylhydroxamates was achieved in the absence
of the DMSO catalyst. This is a novel, mild, less toxic, and facile
strategy for α-hydroxylation of amides.
Introduction
α-Hydroxy carbonyl compounds, including α-hydroxy ketones
amides, are important structural motifs that are present in
many biologically active and pharmaceutically relevant
compounds,[1] such as cefamandole,[1a] paeonilactone B,[1b] LY-
411575,[1c] and daunorubicin,[1d] (Figure 1). Furthermore, they
serve as valuable intermediates in some important organic
syntheses owing to their versatile transformations.[2] Therefore,
the development of methods for synthesizing α-hydroxy
carbonyl compounds has received considerable research
attention.[3,4,5]
Among various α-hydroxy carbonyl compounds, our interest
lies in the synthesis of α-hydroxy amides. The conventional
approach for synthesizing α-hydroxy amides is based on the
oxidation of silylenol ethers using peracids.[2a] Over time, the
chemoselective reduction of α-keto amides has also emerged
as an alternative practical method for obtaining α-hydroxy
amides. However, harsh reaction conditions using transition-
metal and organo-metal reagents are required in most of these
methods. Therefore, milder reactions have been investigated in
recent years. In 2014, Jiao et al. described a transition-metal free
Cs2CO3-initiated α-hydroxylation of carbonyl compounds with
oxygen.[3b] Subsequently, Gnanaprakasam and co-workers re-
ported a transition-metal free α-hydroxylation of ketones and
amides using KO-t-Bu and atmospheric air as oxidant.[4c] And
Maulide et al. established a transition-metal free oxidation of
amides to α-hydroxy amides using TEMPO oxidant.[4d] More
recently, Wu and co-workers developed two methodologies for
synthesizing α-hydroxy amides, i.e., metal-catalyst free chemo-
selective transfer hydrogenation of α-ketoamides using sodium
formate as a hydrogen source[4f] and metal-free reduction of α-
ketoamides using DMF as the hydrogen source.[4g] Nevertheless,
Figure 1. Biologically active α-hydroxy carbonyl compounds.
novel, mild, and efficient methods of synthesizing α-hydroxy
carbonyl compounds are still in demand. Thus, we focus on the
development of an efficient and mild strategy for the synthesis
of α-hydroxy carbonyl compounds.
Recently, the azaoxyallyl cation, which can be formed in situ
from α-halohydroxamates, has been utilized as a versatile
intermediate for the synthesis of heterocycles.[6] We also
exploited the azaoxyallyl cation for developing other various
useful syntheses,[7] such as the catalyst-free and mild synthesis
of hindered α-amino amides, wherein in situ-generated aza-
oxyallyl cations from α-halohydroxamates efficiently reacted
with a variety of amines using trifluorotoluene as solvent
(Scheme 1a).[7b] Subsequently, we reported the metal and
catalyst-free synthesis of hindered α-alkoxy amides via the
nucleophilic alkoxylation of α-halohydroxamates with alcohols
(Scheme 1b).[7d] The hindered α-alkoxy amides synthesized
through this strategy could be utilized for the synthesis of α-
hydroxy amides. In this context, we envisaged that α-hydroxy
amides can be directly obtained by the reaction of α-
halohydroxamates with water as the nucleophile (Scheme 1c).
Herein, we report a novel approach for the synthesis of α-
hydroxy amides utilizing the α-hydrolysis of α-halohydroxa-
[a] C. Yoon Lee, Prof. Dr. S.-G. Kim
Department of Chemistry
Kyonggi University
154-42 Gwanggyosan-ro, Yeongtong-gu, Suwon 16227, Republic of Korea
E-mail: sgkim123@kyonggi.ac.kr
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100088
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this hydroxylation reaction, therefore dimethyl sulfoxide
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(DMSO) was used as the solvent instead. Surprisingly, these
conditions furnished the desired α-hydroxyhydroxamate 3a in
43% yield (Scheme 2, Eq. 3).
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Inspired by the aforementioned results, attempts were
made to systematically set up and optimize the reaction
conditions for the hydrolysis of α-chlorohydroxamate 1a with
water 2 (Table 1). First, to investigate the effect of DMSO, the
reaction was carried out using DMSO as both the solvent and
nucleophile without adding water. Even in this case, the
reaction was completed within 4 h and the desired α-hydrox-
yhydroxamate 3a was obtained in 42% yield (Table 1, entry 1).
In order to gain insight into the role of DMSO, the reaction of
α-halohydroxamate 1a with water 2 was performed in the
presence of Na2CO3 as base and DMSO as an additive in CH3CN;
interesting and satisfactory results were obtained (Table 1,
entries 2–4). The use of 1 equiv. of DMSO provided α-
hydroxyhydroxamate 3a in 59% yield. More surprisingly, the
desired product was obtained in 37% yield when a catalytic
amount of DMSO (10 mol%) was used (Table 1, entry 4). On the
other hand, the reaction did not proceed to form product 3a
when DMSO was not included as an additive (Table 1, entry 5).
From these results, it was surmised that DMSO acted as an
essential catalyst in the hydrolysis of α-halohydroxamate 1a
with water 2. As the amount of DMSO increased, the reaction
yield also increased (Table 1, entries 2–7). The addition of 2
equiv. of DMSO afforded the desired product 3a in the highest
yield (81%). To maximize the outcome, we further attempted to
optimize the reaction conditions. Other solvents such as CH2Cl2,
CHCl3, THF, toluene, and CF3C6H5 were ineffective for generating
3a in higher yield (Table 1, entries 8À 12). Thus, CH3CN was
selected as the optimal solvent for conducting this reaction.
The hydrolysis was also performed using K2CO3 and Cs2CO3
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Scheme 1. Nucleophilic addition of α-halohydroxamates.
mates with water and DMSO as nucleophile and as catalyst,
respectively.[8,9]
Results and Discussion
At the outset, the reaction of α-chlorohydroxamate 1a with
water 2 was attempted in the presence of Na2CO3 as base in
trifluorotoluene (CF3C6H5) at room temperature (Scheme 2,
Eq. 1); these reaction conditions were previously optimized for
the α-alkoxylation of α-halohydroxamates with alcohols.[7d]
However, the reaction did not produce the corresponding α-
hydroxyhydroxamate 3a, despite the complete disappearance
of the starting material 1a. Thereafter, the reaction conditions
previously established for the α-amination of α-halohydroxa-
mates were employed (Scheme 2, Eq. 2).[7b] Specifically, the
addition of 5 equiv. of hexafluoroisopropanol (HFIP) in the
nucleophilic substitution of 1a with 2 was expected to lead to
an accelerated reaction rate. However, contrary to this expect-
ation, α-alkoxyhydroxamate 4, which derived from the sub-
stitution of α-chlorohydroxamate 1a with HFIP, was obtained as
the major product in this reaction. Considering the above
results, it can be assumed that the solubility of water in an
organic solvent may be an important factor for the outcome of
Table 1. Optimization of the reaction conditions.[a,b]
[a] The reactions were carried out in solvent (0.2 M) with 1a (0.1 mmol), 2
(0.3 mmol), and base (0.3 mmol) in the presence of additive at room
temperature. [b] Isolated yield after chromatographic purification.
Scheme 2. Nucleophilic alkoxylation and hydrolysis of α-chlorohydroxamate.
