Benzyl Acetylcarbamate Potassium Salt (BENAC-K): A Simple Nucleophilic N -Acetamide Equivalent

Article abstract of DOI:10.1055/s-0039-1690097

Benzyl acetylcarbamate potassium salt (BENAC-K) has been developed as a simple nucleophilic acetamide equivalent. A broad variety of alkyl halides were converted into benzyloxycarbonyl-protected N -alkylacetamides in high yields by simple treatment with an almost equimolar (1.1 equiv) amount of BENAC-K in a polar solvent.

Full text of DOI:10.1055/s-0039-1690097

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–M
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T. Sakai et al.
Paper
Synthesis
Benzyl Acetylcarbamate Potassium Salt (BENAC-K):
A Simple Nucleophilic N-Acetamide Equivalent
Takeo Sakai*
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Toshiki Tatematsu
Ayumi Fukuta
Satomi Kasai
Kahori Hayashi
Yuji Mori
Faculty of Pharmacy, Meijo University, 150 Yagotoyama,
Tempaku-ku, Nagoya 468-8503, Japan
sakait@meijo-u.ac.jp
Received: 27.05.2019
Accepted after revision: 29.05.2019
Published online: 19.06.2019
the use of the toxic hydrazine for demasking the phthalim-
ide protection. Thus, the development of an easy and safe
procedure for installation of the acetamide moiety is an im-
portant objective to enable efficient syntheses of N-alkylac-
etamide-containing pharmaceuticals and natural products.
N-Acylcarbamates are useful nitrogen nucleophiles.8 We
recently reported a convenient method for the synthesis of
an N-alkylacetamide using benzyl N-acetylcarbamate (1)
during the total synthesis of brevisamide (Scheme 2),6
where 1 was deprotonated with potassium hexamethyldisi-
lazide (KHMDS), and the benzyl acetylcarbamate potassium
salt (BENAC-K) (2) generated in situ was reacted with alkyl
triflate 3 to afford the N-benzyloxycarbonyl-protected acet-
amide derivative 4. The simultaneous deprotection of the
benzyloxycarbonyl and benzyl protecting groups in 4 by
hydrogenation afforded amido alcohol 5. While this method
serves as an effective two-step protocol for the introduction
DOI: 10.1055/s-0039-1690097; Art ID: ss-2019-f0289-op
Abstract Benzyl acetylcarbamate potassium salt (BENAC-K) has been
developed as a simple nucleophilic acetamide equivalent. A broad vari-
ety of alkyl halides were converted into benzyloxycarbonyl-protected
N-alkylacetamides in high yields by simple treatment with an almost
equimolar (1.1 equiv) amount of BENAC-K in a polar solvent.
Key words alkylation, acetamide, SN2 reaction, nitrogen nucleophile,
BENAC-K
The N-alkylacetamide moiety is an important structural
motif present in a wide range of pharmaceutical and natu-
ral products. For example, members of the N-alkylacet-
amide family, such as the antibiotic linezolid1 and the anti-
depressant agomelatine,2 are widely used in clinical prac-
tice. Brevisamide3 and the tamulamides4 are examples of
acetamide-containing marine polyketide alkaloids (Figure
1).
Alkyl halides and alkyl sulfonates are important precur-
sors to N-alkylacetamides. Direct nucleophilic substitution
with acetamide is the most straightforward approach to ac-
cess the N-alkylacetamides from alkyl halides or alkyl sul-
fonates (Scheme 1a).5 However, this strategy has several
limitations, such as the necessity for a large excess of acet-
amide to avoid the formation of the undesired dialkylated
product, and a narrow scope for the direct acetamide in-
stallation, along with low yields reported in several stud-
ies.5e,g,6 Due to such challenges, the acetamide moiety is
typically introduced instead by the acetylation of a primary
amine, prepared by the azidation–reduction protocol
(Scheme 1b). This traditional method is highly reliable but
requires a multistep sequence involving the synthesis of a
potentially explosive organic azide.7 The Gabriel amine syn-
thesis can be used alternatively, but unavoidably involves
O
O
HN
CH3
O
N
N
O
F
NH
O
H3CO
CH3
OH
Linezolid (antibiotic)
Agomelatine (antidepressant)
CHO
H3C
CH3
H
N
CH3
O
OHC
O
H
H
CH3
H
H
(–)-Brevisamide
O
H
O
H
H
H
H
H
R
O
HO
O
H
O
H
H3C
N
H
O
O
Tamulamide A, R = Me
Tamulamide B, R = H
H
H
CH3
H
O
Figure 1 Medicinal and natural products bearing an acetamide moiety
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Sakai et al.
Paper
Synthesis
firmed a good reproducibility for the alkylation reaction
with 2 that was stored for 18 months at –14 °C (Table 1,
footnote b).9
(a) Direct acetamide installation
O
CH3
O
+
I
H3C
NH2
(40 equiv)
O
KHMDS (1.2 equiv)
CH3
H3C
N
O
H
DMF/THF
64%
(b) Typical 3-step acetamide installation from alkyl halides
H
N
H2
Pd/C
R
CH3
Ac2O
NaN3
R
NH2
R
N3
R
X
O
Scheme 1 (a) An example of direct acetamide installation from an al-
kyl iodide, reported by Lévesque and Bélanger.5f (b) A typical three-step
procedure for acetamide installation from alkyl halides.
Scheme 3 Synthesis and isolation of BENAC-K (2)
of the acetamide moiety via N-alkylacetamide synthesis
and debenzylation, the need for BENAC-K (2) formation in
situ under anhydrous conditions is a disadvantage. To cir-
cumvent this challenge, we isolated BENAC-K (2) and devel-
oped it as a straightforward reagent for N-acetamide instal-
lation.
Having prepared BENAC-K (2), we screened the substi-
tution reaction of 3-(benzyloxy)propyl bromide with 2
equivalents of 2 in various solvents in the presence of 18-
crown-6 (Table 1). The reaction rate was faster as the polar-
ity of the solvents increased, a trend indicative of the con-
ventional SN2 reaction (entries 1–6). Notably, an almost
equimolar (1.1 equiv) amount of BENAC-K (2) was suffi-
cient for the substitution reaction in CH3CN or DMF (entries
7 and 8) which highlights the highly efficient alkylation
with 2 in comparison with acetamide alkylation, which re-
quires a large excess of the reagent. Further, at 60 °C in DMF,
18-crown-6 was not necessary for reaction completion (en-
try 9).
KHMDS
18-crown-6
O
O
O
O
H3C
N
OBn
H3C
N
H
OBn
THF
rt, 0.5 h
K+
1
2
H
H
H3C
OTBS
OTf
3
BnO
H
O
H3C
OTBS O
N
H
OBn
CH3
BnO
HO
O
rt, 0.5 h
90%
H
H
H
H
O
4
Table 1 Solvent Screening
H3C
OTBS
20% Pd(OH)2/C
H2
BnO
18-crown-6
Br
O
O
H
N
O
O
CH3
O
EtOAc
rt, 1 h
96%
H3C
N
OBn
OBn
H
H3C
N
K+
OBn
O
solvent
5
2
7a
Scheme 2 Acetamide installation using in situ generated BENAC-K (2)
during the total synthesis of brevisamide
Entry Solvent
2 (equiv) 18-crown- Temp
Time (h) Yield (%)
6 (equiv)
1
2
3
4
5
6
7
8
9
toluene
CPMEa
EtOAc
THF
2.0
2.0
2.0
2.0
2.0
2.0
1.1
1.1
1.1
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
0
50 °C
rt
26
52
77
10
85
88
88
85
84
85
91b
BENAC-K (2) was prepared on a 10-gram scale by a sim-
ple two-step sequence, without column chromatographic
purification (Scheme 3). The commercially available benzyl
carbamate (6) was acetylated with acetic anhydride under
Amberlyst 15 catalysis to afford benzyl N-acetylcarbamate
(1) in 89% yield as a highly crystalline solid after a single re-
crystallization. Treatment of 1 with an equimolar amount
of potassium tert-butoxide in 1,2-dimethoxyethane (1,2-
DME)8i afforded a white precipitate, which upon filtration
furnished BENAC-K (2) as a fine, non-hygroscopic powder,
which is stable at ambient temperature in the presence of
air for 24 hours and can be stored in a refrigerator for more
than a year without change of physical properties. We con-
rt
120
29
rt
CH3CN
DMF
rt
4.5
2.0
26
rt
CH3CN
DMF
rt
rt
1.5
3.0
DMF
60 °C
a Cyclopentyl methyl ether.
b Product 7a was obtained in 87% yield when using an aged BENAC-K that
was stored for 18 months at –14 °C.
