Single-Step Synthesis of Iodinated Oxazoles from N-Propargyl Amides Mediated by I2/Iodosylbenzene/Trimethylsilyl Trifluoromethanesulfonate Systems

Article abstract of DOI:10.1021/acs.joc.7b01563

A combination of I₂, iodosylbenzene, and trimethylsilyl trifluoromethanesulfonate (TMSOTf) is effective for single-step synthesis of iodinated oxazoles from N-propargyl amides via the aromatization of the iodocyclized intermediates, which has difficulty proceeding through conventional iodocyclization methods. Compared to the former method consisting of the metal-catalyzed cyclization of N-propargyl amides followed by halogenation of alkylideneoxazolines, the present reaction provides a facile and metal-free procedure.

Full text of DOI:10.1021/acs.joc.7b01563

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Note
Single-Step Synthesis of Iodinated Oxazoles from N-Propargyl
Amides Mediated by I2/Iodosylbenzene/TMSOTf Systems
Sho Suzuki, and Akio Saito
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01563 • Publication Date (Web): 17 Aug 2017
Downloaded from http://pubs.acs.org on August 18, 2017
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The Journal of Organic Chemistry
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Single-Step Synthesis of Iodinated Oxazoles from N-
Propargyl Amides Mediated by I2/Iodosylbenzene/TMSOTf
Systems
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Sho Suzuki and Akio Saito*
Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo
184ꢀ8588, Japan
ABSTRACT: A combination of I2, iodosylbenzene and TMSOTf is effective on a singleꢀstep synthesis of iodinated oxazoles from
Nꢀpropargyl amides via the aromatization of the iodocyclized intermediates, which is difficult to proceed by the conventional iodoꢀ
cyclization methods. Compared to the former method consisting of the metalꢀcatalyzed cyclization of Nꢀpropargyl amides followed
by halogenation of alkylideneoxazolines, the present reaction provides facile and metalꢀfree procedure.
Iodocyclization of unsaturated compounds bearing heteroatom
nucleophiles provides a facile formation of heterocycles conꢀ
comitant with the introduction of further functionalizable iodo
components.1 For the synthesis of the iodinated aromatic hetꢀ
erocycles, the iodocyclizations of various alkynes via endoꢀdig
modes have been reported.1,2 On the other hand, exoꢀ
iodocyclizations of alkynes generally give rise to exoꢀ
alkylidene products3,4 and such products derived from Nꢀ
propargyl amides hardly aromatize to the corresponding ioꢀ
dinated oxazoles (Scheme 1a).5 The aromatization of these
products has been achieved by further oxidation, which cannot
remain iodo components.6 Thus, there is room for the imꢀ
provement in the exoꢀiodocyclizations of alkynes for the forꢀ
mation of iodinated aromatic heterocycles.
can lead to oxazoles having carbon functional groups such as
aryl and allyl groups in a single operation.9 Also, since Hashꢀ
mi et al. reported the goldꢀcatalyzed formation of alkylideneꢀ
oxazolines,10,11 the authors and other groups have developed
oxazole synthesis methods with the introduction of heteroaꢀ
tomic or carbon functional groups via the functionalization of
the alkylideneoxazolines.12 However, although such methods
can be applied to the twoꢀstep synthesis of halogenated oxaꢀ
zoles (Scheme 1a),5b,c,13 the direct synthesis of the halogenated
oxazoles from Nꢀpropargyl amides has been unknown.
We have researched on the metalꢀfree synthesis of aromatic
heterocycles through the activation of alkynes by hypervalent
iodine(III) reagents14 to find the cycloisomerization–
acetoxylation14a or –fluorination14e sequence of Nꢀpropargyl
amides (Scheme 1b). Further studies on the I(III)ꢀmediated
cycloisomerization–functionalization reaction led to singleꢀ
step synthesis of iodinated oxazoles from Nꢀpropargyl amides
(Scheme 1c), which is described herein.
