A versatile synthesis of α-amino acid derivatives via the ugi four-component condensation with a novel convertible isonitrile

Article abstract of DOI:10.3987/COM-07-S(U)11

The Ugi four-component condensation (4CC) reaction with the carbonate-type isonitrile 9 proceeded smoothly, and subsequent base treatment of the Ugi products 10 provided the N-acyloxazolidinones 11 in high yield. The N-acyloxazolidinone derivatives can be reacted with several hetero-nucleophiles, namely, reaction of 11 with thiolates gave thiol ester derivatives 16 efficiently.

Full text of DOI:10.3987/COM-07-S(U)11

HETEROCYCLES, Vol. 73, 2007
403
HETEROCYCLES, Vol. 73, 2007, pp. 403 - 417. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd June, 2007, Accepted, 6th July, 2007, Published online, 10th July, 2007. COM-07-S(U)11
A VERSATILE SYNTHESIS OF α-AMINO ACID DERIVATIVES VIA
THE UGI FOUR-COMPONENT CONDENSATION WITH A NOVEL
CONVERTIBLE ISONITRILE
Kentaro Rikimaru,a,b Arata Yanagisawa,a,c Toshiyuki Kan,a,d and Tohru
Fukuyama*a
aGraduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, 113-0033, Japan, E-mail: fukuyama@mol.f.u-tokyo.ac.jp
bPresent Address: Medicinal Chemistry Research Laboratories, Pharmaceutical
Research Division, Takeda Pharmaceutical Company, 17-85, Jusohonmachi
2-Chome, Yodogawa-ku, Osaka, 532-0024, Japan
cPresent Address: Medicinal Chemistry Research Laboratories, Pharmaceutical
Research Center, Kyowa Hakko Kogyo Co., Ltd. 1188 Shimotogari,
Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan
dPresent Address: School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka-shi, 422-8526, Japan
Abstract – The Ugi four-component condensation (4CC) reaction with the
carbonate-type isonitrile 9 proceeded smoothly, and subsequent base treatment of
the Ugi products 10 provided the N-acyloxazolidinones 11 in high yield. The
N-acyloxazolidinone derivatives can be reacted with several hetero-nucleophiles,
namely, reaction of 11 with thiolates gave thiol ester derivatives 16 efficiently.
INTRODUCTION
Multi-component reactions (MCRs) have attracted much attention because of their use in the construction
of combinatorial libraries.1 In particular, the Ugi four-component condensation (Ugi 4CC)2 has been
widely employed since it provides various α-amino amide derivatives 1 by a simple experimental
procedure under mild conditions.1b These products possess a drug-like structure and could be responsible
Dedication to the great contribution to organic chemistry of the late professor Ivar Ugi.

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HETEROCYCLES, Vol. 73, 2007
for a variety of important biological activities. Moreover, the great facility of the condensation to form
amide bonds also permits the efficient total synthesis of complex natural products.3
Although numerous reports of the Ugi 4CC reaction have been published, inherent problems in the
stereoselective construction of the α-position4 and cleavage of the C-terminal amide still need to be
solved. Due to the limited variety of isonitriles available in comparison with the other components
(amines, carbonyl compounds and carboxylic acids), incorporation of other diverse functional groups at
the C-terminal amide (R-groups) has been required for the generation of these libraries (Scheme 1).5-10
difficult to
cleave
W-N=C:
Y
N
O
Y
N
O
X-CO2H
Y-NH2
"Ugi's 4CC"
X
X
W
R
N
H
O
Z
O
Z
Z-CHO
1
R = diverse group
Scheme 1. Ugi 4CC Reaction and its Limitation.
Recently, the 4-CC reaction with the convertible isonitriles 2 and 3 was reported by Armstrong and Ugi,
respectively (Figure 1). In the case of Armstrong’s 1-cyclohexenyl isocyanide (2),5 the nucleophilic
addition to the amide bond of the Ugi products was readily carried out under acidic conditions. On the
other hand, the condensation product derived from the isocyanoalkyl alkyl carbonates 3 reported by Ugi
was converted to the corresponding α-amino ester derivatives 6 by treatment with base.6a As shown in
Scheme 2, this reaction would take place via the formation of the N-acyloxazolidinones 5 by cyclization
of the amide anion onto the carbonate of 4 followed by addition of the alkoxide (–OR) and elimination of
the oxazolidinone. Thus, using an isonitrile 9 similar to the Ugi convertible isonitrile (3), we expected
to obtain the N-acyloxazolidinones from the Ugi products.6b Since the C-N bond of the
N-acyloxazolidinones can be cleaved by several nucleophiles under mild conditions, this protocol would
allow the production of numerous analogues.
:C=N
OCO2R
:C=N
R = Me, Et, Allyl, Bn
3
2
Figure 1. Convertible Isonitriles.

HETEROCYCLES, Vol. 73, 2007
405
Y
N
O
O
3
Y
N
O
Y
N
O
X
O
OR
t-BuOK
"Ugi's 4CC"
X-CO2H
X
X
N
H
N
O
OR
Y-NH2
O
Z
O
O
Z
O
Z
Z-CHO
4
RO–
t-BuO–
5
6
R = Me, Et, Allyl, Bn
Scheme 2. Ugi’s Approach.
Here we describe the Ugi 4CC reaction with the novel isonitrile 9 and a convenient procedure for
conversion of the Ugi products by cleavage of the C-terminal amide bond.7
RESULTS AND DISCUSSION
Our working hypothesis for the isonitrile 9 is based on the theory that the phenoxide anion would not
attack the N-acyloxazolidinone of 5, because of its weak nucleophilicity (pKa = 10). Preparation of the
isonitrile 9 was performed according to the Ugi protocol.6 Upon treatment of 4,4-dimethyloxazoline (7)11
with n-BuLi, smooth deprotonation and α-elimination gave the β-isocyanoalkoxide 8. Subsequent
protection of the alkoxide intermediate by phenyl chloroformate afforded the isonitrile 9 (Scheme 3). The
isonitrile 9 has the advantage of being odorless and stable under silica gel chromatographic purification
and storage for several months in air at ambient temperature. Since a similar didemethyl isonitrile7b
should be stored in refrigerator, the stability of 9 would be caused by its geminal dimethyl groups.
Bu–
H
ClCO2Ph
O–
OCO2Ph
N
O
:C=N
:C=N
7
8
9
Reagents and conditions: n-BuLi, THF, –78 °C; ClCO2Ph, 50%
Scheme 3. Preparation of Isonitrile 9.
With the requisite isonitrile 9 in hand, the Ugi 4CC reaction of the combined aromatic and/or aliphatic
amines, aldehydes and carboxylic acids was carried out. As shown in Table 1, the four-component
condensation proceeded smoothly to give the desired α-amino amide derivatives 10a-g in almost
quantitative yields. Furthermore, this protcol has the advantage that aqueous formaldehyde was also
readily available (entry 2), although the first step of the Ugi 4CC reaction should be a dehydrative
reaction of the amine and the carbonyl compound.12 In the case of entry 7, a relatively higher temperature
was needed for the completion of the reaction.

