Development of column-free alkoxycarbonyl, aryloxycarbonyl, and acyl transfer reagents

Article abstract of DOI:10.3987/COM-08-S(N)95

Easy-to-handle alkoxycarbonyl, aryloxycarbonyl, and acyl transfer reagents, which contain 3-nitro-1,2,4-triazole (NT) as a leaving group, were developed. With these reagents (NT reagents), which are stable nonhygroscopic crystalline materials, the reactions can be accomplished in about 5 min, and product can be isolated without tedious column chromatographic purification.

Full text of DOI:10.3987/COM-08-S(N)95

HETEROCYCLES, Vol. 76, No. 2, 2008
1301
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1301 - 1312. © The Japan Institute of Heterocyclic Chemistry
Received, 4th April, 2008, Accepted, 13th May, 2008, Published online, 19th May, 2008. COM-08-S(N)95
DEVELOPMENT OF COLUMN-FREE ALKOXYCARBONYL,
ARYLOXYCARBONYL, AND ACYL TRANSFER REAGENTS
Mamoru Shimizu and Mikiko Sodeoka*
Synthetic Organic Chemistry Laboratory, RIKEN (The Institute of Physical and
Chemical Research), 2-1, Hirosawa, Wako, 351-0198, Japan.
E-mail: sodeoka@riken.jp
Abstract – Easy-to-handle alkoxycarbonyl, aryloxycarbonyl, and acyl transfer
reagents, which contain 3-nitro-1,2,4-triazole (NT) as a leaving group, were
developed. With these reagents (NT reagents), which are stable nonhygroscopic
crystalline materials, the reactions can be accomplished in about 5 min, and
product can be isolated without tedious column chromatographic purification.
INTRODUCTION
In organic synthesis, protecting groups play an important role in permitting selective reaction at one
reactive site in a multifunctional compound. For this purpose, many protecting groups have been, and are
being, developed.1 For example, carbamates are especially useful for the protection of amino groups.
However, introduction of protecting groups does not always proceed selectively or in good yield. In some
cases, products are difficult to separate from the reaction mixture. Furthermore, some commonly used
introducing reagents are toxic and/or unstable, requiring careful handling and storage. Therefore, we have
O
N
O
NO2
N
R2-XH
+
HN
NO2
+
R1O
N
R1O
X-R2
N
N
NT reagents
R1 =
R2-XH = amine,
alcohol,
benzyl (1a),
2,2,2-trichloroethyl (1b),
9-fluorenylmethyl (1c),
2-(trimethylsilyl)ethyl (1d)
or thiol
Scheme 1. Preparation of carbamates, carbonates, and thiocarbonates by using NT reagents
_____________________________________________________________________________________
This paper is dedicated to Professor Ryoji Noyori on the occation of his 70th birthday.

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HETEROCYCLES, Vol. 76, No. 2, 2008
recently reported a novel method to introduce protecting groups.2 To provide a rapid and clean reaction
system, we focused on the leaving group. We selected 3-nitro-1,2,4-triazole (NT),3,4 as a crystalline
compound that is expected to be a good leaving group, and developed novel reagents 1a-1d (NT reagents).
These reagents provide rapid access to protected substrates in highly pure forms without tedious
purification (Scheme 1). Simply by dissolving amine and NT reagent in CH2Cl2 in an open flask,
carbamate was quickly obtained (within 5 min) under neutral conditions, and highly pure products were
obtained without the need for column chromatographic purification. To expand the scope of NT reagents,
synthesis and reaction of other alkoxycarbonyl, aryloxycarbonyl, or acyl NT reagents were examined. In
this paper, full details of these studies are reported.
RESULTS AND DISCUSSION
In addition to the previously reported NT reagents (1a-1d; their yields and melting points are summarized
in Figure 1), we attempted to prepare a transfer reagent for t-butoxycarbonyl (Boc), which is widely used
as an amino protecting group (Boc-NT (1e), Figure 1). Though (Boc)2O and Boc-Cl are usually used to
protect amine with Boc, these reagents are susceptible to thermolysis and hydrolysis. Boc-Cl is especially
unstable and must be prepared just before each use. By analogy with the reported NT reagents (1a-1d),
Boc-NT was expected to be a stable crystalline solid. Therefore, Boc-NT was synthesized by the reaction
O
O
NaH (1.0 equiv)
N
N
NO2
NO2
O
Cl + HN
O
N
THF
N
N
0°C (10 min), then rt (12 h)
(1.0 equiv)
Boc-NT (1e)
55%
mp(dec.): 77-78 °C
Alkoxy-type
O
O
O
O
O
N
NO2
Cl
O
N
N
N
N
Si
NO2
NO2
NO2
N
O
N
O
N
N
Cl
N
Cl
N
N
Z-NT (1a)
Troc-NT (1b)
Fmoc-NT (1c)
Teoc-NT (1d)
95%
mp(dec.): 85-86 °C
95%
92%
95%
mp(dec.): 112-113 °C
mp(dec.): 145-146 °C
mp(dec.): 170-171 °C
Acyl-type
Aryloxy-type
O
O
O
N
O
N
N
N
O
NO2
NO2
N
NO2
NO2
N
N
CH3(CH2)14
N
O
N
N
N
N
MeO
Ani-NT (1g)
Px-NT (1f)
Pac-NT (1h)
Pal-NT (1i)
92%
87%
91%
95%
mp(dec.): 108-109 °C
mp(dec.): 157-158 °C
mp(dec.): 133-134 °C
mp(dec.): 62-63 °C
Figure 1. Synthesis of NT reagents

