Direct β-acyloxylation of enamines via PhIO-mediated intermolecular oxidative C-O bond formation and its application to the synthesis of oxazoles

Article abstract of DOI:10.1021/ol3025583

A direct β-acyloxylation of enamine compounds has been achieved by using iodosobenzene (PhIO) as an oxidant to realize the intermolecular oxidative C(sp²)-O bond formation between enamines and various carboxylic acids, including N-protected amino acids. The transformation tolerates a wide range of functional groups and furnishes a variety of β-acyloxy enamines that can be conveniently converted to oxazole compounds via cyclodehydration.

Full text of DOI:10.1021/ol3025583

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5480–5483
Direct β‑Acyloxylation of Enamines via
PhIO-Mediated Intermolecular Oxidative
CꢀO Bond Formation and Its Application
to the Synthesis of Oxazoles
Xin Liu, Ran Cheng, Feifei Zhao, Daisy Zhang-Negrerie, Yunfei Du,* and Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn
Received September 18, 2012
ABSTRACT
A direct β-acyloxylation of enamine compounds has been achieved by using iodosobenzene (PhIO) as an oxidant to realize the intermolecular
oxidative C(sp2)-O bond formation between enamines and various carboxylic acids, including N-protected amino acids. The transformation
tolerates a wide range of functional groups and furnishes a variety of β-acyloxy enamines that can be conveniently converted to oxazole
compounds via cyclodehydration.
Ketone derivatives are useful buliding blocks for the
construction of the biologically important oxazole com-
pounds. Generally, the formation of an oxazole ring
Scheme 1. General Strategy for the Formation of Oxazoles from
Ketone Derivatives
involving ketone derivatives as the starting materials falls
into one of the following categories: (1) The ketones
substituted with a leaving group at the R-position reacts
with acyl amides or nitriles (Scheme 1, path a).1 (2) The
tandem reactions between 1,3-dicarbonyl compounds
with benzylamine derivatives under oxidative conditions,
in which the benzylic carbon is incorporated into the
oxazole ring (Scheme 1, path b).2 (3) The reaction of
(1) For selected examples, see: (a) Batsila, C.; Kostakis, G.;
Hadjiarapoglou, L. P. Tetrahedron Lett. 2002, 43, 5997. (b) Lee, J. C.;
Choi, H. J.; Lee, Y. C. Tetrahedron Lett. 2003, 44, 123. (c) Herrera, A.;
Martinez-Alvarez, R.; Ramiro, P.; Molero, D.; Almy, J. J. Org. Chem.
2006, 71, 3026. (d) Lee, J. C.; Seo, J.-W.; Baek, J. W. Synth. Commun.
2007, 37, 2159. (e) Ritson, D. J.; Spiteri, C.; Moses, J. E. J. Org. Chem.
2011, 76, 3519.
(2) For selected examples, see: (a) Wang, C.; Zhang, J.; Wang, S.;
R-diazocarbonyl compounds with amides or nitriles in
Fan, J.; Wang, Z. Org. Lett. 2010, 12, 2338. (b) Xie, J.; Jiang, H.;
Chenga, Y.; Zhu, C. Chem. Commun. 2012, 48, 979.
the presence of Rh catalyst (Scheme 1, path c).3 (4) The
cyclodehydration of R-acylaminoketones, esters, or amides,
which is also knonwn as Robinson-Gabriel oxazole syn-
thesis4 (Scheme 1, path d). (5) The reaction of R-acyloxy
ketones5 with ammounium acetate (Scheme 1, path e).
In this last approach, the β-acyloxy enamines have been
(3) For selected examples, see: (a) Shi, B.; Blake, A. J.; Campbell,
I. B.; Judkinsb, B. D.; Moody, C. J. Chem. Commun. 2009, 45, 3291. (b)
Shi, B.; Blake, A. J.; Lewis, W.; Campbell, I. B.; Judkins, B. D.; Moody,
C. J. J. Org. Chem. 2010, 75, 152. (c) Linder, J.; Garner, T. P.; Williams,
H. E. L.; Searle, M. S.; Moody, C. J. J. Am. Chem. Soc. 2011, 133, 1044.
(d) Austeri, M.; Rix, D.; Zeghida, W.; Lacour, J. Org. Lett. 2011, 13,
1394.
r
10.1021/ol3025583
Published on Web 10/25/2012
2012 American Chemical Society

postulated to be the possible intermediate but was never
separated to be confirmed.5a Although β-acyloxylated en-
amines are a class of compounds not yet been extensively
studied, they can logically be envisaged to be useful building
blocks for the synthesis of oxazoles through cyclodehydra-
tion. However, the synthesis of oxazoles from a “real”
β-acyloxy enamines has not been thoroughly studied,6
partially due to the fact that there are limited methods for
the preparation of the N-unprotected β-acyloxy enamines.
