Metal-free [2 + 2 + 1] annulation of alkynes, nitriles, and oxygen atoms: Iodine(III)-mediated synthesis of highly substituted oxazoles

Article abstract of DOI:10.1021/ol4009816

The metal-free [2 + 2 + 1] annulation of alkynes, nitriles, and O-atoms for the regioselective assembly of 2,4-disubstituted and 2,4,5-trisubstituted oxazole compounds has been achieved by the use of PhIO with TfOH or Tf ₂NH. The present reaction could be applied to a facile synthesis of an anti-inflammatory drug.

Full text of DOI:10.1021/ol4009816

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Free [2 þ 2 þ 1] Annulation of
Alkynes, Nitriles, and Oxygen Atoms:
Iodine(III)-Mediated Synthesis of Highly
Substituted Oxazoles
Akio Saito,*,† Akihiro Taniguchi,‡ Yui Kambara,† and Yuji Hanzawa‡
Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture
and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan, and
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical University,
3-3165 Higashi-tamagawagakuen, Machida-shi, Tokyo 194-8543, Japan
akio-sai@cc.tuat.ac.jp
Received April 9, 2013
ABSTRACT
The metal-free [2 þ 2 þ 1] annulation of alkynes, nitriles, and O-atoms for the regioselective assembly of 2,4-disubstituted and 2,4,5-trisubstituted
oxazole compounds has been achieved by the use of PhIO with TfOH or Tf2NH. The present reaction could be applied to a facile synthesis of an
anti-inflammatory drug.
Since oxazole derivatives have found widespread appli-
cations not only as biologically active compounds but also
as synthetic intermediates,1 much effort has been directed
toward devising methods for the synthesis of substituted
oxazoles.2 Among them, oxidative [3 þ 2] annulations of
prefunctionalized ketones or aldehydes with nitriles3,4 or
amines5 have been well studied as straightforward proce-
dures. These procedures, however, have been constrained
by the need to use heavy metal oxidants and/or by the
limitation of the substrates. Recently, Zhang et al. reported
an elegant assembling procedure for the preparation of 2,
5-disubstituted oxazoles, which was achieved by the
gold(I)-catalyzed [2 þ 2 þ 1] annulation of terminal
alkynes, nitriles, and quinoline N-oxides as the oxygen
source (Scheme 1a).6 In similar approaches, Jiang et al.
disclosed that 2,4,5-trisubstituted oxazoles were formed by
the oxidative annulation of internal alkynes with nitriles
under Cu(II)/O2 systems.7,8 To the best of our knowledge,
however, there have been no reports about the formation
† Tokyo University of Agriculture and Technology.
‡ Showa Pharmaceutical University.
(1) (a) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389. (b)
Wipf, P. Chem. Rev. 1995, 95, 2115. (c) Greenblatt, D. J.; Matlis, R.;
Scavone, J. M.; Blyden, G. T.; Harmatz, J. S.; Shader, R. I. Br. J. Clin.
Pharmacol. 1985, 19, 373. (d) Palmer, D. C., Ed. Oxazoles: Synthesis,
reactions, and spectroscopy, Part A; J. Wiley & Sons: Hoboken, NJ, 2003;
Vol. 60. (e) Palmer, D. C., Ed. Oxazoles: Synthesis, reactions, and
spectroscopy, Part B; J. Wiley & Sons: Hoboken, NJ, 2004; Vol. 60.
(2) For recent examples: (a) Liu, X.; Cheng, R.; Zhao, F.; Zhang-
Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2012, 14, 5480. (b) Zhao, F.;
Liu, X.; Qui, R.; Zhang-Negrerie, D.; Huang, J.; Du, Y.; Zhao, K.
J. Org. Chem. 2011, 76, 10338. (c) Davies, P. W.; Cremonesi, A.;
Dumitrescu, L. Angew. Chem., Int. Ed. 2011, 50, 8931. (d) Bartoli, G.;
Cimarelli, C.; Cipolletti, R.; Diomedi, S.; Giovannini, R.; Mari, M.;
Marsili, L.; Marcantoni, E. Eur. J. Org. Chem. 2012, 630.
(5) (a) Wan, C.; Zhang, J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett.