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HETEROCYCLES, Vol. 73, 2007
Table 1. Ugi 4CC reaction with Isonitrile 9.
9 (1.5 eq.)
X-CO2H (1.5 eq.)
Y-NH2 (1 eq.)
Y
N
O
X
OCO2Ph
N
MeOH
H
10a-g
O
Z
Z-CHO (5 eq.)
yield (%)
run
temp.
X
Y
Z
time (min)
91
(10a)
(10b)
(10c)
(10d)
(10e)
(10f)
rt
rt
rt
rt
rt
rt
60
10
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Me
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Ph
Ph
i-Pr
H
88a
quant.
88
10
Me
Ph
i-Pr
i-Pr
Ph
60b
60
98
99
10
60b
89
(10g)
70 °C
a: Small amounts of inseparable impurities were detected by 1H-NMR.
b: The starting material remained.
Next, we turned our attention to the transformation of the Ugi products 10a-g to the N-acyloxazolidinones
11a-g. After several attempts at cyclization, treatment with almost theoretical amount of t-BuOK (1.02
eq.) in THF in the presence of molecular sieves 4A (MS4A) gave the best results. As shown in Table 2,
the desired cyclization proceeded smoothly to afford the N-acyloxazolidinones 11a-g in more than 80%
yield. As expected, the nucleophilic attack of the phenoxide anion on the N-acyloxazolidinones did not
occur. Furthermore, MS4A play a key role in preventing hydrolysis of the starting materials and/or
products by moisture.13 Using an excess amounts of base and/or prolonging the reaction time decreased
the yields, due to the decomposition of the product 11.
Table 2. Formation of Oxazolidinone Rings.
O
Y
N
O
Y
N
O
t-BuOK
MS4A
X
X
OCO2Ph
N
O
N
H
O
Z
THF, 0°C
10 min
O
Z
10a-g
11a-g
X
Y
Z
yield (%)
run
1
83
Ph
Ph
Ph
Ph
Me
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Ph
Ph
i-Pr
H
(11a)
(11b)
(11c)
(11d)
(11e)
(11f)
86
90
89
95
82
86
2
Me
Ph
i-Pr
i-Pr
Ph
3
4
5
6
(11g)
7

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407
Since the C-N bond of N-acyloxazolidinones is activated by two carbonyl groups, cleavage of the amide
bonds was accomplished readily by addition of a heteronucleophile or via LiBH4 reduction, similar to the
Evans oxazolidinones14-16 (Scheme 4).
Y
N
O
nucleophiles
reduction
X
X
Nu
O
Y
N
O
O
O
Z
Z
14
X
N
O
Y
N
O
Z
11
OH
15
Scheme 4. Transformation from N-Acyloxazolidinones.
Among the possible nucleophiles, thiol groups would be attractive, since the thiol esters could be
converted into the corresponding aldehydes17a or ketones17b,c in the presence of a palladium catalyst. The
Pd-mediated reduction by triethylsilane17a and alkylation, with zinc reagents17b or terminal acetylenes,17c of
the thiol esters were developed by our group.17d The conversion of the N-protected α-amino carbonyl
compounds proceeded readily under neutral conditions. Recently, we also reported that thiol esters,
derived from odorless n-dodecanethiol,18 could be applicable to the Pd-mediated reactions instead of
ethanethiol esters.19 Thus, upon treatment of the N-acyloxazolidinones 11a-g with lithium thiolate
generated from n-BuLi and n-dodecanethiol, the conversion proceeded smoothly to give the
n-dodecanethiol esters 16a-g (Table 3).20
Table 3. Formation of Thiol Esters.
SH
(5.0 eq.)
O
11
Y
N
O
Y
N
O
n-BuLi (2.0 eq.)
X
X
S
N
O
11
THF, 0 °C
10 min
O
16a-g
Z
O
Z
11a-g
run
yield (%)
X
Y
Z
83
(16a)
(16b)
(16c)
(16d)
(16e)
(16f)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Me
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Ph
Ph
i-Pr
H
79
75
66
78
86
68
Me
Ph
i-Pr
i-Pr
Ph
(16g)

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HETEROCYCLES, Vol. 73, 2007
In conclusion, we have developed a highly efficient, versatile synthetic method for α-amino acid
derivatives by means of the Ugi 4CC reaction with a newly developed isonitrile 9. As summarized in
Scheme 6, the choice of the appropriate components, acids (X), amines (Y) and aldehydes (Z) and/or
nucleophiles (R) for the N-acyloxazolidinones and thiol esters would allow us to synthesize a variety of
N-acylamino acid derivatives. Further applications of this methodology to the syntheses of a range of
peptidomimetic derivatives and/or natural products are under investigation in our laboratories.
EXPERIMENTAL
13
General. Nuclear magnetic resonance (1H NMR (400 MHz) and C NMR (100 MHz)) spectra were
determined on a JEOL-LA400 instrument. Chemical shifts for 1H NMR were reported in parts per million
(ppm) downfield from tetramethylsilane (δ) in deuteriochloroform as the internal standard and coupling
constants are in hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, br =
13
broad, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Chemical shifts for C NMR were
reported in ppm relative to the centerline of a triplet at 77.0 ppm for deuteriochloroform (CDCl3). Infrared
spectra (IR) were recorded on a JASCO FT/IR-410 Fourier Transform Infrared Spectrometer and are
reported in wavenumbers (cm–1). Mass spectra (MS) were obtained on a JEOL JMS-GCmate MS-DIP20
with polyethylene glycol as the matrix. Analytical thin layer chromatography (TLC) was performed on
Merck precoated analytical plates, 0.25 mm thick, silica gel 60 F254. Preparative TLC separations were
made on Merck precoated analytical plates, 0.25 mm thick, silica gel 60 F254. Compounds were eluted
from the adsorbent with 10% methanol (MeOH) in chloroform (CHCl3). Flash column chromatography
separations were performed on KANTO CHEMICAL Silica Gel 60 (40-100 mesh). All non-aqueous
reactions were carried out in oven-dried glass apparatuses under a slight positive pressure of argon.
MeOH and tetrahydrofuran (THF) were used after dried over molecular sieves 3A or 4A, when especially
no mention. n-dodecanethiol was distilled under reduced pressure. All other reagents were commercially
available and used without further purification, unless otherwise described.
Preparation of 2-isocyano-2-methylpropyl phenyl carbonate (9).
To a stirred solution of 4,4-dimethyloxazoline (7)11 (1.00 g, 10.1 mmol) in THF (10 mL) under argon
atmosphere at –78 °C, was added dropwise 1.1 M solution of n-BuLi (9.60 mL, 10.6 mmol) in hexane for
5 min and stirred at same temperature for 1 h then phenyl chloroformate was slowly added. After stirred
for 5 min, the reaction mixture was warmed to ambient temperature and diluted with Et2O, and water was
added to the mixture. The organic layer was separated and washed with brine, dried over sodium sulfate
and filtered. The solvent was removed under reduced pressure, the resulting residue was purified by silica
gel chromatography (EtOAc/hexane = 1/9-1/4) to afford 1.10 g of 9 (50%) as an yellow oil. IR (film,
1
cm-1): 735, 775, 835, 879, 970, 1024, 1074, 1258, 1378, 1401, 1457, 1496, 1592, 1767, 2136, 2991; H