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T. Sakai et al.
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Synthesis
The scope and limitations of alkyl halides and sulfon-
ates were investigated using 1.1 equivalents of BENAC-K (2)
in DMF under two reaction conditions for each alkylating
reagent. Method A involved heating at 60 °C, and method B
involved stirring at room temperature in the presence of 1.0
equivalent of 18-crown-6 (Table 2). Both alkyl iodide and
alkyl tosylate showed comparable reactivity with the corre-
sponding alkyl bromide to afford 7a (entries 1–4). Alkyla-
tion with alkyl chloride afforded the product 7b in good
yield, albeit at a low reaction rate (entries 5 and 6). The re-
action with alkyl triflate could not be carried out in DMF
due to its reactivity with DMF. In CH3CN, both the N-al-
kylated product 7c and O-alkylated byproduct 8c were ob-
tained in 71% and 19% yield, respectively (entry 7). The
yield of 7c improved to 90% whereas that of 8c decreased to
7% when the reaction was performed in toluene in the pres-
ence of 18-crown-6 (entry 8). The tert-butyldimethylsilyl
ether and acetyl ester functionalities were tolerated under
the reaction conditions, and furnished 7d and 7e, respec-
tively (entries 9–12). The reaction of 3-bromo-1-propanol
with 2 afforded acetyl-migrated product 9 (entry 13). Pred-
nisolone 21-mesylate was transformed to oxetane 10 via a
deprotonation of the tertiary alcohol (entry 14). These re-
actions indicate the necessity of hydroxy group protection.
The highly lipophilic dodecyl bromide required a slightly
extended reaction time (24 h) and delivered the acetamide
7f (entries 15 and 16). Highly reactive alkyl bromides in-
cluding allyl bromide, propargyl bromide, benzyl bromide,
and ethyl bromoacetate furnished the desired products 7g–
j in excellent yields over short reaction times (entries 17–
24). The products 7k and 7l were obtained in moderate
yields starting from phenethyl bromide and 1-bromo-2-
chloroethane due to the propensity of the substrates for
elimination and double substitution (entries 25–28). The
reactivity was markedly decreased with the use of bulky
primary alkyl halides such as isobutyl bromide and cyclo-
hexylmethyl bromide (entries 29–32). Particularly, neopen-
tyl bromide gave only 9% of the N-alkylated product 7o
even after heating at 80 °C for 36 hours with 18-crown-6
(entry 33). Secondary alkyl halides and nosylates also af-
forded the corresponding N-alkylated products 7p–r, al-
though the yields were lower compared to the use of prima-
ry alkyl halides due to the formation of O-alkylated byprod-
ucts 8p–r (entries 34–38). A possible explanation for the
partial O-alkylation is that the rate of the N-alkylation was
decreased kinetically due to steric repulsion between the
secondary alkyl group and the two substituents on the ni-
trogen atom of 2.
Table 2 Scope and Limitations
Method A: DMF, 60 °C
Method B: 18-crown-6, DMF, rt
R
O
O
O
O
O
O
+
R
X
H3C
N
K+
OBn
H3C
N
OBn
H3C
N
OBn
R
2 (1.1 equiv)
(1.0 equiv)
7
8
Entrya R-X
1
Method
A
Time (h)
2.0
Product 7
Yield (%)
91
Byproduct
Yield (%)
O
O
O
O
H3C
N
OBn
OBn
BnO
I
2
3
4
B
A
B
1.0
2.3
98
89
90
7a
O
O
H3C
N
N
OBn
OBn
BnO
OTs
21.0
7a
A
5
6
7
8
18.0
42.0
4.0
77
81
71
90
(100 °C)b
H3C
OBn
Cl
B
7b
A
H
H
H
19
7
(CH3CN)c
H
H
OTBS
O
OTBS
N
Cbz
N
OTBS
OTf
Ac
O
B
O
Cbz
O
0.5
H
CH3
(toluene)d
7c
8c
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

D
T. Sakai et al.
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Synthesis
Table 2 (continued)
Entrya R-X
9
Method
Time (h)
2.0
Product 7
Yield (%)
85
Byproduct
Yield (%)
A
B
A
B
O
O
O
H3C
N
OBn
OTBS
TBSO
Br
10
0.5
0.3
1.0
83
60
73
7d
11
O
H3C
N
OBn
OAc
AcO
Br
12
7e
O
B
HN
OBn
OAc
13
14
4.0
4.0
0
0
50
66
HO
Br
(CH3CN)c
9
O
O
H3C
OH
H3C
HO
OMs
O
HO
H3C
H
B
H3C
H
(CH3CN)c
H
H
H
H
O
10
O
15
16
17
18
19
A
B
A
B
A
24.0
24.0
0.2
90
100
95
O
O
O
H3C
N
OBn
n-C11H23
Br
C12H25
7f
O
H3C
N
N
OBn
Br
Br
2.0
90
7g
1.0
92
O
O
H3C
OBn
20
B
0.5
100
7h
21
22
23
24
A
B
A
B
1.0
1.0
0.2
0.2
100
100
96
O
O
O
H3C
N
N
OBn
OBn
Ph
Br
Ph
O
7i
H3C
EtO2C
Br
97
CO2Et
O
7j
25
26
27
28
A
B
A
B
2.5
1.0
54
54
70
54
O
O
Ph
H3C
N
N
OBn
Br
Ph
7k
3.0
O
Cl
H3C
OBn
Cl
Br
20.0
7l
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Synthesis
Table 2 (continued)
Entrya R-X
29
Method
Time (h)
23.0
Product 7
Yield (%)
79
Byproduct
Yield (%)
A
B
A
B
O
O
H3C
N
OBn
CH3
Br
30
24.0
42.0
42.0
70
89
91
CH3
O
7m
31
32
O
H3C
N
OBn
Br
7n
O
O
H3C
N
OBn
CH3
CH3
B
Br
33
36.0
9
(80 °C)e
CH3
7o
34
Af
Bf
A
4.0
18.5
3.0
24
47
68
80
8
9
CH3
O
O
H3C
O
O
O
O
H3C
N
OBn
35
36
37
I
H3C
CH3
H3C
N
OBn
OBn
OBn
7p
8p
22
19
O
O
CO2CH3
O
H3C
N
OBn
CH3
H3C
H3CO2C
Br
B
19.5
H3CO2C
H3C
N
7q
8q
O
O
C10H21
H3C
N
OBn
CH3
B
H3C
O
38
7.0
55
15
(CH3CN)c,g
n-C10H21
ONs
C10H21
H3C
N
7r
8r
a All reactions were carried out in a 0.2–1.0 M concentration range. Product yields were not influenced by the concentration.
b Reaction was carried out at 100 °C in entry 5.
c Reactions were carried out in CH3CN instead of DMF in entries 7, 13, 14, and 38.
d Reaction was carried out in toluene instead of DMF in entry 8.
e Reaction was carried out at 80 °C, and an excess amount of neopentyl bromide (1.5 equiv) was used relative to 1.0 equivalent of BENAC-K (2) in entry 33.
f A slight excess amount of isopropyl iodide (1.1 equiv) was used relative to 1.0 equivalent of BENAC-K (2) in entries 34 and 35.
g BENAC-K (1.3 equiv) was used in entry 38.
Finally, deprotection of the formed products was exam-
H
H
H3C
BnO
OTBS O
N
H3C
BnO
OTBS
5% Pd/C
H2
ined (Scheme 4). We previously reported the deprotection
of both the benzyl and benzyloxycarbonyl groups of 4 by
hydrogenation with 20% Pd(OH)2 (Scheme 2).6 The benzy-
loxycarbonyl group was selectively hydrogenated using the
milder 5% Pd/C instead of 20% Pd(OH)2, and the selective re-
moval of the acetyl group from 7c was also achieved, by
methanolysis8h under basic conditions.
