TBAI-catalyzed oxidative cross-coupling of phenols and 2-aminoacetophenones

Article abstract of DOI:10.1021/acs.orglett.5b00466

An iodide-catalyzed oxidative cross-coupling between phenols and 2-aminoacetophenones has been developed. Using catalytic amounts of tetrabutylammoniumiodide (TBAI) as an iodine-containing catalyst and aqueous solutions of tert-butyl hydro-peroxide (TBHP)

Full text of DOI:10.1021/acs.orglett.5b00466

Letter
pubs.acs.org/OrgLett
TBAI-Catalyzed Oxidative Cross-Coupling of Phenols and
2‑Aminoacetophenones
Wei Xu and Boris J. Nachtsheim*
Institut fur Organische Chemie, Eberhard Karls Universitat Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: An iodide-catalyzed oxidative cross-coupling between phenols and 2-aminoacetophenones has been developed.
Using catalytic amounts of tetrabutylammoniumiodide (TBAI) as an iodine-containing catalyst and aqueous solutions of tert-
butyl hydro-peroxide (TBHP) as the stoichiometric co-oxidant, a variety of α-phenoxylated 2-aminoacetophenones could be
obtained in yields of up to 92% after remarkably short reaction times (20 min). This is a very rare example for an iodide-catalyzed
intermolecular cross-coupling utilizing phenols. However, this efficient methodology could be further extended toward an
intramolecular variant which gives direct access to a range of dihydro-4H-benzo[e][1,3]oxazin-4-ones.
Table 1. Optimization of the Reaction Conditions for the
Oxidative Coupling of N-Acyl α-Amino Acetophenone 1a
and Phenol
he oxidative construction of C−O bonds from enolizable
Tcarbonyl compounds is a key transformation in organic
synthesis.1,2 Besides organic peroxides and heavy metal salts,
hypervalent iodine compounds have been widely utilized as
effective mediators for these valuable transformations.3,4 It has
recently been found that a simple catalytic system containing
catalytic amounts of an iodide salt or molecular iodine, together
with an external co-oxidant, can be very effective to perform
such transformations.5 In a seminal work, Uyanik and Ishihara
reported an oxidative cycloetherification of ketophenols
mediated by in situ generated chiral quaternary ammonium
hyopoiodites.6b Very recently, the same group could apply this
protocol toward an efficient enantioselective synthesis of α-
tocopherols.6a However, both protocols were restricted toward
intramolecular oxidative C−O bond formations. Intermolecular
oxygenations of sp3hybridized C−H bonds under similar
conditions have been described, but so far all protocols are
strictly limited to amines, carboxylic acids, or activated primary
alcohols as oxygen-containing coupling partners.7−9 In this
communication, we want to enhance the chemical space of
(hypo)iodite-mediated cross-couplings by describing the first
intermolecular oxidative C−O coupling using oxidatively labile
phenols. As a model C-nucleophile we chose to use N-acyl 2-
aminoacetophenone 1a. By using molecular iodine as a catalyst
and an aqueous TBHP solution as a co-oxidant we only
detected traces of the desired product 2a in the crude NMR
(Table 1, entry 1). Changing the catalyst to potassium or
sodium iodide resulted in the formation of 2a in promising 52%
and 48% yields, respectively (Table 1, entries 2 and 3). With
copper(I) iodide no product formation was observed (Table 1,
entry 4), while TBAI was the best iodine-containing catalyst
yielding 2a in 70% yield (Table 1, entry 5).
a
entry
catalyst
oxidant
solvent
yield (%)
1
2
3
4
5
I2
aq TBHP
aq TBHP
aq TBHP
aq TBHP
aq TBHP
aq TBHP
aq H2O2
oxone
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DMSO
DMF
traces
KI
52
NaI
48
CuI
0
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
70
b
6
52
7
0
8
0
9
MeCO3tBu
aq TBHP
aq TBHP
aq TBHP
aq TBHP
traces
10
11
12
13
0
0
CH3CN
1,2-DCE
traces
0
a
General reaction conditions: 1 (0.2 mmol), phenol (1.0 mmol),
catalyst (0.04 mmol), oxidant (0.7 mmol), solvent (3 mL), 80 °C, 20
b
min. 0.4 mmol of K2CO3 was added.
Addition of potassium carbonate as a base did not result in
improved product yields (Table 1, entry 6). With other
oxidants such as hydrogen peroxide, oxone (KHSO5/KHSO4/
Received: February 13, 2015
Published: March 12, 2015
© 2015 American Chemical Society
1585
DOI: 10.1021/acs.orglett.5b00466
Org. Lett. 2015, 17, 1585−1588

