Iodine(III)-Catalyzed Formal [2 + 2 + 1] Cycloaddition Reaction for Metal-Free Construction of Oxazoles

Article abstract of DOI:10.1021/acs.orglett.7b00742

The iodine(III) catalyst, in situ generated from iodoarene as a precatalyst with m-CPBA and Tf₂NH, promoted the metal-free [2 + 2 + 1] cycloaddition-type reactions of alkynes, nitriles, and oxygen atoms for the regioselective formations of 2,4-disubstituted and 2,4,5-trisubstituted oxazole. A first example of iodine catalysis for multicomponent reactions is represented.

Full text of DOI:10.1021/acs.orglett.7b00742

Letter
pubs.acs.org/OrgLett
Iodine(III)-Catalyzed Formal [2 + 2 + 1] Cycloaddition Reaction for
Metal-Free Construction of Oxazoles
Takuma Yagyu,† Yusuke Takemoto,† Akira Yoshimura,‡ Viktor V. Zhdankin,‡ and Akio Saito*,†
†Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho,
Koganei, Tokyo 184-8588, Japan, and
‡Department of Chemistry and Biochemistry, University of Minnesota, Duluth, Minnesota 55812 United States
S
* Supporting Information
ABSTRACT: The iodine(III) catalyst, in situ generated from
iodoarene as a precatalyst with m-CPBA and Tf2NH,
promoted the metal-free [2 + 2 + 1] cycloaddition-type
reactions of alkynes, nitriles, and oxygen atoms for the
regioselective formations of 2,4-disubstituted and 2,4,5-
trisubstituted oxazole. A first example of iodine catalysis for
multicomponent reactions is represented.
ulticomponent cycloaddition reactions, which allow for
chemistry and synthetic chemistry.4 These procedures are
Mmultiple bond formation in a single operation, can regarded as complementary methods: one is gold-catalyzed
preparations of 2,5-disubstituted oxazoles from terminal
alkynes,3a and another is Cu-catalyzed preparations of 2,4,5-
trisubstituted oxazoles from internal alkynes.3b However, these
[2 + 2 + 1] cycloaddition strategies cannot be applied to both
terminal and internal alkynes. Although other multicomponent
cycloaddition-type approaches to oxazoles are also known,5 the
formation of 2,4-disubstituted oxazoles has not been achieved
by these procedures.6
provide more atom-, step-, and time-economical conversion of
simple starting materials to complex and polyfunctionalized
cyclic compounds.1 Based on these reactions, mild and efficient
approaches to substituted pyridines, furans, pyrroles, and some
important azoles using heteroatom-containing unsaturated
compounds as starting materials in the presence of various
metal catalysts have been developed.2 Recently, Zhang’s and
Jiang’s groups independently reported catalytic and regiose-
lective [2 + 2 + 1] cycloaddition-type reactions of alkynes,
nitriles, and oxygen atom as facile and efficient assembling
procedures of highly substituted oxazoles (Scheme 1a),3 which
have found widespread applications in the fields of medicinal
On the other hand, as part of our studies on the metal-free
synthesis of aromatic heterocycles through the activation of
alkynes by hypervalent iodine(III) reagents,7 we have recently
found the regioselective [2 + 2 + 1] cycloaddition-type
reactions of alkynes, nitriles, and oxygen atom from PhI(OH)X
(Scheme 1b), which was in situ generated from iodosylbenzene
and HX (X = TfO or Tf2N, Tf = CF3SO2).7a However, despite
providing the formation not only of 2,4-disubstituted oxazoles
but also of 2,4,5-trisubstituted ones, these reactions release a
large amount of PhI as a waste product and/or require
additional steps for the preparation and purification of
iodosylbenzene. From the viewpoint of atom- and step-
economy, hypervalent iodine(III) catalysts,8 which are
generated from ArI precatalysts and terminal oxidants (mainly,
m-chloroperbenzoic acid: mCPBA), have been employed in
bimolecular oxidative annulations for oxazoles9 and other
heterocycle synthesis.10 However, iodine catalysis for multi-
component reactions has not been achieved. Herein, we report
a metal-free and regioselective [2 + 2 + 1]-type synthesis of
oxazoles based on the iodine(III) catalysis (Scheme 1 c).