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instead of Na2CO3, which afforded product 2a in 34 and 10%
yield, respectively (Table 1, entries 13 and 14).
To further demonstrate the flexibility of the present
approach for the synthesis of α-hydroxyhydroxamates, a variety
of α-halo-α-dialkylhydroxamates were subjected to this hydrol-
ysis. Tertiary α-hydroxycarbonyl groups are important and
useful structural motifs that serve as valuable building blocks
for the biologically active compounds.[1f,3b,4e] The reaction of α-
bromohydroxamate 5a with water 2 under the above-opti-
mized conditions produced the desired sterically hindered α-
hydroxyhydroxamate 6a in moderate yield (54%). However, the
hydrolysis of α-bromohydroxamate 5a was accelerated when
Cs2CO3 was used as base instead of Na2CO3, affording 6a in
good yield (79%, see Supporting Information). Upon modifica-
tion of the optimized reaction conditions, the scope of α-halo-
α-dialkylhydroxamates that could be tolerated in the hydrolysis
reaction was examined (Table 3). Hydroxamates bearing meth-
oxy, ethoxy, and tert-butyloxy N-protecting groups worked well
in this reaction, furnishing the desired products (6b–6d) in
moderate to good yields (55–61%). However, a low product
yield (40%) was obtained with allyloxy-bearing substrates.
Methyethyl, methylpropyl, diethyl, and dipropyl substituents on
the α-bromohydroxamates were tolerated under the reaction
conditions to give the desired products (6f–6i) in moderate
yields (44–57%). Cyclopentyl-substituted α-bromohydroxamate
also underwent smooth α-hydrolysis to furnish the desired
product 6j in 44% yield. However, the cyclohexyl-substituted α-
bromohydroxamate gave 6k in low yield (32%). Unlike the
unsuccessful α-amination and α-alkoxylation of α-bromoamide
bearing a benzyl protecting group, the hydrolysis of α-
bromoamide 5l provided the desired product 6l. Due to the
low reactivity of the α-bromoamide, the reaction did not
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Having optimized the reaction conditions, we next explored
the reaction scope and generality of α-halohydroxamates
(Table 2). When the benzyl group in α-chlorohydroxamates was
replaced by other N-protecting groups such as methoxy,
ethoxy, tert-butyloxy, and allyloxy groups, the reaction pro-
ceeded smoothly to provide the corresponding products (3b–
3e) in moderate to good yields (56–71%). A variety of α-
arylhydroxamates 1f–k bearing electronically distinct substitu-
ents around the phenyl ring were converted to the desired α-
hydroxy products (3f–3k) in moderate to high yields (55–76%).
Generally, electron-donating (À Me, À OMe) and electron-with-
drawing (À F, À Cl, À Br) groups on the phenyl ring had little effect
on the reaction. Substituents at the para- as well as ortho-
position of the aromatic rings did not affect the outcome of the
reaction. Given the satisfactory results obtained with α-halo-α-
arylhydroxamates, we turned our attention to the scope of α-
halo-α-alkylhydroxamates in this hydroxylation reaction. Re-
markably, various α-chloro-α-akylhydroxamates reacted with
water 2 to successfully generate the corresponding products
(3l–3s) in moderate to good yields, although an elevated
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°
temperature of 60 C was required due to the low reactivity of
these reagents.
Table 2. Substrate scope of α-halohydroxamates.[a,b]
°
proceed at room temperature, whereas hydroxylation at 60 C
for 18 h afforded 6l in 61% yield.
In the course of our studies on the hydrolysis of α-halo-α-
dialkylhydroxamates, the reaction of α-bromohydroxamate 5a
with water 2 was found to work well in the presence of Na2CO3
Table 3. Substrate scope of α-halo-α-dialkylhydroxamates.[a,b]
[a] The reactions were carried out in CH3CN (0.2 M) with 1 (0.2 mmol), H2O
(0.6 mmol), DMSO (0.4 mmol), and Na2CO3 (0.6 mmol) at room tempera-
ture. [b] Isolated yield after chromatographic purification. [c] X=Cl. [d] X=
[a] The reactions were carried out in CH3CN (0.2 M) with 5 (0.2 mmol), H2O
(0.6 mmol), DMSO (0.4 mmol), and Cs2CO3 (0.6 mmol) at room temperature.
[b] Isolated yield after chromatographic purification. [c] Using Na2CO3. [d]
°
°
Br and stirred at 60 C.
Stirred at 60 C.
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in trifluorotoluene at room temperature, without requiring
DMSO, affording 5a in moderate yield (40%, Scheme 3).
ing product (6d) in a rather low yield. Notably, the hydrolysis of
α-bromohydroxamate bearing an allyloxy group (5e) pro-
ceeded smoothly under these conditions without DMSO to
afford the corresponding product (6e) in good yield (64%),
compared to the lower yield (40%) obtained in the reaction
using DMSO (see Table 3). The α-hydrolysis proceeded with
methyethyl, methylpropyl, diethyl, and dipropyl substituents on
the α-bromohydroxamates to furnish the corresponding prod-
ucts (6f–6i) in good yields (51–64%), although the reaction
time had to be prolonged to reach completion. Unsatisfactory
results were obtained in the case of the α-hydrolysis of
cyclopentyl- and cyclohexyl-substituted α-bromohydroxamates,
as the products 6j and 6k were obtained in 30 and 21% yields,
respectively. The reaction of α-bromoamide bearing a benzyl
protecting group 5l with water in the absence of DMSO also
did not proceed at all.
To gain a deeper insight into the exact role of DMSO as well
sd the mechanism of this hydrolysis reaction, control experi-
ments using 18O-labeled water were conducted (Table 5). Two
potential products, i.e., 3a and 3a’ could be obtained by
reacting 1a and 2 in which the oxygen atom of the hydroxyl
group derives from the oxygen atom of DMSO and 18O-labeled
water. The ratio between product 3a and 3a’, which depended
on the amount of DMSO and H218O, was measured by LC-MS
analysis. As shown in Table 2, as the amount of DMSO used
increased, the yield of 3a increased. In particular, when the
reaction of 1a was conducted in the presence of 10 mol%
DMSO, product 3a was obtained in 9% yield (Table 5, entry 1).
In addition, when the reaction was performed with 20 mol%
DMSO, 3a was obtained in 21% yield (Table 2, entry 2). This
indicates that DMSO is not just a reaction accelerating solvent
or phase-transfer catalyst but clearly functions as catalyst by
participating in the reaction.
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The reaction conditions for the hydrolysis of α-bromohy-
droxamate 5a in the absence of DMSO were optimized (see
Supporting Information), and the use of CH2Cl2 as solvent was
found to afford optimal results. The scope of the α-halohydrox-
amate component was also evaluated (Table 4). Generally, a
longer reaction time was required than when DMSO was used
as an additive. Replacement of the benzyloxy group in α-
bromohydroxamates by methoxy and ethoxy groups afforded
the desired products 6b and 6c, respectively, in good yields.
However, the tert-butyloxy N-protecting group negatively
impacted this hydroxylation reaction furnishing the correspond-
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Scheme 3. α-Hydrolysis of α-bromo-α-dimethylhydroxamate 5a.