Scheme 1. Synthetic methods of halogenated oxazoles
Based on our examples for the I(III)ꢀmediated cycloisomerꢀ
ization–functionalization reaction (Scheme 1b),14a,b,e the forꢀ
mation of the iodinated oxazole 2a from Nꢀpropargyl amide 1a
using PhIO (1.5 equiv) and the source of iodine (Iꢀsource, 1.5
equiv) was attempted (Table 1, entries 1ꢀ12). Since
PhI(OTBA)I derived from PhIO and TBAI (tetraꢀnꢀ
butylammonium iodide)15 has been reported to promote the
exoꢀiodocyclization of alkynes by Fan et al.,4c we envisaged
that such reagents would work in the cycloisomerization–
iodination reaction of 1a as well as PhIX2. Unfortunately,
PhI(OTBA)I in CH2Cl2 or MeCN at room temperature did not
give 2a but hydroxylated oxazole 4 as a main product (20% or
17%, entry 1 or 2). On the other hand, by the use of acidic
solvent such as HFIP (hexafluoroꢀ2ꢀpropanol, pka = 9.3, bp:
59 ºC) and the addition of TMSOTf (trimethylsilyl trifluoroꢀ
methanesulfonate, 1.5 equiv) as a Lewis acid in CH2Cl2, the
iodocyclized product 3a were formed in 42% and 29% yields,
respectively (entries 3 and 4). Furthermore, under the similar
condition to entry 4, the use of I2 instead of TBAI brought
about the improved yield of 3a up to 62% (entry 5). To our
delight, when the PhIO/I2/TMSOTf system was employed in
DCE (1,2ꢀdichloroethane) at 80 ºC, the desired product 2a was
obtained in 52% yield (entry 7). Among the tested acid addiꢀ
The exoꢀcycloisomerization of Nꢀpropargyl amides have
been widely employed for the effective and versatile synthesis
of 2,5ꢀdisubstituted oxazoles,7 which are prevalent in many
natural products and pharmaceutically active compounds.8
Palladiumꢀcatalyzed cycloisomerization–coupling reactions
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tives in the PhIO/I2/acid systems (entries 7ꢀ11), TMSOTf was tions of propargyl amides has been reported for the direct forꢀ
1
2
3
4
5
6
7
8
the best additive (entry 7). Moreover, each amount of PhIO, I2,
and TMSOTf was reduced to 1 equiv to improve the yield of
2a up to 71% (entry 12). It should be mentioned that, in the
absence of PhIO, the use of iodine reagents such as I2 and NIS
(Nꢀiodosuccinimide) with TMSOTf or HOTf did not show
good results (entries 13ꢀ15).
mation of arylated oxazoles, the introduction of bulky aryl
groups such as mesityl group has not been achieved.9a Also,
the displacement of the iodine atoms to cyano, amino and azꢀ
ido groups was successful to form various functionalized oxaꢀ
zoles 8, 9 and 10 in good yields (72ꢀ86%). Since the direct
synthesis of these functionalized oxazoles from Nꢀpropargyl
amides has not been developed, the present procedure would
be alternative to the previous twoꢀstep methods.16
Table 1. Optimization of the reaction conditionsa
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Table 2. Scope for the formation of 2
H
H
PhIO, I2, TMSOTf
(1 equiv each)
R
N
Ph
N
N
O
or
R
DCE
80 ºC, 24 or 48 h
I
O
O
1a-n
1o
2a-n
Ar
Ph
N
N
entry
Iꢀsource
additive
2a (%)b
3a (%)b
(Ar = 4-ClC6H4)
Ph
O
0c
0
0
I
O
1
2
3
4
5
6
7
8
TBAI
TBAI
TBAI
TBAI
I2
I2
I2
I2
I2
I2
I2
I2
I2
NIS
NIS
ꢀ
ꢀ
ꢀ
I
0d
Ar
Ar
3o
6
0
42
29
62
79
0
entry
1
R
time (h)
2 yield (%)
TMSOTf
TMSOTf
TMSOTf
TMSOTf
HOTf
0e
0
0
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
Ph
24
24
24
24
24
24
24
24
48
48
24
24
24
24
24
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
3o
71
75
78
71
61
77
72
61
65
45
69
42
38
38
42a
oꢀNO2C6H4
52e
34e
21e
9e
mꢀNO2C6H4
pꢀNO2C6H4
mꢀCNC6H4
oꢀClC6H4
mꢀClC6H4
pꢀClC6H4
pꢀMeC6H4
pꢀMeOC6H4
2ꢀthienyl
PhCH2CH2
iPr
0
9
HNTf2
HBF4
10
17
26
0
0
3
10
11
12f
13g
14g
BF3·OEt2
TMSOTf
TMSOTf
TMSOTf
HOTf
7e
71
16
25
32
9
10
11
12
13
14
15
15g
12
a
Solvent: CH2Cl2 (entries 1, 4, 5), MeCN (entry 2),
hexafluoroꢀ2ꢀpropanol (HFIP, entries 3, 6), or 1,2ꢀ
b
tBu
–
dichloroethane (DCE, entries 7ꢀ15). Except for entry 12,
c
d
yields were determined by 1H NMR analysis. 4: 20%. 4:
e
a In addition to 3o, 6 was obtained in 24% yield.
17%. 2ꢀPhenyloxazoleꢀ5ꢀcarbaldehyde (5) was detected
(3ꢀ10% yield). f Each amount of PhIO, I2 and TMSOTf was
reduced to 1 equiv. g PhIO was not added.
