Scope and limitations of a modified hantzsch reaction for the synthesis of oxazole-dehydroamino acid derivatives from dehydroamino acid amides

Article abstract of DOI:10.3987/COM-11-12372

A variety of oxazole derivatives that possess an α,β-unsaturated substituent at the 2-position were conveniently synthesized in good yields via a Hantzsch-type reaction between dehydroamino acid amides and β-bromopyruvate derivatives. Furthermore, oxazole

Full text of DOI:10.3987/COM-11-12372

HETEROCYCLES, Vol. 85, No. 2, 2012
313
HETEROCYCLES, Vol. 85, No. 2, 2012, pp. 313 - 331. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 10th October, 2011, Accepted, 26th December, 2011, Published online, 10th January, 2012
DOI: 10.3987/COM-11-12372
SCOPE AND LIMITATIONS OF A MODIFIED HANTZSCH REACTION
FOR THE SYNTHESIS OF OXAZOLE-DEHYDROAMINO ACID
DERIVATIVES FROM DEHYDROAMINO ACID AMIDES
Akihiro Nagaya, Yoji Yamagishi, Yasuchika Yonezawa, Shoji Akai,*
Chung-gi Shin, and Ken-ichi Sato*
Laboratory of Material and Life Chemistry, Faculty of Engineering, Kanagawa
University, 3-27-1, Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
E-mail: akais001@kanagawa-u.ac.jp, satouk01@kanagawa-u.ac.jp
Abstract – A variety of oxazole derivatives that possess an ,-unsaturated
substituent at the 2-position were conveniently synthesized in good yields via a
Hantzsch-type reaction between dehydroamino acid amides and -bromopyruvate
derivatives. Furthermore, oxazoles with substituents at the 2- and 5-positions were
also obtained in good yields using the corresponding -substituted
-bromopyruvate derivatives. A revised reaction mechanism to explain the
enhanced reactivity of dehydroamino acid amides for the Hantzsch-oxazole-type
reaction is presented.
INTRODUCTION
The synthesis of oxazole–containing bioactive natural products1 has been an important subject over the
last two decades. Among the various synthetic routes for the oxazole ring system that have been
reported,2-4 a popular strategy involves the heterocyclization of a serine or threonine side chain onto a
dehydroamino acid amide carbonyl group to give an oxazoline that is subsequently oxidized to the
oxazole (Scheme 1). Alternatively, thiazole building blocks of natural products can be conveniently
synthesized via a modified Hantzsch reaction of thioamides that are derived from - amino acids with
-halopyruvate (Scheme 2).5
R2
R2
R1
R1 R2
R1
[a] Ph3P,
R3
O
O
H
N
DEAD/THF
R3
MnO2/benzene
CO2Me
OH
BocHN
BocHN
BocHN
or
N
N
O
[b] K3PO4, Tf2O,
Ph2SO/CH2Cl2
CO2Me
CO2Me
R3
Scheme 1. Synthesis of oxazole fragments of the berninamycins, A102554a,b

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HETEROCYCLES, Vol. 85, No. 2, 2012
R1
R1
R1
BrCH2COCO2Et,
TFAA, 2,6-lutidine
/DME, -15 oC
KHCO3/DME, -15 oC
NH2
N
N
RHN
CO2Et
OH
CO2Et
RHN
RHN
S
S
X
X = O
X = S
R1 = Me, i-Pr, i-Bu, Bn
R = protecting groups
Lawesson's reagent/DME
Scheme 2. The modified Hantzsch thiazole synthesis5e-g
However, the application of such conditions on the corresponding acid amides derived from saturated
-amino acids only gave the desired oxazole derivatives in moderate yields.4a,b The differences in the
reactivities are presumably due to the nucleophilic properties of oxygen and sulfur. Therefore, we decided
to develop a general synthetic methodology for preparing oxazole building blocks via Hantzsch-type
reactions of acid amide derivatives that possess conjugated carbonyl oxygens with enhanced
nucleophilicity. In 1996, Panek and co-workers reported on the efficient reaction of cinnamic acid amide
with ethyl -bromopyruvate to give the corresponding oxazole derivative,6a which was further converted
to the tris-oxazole derivative in high yield.6b A similar type of oxazole synthesis based on the Hantzsch
thiazole synthesis was reported by Bagley7 and Hoffman.8 Unfortunately, the enhanced reactivities and
limitations of this special case of the Hantzsch protocol were not discussed. Herein, we describe the scope
and limitations of the Hantzsch-oxazole protocol for synthesizing 2,4- and 2,4,5-substituted oxazole
derivatives (having a dehydroamino substituent at the 2-position) from dehydroamino acid amide
derivatives obtained from N-protected dehydroamino acids9 and methyl or ethyl -bromopyruvate
derivatives (with or without a -substituent).
RESULTS AND DISCUSSION
We initially examined the reaction conditions for the Hantzsch-type reaction between a dehydroamino
acid amide (2a)9 and ethyl -bromopyruvate (3a)10 towards the synthesis of oxazole 1a. Favorable results
were obtained with moderate temperatures and the use of a mild inorganic base. As shown in Table 1,
optimal reaction conditions involved THF under reflux with NaHCO3 as a base (entry 5). Reactions with
NaHCO3 and K2CO3 at room temperature did not proceed (entry 3 and 4). Furthermore, under
homogeneous conditions (entries 1 and 2), 3a rapidly decomposed, even at rt, such that the reaction did
not occur. Reactions at higher or lower temperatures, or in the presence of an organic base (homogeneous
conditions) were not fruitful. In contrast, 2a was relatively stable at higher temperatures. Our results
strongly indicated that both the reaction rate and the decomposition rate of 3a required careful
consideration.

HETEROCYCLES, Vol. 85, No. 2, 2012
315
Table 1. Hantzsch-type reaction conditions between a dehydroamino acid amide (2a) and ethyl
bromopyruvate (3a)
[i] base/solvent, 5 ha
[ii] TFAA, Py./THF
Br
then quenched with 28% NH4OH
/EtOAc at 0 oC
O
N
NH2
CbzHN
O
CO2Et
3a
CbzHN
CO2Et
O
2a
1ac
entry
1
base
solvent
THF
temperature
rt
yield [%]b
no reaction
pyridine
2
3
4
5
6
Et3N
THF
THF
THF
rt
rt
rt
no reaction
no reaction
no reaction
K2CO3
NaHCO3
KHCO3
THF
THF
reflux (66oC)
reflux (66 oC)
49
85
NaHCO3
7
NaHCO3
NaHCO3
NaHCO3
toluene
70 oC
73
8
9
toluene
MeCN
reflux (111oC)
reflux (82 oC)
50
70
a
2a
, 3a
(0.8 mmol)
The reaction was carried out using
b Isolated yield of 1a.
(2 equiv), and base (5 equiv) in solvent (5 mL).
cThe geometric configuration of 1a was deduced from the reaction mechanistic studies using 4e and 4f in Scheme 4.
Consequently, the optimal reaction conditions shown in entry 5, Table 1 were employed to explore the
scope and limitations of the reaction between 3a and various -substituted dehydroamino acid amides
(derivatives of 2a) (Table 2). The reactions were allowed to proceed until the disappearance of substrates
2 (as determined by TLC) to maximize the yields of 1. In some cases, due to the instability of 3a (see
above), extra portions of 3a (2 equiv) were added after 5 and 10 h. Longer reaction times (over 5 h) were
required in many cases, which can be attributed to the steric hindrance between the bulky substituents of
the substrates 2 and -bromopyruvate derivative 3, with the exception of entry 6. Interestingly, the
reactivities of the methoxy (entry 6, enhanced reactivity) and nitro (entry 7, reduced reactivity)
derivatives, compared to that of entry 5 in Table 1. These results may suggested that the reaction rate
decrease with the increasing electron-withdrawing effect of substituents R1 (or/and R2) such as NO2,
CO2Me on the dehydroamino acid amide. (Relative reaction rate for substituents: Me > Ph; Me >