In conclusion, benzyl acetylcarbamate potassium salt
(BENAC-K) (2) has been developed as a new reagent for effi-
cient installation of the N-benzyloxycarbonyl-protected ac-
etamide group.10 BENAC-K afforded N-alkylated products in
good yields with a wide range of alkyl halides and alkyl sul-
OBn
CH3
H
N
CH3
( )3
H
O
( )3
O
EtOAc
rt, 4 h
79%
H
H
H
O
O
4
11
H
H
H
OTBS O
N
OTBS
K2CO3
OBn
CH3
H
N
OBn
O
MeOH
rt, 15 h
79%
O
H
O
7c
O
12
Scheme 4 Selective deprotection of a benzyloxycarbonyl group and an
acetyl group
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

F
T. Sakai et al.
Paper
Synthesis
fonates and will serve as a simple and powerful tool for the
synthesis of alkaloids and bioactive compounds containing
the N-alkylacetamide structure. Further study of the
BENAC-K applications is ongoing in our laboratory.
Method B (Table 1, Entry 8)
A solution of BENAC-K (2) (76 mg, 0.33 mmol, 1.1 equiv), 18-crown-6
(79 mg, 0.30 mmol, 1.0 equiv), and benzyl 3-bromopropyl ether (67
mg, 0.30 mmol, 1.0 equiv) in DMF (0.3 mL) was stirred at rt for 1.5 h.
The reaction was quenched with saturated aqueous NH4Cl solution,
and the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (15% EtOAc in n-hexane)
afforded N-alkylated product 7a (87 mg, 85%) as a colorless oil.
N-Alkylation reactions were carried out in a closed vessel using com-
mercially available, anhydrous solvents. The term ‘dried’ refers to the
drying of an organic solution over MgSO4. Flash chromatography was
carried out with silica gel (spherical, neutral, particle size 40–50 m).
IR spectra were recorded on a JASCO FT/IR-410 spectrophotometer.
NMR spectra were recorded on ACANCE III HD (600 MHz) or JNM-ECA
(500 MHz) spectrometers. Chemical shifts are reported in ppm rela-
tive to internal TMS ( 0.00 ppm) or to the solvent signal  2.50 ppm
(DMSO-d6) for 1H NMR spectra, and to the solvent signals  77.0 ppm
(CDCl3) or  39.5 ppm (DMSO-d6) for 13C NMR spectra. Data are re-
ported as follows: chemical shift, multiplicity (standard abbrevia-
tions), coupling constant(s), integration. High-resolution mass spec-
tra were recorded on a JMS-HX110 magnetic sector FAB mass spec-
trometer, a JMS-700 magnetic sector EI mass spectrometer, or an
Exactive Plus Orbitrap DART mass spectrometer.
IR (film): 3032, 2955, 2859, 1738, 1702, 1353, 1197 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.38–7.26 (m, 10 H), 5.22 (s, 2 H), 4.43
(s, 2 H), 3.88 (AA′XX′, JAA′ = 13.0 Hz, JXX′ = 13.0 Hz, JAX = 8.4 Hz, JAX′ = 6.0
Hz, 2 H), 3.48 (t, J = 6.2 Hz, 2 H), 2.49 (s, 3 H), 1.86 (m, 2 H).
13C NMR (150 MHz, CDCl3):  = 172.9, 154.5, 138.4, 135.1, 128.7,
128.5, 128.3, 128.2, 127.53, 127.47, 72.7, 68.4, 68.0, 41.9, 28.8, 26.8.
HRFABMS: m/z [M + Na]+ calcd for C20H23NO4Na: 364.1525; found:
364.1530.
Benzyl Acetyl(pent-4-yn-1-yl)carbamate (7b)
Method A (Table 2, Entry 5)
A solution of BENAC-K (2) (254 mg, 1.10 mmol, 1.1 equiv) and 5-
chloro-1-pentyne (103 mg, 1.00 mmol, 1.0 equiv) in DMF (1.0 mL)
was stirred at 100 °C for 18 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (20% EtOAc in n-hexane) afforded N-al-
kylated product 7b (199 mg, 77%) as a colorless oil.
Benzyl Acetylcarbamate Potassium Salt (BENAC-K, 2) (Scheme 3)
Benzyl N-acetylcarbamate (1) was prepared according to the litera-
ture method,6 on a larger reaction scale. A solution of benzyl carba-
mate (6) (10.0 g, 66.2 mmol) in acetic anhydride (100 mL) was added
to Amberlyst 15 Dry (1.0 g), and the mixture was stirred at rt for 1 h.
The Amberlyst 15 Dry was removed by filtration and the filtrate was
concentrated under reduced pressure. The resulting white solid was
purified by recrystallization (toluene/hexane, 1:1; ca. 100 mL), which
afforded 1 (11.4 g, 89%) as colorless needles.
Method B (Table 2, Entry 6)
A solution of 1 (11.4 g, 59.1 mmol) in 1,2-DME (60 mL) at 0 °C was
added to t-BuOK (6.63 g, 59.1 mmol), and the mixture was stirred at
0 °C for 10 min. The resulting precipitate was collected by suction fil-
tration and washed with Et2O. The obtained white powder was dried
under reduced pressure (25 °C, 2 mmHg) overnight to afford BENAC-K
(2) (13.5 g, 99%) as a colorless powder. Alkylation reactions were car-
ried out using the powder of BENAC-K without further purification.
A solution of BENAC-K (2) (254 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and 5-chloro-1-pentyne (103 mg,
1.00 mmol, 1.0 equiv) in DMF (1.0 mL) was stirred at rt for 42 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (20% EtOAc in n-hexane)
afforded N-alkylated product 7b (210 mg, 81%) as a colorless oil.
Mp 270–280 °C (dec).
IR (KBr): 3069, 3030, 2990, 2968, 1676, 1622, 1398, 1231 cm–1
.
IR (film): 3291, 1736, 1698, 1176 cm–1
.
1H NMR (600 MHz, DMSO-d6):  = 7.33–7.30 (m, 4 H), 7.24 (m, 1 H),
4.85 (s, 2 H), 1.80 (s, 3 H).
13C NMR (150 MHz, DMSO-d6):  = 178.5, 161.7, 139.3, 128.0, 127.2,
126.9, 64.3, 26.6.
HRDARTMS: m/z [M – K]– calcd for C10H10NO3: 192.0666; found:
192.0668.
1H NMR (600 MHz, CDCl3):  = 7.40–7.34 (m, 5 H), 5.24 (s, 2 H), 3.85
(AA′XX′, JAA′ = 13.4 Hz, JXX′ = 13.4 Hz, JAX = 8.8 Hz, JAX′ = 6.1 Hz, 2 H),
2.50 (s, 3 H), 2.19 (td, J = 7.0, 2.7 Hz, 2 H), 1.90 (t, J = 2.7 Hz, 1 H), 1.76
(m, 2 H).
13C NMR (150 MHz, CDCl3):  = 172.9, 154.4, 135.0, 128.7, 128.6,
128.3, 83.3, 68.6, 68.5, 43.3, 27.3, 26.8, 16.1.
HRDARTMS: m/z [M + H]+ calcd for C15H18NO3: 260.1281; found:
260.1283.
Benzyl Acetyl(3-(benzyloxy)propyl)carbamate (7a)
Method A (Table 1, Entry 9)
Benzyl Acetyl(((2R,3S)-3-((tert-butyldimethylsilyl)oxy)tetrahy-
dro-2H-pyran-2-yl)methyl)carbamate (7c)
A solution of BENAC-K (2) (83 mg, 0.36 mmol, 1.1 equiv) and benzyl
3-bromopropyl ether (74 mg, 0.32 mmol, 1.0 equiv) in DMF (1.7 mL)
was stirred at 60 °C for 3.0 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (15% EtOAc in n-hexane) afforded N-al-
kylated product 7a (99 mg, 91%) as a colorless oil.