Scheme 2. Conversion to other functionalized oxazoles
Under the optimized reaction conditions, the scope for the
formation of 2 from various Nꢀpropargyl amides 1 is summaꢀ
rized in Table 2. Similar to benzamide 1a (entry 1), nitroꢀ
substituted 1b-d, cyanoꢀsubstituted 1e and chloroꢀsubstituted
1f-h were smoothly converted to the corresponding iodinated
oxazoles 2b-h within 24 h in good yields (61ꢀ78%, entries 2ꢀ
8). In cases of methylꢀsubstituted 1i and methoxyꢀsubstituted
1j, although the reaction times were prolonged to 48 h, the
desired 2i and 2j were obtained in 65% and 45% yields, reꢀ
spectively (entries
9
and 10). Furthermore, the
PhIO/I2/TMSOTf systems could be applied not only to hetꢀ
eroaromatic amide 1k but also aliphatic amides 1l-n (entries
11ꢀ14). Unfortunately, internal alkyne 1o gave iodocyclized
product 3o in 42% yield along with iodinated oxazine 6 (24%)
even under the similar conditions (entry 15). This result may
be due to harder isomerization of more substituted alkenes 3o
to oxazole nucleus.14g Also, the iodocyclization of 1o have
been known to proceed via both 5ꢀexo and 6ꢀendo modes.5e
As shown in Table 1, from the results at room temperature
in CH2Cl2 (entry 5) and at 80 ºC in DCE (entries 7 and 12) by
PhIO/I2/TMSOTf system, the iodocyclized product 3 was exꢀ
pected to be involved as an intermediate in the synthesis of the
iodinated oxazole 2a. Therefore, the control experiments using
the isolated 3a were carried out at 80 ºC in DCE (Scheme 3).
As with the Caristi’s report,5a in the absence of any additives,
3a was scarcely aromatized to 2a (4%) along with recovery of
3a (50%). On the other hand, the addition of acid additives led
The obtained oxazole 2a was treated with mesitylene in
MeNO2 to give the arylated product 7 in 67% yield (Scheme
2). Although Pdꢀcatalyzed cycloisomerization–coupling reacꢀ
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to the formation of 2a and particularly the use of HOTf afꢀ sylbenzene and TMSOTf. In these reactions, the iodinated
1
2
3
4
5
6
7
8
forded 2a in 76% yield. Thus, these results indicate that therꢀ
mal and acidic conditions would promote the aromatization of
initially formed 3a to 2a.
oxazoles would be formed by the aromatization of iodocyꢀ
clized intermediates under the thermal and acidic conditions.
Furthermore, the trap experiments of iodonium species using
pyridine and the control experiments using Py2IOTf and HOTf
suggested the possibility of the generation of "IOTf" from
PhIO/I2/TMSOTf systems. Since the direct synthesis of the
halogenated oxazoles from Nꢀpropargyl amides has not been
achieved, our findings provide an attractive procedure for the
access to the halogenated oxazoles.
Since I2 or NIS with TMSOTf or HOTf promoted the forꢀ
mation of 2a from 1a in DCE at 80 ºC albeit lower yields of
2a (Table 1, entries 13ꢀ15), iodonium species such as IOTf
would be generated from PhIO/I2/TMSOTf system possibly.
This would be supported by trap experiments of iodonium
species using pyridine (Py), in which Py2IOTf was detected
from I2 and TMSOTf with PhIO but slightly detected from I2
and TMSOTf without PhIO (see, Supporting Information).
Actually, 1a was exposed with iodonium species generated
from Py2IOTf (1 equiv) and HOTf (2 equiv)17 to give the iodoꢀ
cyclized product 3a in 76% yield at room temperature or to
give the iodinated oxazole 2a in 63% yield at 80 ºC (Scheme
4). These results accord with those using PhIO/I2/TMSOTf
systems (Table 1, entries 5 and 12).
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EXPERIMENTAL SECTION
General information. Iodosylbenzene, molecular iodine and
trimethylsilyl trifluoromethanesulfonate (TMSOTf) are commerꢀ
cially available. According to procedures reported in the literaꢀ
tures, Nꢀpropargyl carboxamides 1a,10a 1b,14e 1c,14e 1d,9f 1e,14e
1f,14e 1g,14e 1h,18a 1i,18a 1j,18b 1k,9f 1l,18c 1m,18d 1n18e and 1o5e
were prepared. Products 3a,5b 412a and 56a are known compounds.
1H and 13C NMR spectra were measured at 300 and 75 MHz in
CDCl3, and the chemical shifts are given in ppm using CHCl3
1
(7.26 ppm) in CDCl3 for H NMR and CDCl3 (77.0 ppm) for 13C
Scheme 3. Aromatization of iodocyclized product 3a
NMR as an internal standard, respectively. Splitting patterns of an
apparent multiplet associated with an averaged coupling constant
were designed as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broadened). Mass spectra and HRMS were
recorded on doubleꢀfocusing magnetic sector by FAB methods.
All reactions were carried out under an argon atmosphere.
