4+1 Cycloaddition of N-acylimine derivatives with isocyanides: Efficient synthesis of 5-aminooxazoles and 5-aminothiazoles

Article abstract of DOI:10.1016/j.tet.2014.03.016

[4+1] Cycloaddition reaction between isocyanides and N-acylimine derivatives generated from N-acyl N,O-acetals acting as isocyanophiles has been developed. These reactions proceeded smoothly and cleanly to afford the corresponding 5-aminooxazoles in high

Full text of DOI:10.1016/j.tet.2014.03.016

Tetrahedron 70 (2014) 3005e3010
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[4þ1] Cycloaddition of N-acylimine derivatives with isocyanides:
efficient synthesis of 5-aminooxazoles and 5-aminothiazoles
*
*
Takahiro Soeta , Kaname Tamura, Yutaka Ukaji
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
[4þ1] Cycloaddition reaction between isocyanides and N-acylimine derivatives generated from N-acyl
N,O-acetals acting as isocyanophiles has been developed. These reactions proceeded smoothly and
cleanly to afford the corresponding 5-aminooxazoles in high yields. This reaction was extended to the
syntheses of 5-aminothiazoles by using N-thioacyl N,O-acetals. A wide range of N-acyl N,O-acetals, N-
thioacyl N,O-acetals, and isocyanides were found to be applicable to this reaction.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 9 February 2014
Received in revised form 3 March 2014
Accepted 5 March 2014
Available online 18 March 2014
Keywords:
Isocyanide
Aminooxazole
Aminothiazole
[4þ1] Cycloaddition
1. Introduction
products in moderate yields.10 More recently, Ciufolini reported
that the nucleophilic attack of isocyanides on N-acylimine pre-
Oxazoles and thiazoles are both important classes of heterocy-
clic compounds and are frequently found in pharmaceuticals and
natural products.1,2 They also have applications in optical materials,
serving as scintillant molecules or fluorescent dyes.3 Owing to
these unique properties, various methods of synthesizing oxazole
derivatives have been investigated, and a number of techniques
have recently been developed, including cyclodehydration re-
actions,4 oxidations of oxazolinones,5 direct derivations of the
parent oxazole,6 and metal-catalyzed cross coupling reactions.7
These methods, however, are all highly limited in terms of the
substrates with which they can be used. The use of isocyanides as
reactive components during the synthesis of oxazoles is well
established and the Passerini-type reaction of aldehydes with iso-
cyanoacetamides in the presence of a chiral catalyst has been
shown to afford enantioenriched oxazole derivatives.8 Yu recently
cursors (the a-chloroglycinates) in the presence of an excess of
a Lewis acid gives the corresponding 5-aminooxazoles in good
yields.11 These reactions show a great contribution for the synthesis
of 5-aminooxazoles, although challenges still remain with regard to
limitations in the range of applicable substrates or the reaction
efficiency, especially an excess amount of Lewis acid was required.
Over the past century, a large number of protocols have also been
developed for the synthesis of 5-aminothiazoles, the S-analogues
of the 5-aminooxazoles.12,13 Nevertheless, many possible 5-
aminothiazole derivatives are not readily accessed by employing
the existing preparative methods. To address this deficiency, we
herein report the [4þ1] cycloaddition of isocyanides to N-acylimine
derivatives, catalyzed by an organosilane compound, to afford
various aminooxazoles. In addition, we expand the scope of this
methodology to also synthesize 5-aminothiazoles.
reported
a
variation of this reaction, which generates 5-
The Passerini and Ugi reactions generally require a carboxylic
acid, which activates an aldehyde or imine and traps a nitrilium
cation to form an acyloxylated intermediate. Subsequent acyl
aminooxazoles upon the addition of isocyanoacetamides to car-
balkoxyketenes, which have been generated in situ.9 The first ex-
ample of the synthesis of 5-aminooxazoles was reported by Deyrup
in 1972 and consisted of the nucleophilic addition of isocyanide to
N-acylimine derivatives in the presence of BF3$OEt2 to afford the
transfer leads to the corresponding a-acyloxy or a
-amino amides.14
In our previous studies, either silanol or borinic acid played the role
of the carboxylic acid in the Passerini-type reaction (Eq. 1).15 Based
on our success with these reactions, we reasoned that a compound
composed of an electrophile (Z) and a nucleophile (X) (which we
write in generic form as ZeX) could also perform essentially the
same function as the carboxylic acid in a Passerini or Ugi-type re-
action. In addition, we expanded this concept to the intramolecular
trapping of the nitrilium intermediate in the Ugi-type reaction.
* Corresponding authors. Tel.: þ81 76 264 5700; fax: þ81 76 264 5742; e-mail
addresses: soeta@se.kanazawa-u.ac.jp (T. Soeta), ukaji@staff.kanazawa-u.ac.jp
(Y. Ukaji).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.016

3006
T. Soeta et al. / Tetrahedron 70 (2014) 3005e3010
Thus, when a molecule contains both an electrophile (such as C]N)
and a potential nucleophilic group (Nuꢀ), intramolecular trapping
of the nitrilium intermediate should be readily achieved in a man-
ner similar to the intermolecular version of the reaction (Eq. 2).