HETEROCYCLES, Vol. 73, 2007
409
NMR (CDCl3, 400 MHz): δ 1.53 (s, 6H), 4.21 (s, 2H), 7.19-7.45 (m, 5H); 13C NMR (CDCl3, 100 MHz): δ
25.6, 56.1, 72.9, 120.8, 126.1, 129.4, 150.8, 153.1, 156.1; HRMS (FAB+): calcd for C12H13NO3 219.0895
(M+), found 219.0900.
General procedure for Ugi’s 4CC reaction.
N-(2-Methyl-1-(1-phenoxycarbonyloxy-2-methylpropan-2-ylcarbamoyl)propyl)-N-benzylbenzamide
(10a).
To a stirred solution of isonitrile 9 (223 mg, 1.02 mmol), isobutyraldehyde (0.31 mL, 3.40 mmol), and
benzoic acid (128 mg, 1.05 mmol) in methanol (2.0 mL) was added dropwise benzylamine (74 µL, 0.679
mmol) over 2 min at ambient temperature (exothermic). After being stirred for 60 min, the solvent was
removed under reduced pressure. The resultant crude mixture was purified by silica gel chromatography
(EtOAc/hexane = 1/9-1/2) to afford 10a (310 mg, 91%) as a pale-yellow paste. IR (film, cm-1): 734, 774,
1
918, 963, 1066, 1211, 1263, 1367, 1457, 1496, 1545, 1620, 1680, 1764, 2968, 3063, 3301; H NMR
(CDCl3, 400 MHz): δ 0.91-1.08 (m, 6H), 1.20-1.39 (m, 6H), 2.72-2.88 (m, 1H), 4.26-4.51 (m, 4H),
4.61-4.71 (m, 1H), 7.05-7.60 (m, 15H); 13C NMR (CDCl3, 100 MHz): δ 19.5, 19.8, 23.8, 24.3, 27.2, 52.8,
54.0, 72.1, 76.7, 121.0, 126.0, 126.7, 127.7, 127.8, 128.4, 128.5, 129.5, 129.8, 136.5, 136.6, 151.1, 153.6,
170.2, 174.0; HRMS (FAB+): calcd for C30H34N2O5 502.2468 (M+), found 502.2485.
N-((1-Phenoxycarbonyloxy-2-methylpropan-2-ylcarbamoyl)methyl)-N-benzylbenzamide (10b).
The reaction of benzylamine (64 µL, 0.587 mmol), formalin (37 wt.% in water, 273 mg, 5.73 mmol),
isonitrile 9 (192 mg, 0.877 mmol) and benzoic acid (104 mg, 0.853 mmol) was carried out following the
general procedure (10 min) to provide 10b (238 mg, 88%) as a white foam with a small amount of
inseparable impurities. For analytical purposes, this mixture was purified by PTLC (EtOAc/hexane = 1/4)
to afford pure 10b as a white foam. IR (film, cm-1): 773, 962, 1007, 1067, 1212, 1370, 1453, 1469, 1496,
1
1548, 1623, 1685, 1763, 2977, 3064, 3310; H NMR (CDCl3, 400 MHz): δ 1.20-1.45 (m, 6H), 4.02 (s,
13
2H), 4.38 (s, 2H), 4.62 (s, 2H), 6.54 (s, 1H), 7.15-7.53 (m, 15H); C NMR (CDCl3, 100 MHz): δ 24.0,
29.7, 50.1, 53.2, 54.0, 72.3, 121.0, 126.1, 126.9, 127.2, 127.9, 128.6, 128.9, 129.5, 130.1, 135.1, 135.8,
151.0, 153.6, 168.4, 173.0; HRMS (FAB+): calcd for C27H28N2O5 460.1998 (M+), found 460.1996.
N-(1-(1-Phenoxycarbonyloxy-2-methylpropan-2-ylcarbamoyl)ethyl)-N-benzylbenzamide (10c).
The reaction of benzylamine (0.120 mL, 1.10 mmol), acetaldehyde (277 mg, 6.30 mmol), isonitrile 9 (364
mg, 1.66 mmol) and benzoic acid (168 mg, 1.37 mmol) was carried out following the general procedure
(10 min) to provide 10c (541 mg, quant.) as an orange oil. IR (film, cm-1): 773, 919, 966, 1025, 1068,
1
1210, 1249, 1370, 1414, 1451, 1495, 1547, 1627, 1683, 1764, 2360, 2931, 2978, 3063, 3316; H NMR
(CDCl3, 400 MHz): δ 1.35-1.41 (m, 9H), 4.30-4.35 (m, 2H), 4.55-4.65 (m, 2H), 4.85 (br s, 1H), 7.15-7.48
13
(m, 15H); C NMR (CDCl3, 100 MHz): δ 23.8, 24.1, 29.7, 31.6, 53.0, 72.3, 121.0, 126.1, 126.6, 127.1,