Method A (Table 2, Entry 7)
A solution of BENAC-K (2) (76 mg, 0.33 mmol, 1.1 equiv) and ((2R,3S)-
3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyltri-
fluoromethanesulfonate11 (113 mg, 0.30 mmol, 1.0 equiv) in CH3CN
(0.3 mL) was stirred at 60 °C for 4 h. After cooling to rt, the reaction
was quenched with saturated aqueous NH4Cl solution, and the result-
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Synthesis
ing mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (20% EtOAc in n-hexane) afforded N-al-
kylated product 7c (89 mg, 71%) and O-alkylated product 8c (24 mg,
19%).
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (30% EtOAc in n-hexane) afforded N-al-
kylated product 7e (175 mg, 60%) as a colorless oil.
Method B (Table 2, Entry 8)
Method B (Table 2, Entry 12)
A solution of BENAC-K (2) (76 mg, 0.33 mmol, 1.1 equiv), 18-crown-6
(79 mg, 0.30 mmol, 1.0 equiv), and ((2R,3S)-3-((tert-butyldimethylsi-
lyl)oxy)tetrahydro-2H-pyran-2-yl)methyl trifluoromethanesulfonate
(113 mg, 0.30 mmol, 1.0 equiv) in toluene (0.3 mL) was stirred at rt
for 0.5 h. The reaction was quenched with saturated aqueous NH4Cl
solution, and the resulting mixture was extracted with EtOAc. The ex-
tract was washed with brine, dried, filtered, and concentrated under
reduced pressure. Flash chromatography on silica gel (20% EtOAc in n-
hexane) afforded N-alkylated product 7c (114 mg, 90%) and O-al-
kylated product 8c (9 mg, 7%). Spectroscopic data for 7c and 8c were
identical with our previous report.6
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and 3-bromopropyl acetate (181
mg, 1.0 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 1 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (30% EtOAc in n-hexane)
afforded N-alkylated product 7e (213 mg, 73%) as a colorless oil.
IR (film): 2965, 2899, 1739, 1702, 1236, 1201 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.41–7.35 (m, 5 H), 5.23 (s, 2 H), 4.05
(t, J = 6.2 Hz, 2 H), 3.85 (t, J = 7.2 Hz, 2 H), 2.51 (s, 3 H), 1.97 (s, 3 H),
1.87 (tt, J = 7.2, 6.2 Hz, 2 H).
13C NMR (150 MHz, CDCl3):  = 172.8, 170.9, 154.3, 134.9, 128.73,
128.68, 128.3, 68.6, 62.1, 41.4, 27.8, 26.8, 20.8.
Benzyl Acetyl(3-((tert-butyldimethylsilyl)oxy)propyl)carbamate
(7d)
HRDARTMS: m/z [M + H]+ calcd for C15H20NO5: 294.1336; found:
294.1339.
Method A (Table 2, Entry 9)
A solution of BENAC-K (2) (270 mg, 1.17 mmol, 1.1 equiv) and (3-bro-
mopropoxy)(tert-butyl)dimethylsilane (271 mg, 1.07 mmol, 1.0
equiv) in DMF (1 mL) was stirred at 60 °C for 2 h. After cooling to rt,
the reaction was quenched with saturated aqueous NH4Cl solution,
and the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (10% EtOAc in n-hexane)
afforded N-alkylated product 7d (334 mg, 85%) as a colorless oil.
3-(((Benzyloxy)carbonyl)amino)propyl Acetate (9)
Method B (Table 2, Entry 13)
A solution of BENAC-K (2) (262 mg, 1.13 mmol, 1.1 equiv), 18-crown-
6 (267 mg, 1.01 mmol, 1.0 equiv), and 3-bromopropanol (140 mg,
1.01 mmol, 1.0 equiv) in CH3CN (1 mL) was stirred at rt for 4 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (30% EtOAc in n-hexane)
afforded 9 (126 mg, 50%) as a colorless oil.
Method B (Table 2, Entry 10)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and (3-bromopropoxy)(tert-bu-
tyl)dimethylsilane (253 mg, 1.00 mmol, 1.0 equiv) in DMF (1 mL) was
stirred at rt for 0.5 h. The reaction was quenched with saturated aque-
ous NH4Cl solution, and the resulting mixture was extracted with
EtOAc. The extract was washed with brine, dried, filtered, and con-
centrated under reduced pressure. Flash chromatography on silica gel
(5% EtOAc in n-hexane) afforded N-alkylated product 7d (304 mg,
83%) as a colorless oil.
IR (film): 3293, 3089, 2963, 1748, 1659, 1652, 1556, 1274 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.39–7.33 (m, 5 H), 5.85 (br s, 1 H),
5.16 (s, 2 H), 4.22 (t, J = 6.1 Hz, 2 H), 3.32 (q, J = 6.4 Hz, 2 H), 1.95 (s, 3
H), 1.88 (quint, J = 6.4 Hz, 2 H).
13C NMR (150 MHz, CDCl3):  = 170.2, 155.2, 135.1, 128.6 (2 ×), 128.3,
69.7, 65.7, 36.3, 28.6, 23.2.
IR (film): 2954, 2929, 2857, 1741, 1705, 1197 cm–1
.
HRDARTMS: m/z [M + H]+ calcd for C13H18NO4: 252.1230; found:
252.1227.
1H NMR (600 MHz, CDCl3):  = 7.39–7.35 (m, 5 H), 5.24 (s, 2 H), 3.81
(AA′XX′, JAA′ = 13.5 Hz, JXX′ = 13.5 Hz, JAX = 9.4 Hz, JAX′ = 5.6 Hz, 2 H),
3.63 (t, J = 6.2 Hz, 2 H), 2.50 (s, 3 H), 1.75 (m, 2 H), 0.88 (s, 9 H), 0.03 (s,
6 H).
13C NMR (150 MHz, CDCl3):  = 172.8, 154.6, 135.2, 128.7, 128.5,
128.2, 68.3, 61.0, 41.9, 31.8, 26.8, 25.8, 18.2, –5.4.
17,21-Anhydroprednisolone (10)
Method B (Table 2, Entry 14)
A solution of BENAC-K (2) (30.0 mg, 0.130 mmol, 1.1 equiv), 18-
crown-6 (31.5 mg, 0.117 mmol, 1.0 equiv), and prednisolone 21-
mesylate12 (51.3 mg, 0.117 mmol, 1.0 equiv) in CH3CN (1 mL) was
stirred at rt for 4 h. The reaction was quenched with saturated aque-
ous NH4Cl solution, and the resulting mixture was extracted with
EtOAc. The extract was washed with brine, dried, filtered, and con-
centrated under reduced pressure. Flash chromatography on silica gel
(30% acetone in n-hexane) afforded 10 (26.4 mg, 66%) as a colorless
solid.
HRDARTMS: m/z [M + H]+ calcd for C19H32NO4Si: 366.2095; found:
366.2094.
3-(N-((Benzyloxy)carbonyl)acetamido)propyl Acetate (7e)
Method A (Table 2, Entry 11)
A solution of BENAC-K (2) (255 mg, 1.1 mmol, 1.1 equiv) and 3-bro-
mopropyl acetate (181 mg, 1.0 mmol, 1.0 equiv) in DMF (1 mL) was
stirred at 60 °C for 0.3 h. After cooling to rt, the reaction was
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Mp 202–205 °C; []D25 +167.5 (c 0.50, CHCl3). Both the melting point
and specific optical rotation are slightly lower than the literature da-
ta13 (mp 243–244 °C, []D23 +182 (CHCl3)), possibly due to trace impu-
rities in our sample.
stirred at 60 °C for 0.2 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (15% EtOAc in n-hexane) afforded N-al-
kylated product 7g (223 mg, 95%) as a colorless oil.
