Iodine(III)-promoted synthesis of oxazoles through oxidative cyclization of N -styrylbenzamides

Article abstract of DOI:10.1055/s-0033-1339491

The hypervalent iodine reagent PhI(OTf)₂, generated in situ, has been successfully utilized in an intramolecular oxidative cyclization of N-styrylbenzamides. In remarkably short reaction times, the desired 2,5-disubstituted oxazoles were isolated in high yields in this metal-free oxidative C-O bond-forming reaction. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339491

LETTER
▌2119
lIeottedr ine(III)-Promoted Synthesis of Oxazoles through Oxidative Cyclization of
N-Styrylbenzamides
Iodine(III)-Promoted Synthesis of Oxazoles
Christian Hempel, Boris J. Nachtsheim*
Institut für Organische Chemie, Eberhard Karls Universität, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295897; E-mail: boris.nachtsheim@uni-tuebingen.de
Received: 14.06.2013; Accepted after revision: 09.07.2013
would be of great interest because oxazoles are an impor-
Abstract: The hypervalent iodine reagent PhI(OTf)2, generated in
tant class of heterocyclic compounds that are present in
situ, has been successfully utilized in an intramolecular oxidative
many biologically active natural products and pharmaceu-
cyclization of N-styrylbenzamides. In remarkably short reaction
times, the desired 2,5-disubstituted oxazoles were isolated in high
yields in this metal-free oxidative C–O bond-forming reaction.
ticals.7 So far, a variety of synthetic methods could be de-
veloped for the de novo synthesis of the oxazole motif.8
Here, the intramolecular annulation of diverse functional-
ized enamides is a widely used approach because it offers
simple and direct access to polysubstituted oxazoles from
readily available starting materials.9,10
Key words: hypervalent iodine, umpolung, oxazoles, cyclization,
heterocycles
Hypervalent iodine(III) compounds (aryl-λ3-iodanes) are
readily available, nontoxic and environmentally benign
reagents that have attracted a lot of interest in organic syn-
thesis over the last decades due to their wide range of ap-
plications in oxidative coupling reactions.1 In particular,
oxidative C–C and C–X bond-forming reactions that con-
tain oxidative phenol dearomatizations have found exten-
sive applications in natural product synthesis.2 Using this
approach as a key step in a novel synthesis of arogenate
(pretyrosine),3 our group could recently show that 2-(4-
hydroxybenzamido)acrylate (1a) undergoes iodine(III)-
mediated oxidative spirolactonization to form δ-spirolac-
tone 2a (Scheme 1).4 Interestingly, when the correspond-
ing 2-(4-methoxybenzamido)acrylate (1b) was used as
substrate, the formation of oxazole 2b could be observed
in low yields under slightly modified reaction conditions.
In particular, copper salts have been used as catalysts in
this context, as reported independently by Buchwald and
Stahl for the oxidative cyclization of enamides through vi-
nylic C–H functionalization.10 An iodobenzenediacetate
(PIDA) mediated synthesis of oxazolylmethyl acetates
was developed by Hanzawa and co-workers that is based
on oxidative cycloisomerization of propargylamides.11
Recently, Zhao and co-workers reported an intramolecu-
lar cyclization of amidoacrylates by utilizing a combina-
tion of PIDA and BF3·OEt2, yielding 2,4,5-trisubstituted
oxazoles.12 Very recently, a similar strategy was applied
by Harned and co-workers who reported the transforma-
tion of N-allyl amides into oxazolines.13 However, N-
styrylbenzamides, which give direct access to 2,5-diaryl
oxazoles, have not yet been described in iodane-mediated
cyclization reactions; their oxidative cyclization is sys-
tematically described in this article.
CO2Me
For our initial optimization studies we chose N-styrylben-
zamide (3a) as substrate (Table 1). In initial experiments
using the hypervalent iodine reagents PIDA and PIFA
[bis(trifluoroacetoxy)iodobenzene] alone, only trace
amounts of the desired oxazole product 4a could be ob-
served. Recently, Wirth and co-workers could show that
the hypervalent iodine compound PhI(OTf)2, which can
be generated in situ from PIDA and TMSOTf,14 is a highly
reactive reagent in iodane-mediated oxyaminations.6o
Therefore, we decided to also test the reactivity of
PhI(OTf)2 in our oxidative cyclization. We were pleased
to observe that when PIDA was combined with TMSOTf
in dichloromethane, 4a could be isolated in a promising
yield of 48% (Table 1, entry 1). Changing the solvent to
Et2O resulted in a slightly increased yield, which could be
further improved by using a twofold excess of oxidant and
additive (entries 2 and 3). The use of a mixture of CH2Cl2
and Et2O, either in a 1:2 or 2:1 ratio, was also beneficial