Table 4. α-Hydrolysis of α-halo-α-dialkylhydroxamates in the absence of
DMSO.[a,b]
Based on the aforementioned experimental results and a
previously reported literature,[3c–e,10] a plausible reaction mecha-
nism was proposed as illustrated in Scheme 4. Initially, azaox-
yallyl cation intermediate 1a' is generated from α-halohydrox-
amate 1a in the presence of a base. The nucleophilic oxygen
atom of DMSO attacks azaoxyallyl cation intermediate 1a' to
[a] The reactions were carried out in CH2Cl2 (0.2 M) with 5 (0.2 mmol), H2O
(0.6 mmol), and Na2CO3 (0.6 mmol) at room temperature. [b] Isolated yield
after chromatographic purification.
Table 5. α-Hydrolysis of α-chlorohydroxamate 1a using 18O-Water.[a,b]
[a] The reactions were carried out in CH3CN (0.2 M) with 1a (0.1 mmol), 2,
DMSO, and Na2CO3 (0.3 mmol) at room temperature. [b] Isolated yield after
chromatographic purification. [c] Determined by LC-MS analysis.
Scheme 4. Proposed mechanism.
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yield intermediate A.[3c,e] The attack of H2O to the electrophilic
sulfur atom of intermediate 1a' then generates intermediate B
through protonation of the nitrogen atom and hydroxylation of
the sulfur atom. However, according to the results of the
aforementioned experiments with 18O-labeled water, the CÀ O
bond cleavage of intermediate 1a' upon the attack of H2O on
its α-carbon, which could provide product 3 and DMSO, can be
excluded. Subsequently, the proton transfer of intermediate B
afforded intermediate C.[3d] Finally, the extraction of DMSO from
intermediate C produces the desired hydroxyl product 3a.
column chromatography (EtOAc : hexanes=1:1) to afford desired
product 3a (195 mg, 76% yield) as white solid.
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N-(Benzyloxy)-2-hydroxy-2-phenylacetamide (3a). Synthesized by
the general procedure I; flash chromatography (EtOAc/hexane=
2:3, 42 mg, yield 81%), White solid; m.p. 99–101 C; 1H NMR
°
(400 MHz, CDCl3) δ 8.51 (s, 1H), 7.42–7.26 (m, 10H), 5.05 (s, 1H), 4.86
(s, 2H), 3.29 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.5, 138.6, 134.7,
129.4, 128.9 (two peaks overlapping), 128.8, 128.6, 126.7, 78.5, 73.5;
IR (neat) 3167, 3060, 3029, 2926, 1681, 1633, 1495, 1449, 1377,
1337, 1267, 1109, 1064, 1023 cmÀ 1; HRMS (EI) m/z calcd for [M]+
C15H15NO3: 257.1052 Found: 257.1067.
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2-Hydroxy-N-methoxy-2-phenylacetamide (3b). Synthesized by
the general procedure I; flash chromatography (EtOAc/hexane=
2:3, 24 mg, yield 66%), Colorless gum; 1H NMR (400 MHz, DMSO-d6)
δ 11.36 (s, 1H), 7.48–7.20 (m, 5H), 6.11 (d, J=4.9 Hz, 1H), 4.89 (d, J=
4.8 Hz, 1H), 3.55 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 169.0, 141.2,
128.5, 128.0, 126.9, 73.1, 63.5; IR (neat) 3197, 3063, 3001, 2939,
1659, 1637, 1492, 1453, 1327, 1260, 1227, 1191, 1063, 1036,
1026 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C9H11NO3: 181.0739 Found:
181.0750.
Conclusions
In summary, we have developed a novel method for the
nucleophilic α-hydroxylation of α-halohydroxamates with water
under metal-free conditions to afford α-hydroxyhydroxamate
derivatives in moderate to good yields (up to 81%). In the
hydroxylation reaction, water acts as the nucleophile. while
DMSO functions as a catalyst. This method was successfully
applied to α-halo-α-arylhydroxamates, α-halo-α-alkylhydroxa-
mates, and α-halo-α-dialkylhydroxamates. Furthermore, the α-
hydroxylation of α-halo-α-dialkylhydroxamates with water was
also achieved without DMSO catalysis.
N-Ethoxy-2-hydroxy-2-phenylacetamide (3c). Synthesized by the
general procedure I; flash chromatography (EtOAc/hexane=2:3,
1
°
30 mg, yield 71%), White solid; m.p. 157–159 C; H NMR (400 MHz,
DMSO-d6) δ 11.23 (s, 1H), 7.47–7.23 (m, 5H), 6.08 (d, J=4.9 Hz, 1H),
4.89 (d, J=4.9 Hz, 1H), 3.76 (q, J=7.0 Hz, 2H), 1.09 (t, J=7.0 Hz, 3H);
13C NMR (100 MHz, DMSO-d6) δ 169.1, 141.3, 128.5, 128.0, 126.9,
73.1, 70.9, 13.8; IR (neat) 3353, 3192, 3062, 2929, 1644, 1486, 1455,
1389, 1269, 1257, 1199, 1128, 1076, 1061, 1021 cmÀ 1; HRMS (EI) m/z
calcd for [M]+ C12H17NO3: 195.0895 Found: 195.0887.
Experimental Section
N-tert-Butoxy-2-hydroxy-2-phenylacetamide (3d). Synthesized by
the general procedure I; flash chromatography (EtOAc/hexane=
General Information: Organic solvents were distilled prior to use.
Organic solutions were concentrated under reduced pressure using
a rotary evaporator. Chromatographic purification of products was
accomplished using forced-flow chromatography on ICN 60 32–
64 mesh silica gel 63. Thin-layer chromatography (TLC) was
performed on EM Reagents 0.25 mm silica gel 60-F plates.
Developed chromatograms were visualized by fluorescence
quenching and with anisaldehyde stain. 1H and 13C NMR spectra
were recorded (400 MHz for 1H and 100 MHz for 13C), and were
2:3, 25 mg, yield 56%), White solid; m.p. 158–160 C; 1H NMR
°
(400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.47–7.40 (m, 2H), 7.37–7.22 (m,
3H), 5.95 (d, J=5.5 Hz, 1H), 4.94 (d, J=5.4 Hz, 1H), 1.09 (s, 9H); 13C
NMR (100 MHz, DMSO-d6) δ 170.5, 141.7, 128.4, 127.9, 126.8, 81.5,
72.8, 26.8; IR (neat) 3420, 3231, 3029, 2927, 1677, 1650, 1488, 1475,
1390, 1364, 1305, 1247, 1206, 1055, 1026 cmÀ 1; HRMS (EI) m/z calcd
for [M]+ C12H17NO3: 223.1208 Found: 223.1192.
1
N-(Allyloxy)-2-hydroxy-2-phenylacetamide (3e). Synthesized by
the general procedure I; flash chromatography (EtOAc/hexane=
internally referenced to residual protic solvent signals. Data for H
NMR are reported as follows: chemical shift (δ ppm), multiplicity
(s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), cou-
pling constant (Hz) and integration. Data for 13C NMR are reported
in terms of chemical shift. IR spectra were recorded on an FT IR
spectrometer and are reported in wave numbers. High-resolution
mass spectroscopy (HRMS) was performed by electron impact (EI).
α-Halohydroxamides[11] were prepared according to literature.