IR (film): 3448, 2934, 1809, 1656, 1615, 753 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.25 (d, J = 10.1 Hz, 1 H), 6.28 (dd, J =
10.1, 1.8 Hz, 1 H), 6.02 (t, J = 1.5 Hz, 1 H), 5.03 and 4.88 (d, J = 14.8 Hz,
each 1 H), 4.54 (m, 1 H), 2.57 (tdd, J = 13.5, 5.5, 1.4 Hz, 1 H), 2.42 (ddd,
J = 15.6, 10.5, 2.6 Hz, 1 H), 2.34 (ddd, J = 13.5, 4.8, 2.0 Hz, 1 H), 2.15
(dd, J = 14.0, 3.3 Hz, 1 H), 2.14–2.10 (m, 2 H), 2.08 (ddd, J = 15.6, 9.1,
6.6 Hz, 1 H), 1.86 (dddd, J = 11.6, 9.1, 6.6, 2.6 Hz, 1 H), 1.71 (dd, J =
14.0, 2.7 Hz, 1 H), 1.47 (s, 3 H), 1.39 (dddd, J = 12.3, 11.6, 10.5, 6.6 Hz,
1 H), 1.33 (ddd, J = 12.3, 10.6, 6.6 Hz, 1 H), 1.32 (br s, 1 H), 1.15 (m, 1
H), 1.14 (s, 3 H), 1.11 (dd, J = 11.2, 3.3 Hz, 1 H).
Method B (Table 2, Entry 18)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and allyl bromide (87 L, 121 mg,
1.00 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 2.0 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (15% EtOAc in n-hexane)
afforded N-alkylated product 7g (210 mg, 90%) as a colorless oil.
13C NMR (150 MHz, CDCl3):  = 205.7, 186.5, 169.9, 156.1, 127.8,
122.4, 118.0, 85.6, 69.9, 55.1, 51.1, 47.9, 44.0, 39.9, 33.8, 33.1, 31.9,
30.8, 24.6, 21.1, 16.2.
IR (film): 3033, 2958, 1737, 1704, 1216 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.40–7.33 (m, 5 H), 5.80 (ddt, J = 17.4,
10.1, 5.7 Hz, 1 H), 5.22 (s, 2 H), 5.102 (dq, J = 17.4, 1.4 Hz, 1 H), 5.101
(dq, J = 10.1, 1.4 Hz, 1 H), 4.35 (dt, J = 5.7, 1.4 Hz, 2 H), 2.52 (s, 3 H).
HRDARTMS: m/z [M + H]+ calcd for C21H27O4: 343.1904; found:
343.1905.
13C NMR (125 MHz, CDCl3):  = 172.5, 154.3, 135.0, 132.9, 128.6,
128.5, 128.2, 116.8, 68.5, 46.0, 26.6.
HRFABMS: m/z [M + Na]+ calcd for C13H15NO3Na: 256.0950; found:
Benzyl Acetyl(1-dodecyl)carbamate (7f)
Method A (Table 2, Entry 15)
256.0956.
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv) and 1-bro-
mododecane (249 mg, 1.00 mmol, 1.0 equiv) in DMF (1 mL) was
stirred at 60 °C for 24 h. After cooling to rt, the reaction was quenched
with saturated aqueous NH4Cl solution, and the resulting mixture
was extracted with EtOAc. The extract was washed with brine, dried,
filtered, and concentrated under reduced pressure. Flash chromatog-
raphy on silica gel (5% EtOAc in n-hexane) afforded N-alkylated prod-
uct 7f (325 mg, 90%) as a colorless oil.
Benzyl Acetyl(prop-2-yn-1-yl)carbamate (7h)
Method A (Table 2, Entry 19)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv) and propar-
gyl bromide (9.2 M in toluene; 0.109 mL, 1.0 mmol, 1.0 equiv) in DMF
(3 mL) was stirred at 60 °C for 1 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (15% EtOAc in n-hexane) afforded N-al-
kylated product 7h (210 mg, 92%) as a colorless oil.
Method B (Table 2, Entry 16)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and 1-bromododecane (249 mg,
1.00 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 24 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (5% EtOAc in n-hexane)
afforded N-alkylated product 7f (361 mg, 100%) as a colorless oil.
Method B (Table 2, Entry 20)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and propargyl bromide (9.2 M in
toluene; 0.109 mL, 1.0 mmol, 1.0 equiv) in DMF (3 mL) was stirred at
rt for 0.5 h. The reaction was quenched with saturated aqueous NH4Cl
solution, and the resulting mixture was extracted with EtOAc. The ex-
tract was washed with brine, dried, filtered, and concentrated under
reduced pressure. Flash chromatography on silica gel (15% EtOAc in n-
hexane) afforded N-alkylated product 7h (231 mg, 100%) as a color-
less oil.
IR (film): 2925, 2854, 1738, 1704, 1148 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.41–7.35 (m, 5 H), 5.23 (s, 2 H), 3.71
(AA′XX′, JAA′ = 12.4 Hz, JXX′ = 12.4 Hz, JAX = 8.8 Hz, JAX′ = 6.4 Hz, 2 H),
2.49 (s, 3 H), 1.50 (m, 2 H), 1.30–1.23 (m, 18 H), 0.88 (t, J = 7.0 Hz, 3
H).
13C NMR (150 MHz, CDCl3):  = 172.9, 154.7, 135.2, 128.7, 128.6,
128.2, 68.4, 44.2, 31.9, 29.63 (2 ×), 29.57, 29.5, 29.35, 29.25, 28.7, 26.9,
26.8, 22.7, 14.1.
IR (film): 3288, 3034, 2961, 1743, 1709, 1214 cm–1
1H NMR (600 MHz, CDCl3):  = 7.43–7.34 (m, 5 H), 5.28 (s, 2 H), 4.52
(d, J = 2.5 Hz, 2 H), 2.53 (s, 3 H), 2.16 (t, J = 2.5 Hz, 1 H).
.
HRFABMS: m/z [M + Na]+ calcd for C22H35NO3Na: 384.2515; found:
384.2504.
13C NMR (150 MHz, CDCl3):  = 171.9, 153.5, 134.8, 128.64, 128.62,
128.2, 79.1, 70.7, 68.8, 33.3, 26.4.
HRDARTMS: m/z [M + H]+ calcd for C13H14NO3: 232.0968; found:
232.0969.
Benzyl Acetyl(allyl)carbamate (7g)
Method A (Table 2, Entry 17)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv) and allyl
bromide (87 L, 121 mg, 1.00 mmol, 1.0 equiv) in DMF (3 mL) was
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Benzyl Acetyl(benzyl)carbamate (7i)
Method A (Table 2, Entry 21)
Benzyl Acetyl(phenethyl)carbamate (7k)
Method A (Table 2, Entry 25)
A solution of BENAC-K (2) (198 mg, 0.84 mmol, 1.1 equiv) and benzyl
bromide (130 mg, 0.76 mmol, 1.0 equiv) in DMF (0.8 mL) was stirred
at 60 °C for 1 h. After cooling to rt, the reaction was quenched with
saturated aqueous NH4Cl solution, and the resulting mixture was ex-
tracted with EtOAc. The extract was washed with brine, dried, fil-
tered, and concentrated under reduced pressure. Flash chromatogra-
phy on silica gel (10% EtOAc in n-hexane) afforded N-alkylated prod-
uct 7i (216 mg, 100%) as a colorless oil.
A solution of BENAC-K (2) (76 mg, 0.33 mmol, 1.1 equiv) and
phenethyl bromide (56 mg, 0.30 mmol, 1.0 equiv) in DMF (1.7 mL)
was stirred at 60 °C for 2.5 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (15% EtOAc in n-hexane) afforded N-al-
kylated product 7k (47 mg, 54%) as a colorless oil.
Method B (Table 2, Entry 22)
Method B (Table 2, Entry 26)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and benzyl bromide (171 mg, 1.00
mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 1 h. The reaction
was quenched with saturated aqueous NH4Cl solution, and the result-
ing mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (10% EtOAc in n-hexane) afforded N-al-
kylated product 7i (283 mg, 100%) as a colorless oil.
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and phenethyl bromide (185 mg,
1.00 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 1 h. The re-
action was quenched with saturated aqueous NH4Cl solution, and the
resulting mixture was extracted with EtOAc. The extract was washed
with brine, dried, filtered, and concentrated under reduced pressure.
Flash chromatography on silica gel (15% EtOAc in n-hexane) afforded
N-alkylated product 7k (161 mg, 54%) as a colorless oil.
IR (film): 3032, 2961, 1739, 1702, 1203 cm–1
.
IR (film): 3029, 2968, 1736, 1698, 1174 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.37–7.35 (m, 3 H), 7.30–7.22 (m, 7 H),
5.21 (s, 2 H), 4.98 (s, 2 H), 2.60 (s, 3 H).