Based on this concept, we have developed the catalyst-free [5þ1]
cycloaddition reaction of isocyanides, using C,N-cyclic N0-acyl azo-
methine imines as the ‘isocyanophile’.16 In the work reported
herein, we demonstrate the use of N-acylimines as isocyanophiles
capable of functioning as 1,4-dipoles to afford the desired hetero-
cycles (Eq. 3).
examined the reaction of 1a and tert-butyl isocyanide (2a) in the
presence of Cu(OTf)2, MgCl2, and ZnCl2 in dichloromethane (entries
1e3). Unfortunately, these reactions were very sluggish or gave
a complex mixture of products. In contrast, when the reaction was
carried out in the presence of chlorotrimethylsilane (TMSCl) in
dichloromethane at room temperature, 5-aminooxazole (3aa) was
obtained in 82% yield after 10 min (entry 4).17 When this same
reaction was performed using 10 mol % TMSCl at room tempera-
ture, lower reactivity was observed (entry 5) while conditions in
dichloroethane under reflux in the presence of 10 mol % TMSCl gave
3aa in 88% yield after 10 min (entry 6). Trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) was also found to be effective in
this reaction, and it was gratifying to observe that 10 mol % of
TMSOTf was sufficient to afford 3aa in 96% yield at room temper-
ature after 10 min (entry 7). This reaction proceeded smoothly in
polar, ether, and cyclic ether solvents to generate 3aa in high yields
(entries 9e12). The reactivity was slightly less when toluene was
used as a solvent, likely due to the reduced solubility of substrate 1a
(entry 13). In addition, we found that 1.1 equiv of isocyanide was
sufficient to afford the product in high yield (entry 14). In contrast,
the use of 10 mol % of triflic acid (TfOH) led to the decomposition of
1a such that the desired product was obtained in only 78% yield
(entry 15).
We next examined the range of isocyanides and N-acyl N,O-
acetals (as the N-acylimine precursors), which were applicable to
the present [4þ1] cyclization reaction when using 10 mol %
TMSOTf, with the results summarized in Table 2. From these results,
we found that the optimized reaction conditions were applicable to
a wide variety of isocyanides. The reactions of tertiary isocyanides
(R2¼t-Bu, t-Oct) with 1a gave the products in high yields after
20 min (entries 1 and 2) while, in the case of secondary and primary
isocyanides 2c and 2d, low reactivities were observed to afford the
corresponding products 3ac and 3ad in 69% and 48% yields,
Z
Z
Z–
O
O
OH
O
OH
N+
O
R1
–
C
+
N
R1
R1
ð1Þ
R2
HN
R2
R2
Intermolecular trapping
Z = Ph3Si or Ph2B
+NH2
N
Nu–
Nu–
R2
N
Nu
R1
R1
R1
–
+
ð2Þ
ð3Þ
N+
C
N
R2
N
R2
Intramolecular trapping
R2
R2
N
O
N
O–
+
R1
R1
“Isocyanophile”
1,4-Dipole
N-Acylimine
2. Results and discussions
Table 2
We initially examined the ability of N-acylimines to act as 1,4-
dipolar equivalents, capable of trapping an isocyanide as a C1
source during the synthesis of the corresponding 5-aminooxazole.
Our early work employed the well-known compound N-acyl N,O-
acetal 1a as the N-acylimine precursor, as shown in Table 1, and we
Summary of isocyanides and N-acyl N,O-acetals investigated
R2
R2
TMSOTf
(10 mol%)
N
CN R3
HN
R1
O
O
Table 1
+
R1
Reaction conditions and results for [4þ1] cycloaddition reactions
CH Cl , rt, Time
OMe (1.1 equiv)
2
2
NHR3
3
Ph
Ph
1
2
Additive (mol%)
Solvent, rt, Time
N
Entrya
R1
R3
Time
Yield/%
HN
Ph
O
O
+
CNt-Bu
1
2
3
4
5
6
7
8
9
10
11
12
13b
14b
15b
16c
17d
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
1-Naphthyl (1b)
2-Naphthyl (1c)
4-MeOC6H4 (1d)
4-BrC6H4 (1e)
2-MeC6H4 (1f)
3-MeC6H4 (1g)
4-MeC6H4 (1h)
Ph (1i)
t-Bu (2a)
20 min
20 min
2 h
2 h
3 h
99 (3aa)
81 (3ab)
69 (3ac)
48 (3ad)
79 (3ae)
95 (3af)
98 (3ag)
Messy
51 (3ba)
97 (3ca)
94 (3da)
73 (3ea)
74 (3fa)
83 (3ga)
89 (3ha)
92 (3ia)
80 (3ja)
Ph
(1.5 equiv)
OMe
1a
NHt-Bu
3aa
t-Oct (2b)
c-Hex (2c)
Bn (2d)
2a
Entry
Additive/mol %
Solvent
Time
Yield/%
Ph (2e)
1
2
3
Cu(OTf)2/120
ZnCl2/120
MgCl2/120
TMSCl/120
TMSCl/10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
CH2Cl2
CH2Cl2
AcOEt
MeCN
THF
10 min
18 h
18 h
10 min
24 h
10 min
10 min
10 min
20 min
20 min
20 min
20 min
10 min
20 min
40 min
Messy
48
75
82
Trace
88
96
99
90
81
4-MeOC6H4 (2f)
4-BrC6H4 (2g)
4-O2NC6H4 (2h)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
3 h
24 h
24 h
1 h
1 h
30 min
1 h
24 h
24 h
24 h
1 h
4
5
6a
7
TMSCl/10
TMSOTf/10
TMSOTf/120
TMSOTf/10
TMSOTf/10
TMSOTf/10
TMSOTf/10
TMSOTf/10
TMSOTf/10
TfOH/10
8
9
10
11
12
13
14b
15
88
80
72
99
t-Bu (2a)
t-Bu (2a)
Et2O
Ph (1j)
2 h
Toluene
CH2Cl2
CH2Cl2
a
R2¼H unless otherwise noted.
b
Reaction was carried out in the presence of 1.0 equiv of TMSCl at room
78
temperature.
a
c
The reaction was carried out under reflux.
1.1 equiv of 2a was used.
R2¼Me.
b
d
R2¼Br.