General procedure for synthesis of iodinated oxazoles 2. In an
aluminum foilꢀcovered test tube, iodosylbenzene (88.0 mg, 0.40
mmol) was treated with trimethylsilyl trifluoromethanesulfonate
(72.4 ꢀL, 0.40 mmol) in 1,2ꢀdichloroethane (4 mL) at room temꢀ
perature for 5 min. And then, to the reaction mixture was added
molecular iodine (101.5 mg, 0.40 mmol) and 1a-o (0.40 mmol) in
turn. After being stirred at 80 ºC for 24 h (48 h in cases of 1i and
1j), the reaction mixture was quenched with sat. NaHCO3 and sat.
Na2S2O3, and then extracted with AcOEt. The organic layer was
washed with brine, dried over MgSO4 and concentrated in vacuo
to dryness. The residue was purified by preparative thin layer
chromatography (PTLC, hexane:AcOEt = 5:1, 3:1 or 2:1) to give
2a-n, or 3o and 6.
Scheme 4. Reactions of 1a with "IOTf" equivalent
5-(Iodomethyl)-2-phenyloxazole (2a). Rf = 0.68 (hexane:AcOEt
= 3:1). Brown solid (82.2 mg, 71%). The 1H and 13C NMR spectra
of the product was identical to those reported in the literature.5b
5-(Iodomethyl)-2-(2-nitrophenyl)oxazole (2b). Rf = 0.37 (hexꢀ
ane:AcOEt = 2:1). Brown solid (99.9 mg, 75%). Mp 105ꢀ106 ºC.
IR (KBr) ν cmꢀ1; 1532, 1358, 535. 1H NMR (300 MHz, CDCl3) δ;
4.45 (s, 2H), 7.21 (s, 1H), 7.59ꢀ7.54 (m, 2H), 7.81 (d, J = 7.9 Hz,
1H), 8.00 (d, J = 7.4 Hz, 1H). 13C {1H} NMR (75 MHz, CDCl3) δ;
ꢀ11.4, 120.8, 124.0, 126.1, 130.4, 131.3, 132.2, 150.5, 157.2 (Note
that two carbon peaks overlap with each other). FABꢀLM m/z:
331 (M++H+). FABꢀHM Calcd for C10H8IN2O3 (M++H+):
330.9580; found: 330.9556.
On the basis of the above results, we propose that the forꢀ
mation of iodinated oxazoles 2 would proceed through the
IOTfꢀmediated iodocyclization of propargyl amides 1 and then
the aromatization of the iodocyclized intermediates 3 promotꢀ
ed by the generated HOTf under thermal conditions (Scheme
5). Compared with TMSOTf having harder acidity, iodine(III)
species A19 generated from PhIO and TMSOTf might be more
effective on the activation of I2. Therefore, IOTf would be
more efficiently formed from the activated iodine B by the
halogenꢀbonding interaction20 with species A.
5-(Iodomethyl)-2-(3-nitrophenyl)oxazole (2c). Rf = 0.43 (hexꢀ
ane:AcOEt = 3:1). Pale yellow solid (103.8 mg, 78%). Mp 102ꢀ
Scheme 5. Proprosed Reaction Mechanism
1
104 ºC. IR (KBr) ν cmꢀ1; 1520, 1348, 523. H NMR (300 MHz,
+
I
-
I
CDCl3) δ; 4.51 (s, 2H), 7.23 (s, 1H), 7.67 (t, J = 8.0 Hz, 1H),
8.30ꢀ8.35 (m, 1H), 8.38 (dt, J = 8.0, 1.9 Hz, 1H), 8.88 (t, J = 1.9
Hz, 1H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ11.3, 121.4, 125.0,
126.4, 128.8, 130.2, 132.0, 148.8, 150.2, 159.6. FABꢀLM m/z:
331 (M++H+). FABꢀHM Calcd for C10H8IN2O3 (M++H+):
330.9580; found: 330.9607.
5-(Iodomethyl)-2-(4-nitrophenyl)oxazole (2d). Rf = 0.54 (hexꢀ
ane:AcOEt = 3:1). Pale yellow solid (94.6 mg, 71%). Mp 133ꢀ135
ºC. IR (KBr) ν cmꢀ1; 1519, 1338, 526. 1H NMR (300 MHz,
CDCl3) δ; 4.51 (s, 2H), 7.26 (s, 1H), 8.22 (d, J = 9.0 Hz, 2H),
I2
TfO
I
OTMS
I
OTMS
IOTf
Ph
Ph
TfO
A (PhIO + TMSOTf)
B
IOTMS, PhI
H
N
TfO
TfO
HN
O
1
I
3
2
R
R
I
O
HOTf
In conclusion, we have developed a singleꢀstep synthesis of
iodinated oxazoles from Nꢀpropargyl amides using I2, iodoꢀ
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1
8.34 (d, J = 8.0 Hz, 2H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ
11.2, 124.3, 126.7, 127.1, 132.5, 148.8, 150.6, 159.7. FABꢀLM
m/z: 331 (M++H+). FABꢀHM Calcd for C10H8IN2O3 (M++H+):
330.9580; found: 330.9556.