HETEROCYCLES, Vol. 76, No. 2, 2008
1303
of Boc-Cl with the sodium salt of NT in THF, and as expected, Boc-NT was isolated as a crystalline
material in 55% yield. The isolated yield was moderate due to the instability of Boc-Cl. Conversion yield
based on recovered NT was almost quantitative. To introduce other commonly used protecting groups, we
similarly synthesized aryloxycarbonyl- and acyl-type NT reagents, i.e., phenoxycarbonyl-NT (Px-NT, 1f),
anisoyl-NT (Ani-NT, 1g), phenoxyacetyl-NT (Pac-NT, 1h), and palmitoyl-NT (Pal-NT, 1i) (Figure 1). In
each case, pure NT reagent was obtained simply by filtration and subsequent recrystallization in excellent
yield without difficulty. These newly synthesized compounds were all nonhygroscopic crystalline
materials, stable at ambient temperature, and could be stored at 4 °C for a long period of time without
decomposition.
With the various NT reagents in
O
O
+
hand, we next examined their
reactivity, using Z-NT as an
example. First, to make a kinetic
comparison of NT reagent with
commercially available reagents,
(R)-1-phenylethylamine (1 equiv)
was allowed to react with Z-NT,
benzyl chloroformate (Z-Cl), or
benzyl succinimidyl carbonate
(Z-OSu) in CDCl3 at room
temperature. The reactions were
Ph
N
OBn
BnO
X
Ph
NH2
CDCl3
rt
H
(1 equiv)
2
4a
X = 3-nitro-1,2,4-triazol-1-yl ; Z-NT,
Cl
; Z-Cl,
; Z-OSu
succinimidyloxy
100
80
60
40
20
0
△
15.5 h, 97%
15.5 h, ～50%
○
○ ： Z-Cl
△ ： Z-OSu
◇ ： Z-NT
1
monitored by H NMR (Figure 2).
0
20
40
60
80
920
940
In the case of Z-Cl, the reaction was
soon saturated at around 50%, and
did not go to completion even after
Time (min)
Figure 2. Comparison the reactivity of NT reagent
with that of known reagents
a prolonged reaction time. It is probably due to the formation of non-reactive (R)-1-phenylethylamine
hydrochloride. For Z-OSu, the reaction was also rapid initially, but soon slowed down, and a long
reaction time was required for completion. In contrast, reaction with Z-NT was rapid and reached
completion in less than 5 min. Furthermore, the by-product NT is poorly soluble in CDCl3, and simple
filtration yielded the carbamate with >99% purity without any further purification.
Next, solvent effect was examined (Table 1). In addition to CHCl3, CH2Cl2 was found to be a very
effective solvent, because the by-product NT is almost insoluble in CH2Cl2. The reaction was completed
within 5 min and highly pure product was obtained by simple filtration. Other organic solvents, such as
THF and MeCN also worked without any problem. The reactions were completed in 15 min, affording

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HETEROCYCLES, Vol. 76, No. 2, 2008
the carbamate in 94% and 96%
yield, respectively (entries 2,
3). But in these cases,
extraction with 5% aq.
NaHCO3 was necessary to
remove NT from the reaction
mixtures, since NT is soluble
in THF and MeCN. In contrast,
when EtOAc was used as a
solvent, the reaction did not
reach completion and only
Table 1. Preparation of carbamates using various solvents
O
N
O
NO2
+
BnO
N
Ph
N
H
OBn
solvents
rt, time
Ph
NH2
N
1a (Z-NT)
2
4a
entry
solvent
time (min)
yield (%)
quant a
94 b
1
2
3
4
CH2Cl2
THF
5
15
15
60
MeCN
EtOAc
96 b
75 c
a Yield after filtration. b Yield after extraction with 5% aq. NaHCO3.
c Reaction did not go to completion.
about 75% yield of carbamate was obtained even after a prolonged reaction time (entry 4). Methanol was
not an appropriate solvent, because the NT reagents were almost insoluble in it at room temperature, and
methyl carbonate was formed at elevated temperature.
Next, reactions of various NT reagents 1a-1i with amine (2) and amino alcohol (3) were investigated. The
results are summarized in Table 2. The reactions of amines with 1 equiv of 1a-1i in CH2Cl2 proceeded
quickly to give the corresponding carbamates and amides in >92% yield. In many cases, highly pure
products (confirmed by 1H and 13C NMR analysis), were obtained by simple filtration and evaporation of
CH2Cl2 (method A). Depending on the solubility of the products in CH2Cl2, they were sometimes
contaminated with a small amount of NT. Though NT is almost insoluble in CH2Cl2, thorough washing
with a considerable amount of CH2Cl2 to dissolve the products might also result in the dissolution of
small amount of NT. In such cases, washing with 5% aq. NaHCO3 was an effective way to remove the
contaminating NT (method B), yielding highly pure (>99%) products without column chromatographic
purification. In some cases (entries 4, 5, 13, 17), the reaction did not go to completion even after a
prolonged reaction time. The details remain obscure, but we speculate that the reason for this may be
partial formation of an insoluble salt between amine and NT. To prevent the formation of such
non-reactive species, the use of a biphasic system (CH2Cl2 / 5% aq. NaHCO3 (1:1, v/v)) was effective
(method C), and the reaction was completed within 5 min in each case. After washing with 5% aq.
NaHCO3 and evaporation of the solvent, highly pure (>99%) products were obtained in 96-94% yield
without column chromatographic purification. A noteworthy feature of the NT reagents is that they react
selectively with the amino group of amino alcohol. Even when an excess amount of NT reagent (5 equiv)
was used, no reaction with alcohol was seen under these conditions, even with primary alcohol.
Next, to demonstrate the usefulness of the NT reagents as esterification reagents, reaction of
chloramphenicol (6) with Pal-NT (1i) was investigated. Palmitic acid is one of the most common saturat-