2:3, 28 mg, yield 68%), White solid; m.p. 68–70 C; 1H NMR
°
(400 MHz, DMSO-d6) δ 11.28 (s, 1H), 7.45–7.37 (m, 2H), 7.36–7.22 (m,
3H), 6.08 (d, J=4.9 Hz, 1H), 5.89 (ddt, J=16.5, 10.4, 6.0 Hz, 1H),
5.29–5.14 (m, 2H), 4.89 (d, J=4.6 Hz, 1H), 4.24 (d, J=6.0 Hz, 2H); 13
C
NMR (100 MHz, DMSO-d6) δ 168.1, 140.2, 132.4, 127.3, 126.9, 125.9,
118.4, 75.1, 72.0; IR (neat) 3272, 3176, 3049, 2990, 2902, 2857, 1660,
1633, 1506, 1496, 1450, 1416, 1363, 1293, 1260, 1115, 1088,
1065 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C11H13NO3: 207.0895
Found: 207.0902.
General Procedure I for the α-hydroxylation of α-Halohydrox-
amates: To a solution of α-halohydroxamate 1 (0.20 mmol), water 2
(0.60 mmol), and DMSO (0.4 mmol) in CH3CN (1 mL) was added
Na2CO3 (0.60 mmol) at room temperature. The reaction mixture was
stirred at the same temperature until α-halohydroxamate 1 was
completely consumed, as determined by TLC. Then, the resulting
mixture was filtered through the plug of celite and concentrated in
vacuo. The crude residue was purified by flash column chromatog-
raphy with EtOAc/hexanes as eluent to afford desired product 3.
N-(Benzyloxy)-2-hydroxy-2-p–tolylacetamide (3f). Synthesized by
the general procedure I; flash chromatography (EtOAc/hexane=
2:3, 36 mg, yield 67%), White solid; m.p. 97–99 C; 1H NMR
°
(400 MHz, CDCl3) δ 8.74 (s, 2H), 7.37–7.25 (m, 11H), 7.16 (dd, J=
21.3, 7.7 Hz, 9H), 4.97 (s, 2H), 4.82 (s, 4H), 3.51 (s, 2H), 2.34 (s, 7H);
13C NMR (100 MHz, CDCl3) δ 169.7, 138.7, 135.7, 134.7, 129.6, 129.4,
128.9, 128.6, 126.7, 78.3, 73.3, 21.2; IR (neat) 3235, 3173, 3031, 2921,
2855, 1661, 1613, 1512, 1496, 1454, 1375, 1306, 1250, 1193, 1180,
1111, 1057, 1029 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C16H17NO3:
271.1208 Found: 271.1215.
Procedure for a 1mmol scale synthesis of 3a: To a solution of α-
chlorohydroxamate 1a (276 mg, 1.0 mmol), water
3.0 mmol), and DMSO (142 μL, 2.0 mmol) in CH3CN (5 mL) was
added Na2CO3 (318 mg, 3.0 mmol) at room temperature. The
reaction mixture was stirred at the same temperature for 6 h. Then,
the resulting mixture was filtered through the plug of celite and
concentrated in vacuo. The crude residue was purified by flash
2 (54 μL,
N-(Benzyloxy)-2-hydroxy-2-(2-methoxyphenyl)acetamide
(3g).
Synthesized by the general procedure I; flash chromatography
(EtOAc/hexane=2:3, 36 mg, yield 62%), White solid; m.p. 98–
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1
°
100 C; H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 7.45 (d, J=7.5 Hz,
1H), 7.38–7.25 (m, 4H), 7.22–7.13 (m, 2H), 7.02 (td, J=7.5, 0.7 Hz,
1H), 6.80 (d, J=8.2 Hz, 1H), 5.39–5.24 (m, 1H), 4.82 (dd, J=26.8,
11.6 Hz, 2H), 4.08 (d, J=5.5 Hz, 1H), 3.63 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.2, 155.2, 134.9, 129.3, 128.8, 128.6, 127.5, 126.9, 121.7,
110.8, 78.1, 66.2, 55.4; IR (neat) 3206, 3007, 2930, 1667, 1602, 1591,
1515, 1490, 1455, 1433, 1373, 1290, 1238, 1189, 1118, 1063,
1025 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C16H17NO3: 287.1158
Found: 287.1156.
2880, 1635, 1485, 1455, 1379, 1328, 1261, 1245, 1220, 1159, 1133,
1062, 1037 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C11H15NO3: 209.1052
Found: 209.1024.
1
2
3
4
5
6
7
8
9
N-(Benzyloxy)-2-hydroxypentanamide (3n). Synthesized by the
general procedure I; flash chromatography (EtOAc/hexane=2:3,
15 mg, yield 33%), White solid; m.p. 85–87 C; 1H NMR (400 MHz,
°
DMSO-d6) δ 11.04 (s, 1H), 7.45–7.26 (m, 5H), 5.31 (d, J=5.8 Hz, 1H),
4.78 (s, 2H), 3.82 (dt, J=7.5, 5.3 Hz, 1H), 1.63–1.38 (m, 2H), 1.34–1.22
(m, 2H), 0.85 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1,
135.0, 129.3, 128.9, 128.7, 78.4, 76.7, 71.6, 36.8, 18.0, 13.7; IR (neat)
3255, 2959, 2933, 2872, 1628, 1506, 1496, 1463, 1453, 1378, 1337,
1262, 1133, 1069, 1030 cmÀ 1; HRMS (EI) m/z calcd for [M]+
C12H17NO3: 223.1208 Found: 223.1194.
N-(Benzyloxy)-2-(4-fluorophenyl)-2-hydroxyacetamide (3h). Syn-
thesized by the general procedure I; flash chromatography (EtOAc/
hexane=2:3, 30 mg, yield 55%), White solid; m.p. 108–110 C; H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
°
NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.46–7.28 (m, 7H), 7.16 (t,
J=8.9 Hz, 2H), 6.15 (d, J=5.0 Hz, 1H), 4.92 (d, J=5.0 Hz, 1H), 4.84–
4.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.0 (d, J1 =243.0 Hz),
159.8, 136.4 (d, J4 =2.9 Hz), 135.1, 128.2, 127.8 (d, J3 =8.2 Hz), 127.6
(two peaks overlapping), 114.1 (d, J2 =21.3 Hz), 76.1, 71.2; IR (neat)
3207, 3065, 2924, 1681, 1633, 1603, 1505, 1463, 1452, 1414, 1228,
1188, 1155, 1100, 1071, 1042 cmÀ 1; HRMS (EI) m/z calcd for [M]+
C15H14FNO3: 275.0958 Found: 275.0969.
N-(Benzyloxy)-2-hydroxy-3-methylbutanamide (3o). Synthesized
by the general procedure I; flash chromatography (EtOAc/hexane=
2:3, 27 mg, yield 60%), White solid; m.p. 104–106 C; 1H NMR
°
(400 MHz, CDCl3) δ 8.92 (s, 1H), 7.48-7.29 (m, 5H), 4.91 (q, J=
11.3 Hz, 2H), 3.98 (s, 1H), 2.66 (d, J=5.0 Hz, 1H), 2.12 (dtd, J=13.8,
6.9, 3.5 Hz, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.4, 135.0, 129.2, 128.9, 128.7, 78.5, 75.9,
31.9, 18.8, 15.5; IR (neat) 3241, 3092, 2966, 2918, 2872, 1632, 1628,
1496, 1418, 1366, 1259, 1178, 1141, 1087, 1023 cmÀ 1; HRMS (EI) m/z
calcd for [M]+ C12H17NO3: 223.1208 Found: 223.1187.