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HETEROCYCLES, Vol. 73, 2007
127.5, 128.6, 128.7, 129.5, 130.0, 136.0, 151.0, 153.6, 170.7, 173.7; HRMS (FAB+): calcd for C28H30N2O5
474.2155 (M+), found 474.2163.
N-((1-Phenoxycarbonyloxy-2-methylpropan-2-ylcarbamoyl)-1-phenylmethyl)-N-benzylbenzamide
(10d).
The reaction of benzylamine (70 µL, 0.642 mmol), benzaldehyde (0.33 mL, 3.27 mmol), isonitrile 9 (212
mg, 0.965 mmol) and benzoic acid (111 mg, 0.909 mmol) was carried out following the general
procedure (60 min) to provide 10d (304 mg, 88%) as a white foam. IR (film, cm-1): 734, 915, 1024, 1067,
1212, 1257, 1370, 1395, 1456, 1496, 1624, 1684, 1763, 2978, 3063, 3313; 1H NMR (CDCl3, 400 MHz): δ
13
1.30-1.45 (m, 6H), 4.34-4.45 (m, 2H), 4.70 (s, 1H), 4.72 (s, 1H), 5.49 (s, 1H), 7.05-7.60 (m, 20H); C
NMR (CDCl3, 100 MHz): δ 23.9, 53.5, 72.3, 76.7, 121.0, 126.0, 126.7, 127.1, 128.3, 128.4, 128.6, 128.8,
129.5, 129.5, 129.8, 130.1, 134.8, 136.1, 151.1, 153.5, 169.0, 173.3; HRMS (FAB+): calcd for C33H32N2O5
536.2311 (M+), found 536.2321.
N-(2-Methyl-1-(1-phenoxycarbonyloxy-2-methylpropan-2-ylcarbamoyl)propyl)-N-benzylacetamide
(10e).
The reaction of benzylamine (60 µL, 0.550 mmol), isobutyraldehyde (0.25 mL, 2.74 mmol), isonitrile 9
(181 mg, 0.826 mmol) and acetic acid (47 µL, 0.821 mmol) was carried out following the general
procedure (10 min) to provide 10e (253 mg, 98%) as a pale-yellow foam. IR (film, cm-1): 728, 777, 966,
1
1024, 1063, 1211, 1263, 1369, 1395, 1418, 1457, 1496, 1540, 1629, 1679, 1763, 2966, 3299; H NMR
(CDCl3, 400 MHz): δ 0.84 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 2.06 (s,
3H), 2.38-2.47 (m, 1H), 4.25 (d, J = 10 Hz, 1H), 4.31 (d, J = 10 Hz, 1H), 4.45 (d, J = 11 Hz, 1H), 4.53 (d,
J = 17 Hz, 1H), 4.74 (d, J = 17 Hz, 1H), 6.66 (s, 1H), 7.15-7.40 (m, 10H); 13C NMR (CDCl3, 100 MHz): δ
19.1, 19.6, 22.7, 23.8, 24.3, 27.2, 50.2, 53.1, 71.8, 121.0, 126.0, 126.4, 127.3, 128.3, 128.6, 129.5, 137.3,
151.1, 153.5, 170.0, 173.3; HRMS (FAB+): calcd for C25H32N2O5 440.2311 (M+), found 440.2315.
N-(2-Methyl-1-(1-phenoxycarbonyloxy-2-methylpropan-2-ylcarbamoyl)propyl)-N-phenylbenzamide
(10f).
The reaction of aniline (52 µL, 0.570 mmol), isobutyraldehyde (0.26 mL, 2.85 mmol), isonitrile 9 (187
mg, 0.853 mmol) and benzoic acid (114 mg, 0.934 mmol) was carried out following the general
procedure (10 min) to provide 10f (277 mg, 99%) as a pale-yellow oil. IR (film, cm-1): 773, 918, 965,
1
1024, 1064, 1212, 1247, 1371, 1457, 1493, 1540, 1577, 1631, 1684, 1764, 2970, 3064, 3324; H NMR
(CDCl3, 400 MHz): δ 1.06 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H), 1.43 (s, 6H), 2.58-2.71 (m, 1H),
13
4.31-4.36 (m, 1H), 4.45-4.51 (m, 2H), 7.06-7.37 (m, 15H); C NMR (CDCl3, 100 MHz): δ 19.8, 20.1,
24.2, 24.4, 26.9, 52.9, 71.9, 76.7, 121.0, 126.0, 127.2, 127.8, 128.4, 128.6, 128.9, 129.4, 129.6, 130.0,
136.3, 151.1, 153.6, 170.3, 172.6; HRMS (FAB+): calcd for C29H32N2O5 488.2311 (M+), found 488.2321.

HETEROCYCLES, Vol. 73, 2007
411
N-((1-Phenoxycarbonyloxy-2-methylpropan-2-ylcarbamoyl)-1-phenylmethyl)-N-phenylbenzamide
(10g).
The reaction of aniline (54 µL, 0.592 mmol), benzaldehyde (0.30 mL, 2.97 mmol), isonitrile 9 (193 mg,
0.880 mmol) and benzoic acid (113 mg, 0.925 mmol) was carried out following the general procedure
(70 °C, 1 h) to provide 10g (276 mg, 89%) as a pale-yellow foam. IR (film, cm-1): 778, 915, 965, 1030,
1066, 1211, 1244, 1371, 1456, 1493, 1595, 1639, 1689, 1762, 2360, 2977, 3063, 3330; 1H NMR (CDCl3,
13
400 MHz): δ 1.43 (s, 3H), 1.46 (s, 3H), 4.47 (s, 2H), 6.14 (s, 1H), 6.17 (s, 1H), 7.00-7.36 (m, 20H); C
NMR (CDCl3, 100 MHz): δ 24.1, 53.5, 67.3, 67.4, 72.2, 120.9, 121.0, 121.1, 127.0, 127.1, 127.5, 127.6,
128.4, 129.4, 130.0, 134.6, 135.9, 141.3, 151.1, 153.5, 169.3, 171.2; HRMS (FAB+): calcd for C32H30N2O5
522.2155 (M+), found 522.2158.
General procedure for the synthesis of N-acyloxazolidinones 11a-g.
N-(1-(4,4-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl-2-methylpropyl)-N-benzylbenzamide (11a).
To a stirred solution of 10a (220 mg, 0.439 mmol) in anhydrous THF (2.0 mL) at 0 °C was added freshly
activated molecular sieves 4A (powder, 280 mg), and stirred for 10 min so as to trap any moisture, then
added 1.0 M of KOt-Bu in t-BuOH (0.450 mL, 0.450 mmol) dropwise over 2 min. After being stirred for
10 min, 10% w/v aqueous citric acid was added and the mixture was extracted with EtOAc. The combine
organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was
removed under reduced pressure, the resultant crude mixture was purified by silica gel chromatography
(EtOAc/hexane = 1/9-1/2) to afford 11a (149 mg, 83%) as a pale yellow foam. IR (film, cm-1): 734, 761,
1031, 1089, 1173, 1231, 1305, 1374, 1496, 1646, 1701, 1779, 2360, 2968; 1H NMR (CDCl3, 400 MHz): δ
0.90 (s, 3H), 0.97 (s, 3H), 1.33 (s, 3H), 1.49 (s, 3H), 2.38-2.52 (m, 1H), 3.89-4.00 (m, 2H), 4.74-5.03 (m,
13
2H), 5.63 (br s, 1H), 7.19-7.36 (m, 10H); C NMR (CDCl3, 100 MHz): δ 18.6, 19.4, 23.8, 24.3, 29.5,
61.0, 75.1, 126.3, 126.8, 127.4, 128.2, 128.3, 128.6, 129.6, 136.7, 138.7, 152.9, 172.3, 173.9, 175.8;
HRMS (FAB+): calcd for C24H28N2O4 408.2049 (M+), found 408.2033.
N-((4,4-Dimethyl-2-oxo-3-oxazolidinyl)carbonylmethyl)-N-benzylbenzamide (11b).
The reaction of Ugi product 10b (200 mg, 0.434 mmol), 1.0 M of KOt-Bu/t-BuOH (0.460 mL, 0.460
mmol) and freshly activated molecular sieves 4A (powder, 230 mg) in anhydrous THF (2.0 mL) was
carried out following the general procedure (10 min) to provide 11b (137 mg, 86%) as a pale-yellow oil.
IR (film, cm-1): 1008, 1034, 1095, 1181, 1244, 1310, 1382, 1429, 1641, 1656, 1711, 1777, 2360, 2974; 1H
NMR (CDCl3, 400 MHz, a mixture of amide rotamers): δ 1.51 (s, 6H of a rotamer), 1.54 (s, 6H of a
rotamer), 3.97 (s, 2H of a rotamer), 4.07 (s, 2H of a rotamer), 4.41 (s, 2H of a rotamer), 4.61 (s, 2H of a
13
rotamer), 4.64 (s, 2H of a rotamer), 4.81 (s, 2H of a rotamer), 4.61 (m, 10H); C NMR (CDCl3, 100
MHz): δ 24.7, 24.7, 50.0, 54.2, 60.6, 76.0, 126.3, 126.9, 127.8, 128.3, 128.5, 128.8, 129.0, 129.9, 135.4,
136.2, 153.9, 169.0, 169.7, 172.7; HRMS (FAB+): calcd for C21H22N2O4 366.1580 (M+), found 366.1562.