Literature survey shows that the existed approaches include
only the phenyliodine(III) diacetate (PIDA)-mediated
R-acyloxylation of β-monosubstituted enamines6,7 and the
enamination of R-acetoxylated dicarbonyl compound using
ammonium acetate.8 Unfortunately, neither of the above
two strategies can provide a general or efficient synthesis of
β-acyloxy enamines bearing versatile acyloxy moiety since
the former methods are only applicable to the synthesis
of β-acetoxy enamines, while the latter only describe one
example of the formation β-acetoxy-β-enamino ester in a
poor yield. Obviously, direct β-acyloxylation of the readily
available enamine compounds through the oxidative inter-
molecular coupling with various carboxylic acids will be
highly valuable and strongly desired. However, to the best
of our knowledge, this strategy has been less studied and
there is no report on the intermolecular oxidative coupling
of an enamine compound with carboxylic acid;9 even the
powerful palladium-catalyzed oxidative cross-coupling has
not touched on this transformation. As a continuation
of our study on oxidative reactions mediated by hypervalent
iodine reagents,6,7b,10 we described herein a mild and con-
venient synthesis of β-acyloxy enamines using iodosoben-
zene (PhIO) as the oxidant, which has realized the direct
oxidative C(sp2)-O bond formation between enamine com-
pounds with carboxylic acids. The application of the ob-
tained β-acyloxy enamines to the synthesis of oxazoles was
Table 1. Optimization of Reaction Conditionsa
entry
oxidant (equiv)
solvent
DCE
time (h)
yieldb(%)
1
PIDA (1.2)
PIFA (1.2)
PhICl2 (1.2)
PhIO (1.2)
PhIO (1.4)
PhIO (1.2)
PhIO (1.2)
PhIO (1.2)
PhIO (1.2)
PhIO (1.2)
PhIO (1.2)
1
3
3
1
1
1
1
2
1
6
1
29
ND
ND
75
59
85
79
49
34
21
81
2
DCE
3
DCE
4
DCE
5
DCE
6c
7d
8c
9c
10c
11c
DCE
DCE
EtOAc
toluene
DMF
acetonitrile
a All reactions were carried out by adding 2a (0.5 mmol) to a mixture
of 1a (0.5 mmol) and oxidant (0.6 mmol) in solvent (2.5 mL) unless
otherwise stated. b Isolated yields. c 1.2 equiv of 2a was used. d 1.5 equiv
of 2a was used.
also established (Scheme 1, path f). Notably, the N-atom
was introduced early by using enamines as starting materi-
als and the carboxylic acids were installed into the enamines
at a later stage in this process.
We have recently described a direct method for the
synthesis of 2-(trifluoromethyl)oxazoles from β-monosub-
stituted enamines and phenyliodine(III) bistrifluoroace-
tate (PIFA),6 in which the trifluoroacetoxylated enamine
intermediate is postulated to be generated but too reactive
to be separated and thus undergoes simultaneous conden-
sation to give the cyclized oxazole product. Replacing
PIFA with another readily available iodine(III) oxidant,
i.e., PIDA gave the stable β-acetyloxy enamine intermedi-
ate, which could also cyclize to give 2-methyloxazole
compound under reflux in AcOH.6 In both cases, one of
the ligands in the iodine(III) oxidant was incorporated into
the final product. One can easily envisage that by changing
the ligand of PIDA with another carboxylate moiety,
various β-acyloxy enamines bearing different R2 groups
can be synthesized using the above strategy which thus
provides an convenient route for the synthesis of 2-substi-
tuted oxazole compounds. However, the preparation of the
analogs of PIDA with different ligands turns out to be a
time-consuming and troublesome process. To get around,
We rationalized that the reaction of the β-monosubstituted
enamine with various carboxylic acid in the presence of an
appropriate iodine(III) oxidant may very well undergo a
similar pathway to give the desired β-acyloxy enamine
products. If succeeded, such tranformation will stand out
for its significant advantage of eliminating the participation
of any transition metal while facilitating a direct intermole-
cular oxidative coupling of an enamine with carboxylic acid.