Our initial effort was focused on the evaluation of ArI
precatalysts (20 mol %) with mCPBA and Tf2NH (1.5 equiv
each) in the reaction of ethynylbenzene (1a) and acetonitrile
Scheme 1. [2 + 2 + 1]-Type Synthesis of Oxazoles
Received: March 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00742
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(MeCN) as a solvent at ambient temperature for 24 h (Table
1). Note that mCPBA was dried in vacuo prior to use because
Table 2. Reaction Scope of Alkynes and Nitriles
Table 1. Evaluation of ArI Precatalysts
a
product yield (%)
b
entry
1
R1
R2
A
B
C
a
entry
ArI
yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Ph
H
2a
2b
2c
2d
2e
2f
61
72
47
63
75
35
37
44
24
44
47
60
58
69
24
59
58
74
50
60
81
36
28
60
45
54
39
57
40
68
26
66
60
80
52
70
73
64
42
70
NE
68
57
76
NE
NE
40
52
b
1
PhI
61
(CH2)2Ph
H
2
2-ClC6H4I
52
37
(CH2)5Me
H
3
3-ClC6H4I
Ph
Me
Ph
Pr
Br
Bz
Bz
Ac
H
b
4
4-ClC6H4I
58
Ph
5
2-IC6H4I
34
52
43
42
49
41
57
46
Pr
6
3-NO2C6H4I
4-MeC6H4I
1g
1h
1i
Ph
2g
2h
2i
c
7
8
Ph
c
8
2,4-Me2C6H3I
2,6-(MeO)2C6H3I
2,2′-diiodobipenyl
9
(CH2)5Me
c
9
10
1j
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2j
c
10
11
12
13
11
12
13
14
15
16
1a
1d
1a
1d
1a
1d
3a
3d
4a
4d
5a
5d
c
PhI
Me
H
d
PhI
e
none
7
Me
H
f
14
PhI
30
a
Yields were determined by 1H NMR analysis, unless stated otherwise.
Isolated yields. 10 mol %. 5 mol %. 2,4-Dimethyl-6-phenyl-
pyrimidine: 30% (5−16% in other cases). In the presence of 20 equiv
of MeCN, CH2Cl2 was used as a solvent (CH2Cl2:MeCN = ca. 4:1).
Me
b
c
d
e
a
b
Isolated yields. Yields found in the ref 7a. NE: not examined.
c
f
Tf2NH: 3 equiv.
conditions B showed good results (2h,i: 45−60%, entries 8−
10). Propionitrile and isobutyronitrile instead of acetonitrile
reacted well with terminal and internal alkynes 1a and 1d under
conditions A (3, 4: 47−69%, entries 11−14), and benzonitrile
did well with 1a and 1d under conditions B (5a: 26%, 5d: 66%,
entries 15, 16). Notably, in all cases, products 2−5 were
obtained with complete regioselectivities. Except for aliphatic
internal alkyne 1f, catalytic conditions A and/or B brought
about nearly the same results as conditions C.
In order to gain additional information on the present
catalytic cycle for the [2 + 2 + 1]-type synthesis of oxazoles, we
attempted the isolation of iodine(III) species generated from
PhI, mCPBA, and Tf2NH. PhI was treated with mCPBA and
Tf2NH (1.1 equiv each) in the presence of 18-crown-6 ether
(18C6) at −40 to 0 °C for 4 h to give PhI(OH)NTf2 as an
aquo-[18C6] complex 6 in 43% yield (Scheme 2), although
the use of commercially available mCPBA (contains ca. 30%
water) or the positive addition of water brought about the
reduced yield of desired products (see the Supporting
Information for details of condition optimization). At the
outset, the use of PhI as a precatalyst was found to produce the
2,4-disubstituted oxazole 2a in 61% yield as a sole regioisomer
(entry 1). On the other hand, although 4-ClC6H4I led to a
relatively good yield of 2a (58%, entry 4), ArI having electron-
withdrawing groups such as halogens and a nitro group gave
reduced yields of 2a (34−52%, entries 2, 3, 5, and 6). Also, in
the case of ArI having electron-donating groups, 2a was
obtained in 42−49% yield (entries 7−9). Furthermore,
bisiodine(III) catalysts, which showed superior results to
monoiodine(III) catalysts in some cases,11 did not bring
about improved yields of 2a (entries 5 and 10). Unfortunately,
when the catalytic amount (10 or 5 mol %, entry 11 or 12) of
PhI or the amount of MeCN (20 equiv in CH2Cl2, entry 14)
was decreased, the yield of 1a was reduced. It should be
mentioned that no addition of ArI afforded 2,4-dimethyl-6-
phenylpyrimidine, generated from 2a and MeCN under acidic
conditions,12 as a main product (entry 13).