Organic Letters
Letter
K2SO4), or tert-butyl peracetate no product formation was
observed (Table 1, entries 7−9). As solvent only ethyl acetate
can be used in this transformation, whereas other polar aprotic
solvents such as DMSO, DMF, MeCN, or 1,2-dichloroethane
did not result in product formation (Table 1, entries 10−13).
Therefore, we chose to take the optimal conditions as noted in
Table 1 (entry 5) and investigated the substrate scope of this
transformation (Scheme 1).
desired products 2g and 2h in 53% and 55% yield, respectively.
Next, we introduced different substituents on the arene moiety
of acetophenone. 4′-Nitro substitution resulted in decreased
reactivity giving coupling products 2i−2k in moderate yields
(47−54%). The 4′-bromo substituted 2-aminoacetophenone
derivative gave 2l−2n in good yields between 68% and 81%.
However, electron-rich 2-aminoacetophenones seem to be
nonbeneficial for this transformation since its 4′-methoxy
derivative gave 2o in only 58% isolated yield. α-Amino-2-
acetonaphthone gave a variety of cross-coupling products 2p−
2r in good to excellent yields (71−90%). Finally, we changed
the nitrogen protecting group to N-benzoyl and observed a
similar reactivity giving the desired products 2s−2w in 62−82%
yield. To further expand the substrate scope, we also
investigated an intramolecular version of this reaction (Scheme
2).
Scheme 1. Substrate Scope for the Direct Phenoxylation of
a
2-Aminoacetophenones 1
For this purpose, we synthesized a variety of N-(2-
hydroxybenzoyl)-protected α-aminoacetophenones 3 and re-
acted them under our optimized reaction conditions. To our
delight, the desired dihydro-4H-benzo[e][1,3]oxazin-4-ones 4
can be formed directly in good yields (Scheme 2). Variation of
the aryl substituent of the 2-aminoacetophenone with electron-
Scheme 2. Substrate Scope for the Direct Oxidative
Synthesis of Dihydro-4H-benzo[e][1,3]oxazin-4-ones
a
a
Reaction conditions: 1 (0.2 mmol), Ar−OH (1.0 mmol), TBAI (0.04
mmol), aq TBHP (0.7 mmol), EtOAc, 80 °C.
First, a variety of differently substituted phenols were
investigated. Halogenated phenol derivatives such as 4-chloro-,
3-bromo-, or 2-iodophenols can be applied giving the desired
coupling products 2b−2d in 73−81% yield. 4-Nitrophenol
shows decreased reactivity; however, the desired product 2e
can be observed in 53% yield. 4-Carboxyethyl-substituted
phenol reacted superior yielding 2f (92%). Electron-rich
phenols such as 2-methyl- and 4-methoxyphenol gave the
a
Reaction conditions: 3 (0.2 mmol), TBAI (0.04 mmol), aq TBHP
(0.7 mmol), EtOAc, 80 °C.
1586
DOI: 10.1021/acs.orglett.5b00466
Org. Lett. 2015, 17, 1585−1588