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HETEROCYCLES, Vol. 85, No. 2, 2012
CH2CO2Me; p-MeO-Ph > Ph > p-NO2-Ph). Futhermore, this Hantzsch-type reaction of N-Cbz-L-alanine
amide11 did not proceed (Scheme 3). Therefore, the conjugated double bond seems to play an important
role in our Hantzsch-type reaction. Overall, oxazole-dehydroamino acid derivatives 1a-i were
conveniently synthesized in good yields via the Hantzsch-type reaction, but with careful attention to the
conditions. As shown in Table 2, satisfactory yields and reaction times were observed for entries 1, 2, and
6.
[i] NaHCO3/solvent, 5 h
[ii] TFAA, Py./THF
then quenched with 28% NH4OH
/EtOAc at 0 oC
Br
O
N
NH2
CbzHN
O
CO2Et
3a
CbzHN
CO2Et
no reaction
O
N-Cbz- -alanine amide
1a
L
Scheme 3. The Hantzsch-type reaction of N-Cbz-L-alanine amide
Subsequently, the Hantzsch-type reaction was applied towards the synthesis of a 5-substituted oxazole
backbone, which is found in various natural products. As shown in Table 2, we first investigated the
synthesis of 5-substituted oxazole dehydroamino acid derivatives using methyl -substituted
-bromopyruvates (3b-d), which were readily prepared from the dehydroamino acids.12 Methyl
-substituted -bromopyruvates 3b-d were reacted with dehydroamino acid amide 2a to give the
corresponding oxazole derivatives in moderate yields. The influence of steric hindrance in the SN2
reactions was evident from the long reaction times required for 3b (entry 10) and 3c (entry 11). In
contrast to the unsubstituted substrate, the methyl-substituted -bromopyruvates were relatively stable.
In the case of entry 12, the faster reaction rate can be explained by the enhanced SN2 reaction at the
benzylic position of 3d. It is generally known that SN2 reactions of halogenated substrates that involve
either an allyl or benzyl group at the reaction center are enhanced by the stable  conjugation between
the sp2 transition state and the -electrons of the double bond. To improve the speed of the oxazole
formation, these reactions were repeated under microwave irradiation at reflux conditions using a
microwave apparatus.13,14 As shown in Table 2, improved yields and reaction times were obtained in all
cases under such conditions.
Newly proposed reaction mechanisms are shown in Scheme 3 to explain the enhanced reactivities of the
Hantzsch-type reactions towards oxazole synthesis. The mechanism with the resonance contributor [A] is
inferred from Babadjamian and co-workers’ report15 for the modified Hantzsch reaction of saturated
amino thioacid amide derivatives to give the corresponding thiazole derivatives. An alternate mechanism

HETEROCYCLES, Vol. 85, No. 2, 2012
317
with the consideration of resonance contributor [B], which involves stabilized resonance hybrid oxyanion
intermediates, might support the enhanced reactivities.
Table 2. Hantzsch-type reaction of various dehydroamino acid amides (2a-i) with ethyl -bromopyruvate
(3a) and its -substituted derivatives (3b-d)
[ii] TFAA-Py./THF
then quenched with
28% NH3 aq/EtOAc
R1
R1
R2 R1
NH2
Br
O
R3
R2
R2
[i] NaHCO3/THFa
thermal
or
microwave assisted reaction
R3
OH
CO2R4
R3
O
O
RHN
RHN
CO2R4
RHN
N
N
CO2R4
O
2a i
3ad

1ai, 4bd
microwave assisted reactiong
time [h]d yield [%]e 3 [equiv] time [h]d yield[%]e
thermal reaction


3a d
2a i
entry
productsi
R1
R2
R3
R4
[equiv]
3
R
85
83
2
2
5
5
8
85
1
2
3
:
Cbz
Boc
H
Me
Me
Me
1a
1b
1c
2+2f
2+2f
1
1
2a
H
88
84
:
2b
2+2b
85
88
88
89
2+2+2f
1.5
Me
2c: Cbz
2+2b
8
4
Cbz
H
1d
2+2+2f
2+2+2f
2+2f
84
:
i-Pr
Ph
1.5
1.5
1
2d
2+2b
2
9
4
5
6
7
8
9
Cbz
Cbz
Cbz
H
H
H
H
H
:
3a
H
Et
1e
1f
:
2e
88
84
:
p-MeOPh
2f
2+2+2b
2+2b
2+2b
14
9
87
69
86
:
1g
1h
1i
2+2+2+2f
3
2g
2h
2i
p-NO2Ph
CH2CO2Me
C2H4NHCbz
87
66
: Cbz
2+2+2f
2+2+2f
2
7
1.5
:
Cbz
91
10
11
12
2+2c
2+2+2c
2
22
72
7
2+2+2f
2+2f
5
71
: Me Me
4b
4c
4d
74
62
78
3b
NDh
80
H
Me
Me
Me
: Cbz
2a
: i-Pr
3c
Ph
2.5
:
3d
aA mixture of
2a i
- (0.8 mmol),
3a
(2 equiv), and base (5 equiv) was stirred in THF (5 mL) at reflux conditions.
bAdditional portions (2 equiv) of 3a were added after 5 h and 10 h.
cAdditional portions (2 equiv) of 3b-d were added after 12 h and 36 h.
dTime until the disapperance of 2 on TLC.
eIsolated yield of 1 and 4.
f
Additional portions (2 equiv) of 3 were added after 20 min, 1 h, and 2 h.
gReflux conditions (100 W max initial MW power).
hNot determined (The resulting product was unstable under these conditions.).
iThe geometric configurations of - and
1a i
4b d
-
4e 4f
were deduced from the reaction mechanistic studies using and in Scheme 4.
The reaction mechanism was further investigated using configurational isomers, as shown in Scheme 4.
Because of the difficulty of preparing both (E)- and (Z)-isomers of the dehydroamino esters, the (E)- and
(Z)-isomers of the -unsaturated acid amides [2-methylbutenamide (2j and 2k)]16 were synthesized first
as model compounds in good yields from the corresponding commercially available (E)- and (Z)-acids by
treatment with DCC (N,N-dicyclohexylcarbodiimide) and HOSu (N-hydroxysuccinimide) in aqueous NH3
solution. These olefins apparently do not undergo isomerization because the corresponding products were
exclusively obtained.16 To prepare such substrates 2a-i, three established methods, such as (1)
-elimination (anti-elimination) of Ser, Thr, and Cys,9 (2) condensation of -ketoester and protected
amine (CbzNH2),9,17 (3) Wittig reaction of N-protected diethylphospholylglycine ester to the