T. Soeta et al. / Tetrahedron 70 (2014) 3005e3010
3007
Table 3
respectively (entries 3 and 4). Phenyl isocyanide (2e) and aromatic
Summary of isocyanides and N-thioacyl N,O-acetals investigated
isocyanides bearing electron donating or withdrawing groups at
the para position also generated the corresponding heterocycles in
high yields, although the reactivities of these compounds were
lower than those exhibited by the aliphatic isocyanides (entries
5e7). Especially in the case of 4-nitrophenyl isocyanide (2h), a very
complex mixture of products was produced (entry 8). The reactivity
of various N-acyl N,O-acetals functioning as N-acylimine precursors
with tert-butyl isocyanide (2a) was next examined by combining
1.0 equiv of the N-acyl N,O-acetals 1aej and 1.1 equiv of 2a. In the
case of the N-acylimine precursor 1b, derived from 1-
naphthaldehyde, the reaction was somewhat complex and the
desired product 3ba was obtained in only 51% yield. In contrast, 1c
(from 2-naphthaldehyde) was found to work well as a substrate
and the respective product 3ca was obtained in 97% yield (entries 9
and 10). We also examined substituted N-acyl N,O-acetals bearing
electron-donating groups on the aromatic ring and similar levels of
reactivity were observed with the 4-methoxyphenyl-substituted N-
acyl N,O-acetal 1d (entry 11). In the case of the substituted N-acyl
N,O-acetal 1e (with an electron-withdrawing group on the aro-
matic ring), the desired product 3ea was obtained in 73% yield
(entry 12).
TMSOTf was found to be ineffective when reacting
methylphenyl-substituted substrates and generated a complex
mixture of products. We therefore performed subsequent reactions
using 1.0 equiv of TMSCl as the promoter, which fortunately,
allowed the reactions to proceed cleanly to afford the appropriate
products. With regard to the substitution pattern of the N-acyl N,O-
acetal, the 2-, 3-, and 4-methylphenyl substituents were all well
tolerated, furnishing the corresponding 5-aminooxazoles in good
yields (entries 13e15).
The effects of varying the substituent on the benzoyl group at-
tached to the nitrogen were also examined and demonstrated that
a methyl group on the aromatic moiety was more effective than
a bromide, since these two groups resulted in 92% and 80% yields,
respectively (entries 16 and 17). From these results, it was de-
termined that the electron density of the N-acyl moiety plays an
important role in trapping the nitrilium intermediate prior to the
cyclization.
We have also attempted to use the reaction of N-thioacyl N,O-
acetals with isocyanides in the presence of organosilane com-
pounds as a means of preparing 5-aminothiazoles, with the results
summarized in Table 3. The general reactivities of the N-thioacyl
N,O-acetals were observed to be lower than those of the N-acyl
N,O-acetals, such that the reaction of 4a with 1.1 equiv of 2a in the
presence of 10 mol % of TMSOTf gave the desired 5-aminothiazole
5aa in approximately 60% yield even when refluxing in CH2Cl2
(entries 1 and 2). The decomposition of 4a was also observed
under these conditions. Substituting TMSCl for TMSOTf allowed
the intact recovery of the original 4a although the reaction did not
proceed at all (entry 3). We eventually determined that the re-
action of 4a with 2a in the presence of 10 mol % of TMSCl in di-
chloroethane under reflux conditions gave the product 5aa in 94%
yield (entry 4).
Ph
Ph
TMSCl
N
(10 mol%)
HN
R1
S
CN R3
S
+
R1
(CH2Cl)2, reflux, 24 h
OMe (1.1 equiv)
NHR3
5
4
2
Entry
R1
R3
Yield/%
1a
2b
3c
4
5
6
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Oct (2b)
c-Hex (2c)
Bn (2d)
60 (5aa)
58 (5aa)
No reaction
94 (5aa)
84 (5ab)
83 (5ac)
Messy
7
8
Ph (4a)
Ph (2e)
Messy
9d
10d
11
12
13
14
1-Naphthyl (4b)
2-Naphthyl (4c)
2-MeC6H4 (4d)
3-MeC6H4 (4e)
4-MeC6H4 (4f)
4-BrC6H4 (4g)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
90 (5ba)
93 (5ca)
72 (5da)
63 (5ea)
78 (5fa)
No reaction
a
Reaction was carried out in the presence of 10 mol % of TMSOTf at room tem-
perature in CH2Cl2.
b
Reaction was carried out in the presence of 10 mol % of TMSOTf in CH2Cl2 under
reflux.
c
Reaction was carried out at room temperature in CH2Cl2.
Reactions were carried out in the presence of 1.0 equiv of TMSCl at room
d
temperature.
obtained from 2-naphthaldehyde were found to work well as
substrates by the use of 1.0 equiv of TMSCl and the respective
products 5ba and 5ca were obtained in 90% and 93% yields, re-
spectively (entries 9 and 10). Regarding the substitution pattern of
the N-thioacyl N,O-acetal, the reaction proceeded despite the ad-
dition of 2-, 3-, and 4-methylphenyl substituents to the aromatic
ring, furnishing the corresponding products (entries 11e13). In
contrast, when an N-thioacyl N,O-acetal 4g with an electron-
withdrawing aromatic substituent was applied, the reaction did
not proceed at all and only the starting material was recovered
(entry 14).
In Scheme 1, we present our proposed mechanism for the [4þ1]
cycloaddition. In this mechanism, the methoxy group of the N-acyl
N,O-acetal (Y¼O) is activated by the organosilane compound and
leaves, giving the N-acylimine derivative, which subsequently re-
acts with the isocyanide. The nitrilium intermediate thus generated
is then trapped in an intramolecular fashion by the oxygen of the
amide group to form the desired product. Based on the data pre-
sented in Table 1 (entry 15), triflic acid was not particularly effec-
tive, whereas TMSCl and TMSOTf may be able to regenerate during
the reaction process and thus act as efficient catalysts.18 The re-
action mechanism associated with the syntheses of 5-
aminothiazoles (Y¼S) may well be the same as the above mecha-
nism proposed for N-acyl N,O-acetals.