Organic Letters
Letter
donating and -withdrawing substituents gave products 4a−4d
in a close range of isolated yields between 50% and 67%. The
N-(2-hydroxyaroyl) protecting group can be varied with
halogen substituents, for example, to give 4e in 52% yield. In
addition, alkyl and alkoxy side chains are tolerated to yield
products 4f−4j in yields ranging from 49% to 55%.
To prove the structure of our cyclized products, in particular
to verify that no further oxidation to the corresponding fully
unsaturated 4H-benzo[e][1,3]oxazin-4-one occurred, we per-
formed single crystal X-ray analysis. Compound 4h formed
single crystals which could be analyzed by X-ray diffraction
analysis (Figure 1). Here we were happy to find that the X-ray
diffraction data undoubtedly indicated formation of the
proposed dihydro derivative.
significantly lower than the yield observed with the original
protocol (72%). However, as already stated by Uyanik and
Ishihara in their hypoiodite-mediated transformations,6 for-
mation of 2p under these conditions can be seen as a strong
indicator that hypoiodite species are involved in the catalytic
cycle.
Therefore, we propose a reaction mechanism as shown in
Scheme 4. The enolized form of the starting material 1a′
Scheme 4. Proposed Reaction Mechanism
Figure 1. Plot of the X-ray crystallographic data of 4h.
condensates with an in situ generated (hypo)iodite species to
generate oxygen- or carbon-iodinated species A or B.
Depending on the nature of this intermediate a subsequent
SN2′ or SN2 reaction occurs at the α-carbon to generate the
desired product 2a.
In summary we have described a convenient method for the
direct oxidative coupling between phenols and α-amino-
acetophenones. This reaction is a very rare example for a
metal-free oxidative coupling between an oxidatively labile
phenol and an α-enolic carbon atom. The unique substrate
scope, the use of simple tetraalkylammonium iodides as
oxidation catalysts, and the fact that easy to handle aqueous
oxidants (TBHP) can be used render this novel transformation
a convenient alternative to existing hypervalent iodine mediated
α-oxygenations.
To elucidate the underlying reaction mechanism we
performed two distinct control experiments. To exclude a
radical-based mechanism we reacted N-acyl protected 2-amino-
2-naphtophenone 1p under our standard reaction protocol and
additionally added TEMPO as a radical scavenger (Scheme 3a).
Scheme 3. Control Experiments
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, spectroscopic data as well as H and
13C NMR spectra of compounds 2a−2w and 4a−4g. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: boris.nachtsheim@uni-tuebingen.de.
Notes
In this experiment, we observed the formation of 2p in 55%
yield and no TEMPO-bound intermediate such as 5 was
detected. Therefore, we think that a radical-based reaction
mechanism can be excluded. To prove the possible existence of
hypoiodites (IO−) as active species in this transformation, we
reacted 1p with stoichiometric amounts of molecular iodine
and a 2-fold excess of nBu4NOH without an additional co-
oxidant (Scheme 3b). In this experiment the desired product
2p could be obtained in an isolated yield of 41%, which is
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding by the DFG (NA 955/1-1) and the Fonds der
Chemischen Industrie (Sachkostenzuschuss) is gratefully
acknowledged.
1587
DOI: 10.1021/acs.orglett.5b00466
Org. Lett. 2015, 17, 1585−1588