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HETEROCYCLES, Vol. 85, No. 2, 2012
corresponding aldehyde, and subsequent amidation,9,17 were employed. It is known that these reactions
predominantly give (Z)-dehydroamino esters. The preference for the (Z)-isomer may be attributed to the
thermodynamic stability of the configuration by a similar isomerization mechanism via the sp2
carbocation resonance contributor [B] as shown in Scheme 4. If the subsequent Hantzsch-type reaction
proceeds with the resonance contributor [A] without participation of resonance contributor [B], the
configuration of R1 and R2 (E, Z) will be retained in the products (4e and 4f),18 whereas if the reaction
proceeds via resonance contributor [B], the configuration will be influenced (scrambled) by the sp2
intermediate to give the thermodynamically stable products. Our results show that both starting isomers
afforded oxazole products with similar ratios between the (E)- and (Z)-isomers. In other words, the
reaction proceeded via resonance contributor [B] with isomerization. The configurations of 4e and 4f
were determined using NMR experiments (1H and NOESY) and the results were compared to reported
spectral data.18 Other possibilities still remain, for example, that isomerization occurs via Michael
addition – elimination reactions of oxazolines or oxazoles. However this mechanism cannot explain the
enhanced reactivities.
Scheme 4. Proposed reaction mechanisms of the Hantzsch-type reactions
Although the configurations of the oxazole-dehydroamino acid derivative products 1a-i have yet to be
established by NMR and X-ray structure analyses, because of the absence of critical NOE correlations
and the difficulties in getting single crystals, the stable configurations of the starting dehydroamino esters

HETEROCYCLES, Vol. 85, No. 2, 2012
319
may be retained by deducing from the reaction mechanistic study using 4e and 4f (Scheme 5). The
preference for the (Z)-isomer may also be in good agreement with the thermodynamically stable
configuration of the corresponding starting dehydroamino ester by the mechanism via resonance
contributor [B].
Br
[i] NaHCO3/THF, reflux
[ii] TFAA-Py./THF
NH2
+
O
CO2Et
O
3a
3a
2j (E isomer)
O
N
O
N
+
CO2Et
CO2Et
Br
+
4e (E isomer)
4f (Z isomer)
NH2
[i] NaHCO3/THF, ref lux
[ii] TFAA-Py./THF
O
CO2Et
main-product
by-product
O
2k (Z isomer)
E : Z ratio =

97 : 3 94 : 6
Scheme 5. Further investigation of the reaction mechanism using (E)- and (Z)-isomers of the
,-unsaturated acid amides [2-methylbutenamides (2j and 2k)]
In conclusion, various oxazole-dehydroamino acid derivatives were efficiently synthesized from
-bromopyruvates and dehydroamino acid amides (easily derived from the corresponding dehydroamino
acids) via a Hantzsch-type reaction with microwave irradiation. Using -substituted -bromopyruvates,
this methodology was applied towards the synthesis of various 5-substituted oxazole derivatives, which
can be found in the structures of various natural products.4d,19 Additional investigations indicated that the
reaction mechanism of our Hantzsch-type reaction, due to the contribution of the -unsaturated bond on
the dehydroamino moiety, might differ from that of the modified Hantzsch reaction in thiazole synthesis.
Because the synthesized oxazole-dehydroamino ester intermediate itself can serve as an activated
substrate, it is our belief that this Hantzsch-type oxazole synthetic methodology can contribute towards
the synthesis of various natural products that possess substituted mono-, bis-, and tris-oxazole moieties.
EXPERIMENTAL
All melting points were measured using a Yanaco Model MP-J3 micro-melting point apparatus, and are
1
uncorrected. IR spectra were recorded using a Jasco FT/IR-4200 spectrometer in KBr. H NMR spectra
were recorded on spectrometers operating at 500 MHz and 600 MHz in chloroform-d or
dimethylsulfoxide-d6 referenced to tetramethylsilane (0.00 ppm). 13C NMR spectra were recorded on
spectrometers operating at 125 MHz and 150 MHz in chloroform-d or dimethylsulfoxide-d6. The

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HETEROCYCLES, Vol. 85, No. 2, 2012
assignments of various NMR spectra were assisted by homonuclear (1H/1H) correlation spectroscopy
(COSY), nuclear Overhuser and exchange spectroscopy (NOESY), nuclear Overhauser effect (NOE),
and/or heteronuclear (1H/13C) correlation spectroscopy (HETCOR) experiments. The chemical shifts,
coupling constants, and IR frequencies were recorded in , Hz, and cm-1 units, respectively. Column
chromatography was performed on silica gel (Silica gel 60, 70-230 mesh; Silica gel 60N, spherical,
neutral, 70-230 mesh). Thin-layer chromatography (TLC) on Silica gel 60F254 was used to monitor the
reactions and to certify the purity of the reaction products by heating after spraying with
ninhydrin-ethanol solution, phosphomolybdic acid ethanol-H2SO4 solution, and cerium ammonium
molybdate water-H2SO4 solution.
Microwave Irradiation Experiments. All microwave experiments were performed with the Wave
Magic (EYELA MWO-1000S). Experiments were carried out in standard microwave process with Pyrex
flask. Reaction time reflects irradiation times at the set reaction temperature (fixed hold times). Reaction
temperature was measured using a teflon-coated thermocouple of type K.
General procedure for the reaction of dehydroamino acid amides (2a-i) and ethyl -bromopyruvate
(3a)
Thermal reaction: To a stirred solution of compound 2a-i (0.8 mmol) in THF (5 mL) were added
NaHCO3 (336 mg, 5 equiv) and a solution of ethyl -bromopyruvate (3a) (312 mg, 2 equiv) at 0 °C.
After stirring for 5-11 h at reflux, the resulting solution was diluted with CHCl3 (10 mL) and organic
layer was washed with brine and water (10 mL), dried over anhydrous MgSO4, concentrated in vacuo to
give a yellow syrup as crude oxazoline. Crude oxazoline was dissolved in THF (5 mL), TFAA
(trifluoroacetic anhydride) (333 L, 3 equiv) and pyridine (388 L, 6 equiv) were added to the above
THF solution with stirring at 0 °C for 30 min. After the disappearance of oxazoline on TLC, the reaction
mixture was concentrated in vacuo to give a brown syrup. Resulting residue was further dissolved in
EtOAc (5 mL), 28% NH4OH (1 mL) was added to the mixture and stirred at 0 °C for 15 min. The
reaction mixture was poured into brine, washed with water, brine, dried over anhydrous MgSO4,
concentrated in vacuo to give oxazole-dehydroamino acid derivatives 1a-i (69-89%), which were purified
on a silica gel column with hexanes-EtOAc.
Microwave assisted reaction: To a stirred solution of 2a-i (0.8 mmol) in THF (5 mL) were added
NaHCO3 (336 mg, 5 equiv) and a solution of ethyl -bromopyruvate (3a) (312 mg, 2 equiv) in THF (1
mL) at 0 °C. The flask was flushed with argon, heated with stirring at reflux under microwave irradiation
for 5-72 min. After cooling to rt, the reaction mixture was diluted with CHCl3 (10 mL) and the organic
layer was washed with brine and water, dried over anhydrous MgSO4, and concentrated in vacuo to give a