To begin with, enamine 1a and benzoic acid were used as
the model substrates to test the feasibility of this transfor-
mation. Subjecting 1.0 equiv of 1a to a mixture of 1.0 equiv
of benzoic acid and 1.2 equiv of PIDA in DCE at room
(4) For selected examples, see: (a) Morwick, T.; Hrapchak, M.; Turi,
M. D.; Campbell, S. Org. Lett. 2002, 4, 2665. (b) Keni, M.; Tepe, J. J.
J. Org. Chem. 2005, 70, 4211. (c) Li, W.; Lam, Y. J. Comb. Chem. 2005, 7,
644. (d) Biron, E.; Chatterjee, J.; Kessler, H. Org. Lett. 2006, 8, 2417. (e)
ꢀ~
Sanz-Cervera, J. F.; Blasco, R.; Piera, J.; Cynamon, M.; Ibanez, I.;
Murguıa, M.; Fustero, S. J. Org. Chem. 2009, 74, 8988. (f) Thompson,
´
M. J.; Adams, H.; Chen, B. J. Org. Chem. 2009, 74, 3856. (g) Clapham,
B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3, 2173.
(5) For selected examples, see: (a) Strzybny, P. P. E.; van Es, T.;
Backeberg, O. G. J. Org. Chem. 1963, 20, 3381. (b) Huang, W.; Pei, J.;
Chen, B.; Pei, W.; Ye, X. Tetrahedron 1996, 52, 10131.
(6) For our preliminary probe into the reaction, see: Zhao, F.; Liu,
X.; Qi, R.; Zhang-Negrerie, D.; Huang, J.; Du, Y.; Zhao, K. J. Org.
Chem. 2011, 76, 10338.
(7) For selected examples, see: (a) Zhang, P. F.; Chen, Z. C. J. Chem.
Res.-S 2001, 150. (b) Chen, Y.; Ju, T.; Wang, J.; Yu, W.; Du, Y.; Zhao,
K. Synlett 2010, 231.
(8) Zhao, Y.; Zhao, J.; Zhou, Y.; Lei, Z.; Li, L.; Zhang, H. New J.
Chem. 2005, 29, 769.
(9) For selected examples describing the intramolecular and inter-
moleculatr condensation of carboxylic acids with ketones, ethers and
alkenes catalyzed by iodine reagents, see: (a) Uyanik, M.; Suzuki, D.;
Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2011, 50, 5331. (b) Shi, E.;
Shao, Y.; Chen, S.; Hu, H.; Liu, Z.; Zhang, J.; Wan, X. Org. Lett. 2012,
14, 3384. (c) Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.;
Wan, X. Chem.;Eur. J. 2011, 17, 4085.
(10) (a) Du, Y.; Liu, R.; Linn, G.; Zhao, K. Org. Lett. 2006, 8, 5919.
(b) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417. (c) Li, X.; Du, Y.;
Liang, Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, 2643. (d) Wang,
J.; Yuan, Y.; Xiong, R.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org. Lett.
2012, 111, 2210.
Org. Lett., Vol. 14, No. 21, 2012
5481

due to the existence of an internal H-bond) in good yields
(Table 2, entries 2ꢀ3). The reaction of an enamine bearing
a cyano group needs much longer reaction time and the
corresponding product was obtained in a relatively lower
yield (Table 1, entry 4). When the methyl group in enamine
1a was replaced with a bulky phenyl group, the coupled
products were obtained as two separable isomers in an
overall 74% yield (Table 2, entry 5).