(entries 4 and 5). However, the best yield was obtained by
using a 1:1 mixture of both solvents (entry 6). Applying a
twofold excess of the additive gave no further improve-
ment (entry 7), whereas using two equivalents of oxidant
Bn
N
O
Bn
O
O
N
O
N
O
iodine(III)
(R = H, 1a)
iodine(III)
OMe
O
(R = Me, 1b)
O
OMe
OR
2a
2b
1
Scheme 1 Diversity in the iodine(III)-mediated reaction of benz-
amidoacrylates
As iodine(III) reagents have become more attractive in the
oxidative transformation of olefins, we wondered whether
this remarkable reactivity could be generalized towards an
oxidative cyclization of only moderately functionalized
enamides, such as easily accessible N-styrylbenzamides,5
giving fast access to 2,5-diaryl oxazoles.6 Such a reaction
SYNLETT 2013, 24, 2119–2123
Advanced online publication: 14.08.2013
DOI: 10.1055/s-0033-1339491; Art ID: ST-2013-D0547-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2120
C. Hempel, B. J. Nachtsheim
LETTER
Table 1 Optimization Studiesa
Ph
O
iodine(III)
additive
O
Ph
N
H
solvent, temperature
N
3a
4a
Entry
Iodine(III) (equiv)
Solvent
Additive (equiv)
Temp. (°C)
Time (h)
Yield (%)b
1
2
PIDA
CH2Cl2
Et2O
TMSOTf
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to 0
24
48
51
55
57
58
72
68
65
44
62
67
75
30
PIDA
TMSOTf
20
3
PIDA (2.0)
PIDA
Et2O
TMSOTf (2.0)
TMSOTf
16.5
16.5
22
4
CH2Cl2–Et2O (1:2)
CH2Cl2–Et2O (2:1)
CH2Cl2–Et2O (1:1)
CH2Cl2–Et2O (1:1)
CH2Cl2–Et2O (1:1)
CH2Cl2–Et2O (1:1)
CH2Cl2–Et2O (1:1)
CH2Cl2–Et2O (1:1)
5
PIDA
TMSOTf
6
PIDA
TMSOTf
20
7
PIDA
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf
20
8
PIDA (2.0)
PIDA
20
9
5.5
0.15
0.25
0.25
1
10
11
12
13
PIFA
TMSOTf
PIFA
TMSOTf
PIFA
CH2Cl2–Et2O (1:1)
TMSOTf (2.2)
BF3·OEt2
–78 to 0
PIDA
DCE
reflux
a Reaction conditions: 3a (0.15 mmol), oxidant (1.2 equiv), additive (1.2 equiv), solvent (3 mL).
b Isolated yield after column chromatography.
and additive lowered the yield (entry 8). Although reac- tively (entries 10 and 11). Cyclization of N-styryl nicotin-
tion monitoring showed full conversion of the starting ma- amide gave 4m in only low yields of 27% (entry 12).
terial, the yield was diminished when the reaction time Furthermore, it is worth mentioning that the conformation
was decreased (see below; entry 9). When PIFA was used of the enamide double bond had no influence on the out-
as the oxidant, yields dropped further but the reaction time come of this transformation since the reaction of (Z)-3a
could be decreased significantly from 20 hours to gave 4a in comparable yields (72%).
15 minutes (entry 10). When the reaction was performed
at 0 °C a significantly higher yield of 4a was observed
(67%, entry 11). Finally, using 2.2 equiv TMSOTf gave
Finally, we further investigated the underlying reaction
mechanism. As shown in the optimization studies, when
using PIDA as the oxidant, high yields of the oxazole
an optimized yield of 75% (entry 12). The combination of
product were observed only after long reaction times. Ex-
PIDA and BF3·OEt2 in dichloroethane (DCE) at reflux, as
tensive reaction monitoring by TLC revealed that the
starting material 3a was consumed within minutes upon
stirring at room temperature. However, only trace
amounts of the oxazole product could be detected at this
described by Zhao and co-workers,12 afforded only a poor
yield of 4a (entry 13). This result clearly indicates that the
mild and selective reaction conditions that we have devel-
oped are complementary to other oxidative enamide cycli-
point, whereas a byproduct with an Rf value similar to that
zation reactions. With these optimized conditions in hand,
of the starting material seemed to evolve in the reaction
we investigated the influence of the aryl group R1 in the
mixture. After stirring overnight, the initially formed by-
product disappeared and only the desired oxazole could be
oxidative cyclization (Table 2).
Both, electron-rich as well as electron-poor aromatic sub- observed. When the reaction was stopped within minutes
stituents in the substrate were tolerated under the reaction
conditions, giving the desired 2,5-diaryl oxazoles in up to
AcO
Ph
O
PIDA (1.2 equiv)
77% yield (Table 2, entries 1, 2, 4, 6, and 7). Only sub-
strates bearing a substituent in the 3-position gave lower
yields (entries 3, 5 and 8). However, a 3-nitro substituent
seemed to have no negative influence on the outcome of
the reaction (entry 9). CF3-substituted substrates were also
tolerated, giving 4k and 4l in 77 and 54% yield, respec-
TMSOTf (1.2 equiv)
Ph
N
N
O
H
CH2Cl2–Et2O (1:1)
–78 °C to r.t., 15 min
Ph
up to 54%
3a
5
Scheme 2 Formation of oxazoline
Synlett 2013, 24, 2119–2123
© Georg Thieme Verlag Stuttgart · New York