2973, 519. H NMR (300 MHz, CDCl3) δ; 1.33 (d, J = 7.0 Hz,
3H), 3.03 (septet, J = 7.0 Hz, 1H), 4.38 (s, 2H), 6.92 (s, 1H). 13
C
1
2
3
4
5
6
7
8
{1H} NMR (75 MHz, CDCl3) δ; ꢀ9.8, 20.2, 28.4, 124.3, 148.1,
169.6. FABꢀLM m/z: 251 (M++H+). FABꢀHM Calcd for
C7H11INO (M++H+): 251.9885; found: 251.9889.
2-(3-Cyanophenyl)-5-(iodomethyl)oxazole (2e). Rf = 0.47 (hexꢀ
ane:AcOEt = 2:1). Brown solid (76.0 mg, 61%). Mp 99ꢀ100 ºC.
2-tert-Butyl-5-(iodomethyl)oxazole (2n). Rf
= 0.67 (hexꢀ
1
IR (KBr) ν cmꢀ1; 2228, 533. H NMR (300 MHz, CDCl3) δ; 4.49
ane:AcOEt = 3:1). Brown oil (40.1 mg, 38%). IR (neat) ν cmꢀ1;
1
(s, 2H), 7.24 (s, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.75 (d, J = 7.9 Hz,
1H), 8.27 (d, J = 7.9 Hz, 1H), 8.32 (s, 1H). 13C {1H} NMR (75
MHz, CDCl3) δ; ꢀ11.0, 113.4, 118.0, 126.2, 128.4, 129.8, 129.9,
130.3, 133.7, 150.0, 159.6. FABꢀLM m/z: 311 (M++H+). FABꢀ
HM Calcd for C11H8IN2O (M++H+): 310.9681; found: 310.9673.
2-(2-Chlorophenyl)-5-(iodomethyl) oxazole (2f). Rf = 0.64
(hexane:AcOEt = 3:1). Brown solid (98.5 mg, 77%). Mp 59ꢀ61 ºC.
IR (KBr) ν cmꢀ1; 738, 510. 1H NMR (300 MHz, CDCl3) δ; 4.49 (s,
2H), 7.20 (s, 1H), 7.31ꢀ7.44 (m, 2H), 7.51 (dd, J = 7.2, 1.9 Hz,
1H), 7.99 (dd, J = 6.9, 1.9 Hz, 1H). 13C {1H} NMR (75 MHz,
CDCl3) δ; ꢀ10.6, 125.8, 125.9, 126.9, 130.8, 131.3, 131.4, 132.5,
149.3, 159.6. FABꢀLM m/z: 320 (M++H+). FABꢀHM Calcd for
C10H8ClINO (M++H+): 319.9339; found: 319.9362.
2-(3-Chlorophenyl)-5-(iodomethyl) oxazole (2g). Rf = 0.70
(hexane:AcOEt = 3:1). Brown solid (92.3 mg, 72%). Mp 75ꢀ77 ºC.
IR (KBr) ν cmꢀ1; 738, 510. 1H NMR (300 MHz, CDCl3) δ; 4.48 (s,
2H), 7.17 (s, 1H), 7.34ꢀ7.47 (m, 2H), 7.92 (d, J = 7.1 Hz, 1H),
8.02 (s, 1H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ10.5, 124.5,
126.1, 126.4, 128.7, 130.2, 130.7, 135.0, 149.4, 160.6. FABꢀLM
m/z: 320 (M++H+). FABꢀHM Calcd for C10H8ClINO (M++H+):
319.9339; found: 319.9341.
2971, 521. H NMR (300 MHz, CDCl3) δ; 1.37 (s, 9H), 4.39 (s,
2H), 6.92 (s, 1H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ9.7, 28.4,
33.8, 124.0, 148.1, 171.8. FABꢀLM m/z: 266 (M++H+). FABꢀHM
Calcd for C8H13INO (M++H+): 266.0042; found: 266.0012.
(E)-5-[(4-Chlorophenyl)iodomethylene]-4,5-dihydro-2-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
phenyloxazole (3o). Rf = 0.56 (hexane:AcOEt = 5:1). White solid
(65.7 mg, 42%). The 1H and 13C NMR spectra of the product was
identical to those reported in the literature.5e
6-(4-Chlorophenyl)-5-iodo-2-phenyl-4H-1,3-oxazine (6). Rf =
0.71 (hexane:AcOEt = 5:1). White solid (37.4 mg, 24%). The 1H
and 13C NMR spectra of the product was identical to those reportꢀ
ed in the literature.5e
Synthesis of 2-phenyl-5-(2,4,6-trimethylbenzyl)oxazole (7). A
solution of 2a (114.0 mg, 0.4 mmol) and mesitylene (167 ꢀL, 1.2
mmol) in nitromethane (4 mL) was stirred at 100 ºC for 24 h. And
then, the reaction mixture was concentrated in vacuo to dryness.