HETEROCYCLES, Vol. 76, No. 2, 2008
1305
Table 2. Reactions of 1a-1i with amines
OH
NH2
OH
O
O
O
N
R1
or
or
NO2
+
R1
N
N
Ph
N
H
R1
CH2Cl2
rt, 5 min
Ph
NH2
H
N
1a-1i
2
3
4a-4i
5a-5i
reaction with amine 2
product method a yield (%)
reaction with amine 3
product method a yield (%)
entry
entry
reagent
reagent
1
2
3
4
5
6
7
8
9
Z-NT (1a)
Troc-NT (1b)
Fmoc-NT (1c)
Teoc-NT (1d)
Boc-NT (1e)
Px-NT (1f)
4a
4b
4c
4d
4e
4f
A
quant
10
11
12
13
14
15
16
17
18
Z-NT (1a)
Troc-NT (1b)
Fmoc-NT (1c)
Teoc-NT (1d)
Boc-NT (1e)
Px-NT (1f)
5a
5b
5c
5d
5e
5f
A
95
A
B
A
B
quant b
88
quant b
96
A
B
A
B
95 b
92
quant b
94
C
C
95
C
A
96
94
92
A
B
A
B
A
B
A
B
quant b
95
quant b
92
quant b
quant
quant b
93
A
B
A
B
quant b
90
quant b
92
Ani-NT (1g)
Pac-NT (1h)
Pal-NT (1i)
4g
4h
4i
Ani-NT (1g)
Pac-NT (1h)
Pal-NT (1i)
5g
5h
5i
C
94
A
B
quant b
92
a See experimental section. b Containing a small amount of NT (<10%).
ed fatty acids in animals and plants, and palmitate-modified biologically/physiologically active
substances and antibiotics are used as drugs and cosmetics.5,6 Chloramphenicol (6)6,7 is a natural
antibiotic derived from a strain of Streptomyces isolated by Gottlieb. Though use of 6 for human therapy
is limited (it can cause aplastic anemia), it is used in eye drops or in ointment to treat bacterial
conjunctivitis. In the case of oral administration, 6 is usually used as the water-insoluble 3-O-palmitate
ester in order to adjust plasma concentration. The methods previously reported for the synthesis of
3-O-palmitate ester of 6 are either enzymatic8-10 or chemical,11 but in each case, carefully controlled
reaction conditions and a long reaction time, or tedious purification steps are essential. On the other hand,
our new NT reagent made it possible to obtain the product more conveniently. As mentioned above, 1 did
not react with alcohols in the absence of base; however, a stoichiometric amount of 1i selectively and
quickly reacted with the primary alcohol of 6 in the presence of Et3N to afford 7i in a highly pure form
(>95% purity) without column chromatographic purification (Scheme 2).
In conclusion, we have developed new reagents which enable rapid and easy preparation of highly pure
carbamates, amides, and esters without the need for column chromatographic purification. Characteristic

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HETEROCYCLES, Vol. 76, No. 2, 2008
O
OH OH
OH
O
O
(CH2)14CH3
O
Et3N
Cl
Cl
N
NO2
+
CH3(CH2)14
N
HN
HN
THF
rt, 1 h
quant
O2N
Cl
O2N
Cl
N
O
1i
7i
6
Scheme 2. Selective palmitoylation of chloramphenicol
features of these newly introduced reagents are: (1) they are highly stable and can be stored for long
periods without decomposition; (2) since they are nonhygroscopic crystalline materials, they are easy to
handle and weigh accurately even on a milligram scale; (3) the reactions can be carried out even in an
open flask; (4) the co-product NT can be recycled; (5) generally, carbamate and amide formation
proceeds quickly (within 5 min) under neutral conditions; (6) highly pure carbamates and amides can be
obtained without tedious column chromatographic purification. An NT reagent also enabled simple,
regioselective esterification of chloramphenicol in a highly pure form. In addition to the examples of
acylation reported here, NT reagents are expected to be especially useful for the synthesis of
polyfunctionalized compounds that are difficult to access by conventional procedures.12
EXPERIMENTAL
1
General Information. H NMR spectra were obtained at 300, 400, or 500 MHz with tetramethylsilane
13
(TMS) as an internal standard. C NMR spectra were obtained at 100 or 125 MHz with CDCl3 as an
internal standard (δ 77.0) in CDCl3, with CD3CN as an internal standard (δ 1.3) in CD3CN, or with
CD3COCD3 as an internal standard (δ 29.8) in CD3COCD3. Thin layer chromatography (TLC) was
performed on TLC plates silica gel 60 F254 (Merck, No. 5715). Silica gel column chromatography was
carried out by using silica gel 60N (Cica-Reagent, 40-100 µm). Organic solvents were purified and dried
by usual procedures.
Benzyl 3-nitro-1H-1,2,4-triazole-1-carboxylate (Z-NT: 1a).
To powdery NaH (0.250 g, 10.4 mmol), prepared from NaH dispersion in mineral oil prior to use, was
added a solution of 3-nitro-1,2,4-triazole (1.19 g, 10.4 mmol), which had been dried by repeated
coevaporations with pyridine and toluene, in THF (30 mL) at 0 °C under an Ar atmosphere. The mixture
was stirred for 10 min, then Z-Cl (1.48 mL, 10.4 mmol) was added dropwise with stirring. After 30 min,
the solution was allowed to warm to rt and stirring was continued for 12 h. The insoluble solid was
filtered off and thoroughly washed with EtOAc (ca. 50 mL). The combined filtrate was evaporated to give
a residue, which was recrystallized from EtOAc to afford Z-NT (2.44 g, 95%) as a light yellow crystalline