HETEROCYCLES, Vol. 85, No. 2, 2012
321
yellow syrup. Resulting syrup was dissolved in THF (5 mL), TFAA (333 L, 3 equiv) and pyridine (388
L, 6 equiv) were added to the mixture at 0 °C, and stirred for 30 min. The reaction mixture was
concentrated in vacuo to give brown syrup. Resulting syrup was further dissolved in EtOAc (5 mL), 28%
NH4OH (1 mL) was added to the above mixture at 0 °C, and stirred for 15 min. Reaction mixture was
poured into brine, washed with brine and water, dried over anhydrous MgSO4, concentrated in vacuo.
Resulting brown syrup was purified on a silica gel column to give 5-substituted oxazole derivatives 1a-i
(66-91%).
Ethyl
(Z)-2-[1-((1-(Benzyloxy)carbonyl)amino)prop-1-en-1-yl]oxazole-4-carboxylate
(Cbz-Abu-Ozl-OEt) (1a): Yield 85%; white solid; mp 95-97 °C (acetone-hexanes); IR (KBr, disk) max
1
3302, 2959, 1732, 1505, 1313 cm-1; H NMR (600 MHz, CDCl3) 1.37 (3H, t, J = 7.2 Hz, Et’s CH3),
1.67 (3H, d, J = 7.2 Hz, Abu’s CH3), 4.39 (2H, q, J = 7.2 Hz, Et’s CH2), 5.16 (2H, s, Cbz’s CH2), 6.48
(1H, br s, NH), 6.62 (1H, q, J = 7.2 Hz, vinyl’s H), 7.33-7.39 (5H, m, Cbz’s PhH), 8.12 (1H, s, ring-H);
13C NMR (150 MHz, CDCl3)  14.3, 61.3, 67.5, 67.5, 122.8, 128.2, 128.3, 128.5, 134.1, 135.9, 143.7,
153.9, 160.5, 161.1. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H18N2NaO5 353.1113, found 353.1095.
Anal. Calcd for C17H18N2O5 (330.12): C, 61.81; H, 5.49; N, 8.48. Found: C, 61.74; H, 5.30; N, 8.21.
Ethyl
(Z)-2-[1-(((tert-Butoxy)carbonyl)amino)prop-1-en-1-yl]oxazole-4-carboxylate
(Boc-Abu-Ozl-OEt) (1b): Yield 83%; white solid; mp 130.5-132 °C (acetone-hexanes); IR (KBr, disk)
max 3322, 2980, 1724, 1498, 1317 cm-1; 1H NMR (600 MHz, CDCl3) 1.38 (3H, t, J = 7.1 00Hz, Et’s
CH3), 1.47 (9H, s, Boc’s t-Bu), 1.87 (3H, d, J = 7.2 Hz, Abu’s CH3), 4.39 (2H, q, J = 7.1 Hz, Et’s CH2),
6.26 (1H, br s, NH), 6.55 (1H, q, J = 7.2 Hz, vinyl’s H), 8.14 (1H, s, ring-H); 13C NMR (150 MHz,
CDCl3) 14.1, 14.2, 28.1, 61.3, 80.6, 123.0, 127.1, 134.0, 143.5, 152.9, 160.8, 161.2. HRMS (ESI-TOF)
m/z: [M+Na]+ calcd for C14H20N2NaO5 319.1270, found 319.1256. Anal. Calcd for C14H20N2O5 (296.14):
C, 56.75; H, 6.80; N, 9.45. Found: C, 56.71; H, 6.58; N, 9.29.
Ethyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)-2-methylprop-1-en-1-yl]oxazole-4-carboxylate
(Cbz-Val-Ozl-OEt) (1c): Yield 85%; white solid; mp 108-109 °C (acetone-hexanes); IR (KBr, disk)
1
max 3160, 2981, 1733, 1506, 1317 cm-1; H NMR (600 MHz, DMSO-d6 at 60 °C) 1.29 (3H, t, J = 7.1
Hz, Et’s CH3), 1.86, 2.10 (3H × 2, each s, Val’s CH3 × 2), 4.29 (2H, q, J = 7.1 Hz, Et’s CH2), 5.05 (2H,
13
s, Cbz’s CH2), 7.31-7.36 (5H, m, Cbz’s PhH), 8.66 (1H, bs, NH), 8.80 (1H, s, ring-H); C NMR (150
MHz, DMSO-d6, 60 °C)  13.9, 20.4, 20.7, 60.2, 65.5, 117.5, 127.3, 127.5, 128.0, 132.7, 136.6, 138.8,
143.7, 154.3, 159.9, 160.4.HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H20N2NaO5 367.1270, found
367.1251. Anal. Calcd for C18H20N2O5 (344.14): C, 62.78; H, 5.85; N, 8.13. Found: C, 62.44; H, 5.47; N,
7.84.