The residue was purified by PTLC (hexane:AcOEt = 8:1) to give
7 (Rf = 0.36, 74.2 mg, 67%) as a white solid: Mp 76ꢀ77 ºC. IR
(KBr) ν cmꢀ1; 2919, 1488. 1H NMR (300 MHz, CDCl3) δ; 2.30 (s,
3H), 2.38 (s, 6H), 4.05 (d, J = 1.1 Hz, 2H), 6.65 (t, J = 1.1 Hz,
1H), 6.92 (s, 2H), 7.38ꢀ7.50 (m, 3H), 7.96ꢀ8.06 (m, 2H). 13C {1H}
NMR (75 MHz, CDCl3) δ; 19.8, 20.8, 25.9, 124.3, 126.0, 127.8,
128.8, 129.2, 130.0, 136.5, 136.9, 151.0, 161.0 (Note that two
carbon peaks overlap with each other). FABꢀLM m/z: 278
(M++H+). FABꢀHM Calcd for C19H20NO (M++H+): 278.1545;
found: 278.1537.
2-(4-Chlorophenyl)-5-(iodomethyl) oxazole (2h). Rf = 0.68
(hexane:AcOEt = 3:1). Brown solid (77.7 mg, 61%). Mp 95ꢀ96 ºC.
1
IR (KBrt) ν cmꢀ1; 733, 521. H NMR (300 MHz, CDCl3) δ; 4.49
(s, 2H), 7.17 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 8.5 Hz,
2H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ10.3, 125.6, 126.1,
127.7, 129.2, 136.8, 149.1, 161.0. FABꢀLM m/z: 320 (M++H+).
FABꢀHM Calcd for C10H8ClINO (M++H+): 319.9339; found:
319.9341.
Synthesis of 2-(2-phenyloxazol-5-yl)acetonitrile (8). To a soluꢀ
tion of 2a (114.0 mg, 0.4 mmol) and trimethylsilyl cyanide (107
ꢀL, 0.8 mmol) in acetonitrile (4 mL) was added K2CO3 (110.6
mg, 0.8 mmol). After being stirred at 80 ºC for 24 h, the reaction
mixture was quenched with sat. NaHCO3 and extracted with Acꢀ
OEt. The organic layer was washed with brine, dried over MgSO4
and concentrated in vacuo to dryness. The residue was purified by
PTLC (hexane:AcOEt = 3:1) to give 8 (Rf = 0.26, 72.1 mg, 72%)
5-(Iodomethyl)-2-(4-methylphenyl)oxazole (2i). Rf = 0.69 (hexꢀ
ane:AcOEt = 3:1). Pale yellow solid (78.3 mg, 65%). Mp 72ꢀ73
1
ºC. IR (KBr) ν cmꢀ1; 3033, 523. H NMR (300 MHz, CDCl3) δ;
2.40 (s, 3H), 4.49 (s, 2H), 7.14 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H),
7.93 (d, J = 8.0 Hz, 2H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ9.7,
21.5, 124.5, 126.0, 126.4, 129.6, 141.1, 148.5, 162.3. FABꢀLM
m/z: 300 (M++H+). FABꢀHM Calcd for C11H11INO (M++H+):
299.9885; found: 299.9898.
5-(Iodomethyl)-2-(4-methoxyphenyl)oxazole (2j). Rf = 0.53
(hexane:AcOEt = 3:1). Brown solid (56.9 mg, 45%). Mp 82ꢀ84 ºC.
IR (KBr) ν cmꢀ1; 1256, 1024, 528. 1H NMR (300 MHz, CDCl3) δ;
3.86 (s, 3H), 4.49 (s, 2H), 6.97 (d, J = 8.9 Hz, 2H), 7.12 (s, 1H),
7.99 (d, J = 8.9 Hz, 2H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ9.6,
55.3, 114.3, 119.9, 125.9, 128.1, 148.2, 161.6, 162.1. FABꢀLM
m/z: 316 (M++H+). FABꢀHM Calcd for C11H11INO2 (M++H+):
315.9834; found: 315.9847.
as a pale yellow solid. The H and 13C NMR spectra of the prodꢀ
1
uct was identical to those reported in the literature.16a
Synthesis of N-[(2-phenyloxazol-5-yl)methyl]benzenamine (9).
To a solution of 2a (114.0 mg, 0.4 mmol) and aniline (73 ꢀL, 0.8
mmol) in N,Nꢀdimethylformamide (4 mL) was added K2CO3
(110.6 mg, 0.8 mmol). After being stirred at 80 ºC for 24 h, the
reaction mixture was quenched with H2O and extracted with Acꢀ
OEt. The organic layer was washed with brine, dried over MgSO4
and concentrated in vacuo to dryness. The residue was purified by
PTLC (hexane:AcOEt = 3:1) to give 9 (Rf = 0.39, 87.3 mg, 86%)
as a pale yellow solid. Mp 86ꢀ87 ºC. IR (KBr) νcmꢀ1; 3322, 1604,
1322. 1H NMR (300 MHz, CDCl3) δ; 4.10 (br.s, 1H), 4.46 (s, 2H),
6.74 (d, J = 7.7 Hz, 2H), 6.80 (t, J = 7.7 Hz, 1H), 7.08 (s, 1H),
7.24 (t, J = 7.7 Hz, 2H), 7.40ꢀ7.53 (m, 3H), 7.98ꢀ8.13 (m, 2H).