HETEROCYCLES, Vol. 76, No. 2, 2008
1307
solid. mp 112-113 °C (dec.); 1H NMR (400 MHz, CDCl3) δ 8.99 (1H, s), 7.55-7.42 (5H, m), 5.54 (2H, s);
13C NMR (125 MHz, CDCl3) δ 163.1, 147.1, 146.0, 132.4, 129.9, 129.4, 129.0, 72.5; IR (neat) ν 3142,
1787, 1556, 1514, 1385, 1292, 1227, 1175, 1014 cm-1; Anal. Calcd for C10H8N4O4·1/4H2O: C, 47.53; H,
3.39; N, 22.17. Found: C, 47.37; H, 3.32; N, 22.04. The crystallographic data of 1a have been deposited
with the Cambridge Crystallographic Data Centre as supplementary no. CCDC 675625. This data can be
obtained online free of charge. X-Ray structure of Z-NT (1a) is as follows.
2,2,2-Trichloroethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate (Troc-NT: 1b).
This compound was obtained from Troc-Cl as a pale yellow crystalline solid (92% yield) in a similar
1
13
manner to Z-NT. mp 145-146 °C (dec.); H NMR (400 MHz, CDCl3) δ 8.96 (1H, s), 5.17 (2H, s); C
NMR (125 MHz, CD3CN) δ 164.2, 149.6, 146.1, 94.0, 78.0; IR (neat) ν 3114, 1783, 1553, 1523, 1438,
1390, 1276, 1238, 1019 cm-1; Anal. Calcd for C5H3Cl3N4O4: C, 20.75; H, 1.04; N, 19.36. Found: C,
20.68; H, 1.07; N, 19.65. The crystallographic data of 1b have been deposited with the Cambridge
Crystallographic Data Centre as supplementary no. CCDC 675624. This data can be obtained online free
of charge. X-Ray structure of Troc-NT (1b) is as follows.
9-Fluorenylmethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate (Fmoc-NT: 1c).
This compound was obtained from Fmoc-Cl as a pale yellow crystalline solid (95% yield) in a similar
manner to Z-NT. mp 170-171 °C (dec.); 1H NMR (400 MHz, CDCl3) δ 8.71 (1H, s), 7.80 (2H, d, J = 7.3
Hz), 7.64 (2H, d, J = 7.3 Hz), 7.45 (2H, t, J = 7.3 Hz), 7.35 (2H, t, J = 7.3 Hz), 4.86 (2H, d, J = 7.1 Hz),
13
4.45 (1H, t, J = 7.1 Hz); C NMR (125 MHz, CD3COCD3) δ 164.1, 149.1, 147.1, 143.7, 142.1, 129.0,
128.2, 126.2, 121.0, 72.4, 47.1; IR (neat) ν 3130, 1789, 1563, 1512, 1386, 1360, 1293, 1263 cm-1; Anal.
Calcd for C17H12N4O4: C, 60.71; H, 3.60; N, 16.66. Found: C, 60.57; H, 3.69; N, 16.87.
2-(Trimethylsilyl)ethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate (Teoc-NT: 1d).
This compound was obtained from Teoc-Cl13 as a light yellow crystalline solid (96% yield) in a similar
manner to Z-NT (instead of recrystallization, reprecipitation from n-hexane-EtOAc). mp 85-86 °C (dec.);
13
1H NMR (500 MHz, CD3CN) δ 8.97 (1H, s), 4.67-4.60 (2H, m), 1.27-1.20 (2H, m), 0.08 (9H, s); C
NMR (125 MHz, CD3CN) δ 164.0, 148.8, 147.2, 70.8, 17.9, -1.7; IR (neat) ν 3137, 2958, 1777, 1564,