LETTER
Iodine(III)-Promoted Synthesis of Oxazoles
2121
Table 2 Reaction Scopea
philic attack by the amide oxygen forms alkyl iodane 7.
The ability of the iodine(III) nucleus to act as a supernu-
cleofuge makes further nucleophilic attack by acetate fa-
vorable, leading to the oxazoline 5 (pathway A).15 In the
final step, HOAc is eliminated to form 4a. In a competing
pathway, the oxazole is generated directly from alkyl
iodane 7 through elimination, liberating iodobenzene
and triflate (pathway B).
Ph
PIFA (1.2 equiv)
O
O
TMSOTf (2.2 equiv)
Ph
CH2Cl2–Et2O (1:1)
–78 to 0 °C
R
N
R
N
H
3
4
10–15 min
Entry
R
Oxazole
Yield (%)b
To verify that oxazoline 5 is truly an intermediate in the
formation of the oxazole, attempts were made to convert
5 into 4a under reaction conditions mimicking those of the
oxidative cyclization. No reaction of 5 was observed in
the presence of either NaOAc or NaOAc/TMSOTf. How-
ever, using solely TMSOTf, oxazoline 5 was completely
consumed and oxazole 4a could be isolated in quantitative
yield (Scheme 4). These results suggest a Lewis acid pro-
moted (i.e., TMS+) abstraction of acetate in the formation
of oxazole 4a rather than elimination involving acetate
acting as base. Further evidence for this conclusion is the
enhanced reactivity observed for PIFA in the cyclization
reaction. Because trifluoroacetate is a much worse nucleo-
phile than acetate, pathway A can be neglected and direct
elimination seems to be more favorable.
1
2
4-MeC6H4
4b
4c
4d
4e
4f
68
70
65
77
59
77
72
55
72
77
54
27
2-EtOC6H4
3-MeOC6H4
4-MeOC6H4
3-FC6H4
3
4
5
6
4-FC6H4
4g
4h
4i
7
2-ClC6H4
8
3-ClC6H4
9
3-O2NC6H4
4-F3CC6H4
3,5-(CF3)2C6H3
3-pyridyl
4j
10
11
12c
4k
4l
Ph
Ph
OAc
4m
O
TMSOTf (1.2 equiv)
a Reaction conditions: 3 (0.15 mmol), solvent (3 mL).
b Isolated yield after column chromatography.
c Reaction time 2.5 h.
O
N
CH2Cl2–Et2O (1:1)
N
–78 °C to r.t., 15 min
Ph
5
quant.
4a
after stirring at room temperature, oxazoline acetate 5
could be isolated as a single diastereoisomer (cis) and this
proved to be the byproduct initially formed in the reaction
(Scheme 2). According to these results, we propose a
mechanism for the oxidative cyclization as shown in
Scheme 3. PhI(OTf)2 generated in situ interacts with the
alkene moiety of the enamide to form either activated ole-
fin complex 6a or iodonium ion 6b, then 5-endo nucleo-
Scheme 4 Lewis acid promoted conversion of oxazoline
In conclusion, we have developed an efficient iodine(III)-
mediated synthesis of 2,5-disubstituted oxazoles by an ox-
idative cyclization of N-styrylbenzamides.16 By applying
mild reaction conditions, a variety of oxazoles bearing
electron-poor or electron-rich aromatic substituents in the
Ph
O
iodine(III)
TMSOTf
O
Ph
N
H
N
4a
3a
OAc
I
OTf
+ 2 TMSOTf
AcO
Ph
Ph
Ph
I
– 2 TMSOAc
– H+
OAc
OTf
N
O
pathway B
(elimination)
– PhI
– TfO–
Ph
OTf
I
5
OTf
I
Ph
H
OTf
Ph
H
Ph
I
Ph
Ph
Ph
or
HN
HN
N
O
– H+
Ph
O
Ph
O
AcO–
Ph
6b
6a
7
Scheme 3 Proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2119–2123