Organic Letters
Letter
REFERENCES
■
(1) For reviews about the oxidative construction of C−O bonds, see:
(a) Krylov, I. B.; Vil’, V. A.; Terent’ev, A. O. Beilstein J. Org. Chem.
2015, 11, 92. (b) Mehta, V. P.; Punji, B. RSC Adv. 2013, 3, 11957.
(c) Song, G. Y.; Wang, F.; Li, X. W. Chem. Soc. Rev. 2012, 41, 3651.
(d) Turner, N. J. Chem. Rev. 2011, 111, 4073. (e) Yoo, W. J.; Li, C. J.
Top. Curr. Chem. 2010, 292, 281.
(2) For reviews about oxygenation of α-carbonyl bonds, see:
(a) Streuff, J. Synlett 2013, 24, 276. (b) Smith, A. M. R.; Hii, K. K.
Chem. Rev. 2011, 111, 1637. (c) Christoffers, J.; Baro, A.; Werner, T.
Adv. Synth. Catal. 2004, 346, 143. (d) Davis, F. A.; Chen, B. C. Chem.
Rev. 1992, 92, 919.
(3) Hypervalent Iodine Chemistry: Topics in Current Chemistry, Vol.
224; Wirth, T., Ed.; Springer: Berlin, 2003.
(4) For reviews, see: (a) Singh, F. V.; Wirth, T. Chem.Asian J.
2014, 9, 950. (b) Dong, D. Q.; Hao, S. H.; Wang, Z. L.; Chen, C. Org.
Biomol. Chem. 2014, 12, 4278. (c) Brown, M.; Farid, U.; Wirth, T.
Synlett 2013, 24, 424. (d) Merritt, E. A.; Olofsson, B. Synthesis 2011,
517. (e) Quideau, S.; Wirth, T. Tetrahedron 2010, 66, 5737. (f) Dohi,
T.; Kita, Y. Chem. Commun. 2009, 2073. (g) Richardson, R. D.; Wirth,
T. Angew. Chem., Int. Ed. 2006, 45, 4402. (h) Moriarty, R. M. J. Org.
Chem. 2005, 70, 2893.
(5) For reviews, see: (a) Wu, X. F.; Gong, J. L.; Qi, X. X. Org. Biomol.
Chem. 2014, 12, 5807. (b) Finkbeiner, P.; Nachtsheim, B. J. Synthesis
2013, 45, 979. (c) Uyanik, M.; Ishihara, K. ChemCatChem 2012, 4,
177.
(6) (a) Uyanik, M.; Hayashi, H.; Ishihara, K. Science 2014, 345, 291.
(b) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328,
1376.
(7) Recent examples for C−O bond forming reactions with iodione-
containing catalysts, see: (a) Majji, G.; Guin, S.; Rout, S. K.; Behera,
A.; Patel, B. K. Chem. Commun. 2014, 50, 12193. (b) Boominathan, S.
S. K.; Hu, W.-P.; Senadi, G. C.; Vandavasi, J. K.; Wang, J.-J. Chem.
Commun. 2014, 50, 6726. (c) Yu, H.; Huang, W. H.; Zhang, F. L. Eur.
J. Org. Chem. 2014, 2014, 3156. (d) Yu, H.; Shen, J. Org. Lett. 2014,
16, 3204. (e) Yu, H.; Zhang, F. L.; Huang, W. H. Synlett 2014, 25, 843.
(f) Dhineshkumar, J.; Lamani, M.; Alagiri, K.; Prabhu, K. R. Org. Lett.
2013, 15, 1092. (g) Majji, G.; Guin, S.; Gogoi, A.; Rout, S. K.; Patel, B.
K. Chem. Commun. 2013, 49, 3031. (h) Zhang, S.; Guo, L. N.; Wang,
H.; Duan, X. H. Org. Biomol. Chem. 2013, 11, 4308. (i) Yoshimura, A.;
Zhu, C. J.; Middleton, K. R.; Todora, A. D.; Kastern, B. J.; Maskaev, A.
V.; Zhdankin, V. V. Chem. Commun. 2013, 49, 4800. (j) Feng, J.;
Liang, S.; Chen, S. Y.; Zhang, J.; Fu, S. S.; Yu, X. Q. Adv. Synth. Catal.
2012, 354, 1287. (k) Li, X. Q.; Zhou, C.; Xu, X. S. ARKIVOC 2012,
150. (l) Liu, X.; Cheng, R.; Zhao, F. F.; Zhang-Negrerie, D.; Du, Y. F.;
Zhao, K. Org. Lett. 2012, 14, 5480. (m) Uyanik, M.; Suzuki, D.; Yasui,
T.; Ishihara, K. Angew. Chem., Int. Ed. 2011, 50, 5331.
(8) Recent examples for (hypo)iodite-mediated oxidative aminations:
(a) Chen, J.; Yan, W.-Q.; Lam, C. M.; Zeng, C.-C.; Hu, L.-M.; Little,
R. D. Org. Lett. 2015, 17, 986. (b) Zhang, J.; Shao, y.; Wang, Y.; Li, H.;
Xu, D.; Wan, X. Org. Biomol. Chem. 2015, DOI: 10.1039/
C5OB00109A. (c) Sharif, M.; Gong, J.-L.; Langer, P.; Beller, M.;
Wu, X.-F. Chem. Commun. 2014, 50, 4747. (d) Yuan, Y.; Hou, W.;
Zhang-Negrerie, D.; Zhao, K.; Du, Y. Org. Lett. 2014, 16, 5410.
(e) Sharif, M.; Chen, J.; Langer, P.; Beller, M.; Wu, X.-F. Org. Biomol.
Chem. 2014, 12, 6359. (f) Wang, L.; Zhu, K.; Chen, Q.; He, M. J. Org.
Chem. 2014, 79, 11780. (g) Li, D.; Yang, T.; Su, H.; Yu, W. Adv. Synth.
Catal. 2014, 356, 3148. (h) Sun, K.; Wang, X.; Li, G.; Zhu, Z.; Jiang,
Y.; Xiao, B. Chem. Commun. 2014, 50, 12880.
(9) Recent examples for (hypo)iodite catalysis in the synthesis of
heterocycles: (a) Li, X.; Fang, M.; Hu, P.; Hong, G.; Tang, Y.; Xu, X.
Adv. Synth. Catal. 2014, 356, 2103. (b) Naresh, G.; Kant, R.; Narender,
T. J. Org. Chem. 2014, 79, 3821. (c) Huang, H.-M.; Li, Y.-J.; Ye, Q.;
Yu, W.-B.; Han, L.; Jia, J.-H.; Gao, J.-R. J. Org. Chem. 2014, 79, 1084.
(d) Gogoi, A.; Modi, A.; Guin, S.; Rout, S. K.; Das, D.; Patel, B. K.
Chem. Commun. 2014, 50, 10445. (e) Zhao, D.; Wang, T.; Shen, Q.;
Li, J.-X. Chem. Commun. 2014, 50, 4302. (f) Naresh, G.; Narender, T.
RSC Adv. 2014, 4, 11862.
1588
DOI: 10.1021/acs.orglett.5b00466
Org. Lett. 2015, 17, 1585−1588