We subsequently examined the ranges of isocyanides and N-
thioacyl N,O-acetals applicable to the present [4þ1] cyclization
reaction, as shown in entries 5e14. The reactions of the aliphatic
isocyanides (R3¼t-Bu, t-Oct or c-Hex) with 4a gave the corre-
sponding 5-aminothiazole derivatives in high yields (entries 4e6).
In the cases of benzyl isocyanide (2d) and phenyl isocyanide (2e),
however, the reactions were complicated and the desired 5-
aminothiazoles were not obtained (entries 7 and 8). The re-
activities of various N-thioacyl N,O-acetals with tert-butyl iso-
cyanide (2a) were also examined by combining these compounds
with 1.1 equiv of 2a in the presence of TMSCl. Both the N-thio-
acylimine precursor 4b derived from 1-naphthaldehyde and that 4c
3. Conclusion
In conclusion, we have developed and demonstrated a [4þ1]
cycloaddition reaction between isocyanides and N-acylimine de-
rivatives generated from N-acyl N,O-acetals acting as iso-
cyanophiles. These reactions proceeded smoothly and cleanly to
afford the corresponding 5-aminooxazoles in high yields. This re-
action was extended to the syntheses of 5-aminothiazoles by using
N-thioacyl N,O-acetals. A wide range of N-acyl N,O-acetals, N-thi-
oacyl N,O-acetals, and isocyanides were found to be applicable to
this reaction.

3008
T. Soeta et al. / Tetrahedron 70 (2014) 3005e3010
Scheme 1. Proposed reaction mechanism.
4. Experimental section
1190, 1070, 970 cmꢀ1. HRMS-FAB (m/z): calcd for C19H21N2O
[MþþH]: 293.1654. Found: 293.1652.
4.1. General
4.2.2. 2,4-Diphenyl-N-(2,4,4-trimethylpentan-2-yl)oxazol-5-amine
1H NMR was recorded on a JEOL ECS 400 (400 MHz) NMR
(3ab). Silica gel column chromatography (hexane/ethyl acetate¼5/
spectrometer. Chemical shifts
d
are reported in parts per million
1) gave 3ab (85 mg, 81% yield) as a white solid of
using TMS as an internal standard. Data are reported as follows:
chemical shift, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet), coupling constant (J), and integration.
13C NMR spectra were recorded on JEOL ECS 400 (100 MHz) NMR
mp¼135.2e136.0 ꢂC (hexane/ethyl acetate). 1H NMR (CDCl3): 1.07
(s, 9H),1.38 (s, 6H),1.72 (s, 2H), 7.25 (m, 2H), 7.37e7.45 (m, 5H), 7.83
(d, J¼8.2 Hz, 2H), 8.00 (d, J¼8.2 Hz, 2H). 13C NMR (CDCl3): 30.2, 31.7,
31.8, 55.0, 57.8, 125.5, 125.6, 127.8, 127.9, 128.6, 128.7, 128.9, 129.3,
132.9, 148.2, 154.4. IR (KBr): 3280, 2940, 1630, 1540, 1450, 1340,
1070, 970 cmꢀ1. HRMS-ESI (m/z): calcd for C23H28N2ONa [MþþNa]:
371.2099. Found: 371.2101.
spectrometer. The chemical shifts were determined in the
d-scale
relative to CDCl3
(
d
¼77.0 ppm). The IR spectra were measured on
JASCO FT/IR-230 spectrometers. The MS spectra were recorded
with JEOL SX-102A mass spectrometer and Bruker microtof II. All
of the melting points were measured with YANAGIMOTO micro
melting point apparatus. Dehydrated solvents were purchased for
the reactions and used without further desiccation. Flash column
chromatography was performed by using Cica silica gel 60N,
spherical neutral (37563-84).
4.2.3. N-Cyclohexyl-2,4-diphenyloxazol-5-amine (3ac). Silica gel
column chromatography (benzene/ethyl acetate¼20/1) gave 3ac
(132 mg, 69% yield, 0.6 mmol scale) as a white amorphous. 1H NMR
(benzene-d6): 0.74e1.37 (m, 8H), 1.55e1.66 (m, 2H), 3.02 (m, 1H),
6.87 (m, 1H), 7.02e7.10 (m, 6H), 7.26 (t, J¼7.8 Hz, 2H), 8.10 (t,
J¼7.8 Hz, 2H). 13C NMR (benzene-d6): 24.9, 25.8, 34.0, 54.9, 125.8,
125.9, 126.4, 127.8, 128.5, 128.9, 129.3, 132.5, 133.9, 149.3, 154.0. IR
(KBr): 3320, 2930, 2850, 1740, 1650, 1600, 1450, 1220 cmꢀ1. HRMS-
ESI (m/z): calcd for C21H22N2ONa [MþþNa]: 341.1630. Found:
341.1633.
N-Acyl N,O-acetals 1 and N-thioacyl N,O-acetals 4 were prepared
following the literature.19
4.2. General procedure for the [4D1] cycloaddition reaction
of N-acylimine precursor with isocyanide
4.2.4. N-Benzyl-2,4-diphenyloxazol-5-amine (3ad). Silica gel col-
umn chromatography (benzene/ethyl acetate¼20/1) gave 3ad
(47 mg, 48% yield) as a white amorphous. 1H NMR (benzene-d6):
4.88 (s, 2H), 7.18e7.26 (m, 7H), 7.40e7.47 (m, 6H), 7.92 (m, 2H), 8.24
(s, 1H). 13C NMR (benzene-d6): 49.0, 126.0, 126.4, 126.8, 128.2, 128.6,
128.7, 128.8, 129.2, 129.5, 130.1, 133.5, 135.1, 140.4, 158.9, 162.4. IR
(KBr): 3340, 2930, 1700, 1640, 1550, 1500, 1450, 1330 cmꢀ1. HRMS-
ESI (m/z): calcd for C22H18N2ONa [MþþNa]: 349.1317. Found:
349.1322.