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N-(1-(4,4-Dimethyl-2-oxo-3-oxazolidinyl)carbonylethyl)-N-benzylbenzamide (11c).
The reaction of Ugi product 10c (57 mg, 0.12 mmol), 1.0 M of KOt-Bu/t-BuOH (0.120 mL, 0.120 mmol)
and freshly activated molecular sieves 4A (powder, 55 mg) in anhydrous THF (0.30 mL) was carried out
following the general procedure (10 min) to provide 11c (41 mg, 90%) as a pale-yellow foam. IR (film,
cm-1): 733, 765, 918, 974, 1039, 1096, 1179, 1240, 1311, 1394, 1639, 1708, 1775, 2358, 2973; 1H NMR
(CDCl3, 400 MHz): δ 1.25-1.37 (m, 6H), 1.57 (s, 3H), 4.02 (s, 2H), 4.67-4.82 (m, 2H), 5.33 (br s, 1H),
13
7.23-7.45 (m, 10H); C NMR (CDCl3, 100 MHz): δ 14.6, 23.8, 24.9, 52.8, 56.4, 61.1, 75.7, 76.7, 126.6,
126.9, 127.4, 128.5, 128.7, 129.7, 136.2, 138.3, 153.9, 172.6, 173.5; HRMS (FAB+): calcd for C22H24N2O4
380.1736 (M+), found 380.1741.
N-((4,4-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl-1-phenylmethyl)-N-benzylbenzamide (11d).
The reaction of Ugi product 10d (270 mg, 0.503 mmol), 1.0 M of KOt-Bu/t-BuOH (0.520 mL, 0.520
mmol) and freshly activated molecular sieves 4A (powder, 290 mg) in anhydrous THF (2.5 mL) was
carried out following the general procedure (10 min) to provide 11d (198 mg, 89%) as a colorless oil. IR
(film, cm-1): 731, 913, 980, 1035, 1093, 1177, 1235, 1307, 1379, 1396, 1455, 1496, 1636, 1706, 1777,
2928; 1H NMR (CDCl3, 400 MHz): δ 1.52 (s, 3H), 1.65 (s, 3H), 3.86 (s, 1H), 3.98 (s, 1H), 4.31 (d, J = 17
13
Hz, 1H), 4.73 (d, J = 16 Hz, 1H), 6.70-7.46 (m, 16H); C NMR (CDCl3, 100 MHz): δ 23.7, 24.7, 29.7,
48.2, 51.8, 60.7, 60.8, 62.8, 65.7, 75.2, 126.4, 126.6, 126.8, 127.9, 128.1, 128.3, 128.4, 128.7, 129.7,
131.2, 131.9, 136.2, 137.8, 153.1, 171.0, 173.6; HRMS (FAB+): calcd for C27H26N2O4 442.1893 (M+),
found 442.1887.
N-(1-(4,4-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl-2-methylpropyl)-N-benzylacetamide (11e).
The reaction of Ugi product 10e (183 mg, 0.391 mmol), 1.0 M of KOt-Bu/t-BuOH (0.40 mL, 0.40 mmol)
and freshly activated molecular sieves 4A (powder, 210 mg) in anhydrous THF (1.5 mL) was carried out
following the general procedure (10 min) to provide 11e (129 mg, 95%) as a pale-yellow oil. IR (film,
1
cm-1): 735, 764, 1032, 1092, 1179, 1228, 1310, 1371, 1506, 1654, 1700, 1776, 2966; H NMR (CDCl3,
400 MHz): δ 0.90-1.00 (m, 6H), 1.42 (s, 6H), 2.52 (s, 3H), 2.53-2.61 (m, 1H), 3.74 (d, J = 8.3 Hz, 1H),
3.89 (d, J = 8.3 Hz, 1H), 4.27 (d, J = 16 Hz, 1H), 5.05 (d, J = 16 Hz, 1H), 5.44 (d, J = 10 Hz, 1H),
13
7.11-7.36 (m, 5H); C NMR (CDCl3, 100 MHz): δ 18.6, 19.4, 22.0, 22.9, 24.4, 28.8, 45.3, 61.1, 64.4,
74.9, 125.8, 126.6, 127.0, 128.2, 128.6, 138.4, 153.6, 170.2, 173.2; HRMS (FAB+): calcd for C19H26N2O4
346.1893 (M+), found 346.1896.
N-(1-(4,4-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl-2-methylpropyl)-N-phenylbenzamide (11f).
The reaction of Ugi product 10f (740 mg, 1.51 mmol), 1.0 M of KOt-Bu/t-BuOH (1.60 mL, 1.60 mmol)
and freshly activated molecular sieves 4A (powder, 890 mg) in anhydrous THF (7.2 mL) was carried out
following the general procedure (10 min) to provide 11f (487 mg, 82%) as a pale-yellow solid. IR (film,
cm-1): 729, 764, 917, 1037, 1089, 1129, 1178, 1230, 1310, 1370, 1472, 1492, 1559, 1595, 1653, 1701,