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Ethyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)-2,3-dimethylbut-1-en-1-yl]oxazole-4-carboxylate
(Cbz-Lue-Ozl-OEt) (1d): Yield 88%; yellow syrup; IR (KBr, neat) max 3305, 2962, 1730, 1500, 1320
1
cm-1; H NMR (600 MHz, CDCl3) 1.08 (6H, d, J = 6.6 Hz, Leu’s CH3), 1.38 (3H, t, J = 7.2 Hz, Et’s
CH3), 2.78 (1H, dqq, J = 10.2, 6.6, 6.6 Hz, Leu’s H), 4.39 (2H, q, J = 7.2 Hz, Et’s CH3), 5.15 (2H, s,
Cbz’s CH2), 6.27 (1H, bs, NH), 6.39 (1H, d, J = 10.2 Hz, vinyl’s H), 7.26-7.36 (5H, m, Cbz’s PhH), 8.11
13
(1H, s, ring-H); C NMR (150 MHz, CDCl3) 14.7, 22.3, 27.9, 61.7, 67.9, 120.4, 128.6, 128.6, 128.9,
134.6, 136.3, 141.3, 144.0, 155.0, 161.1, 161.6. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22N2NaO5
381.1426, found 381.1395.
Ethyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)-2-phenylethen-1-yl]oxazole-4-carboxylate
(Cbz-Phe-Ozl-OEt) (1e): Yield 88%; colorless amorphous; IR (KBr, disk) max 3254, 2980, 1733, 1506,
1317 cm-1; 1H NMR (600 MHz, CDCl3)  1.39 (3H, t, J = 7.2 Hz, Et’s CH3), 4.40 (2H, q, J = 7.2 Hz, Et’s
CH2), 5.11 (2H, s, Cbz’s CH2), 6.68 (1H, s, NH), 7.29 (1H, s, vinyl’s H), 7.29-7.53 (10H, m, Cbz’s PhH,
13
Phe’s PhH), 8.16 (1H, s, ring-H); C NMR (150 MHz, CDCl3) 14.3, 61.4, 67.6, 120.9, 128.0, 128.2,
128.2, 128.5, 128.7, 129.1, 129.4, 133.8, 134.5, 135.8, 143.9, 153.8, 160.9, 161.1. HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C22H20N2NaO5 415.1270, found 415.1279.
Ethyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)-2-(4-methoxyphenyl)vinyl]oxazole-4-carboxylate
(Cbz-Tyr(OMe)-Ozl-OEt) (1f): Yield 89%; colorless amorphous; IR (KBr, disk) max 3291, 2981,
1
1728, 1511, 1318 cm-1; H NMR (600 MHz, DMSO-d6 at 80 °C)  1.31 (3H, t, J = 7.1 Hz, Et’s CH3),
3.80 (3H, s, Tyr’s OMe), 4.32 (2H, q, J = 7.1 Hz, Et’s CH2), 5.10 (2H, br s, Cbz’s CH2), 6.94-7.66 (10H,
13
m, Cbz’s PhH , Tyr’s PhH, Vinyl’s H), 8.73 (1H, s, ring-H), 9.17 (1H, s, NH); C NMR (150 MHz,
DMSO-d6 at 80°C) 13.7, 55.0, 60.2, 65.6, 113.8, 119.6, 126.0, 127.1, 127.4, 127.9, 128.9, 131.0, 133.4,
136.4, 144.5, 154.1, 159.7, 160.3, 161.1. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H22N2NaO6
445.1376, found 445.1353.
Ethyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)-2-(4-nitrophenyl)vinyl]oxazole-4-carboxylate
(Cbz-p-NO2Phe-Ozl-OEt) (1g): Yield 87%; yellow solid; mp 162-164 °C (acetone-hexanes); IR (KBr,
disk) max 3255, 3150, 1724, 1704, 1521, 1347, 1108, 738 cm-1; 1H NMR (600 MHz, CDCl3)  1.39 (3H,
t, J = 7.2 Hz, Et’s CH3), 4.41 (2H, q, J = 7.2 Hz, Et’s CH2), 5.06 (2H, s, Cbz’s CH2), 7.20 (1H, br s, NH),
7.24 (1H, s, vinyl’s H), 7.33 (5H, br s, Cbz’s PhH), 7.59 (2H, d, J = 8.6 Hz, PhH), 8.09 (2H, d, J = 8.6 Hz,
13
PhH), 8.22 (1H, s, ring-H); C NMR (150 MHz, CDCl3) 14.3, 61.6, 67.9, 123.2, 123.5, 123.7, 128.5,
128.5, 128.6, 129.6, 134.8, 135.5, 141.0, 144.5, 147.0, 152.9, 160.0, 160.7. HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C22H19N3NaO7 460.1120, found 460.1150. Anal. Calcd for C22H19N3O7 (437.12): C,
60.41; H, 4.38; N, 9.61; O, 25.60. Found: C, 60.34; H, 4.34; N, 9.51.

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Ethyl (Z)-2-[1-(((Benzyloxy)carbonyl)amino)-4-methoxy-4-oxobut-1-en-1-yl]oxazole-4-carboxylate
(Cbz-Glu(OMe)-Ozl-OEt) (1h): Yield 69%; colorless syrup; IR (KBr, neat) max 3307, 2954, 1733,
1
1508 cm-1; H NMR (600 MHz, CDCl3)  1.38 (3H, t, J = 7.1 Hz, Et’s CH 3), 3.37 (2H, d, J = 7.2 Hz,
-H), 3.73 (3H, s, COOCH3), 4.39 (2H, q, J = 7.2 Hz, Et’s CH2), 5.16 (2H, s, Cbz’s CH2), 6.67 (1H, t, J =
13
7.2 Hz, vinyl’s H), 6.79 (1H, br s, NH), 7.32-7.42 (5H, m, Cbz’s PhH), 8.15 (1H, s, ring-H); C NMR
(150 MHz, CDCl3) 14.3, 33.7, 52.2, 61.4, 67.8, 122.1, 123.9, 128.3, 128.4, 128.6, 134.2, 135.6, 144.1,
153.6, 159.7, 161.0, 170.1 HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H20N2NaO7 411.1168, found
411.1128.
Ethyl
(Z)-2-[[1,4-Bis(((benzyloxy)carbonyl)amino)]but-1-en-1-yl]oxazole-4-carboxylate
(Cbz-Orn(NCbz)-Ozl-OEt) (1i): Yield 91%; colorless syrup; IR (KBr, neat) max 3320, 2981, 1719,
1525, 1249 cm-1; 1H NMR (600 MHz, CDCl3)  1.37 (3H, t, J = 7.1 Hz, Et’s CH3), 2.51 (2H, dt, J = 6.4,
7.4 Hz, Orn’s -CH2), 3.39 (2H, dt, J = 4.8, 6.4 Hz, Orn’s -CH2), 4.38 (2H, q, J = 7.1 Hz, Et’s CH2),
5.09, 5.14 (4H, each s, Cbz’s CH2 × 2), 5.32 (1H, br s, NH), 6.46 (1H, t, J = 7.4 Hz, vinyl’s H), 6.66 (1H,
br s, NH), 7.28-7.36 (10H, m, Cbz’s PhH × 2), 8.12 (1H, s, ring-H); 13C NMR (150 MHz, CDCl3) 14.3,
28.6, 39.8, 61.4, 66.6, 67.7, 123.5, 128.0, 128.0, 128.3, 128.4, 128.5, 128.6, 129.1, 134.2, 135.7, 136.6,
143.9, 154.2, 156.5, 160.0, 161.0. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C26H27N3NaO7 516.1747,
found 516.1720.
General procedure for the preparation of dehydroamino acid amides (2a-i). To a solution of
N-protected dehydroamino acid (AA-OH) (4.0 mmol) in THF (10 mL) was added a solution of DCC
(1.1 equiv) in THF at 0 °C. After stirring for 30 min, HOSu (N-hydroxysuccinimide) (1.1 equiv) was
added to the resulting mixture. After stirring at room temperature for 5 min, the precipitates
(dicyclohexylurea: DCU) was filtrated off through a pad of Celite. The filtrate was concentrated in vacuo
to give a residue. The resulting residue was dissolved in EtOAc (10 mL), added 28% NH4OH (1 mL), and
stirred continuously for 30 min at room temperature. The reaction mixture was washed with brine water,
dried over anhydrous MgSO4, concentrated in vacuo to give a N-protected AA-NH2 (2a-i)(70-92%),
which was recrystallized from acetone-hexanes.
(Z)-2-((Benzyloxy)carbonyl)amino-2-butenamide (Cbz-Abu-NH2) (2a): Yield 82%; white solid; mp
1
109-110 °C (acetone-hexanes); IR (KBr, disk) max 3468, 3144, 1692, 1657, 1503 cm-1; H NMR (600
MHz, DMSO-d6) 1.62 (3H, d, J = 7.0 Hz, Abu’s CH3), 5.05 (2H, s, Cbz’s CH2), 6.23 (1H, q, J = 7.0
Hz, vinyl’s H), 7.01 (1H, s, NH2’s H), 7.317.38 (6H, m, Cbz’s PhH, NH2), 8.50 (1H, s, NH); 13C NMR
(150 MHz, DMSO-d6) 12.9, 65.7, 126.0, 127.7, 127.8, 128.3, 131.4, 136.8, 154.1, 166.4. HRMS
(ESI-TOF) m/z: [M+Na]+ calcd for C12H14N2NaO3 257.0902, found 257.0882. Anal. Calcd for
C12H14N2O3 (234.10): C, 61.53; H, 6.02; N, 11.96. Found: C, 61.47; H, 6.02; N, 11.70.