Table 2. Synthesis of β-Acyloxy Enamines from the PhIO-
mediated Oxidative Coupling of Enamines with Carboxylic
Acidsa
Our next study was aimed at extending the scope of the
reactants from, benzoic acid to a range of substituted
benzoic acids. Results show that the presence of either
electron-donating or electron-withdrawing substituents in
the phenylringof the carboxylicaciddoes not influence the
reaction to any significant extent as the desired products
3fꢀi were all obtained in moderate to good yields (Table 2,
entries 6ꢀ9). The phenyl group of the carboxylic acid
can be further replaced with thienyl, furfuryl and pyridinyl
rings (Table 2, entries 10ꢀ12). However, the yields
achieved for these β-acyloxyenamines bearing heterocyclic
moiety were relatively lower. Furthermore, the aliphatic
carboxylic acids can also be applied to the method and the
desired products that bear a methyl, decanyl, cyclopropyl or
tert-butyl groups can be achieved (Table 2, entries 13ꢀ16).
When the long-chained or bulkyl aliphatic acids were used,
much more reaction time was required for the reaction
to complete (Table 2, entries 14 and 16). Notably, other
substituted carboxylic acids, such as cinnamic acid, chloro-
acetic acid, fumaric acid monoethyl ester and even N-pro-
tected amino acid could also be well tolerated in the process
and the desired products could be furnished in moderate
yields under the same conditions (Table 2, entries 17ꢀ20).
Moreover, the E substituent in the substrate can also be
extended to a benzyloxycarbonyl group (Table 2, entry 21),
in which the benzyl group can be easily removed.
entry R1
E
R2
3
time (h) yieldb (%)
1
Me CO2Me Ph
Me COMe Ph
Me COPh Ph
3a
1
1
1
2
1
2
3
1
1
6
2
4
1
4
1.5
2
1
1
1
1
1
85
80
62
56
74c
72
63
80
65
55
61
45
70
59
67
65
67
66
76
61f
71
2
3b
3c
3
4
Me CN
Ph
3d
3e/3e0
3f
5
Ph CO2Me Ph
6
Me CO2Me o-Me-Ph
Me CO2Me p-MeO-Ph
Me CO2Me p-F-Ph
Me CO2Me m-NO2ꢀPh
Me CO2Me 2-thienyl
Me CO2Me 2-furfuryl
Me CO2Me 4-pyridinyl
Me CO2Me Me
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
3j
3k
3l
3m
3n
3o
3p
3q
3r
Me CO2Me n-decanyl
Me CO2Me cyclopropyl
Me CO2Me t-Bu
17d Me CO2Me PhCHdCH-
18 Me CO2Me ClCH2-
19e Me CO2Me EtO2CCHdCH- 3s
20
21
Me CO2Me BocNHCH2-
Me CO2Bn Ph
3t
3u
a General conditions: PhIO (0.6 mmol), 2a (0.6 mmol), 1a (0.5 mmol)
in DCE (2.5 mL), rt. b Isolated yields. c Mixture of two separable isomers
(3e/3e0 = 5/2). d Cinnamic acid was used. e Fumaric acid was used.
f Mixture of two inseparable isomers (Z/E = 1/4).
temperature for 1 h afforded the desired cross-coupled
product 3a in 29% (Table 1, entry 1), along with the
formation of other unidentified byproducts. No desired
product was detected when PIDA was replaced with PIFA
or PhICl2 (Table 1, entries 2ꢀ3). To our delight, when
PhIO was used as the oxidant, the reaction became very
clean and the coupled product could be furnished in a
satisfactory yield (Table 1, entry 4). Increasing the dosage
of PhIO from 1.2 equiv to 1.4 equiv did not benefit the
yield due to the obvious formation of more byproducts
(Table 1, entry 5). However, when an excess of benzoic
acid (1.2 equiv) was used, the yield was greatly improved to
85% (Table 1, entry 6). Attempt to further improve the
yield by increasing the amount of the acid to 1.5 equiv was
unsuccessful (Table 1, entry 7). Further solvent screening
showed that other solvents including EtOAc, toluene and
DMF were not desired for this reaction, while acetonitrile
also gave a relatively good result (Table 1, entries 8ꢀ11).