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413
1779, 2968; 1H NMR (CDCl3, 400 MHz): δ 1.07 (d, J = 6.6 Hz, 6H), 1.31 (s, 3H), 1.56 (s, 3H), 2.32-2.41
(m, 1H), 3.91 (d, J = 8.3 Hz, 1H), 3.97 (d, J = 8.3 Hz, 1H), 6.19 (d, J = 9.8 Hz, 1H), 7.08-7.36 (m, 10H);
13C NMR (CDCl3, 100 MHz): δ 19.3, 19.9, 23.9, 24.9, 29.2, 60.9, 64.6, 75.1, 127.2, 127.6, 127.8, 128.2,
128.3, 128.4, 128.5, 128.8, 129.2, 129.7, 136.5, 140.5, 153.5, 171.1, 172.2; HRMS (FAB+): calcd for
C23H26N2O4 394.1893 (M+), found 394.1894.
N-((4,4-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl-1-phenylmethyl)-N-phenylbenzamide (11g).
The reaction of Ugi product 10g (840 mg, 1.61 mmol), 1.0 M of KOt-Bu/t-BuOH (1.65 mL, 1.65 mmol)
and freshly activated molecular sieves 4A (powder, 800 mg) in anhydrous THF (8.0 mL) was carried out
following the general procedure (10 min) to provide 11g (593 mg, 86%) as a pale-yellow amorphous. IR
(film, cm-1): 718, 764, 913, 1037, 1093, 1179, 1234, 1311, 1380, 1456, 1493, 1577, 1595, 1646, 1708,
1776, 3063; 1H NMR (CDCl3, 400 MHz): δ 1.54 (d, J = 4.4 Hz, 3H), 1.72 (d, J = 4.9 Hz, 3H), 3.91 (d, J =
13
8.5 Hz, 1H), 4.04 (d, J = 8.3 Hz, 1H), 6.92-7.36 (m, 16H); C NMR (CDCl3, 100 MHz): δ 24.7, 24.9,
60.8, 65.1, 75.3, 115.4, 126.9, 127.5, 127.9, 128.2, 128.3, 128.4, 128.6, 129.4, 131.2, 131.3, 132.6, 136.9,
140.3, 153.1, 171.1, 171.3; HRMS (FAB+): calcd for C26H24N2O4 428.1736 (M+), found 428.1733.
General procedure for the synthesis of thiol esters 16a-g.
S-1-Dodecyl 2-(N-benzylbenzamido)-3-methylbutanethioate (16a).
To a solution of n-dodecanethiol (0.26 mL, 1.1 mmol) in THF (2.5 mL) at 0 °C was added dropwise
n-BuLi (1.0 M solution in hexane, 0.40 mL, 0.40 mmol) for 2 min. After being stirred for 5 min, the
resulting white suspension was added to a solution of N-acyloxazolidinone 11a (93 mg, 0.23 mmol) in
THF (4.0 mL) at 0 °C. After stirring for 10 min, 10% w/v aqueous citric acid was added and the mixture
was extracted with EtOAc. The combined organic layer was washed with brine, dried over magnesium
sulfate and filtered. The solvent was removed under reduced pressure, the resultant crude mixture was
purified by silica gel chromatography (EtOAc/hexane = 1/19-1/9) to afford 16a (94 mg, 83%) as a
1
pale-yellow oil. IR (film, cm-1): 731, 1129, 1300, 1457, 1653, 1684, 2854, 2925; H NMR (CDCl3, 400
MHz): δ 0.77 (s, 3H), 0.80 (s, 3H), 0.88 (t, J = 6.8 Hz, 3H), 1.26-1.30 (m, 18H), 1.37-1.52 (m, 2H),
2.35-2.50 (m, 1H), 2.77 (t, J = 7.3 Hz, 2H), 4.65 (d, J = 15 Hz, 1H), 4.88 (d, J = 14 Hz, 1H), 5.05 (br s,
13
1H), 6.98-7.58 (m, 10H); C NMR (CDCl3, 100 MHz): δ 14.1, 19.1, 19.5, 22.7, 28.9, 29.0, 29.1, 29.4,
29.5, 29.6, 31.9, 45.8, 62.7, 73.5, 126.8, 127.5, 127.8, 128.1, 128.3, 128.5, 129.7, 136.2, 138.1, 173.5,
196.8; HRMS (FAB+): calcd for C31H45NO2S495.3171 (M+), found 495.3169.
S-1-Dodecyl 2-(N-benzylbenzamido)ethanethioate (16b).
The reaction of N-acyloxazolidinone 11b (108 mg, 0.296 mmol), n-BuLi (1.0 M solution in hexane, 0.45
mL, 0.45 mmol) and n-dodecanethiol (0.36 mL, 1.50 mmol) in THF (net 4.0 mL) was carried out
following the general procedure (10 min) to provide 16b (105 mg, 79%) as a pale yellow oil. IR (film,
1
cm-1): 1003, 1249, 1423, 1456, 1496, 1652, 1695, 2853, 2925; H NMR (CDCl3, 400 MHz, a mixture of