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(Z)-2-((tert-Butoxy)carbonyl)amino-2-butenamide (Boc-Abu-NH2) (2b): Yield 86%; white solid; mp
1
116-117 °C (acetone-hexanes); IR (KBr, disk) max 3293, 2979, 1677, 1647 cm-1; H NMR (600 MHz,
DMSO-d6) 1.39 (9H, s, Boc’s t-Bu), 1.59 (3H, d, J = 6.9 Hz, Abu’s CH3), 6.11 (1H, br s, NH), 6.95,
13
7.20 (2H, each s, NH2), 8.00 (1H, br s, vinyl’s H); C NMR (150 MHz, DMSO-d6) 12.9, 28.1, 78.5,
125.0, 131.7, 153.3, 166.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C9H16N2NaO3 2223.1058, found
2223.1081. Anal. Calcd for C9H16N2O3 (200.24): C, 53.98; H, 8.05; N, 13.99. Found: C, 53.63; H, 8.42;
N, 13.70.
2-((Benzyloxy)carbonyl)amino-3-methyl-2-butenamide (Cbz-Val-NH2) (2c): Yield 87%; white
1
solid; mp 146-148 °C (acetone-hexanes); IR (KBr, disk) max 3451, 2903, 1667, 1641, 1599 cm-1; H
NMR (600 MHz, DMSO-d6)  1.66, 1.92 (3H × 2, each s, Val’s CH3 × 2), 5.04 (2H, s, Cbz’s CH2),
7.01, 7.11 (1H × 2, each s, NH2), 7.31-7.38 (5H, m, Cbz’s PhH); 8.48 (1H, s, NH); 13C NMR (150 MHz,
DMSO-d6) 20.4, 20.7, 65.5, 125.6, 127.7, 127.8, 128.3, 133.6, 137.0, 154.3, 167.3. HRMS (ESI-TOF)
m/z: [M+Na]+ calcd for C13H16N2NaO3 271.1059, found 271.1030.
(Z)-2-((Benzyloxy)carbonyl)amino-4-methyl-2-pentenamide (Cbz-Lue-NH2) (2d): Yield 92%; white
solid; mp 117-118 °C (acetone-hexanes); IR (KBr, disk) max 3278, 2961, 1684, 1507 cm-1; 1H NMR (600
MHz, DMSO-d6)  0.94 (6H, d, J = 6.4 Hz, Leu’s CH3), 2.56 (1H, m, Leu’s H), 5.04 (2H, s, Cbz’s
CH2), 6.02 (1H, d, J = 6.9 Hz, vinyl’s H), 7.01 (1H, s, NH2), 7.30-7.38 (6H, m, Cbz’s PhH, NH2), 8.49
(1H, s, NH); 13C NMR (150 MHz, DMSO-d6) 21.8, 26.2, 65.6, 127.6, 127.8, 128.2, 128.3, 136.9, 138.5,
154.6, 166.6. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C14H18N2NaO3 285.1215, found 285.1256.
(Z)-2-((Benzyloxy)carbonyl)amino-3-phenyl-2-propenamide (Cbz-Phe-NH2) (2e): Yield 87%; white
solid; mp 166-167 °C (acetone-hexanes); IR (KBr, disk) max 3337, 1713, 1607 cm-1; 1H NMR (500MHz,
DMSO-d6)  5.06 (2H, s, Cbz’s CH2), 7.06 (1H, s, vinyl’s H), 7.23 (2H, s, NH2), 7.30-7.56 (10H, m,
Cbz’s PhH, Phe’s PhH), 7.59 (1H, s, NH); 13C NMR (150 MHz, DMSO-d6)  65.7, 127.5, 127.7, 127.9,
128.3, 128.4, 128.5, 129.4, 129.5, 134.2, 136.9, 154.4, 167.0.HRMS (ESI-TOF) m/z : [M+Na]+ calcd for
C17H16N2NaO3 319.1059, found 319.1044.
(Z)-2-((Benzyloxy)carbonyl)amino-3-(4-methoxyphenyl)-2-propenamide (Cbz-p-Tyr(OMe)-NH2)
(2f): Yield 77%; white solid; mp 147-149 °C (acetone-hexanes); IR (KBr, disk) max 3452, 3336, 3208,
3105, 2898, 1720, 1662, 1578 cm-1; １H NMR (600 MHz, CDCl3)  3.86 (3H, s, Tyr’s OMe), 5.20 (2H, s,
Cbz’s CH2), 5.66 (2H, br s, NH2), 6.89 (2H, d, J = 8.7 Hz, Tyr’s PhH), 7.27 (1H, s, vinyl’s H), 7.27-7.37
13
(5H, m, Cbz’s PhH), 7.44 (2H, d, J = 8.7 Hz, Tyr’s PhH); C NMR (150 MHz, CDCl3) 24.9, 25.6,
34.0, 55.3, 67.8, 114.3, 125.8, 128.3, 128.4, 128.6, 131.3, 131.3, 135.8, 160.4, 167.6; 13C NMR (150
MHz, DMSO-d6)  14.4, 55.2, 65.7, 113.9, 126.6, 127.2, 127.6, 127.7, 128.3, 128.5, 131.2, 137.0, 154.4,