2010, 12, 2338. (b) Xie, J.; Jiang, H.; Cheng, Y.; Zhu, C. Chem. Commun.
2012, 48, 979. (c) Xu, Z.; Zhang, C.; Jiao, N. Angew. Chem., Int. Ed.
2012, 51, 11367. (d) Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z.
Org. Lett. 2010, 12, 3902. (e) Xue, W.-J.; Li, Q.; Zhu, Y.-P.; Wang, J.-G.;
Wu, A.-X. Chem. Commun. 2012, 48, 3485.
(6) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
(7) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang, H.; Jiang, H. Chem.
Sci. 2012, 3, 3463.
(3) Heavy metal oxidant-mediated reactions: (a) Lee, J. C.; Hong, T.
Tetrahedron Lett. 1997, 38, 8959. (b) Lee, J. C.; Hong, T. Tetrahedron
Lett. 1997, 38, 8959. (c) Kotani, E.; Kobayashi, S.; Adachi, M.;
Tsujioka, T.; Nakamura, K.; Tobinaga, S. Chem. Pharm. Bull. 1989,
37, 606. (d) Nagayoshi, K.; Sato, T. Chem. Lett. 1983, 1355.
(4) Iodine(III)-mediated reactions: (a) Varma, R. S.; Kumar, D. J.
Heterocycl. Chem. 1998, 35, 1533. (b) Kawano, Y.; Togo, H. Tetrahe-
dron 2009, 65, 6251. (c) Ishiwata, Y.; Togo, H. Tetrahedron 2009, 65,
10720. (d) Saito, A.; Hyodo, N.; Hanzawa, Y. Molecules 2012, 17, 11046.
(8) Trisubstituted oxazoles have been reported to be formed by the
oxidative annulation of internal alkynes and acetontrile using stoichio-
metric amounts of toxic PhTe(O)OTf. See: Fukumoto, T.; Aso, Y.;
Otsubo, T.; Ogura, F. J. Chem. Soc., Chem. Commun. 1992, 1070.
r
10.1021/ol4009816
XXXX American Chemical Society

of 2,4-disubstituted oxazoles by oxidative annulation
strategies9 and applicable procedures to both terminal
and internal alkynes until very recently. We herein describe
the metal-free [2 þ 2 þ 1] synthesis of 2,4-disubstituted or
2,4,5-trisubstituted oxazoles from terminal or internal
alkynes and nitriles with iodine(III) reagents (Scheme 1b).
catalyzed by TfOH,13 the slight increase in the amount of
PhIO was examined under similar conditions to those for
entry 3. Thus, 1.5 equiv of PhIO with 1.2 equiv of TfOH
afforded 2a in 31% yield without forming 5 (entry 4).
Furthermore, the treatment of PhIO with TfOH at 0 °C for
a short time is crucial to the improved yield of 2a (entries 5
and 6), and the yield of 2a was increased to 80% using
1.8 equiv of PhIO with 1.5 equiv of TfOH (entry 7).14,15 It
should be mentioned that triflic imide (Tf2NH) or HBF4
led to the formation of 2a at ambient temperature, albeit in
a reduced yield (entry 8 or 9).