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HETEROCYCLES, Vol. 76, No. 2, 2008
1514, 1290, 1230, 1170, 1015 cm-1. The crystallographic data of 1d have been deposited with the
Cambridge Crystallographic Data Centre as supplementary no. CCDC 675623. This data can be obtained
online free of charge. X-Ray structure of Teoc-NT (1d) is as follows.
t-Butyl 3-nitro-1H-1,2,4-triazole-1-carboxylate (Boc-NT: 1e).
This compound was obtained from Boc-Cl as a pale yellow crystalline solid (55% yield) in a similar
manner to Z-NT. mp 77-78 °C (dec.); 1H NMR (400 MHz, CDCl3) δ 8.81 (1H, s), 1.71 (9H, s); 13C NMR
(125 MHz, CDCl3) δ 162.9, 146.6, 144.0, 90.5, 27.7. HRMS (FAB+) m/z Calcd for C7H10N4NaO4
[M+Na]+ 237.0600, found 237.0599; IR (neat) ν 3159, 2988, 1776, 1553, 1513, 1367, 1281, 1144, 1014
cm-1.
3-Nitro-1-phenoxycarbonyl-1H-1,2,4-triazole (Px-NT: 1f).
This compound was obtained from phenoxycarbonyl chloride as a pale yellow crystalline solid (87%
1
yield) in a similar manner to Z-NT. mp 157-158 °C (dec.); H NMR (400 MHz, CDCl3) δ 9.06 (1H, s),
13
7.56-7.49 (2H, m), 7.44-7.39 (1H, m), 7.37-7.32 (2H, m); C NMR (100 MHz, CDCl3) δ 163.2, 149.3,
147.3, 144.6, 130.0, 127.7, 120.3. HRMS (FAB+) m/z Calcd for C9H7N4O4 [M+H]+ 235.0467, found
235.0469; IR (neat) ν 3126, 1779, 1553, 1513, 1482, 1437, 1370, 1239, 1186 cm-1.
1-Anisoyl-3-nitro-1H-1,2,4-triazole (Ani-NT: 1g).
This compound was obtained from anisoyl chloride as a pale yellow crystalline solid (92% yield) in a
similar manner to Z-NT. mp 108-109 °C (dec.); 1H NMR (400 MHz, CDCl3) δ 9.10 (1H, s), 8.36 (2H, d, J
13
= 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz), 3.95 (3H, s); C NMR (100 MHz, CDCl3) δ 165.3, 162.5, 161.4,
146.7, 134.7, 119.3, 114.3, 55.7; MS (MALDI TOF) m/z Calcd for C10H8N4NaO4 [M+Na]+ 271.04, found
271.00; IR (neat) ν 3139, 1721, 1589, 1510, 1424, 1346, 1288, 1240, 1173, 1012 cm-1.
3-Nitro-1-phenoxyacetyl-1H-1,2,4-triazole (Pac-NT: 1h).
This compound was obtained from phenoxyacetyl chloride as a pale yellow crystalline solid (% yield) in
1
a similar manner to Z-NT. mp 133-134 °C (dec.); H NMR (400 MHz, CD3CN) δ 9.10 (1H, s),
7.37-7.29 (2H, m), 7.08-6.98 (3H, m), 5.49 (2H, s); 13C NMR (100 MHz, CD3CN) δ 166.3, 163.4, 157.9,
146.7, 130.3, 122.7, 115.4, 66.7; MS (MALDI TOF) m/z Calcd for C10H8N4NaO4 [M+Na]+ 271.04, found
270.90; IR (neat) ν 3133, 2905, 1788, 1562, 1491, 1421, 1393, 1345, 1287, 1233, 1195 cm-1.
3-Nitro-1-palmitoyl-1H-1,2,4-triazole (Pal-NT: 1i).
This compound was obtained from parmitoyl chloride as a pale yellow crystalline solid (95% yield) in a
similar manner to Z-NT. mp 62-63 °C (dec.); 1H NMR (400 MHz, CDCl3) δ 8.94 (1H, s), 3.18 (2H, t, J =