1H NMR (600 MHz, CDCl3):  = 7.41–7.36 (m, 5 H), 7.26–7.24 (m, 2 H),
7.19 (m, 1 H), 7.13–7.12 (m, 2 H), 5.15 (s, 2 H), 3.95 (AA′XX′, JAA′ = 13.2
Hz, JXX′ = 13.2 Hz, JAX = 9.8 Hz, JAX′ = 6.0 Hz, 2 H), 2.80 (AA′XX′, JAA′
13.2 Hz, JXX′ = 13.2 Hz, JAX = 9.8 Hz, JAX′ = 6.0 Hz, 2 H), 2.51 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.7, 154.4, 138.6, 135.0, 128.9,
128.70, 128.66, 128.4, 128.3, 126.4, 68.5, 45.6, 34.9, 26.8.
HRDARTMS: m/z [M + H]+ calcd for C18H20NO3: 298.1438; found:
=
13C NMR (150 MHz, CDCl3):  = 173.0, 154.4, 137.6, 134.8, 128.62,
128.59, 128.4, 128.3, 127.8, 127.3, 68.7, 47.0, 26.8.
HRFABMS: m/z [M + Na]+ calcd for C17H17NO3Na: 306.1106; found:
306.1112.
298.1440.
Ethyl N-Acetyl-N-((benzyloxy)carbonyl)glycinate (7j)
Benzyl Acetyl(2-chloroethyl)carbamate (7l)
Method A (Table 2, Entry 27)
Method A (Table 2, Entry 23)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv) and ethyl
bromoacetate (167 mg, 1.00 mmol, 1.0 equiv) in DMF (1 mL) was
stirred at 60 °C for 0.2 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (20% EtOAc in n-hexane) afforded N-al-
kylated product 7j (267 mg, 96%) as a colorless oil.
A solution of BENAC-K (2) (79 mg, 0.34 mmol, 1.1 equiv) and 1-bro-
mo-2-chloroethane (45 mg, 0.31 mmol, 1.0 equiv) in DMF (1.7 mL)
was stirred at 60 °C for 3 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (20% EtOAc in n-hexane) afforded N-al-
kylated product 7l (55 mg, 70%) as a colorless oil.
Method B (Table 2, Entry 24)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and ethyl bromoacetate (167 mg,
1.00 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 0.2 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (20% EtOAc in n-hexane)
afforded N-alkylated product 7j (271 mg, 97%) as a colorless oil.
Method B (Table 2, Entry 28)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and 1-bromo-2-chloroethane (143
mg, 1.00 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 20 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (20% EtOAc in n-hexane)
afforded N-alkylated product 7l (137 mg, 54%) as a colorless oil.
IR (film): 2964, 1738, 1702, 1171 cm–1
1H NMR (600 MHz, CDCl3):  = 7.41–7.36 (m, 5 H), 5.25 (s, 2 H), 4.10
(t, J = 6.8 Hz, 2 H), 3.59 (t, J = 6.8 Hz, 2 H), 2.52 (s, 3 H).
IR (film): 2920, 2851, 1715, 1682, 1671, 1192 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.40–7.33 (m, 5 H), 5.23 (s, 2 H), 4.50
(s, 2 H), 4.13 (q, J = 7.2 Hz, 2 H), 2.58 (s, 3 H), 1.20 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 172.6, 168.7, 153.7, 134.9, 128.8 (2 ×),
128.3, 69.0, 61.5, 45.1, 26.3, 14.1.
HRFABMS: m/z [M + Na]+ calcd for C14H17NO5Na: 302.1004; found:
.
13C NMR (150 MHz, CDCl3):  = 172.8, 154.0, 134.7, 128.80, 128.77,
128.4, 68.9, 45.1, 41.1, 26.6.
302.1016.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

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T. Sakai et al.
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Synthesis
HRFABMS: m/z [M + Na]+ calcd for C12H14ClNO3Na: 278.0560; found:
13C NMR (150 MHz, CDCl3):  = 173.1, 155.0, 135.1, 128.64, 128.57,
278.0565.
128.3, 68.4, 49.7, 37.2, 30.6, 26.8, 26.3, 25.8.
HRDARTMS: m/z [M + H]+ calcd for C17H24NO3: 290.1751; found:
290.1750.
Benzyl Acetyl(isobutyl)carbamate (7m)
Method A (Table 2, Entry 29)
Benzyl Acetyl(neopentyl)carbamate (7o)
Method B (Table 2, Entry 33)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv) and isobu-
tyl bromide (137 mg, 1.00 mmol, 1.0 equiv) in DMF (3 mL) was stirred
at 60 °C for 23 h. After cooling to rt, the reaction was quenched with
saturated aqueous NH4Cl solution, and the resulting mixture was ex-
tracted with EtOAc. The extract was washed with brine, dried, fil-
tered, and concentrated under reduced pressure. Flash chromatogra-
phy on silica gel (10% EtOAc in n-hexane) afforded N-alkylated prod-
uct 7m (195 mg, 79%) as a colorless oil.
A solution of BENAC-K (2) (231 mg, 1.00 mmol, 1.0 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and neopentyl bromide (189 L,
1.50 mmol, 1.5 equiv) in DMF (1 mL) was stirred at 80 °C for 36 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (2% EtOAc in benzene)
afforded N-alkylated product 7o (25 mg, 9%) as a colorless oil.
Method B (Table 2, Entry 30)
IR (film): 2963, 2870, 1737, 1707, 1196 cm–1
1H NMR (600 MHz, CDCl3):  = 7.39–7.36 (m, 5 H), 5.20 (s, 2 H), 3.70
(s, 2 H), 2.49 (s, 3 H), 0.84 (s, 9 H).
13C NMR (150 MHz, CDCl3):  = 173.1, 155.5, 134.8, 128.7 (2 ×), 128.6,
68.6, 53.1, 33.5, 28.1, 26.7.
HRDARTMS: m/z [M + H]+ calcd for C15H22NO3: 264.1594; found:
264.1594.
.
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and isobutyl bromide (137 mg, 1.00
mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 24 h. The reaction
was quenched with saturated aqueous NH4Cl solution, and the result-
ing mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (10% EtOAc in n-hexane) afforded N-al-
kylated product 7m (173 mg, 70%) as a colorless oil.
IR (film): 2961, 1736, 1703, 1686, 1233, 1159 cm–1
.
Benzyl Acetyl(isopropyl)carbamate (7p)
Method A (Table 2, Entry 34)
1H NMR (600 MHz, CDCl3):  = 7.42–7.34 (m, 5 H), 5.22 (s, 2 H), 3.60
(d, J = 7.5 Hz, 2 H), 2.51 (s, 3 H), 1.93 (t-spt, J = 7.5, 6.8 Hz, 1 H), 0.84 (d,
J = 6.8 Hz, 6 H).
13C NMR (150 MHz, CDCl3):  = 173.1, 155.0, 135.1, 128.7, 128.6,
128.3, 68.4, 50.7, 27.8, 26.9, 19.9.
HRDARTMS: m/z [M + H]+ calcd for C14H20NO3: 250.1438; found:
250.1439.
A solution of BENAC-K (2) (231 mg, 1.00 mmol, 1.0 equiv) and isopro-
pyl iodide (110 L, 1.10 mmol, 1.1 equiv) in DMF (1 mL) was stirred at
60 °C for 4 h. After cooling to rt, the reaction was quenched with satu-
rated aqueous NH4Cl solution, and the resulting mixture was extract-
ed with EtOAc. The extract was washed with brine, dried, filtered, and
concentrated under reduced pressure. Flash chromatography on silica
gel (10% EtOAc in n-hexane) afforded N-alkylated product 7p (57 mg,
24%) and O-alkylated product 8p (18 mg, 8%).
Benzyl Acetyl(cyclohexylmethyl)carbamate (7n)
Method A (Table 2, Entry 31)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv) and (bro-
momethyl)cyclohexane (177 mg, 1.00 mmol, 1.0 equiv) in DMF (1 mL)
was stirred at 60 °C for 42 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (10% EtOAc in n-hexane) afforded N-al-
kylated product 7n (258 mg, 89%) as a colorless oil.