To a solution of 1 (0.30 mmol) and 2 (0.33 mmol) in CH2Cl2
(2.7 mL), TMSOTf (0.03 mmol, 10 mol %) in CH2Cl2 (0.3 mL) was
added and the whole was stirred at room temperature. The reaction
mixture was diluted with satd NaHCO3 aq (3 mL), then, organic
layer was separated. The aqueous layer was extracted with CHCl3
(3 mLꢁ3) and combined organic layers were washed with brine,
dried over Na2SO4 then, concentrated. The residue was purified by
silica gel column chromatography.
4.2.1. N-(tert-Butyl)-2,4-diphenyloxazol-5-amine (3aa). Silica gel
column chromatography (hexane/ethyl acetate¼5/1) gave 3aa
(87 mg, 99% yield) as a white solid of mp¼108.5e109.0 ꢂC (hexane/
ethyl acetate). 1H NMR (CDCl3): 1.36 (s, 9H), 7.25 (m, 2H), 7.39e7.47
(m, 5H), 7.92 (d, J¼8.7 Hz, 2H), 8.04 (d, J¼8.7 Hz, 2H). 13C NMR
(CDCl3): 30.3, 54.2, 125.1, 125.6, 125.8, 126.5, 127.9, 128.5, 128.6,
129.5, 132.6, 147.9, 155.0. IR (KBr): 3260, 2960, 1630, 1450, 1340,
4.2.5. N,2,4-Triphenyloxazol-5-amine (3ae). Silica gel column
chromatography (hexane/ethyl acetate¼5/1) gave 3ae (74 mg, 79%
yield) as a yellow solid of mp¼130.1e131.0 ꢂC (EtOH). 1H NMR
(CDCl3): 5.66 (br s, 1H), 6.82 (d, J¼7.8 Hz, 2H), 6.92 (t, J¼7.8 Hz, 1H),
7.23e7.29 (m, 3H), 7.37 (t, J¼7.8 Hz, 2H), 7.43e7.48 (m, 3H), 7.91 (d,
J¼8.7 Hz, 2H), 8.06 (m, 2H). 13C NMR (CDCl3): 114.5, 120.6, 126.1,
126.1, 127.5, 127.6, 128.5, 128.7, 129.5, 130.2, 130.8, 131.1, 141.4, 143.5,

T. Soeta et al. / Tetrahedron 70 (2014) 3005e3010
3009
157.4. IR (KBr): 3230, 3030,1640, 1600,1540,1500,1330, 1260,1080,
990 cmꢀ1. HRMS-ESI (m/z): calcd for C21H16N2ONa [MþþNa]:
335.1160. Found: 335.1156.
FAB (m/z): calcd for C19H20BrN2O [MþþH]: 371.0759. Found:
371.0766.
4.2.12. N-(tert-Butyl)-2-phenyl-4-(o-tolyl)oxazol-5-amine
4.2.6. N-(4-Methoxyphenyl)-2,4-diphenyloxazol-5-amine
(3fa). Silica
gel
column
chromatography
(hexane/ethyl
(3af). Silica gel column chromatography (hexane/ethyl acetate¼5/
acetate¼10/1) gave 3fa (67 mg, 73% yield) as a yellow amorphous.
1H NMR (CDCl3): 1.21 (s, 9H), 2.31 (s, 3H), 7.12e7.21 (m, 3H),
7.24e7.38 (m, 5H), 7.94 (d, J¼7.3 Hz, 2H). 13C NMR (CDCl3): 20.5,
30.1, 53.8, 123.0, 125.4, 125.8, 127.9, 128.6, 129.3, 129.6, 130.6, 131.2,
133.6, 137.6, 149.1, 154.1. IR (KBr): 3230, 2970, 1720, 1680, 1600,
1510, 1230, 1030 cmꢀ1. HRMS-ESI (m/z): calcd for C20H22N2ONa
[MþþNa]: 329.1630. Found: 329.1633.
1) gave 3af (97 mg, 95% yield) as
a yellow solid of
mp¼110.5e111.3 ꢂC (EtOH). 1H NMR (CDCl3): 3.70 (s, 3H), 5.47 (br s,
1H), 6.71e6.77 (m, 4H), 7.20 (m, 1H), 7.31 (t, J¼8.2 Hz, 2H),
7.37e7.40 (m, 3H), 7.83 (d, J¼8.2 Hz, 2H), 7.98 (m, 2H). 13C NMR
(CDCl3): 55.5, 114.8, 116.0, 126.0, 127.3, 127.4, 128.4, 128.6, 128.7,
129.5, 130.0, 131.2, 137.0, 142.5, 154.0, 156.9. IR (KBr): 3340, 2830,
1640, 1510, 1290, 1230, 1080, 1040, 990 cmꢀ1. HRMS-FAB (m/z):
calcd for C22H19N2O2 [MþþH]: 343.1447. Found: 343.1441.
4.2.13. N-(tert-Butyl)-2-phenyl-4-(m-tolyl)oxazol-5-amine
(3ga). Silica gel column chromatography (hexane/ethyl acetate¼5/
1) gave 3ga (76 mg, 83% yield) as a yellow oil. 1H NMR (CDCl3): 1.29
(s, 9H), 2.33 (s, 3H), 6.99 (d, J¼7.3 Hz, 1H), 7.22 (t, J¼7.8 Hz, 1H),
7.30e7.39 (m, 4H), 7.60 (d, J¼7.8 Hz, 1H), 7.68 (br s, 1H), 7.95 (m,
2H). 13C NMR (CDCl3): 21.6, 30.3, 54.1, 122.6, 125.0, 125.6, 126.6,
127.3, 127.9, 128.4, 128.6, 129.4, 132.5, 138.1, 147.9, 154.9. IR (KBr):
3290, 2970, 1640, 1550, 1450, 1370, 1210, 1070 cmꢀ1. HRMS-ESI (m/
z): calcd for C20H23N2O [MþþH]: 307.1810. Found: 307.1809.