N-(Benzyloxy)-2-(4-chlorophenyl)-2-hydroxyacetamide (3i). Syn-
thesized by the general procedure I; flash chromatography (EtOAc/
hexane=2:3, 40 mg, yield 68%), White solid; m.p. 131–135 C; H
NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 7.47–7.27 (m, 9H), 6.21 (d,
J=5.1 Hz, 1H), 4.92 (d, J=5.1 Hz, 1H), 4.81–4.61 (m, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 167.8, 139.2, 135.1, 131.5, 128.2, 127.7, 127.6
(two peaks overlapping), 127.4, 76.1, 71.1; IR (neat) 3216, 3063,
2925, 1681, 1650, 1631, 1489, 1459, 1407, 1326, 1251, 1158, 1067,
1013 cmÀ 1; C15H14ClNO3: 291.0662 Found: 291.0649.
1
°
N-(Benzyloxy)-2-hydroxyhexanamide (3p). Synthesized by the
general procedure I; flash chromatography (EtOAc/hexane=2:3,
27 mg, yield 58%), White solid; m.p. 88–90 C; 1H NMR (400 MHz,
°
DMSO-d6) δ 11.03 (s, 1H), 7.51–7.25 (m, 5H), 5.31 (d, J=5.7 Hz, 1H),
4.78 (s, 2H), 3.80 (dt, J=7.3, 5.3 Hz, 1H), 1.63–1.40 (m, 2H), 1.33–1.17
(m, 4H), 0.85 (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1,
135.0, 129.3, 128.9, 128.7, 78.4, 71.8, 34.5, 26.8, 22.4, 13.9; IR (neat)
3274, 3217, 2957, 2930, 2873, 2858, 1627, 1497, 1433, 1377, 1333,
1230, 1158, 1069, 1019 cmÀ 1; HRMS (EI) m/z calcd for [M]+
C12H17NO3: 237.1365 Found: 237.1393.
N-(Benzyloxy)-2-(4-bromophenyl)-2-hydroxyacetamide (3j). Syn-
thesized by the general procedure I; flash chromatography (EtOAc/
hexane=2:3, 39 mg, yield 58%), White solid; m.p. 139–141 C; H
NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.60 (d, J=8.4 Hz, 2H),
7.48–7.36 (m, 7H), 6.27 (d, J=5.1 Hz, 1H), 4.97 (d, J=5.0 Hz, 1H),
4.86–4.76 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 170.0, 139.3,
135.31, 131.0, 129.1, 128.3, 128.2, 128.0, 121.5, 77.4, 72.6; IR (neat)
3216, 3063, 2924, 2854, 1651, 1630, 1590, 1498, 1488, 1404, 1287,
1108, 1066 cmÀ 1; C15H14BrNO3: 335.0157 Found: 335.0160.
1
°
N-(Benzyloxy)-2-hydroxyoctanamide (3q). Synthesized by the
general procedure I; flash chromatography (EtOAc : hexane=2:3,
30 mg, yield 57%), White solid; m.p. 96–98 C; 1H NMR (400 MHz,
°
DMSO-d6) δ 11.03 (s, 1H), 7.43–7.25 (m, 5H), 5.31 (d, J=5.7 Hz, 1H),
4.78 (s, 2H), 3.80 (dt, J=7.3, 5.3 Hz, 1H), 1.52 (ddd, J=27.2, 13.2,
6.0 Hz, 2H), 1.25 (d, J=14.9 Hz, 8H), 0.86 (t, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 171.0, 135.0, 129.3, 128.9, 128.7, 78.4, 71.8, 34.9,
31.7, 29.0, 24.7, 22.6, 14.1; IR (neat) 3201, 2952, 2939, 2871, 2851,
1644, 1626, 1514, 1497, 1466, 1453, 1377, 1366, 1137, 1078,
1049 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C15H23NO3: 265.1678
Found: 265.1703.
N-(Benzyloxy)-2-(2-chlorophenyl)-2-hydroxyacetamide (3k). Syn-
thesized by the general procedure I; flash chromatography (EtOAc/
hexane=2:3, 48 mg, yield 76%), White solid; m.p. m 123–125 C; H
NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.45–7.24 (m, 9H), 5.45 (d, J=
3.9 Hz, 1H), 4.86 (q, J=11.2 Hz, 2H), 3.92 (d, J=4.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 169.0, 136.5, 134.5, 132.4, 129.9, 129.8, 129.4,
129.0, 128.7, 128.5, 127.7, 78.5, 69.0; IR (neat) 3273, 3176, 3064,
2925, 1675, 1591, 1494, 1474, 1447, 1363, 1339, 1265, 1235, 1131,
1084, 1064, 1050 cmÀ 1; C15H14ClNO3: 291.0662 Found: 291.0675.
1
°
N-(Benzyloxy)-2-hydroxy-3-phenylpropanamide (3r). Synthesized
by the general procedure I; flash chromatography (EtOAc/hexane=
2:3, 22 mg, yield 41%), White solid; m.p. 136–138 C; 1H NMR
°
N-(Benzyloxy)-2-hydroxypropanamide (3l). Synthesized by the
general procedure I; flash chromatography (EtOAc/hexane=2:3,
22 mg, yield 56%), Colorless gum; H NMR (400 MHz, CDCl3) δ 9.08
(s, 1H), 7.47–7.30 (m, 5H), 4.88 (s, 2H), 4.23 (dd, J=13.3, 6.5 Hz, 1H),
3.21 (s, 1H), 1.39 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
171.8, 134.9, 129.30, 128.9, 128.7, 78.4, 68.0, 21.2; IR (neat) 3307,
3245, 2948, 2896, 2855, 1635, 1485, 1455, 1379, 1328, 1261, 1245,
1220, 1133, 1093, 1062, 1037 cmÀ 1; C10H13NO3: 195.0895 Found:
195.0872.
(400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.43–7.14 (m, 10H), 5.52 (d, J=
6.3 Hz, 1H), 4.70 (s, 2H), 4.03 (dt, J=7.7, 6.2 Hz, 1H), 2.93 (dd, J=
13.6, 4.7 Hz, 1H), 2.76 (dd, J=13.6, 7.9 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 169.2, 137.4, 135.3, 128.9, 128.1, 127.64, 127.59, 127.4,
125.5, 76.1, 70.6; IR (neat) 3224, 3220, 3059, 2918, 2889, 1661, 1516,
1496, 1454, 1362, 1319, 1289, 1090, 1071, 1026 cmÀ 1; HRMS (EI) m/z
calcd for [M]+ C16H17NO3: 271.1208 Found: 271.1223.