HETEROCYCLES, Vol. 76, No. 2, 2008
1309
7.4 Hz), 1.82 (2H, quintet, J = 7.4 Hz), 1.47-1.22 (24H, m), 0.88 (3H, t, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 169.6, 162.5, 144.4, 34.3, 32.0, 29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 29.2, 28.9, 23.6, 22.8, 14.3.
HRMS (FAB+) m/z Calcd for C18H32N4NaO3 [M+Na]+ 375.2372, found 375.2375; IR (neat) ν 3139, 2913,
2849, 1768, 1565, 1512, 1471, 1383, 1294, 1182 cm-1.
General Procedure for the Preparation of Carbamate and Amide.
Method A
To a solution of 1 (100 µmol) in CH2Cl2 (500 µL) was slowly added substrate (100 µmol) at rt and the
solution was stirred for 5 min. Insoluble NT was filtered off, and the filtrate was evaporated to give the
desired compound.
Method B
To a solution of 1 (100 µmol) in CH2Cl2 (500 µL) was slowly added substrate (100 µmol) at rt and the
solution was stirred for 5 min, then quenched with 5% aq. NaHCO3 and diluted with CH2Cl2. The organic
layer was washed with 5% aq. NaHCO3 (3 mL x 3). The aqueous layer was back-extracted with CH2Cl2
(3 mL x 2), and the combined organic layer was dried over Na2SO4, filtered, and evaporated under
reduced pressure to give the desired compound.
Method C
To a solution of 1 (100 µmol) in CH2Cl2 (500 µL) and 5% aq. NaHCO3 (500 µL) was slowly added
substrate (100 µmol) at rt and the solution was stirred for 5 min. The organic layer was washed with 5%
aq. NaHCO3 (3 mL x 3). The aqueous layer was back-extracted with CH2Cl2 (3 mL x 2), and the
combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give
the desired compound.
t-Butyl (R)-1-phenylethylcarbamate (4e).
This compound was prepared by Method C: 94% yield; white powder. mp 81-82 °C; 1H NMR (300 MHz,
CDCl3) δ 7.40-7.19 (5H, m), 4.92-4.67 (2H, m), 1.57-1.29 (12H, m); 13C NMR (100 MHz, CDCl3)
δ 154.9, 143.8, 128.4, 126.9, 125.7, 79.4, 50.2, 28.5, 22.8; MS (FAB) m/z Calcd for C13H19NNaO2
[M+Na]+ 244.13, found 243.95; IR (neat) ν 3382, 2983, 1687, 1514, 1448, 1363, 1311, 1245, 1170, 1059
cm-1.
Phenyl (R)-1-phenylethylcarbamate (4f).
This compound was prepared by Method A: quantitative yield; Method B: 95% yield; white solid. mp
1
75-76 °C; H NMR (300 MHz, CDCl3) δ 7.39-7.06 (10H, m), 5.33 (1H, brs), 4.91 (1H, quintet, J = 7.0
13
Hz), 1.55 (3H, d, J = 7.0 Hz); C NMR (100 MHz, CDCl3) δ 153.5, 150.7, 142.8, 129.1, 128.6, 127.3,
125.9, 125.1, 121.4, 51.0, 22.3; MS (MALDI TOF) m/z Calcd for C15H16NO2 [M+H]+ 242.12, found
241.93; IR (neat) ν 3319, 1711, 1530, 1493, 1207, 1032 cm-1.
4-Methoxy-N-[(R)-1-phenylethyl]benzamide (4g).

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HETEROCYCLES, Vol. 76, No. 2, 2008
This compound was prepared by Method A: quantitative yield; Method B: 92% yield; white powder. mp
154-155 °C; 1H NMR (300 MHz, CDCl3) δ 7.73 (2H, d, J = 8.8 Hz), 7.44-7.21 (5H, m), 6.88 (2H, d, J =
8.8 Hz), 6.40 (1H, brd, J = 6.8 Hz), 5.31 (1H, quintet, J = 6.8 Hz), 3.82 (3H, s), 1.57 (3H, d, J = 6.8 Hz);
13C NMR (100 MHz, CDCl3) δ 165.8, 161.8, 143.1, 128.6, 128.5, 127.1, 126.7, 126.1, 113.5, 55.4, 49.1,
21.9; MS (MALDI TOF) m/z Calcd for C16H18NO2 [M+H]+ 256.13, found 256.00; IR (neat) ν 3334, 1625,
1607, 1531, 1502, 1255, 1175, 1026 cm-1.
2-Phenoxy-N-[(R)-1-phenylethyl]acetamide (4h).
This compound was prepared by Method A: quantitative yield; Method B: quantitative yield; white solid.
1
mp 73-74 °C; H NMR (300 MHz, CDCl3) δ 7.39-7.24 (7H, m), 7.07-7.01 (1H, m), 6.95-6.90 (2H, m),
6.82 (1H, d, J = 7.3 Hz), 5.25 (1H, quintet, J = 7.3 Hz), 4.53 (1H, d, J = 14.6 Hz), 4.48 (1H, d, J = 14.6
13
Hz), 1.54 (3H, d, J = 7.3 Hz); C NMR (100 MHz, CDCl3) δ 167.0, 156.9, 142.5, 129.6, 128.5, 127.3,
125.9, 122.0, 114.6, 67.4, 48.3, 21.9; MS (MALDI TOF) m/z Calcd for C16H18NO2 [M+H]+ 256.13, found
256.00; IR (neat) ν 3295, 3063, 3023, 2974, 2936, 1659, 1599, 1529, 1493, 1442, 1239, 1060 cm-1.
N-[(R)-1-Phenylethyl]palmitamide (4i).
This compound was prepared by Method A: quantitative yield; Method B: 93% yield; white solild. mp
79-80 °C; 1H NMR (300 MHz, CDCl3) δ 7.37-7.22 (5H, m), 5.78 (1H, brd, J = 7.1 Hz), 5.13 (1H, quintet,
J = 7.1 Hz), 2.16 (2H, t, J = 7.7 Hz), 1.67-1.56 (2H, m), 1.48 (3H, d, J = 7.1 Hz), 1.34-1.18 (24H, m),
13
0.88 (3H, t, J = 6.7 Hz); C NMR (100 MHz, CDCl3) δ 171.9, 143.1, 128.4, 127.1, 126.0, 48.5, 37.0,
32.0, 29.8, 29.7, 29.7, 29.6, 29.4, 29.4, 25.8, 22.8, 21.8, 14.2; MS (MALDI TOF) m/z Calcd for
C24H42NO [M+H]+ 360.33, found 360.30; IR (neat) ν 3308, 2916, 2849, 1641, 1547 cm-1.
t-Butyl (2R,3S)-2,3-dihydro-2-hydroxy-1H-inden-3-ylcarbamate (5e).
1
This compound was prepared by Method A: 92% yield; colorless oil. H NMR (300 MHz, CDCl3) δ
7.34-7.19 (4H, m), 5.19-5.02 (2H, m), 4.63-4.56 (1H, m), 3.13 (1H, dd, J = 16.6, 4.9 Hz), 2.93 (1H, brd, J
= 16.6 Hz), 2.13 (1H, brs), 1.51 (9H, s); 13C NMR (100 MHz, CDCl3) δ 156.1, 140.6, 139.6, 128.0, 127.0,
125.2, 124.3, 79.9, 73.7, 58.9, 39.5, 28.5; MS (MALDI TOF) m/z Calcd for C14H19NNaO3 [M+Na]+
272.13, found 272.00; IR (neat) ν 3407, 2976, 2930, 1690, 1502, 1366, 1245, 1165, 1049 cm-1.
Phenyl (2R,3S)-2,3-dihydro-2-hydroxy-1H-inden-3-ylcarbamate (5f).
This compound was prepared by Method A: quantitative yield; Method B: 90% yield; white solid. mp
111-112 °C; 1H NMR (300 MHz, CDCl3) δ 7.41-7.15 (9H, m), 5.80 (1H, d, J = 8.6 Hz), 5.14 (1H, dd, J =
8.6, 5.1 Hz), 4.62-4.55 (1H, m), 3.12 (1H, dd, J = 16.6, 5.1 Hz), 2.91 (1H, dd, J = 16.6, 2.0 Hz), 2.37 (1H,
brs); 13C NMR (100 MHz, CDCl3) δ 154.9, 150.7, 140.1, 139.5, 129.2, 128.2, 127.1, 125.3, 125.2, 124.4,
121.4, 73.4, 59.3, 39.6; MS (MALDI TOF) m/z Calcd for C16H15NNaO3 [M+Na]+ 292.09, found 292.00;
IR (neat) ν 3380, 3295, 2943, 2915, 1703, 1536, 1492, 1207 cm-1.