Scheme 1. Comparison of Zhang’s and Our Work for [2 þ 2 þ 1]
Annulations of Alkynes, Nitriles, and O-Atoms
Table 1. Evaluation of Oxidants for the Formation of 2a from 1a
In modern organic chemistry with the increasing impor-
tance of greener synthetic processes, hypervalent iodine
reagents have gained much attention as eco-friendly
oxidants.10 From this standpoint, we have developed the
metal-free synthesis of heterocyclic compounds based on
the activation of alkynes by iodine(III) reagents.11 On the
basis of our study for the iodine(III)-mediated heterocycle
formation, we envisaged that the metal-free [2 þ 2 þ 1]
annulation would be achieved through Ritter-type addi-
tion of nitriles to intermediates formed by alkynes and
iodine(III) reagents PhI(OH)X, which is generated in situ
from iodosobenzene (PhIO) and a Brønsted acid (HꢀX).12
At the outset, we focused our initial efforts on the evalua-
tion of oxidants, which were generated in situ from PhIO
(1.2 equiv) and various Brønsted acids (HꢀX, 1.2 equiv) at
ambient temperature for 30 min, in the reaction of ethy-
nylbenzene (1a) and acetonitrile (MeCN) as the solvent
(Table 1). The use of p-toluenesulfonic acid (TsOH) or
triflic acid (TfOH) gave 2,4-disubstituted oxazole 2a along
with ketone 4 or pyrimidine 5 (entry 2 or 3). Since the
formation of 5 from 1a and MeCN is known to be
yield (%)a
PhIO
HꢀX
time
(h)
entry
(equiv)
(equiv)
2a
other
38
1
1.2
1.2
1.2
1.5
1.5
1.5
1.8
1.8
1.8
CF3CO2H (1.2)
TsOH (1.2)
TfOH (1.2)
TfOH (1.2)
TfOH (1.2)
TfOH (1.2)
TfOH (1.5)
Tf2NH (1.5)
HBF4e (1.5)
20
22
14
8
0
3
4
5
2
4
7
3
7
25
4
31
56
63
80
60
54
5b
6c
7c
8c
9c
8
8
8
20d
18d
6
26
a The yield was determined by 1H NMR analysis using toluene as the
internal standard. Unless otherwise noted, PhIO was treated with HꢀX
in MeCN at rt for 30 min before addition of 1a. b PhIO was treated with
HꢀX in MeCN at 0 °C for 5 min before addition of 1a. c HꢀX was added
to the mixture of PhIO and alkyne in MeCN at 0 °C. d Reaction
temperature: rt. e Et2O solution.
We next investigated the scope of alkynes and nitriles
under the PhIO/acid-mediated conditions A (TfOH as acids)
or B (Tf2NH as acids) (Table 2). Both conditions could be
applied to the [2 þ 2 þ 1] annulations of not only terminal
alkynes 1aꢀcbut also internal alkynes 1dꢀj, regardless of the
kind of nitriles employed (MeCN, propionitrile, succinoni-
trile, benzonitrile). In addition to 1aꢀc, 1d and 1gꢀj were
regioselectively converted to the corresponding 2,4-disubsti-
tuted (2aꢀc, 7a, and 9a) and 2,4,5-trisubstituted oxazoles
(2d, 2eꢀj, 7d, and 9d) as a single isomer with the illustrated
structures. Under conditions B as compared to conditions A,
(9) Very recently, oxidative [3 þ 2] annulations of alkynes and
carboxamides were reported for the formation of 2,4-disubstituted
oxazoles; see: Luo, Y.; Ji, K.; Li, Y.; Zhang, L. J. Am. Chem. Soc.
2012, 134, 17412.
(10) Recent reviews: (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44,
3656. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (c)
Dohi, T.; Kita, Y. Chem. Commun. 2009, 45, 2073. (d) Miyamoto, K.;
Ochiai, M. J. Syn. Org. Chem., Jpn. 2010, 68, 228. (e) Brand, J. P.;
ꢀ
Gonzalez, D. F.; Nicolai, S.; Waser, J. Chem. Commun. 2011, 47, 102. (f)
Satam, V.; Harad, A.; Rajule, R.; Pati, H. Tetrahedron2010, 66, 7659. (g)
Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185.
(11) (a) Saito, A.; Matsumoto, A.; Hanzawa, Y. Tetrahedron Lett.
2010, 51, 2247. (b) Saito, A.; Anzai, T.; Matsumoto, A.; Hanzawa, Y.
Tetrahedron Lett. 2011, 52, 4658.
(13) Garcia Martinez, A.; Herrera, A.; Martinez, R.; Teso, E.;
Garcia, A.; Osio, J.; Pargada, L.; Unanue, R.; Subramanian, L. R.;
Hanack, M. J. Heterocycl. Chem. 1988, 25, 1237.
(14) The addition of AcNH2 (1.2 equiv) under similar conditions to
entry 7 gave a trace amount of 2a.
(15) The use of 10 equiv of MeCN in 1,2-dichloroethane instead of
MeCN solvent reduced the yield of 2a (9%), even at 80 °C for 14 h under
similar conditions mediated by PhIO with TfOH.