13C {1H} NMR (75 MHz, CDCl3) δ; 39.3, 113.3, 118.5, 125.7,
126.3, 127.5, 128.8, 129.4, 130.4, 147.2, 149.8, 161.6. FABꢀLM
m/z: 251 (M++H+). FABꢀHM Calcd for C16H15N2O (M++H+):
251.1184; found: 251.1170.
5-(Iodomethyl)-2-(thiophen-2-yl)oxazole (2k). Rf = 0.66 (hexꢀ
1
ane:AcOEt = 3:1). Yellow solid (79.8 mg, 69%). The H and 13C
NMR spectra of the product was identical to those reported in the
literature.5b
5-(Iodomethyl)-2-phenethyloxazole (2l). Rf
= 0.63 (hexꢀ
ane:AcOEt = 2:1). Brown oil (52.6 mg, 42%). IR (neat) ν cmꢀ1;
1
2933, 2866, 520. H NMR (300 MHz, CDCl3) δ; 2.99ꢀ3.15 (m,
Synthesis of 5-(azidomethyl)-2-phenyloxazole (10). A solution
of 2a (114.0 mg, 0.4 mmol) and sodium azide (39.0 mg, 0.6
mmol) in N,Nꢀdimethylformamide (4 mL) was stirred at room
temperature for 24 h. And then, the reaction mixture was
quenched with H2O and extracted with AcOEt. The organic layer
was washed with brine, dried over MgSO4 and concentrated in
vacuo to dryness. The residue was purified by PTLC (hexꢀ
4H), 4.38 (s, 2H), 6.94 (s, 1H), 7.17ꢀ7.25 (m, 3H), 7.26ꢀ7.34 (m,
2H). 13C {1H} NMR (75 MHz, CDCl3) δ; ꢀ10.2, 30.1, 32.9, 124.4,
126.5, 128.4, 128.6, 140.2, 148.5, 164.6. FABꢀLM m/z: 314
(M++H+). FABꢀHM Calcd for C12H13INO (M++H+): 314.0042;
found: 314.0030.
5-(Iodomethyl)-2-isopropyloxazole (2m). Rf
= 0.59 (hexꢀ
ane:AcOEt = 3:1). Yellow oil (38.3 mg, 38%). IR (neat) ν cmꢀ1;
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(3) Recent representative examples: (a) Yao, T.; Larock, R. C. J.
Org. Chem. 2005, 70, 1432. (b) Barluenga, J.; VázquezꢀVilla, H.;
Merino, I.; Ballesteros, A.; González, J. M. Chem. Eur. J. 2006, 12,
5790. (c) Cherry, K.; Duchêne, A.; Thibonnet, J.; Parrain, J.ꢀL.; Anꢀ
selmi, E.; Abarbri, M. Syntheis 2009, 257. (d) Mancuso, R.; Mehta,
S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. J. Org.
Chem. 2010, 75, 897. (e) Schlemmer, C.; Andernach, L.; Schollmeyꢀ
er, D.; Straub, B. F.; Opatz, T. J. Org. Chem. 2012, 77, 10118. (f)
Vandavasi, J. K.; Kuo, K.ꢀK.; Hu, W.ꢀP.; Shen, H.ꢀC.; Lo, W.ꢀS.;
Wang, J.ꢀJ. Org. Biomol. Chem. 2013, 11, 6520. (g) Rode, N. D.;
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P. Tetrahedron Lett. 2015, 56, 5140. (h) Matsumoto, S.; Kikuchi, S.;
Norita, N.; Masu, H.; Akazome, M. J. Org. Chem. 2016, 81, 5322.
(4) Examples for exoꢀiodocyclization of alkynes using iodine(III)
reagents: (a) Djuardi, E.; Mc Nelis, E. Tetrahedron Lett. 1999, 40,
7193. (b) Liu, H.; Tan, C.ꢀH. Tetrahedron Lett. 2007, 48, 8220. (c)
Zheng, C.; Fan, R. Chem. Commun. 2011, 47, 12221.
(5) (a) Capozzi, G.; Caristi, C.; Gattuso, M. J. Chem. Soc. Perkin
Trans. 1 1984, 255. (b) Hashmi, A. S. K.; Weyrauch, J. P.; Schuster,
A.; Hengst, T.; Schetter, A.; Littmann, A.; Rudolph, M.; Hamzic, M.;
Visus, J.; Rominger, F.; Frey, W.; Bats, J. W. Chem. Eur. J. 2010, 16,
956. (c) Hashmi, A. S. K.; Schuster, A. M.; Schmuck, M.; Rominger,
F. Eur. J. Org. Chem. 2011, 4595. (d) Gazzola, S.; Beccalli, E. M.;
Borelli, T.; Castellano, C.; Chiacchio, M. A.; Diamante, D.; Broggini,
G. J. Org. Chem. 2015, 80, 7226. (e) Urbanaitė, A.; Jonušis, M.;
Bukšnaitienė, R.; Balkaitis, S; Čikotienė, I. Eur. J. Org. Chem. 2015,
7091.