HETEROCYCLES, Vol. 76, No. 2, 2008
1311
N-[(2R,3S)-2,3-Dihydro-2-hydroxy-1H-inden-3-yl]-4-methoxybenzamide (5g).
This compound was prepared by Method A: quantitative yield; Method B: 92% yield; white solid. mp
1
156-157 °C; H NMR (300 MHz, CDCl3) δ 7.78-7.72 (2H, m), 7.32-7.17 (4H, m), 6.91-6.82 (3H, m),
5.50 (1H, dd, J = 8.1, 5.2 Hz), 4.65 (1H, dt, J = 5.2, 2.2 Hz), 3.82 (3H, s), 3.17 (1H, dd, J = 16.6, 5.2 Hz),
3.03 (1H, brs), 2.95 (1H, dd, J = 16.6, 2.2 Hz); 13C NMR (100 MHz, CDCl3) δ 167.3, 162.0, 140.7, 139.9,
128.8, 128.0, 127.0, 126.1, 125.1, 124.5, 113.6, 73.6, 57.9, 55.4, 39.9; MS (MALDI TOF) m/z Calcd for
C17H18NO3 [M+H]+ 284.13, found 284.01; IR (neat) ν 3404, 3256, 2943, 2913, 2841, 1608, 1536, 1502,
1251, 1180, 1025 cm-1.
N-[(2R,3S)-2,3-Dihydro-2-hydroxy-1H-inden-3-yl]-2-phenoxyacetamide (5h).
1
This compound was prepared by Method C: 94% yield; white powder. mp 176-177 °C; H NMR (300
MHz, CDCl3) δ 7.33-7.15 (7H, m), 7.04-6.98 (1H, m), 6.93-6.87 (2H, m), 5.47 (1H, dd, J = 8.7, 5.1 Hz),
4.65 (1H, brs), 4.63 (1H, d, J = 14.9 Hz), 4.58 (1H, d, J = 14.9 Hz), 3.18 (1H, dd, J = 16.6, 5.1 Hz), 2.96
13
(1H, dd, J = 16.6, 2.0 Hz), 2.17 (1H, brs); C NMR (100 MHz, CDCl3) δ 168.8, 156.9, 139.9, 139.8,
129.6, 128.3, 127.1, 125.2, 124.3, 122.0, 114.6, 73.6, 67.4, 57.2, 39.9; MS (MALDI TOF) m/z Calcd for
C17H18NO3 [M+H]+ 284.13, found 284.00; IR (neat) ν 3351, 3223, 2948, 2905, 2030, 1643, 1599, 1536,
1497, 1243 cm-1.
N-[(2R,3S)-2,3-Dihydro-2-hydroxy-1H-inden-3-yl]palmitamide (5i).
This compound was prepared by Method A: quantitative yield; Method B: 92% yield; white solid. mp
120-121 °C; 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (4H, m), 6.09 (1H, brd, J = 8.1 Hz), 5.41 (1H, dd, J
= 8.1, 5.4 Hz), 4.65 (1H, dt, J = 5.4, 2.4 Hz), 3.19 (1H, dd, J = 16.5, 5.4 Hz), 2.95 (1H, dd, J = 16.5, 2.4
Hz), 2.31 (1H, brs), 2.30 (2H, t, J = 7.7 Hz), 1.75-1.60 (2H, m), 1.41-1.22 (24H, m), 0.88 (3H, t, J = 6.8
13
Hz); C NMR (100 MHz, CDCl3) δ 173.8, 140.5, 139.7, 128.2, 127.1, 125.2, 124.4, 73.8, 57.5, 39.8,
37.0, 32.0, 29.8, 29.8, 29.7, 29.6, 29.5, 29.4, 26.0, 22.8, 14.3; MS (MALDI TOF) m/z Calcd for
C25H42NO2 [M+H]+ 388.32, found 382.33; IR (neat) ν 3448, 3312, 2917, 2849, 1639, 1615, 1547, 1462,
1047 cm-1.
threo-(1R,2R)-1-(4-Nitrophenyl)-2-(dichloroacetamido)-1,3-propandiol 3-palmitate (7i).
To a mixture of Pal-NT (1i) (35.2 mg, 100 µmol) and chloramphenicol (6) (32.3 mg, 100 µmol) in THF
(1 mL) was added Et3N (28.0 µL, 200 µmol) at rt and the solution was stirred for 1 h. The organic layer
was washed with 5% aq. NaHCO3 (4 mL x 3). The aqueous layer was back-extracted with CH2Cl2 (4 mL
x 1), and the combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced
pressure to give 7i in quantitative yield (>95% purity). For measurement of analytical data, 7i was further
purified by preparative thin layer chromatography (MeOH : CH2Cl2 = 5 : 95). 94% yield; white powder.
mp 88-89 °C; 1H NMR (300 MHz, CDCl3) δ 8.20 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz), 6.89 (1H,
d, J = 8.6 Hz), 5.76 (1H, s), 5.06 (1H, brs), 4.49-4.36 (2H, m), 4.20 (1H, dd, J = 10.9, 5.9 Hz), 3.41 (1H, d,