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HETEROCYCLES, Vol. 73, 2007
amide rotamers): δ 0.88 (t, J = 6.9 Hz, 3H), 1.23-1.38 (m, 18H), 1.58-1.60 (m, 2H), 2.90-3.00 (m, 2H),
4.01 (s, 2H of a rotamer), 4.33 (s, 2H of a rotamer), 4.63 (s, 2H of a rotamer), 4.83 (s, 2H of a rotamer),
13
7.13-7.54 (m, 10H); C NMR (CDCl3, 100 MHz): δ 14.1, 22.7, 28.7, 28.9, 29.1, 29.3, 29.5, 29.6, 31.9,
49.2, 54.0, 57.5, 126.9, 129.0, 128.6, 128.3, 128.0, 127.1, 130.0, 135.2, 135.9, 172.4, 196.4; HRMS
(FAB+): calcd for C28H39NO2S453.2701 (M+), found 453.2722.
S-1-Dodecyl 2-(N-benzylbenzamido)propanethioate (16c).
The reaction of N-acyloxazolidinone 11c (130 mg, 0.342 mmol), n-BuLi (1.0 M solution in hexane, 0.35
mL, 0.35 mmol) and n-dodecanethiol (0.41 mL, 1.71 mmol) in THF (net 4.0 mL) was carried out
following the general procedure (10 min) to provide 16c (120 mg, 75%) as a white solid. IR (film, cm-1):
1
955, 1316, 1402, 1452, 1462, 1651, 1656, 1680, 1691, 1726, 2314, 2854, 2925; H NMR (CDCl3, 400
MHz): δ 0.86-0.90 (m, 3H), 1.26-1.36 (m, 21H), 1.50-1.64 (m, 2H), 2.83-2.96 (m, 2H), 4.62 (d, J = 6.8
Hz, 1H), 4.66 (d, J = 7.0 Hz, 1H), 5.27-5.42 (m, 1H), 7.25-7.50 (m, 10H); 13C NMR (CDCl3, 100 MHz): δ
14.1, 22.7, 28.9, 29.1, 29.4, 29.5, 29.6, 29.7, 31.9, 46.9, 126.6, 126.8, 127.1, 127.5, 128.6, 129.8, 136.0,
137.3, 170.9, 199.5; HRMS (FAB+): calcd for C29H41NO2S467.2858 (M+), found 467.2871.
S-1-Dodecyl 2-(N-benzylbenzamido)-2-phenylethanethioate (16d).
The reaction of N-acyloxazolidinone 11d (48 mg, 0.109 mmol), n-BuLi (1.37 M solution in hexane, 0.16
mL, 0.22 mmol) and n-dodecanethiol (0.14 mL, 0.58 mmol) in THF (net 2.5 mL) was carried out
following the general procedure (10 min) to provide 16d (38 mg, 66%) as a pale-yellow oil. IR (film,
1
cm-1): 723, 1001, 1395, 1454, 1496, 1647, 1685, 2854, 2925; H NMR (CDCl3, 400 MHz): δ 0.88 (t, J =
6.8 Hz, 3H), 1.25-1.31 (m, 18H), 1.53-1.62 (m, 2H), 2.93 (t, J = 5.3 Hz, 2H), 4.33 (s, 1H), 4.37 (s, 1H),
13
5.74 (s, 1H), 6.83-6.92 (m, 2H), 7.11-7.12 (m, 3H), 7.25-7.49 (m, 8H), 7.49-7.52 (m, 2H); C NMR
(CDCl3, 100 MHz): δ 14.1, 22.7, 28.9, 29.1, 29.3, 29.4, 29.5, 29.6, 31.9, 52.2, 69.6, 126.8, 128.2, 128.5,
128.6, 128.9, 129.9, 130.2, 130.5, 130.6, 133.8, 135.9, 137.2, 173.0, 197.3; HRMS (FAB+): calcd for
C34H43NO2S529.3014 (M+), found 529.3004.
S-1-Dodecyl 2-(N-benzylacetamido)-3-methylbutanethioate (16e).
The reaction of N-acyloxazolidinone 11e (59 mg, 0.17 mmol), n-BuLi (1.37 M solution in hexane, 0.25
mL, 0.34 mmol) and n-dodecanethiol (0.21 mL, 0.88 mmol) in THF (net 3.0 mL) was carried out
following the general procedure (10 min) to provide 16e (61 mg, 78%) as a pale yellow oil. IR (film,
1
cm-1): 728, 802, 1144, 1255, 1405, 1457, 1662, 1684, 2854, 2925; H NMR (CDCl3, 400 MHz): δ
0.77-0.97 (m, 9H), 1.25-1.27 (m, 18H), 1.41-1.47 (m, 2H), 2.02 (s, 3H), 2.32-2.33 (m, 1H), 2.69-2.76 (m,
2H), 4.50-4.73 (m, 2H), 5.23 (d, J = 11 Hz, 1H), 7.15-7.30 (m, 5H); 13C NMR (CDCl3, 100 MHz): δ 14.1,
18.8, 19.4, 22.3, 22.7, 27.6, 28.9, 29.0, 29.1, 29.4, 29.5, 29.6, 31.9, 48.2, 67.1, 73.6, 125.8, 126.4, 126.7,
127.1, 128.0, 128.6, 137.4, 138.0, 171.5, 172.4, 196.3, 197.5; HRMS (FAB+): calcd for C26H43NO2S
433.3014 (M+), found 433.2997.

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415
S-1-Dodecyl 2-(N-phenylbenzamido)-3-methylbutanethioate (16f).
The reaction of N-acyloxazolidinone 11f (46 mg, 0.12 mmol), n-BuLi (1.0 M solution in hexane, 0.35 mL,
0.35 mmol) and n-dodecanethiol (0.42 mL, 1.8 mmol) in THF (net 3.0 mL) was carried out following the
general procedure (10 min) to provide 16f (48 mg, 86%) as a pale-yellow oil. IR (film, cm-1): 735, 764,
1032, 1092, 1179, 1228, 1310, 1371, 1506, 1654, 1700, 1776, 2966; 1H NMR (CDCl3, 400 MHz): δ 0.88
(t, J = 6.9 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.24-1.33 (m, 18H), 1.51-1.58 (m,
2H), 2.52-2.58 (m, 1H), 2.88 (d, J = 7.4 Hz, 2H), 5.07 (d, J = 10.0 Hz, 1H), 7.09-7.31 (m, 10H); 13C NMR
(CDCl3, 100 MHz): δ 14.1, 19.8, 20.7, 22.7, 28.3, 28.9, 29.0, 29.1, 29.3, 29.4, 29.5, 29.6, 31.9, 72.8,
127.1, 127.7, 128.6, 128.7, 129.7, 136.0, 141.7, 170.9, 197.3; HRMS (FAB+): calcd for C30H43NO2S
481.3014 (M+), found 481.3034.
S-1-Dodecyl 2-(N-phenylbenzamido)-2-phenylethanethioate (16g).
The reaction of N-acyloxazolidinone 11g (50 mg, 0.12 mmol), n-BuLi (1.37 M solution in hexane, 0.15
mL, 0.21 mmol) and n-dodecanethiol (0.12 mL, 0.50 mmol) in THF (net 5.0 mL) was carried out
following the general procedure (10 min) to provide 16g (41 mg, 68%) as a pale-yellow oil. IR (film,
1
cm-1): 976, 1339, 1455, 1492, 1596, 1652, 1695, 2853, 2925; H NMR (CDCl3, 400 MHz): δ 0.88 (t, J =
7.0 Hz, 3H), 1.25-1.33 (m, 18H), 1.59-1.63 (m, 2H), 2.99 (t, J = 7.3 Hz, 2H), 6.43 (s, 1H), 6.92-7.36 (m,
13
15H); C NMR (CDCl3, 100 MHz): δ 14.1, 22.7, 28.9, 29.1, 29.4, 29.5, 29.6, 29.7, 31.9, 71.7, 115.4,
127.2, 127.6, 128.3, 128.4, 128.6, 129.6, 130.5, 130.9, 133.7, 135.7, 140.8, 170.9, 197.6; HRMS (FAB+):
calcd for C33H41NO2S515.2858 (M+), found 515.2853.
ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for Scientific Research on Priority Areas 16073205 from The
Ministry of Education, Culture, Sports, Science and Technology (MEXT).
REFERENCES AND NOTES
1. For reviews of multicomponent reactions with isonitriles, see: (a) C. Hulme and V. Gore, Curr. Med.
Chem., 2003, 10, 51. (b) A. Dömling and I. Ugi, Angew. Chem. Int. Ed., 2000, 39, 3168. (c) G.
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1971, pp. 145-199. (d) 'Multicomponent Reactions,' ed. by J. Zhu and H. Bienaymé, Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim, 2005.
2. (a) I. Ugi, R. Myer, U. Fetzer, and C. Steinbrückner, Angew. Chem., 1959, 71, 386. (b) I. Ugi and C.
Steinbrückner, Angew. Chem., 1960, 72, 267.
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124, 6552. (b) K. Mori, K. Rikimaru, T. Kan, and T. Fukuyama, Org. Lett., 2004, 6, 3095. (c) K.