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159.5, 167.2. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H18N2NaO4 349.1164, found: 349.1134.
(Z)-2-((Benzyloxy)carbonyl)amino-3-(4-nitrophenyl)-2-propenamide (Cbz-p-NO2Phe-NH2) (2g):
Yield 82%; yellow solid; mp 182-184 °C (acetone-hexanes); IR (KBr, disk) max 3294, 3466, 3245, 3145,
1
1688, 1522, 1342, 1255 cm-1; H NMR (600 MHz, DMSO-d6)  5.06 (2H, s, Cbz’s CH2), 7.01 (1H, s,
vinyl’s H) 7.32-7.40 (6H, m, Cbz’s PhH, NH2’s H), 7.75 (2H, d, J = 8.8 Hz, Tyr’s PhH), 7.78 (1H, s,
NH2’s H), 8.18 (2H, d, J = 8.8 Hz, Tyr’s PhH); 9.18 (1H, s, NH ); 13C NMR (150 MHz, DMSO-d6)
66.0, 123.5, 123.7, 127.7, 127.8, 128.3, 130.1, 133.0, 136.6, 141.4, 146.4, 154.0, 166.8; HRMS
(ESI-TOF) m/z: [M+Na]+ calcd for C17H15N3NaO5 364.0909, found 364.0946.
Methyl (Z)-5-Amino-4-[((benzyloxy)carbonyl)amino]-5-oxo-3-pentenoate (Cbz-Glu(OMe)-NH2)
(2h): Yield 70%; white solid; mp 110-111 °C; IR (KBr, disk) max 3435, 3388, 3191, 2997, 1725, 1701,
1670, 1655, 1609, 1278 cm-1; 1H NMR (600 MHz, DMSO-d6)  3.18 (2H, d, J = 7.0 Hz, -H), 3.61 (3H,
s, COOCH3), 5.05 (2H, s, Cbz’s CH2), 6.21 (1H, t, J = 7.0 Hz, vinyl’s H), 7.14 (1H, s, NH2), 7.32-7.38
13
(5H, m, Cbz’s PhH), 7.48 (1H, s, NH2), 8.70 (1H, s, CbzNH); C NMR (150 MHz, DMSO-d6) 32.2,
51.7, 65.9, 121.4, 127.7, 127.8, 128.3, 132.3, 136.7, 153.9, 165.9, 170.7; HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C14H16N2NaO5 315.0956, found 315.1022. Anal. Calcd for C14H16N2O5 (292.29): C,
57.53; H, 5.52; N, 9.58. Found: C, 57.52; H, 5.52; N, 9.75.
(Z)-2,5-Di[((benzyloxy)carbonyl)amino]-2-pentenamide (Cbz-Orn(NCbz)-NH2) (2i): Yield: 71%;
white solid; mp 128-130 °C (acetone-hexanes); IR (KBr, disk) max 3296, 3036, 1686, 1509, 1249 cm-1;
1H NMR (600 MHz, DMSO-d6) 2.21 (2H, dd, J = 6.9, 13.5 Hz, -H), 3.08 (2H, dd, J = 6.6, 13.5 Hz,
-H), 5.01, 5.04 (2H × 2, each s, Cbz’s CH2), 6.09 (1H, t, J = 6.9 Hz, vinyl’s H), 7.06 (1H, s, NH2),
13
7.29-7.37 (12H, m, Cbz’s PhH × 2, NH2’s H, NH), 8.57 (1H, s, NH); C NMR (150 MHz, DMSO-d6)
27.6, 39.3, 65.2, 65.7, 127.3, 127.6, 127.7, 127.7, 127.7, 127.8, 128.3, 128.3, 131.5, 136.8, 137.2, 154.2,
156.1, 166.4. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H23N3NaO5 420.1535, found 420.1537.
(E)-2-Methyl-2-butenamide (2j) (Tiglic acid amide): The preparation procedure was the same as 2a-i.
Yield 81 %; white solid; mp 126.5-127.5 °C (acetone-hexanes); IR (KBr, disk) max 3376, 3181, 2921,
1666, 1612 cm-1; 1H NMR (600 MHz, CDCl3)  1.87 (3H, dq, J = 1.5, 7.1 Hz,-CH3), 1.91 (3H, dq, J =
1.5, 1.5 Hz, CH3), 5.63 (1H, s, NH2’s H), 5.71 (1H, br qq, J = 1.5, 7.1 Hz, vinyl’s H), 6.30 (1H, s, NH2’s
H).
(Z)-2-Methyl-2-butenamide (2k) (Angelic acid amide): The preparation procedure was the same as 2a-i.
Yield 88 %; white solid; mp 164.5-166.5 °C (acetone-hexanes); IR (KBr, disk) max 3344, 3178, 2935,
1676, 1597 cm-1; 1H NMR (600 MHz, CDCl3)  1.77 (3H, dq, J = 1.2, 6.9 Hz,-CH3), 1.85 (3H, dq, J =
1.2, 1.2 Hz, CH3), 5.88, 6.22 (1H × 2, each s, NH2’s H × 2), 6.52 (1H, br qq, J = 1.2, 6.9 Hz, vinyl’s H).

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1
Methyl 3-Bromo-2-oxobutanoate (3b). H NMR (600 MHz, CDCl3) 1.82 (3H, d, J = 6.8 Hz,
CHBrCH3), 3.94 (3H, s, OCH3), 5.17 (1H, q, J = 6.8 Hz, CHBr). This compound was used in the next
step without further purification after usual workup, because this compound was unstable.
1
Methyl 3-Bromo-2-oxo-4-methylpentanoate (3c): H NMR (600 MHz, CDCl3) 1.06, 1.14 (3H × 2,
each d, J = 6.6 Hz, (CH3)2CH), 2.36 (1H, dq, J = 7.9, 6.6 Hz, (CH3)2CH), 3.93 (3H, s, OCH3), 4.85 (1H, d,
CHBr, J = 7.9 Hz). This compound was used in the next step without further purification after usual
workup, because this compound was unstable.
1
Methyl 3-Bromo-2-oxo-3-phenylpropanoate (3d): H NMR (600 MHz, CDCl3) 3.94 (3H, s, OCH3),
6.21 (1H, s, CHBr), 7.38-7.47 (5H, m, PhH). This compound was used in the next step without further
purification after usual workup, because this compound was unstable.
General procedure for the reaction of dehydroamino acid amides (2a) and -substituted
-bromopyruvate (3b-d).
Conventional heating: To a stirred solution of 2a (0.8 mmol) in THF (5 mL) were added NaHCO3 (336
mg, 5 equiv) and a solution of methyl -substituted -bromopyruvate (3b-d) (2 equiv) in THF (1 mL) at
0 °C. After stirring for 5-72 h at reflux, the resulting solution was diluted with CHCl3 (10 mL) and the
organic layer was washed with brine and water, dried over anhydrous MgSO4, and concentrated in vacuo
to give a yellow syrup. Resulting syrup was dissolved in THF (5 mL), TFAA (trifluoracetic anhydride)
(333 L, 3 equiv) and pyridine (388 L, 6 equiv) were added to the mixture at 0 °C, and stirred for 30
min. The reaction mixture was concentrated in vacuo to give brown syrup. Resulting syrup was further
dissolved in EtOAc (5 mL), 28% NH4OH (1 mL) was added to the above mixture at 0 °C, and stirred for
15 min. reaction mixture was poured into brine, washed with brine and water, dried over anhydrous
MgSO4, concentrated in vacuo. Resulting brown syrup was purified on a silica gel column to give
5-substituted oxazole derivatives (4b-d) (62-78%).
Microwave heating: To a stirred solution of 2a (0.8 mmol) in THF (5 mL) were added NaHCO3 (336 mg,
5 equiv) and a solution of methyl -substituted -bromopyruvate (3b-d) (2 equiv) in THF (1 mL) at 0 °C.
The flask was flushed with argon, heated with stirring at reflux under microwave irradiation for 5-72 min.
After cooling to rt, the reaction mixture was diluted with CHCl3 (10 mL) and the organic layer was
washed with brine and water, dried over anhydrous MgSO4, and concentrated in vacuo to give a yellow
syrup. Resulting syrup was dissolved in THF (5 mL), TFAA (trifluoracetic anhydride) (333 L, 3 equiv)
and pyridine (388 L, 6 equiv) were added to the mixture at 0 °C, and stirred for 30 min. The reaction
mixture was concentrated in vacuo to give brown syrup. Resulting syrup was further dissolved in EtOAc
(5 mL), 28% NH4OH (1 mL) was added to the above mixture at 0 °C, and stirred for 15 min. reaction
mixture was poured into brine, washed with brine and water, dried over anhydrous MgSO4, concentrated