Method B (Table 2, Entry 35)
A solution of BENAC-K (2) (231 mg, 1.00 mmol, 1.0 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and isopropyl iodide (110 L, 1.10
mmol, 1.1 equiv) in DMF (1 mL) was stirred at rt for 18.5 h. The reac-
tion was quenched with saturated aqueous NH4Cl solution, and the
resulting mixture was extracted with EtOAc. The extract was washed
with brine, dried, filtered, and concentrated under reduced pressure.
Flash chromatography on silica gel (5% EtOAc in benzene) afforded N-
alkylated product 7p (110 mg, 47%) and O-alkylated product 8p (21
mg, 9%).
Method B (Table 2, Entry 32)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and (bromomethyl)cyclohexane
(177 mg, 1.00 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 42
h. The reaction was quenched with saturated aqueous NH4Cl solution,
and the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (10% EtOAc in n-hexane)
afforded N-alkylated product 7n (263 mg, 91%) as a colorless oil.
N-Alkylated Product 7p
Colorless oil.
IR (film): 2972, 2938, 1732, 1697, 1261, 1149 cm–1
1H NMR (600 MHz, CDCl3):  = 7.40–7.36 (m, 5 H), 5.24 (s, 2 H), 4.87
(spt, J = 6.8 Hz, 1 H), 2.40 (s, 3 H), 1.28 (d, J = 6.8 Hz, 6 H).
13C NMR (150 MHz, CDCl3):  = 172.9, 155.1, 134.9, 128.72, 128.67,
.
IR (film): 2925, 2851, 1735, 1703, 1203, 1149 cm–1
.
128.6, 68.5, 46.9, 27.1, 20.4.
HRFABMS: m/z [M + Na]+ calcd for C13H17NO3Na: 258.1106; found:
258.1111.
1H NMR (600 MHz, CDCl3):  = 7.40–7.34 (m, 5 H), 5.22 (s, 2 H), 3.61
(d, J = 6.8 Hz, 2 H), 2.49 (s, 3 H), 1.68–1.65 (m, 2 H), 1.63–1.50 (m, 4
H), 1.18–1.06 (m, 3 H), 0.96–0.84 (m, 2 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

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T. Sakai et al.
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Synthesis
O-Alkylated Product 8p
2-Dodecyl 2-Nitrobenzenesulfonate
Colorless oil.
IR (film): 2980, 2936, 1720, 1669, 1244 cm–1
1H NMR (600 MHz, CDCl3):  = 7.42–7.40 (m, 2 H), 7.38–7.35 (m, 2 H),
7.33 (m, 1 H), 5.19 (s, 2 H), 5.07 (spt, J = 6.2 Hz, 1 H), 2.03 (s, 3 H), 1.25
(d, J = 6.2 Hz, 6 H).
To a solution of 2-dodecanol (670 L, 2.99 mmol) in THF (7 mL) at
–78 °C was added n-BuLi (1.63 M in n-hexane; 2.20 mL, 3.59 mmol)
under argon, and the mixture was stirred for 10 min at –78 °C. A solu-
tion of 2-nitrobenzenesulfonyl chloride (730 mg, 3.29 mmol) in THF
(3 mL) was added, and the mixture was warmed to rt. After 1 h, the
reaction was quenched with water, and the resulting mixture was ex-
tracted with EtOAc. The extract was washed with brine, dried, fil-
tered, and concentrated. A byproduct, 2-chlorododecane, was re-
moved by flash chromatography on silica gel (0 → 20% EtOAc in n-
hexane) to afford a mixture of 2-dodecyl 2-nitrobenzenesulfonate
and 2-dodecanol, that was separated by flash chromatography
(0 → 2% EtOAc in CH2Cl2). 2-Dodecyl 2-nitrobenzenesulfonate (465
mg, 42%) was obtained as a pale yellow oil.
.
13C NMR (150 MHz, CDCl3):  = 167.2, 161.7, 136.0, 128.54, 128.45,
128.3, 70.3, 68.1, 21.5, 18.9.
HREIMS: m/z [M+] calcd for C13H17NO3: 235.1208; found: 235.1217.
Methyl N-Acetyl-N-((benzyloxy)carbonyl)alaninate (7q)
Method A (Table 2, Entry 36)
IR (film): 2926, 2854, 1549, 1372, 1188, 909 cm–1
.
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv) and methyl
2-bromopropionate (167 mg, 1.00 mmol, 1.0 equiv) in DMF (1 mL)
was stirred at 60 °C for 3 h. After cooling to rt, the reaction was
quenched with saturated aqueous NH4Cl solution, and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (20% EtOAc in n-hexane) afforded N-al-
kylated product 7q (187 mg, 68%) and O-alkylated product 8q (60 mg,
22%).
1H NMR (600 MHz, CDCl3):  = 8.14 (m, 1 H), 7.80–7.72 (m, 3 H), 4.94
(sxt, J = 6.3 Hz, 1 H), 1.74 (m, 1 H), 1.60 (m, 1 H), 1.39 (d, J = 6.3 Hz, 3
H), 1.34–1.18 (m, 16 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 148.3, 134.4, 132.0, 130.93, 130.88,
124.6, 83.8, 36.5, 31.9, 29.54, 29.47, 29.4, 29.3, 29.2, 24.8, 22.7, 20.8,
14.1.
HRDARTMS: m/z [M + H]+ calcd for C18H30NO5S: 372.1839; found:
372.1840.
Method B (Table 2, Entry 37)
Benzyl Acetyl(dodecan-2-yl)carbamate (7r)
Method B (Table 2, Entry 38)
A solution of BENAC-K (2) (255 mg, 1.10 mmol, 1.1 equiv), 18-crown-
6 (264 mg, 1.00 mmol, 1.0 equiv), and methyl 2-bromopropionate
(110 L, 1.00 mmol, 1.0 equiv) in DMF (1 mL) was stirred at rt for 19.5
h. The reaction was quenched with saturated aqueous NH4Cl solution,
and the resulting mixture was extracted with EtOAc. The extract was
washed with brine, dried, filtered, and concentrated under reduced
pressure. Flash chromatography on silica gel (20% EtOAc in benzene)
afforded N-alkylated product 7q (223 mg, 80%) and O-alkylated prod-
uct 8q (53 mg, 19%).
To a solution of 2-dodecyl 2-nitrobenzenesulfonate (200 mg, 0.539
mmol, 1.0 equiv) and 18-crown-6 (142 mg, 0.539 mmol, 1.0 equiv) in
CH3CN (1 mL) was added BENAC-K (2) (160 mg, 0.693 mmol, 1.3
equiv), and the mixture was stirred at rt for 7 h. The reaction was
quenched with saturated aqueous NH4Cl solution and the resulting
mixture was extracted with EtOAc. The extract was washed with
brine, dried, and concentrated. Flash chromatography on silica gel
(benzene) afforded N-alkylated product 7r (107 mg, 55%) and O-al-
kylated product 8r (30 mg, 15%).
N-Alkylated Product 7q
Colorless oil.
IR (film): 2998, 2951, 1757, 1703, 1390, 1263, 1175, 1119, 1085 cm–1
.
N-Alkylated Product 7r
1H NMR (600 MHz, CDCl3):  = 7.43–7.38 (m, 5 H), 5.34 (q, J = 7.0 Hz, 1
H), 5.29 and 5.21 (d, J = 11.9 Hz, each 1 H), 3.55 (s, 3 H), 2.56 (s, 3 H),
1.49 (d, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.2, 171.1, 153.5, 134.5, 128.8,
128.7, 128.6, 68.9, 52.1, 51.7, 26.5, 15.4.
Colorless oil.
IR (film): 2925, 2854, 1732, 1702, 1685, 1247 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.40–7.35 (m, 5 H), 5.24 and 5.22 (d, J =
12.1 Hz, each 1 H), 4.69 (sxt, J = 7.0 Hz, 1 H), 2.41 (s, 3 H), 1.75 (m, 1
H), 1.52 (m, 1 H), 1.31–1.10 (m, 19 H), 0.88 (d, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 173.2, 155.3, 135.0, 128.69, 128.66,
128.6, 68.4, 51.4, 34.3, 31.9, 29.58, 29.56, 29.5, 29.4, 29.3, 27.1, 26.8,
22.7, 19.0, 14.1.