Scheme 2. Iodine(III) Species Generated from PhI, m-
CPBA, and Tf2NH
Based on the above results, we next investigated the scope of
alkynes and nitriles under conditions A using PhI or B using 4-
ClC6H4I with mCPBA and Tf2NH (1.5 equiv each, Table 2). In
addition, our previous procedure utilizing iodosylbenzene (1.8
equiv) with Tf2NH (1.5 equiv) is shown as conditions C in
Table 2.7a Both catalytic conditions A and B were successfully
applied to the oxidative annulations of not only terminal
alkynes 1a−c but also internal alkynes 1d−g with acetonitrile to
give the corresponding 2,4-disubstituted or 2,4,5-trisubstituted
oxazoles 2a−g in 28−81% yields (entries 1−7). In the cases of
1h−j bearing electron-withdrawing groups such as benzoyl and
acetyl groups, the addition of 3 equiv of Tf2NH under
iodine(III) species could not be isolated in the absence of
18C6. Miyamoto et al. reported that complex 6 was generated
from PhI(OAc)2 and Tf2NH in the presence of 18C6.13 These
observations suggest that m-chlorobenzoic acid (mCBA) as a
byproduct would not be involved in the present catalytic cycle.
This conclusion is supported by the fact that, regardless of the
addition of mCBA, iodosylbenzene with Tf2NH (conditions C)
B
DOI: 10.1021/acs.orglett.7b00742
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afforded oxazole 2a in the same yields from 1a and acetonitrile
(Scheme 3).
alkynes and some iodine(III) reagents,15 the deuterium-labeling
experiment using d-1a (Scheme 5) suggests the negative
Scheme 5. Deuterium-Labeling Experiment
Scheme 3. Control Experiments
On the basis of these results and our previous reports about
the PhIO/acid-mediated [2 + 2 + 1]-type synthesis of oxazoles,
the proposed catalytic cycle for the present [2 + 2 + 1]
cycloaddition-type reaction is shown in Scheme 4. That is,
involvement of intermediate H in the present oxazole
formation. Thus, d-1a was treated with mCPBA and Tf2NH
(1.1 equiv each) in the presence of PhI (20 mol %) at rt for 24
h not to give undeuterated 2a, which would be expected to be
derived from intermediate H, but rather to give deuterated d-2a
(>96% D).
Scheme 4. Proposed Catalytic Cycle
In summary, we have developed the metal-free and
regioselective [2 + 2 + 1] cycloaddition-type reactions of
alkynes, nitriles, and oxygen atoms catalyzed by iodine(III)
species, which is in situ generated from iodoarene precatalyst
with mCPBA and Tf2NH. These catalytic systems could be
applied to both terminal and internal alkynes with various
nitriles, thereby leading to 2,4-disubstituted and 2,4,5-
trisubstituted oxazoles. Since iodine catalysis for multi-
component reactions has not been previously achieved, our
findings not only provide an attractive procedure for the access
to highly substituted oxazoles but also open a new possibility
for the use of λ3-iodane catalyst in organic synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00742.
Experimental procedures, characterization data of new
compounds, and NMR spectra (PDF)
PhI(OH)NTf2, in situ generated from ArI and mCPBA in the
presence of Tf2NH, would react with alkyne 1 to form
intermediate B through the iodoimidation of 1 followed by the
ligand exchange of the OH group in intermediate A. Then, the
alkenyl(phenyl)iodonium intermediate B would serve as the
highly reactive electrophile14 to undergo the nucleophilic
vinylic substitution at the β-position with R3CN. Subsequently,
the formed intermediate trans-C may be converted to generate
cis-C by repeating the addition and elimination of R3CN and
then intermediate cis-D and/or E by the ligand exchange of
NTf2 group and/or the addition to nitrenium ion with H2O.
Finally, after cyclization of intermediate D and/or E, the
reductive elimination from intermediate F would lead to the
regeneration of ArI along with target oxazoles 2.
As an alternative route from trans-C to oxazoles 2, the
nucleophilic vinylic substitution at the α-position of trans-C
with H2O and/or the ligand coupling of trans-D giving rise to
enol trans-G is possibly involved. After trans-G is isomerized to
cis-G via keto−enol tautomerization, the cyclization of cis-G
yields 2.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: akio-sai@cc.tuat.ac.jp.
ORCID
Akio Saito: 0000-0002-8291-2059
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a JSPS Grants-in-Aid for
Scientific Research (C) (Grant No. 15K07852) and by the
Asahi Glass Foundation. V.V.Z. is also thankful to the National
Science Foundation (CHE-1262479).
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