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in vacuo. Resulting brown syrup was purified on a silica gel column to give 5-substituted oxazole
derivatives (4b-d)(71-80%).
Methyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)prop-1-en-1-yl]-5-methyloxazole-4-carboxylate
(Cbz-Abu-MeOzl-OMe) (4b): Yield 74%; colorless crystals; mp 136-138 °C (acetone-hexanes); IR
1
(KBr, disk) max 3307, 2953, 1717, 1507 cm-1; H NMR (600 MHz, CDCl3) 1.85 (3H, d, J = 7.2 Hz,
Abu’s CH3), 2.60 (3H, s, ring-CH3), 3.90 (3H, s, OCH3), 5.15 (2H, s, Cbz’s CH2), 6.45 (1H, br s, NH),
6.54 (1H, q, J = 7.2 Hz, vinyl’s H), 7.32-7.37 (5H, m, Cbz’s PhH); 13C NMR (150 MHz, CDCl3) 12.1,
14.0, 52.0, 67.4, 122.8, 127.4, 128.0, 128.2, 128.2, 128.5, 136.0, 153.9, 156.5, 157.8, 162.6. HRMS
(ESI-TOF) m/z: [M+Na]+ calcd for C17H18N2NaO5 353.1113, found 353.1118.
Methyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)prop-1-en-1-yl]-5-isopropyloxazole-4-carboxylate
(Cbz-Abu-i-PrOzl-OMe) (4c): Yield 62%; yellow amorphous; IR (KBr, disk) max 3567, 2979, 1717,
1507 cm-1; 1H NMR (600 MHz, CDCl3) 1.28 (6H, d, J = 7.0 Hz, i-Pr’s CH3 × 2), 1.87 (3H, d, J = 7.2 Hz,
Abu’s CH3), 3.76 (1H, dq, J = 7.0, 7.0 Hz, i-Pr’s CH), 3.90 (3H, s, COOCH3), 5.16 (2H, s, Cbz’s CH2),
13
6.51 (1H, br s, NH), 6.55 (1H, q, J = 7.2 Hz, vinyl’s H), 7.32-7.39 (5H, m, Cbz’s PhH); C NMR (150
MHz, CDCl3) 14.0, 20.6, 26.1, 52.0, 67.4, 122.9, 126.1, 127.3, 128.2, 128.2, 128.5, 136.0, 153.9, 157.5,
162.6, 164.6. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22N2NaO5 381.1426, found: 381.1401.
Methyl
(Z)-2-[1-(((Benzyloxy)carbonyl)amino)prop-1-en-1-yl]-5-phenyloxazole-4-carboxylate
(Cbz-Abu-PhOzl-OMe) (4d): Yield 80%; coloeless needles; mp 148.5-151 °C (acetone-hexanes); IR
1
(KBr, disk) max 3301, 2955, 1724, 1493 cm-1; H NMR (600 MHz, CDCl3) 1.90 (3H, d, J = 7.2 Hz,
Abu’s CH3), 3.93 (3H, s, OCH3), 5.18 (2H, s, Cbz’s CH2), 6.49 (1H, br s, NH), 6.68 (1H, d, J = 7.3 Hz,
vinyl’s H), 7.26-7.48 and 8.00-8.02 (10H, m, Cbz’s PhH); 13C NMR (150 MHz, CDCl3)  14.1, 52.2, 52.3,
67.5, 122.8, 126.7, 127.4, 128.2, 128.3, 128.4, 128.4, 128.5, 128.5, 130.3, 130.5, 135.9, 153.9, 155.4,
157.8, 162.4. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C22H20N2NaO5 415.1270, found 415.1251.
Reaction of 2-methylbutenamide (2j, k) and ethyl -bromopyruvate (3a). To a solution of 2j (2k), (80
mg, 0.8 mmol) in THF (5 mL) were added NaHCO3 (336 mg, 5 equiv) and ethyl -bromopyruvate (3a)
(312 mg, 2 equiv) at 0 °C, and stirred for 2 h at reflux conditions. After cooling to room temperature, the
reaction mixture was diluted with CHCl3 (10 mL), washed with water (10 mL) and brine (10 mL), dried
over anhydrous MgSO4 and concentrated in vacuo to give a yellow syrup. Remaining residue was
dissolved in THF (5mL), TFAA (178 L, 3 equiv) and pyridine (390 L, 6 equiv) were added to the
mixture at 0 °C, and stirred for 30 min. the reaction mixture was concentrated in vacuo to give a brown
syrup. The resulting syrup was further dissolved in EtOAc (5 mL), 28% NH4OH (1 mL) was added to the
mixture at 0 °C. After stirring for 15 min, the reaction mixture was washed with brine and dried over
anhydrous MgSO4, concentrated in vacuo to give 4e and 4f, which were purified on a silica gel column

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HETEROCYCLES, Vol. 85, No. 2, 2012
with hexanes-EtOAc (1:1 v/v).
Ethyl (E)-2-(1-Methyl-1-propen-1-yl)-4-oxazolecarboxylate (4e) (main product): Yield 88%; colorless
1
syrup; IR (KBr, neat) max 3469, 3157, 2983, 2930, 2858, 1742, 1719, 1576, 1541, 1317 cm-1; H NMR
(600 MHz, CDCl3)  1.39 (3H, t, J = 7.1 Hz, Et’s CH3), 1.87 (3H, dq, J = 7.2, 1.1 Hz,-CH3), 2.10 (3H,
dq, J = 1.1, 1.1 Hz, CH3), 4.39 (2H, q, J = 7.1 Hz, Et’s CH2), 6.73 (1H, qq, J = 1.1, 7.2 Hz, vinyl’s H),
13
8.12 (1H, s, ring-H); C NMR (150 MHz, CDCl3)  12.7, 14.1, 14.3, 61.1, 123.9, 131.1, 134.1, 143.0,
161.6, 164.4. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C10H13NNaO3 218.0793, found 218.0748.
NOE correlation: -CH3 ←→ CH3, -CH3 ←no observation→ vinyl’s H
Ethyl (Z)-2-(1-Methyl-1-propen-1-yl)-4-oxazolecarboxylate (4f) (by-product): Yield 5%; colorless
1
syrup; IR (KBr, neat) max 3448, 3157, 2981, 2923, 2852, 1742, 1720, 1575, 1151, 1113 cm-1; H NMR
(600 MHz, CDCl3) 1.39 (3H, t, J = 7.1 Hz, Et’s CH3), 2.11 (3H, dq, J = 7.3, 1.5 Hz,-CH3), 2.15 (3H,
dq, J = 1.5, 1.5 Hz, CH3), 4.40 (2H, q, J = 7.1 Hz, Et’s CH2), 6.04 (1H, qq, J = 1.5, 7.3 Hz, vinyl’s H),
13
8.19 (1H, s, ring-H); C NMR (150 MHz, CDCl3)  14.3, 15.7, 21.2, 61.1, 122.6, 133.2, 133.8, 142.7,
161.6, 163.5. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C10H13NNaO3 218.0793, found 218.0748.
NOE correlation: -CH3 ←no observation→ CH3, -CH3 ←→ vinyl’s H
ACKNOWLEDGEMENTS
This work was supported by the Science Frontier Project of Kanagawa University. We thank Dr. S.
Hanashima (RIKEN Advanced Science Institute) for helpful discussions.
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