HRFABMS: m/z [M + Na]+ calcd for C14H17NO5Na: 302.1004; found:
302.1013.
O-Alkylated Product 8q
HRDARTMS: m/z [M + H]+ calcd for C22H36NO3: 362.2690; found:
362.2690.
Colorless oil.
IR (film): 2993, 2953, 1745, 1723, 1676, 1232 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.39–7.32 (m, 5 H), 5.171 and 5.169 (d,
J = 12.3 Hz, each 1 H), 5.17 (q, J = 7.0 Hz, 1 H), 3.74 (s, 3 H), 2.11 (s, 3
H), 1.50 (d, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 171.1, 166.7, 160.7, 135.7, 128.5,
128.4, 128.3, 70.7, 68.2, 52.3, 18.1, 17.0.
O-Alkylated Product 8r
Colorless oil.
IR (film): 2927, 2854, 1725, 1669, 1240, 1027 cm–1
1H NMR (600 MHz, CDCl3):  = 7.42–7.40 (m, 2 H), 7.38–7.35 (m, 2 H),
7.32 (m, 1 H), 5.19 (s, 2 H), 4.95 (sxt, J = 6.3 Hz, 1 H), 2.03 (s, 3 H), 1.61
(m, 1 H), 1.47 (m, 1 H), 1.31–1.25 (m, 16 H), 1.22 (d, J = 6.2 Hz, 3 H),
0.88 (t, J = 7.0 Hz, 3 H).
.
HRFABMS: m/z [M + Na]+ calcd for C14H17NO5Na: 302.1004; found:
302.1013.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

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T. Sakai et al.
Paper
Synthesis
13C NMR (150 MHz, CDCl3):  = 167.5, 161.8, 136.0, 128.5, 128.4,
128.3, 73.8, 68.0, 35.7, 31.9, 29.59, 29.55, 29.51, 29.49, 29.3, 25.3,
22.7, 19.3, 18.8, 14.1.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690097.
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HRDARTMS: m/z [M + H]+ calcd for C22H36NO3: 362.2690; found:
362.2692.
References
Acetamide 11 (Scheme 4)
A solution of 46 (57.0 mg, 0.0978 mmol) and 5% Pd/C (6 mg) in EtOAc
(1 mL) was stirred under H2 atmosphere at rt for 4 h. The reaction
mixture was filtered through a Celite pad and the filtrate was concen-
trated under reduced pressure. Flash chromatography (70 → 80%
EtOAc in n-hexane) afforded acetamide 11 (34.5 mg, 79%) as a color-
less oil.
(1) (a) Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.;
Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega, K. C.;
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(2) (a) Yous, S.; Andrieux, J.; Howell, H. E.; Morgan, P. J.; Renard, P.;
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(5) (a) Isele, G. L.; Lüttringhaus, A. Synthesis 1971, 266.
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USSR 1984, 20, 456. (c) Sukata, K. Bull. Chem. Soc. Jpn. 1985, 58,
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[]D26 +24.6 (c 1.11, CHCl3).
IR (film): 3302, 3031, 2953, 2856, 1651, 1104 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.36–7.32 (m, 4 H), 7.28 (m, 1 H), 5.84
(br s, 1 H), 4.51 (s, 2 H), 3.76 (m, 1 H), 3.50 (dt, J = 9.2, 6.4 Hz, 1 H),
3.48 (dt, J = 9.2, 6.4 Hz, 1 H), 3.53 (ddd, J = 11.0, 8.6, 4.6 Hz, 1 H), 3.40
(ddd, J = 7.9, 5.3, 2.2 Hz, 1 H), 3.13–3.07 (m, 2 H), 1.95 (s, 3 H), 1.87
(ddd, J = 12.7, 4.8, 2.6 Hz, 1 H), 1.83 (qddd, J = 7.0, 4.6, 2.6, 2.2 Hz, 1 H),
1.71 (m, 1 H), 1.65–1.54 (m, 3 H), 1.42 (m, 1 H), 0.94 (d, J = 7.0 Hz, 3
H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 169.7, 138.4, 128.3, 127.61, 127.55,
81.2, 79.5, 72.9, 70.1, 65.7, 41.4, 40.8, 32.5, 29.3, 26.5, 25.7, 23.3, 17.9,
12.6, –4.2, –4.8.
HRFABMS: m/z [M + H]+ calcd for C25H44NO4Si: 450.3040; found:
450.3022.
Benzyl Carbamate 12 (Scheme 4)
To a solution of 7c (27.7 mg, 0.0658 mmol) in MeOH (1 mL) was added
K2CO3 (1.6 mg, 0.012 mmol, 0.18 equiv), and the reaction mixture was
stirred at rt. After 15 h, the mixture was concentrated under reduced
pressure. Flash chromatography on silica gel (6 → 20% EtOAc in n-
hexane) afforded benzyl carbamate 12 (19.7 mg, 79%) as a colorless
oil.
[]D24 +47.7 (c 1.64, CHCl3).
(6) Sakai, T.; Fukuta, A.; Nakamura, K.; Nakano, M.; Mori, Y. J. Org.
Chem. 2016, 81, 3799.
IR (film): 3344, 2929, 2856, 1728, 1098 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.38–7.33 (m, 4 H), 7.30 (m, 1 H), 5.14
(br s, 1 H), 5.11 and 5.09 (d, J = 12.3 Hz, each 1 H), 3.86 (ddt, J = 11.9,
3.4, 1.7 Hz, 1 H), 3.71 (m, 1 H), 3.35 (ddd, J = 10.2, 8.3, 5.1 Hz, 1 H),
3.30 (m, 1 H), 3.14–3.09 (m, 2 H), 2.01 (m, 1 H), 1.65–1.60 (m, 2 H),
1.43 (m, 1 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 156.3, 136.7, 128.5, 128.1, 128.0, 81.1,
69.0, 67.6, 66.5, 42.8, 33.2, 25.8, 25.4, 17.9, –4.1, –4.9.
(7) For example, an azidation–reduction–acetylation protocol was
employed in the initial synthesis of linezolid.1a In most previous
total syntheses of brevisamide, the acetamide functional group
was furnished via an azide, as described in our review.3b
(8) (a) Iwakura, Y.; Izawa, S.; Hayano, F. Bull. Chem. Soc. Jpn. 1966,
39, 2485. (b) Wada, M.; Mitsunobu, O. Tetrahedron Lett. 1972,
13, 1279. (c) Mitsunobu, O.; Takizawa, S.; Morimoto, H. J. Am.
Chem. Soc. 1976, 98, 7858. (d) Ragnarsson, U.; Grehn, L. Acc.
Chem. Res. 1991, 24, 285. (e) Koppel, I.; Koppel, J.; Koppel, I.;
Leito, I.; Pihl, V.; Wallin, A.; Grehn, L.; Ragnarsson, U. J. Chem.
Soc., Perkin Trans. 2 1993, 655. (f) Berrée, F.; Michelot, G.; Le
Corre, M. Tetrahedron Lett. 1998, 39, 8275. (g) Berrée, F.;
Bazureau, J.-P.; Michelot, G.; Le Corre, M. Synth. Commun. 1999,
29, 2685. (h) Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48,
7094. (i) Breugst, M.; Tokuyasu, T.; Mayr, H. J. Org. Chem. 2010,
75, 5250.
HRFABMS: m/z [M + H]+ calcd for C20H34NO4Si: 380.2257; found:
380.2241.
Funding Information
This research was partially supported by Grants-in-Aid for Scientific
Research (C) (16K08182 and 16K08183) from the Japan Society for
the Promotion of Science (JSPS) and the Research Foundation for
(9) tert-Butyl acetylcarbamate potassium salt (Boc(Ac)N–K+) could
not be developed as a reagent for the synthesis of N-alkylacet-
amides, because Boc(Ac)N–K+ gradually decomposes under air
atmosphere due to its hygroscopic nature.
Pharmaceutical Sciences.
J
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

M
T. Sakai et al.
Paper
Synthesis
(10) For the related patent application, see: Mori, Y.; Sakai, T.;
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Fukuta, A.; Kasai, S. Jpn. Kokai Tokkyo Koho. JP2018-95576,
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(11) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996, 118,
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M