(6) (a) Hu, Y.; Yi, R.; Wang, C.; Xin, X.; Wu, F.; Wan, B. J. Org.
Chem. 2014, 79, 3052. Other heterocycles: (b) Hessian, K. O.; Flynn,
B. L. Org. Lett. 2006, 8, 243. (c) Kim, I.; Kim, S. G.; Kim, J. Y.; Lee,
G. H. Tetrahedron Lett. 2007, 48, 8976.
(7) Recent reviews: (a) Hu, Y.; Xin, X.; Wan, B. Tetrahedron Lett.
2015, 56, 32. (b) Bresciani, S.; Tomkinson, N. C. O. Heterocycles
2014, 89, 2479. (c) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.;
Gevorgyan, V. Chem. Rev. 2013, 113, 3084.
(8) (a) Wipf, P. Chem. Rev. 1995, 95, 2115. (b) Yeh, V. S. C. Tet-
rahedron 2004, 60, 11995. (c) Jin, Z. Nat. Prod. Rep. 2006, 23, 464.
(d) Jin, Z. Nat. Prod. Rep. 2009, 26, 382. (e) Jin, Z. Nat. Prod. Rep.
2011, 28, 1143. (f) Heng, S.; Gryncel, K. R.; Kantrowitz, E. R.
Bioorg. Med. Chem. 2009, 17, 3916.
(9) (a) Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F.
Org. Lett. 2001, 3, 2501. (b) Saito, A.; Iimura, K.; Hanzawa, Y. Tet-
rahedron Lett. 2010, 51, 1471. See also, (c) Bonardi, A.; Costa, M.;
Gabriele, B.; Salerno, G.; Chiusoli, G. P. Tetrahedron Lett. 1995, 36,
7495. (d) Bacchi, A.; Costa, M.; Gabriele, B.; Pelizzi, G.; Salerno, G.
J. Org. Chem. 2002, 67, 4450. (e) Yasuhara, S.; Sasa, M.; Kusakabe,
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See: Beccalli, E. M.; Borsini, E.; Broggini, G.; Palmisano, G.; Sotꢀ
tocornola, S. J. Org. Chem. 2008, 73, 4746.
ane:AcOEt = 8:1) to give 10 (Rf = 0.23, 65.9 mg, 82%) as a pale
1
yellow solid. The H and 13C NMR spectra of the product was
1
2
3
4
5
6
7
8
identical to those reported in the literature.12d
Aromatization of iodocyclized product 3a to 2a. A solution of 3
(114.0 mg, 0.4 mmol) and trifluoromethanesulfonic acid (53 ꢀL,
0.6 mmol) in 1,2ꢀdichloroethane (4 mL) at 80 ºC for 24 h. And
then, the reaction mixture was quenched with sat. NaHCO3 and
extracted with AcOEt. The organic layer was washed with brine,
dried over MgSO4 and concentrated in vacuo to dryness. The
residue was purified by PTLC to give 2a (86.6 mg, 76%) as a
1
brown solid. The H and 13C NMR spectra of the product was
9
identical to those reported in the literature.5b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for reactions of 1a with "IOTf" equivalent.
In an aluminum foilꢀcovered test tube, bis(pyridine)iodonium
trifluoromethanesulfonate18f (173.7 mg, 0.40 mmol) was treated
with trifluoromethanesulfonic acid (71.0 ꢀL, 0.80 mmol) in diꢀ
chloromethane (or 1,2ꢀdichloroethane, 4 mL) at room temperature
for 5 min. And then, to the reaction mixture was added 1a (63.7
mg, 0.40 mmol). After being stirred at room temperature (or 80
ºC) for 24 h, the reaction mixture was quenched with sat. Naꢀ
HCO3 and sat. Na2S2O3, and then extracted with AcOEt. The orꢀ
ganic layer was washed with brine, dried over MgSO4 and conꢀ
centrated in vacuo to dryness. The residue was purified by preparꢀ
ative thin layer chromatography (PTLC) to give 3 (86.6 mg, 76%)
1
as a yellow solid [or 2 (71.8 mg, 63%) as a brown solid]. The H
and 13C NMR spectra of the product was identical to those reportꢀ
ed in the literature.5b
ASSOCIATED CONTENT
Supporting Information. Spectra for all new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail for A.S.: akioꢀsai@cc.tuat.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was partially supported by JSPS GrantsꢀinꢀAid for
Scientific Research (C) (Grant No 15K07852), by the Society of
Iodine Science and by the Takeda Science Foundation.
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