4.2.7. N-(4-Bromophenyl)-2,4-diphenyloxazol-5-amine (3ag). Silica
gel column chromatography (hexane/ethyl acetate¼10/1) gave 3ag
(115 mg, 98% yield) as a yellow amorphous. 1H NMR (CDCl3): 5.67
(br s, 1H), 6.59 (d, J¼8.7 Hz, 2H), 7.18e7.32 (m, 5H), 7.34e7.37 (m,
3H), 7.79 (d, J¼6.8 Hz, 2H), 7.97 (m, 2H). 13C NMR (CDCl3): 112.7,
116.2, 126.1, 126.2, 127.2, 127.8, 128.6, 128.7, 130.4, 130.7, 131.1, 132.3,
141.7,142.6,157.7. IR (KBr): 3370, 3060,1640,1600,1490,1330,1240,
1070 cmꢀ1. HRMS-ESI (m/z): calcd for C21H16BrN2O [MþþH]:
391.0446. Found: 391.0443.
4.2.14. N-(tert-Butyl)-2-phenyl-4-(p-tolyl)oxazol-5-amine
(3ha). Silica
gel
column
chromatography
(hexane/ethyl
4.2.8. N-(tert-Butyl)-4-(naphthalen-1-yl)-2-phenyloxazol-5-amine
acetate¼10/1) gave 3ha (81 mg, 89% yield) as a yellow amorphous.
1H NMR (CDCl3): 1.26 (s, 9H), 2.29 (s, 3H), 7.14 (d, J¼8.3 Hz, 2H), 7.18
(s, 1H), 7.30e7.39 (m, 3H), 7.74 (d, J¼7.8 Hz, 2H), 7.96 (d, J¼7.8 Hz,
2H). 13C NMR (CDCl3): 21.3, 30.3, 54.2, 125.5, 125.6, 125.8, 127.8,
128.0, 129.2, 129.5, 133.0, 136.3, 147.5, 155.0. IR (KBr): 3260, 2970,
1640, 1550, 1480, 1360, 1230, 1070 cmꢀ1. HRMS-ESI (m/z): calcd for
(3ba). Silica gel column chromatography (hexane/ethyl acetate¼5/
1) gave 3ba (52 mg, 51% yield) as
a white solid of
mp¼133.3e134.5 ꢂC (hexane/ethyl acetate). 1H NMR (CDCl3): 1.20
(s, 9H), 7.35e7.46 (m, 7H), 7.72 (d, J¼6.7 Hz, 1H), 7.77 (d, J¼7.8 Hz,
1H), 7.81 (m, 1H), 7.99 (d, J¼6.7 Hz, 2H), 8.03 (m, 1H). 13C NMR
(CDCl3): 30.2. 53.8, 120.8, 125.4, 125.5, 125.7, 126.0, 126.3, 127.4,
127.7, 128.3, 128.4, 128.7, 129.3, 129.4, 131.7, 134.0, 150.2, 154.3. IR
(KBr): 3290, 1650, 1550, 1330, 1170, 1080 cmꢀ1. HRMS-ESI (m/z):
calcd for C23H23N2O [MþþH]: 343.1810. Found: 343.1809.
C
20H22N2ONa [MþþNa]: 329.1630. Found: 329.1632.
4.2.15. N-(tert-Butyl)-4-phenyl-2-(p-tolyl)oxazol-5-amine
(3ia). Silica gel column chromatography (hexane/ethyl acetate¼5/
1) gave 3ia (84 mg, 92% yield) as
a white solid of
4.2.9. N-(tert-Butyl)-4-(naphthalen-2-yl)-2-phenyloxazol-5-amine
mp¼110.0e110.6 ꢂC (hexane/ethyl acetate). 1H NMR (CDCl3): 1.27
(s, 9H), 2.33 (s, 3H), 7.16e7.19 (m, 4H), 7.33 (t, J¼7.8 Hz, 2H),
7.83e7.86 (m, 4H). 13C NMR (CDCl3): 21.4, 30.3, 54.2, 125.2, 125.6,
125.8, 126.5, 128.4, 128.8, 129.3, 132.7, 139.7, 147.5, 155.4. IR (KBr):
3260, 2970, 1640, 1500, 1360, 1200, 1070, 970 cmꢀ1. HRMS-ESI (m/
z): calcd for C20H22N2O [MþþNa]: 329.1630. Found: 329.1629.
(3ca). Silica
gel
column
chromatography
(hexane/ethyl
acetate¼10/1) gave 3ca (100 mg, 97% yield) as a yellow solid of
mp¼138.0e139.0 ꢂC (hexane/ethyl acetate). 1H NMR (CDCl3): 1.38
(s, 9H), 7.42e7.49 (m, 6H), 7.82 (d, J¼7.7 Hz, 1H), 7.88 (m, 2H), 8.06
(d, J¼7.7 Hz, 2H), 8.14 (d, J¼8.7 Hz, 1H), 8.36 (s, 1H). 13C NMR
(CDCl3): 30.4, 54.4, 124.3, 125.6, 125.7, 125.8, 126.1, 127.6, 127.9,
128.0, 128.1, 128.7, 128.9, 129.2, 130.2, 132.3, 133.6, 148.2, 155.3. IR
(KBr): 3260, 2960, 1630, 1340, 1200, 1070 cmꢀ1. HRMS-ESI (m/z):
calcd for C23H22N2ONa [MþþNa]: 365.1630. Found: 365.1633.