1
N,3-Bis(benzyloxy)-2-hydroxypropanamide (3s). Synthesized by
the general procedure I; flash chromatography (EtOAc/hexane=
2:3, 32 mg, yield 53%), White solid; m.p. 57–59 C; 1H NMR
°
N-(Benzyloxy)-2-hydroxybutanamide (3m). Synthesized by the
general procedure I; flash chromatography (EtOAc/hexane=2:3,
(400 MHz, DMSO-d6) δ 11.17 (s, 1H), 7.47–7.23 (m, 10H), 5.65 (d, J=
5.9 Hz, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.06 (dd, J=10.0, 5.8 Hz, 1H),
3.56 (ddd, J=15.9, 10.0, 5.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ
168.9, 138.8, 136.3, 129.2, 128.72, 128.66 (two peaks overlapping),
128.0, 127.9, 77.2, 72.7, 72.6, 70.6; IR (neat) 3248, 3065, 3034, 2913,
2870, 1660, 1515, 1495, 1454, 1368, 1325, 1260, 1243, 1208, 1179,
24 mg, yield 57%), White solid; m.p.71–73 C; 1H NMR (400 MHz,
°
CDCl3) δ 8.87 (s, 1H), 7.38 (d, J=5.3 Hz, 5H), 4.92 (s, 2H), 4.10 (s, 1H),
2.54 (d, J=3.7 Hz, 1H), 1.91–1.79 (m, 1H), 1.74–1.64 (m, 1H), 0.96 (t,
J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 134.9, 129.3,
128.9, 128.7, 78.4, 72.6, 27.9, 8.9; IR (neat) 3307, 3245, 3070, 2943,
Eur. J. Org. Chem. 2021, 1607–1614
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1118, 1094, 1026 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C12H17NO3:
301.1314 Found: 301.1318.
1196, 1183, 1150, 1039 cmÀ 1; HRMS (EI) m/z calcd for [M]+
C7H13NO3: 159.0895 Found: 159.0876.
1
2
3
4
5
6
7
8
9
General Procedure II for the α-hydroxylation of α-dialkyl-α-
halohydroxamates. To a solution of α-dialkyl-α-halohydroxamate 5
(0.20 mmol), water 2 (0.60 mmol), and DMSO (0.4 mmol) in CH3CN
(1 mL) was added Cs2CO3 (0.60 mmol) at room temperature. The
reaction mixture was stirred at the same temperature until α-
halohydroxamate 5 was complete consumed, as determined by
TLC. Then, the resulting mixture was filtered through the plug of
celite and concentrated in vacuo. The crude residue was purified by
flash column chromatography with EtOAc/hexanes as eluent to
afford desired product 6.
N-(Benzyloxy)-2-hydroxy-2-methylbutanamide (6f). Synthesized
by the general procedure II; flash chromatography (EtOAc/hexane=
2:3, 22 mg, yield 49%), White solid; m.p. 63–65 C; 1H NMR
°
(400 MHz, CDCl3) δ 9.07 (s, 1H), 7.45–7.29 (m, 5H), 5.00–4.83 (m, 2H),
2.15 (s, 1H), 1.89 (dq, J=14.9, 7.5 Hz, 1H), 1.58 (dq, J=14.8, 7.4 Hz,
1H), 1.41 (s, 3H), 0.89 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.6, 135.1, 129.3, 128.8, 128.6, 78.3, 76.5, 33.3, 26.5, 7.7; IR (neat)
3269, 3033, 2974, 2931, 1658, 1652, 1485, 1456, 1387, 1361, 1349,
1274, 1241, 1194, 1163, 1134, 1057, 1040 cmÀ 1; HRMS (EI) m/z calcd
for [M]+ C12H17NO3: 223.1208 Found: 223.1208.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Procedure for a 1mmol scale synthesis of 6a. To a solution of α-
N-(Benzyloxy)-2-hydroxy-2-methylpentanamide (6g). Synthesized
by the general procedure II; flash chromatography (EtOAc/hexane=
2:3, 21 mg, yield 44%), Colorless gum; H NMR (400 MHz, CDCl3) δ
bromohydroxamate 5a (272 mg, 1.0 mmol), water
2 (54 μL,
1
3.0 mmol), and DMSO (14 μL, 2.0 mmol) in CH3CN (5 mL) was added
Cs2CO3 (978 mg, 3.0 mmol) at room temperature. The reaction
mixture was stirred at the same temperature for 6 h. Then, the
resulting mixture was filtered through the plug of celite and
concentrated in vacuo. The crude residue was purified by flash
column chromatography (EtOAc : hexanes=1:1) to afford desired
product 5a (148 mg, 71% yield) as white solid.
9.12 (s, 1H), 7.51–7.29 (m, 5H), 4.99–4.82 (m, 2H), 2.33 (s, 1H), 1.82
(ddd, J=13.8, 12.2, 4.7 Hz, 1H), 1.52 (ddd, J=13.8, 12.2, 4.5 Hz, 1H),
1.44–1.36 (m, 1H), 1.40 (s, 1H), 1.27–1.21 (m, 1H), 0.90 (t, J=7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 135.1, 129.3, 128.8, 128.6,
78.2, 76.2, 42.7, 26.9, 16.8, 14.2; IR (neat) 3350, 3033, 2959, 2931,
2873, 1657, 1467, 1455, 1368, 1245, 1209, 1139, 1082, 1055,
1025 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C13H19NO3: 237.1365
Found: 237.1362.
N-(Benzyloxy)-2-hydroxy-2-methylpropanamide (6a). Synthesized
by the general procedure II; flash chromatography (EtOAc/hexane=
2:3, 33 mg, yield 79%), White solid; m.p. 99–101 C; 1H NMR
N-(Benzyloxy)-2-ethyl-2-hydroxybutanamide (6h). Synthesized by
the general procedure II; flash chromatography (EtOAc/hexane=
°
(400 MHz, CDCl3) δ 9.22 (s, 1H), 7.46–7.30 (m, 5H), 4.88 (s, 2H), 2.78
(s, 1H), 1.42 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 173.6, 135.0, 129.3,
128.9, 128.6, 78.1, 73.7, 27.8; IR (neat) 3264, 3228, 2973, 2925, 2853,
2:3, 27 mg, yield 56%), White solid; m.p. 95–97 C; 1H NMR
°
(400 MHz, CDCl3) δ 9.09 (s, 1H), 7.47–7.30 (m, 5H), 4.92 (s, 2H), 2.11
(s, 1H), 1.87 (dq, J=14.9, 7.5 Hz, 2H), 1.56 (dq, J=14.7, 7.4 Hz, 2H),
0.88 (t, J=7.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 171.7, 135.1,
129.2, 128.8, 128.6, 79.4, 78.4, 32.4, 7.6; IR (neat) 3341, 3286, 3244,
2969, 2936, 2881, 1662, 1498, 1454, 1414, 1377, 1335, 1281, 1159,
1111, 1041, 1008 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C13H19NO3:
237.1365 Found: 237.1351.
1653, 1486, 1454, 1357, 1332, 1272, 1187, 1146, 1082, 1040 cmÀ 1
;
HRMS (EI) m/z calcd for [M]+ C11H15NO3: 209.1052 Found: 209.1033.
2-Hydroxy-N-methoxy-2-methylpropanamide (6b). Synthesized by
the general procedure II; flash chromatography (EtOAc/hexane=
2:3, 15 mg, yield 55%), White solid; m.p. 74–76 C; 1H NMR
°
(400 MHz, CDCl3) δ 9.25 (s, 1H), 3.78 (s, 3H), 2.27 (s, 1H), 1.49 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 173.3, 73.9, 64.4, 27.9; IR (neat) 3249,
2986, 2939, 1651, 1506, 1473, 1450, 1369, 1358, 1197, 1182, 1155,
1109, 1057 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C5H11NO3: 133.0739
Found: 133.0734.