2122
C. Hempel, B. J. Nachtsheim
LETTER
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5-position were obtained in good to high yields in remark-
ably short reaction time.
Acknowledgment
This work was financially supported by the DFG (NA 955/1-1), the
Fonds der Chemischen Industrie (Sachkostenzuschuss) and the
BMBF (GenBioCom FKZ0315585A).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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(16) Synthesis of Oxazoles 4a–m; General Procedure: The
appropriate N-styrylbenzamide (3a–m; 0.015 mmol,
1.0 equiv) was suspended in a 1:1 mixture of anhydrous
CH2Cl2 and Et2O (3 mL) and cooled to –78 °C. PIFA (1.2
equiv) and TMSOTf (2.2 equiv) were added and the reaction
mixture was stirred at 0 °C until full conversion of the
starting material was observed by TLC monitoring. The
reaction mixture was diluted with CH2Cl2 (3 mL), washed
with NaHCO3 (1 M, 3 mL) and the aqueous phase was
extracted with CH2Cl2 (3 × 3 mL). The combined organic
layers were dried over Na2SO4 and the solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography (cyclohexane–EtOAc).
Compound 4l: Mp 130–132 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.54 (s, 2 H), 7.95 (s, 1 H), 7.78–7.75 (m, 2 H),
Synlett 2013, 24, 2119–2123
© Georg Thieme Verlag Stuttgart · New York

LETTER
7.52–7.47 (m, 3 H), 7.43–7.38 (m, 1 H). 13C NMR
Iodine(III)-Promoted Synthesis of Oxazoles
2123
IR: 1736, 1380, 1277, 1130, 943, 901, 843, 767, 730,
(100 MHz, CDCl3): δ = 158.4, 152.9, 132.7 (q, J = 34.0 Hz),
129.5, 129.4, 129.3, 127.4, 126.3, 124.7, 124.1, 123.6-123.4
(m), 123.1 (q, J = 271 Hz). MS (FAB): m/z = 358.1 [M+H]+.
681 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C17H9F6NO:
358.06611; found: 358.06579.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2119–2123

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