4.2.16. 2-(4-Bromophenyl)-N-(tert-butyl)-4-phenyloxazol-5-amine
(3ja). Silica gel column chromatography (hexane/ethyl acetate¼5/
1) gave 3ja (89 mg, 80% yield) as
a white solid of
mp¼115.2e115.9 ꢂC (EtOH). 1H NMR (CDCl3): 1.29 (s, 9H), 7.15e7.22
(m, 2H), 7.35 (t, J¼7.8 Hz, 2H), 7.54 (d, J¼8.2 Hz, 2H), 7.84 (d,
J¼8.2 Hz, 2H), 7.92 (d, J¼7.8 Hz, 2H). 13C NMR (CDCl3): 30.3, 54.2,
123.8, 124.9, 125.7, 126.7, 127.1, 128.5, 128.6, 131.9, 132.3, 148.2,
4.2.10. N-(tert-Butyl)-4-(4-methoxyphenyl)-2-phenyloxazol-5-
amine (3da). Silica gel column chromatography (hexane/ethyl
acetate¼10/1) gave 3da (90 mg, 94% yield) as a white solid of
mp¼78.4e79.1 ꢂC (EtOH). 1H NMR (CDCl3): 1.25 (s, 9H), 3.77 (s, 3H),
6.88 (d, J¼9.1 Hz, 2H), 7.19 (s, 1H), 7.32e7.38 (m, 3H), 7.83 (d,
J¼9.1 Hz, 2H), 7.96 (m, 2H). 13C NMR (CDCl3): 30.3, 54.2, 55.2, 113.4,
125.2, 125.6, 126.6, 127.3, 128.0, 128.6, 129.5, 146.7, 155.4, 158.4. IR
154.0. IR (KBr): 3260, 2960, 1630, 1540, 1500, 1440, 1360, 1190 cmꢀ1
.
HRMS-DART (m/z): calcd for C19H20BrN2O [MþþH]: 371.0759.
Found: 371.0751.
(KBr): 3260, 2960, 1640, 1600, 1540, 1510, 1360, 1250, 1070 cmꢀ1
.
4.2.17. N-(tert-Butyl)-2,4-diphenylthiazol-5-amine (5aa). Silica gel
column chromatography (hexane/ethyl acetate¼10/1) gave 5aa
(87 mg, 94% yield) as a yellow oil. 1H NMR (CDCl3): 1.25 (s, 9H),
HRMS-DART (m/z): calcd for C20H23N2O2 [MþþH]: 323.1760. Found:
323.1759.
7.24e7.39 (m, 7H), 7.72 (d, J¼7.8 Hz, 2H), 7.83 (d, J¼7.8 Hz, 2H). 13
C
4.2.11. 4-(4-Bromophenyl)-N-(tert-butyl)-2-phenyloxazol-5-amine
(3ea). Silica gel column chromatography (hexane/ethyl
acetate¼5/1) gave 3ea (81 mg, 73% yield) as a white solid
of mp¼118.4e119.0 ꢂC (hexane/ethyl acetate). 1H NMR (CDCl3):
1.27 (s, 9H), 7.34e7.38 (m, 4H), 7.45 (d, J¼8.2 Hz, 2H), 7.78 (d,
J¼8.2 Hz, 2H), 7.94 (m, 2H). 13C NMR (CDCl3): 30.3, 54.3, 120.2,
125.2, 125.7, 127.4, 127.6, 128.7, 129.7, 131.4, 147.7, 155.4. IR (KBr):
3260, 2970, 1640, 1540, 1490, 1360, 1200, 1070, 970 cmꢀ1. HRMS-
NMR (CDCl3): 29.5, 53.5, 125.6, 127.1, 127.1, 127.9, 128.7, 128.8, 128.9,
134.2, 135.2, 141.2, 155.2. IR (KBr): 3360, 3060, 2970, 1700, 1600,
1520, 1370, 1200 cmꢀ1. HRMS-ESI (m/z): calcd for C19H20N2SNa
[MþþNa]: 331.1245. Found: 331.1247.
4.2.18. 2,4-Diphenyl-N-(2,4,4-trimethylpentan-2-yl)thiazol-5-amine
(5ab). Silica
gel
column
chromatography
(hexane/ethyl
acetate¼10/1) gave 5ab (92 mg, 84% yield) as a yellow oil. 1H NMR

3010
T. Soeta et al. / Tetrahedron 70 (2014) 3005e3010
(CDCl3): 0.92 (s, 9H), 1.29 (s, 6H), 1.58 (s, 2H), 7.20e7.26 (m, 2H),
1370,1220 cmꢀ1. HRMS-ESI (m/z): calcd for C20H22N2SNa [MþþNa]:
7.28e7.38 (m, 5H), 7.66 (d, J¼7.3 Hz, 2H), 7.82 (d, J¼7.3 Hz, 2H). 13
C
345.1401. Found: 345.1402.
NMR (CDCl3): 29.5, 31.5, 31.6, 53.2, 57.0, 125.4, 127.0, 127.9, 128.6,
128.7, 128.7, 134.2, 135.2, 138.5, 141.9, 153.9. IR (KBr): 3390, 2960,
1660, 1600, 1580, 1490, 1370, 1220, 1070 cmꢀ1. HRMS-ESI (m/z):
calcd for C23H28N2SNa [MþþH]: 387.1871. Found: 387.1879.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Young
Scientists (B) (24750037) and a Grant-in-Aid for Scientific Research
(B) (24350022) from the Japan Society for the Promotion of Science.
4.2.19. N-Cyclohexyl-2,4-diphenylthiazol-5-amine (5ac). Silica gel
column chromatography (hexane/ethyl acetate¼10/1) gave 5ac
(83 mg, 83% yield) as a yellow oil. 1H NMR (CDCl3): 1.14e1.32 (m,
5H), 1.55 (m, 1H), 1.68 (m, 2H), 2.07 (m, 2H), 3.00 (m, 1H), 4.10 (d,
J¼7.3 Hz, 1H), 7.20e7.25 (m, 2H), 7.30 (t, J¼7.8 Hz, 2H), 7.38 (t,
J¼7.8 Hz, 2H), 7.69 (d, J¼8.2 Hz, 2H), 7.79 (d, J¼8.2 Hz, 2H). 13C NMR
(CDCl3): 24.7, 25.6, 33.4, 59.1, 125.2, 126.5, 127.1, 128.4, 128.6, 129.2,
133.9, 134.4, 135.4, 145.8, 151.6. IR (KBr): 3380, 2930, 2860, 1670,
Supplementary data
A Supplementary data file (1H and 13C NMR) of newly synthe-
sized is available. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2014.03.016.