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HETEROCYCLES, Vol. 76, No. 2, 2008
J = 4.2 Hz), 2.37 (2H, t, J = 7.6 Hz), 1.68-1.58 (2H, m), 1.36-1.25 (24H, m), 0.88 (3H, t, J = 7.1 Hz); 13C
NMR (100 MHz, CDCl3) δ 174.1, 164.1, 147.4, 146.8, 126.6, 123.5, 70.7, 66.0, 62.4, 54.2, 34.2, 32.0,
29.8, 29.7, 29.7, 29.5, 29.5, 29.3, 29.2, 25.0, 22.8, 14.3; MS (MALDI TOF) m/z Calcd for
C27H42Cl2N2NaO6 [M+Na]+ 583.23, found 583.40; IR (neat) ν 3476, 3315, 2916, 2849, 1732, 1678, 1518,
1467, 1350 cm-1.
ACKNOWLEDGEMENTS
We thank Dr. Daisuke Hashizume (RIKEN) for obtaining X-ray crystallographic data, and Ms. Kumiko
Harata (RIKEN) for obtaining HRMS data. This work was partially supported by a Grant-in-Aid for
Scientific Reseach on Priority Areas from MEXT, and Special Project Funding for Basic Science.
REFERENCES AND NOTES
1. P. G. M. Wuts and T. W. Greene, 'Greene’s Protecting Groups in Organic Synthesis', 4th ed., Wiley,
New Jersey, 2007.
2. M. Shimizu and M. Sodeoka, Org. Lett., 2007, 9, 5231.
3. In 'Physical Methods in Heterocyclic Chemistry', ed. by A. R. Katritsky, Academic Press: New York,
1963; Vol. 1.
4. E. J. Brown, Aust. J. Chem., 1969, 22, 2251.
5. (a) P. P. Fu, Q. Xia, M. D. Boudreau, P. C. Howard, W. H. Tolleson, and W. G. Wamer, Vitam
Horm, 2007, 75, 223. (b) L. Sangkil, L. Jaehwi, and W. C. Young, Biol. Pharm. Bull., 2007, 30, 393.
6. L. S. Goodman and A. Gilman, 'The Pharmacological Basis of Therapeutics', 5th ed. MacMillan
Publishing Co., Inc., New York, 1975, pp. 1194-1198.
7. 'The Merck Index', 14th ed., Merck & Co., Inc., NJ, 2006, p. 2078 entry 2077.
8. T. A. El-Kersh and J. R. Plourde, J. Antibiot., 1976, 29, 292.
9. Y. Nakagawa, Chem. Abstr., 1980, 93, 62307j.
10. G. Ottolina, G. Carrea, and S. Riva, J. Org. Chem., 1990, 55, 2366.
11. (a) W. H. Edgerton, Chem. Abstr., 1954, 48, 12793e. (b) I. Farmaceutici, Chem. Abstr., 1957, 51,
10575g. (c) M. T. Goebel, Chem. Abstr., 1959, 53, 1650h. (d) G. Glazer and J. Neudorffer, Chem.
Abstr., 1961, 55, 14387f. (e) I. Villax, Chem. Abstr., 1965, 63, 14948h.
12. Teoc-NT (1d) is now commercially available from Tokyo Chemical Industry Co., Ltd.
13. M. Sekine, M. Tobe, T. Nagayama, and T. Wada, Lett. Org. Chem., 2004, 1, 179.