Under the most optimal conditions (Table 1, entry 6),
various enamines and carboxylic acids were examined
to probe the scope and generality of the method. The
reaction of the enamines bearing other electron-withdraw-
ing groups such as acyl or benzoyl groups with benzoic
acid also provided the desired products (the presence of
the carbonyl moiety keeps the products an E configuration
One important application of the obtained β-acyloxy
enamines is the capacity to be transformed into various
oxazole compounds via intramolecular condensation in
boiling AcOH.5,6 The results listed in Table 3 demonstrated
that by heating at reflux temperature in AcOH, all the
selected β-acyloxy enamines could be efficiently converted
to the corresponding oxazoles in acceptable to excellent
yields. All these reactions went to completion very fast
(within 30 min) except for the case in entry 4 (Table 3),
which needed relatively longer reaction time (1 h). It is
worthy to note that the alkenyl, chloro and the protected
amino functionality have no influence on the outcome of
the reaction (Table 3, entries 7ꢀ10).
Furthermore, a one-pot sequence for synthesizing ox-
azoles directly from the readily available β-monosubsti-
tuted enamine 1a and N-protected amino acids were exa-
mined. enamines intermediates in chlorobenzene, the reac-
tion mixture was refluxed and the desired oxazole products
could be obtained in moderate to good yields (Table 4).
However, the reaction time was prolonged due to the
sluggish dehydration process under the given conditions.11
The presence of a biologically important oxazole ring as
well as an amino residue of a biologically active amino acid
might render this class of oxazoles some potential applica-
tions in pharmacuetical studies.
5482
Org. Lett., Vol. 14, No. 21, 2012

Table 3. Synthesis of Oxazoles via Intramolecular Condensation of β-Acyloxy Enaminesa
a General conditions: 3 (0.5 mmol), AcOH (2.5 mL), reflux, 30 min unless otherwise stated. b Isolated yields. c The reaction time was 1 h.
fact that no reaction occurred when benzoic acid was
not applied. While the reaction between PIDA and benzoic
acid was found to undergo ligand replacement to give
PhI(OCOPh)2 intermediate.12 On the basis of these results,
Table 4. One-pot Synthesis of Oxazoles from Enamines and
N-Protected Amino Acidsa
we tentatively propose that the reaction adopts a sequence
process involving the in situ generation of PhI(OCOR)2
from the reaction of PhIO and carboxylic acid (RCO2H),
and the subsequent β-acyloxylation of enamines.6
entry
2
R
4
time (h)
yield (%)b,c
In summary, we have developed an iodine(III)-mediated
cross-coupling of enamines with various carboxylic acids
through the intermolecular C(sp2)-O bond formation.
Advantages of the method include the readily availability
of the starting materials, the mild reaction conditions and
the much desired transition-metal-free feature. Moreover,
the transformation can tolerate a wide range of functional
groups and furnish a variety of β-acyloxy enamines that
can be further cyclized to oxazole compounds, showing the
value and practicality of this cross-coupling method.
1
2
3
4
Boc-Gly
H
4t
10
8
62
Boc-L-Phe
Boc-L-Ala
Boc-L-ILe
Ph
4u
4v
4w
65d
87e
75d
Me
12
10
sec-Bu
a General conditions: PhIO (0.6 mmol), 2 (0.5 mmol), 1a (0.6 mmol)
in PhCl (10 mL), rt and then reflux. b Isolated yields. c Calculated based
on 2. d No racemization occurred. e Partial racemization occurred, 84% ee.
Control experiments were carried out for understanding
the mechanistic pathway. The enamine substrate 1a,
although underwent β-trifluoroacetoxylation and β-acet-
yloxylation with PIFA and PIDA, respectively, was found
to be inert in the presence of PhIO based on the experimental
Acknowledgment. We acknowledge the National Nat-
ural Science Foundation of China (#21072148) for financial
support.
(11) The reaction time could be shortened to 2 h if an excess of Boc-
glycine was used; however, the yield of the desired oxazole 4u was
reduced to 59%.
(12) For evidence of such ligand replacement reactions, see: (a) Bell,
R.; Morgan, K. J. J. Chem. Soc. 1960, 1209. (b) Baker, G. P.; Mann,
F. G.; Sheppard, M. N.; Tetlow, A. J. J. Chem. Soc. 1965, 3721. (c)
Leffler, J. E.; Ward, D. C.; Burduroglu, A. J. Am. Chem. Soc. 1972, 94,
5339.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5483