1590, 1490, 1360, 1070 cmꢀ1
C
. HRMS-ESI (m/z): calcd for
References and notes
21H22N2SNa [MþþNa]: 357.1401. Found: 357.1399.
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(5ba). Silica gel column chromatography (hexane/ethyl
acetate¼10/1) gave 5ba (97 mg, 90% yield) as a yellow oil. 1H NMR
(benzene-d6): 1.15 (s, 9H), 7.29e7.34 (m, 8H), 7.78 (d, J¼7.8 Hz, 1H),
7.84 (d, J¼7.3 Hz, 2H), 7.89 (d, J¼7.3 Hz, 2H). 13C NMR (benzene-d6):
29.4, 53.7, 125.6, 125.8, 126.1, 126.5, 127.6, 128.3, 128.3, 128.4, 128.9,
129.2, 131.1, 132.1, 133.5, 134.1, 137.8, 142.7, 155.4. IR (KBr): 3380,
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(5ca). Silica
gel
column
chromatography
(hexane/ethyl
8. (a) Zeng, X.; Ye, K.; Lu, M.; Chua, P. J.; Tan, B.; Zhong, G. Org. Lett. 2010, 12,
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(benzene-d6): 1.24 (s, 9H), 7.26e7.41 (m, 6H), 7.75e7.96 (m, 6H),
8.18 (br s, 1H). 13C NMR (benzene-d6): 29.5, 53.7, 125.7, 125.9, 126.1,
126.4, 126.5, 127.6, 128.0, 128.3, 128.7, 129.9, 132.4, 132.5, 133.4,
134.0, 140.1, 142.0, 155.6. IR (KBr): 3380, 2970, 1600, 1520, 1500,
1470, 1400, 1220 cmꢀ1. HRMS-ESI (m/z): calcd for C23H22N2SNa
[MþþNa]: 381.1401. Found: 381.1405.
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4.2.22. N-(tert-Butyl)-2-phenyl-4-(o-tolyl)thiazol-5-amine
(5da). Silica gel column chromatography (benzene/ethyl
acetate¼10/1) gave 5da (70 mg, 72% yield) as a yellow oil. 1H NMR
(CDCl3): 1.19 (s, 9H), 2.23 (s, 3H), 7.18e7.34 (m, 8H), 7.83 (d,
J¼6.9 Hz, 2H). 13C NMR (CDCl3): 20.0, 29.4, 53.2, 125.4, 125.9, 128.2,
128.6, 129.9, 130.8, 133.5, 134.1, 138.1, 139.7, 142.1, 154.5. IR (KBr):
3350, 2970, 1690, 1600, 1540, 1360, 1220 cmꢀ1. HRMS-ESI (m/z):
calcd for C20H22N2SNa [MþþNa]: 345.1401. Found: 345.1400.
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4.2.23. N-(tert-Butyl)-2-phenyl-4-(m-tolyl)thiazol-5-amine
(5ea). Silica gel column chromatography (benzene/ethyl
acetate¼10/1) gave 5ea (61 mg, 63% yield) as a yellow oil. 1H NMR
(CDCl3): 1.19 (s, 9H), 2.23 (s, 3H), 7.18e7.34 (m, 8H), 7.84 (d,
J¼6.9 Hz, 2H). 13C NMR (CDCl3): 21.5, 29.4, 53.7, 124.8, 125.7, 128.1,
128.6, 128.7, 129.0, 129.1, 129.2, 133.8, 134.5, 138.5, 141.4, 155.3. IR
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4341e4343.
16. (a) Soeta, T.; Tamura, K.; Fujinami, S.; Ukaji, Y. Org. Biomol. Chem. 2013, 11,
2168e2174; (b) Soeta, T.; Tamura, K.; Ukaji, Y. Org. Lett. 2012, 14, 1226e1229.
17. We have already revealed that TMSCl functions as an excellent promoter to-
ward the addition reaction of isocyanide in the Ugi-type reaction: Soeta, T.;
Fujinami, S.; Ukaji, Y. J. Org. Chem. 2012, 77, 9878e9883.
18. When we have examined the reaction of 1a with 2a in the presence of TMSOMe
(1.0 equiv) in CH2Cl2 at room temperature, the desired 3aa was not obtained
and the most of starting 1a was recovered.
19. (a) Gizecki, P.; Dhal, R.; Poulard, C.; Gosselin, P.; Dujardin, G. J. Org. Chem. 2003,
68, 4338e4344; (b) Erbea, R.; Panossian, S.; Giordano, C. Synthesis 1977,
250e252.
(m/z): calcd for
345.1398.
C
20H22N2SNa [MþþNa]: 345.1401. Found:
4.2.24. N-(tert-Butyl)-2-phenyl-4-(p-tolyl)thiazol-5-amine
(5fa). Silica gel column chromatography (benzene/ethyl
acetate¼10/1) gave 5fa (75 mg, 78% yield) as a yellow oil. 1H NMR
(CDCl3): 1.25 (s, 9H), 2.32 (s, 3H), 7.17e7.19 (m, 3H), 7.25e7.34 (m,
3H), 7.60 (d, J¼8.2 Hz, 2H), 7.85 (d, J¼8.2 Hz, 2H). 13C NMR (CDCl3):
21.2, 29.4, 53.5, 125.2, 125.4, 127.8, 128.7, 129.3, 132.1, 134.1, 136.8,
140.3, 141.2, 155.2. IR (KBr): 3320, 2970, 1660, 1600, 1530, 1500,