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Rikimaru, K. Mori, T. Kan, and T. Fukuyama, Chem. Comm., 2005, 394.
4. (a) For a recent example of the stereoselective Ugi 4CC reaction using a chiral amine component,
see: G. F. Ross, E. Herdtweck, and I. Ugi, Tetrahedron, 2002, 58, 6127; Recently, the first example
of catalytic asymmetric α-addition of isonitrile to an aldehyde was reported, see: S. E. Denmark and
Y. Fan, J. Am. Chem. Soc., 2003, 125, 7825. (b) For a review of asymmetric isocyanide-based
multicomponent reactions, see pp. 1-32 in ref. 1(d).
5. (a) T. A. Keating and R. W. Armstrong, J. Am. Chem. Soc., 1996, 118, 2574. (b) A. M. Strocker, T.
A. Keating, P. A. Tempest, and R. W. Armstrong, Tetrahedron Lett., 1996, 37, 1149.
6. (a) T. Lindhorst, H. Bock, and I. Ugi, Tetrahedron, 1999, 55, 7411. (b) During the course of this
investigation, the resin-bound Ugi-type carbonate convertible isonitrile was reported, in which
N-acyloxazolidinones were obtained as intermediates: A. L. Kennedy, A. M. Fryer, and J. A. Josey,
Org. Lett., 2002, 4, 1167.
7. For the first report of isonitrile 9: K. Rikimaru, A. Yanagisawa, T. Kan, and T. Fukuyama, Synlett,
2004, 41, and the application of the lacking dimethyl analogue of 9 to the synthetic studies on
(-)-lemonomycin, see ref. 3(c).
8. For other examples of convertible isonitriles: J. Geller and I. Ugi, Chem. Scr., 1983, 22, 85; A. M. M.
Mjalli, S. Sarshar, and T. J. Baiga, Tetrahedron Lett., 1996, 37, 2943; R. J. Linderman, S. Binet, and
S. R. Petrich, J. Org. Chem., 1999, 64, 336; M. C. Pirrung and S. Ghorai, J. Am. Chem. Soc., 2006,
128, 11772; See also pp. 33-75 in ref. 1(d).
9. For the use of N-tert-butoxycarbonylation to activate amides, see: D. L. Flynn, R. E. Zelle, and P. A.
Grieco, J. Org. Chem., 1983, 48, 2424; and its application to the Ugi 4CC reaction, see: C. Hulme, L.
Ma, M.-P. Cherrier, J. J. Romano, G. Morton, C. Duquenne, J. Salvino, and R. Labaudiniere
Tetrahedron Lett., 2000, 41, 1883.
10. For the use of N-nitrosation to activate amides, see: (a) E. H. White, J. Am. Chem. Soc., 1955, 77,
6011. (b) D. A. Evans, P. H. Carter, C. J. Dinsmore, J. C. Barrow, J. L. Katz, and D. W. Kung,
Tetrahedron Lett., 1997, 38, 4535. (c) R. Berenguer, J. Garcia, and J. Vilarrasa, Synthesis, 1989, 305.
And its applications to the Ugi 4CC reaction, see: (d) H. P. Isenring and W. Hofheinz, Synthesis,
1981, 385. (e) Also, see: H. P. Isenring and W. Hofheinz, Tetrahedron, 1983, 39, 2591.
11. A. I. Meyers and E. W. Collington, J. Am. Chem. Soc., 1970, 92, 6676.
12. (a) Rate acceleration of Ugi 4CC reaction in water was reported: M. C. Pirrung and K. D. Sarma, J.
Am. Chem. Soc., 2004, 126, 444. (b) Use of paraformaldehyde instead of formalin failed to give
complex mixture.
13. In the absence of MS4A, the reaction resulted in low yields, accompanied by the N-acylamino
alcohols 12 and/or carboxylic acid 13.

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417
Y
N
O
Y
N
O
X
OH
X
N
H
OH
O
Z
O
Z
13
12
14. D. A. Evans, J. Bartroli, and T. L. Shih, J. Am. Chem. Soc., 1981, 103, 2127.
15. For recent examples, see: A. Orita, Y. Nagano, J. Hirano, and J. Otera, Synlett, 2001, 637, and the
detailed references were cited therein.
16. For the C-N bond cleavage of N-acyl-4,4-dimethyl-2-oxazolidinones, see: MeOMgBr, (a) M. V.
Chevliakov and J. Montgomery, J. Am. Chem. Soc., 1999, 121, 11139. Me(OMe)2, (b) S. Kanemasa
and T. Kanai, J. Am. Chem. Soc., 2000, 122, 10710. Sm(OTf)3/MeOH, (c) M. P. Sibi, U. Gorikunti
and M. Liu, Tetrahedron, 2002, 58, 8357. NaOH/t-BuOH, (d) Y. Ito and S. Terashima, Tetrahedron,
1991, 47, 2821.
17. (a) H. Tokuyama, S. Yokoshima, S.-C. Lin, L. Li, and T. Fukuyama, Synthesis, 2002, 1121. (b) H.
Tokuyama, S. Yokoshima, T. Yamashita, and T. Fukuyama, Tetrahedron Lett., 1998, 39, 3189. (c) H.
Tokuyama, T. Miyazaki, S. Yokoshima, and T. Fukuyama, Synlett, 2003, 1512. (d) For a recent
review, see: H. Tokuyama and T. Fukuyama, Aldrichimica Acta, 2004, 37, 87.
18. (a) K. Nishide, S. Ohsugi, H. Shiraki, H. Tamakita, and M. Node, Org. Lett., 2001, 3, 3121. (b) M.
Node, K. Kumar, K. Nishide, S. Ohsugi, and T. Miyamoto, Tetrahedron Lett., 2001, 42, 9207.
19. T. Miyazaki, Y. Han-ya, H. Tokuyama, and T. Fukuyama, Synlett, 2004, 477.
20. In order to avoid the thiolate addition to the carbonyl group on the oxazolidinone ring, the reaction
should be carried out at lower than 0 °C. Reactions at higher temperature often provided the
undesired N-acylamino alcohols 12. This tendency was notably observed in compounds possessing a
bulky substituent at the Z-position.