(12) (a) PhI(OH)OTf: Kitamura, T.; Furuki, R.; Taniguchi, H.;
Stang, P. J. Tetrahedron 1992, 48, 7149. (b) PhI(OH)OTs (Koser’s
reagent): Koser, G. F. Aldrich. Acta 2001, 34, 89. (c) Koser’s-type
reagent: Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.;
Kita, Y. Tetrahedron 2009, 65, 10797. (d) PhI(OAc)NMs2 and PhI(OAc-
€
ꢀ
~
)NTs2: Roben, C.; Souto, J. A.; Gonzalez, Y.; Lishchynskyi, A.; Muniz,
K. Angew. Chem., Int. Ed. 2011, 50, 9478.
B
Org. Lett., Vol. XX, No. XX, XXXX

TfOH-mediated conditions at 80°C for 5 min. As shown in
Scheme 3, after the recrystallization of the precipitate from
hexane/Et2O, the obtained crystal was found to be alke-
nyliodonium triflate 12c by single-crystal X-ray structure
analysis.16 Since 12c has been known to be formed by the
treatment of 1c with PhI(OH)OTf in CH2Cl2,12a PhI(OH)-
OTf and the alkenyliodonium intermediates 12 would be
involved in the formation of oxazoles. This is supported by
the formation of 2a from the isolated 12a. Thus, the
treatment of 12a with H2O (1.0 equiv) in MeCN at 80 °C
for 8 h gave 2ain69% yield (Scheme4a). Sincethe addition
of AcNH2 instead of H2O in MeCN or DCE also gave 2a,
albeit in reduced yields (Schemes 4b and 4c), AcNH2 might
be responsible in part for the formation of 2a from 12a.
Table 2. Formation of Oxazoles from Various Alkynes and
Nitriles under the PhIO/Acid-Mediated Conditions A or B
yield (%)a
1
R1
R2
R3CN
product
Ab
Bb
1a Ph
H
H
H
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2a
2b
2c
81c
74
48
82c
61
62
67
54
37e
26
74
77
57
48
51
60
80
52
70
73
64
70
68
37
42
57
76
53
40
52
1b (CH2)2Ph
1c (CH2)5Me
1d Ph
Me
2d
2e
2f
2gd
2hd
2id
2j
1e
1f
Ph
nPr
Ph
nPr
Scheme 3. Formation of 12c from 1c
1g Ph
1h Ph
COPh
COMe
1i
1j
Ph
Ph
CO2Me MeCN
Br
H
MeCN
EtCN
1a Ph
1d Ph
7a
7d
8e
9a
9d
Me
Ph
H
EtCN
1e
Ph
(CH2CN)2
PhCN
PhCN
1a Ph
1d Ph
Me
a Isolated yields. b Conditions: (A) TfOH as acids, 80 °C; (B) Tf2NH
as acids, rt. c Reaction time: 8 h. d PhIO, 1.5 equiv; acid, 3.0 equiv.
e Reaction time: 42 h.
Scheme 4. Formation of 2a from 12a
all the attempted reactions proceeded at ambient tempera-
ture and in some cases brought about improved product
yields (2e, 2h, and 2j). In cases using other nitriles, except for
MeCN, conditions A showed similar or superior results to
conditions B. Conditions A provided a facile synthesis of an
anti-inflammatory drug, Oxaprodine (11),1c from commer-
cially available compounds in two steps (Scheme 2). Thus, in
the presence of TfOH, 1e treated with PhIO in methyl
3-cyanopropanoate gave oxazole 10e, which was converted
to 11 by hydrolysis.
On the basis of these results and previous reports
regarding nucleophilic vinylic substitutions of (β-haloalkenyl)-
iodonium species,17 a plausible mechanism for the present
oxazole formation is illustrated in Scheme 5. That is, 12 is
formed through the iodooxidation of alkyne 1 activated
by PhI(OH)OTf and the subsequent ligand exchange in
Int-A.18 And then, the nucleophilic vinylic substitution of 12
with R3CN, which contributes to the Michael-acceptor
ability of 12,17 leads to Int-B. The lower leaving abilities of
CF3COO and TsO groups might bring about the formation
of ketone 3 or 4, which would proceed via the R-iodanyl
ketone formed by the hydrolysis or the related reaction of
the analog of Int-A and/or 12 (CF3COO or TsO instead of
TfO group).19 Subsequently, Int-B reacts with H2O to
generate Int-C and/or Int-D, which are converted to Int-E.