N-(Benzyloxy)-2-hydroxy-2-propylpentanamide (6i). Synthesized
by the general procedure II; flash chromatography (EtOAc/hexane=
2:3, 30 mg, yield 57%), White solid; m.p. 81–83 C; 1H NMR
°
(400 MHz, CDCl3) δ 8.99 (s, 1H), 7.47–7.30 (m, 5H), 4.92 (s, 2H), 1.96
(s, 1H), 1.81 (ddd, J=13.7, 12.2, 4.6 Hz, 2H), 1.54–1.44 (m, 2H), 1.39
(ddd, J=12.1, 8.7, 4.8 Hz, 2H), 1.29–1.18 (m, 2H), 0.89 (t, J=7.3 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 171.9, 135.2, 129.3, 128.8, 128.6,
78.9, 78.4, 42.2, 16.6, 14.2; IR (neat) 3359, 3272, 2957, 2922, 2872,
1665, 1497, 1471, 1454, 1409, 1374, 1311, 1286, 1231, 1177, 1100,
1060, 1026 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C15H23NO3: 265.1678
Found: 265.1649.
N-Ethoxy-2-hydroxy-2-methylpropanamide (6c). Synthesized by
the general procedure II; flash chromatography (EtOAc : hexane=
2:3, 16 mg, yield 55%), White solid; m.p. 63–65 C; 1H NMR
°
(400 MHz, CDCl3) δ 9.38 (s, 1H), 3.97 (q, J=7.1 Hz, 2H), 2.96 (s, 1H),
1.47 (s, 6H), 1.28 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.6, 73.8, 72.2, 27.9, 13.4; IR (neat) 3210, 2976, 2923, 2853, 1652,
1496, 1455, 1373, 1360, 1260, 1188, 1171, 1153, 1088, 1055,
1020 cmÀ 1; HRMS (EI) m/z calcd for [M]+ C6H13NO3: 147.0895 Found:
147.0882.
N-(Benzyloxy)-1-hydroxycyclopentanecarboxamide (6j). Synthe-
sized by the general procedure II; flash chromatography (EtOAc/
1
°
hexane=2:3, 21 mg, yield 44%), White solid; m.p. 104–106 C; H
N-tert-Butoxy-2-hydroxy-2-methylpropanamide (6d). Synthesized
by the general procedure II; flash chromatography (EtOAc/hexane=
NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.51–7.26 (m, 5H), 5.17 (s,
1H), 4.80 (s, 2H), 2.02–1.84 (m, 2H), 1.81–1.55 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 173.2, 135.1, 129.3, 128.8, 128.6, 83.8, 78.1, 39.9,
24.5; IR (neat) 3282, 2960, 2924, 2853, 1731, 1650, 1486, 1456, 1405,
1373, 1275, 1200, 1089, 1022, 1012 cmÀ 1; HRMS (EI) m/z calcd for
[M]+ C13H17NO3: 235.1208 Found: 235.1198.
2:3, 21 mg, yield 61%), White solid; m.p. 152–154 C; 1H NMR
°
(400 MHz, CDCl3) δ 8.88 (s, 1H), 2.78 (s, 1H), 1.48 (s, 6H), 1.29 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 174.5, 82.4, 74.1, 28.1, 26.2; IR (neat)
3250, 2978, 2926, 2854, 1650, 1494, 1471, 1454, 1386, 1363, 1266,
1247, 1198, 1182, 1150, 1047, 1026 cmÀ 1; HRMS (EI) m/z calcd for
[M]+ C8H17NO3: 175.1208 Found: 175.1206.
N-(Benzyloxy)-1-hydroxycyclohexanecarboxamide (6k). Synthe-
sized by the general procedure II; flash chromatography (EtOAc/
N-(Allyloxy)-2-hydroxy-2-methylpropanamide (6e). Synthesized
by the general procedure II; flash chromatography (EtOAc/hexane=
1
°
hexane=2:3, 16 mg, yield 32%), White solid; m.p. 134–136 C; H
NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.51–7.24 (m, 5H), 5.02 (s,
1H), 4.77 (s, 2H), 1.70–1.60 (m, 2H), 1.57–1.51 (m, 2H), 1.49–1.40 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 173.5, 135.1, 129.3, 128.8, 128.6,
78.1, 75.3, 34.3, 24.8, 20.8; IR (neat) 3359, 3269, 2950, 2920, 2849,
2:3, 13 mg, yield 40%), White solid; m.p. 53–55 C; 1H NMR
°
(400 MHz, CDCl3) δ 9.36 (s, 1H), 5.99 (ddt, J=16.8, 10.3, 6.5 Hz, 1H),
5.45–5.21 (m, 2H), 4.47–4.31 (m, 2H), 2.96 (s, 1H), 1.46 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 173.7, 131.9, 121.0, 77.3, 73.7, 27.8; IR
(neat) 3252, 2980, 2925, 2855, 1650, 1503, 1470, 1421, 1368, 1240,
1650, 1487, 1452, 1293, 1267, 1265, 1184, 1160, 1062, 1037 cmÀ 1
;
HRMS (EI) m/z calcd for [M]+ C14H19NO3: 249.1365 Found: 249.1359.
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Full Papers
doi.org/10.1002/ejoc.202100088
1329; g) A. S.-K. Tsang, A. Kapat, F. Schoenebeck, J. Am. Chem. Soc.
2016, 138, 518–526.
N-Benzyl-2-hydroxy-2-methylpropanamide (6l). Synthesized by
the general procedure II; flash chromatography (EtOAc/hexane=
1
2
3
4
5
6
7
8
9
2:3, 24 mg, yield 61%), White solid; m.p. 76–78 C; 1H NMR
[4] For selected examples for synthesis of α-hydroxyamides, see: a) J. S.
Kumar, S. C. Jonnalagadda, V. R. Mereddy, Tetrahedron Lett. 2010, 51,
779–782; b) H. Asahara, N. Nishiwaki, J. Org. Chem. 2014, 79, 11735–
11739; c) S.-M. Yu, K. Cui, F. Lv, Z.-Y. Yang, Z.-J. Yao, Tetrahedron Lett.
2016, 57, 2818–2821; d) M. B. Chaudhari, Y. Sutar, S. Malpathak, A.
Hazra, B. Gnanaprakasam, Org. Lett. 2017, 19, 3628–3631; e) A.
de la Torre, D. Kaiser, N. Maulide, J. Am. Chem. Soc. 2017, 139, 6578–
6581; f) X. Li, F. Lin, K. Huang, J. Wei, X. Li, X. Wang, X. Geng, N. Jiao,
Angew. Chem. Int. Ed. 2017, 56, 12307–12311; Angew. Chem. 2017, 129,
12475–12479; g) W.-M. Zhu, W.-H. Bao, W.-W. Ying, W.-T. Chen, Y.-L.
Huang, G.-P. Ge, G.-P. Chen, W.-T. Wei, Asian J. Org. Chem. 2018, 7, 337–
340; h) T. Kanda, A. Naraoka, H. Naka, J. Am. Chem. Soc. 2019, 141, 825–
830; i) R. Ye, F. Hao, G. Liu, Q. Zuo, L. Deng, Z. Jin, J. Wu, Org. Chem.
Front. 2019, 6, 3562–3565; j) F. Hao, Z. Gu, G. Liu, W. Yao, H. Jiang, J. Wu,
Eur. J. Org. Chem. 2019, 5986–5991.
[5] For selected examples for asymmetric synthesis of α-hydroxyamides,
see: a) C. De Fusco, S. Meninno, C. Tedesco, A. Lattanzi, Org. Biomol.
Chem. 2013, 11, 896–899; b) L. Zhang, L. Zhu, J. Yang, J. Luo, R. Hong, J.
Org. Chem. 2016, 81, 3890–3900; c) Y. Wang, Z. Zheng, M. Lian, H. Yin, J.
Zhao, Q. Meng, Z. Gao, Green Chem. 2016, 18, 5493–5499; d) H. Guo, J.
Li, D. Liu, W. Zhang, Adv. Synth. Catal. 2017, 359, 3665–3673; e) G. Gu, T.
Yang, O. Yu, H. Qian, J. Wang, J. Wen, L. Dang, X. Zhang, Org. Lett. 2017,
19, 5920–5923.
[6] For review of cycloaddition using azaoxyallyl cation, see: a) J. Xuan, X.
Cao, X. Cheng, Chem. Commun. 2018, 54, 5154–5163; b) A. E. Bouakher,
A. Martel, S. Comesse, Org. Biomol. Chem. 2019, 17, 8467–8485.
[7] a) E. Kim, D. Mun, S.-G. Kim, Asian J. Org. Chem. 2019, 8, 2037–2041;
b) Y. I. Kwon, S. Choi, H. S. Jang, S.-G. Kim, Org. Lett. 2020, 22, 1420–
1425; c) E. C. Son, J. Lee, S.-G. Kim, Eur. J. Org. Chem. 2020, 3090–3100;
d) E. C. Son, S.-G. Kim, Asian J. Org. Chem. 2020, 9, 914–917; e) H. S.
Jang, Y. I. Kwon, S.-G. Kim, Bull. Korean Chem. Soc. 2020, 41, 727–734;
f) E. Kim, C. Y. Lee, S.-G. Kim, Adv. Synth. Catal. 2020, 362, 3594–3603.
[8] For selected examples of hydroxylation of alkyl halide with water, see:
a) D. W. Kim, D. J. Hong, J. W. Seo, H. S. Kim, H. K. Kim, C. E. Song, D. Y.
Chi, J. Org. Chem. 2004, 69, 3186–3189; b) V. H. Jadhav, J. G. Kim, H. J.
Jeong, D. W. Kim, J. Org. Chem. 2015, 80, 7275–7280; c) B. M. Chougala,
S. Samundeeswari, M. Holiyachi, L. A. Shastri, ChemistrySelect 2017, 2,
1290–1296; d) H. Liu, J. Liu, X. Cheng, X. Jia, L. Yu, Q. Xu, ChemSusChem
2019, 12, 2994–2998.
°
(400 MHz, CDCl3) δ 7.39–7.24 (m, 5H), 7.03 (s, 1H), 4.44 (d, J=5.9 Hz,
2H), 2.39 (s, 1H), 1.48 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 176.1,
138.2, 128.7, 127.7, 127.5, 73.7, 43.3, 28.0; IR (neat) 3342, 3193,
2969, 2922, 2854, 1645, 1539, 1496, 1451, 1425, 1375, 1360, 1286,
1197, 1181, 1143, 1066, 1030 cmÀ 1; HRMS (EI) m/z calcd for [M]+
C18H22N2O2: 193.1103 Found: 193.1117.
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33
34
35
36
37
38
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Acknowledgments
This research was supported by the National Research Foundation
of Korea (NRF-2020R1A2C1005438) and NRF Nano Material
Technology Development Program (NRF-2012M3A7B4049645),
and by Kyonggi University’s Graduate Research Assistant Fellow-
ship 2020.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Azaoxyallyl cation
· Dimethyl sulfoxide · α–
Halohydroxamate · α-Hydrolysis · α–Hydroxyhydroxamate
[1] For selected examples for biological activities of α-hydroxyamides, see:
a) H. C. Neu, Antimicrob. Agents Chemother. 1974, 6, 177–182; b) T.
Hayashi, T. Shino, M. Shimizu, M. Arisawa, N. Morita, M. Kimura, S.
Matsuda, T. Kikuchi, Tetrahedron Lett. 1985, 26, 3699–3702; c) G. T.
Wong, D. Manfra, F. M. Poulet, Q. Zhang, H. Josien, T. Bara, L. Engstrom,
M. Pinzon-Ortiz, J. S. Fine, H.-J. J. Lee, L. Zhanf, G. Higgins, E. M. Parker, J.
Biol. Chem. 2004, 279, 12876–12882; d) G. Minotti, P. Menna, E.
Salvatorelli, G. Cairo, L. Gianni, Pharmacol. Rev. 2004, 56, 185–229;
e) S. D. Kuduk, R. K. Chang, R. M. Dipardo, K. L. Murphy, R. W. Ransom,
D. R. Reiss, C. Tang, T. Prueksaritanont, D. J. Pettibone, M. G. Bock,
Bioorg. Med. Chem. Lett. 2008, 18, 5107–5110; f) V. Pastore, C. Wasowski,
P. Martin, A. Enrique, J. Higgs, L. E. Bruno-Blanch, V. Milesi, M. Marder,
Eur. J. Pharmacol. 2018, 819, 270–280.
[9] For review of dimethyl sulfoxide as a reagent in organic synthesis, see:
a) X. F. Wu, K. Natte, Adv. Synth. Catal. 2016, 358, 336–352; b) Z. Tashrifi,
M. M. Khanaposhtani, B. Larijani, M. Mahdavi, Adv. Synth. Catal. 2020,
362, 65–86.
[10] a) Y. Ashikari, T. Nokami, J. Yoshida, J. Am. Chem. Soc. 2011, 133, 11840–
11843; b) Y. Ashikari, T. Nokami, J. Yoshida, Org. Lett. 2012, 14, 938–941.
[11] a) C. S. Jeffrey, K. Barnes, J. Eickhoff, C. Carson, J. Am. Chem. Soc. 2011,
133, 7688–7691; b) M. C. DiPoto, J. Wu, Org. Lett. 2018, 20, 499–501; c) F.
Mirhashemi, M. A. Amrollahi, Tetrahedron Lett. 2018, 15, 2661–2663;
d) Y. Murata, K. Takeuchi, T. Nishikata Tetrahedron 2019, 75, 2726–2736.
[2] a) B.-C. Chen, P. Zhou, F. A. Davis, E. Ciganek, Org. React. 2003, 62, 1–
356; b) L. A. Paquette, Org. React. 2003, 62, 477–567.
[3] For selected examples for synthesis of α-hydroxylation of ketones, see:
a) G. J. Chuang, W. Wang, E. Lee, T. Ritter, J. Am. Chem. Soc. 2011, 133,
1760–1762; b) Y.-F. Liang, N. Jiao, Angew. Chem. Int. Ed. 2014, 53, 548–
552; Angew. Chem. 2014, 126, 558–562; c) H.-L. Li, X.-L. An, L.-S. Ge, X.
Luo, W.-P. Deng, Tetrahedron 2015, 71, 3247–3252; d) Y. Siddaraju, K. R.
Prabhu, Org. Biomol. Chem. 2015, 13, 6749–6753; e) Y.-F. Liang, K. Wu, S.
Song, X. Li, X. Huang, N. Jiao, Org. Lett. 2015, 17, 876–879; f) J. Yang, D.
Xie, H. Zhou, S. Chen, C. Huo, Z. Li, Org. Chem. Front. 2018, 5, 1325–
Manuscript received: January 25, 2021
Revised manuscript received: January 30, 2021
Accepted manuscript online: February 2, 2021
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