The vinylic substitutions of 12 with R3CONH2 derived from
R3CN and H2O might be possible as an alternative route to
Int-D. Finally, the reductive elimination of Int-E gives the
target oxazoles. Therefore, the regiochemistry of oxazoles
depends on the outcome of the iodooxidation step,
Scheme 2. A Facile Synthesis of Anti-Inflammatory Drug 11
Observations of a precipitate formed during the early
stage of the reaction time in many cases in the present
reactions encouraged us to confirm the structure of the
precipitate obtained from 1c in MeCN under the PhIO/
(17) Ochiai, M.; Kitagawa, Y.; Toyonari, M.; Uemura, K.; Oshima,
K.; Shiro, M. J. Org. Chem. 1997, 62, 8001.
(18) Such ligand exchanges of OH at iodine have been known. See:
Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365.
(19) The formation of R-iodanyl ketone from (β-acetoxyalkenyl)
iodonium species, see: Ochiai, M.; Kitagawa, Y.; Yamamoto, S.
J. Am. Chem. Soc. 1997, 119, 11598.
(16) CCDC 924418 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Proposed Mechanism for the Oxazole Formation
Scheme 6. Formation of d-2a and 2a from d-1a
Michael addition of thioamides to alkynyliodonium salts.22a
Thus, the oxazole formation from the terminal alkynes
might take part in the Michael addition of R3CONH2 to
alkynyliodonium intermediates besides the route via 12.
In conclusion, we have developed a metal-free, regiose-
lective procedure for [2 þ 2 þ 1] annulations of alkynes,
nitriles, and O-atoms mediated by PhIO with TfOH or
Tf2NH. The present procedure could be applied to both
terminal and inner alkynes with various nitriles, thereby
leading to 2,4-di- and 2,4,5-trisubstituted oxazoles. Further-
more, a new route for the synthesis of a nonsteroidal anti-
inflammatory drug was demonstrated. In light of the isola-
tion of an alkenyliodonium triflate and experimental results,
a plausible mechanism for the present oxazole formation
was proposed. Particularly, a deuterium labeling experi-
ment suggests that alkynyliodonium intermediates along
with alkenyliodonium intermediates would be involved in
cases of terminal alkyne substrates. We believe that the
present study not only provides an attractive procedure for
access to the highly substituted oxazoles but also broadens
the reactivity of iodine(III) reagents.
in which the bulky iodonium ion would bind to the less
stercially hindered R2 side of the alkyne carbon in 1aꢀc
(R1 = Ph, (CH2)2Ph, or (CH2)5CH3, R2 = H) or 1d (R1 =
Ph, R2 = Me).
To gain a better understanding of the oxazole formation
from the terminal alkynes, we examined the reaction of the
deuterated d-1ainMeCNunderthe PhIO/TfOH-mediated
conditions (Scheme 6). The reaction at 80 °C for 8 h gave
the undeuterated 2a along with d-2a (d-2a:2a = 62:38).
Since the hydrogen/deuterium exchange of d-2a was not
observedinthepresenceofTfOH undersimilar conditions,
the formation of the undeuterated 2a would be a result of
an intervention of the alkynyliodonium intermediate 13.
Actually, 13wastreated withAcNH2 inMeCNat80°C for
8 h giving rise to 2a in 34% yield.20 Similar observations
have been reported in the synthesis of thiazoles from
alkynyliodonium salts and thioamides by Wipf’s21 and
Ochiai’s groups.22 For the synthesis of thiazoles, Ochiai
et al. proposed a reaction mechanism that involves a
Acknowledgment. This work was supported by a
Grant-in-Aid for Young Scientists (B), MEXT Japan
(No 24790024). We are grateful to Dr. Hiroyasu Satoh
(Rigaku Co., Ltd.) for the support of X-ray structure
analysis.
Supporting Information Available. Experimental pro-
cedures and physical data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) The treatment of 13 with H2O instead of AcNH2 in MeCN under
similar conditions did not afford 2a.
(21) Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 8004.
(22) (a) Miyamoto, K.; Nishi, Y.; Ochiai, M. Angew. Chem., Int. Ed.
2005, 44, 6896. (b) Ochiai, M.; Nishi, Y.; Hashimoto, S. J. Org. Chem.
2003, 68, 7887.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX