Copper-catalyzed oxidative ring closure and carboarylation of 2-ethynylanilides

Article abstract of DOI:10.1021/ol402600r

A new copper-catalyzed oxidative ring closure of ethynyl anilides with diaryliodonium salts was developed for the highly modular construction of benzoxazines bearing a fully substituted exo double bond. The oxidative transformation includes an unusual 6-exo-dig cyclization step with the formation of C-O and C-C bonds.

Full text of DOI:10.1021/ol402600r

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5654–5657
Copper-Catalyzed Oxidative Ring Closure
and Carboarylation of 2‑Ethynylanilides
†
Adam Sinai, Adam Meszaros, Tamas Gati, Veronika Kudar, Anna Pallo, and
†
‡
§
ꢀ §
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ
,†
ꢀ
Zoltan Novak*
ꢀ
MTA-ELTE “Lendu€let” Catalysis and Organic Synthesis Research Group, Institute
€ €
ꢀ
ꢀ
of Chemistry, Eotvos University, Pazmany Peter stny. 1/a, H-1117 Budapest, Hungary,
Servier Research Institute of Medicinal Chemistry, Zahony utca 7, H-1031 Budapest,
ꢀ
ꢀ
Hungary, and Research Centre for Natural Sciences, Hungarian Academy of Sciences,
Pusztaszeri uꢀt 59-67, H-1025 Budapest, Hungary
novakz@elte.hu
Received September 9, 2013
ABSTRACT
A new copper-catalyzed oxidative ring closure of ethynyl anilides with diaryliodonium salts was developed for the highly modular construction of
benzoxazines bearing a fully substituted exo double bond. The oxidative transformation includes an unusual 6-exo-dig cyclization step with the
formation of CÀO and CÀC bonds.
Synthesis and functionalization of aromatic and hetero-
aromatic systems through oxidative couplings are one of
the most important areas of current organic syntheses.1
Iodonium salts2 are useful coupling partners, and their use
enables the introduction of ethynyl3 and aryl4 moieties into
the aromatic and heteroaromatic substrates via transition-
metal-catalyzed oxidative transformations. In the presence
of directing groups with the appropriate choice of metal
catalyst, the incoming functional group can be directed
selectively into the aromatic ring. As described by
Daugulis, the palladium-catalyzed arylation of anilides gives
o-arylacetanilides,5 while copper-triflate catalyzed arylation
of pivalanilides provides selectively meta-directed arylpiva-
lanilides, as demonstrated by Gaunt and Phipps.6 In most
cases of the meta selective arylation, the pivalanilides bear
†
€
€
Eotvos University.
‡ Servier Research Institute of Medicinal Chemistry.
§ Research Centre for Natural Sciences, Hungarian Academy of Sciences.
€
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r
10.1021/ol402600r
Published on Web 11/04/2013
2013 American Chemical Society

functional groups in the ortho position next to the protected
amino group.
Scheme 1. Possible Functionalization Modes of Alkynylanilides
We aimed to examine the chemoselective functionaliza-
tion of o-alkynylanilides with iodonium salts via copper-
catalyzed oxidative coupling. The alkynylanilide motif
offers multiple sites of reactivity, either with the anilide
aromatic system or using the triple bond (Scheme 1).
Considering the available synthetic pathways, meta-selective
arylation6 would provide meta-arylated ethynyl anilides
(path 1) while the copper-catalyzed electrophilic carbo-
functionalization of alkynes with diaryl iodonium triflates
would form 2,3-diarylindoles (path 2) or benzoxazines
with fully substituted exo double bond (path 3). A similar
carboarylation strategy has been described by Gaunt
and utilized for the synthesis of highly functionalyzed
tetrasubstituted alkenyl triflates7 and the construction of
heterocycles and carbacycles.8
Transition-metal-accelerated ring closure with the par-
ticipation of the triple bond can occur through two possi-
ble pathways: the preferred 5-endo-dig cyclization provides
indoles9 while in the presence of Au,10 Pd,11 or iodine12
catalysts the relatively rare 6-exo-dig ring closure affords
benzoxazines,13 which have been shown to possess signifi-
cant biological activity.14
with full conversion in the presence of 10 mol % of
Cu(OTf)2 in dichloroethane at 50 °C.15 The reaction
product was isolated in 59% yield and determined to be
benzoxazine 3a through NMR analysis. Other solvents
(DCM, chloroform, DMF, dioxane, THF) and other
catalysts (Pd(OAc)2, AuCl, CuSO4, CuI, Cu(MeCN)4OTf)
proved to be unsuitable for the efficient transformation of
the pivalanilide.16
Scheme 2. Model Reaction for Optimization Studies
As a model substrate, 2-phenylethynylpivalanilide (1a)
was reacted with phenylmesityliodonium triflate(2a) in the
presence of transition-metal catalysts in various solvents
(Scheme 2.). We found that the alkyne was transformed
(7) Suero, M. G.; Bayle, E. D.; Collins, S. L.; Gaunt, M. J. J. Am.
Chem. Soc. 2013, 135, 5332.
(8) (a) Cahard, E.; Bremeyer, N.; Gaunt, M. J. Angew. Chem., Int. Ed.
2013, 52, 9284. (b) Walkingshaw, A. J.; Xu, W.; Suero, M. G.; Gaunt,
M. J. J. Am. Chem. Soc. 2013, 135, 12532.
(9) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(b) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (c) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873. (d) Zeni, G.; Larock, R. C.
Chem. Rev. 2004, 104, 2285. (e) Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127. (f) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008,
108, 3395.
(10) Hashmi, A. S. K.; Schuster, A. M.; Schmuck, M.; Rominger, F.
Eur. J. Org. Chem. 2011, 4595.
(11) (a) Saito, T.; Ogawa, S.; Takei, N.; Katsumura, N.; Otani, T.
To examine the scope and limitation of the developed
methodology, we reacted different alkynylanilides with
phenylmesityliodonium triflate in the presence of 10 mol
% of Cu(OTf)2 in DCE at 50 °C (Scheme 3). The presence
of a methyl group in any position of the arylethynyl part
caused lower efficiency compared to the unsubstituted
phenylethynyl derivative, but we obtained the desired
compounds (3bÀd) in 65%, 63%, and 44% yields, respec-
tively. Arylethynylpivalanilides substituted with halogens
(Br, Cl, F) were also transformed to the appropriate
benzoxazines (3eÀi) in 40À63% yield. Both strongly elec-
tron-withdrawing and -donating groups are compatible
with the reaction. In the case of nitro and methoxy group
we obtained the appropriate products (3j and 3k) in 34 and
48% yield.
However, when the arylethynyl reactant was substituted
with an ester group, benzoxazine 3l was obtained in 65%
yield. When an extended aromatic ring system such as
naphthalene was present in the substrate, the appropriate
benzoxazine (3m) was prepared in good yield (79%). In the
case of these nonsymmetrically substituted diaryl deriva-
tives, the NMR measurements showed the presence of
mixture of geometric isomers.17 Careful analysis revealed
that the products undergo light-induced isomerization in
solution.18
ꢁ
Org. Lett. 2011, 13, 1098. (b) Costa, M.; Ca, N. D.; Massera, C.; Salerno,
G.; Soliani, M. J. Org. Chem. 2004, 69, 2469. (c) Cacchi, S.; Fabrizi, G.;
Marinelli, F. Synlett 1999, 401.
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Vandavasi, J. K.; Wang, J.-J. Adv. Synth. Catal. 2012, 354, 2218.
(13) For synthesis of 4-alkylidene-4H-3,1-benzoxazines, see: (a)
Fresneda, P. M.; Bleda, J. A.; Sanz, M. A.; Molina, P. Synlett 2007,
1541. (b) Kobayashi, K.; Okamura, Y.; Konishi, H. Synthesis 2009, 41,
1494. (c) Kobayashi, K.; Okamura, Y.; Fukamachi, S.; Konishi, H.
Heterocycles 2010, 81, 1253.
(14) (a) Fensome, A.; Bender, R.; Chopra, R.; Cohen, J.; Collins,
M. A.; Hudak, V.; Malakian, K.; Lockhead, S.; Olland, A.; Svenson, K.;
Terefenko, E. A.; Unwalla, R. J.; Wilhelm, J. M.; Wolfrom, S.; Zhu, Y.;
Zhang, Z.; Zhang, P.; Winneker, R. C.; Wrobel, J. J. Med. Chem. 2005,
48, 5092. (b) Hays, S. J.; Caprethe, B. W.; Gilmore, J. L.; Amin, N.;
Emmerling, M. R.; Michael, W.; Nadimpali, R.; Nath, R.; Raser, K. J.;
Stafford, D.; Watson, D.; Wang, K.; Jaen, J. C. J. Med. Chem. 1998, 41,
1060. (c) Patel, M.; Ko, S. S.; McHugh, R. J.; Markwalder, J. A.;
Srivasta, A. S.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.;
Trainor, G. L.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1999, 9, 2805. (d)
Dias, N.; Goossens, J. F.; Baldeyrou, B.; Lansiaux, A.; Colson, P.; Di
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gate Chem 2005, 16, 949. (e) Zhang, P.; Terefenko, T. A.; Fensome, A.;
Zhang, Z.; Zhu, Y.; Cohen, J.; Winneker, R.; Wrobel, J.; Yardley
J. Bioorg. Med. Chem. Lett. 2002, 12, 787.
(16) Cu(OTf)2ÀDCE was found to be the optimal catalystÀsolvent
combination. For further details of optimization studies, see the Sup-
porting Information.
(15) 50 °C is the optimal temperature. For further details of optimi-
zation studies, see the Supporting Information.
Org. Lett., Vol. 15, No. 22, 2013
5655

electronic properties. With an electron-withdrawing ester
functionality present in the anilide part, benzoxazine 3q
was isolated in 44% yield, and the methoxy derivative 3r
was obtained in 60% yield. When the tert-butyl group
of the amide moiety was replaced with methyl, phenyl,
p-methoxyphenyl, and p-nitrophenyl groups the reactions
provided the appropriate benzoxazine products (3sÀv)
with efficiency similar to that pivalanilide 3a (53À88%).
After examining the applicability of different ethynyl ani-
lides we studied the reactivity of different arylmesityliodonium
Scheme 3. Copper-Catalyzed Coupling of Ethynylanilides with
Phenyl Mesityl Iodonium Triflatea
Scheme 4. Copper-Catalyzed Coupling of Arylethynyl
Pivalanilides with Different Aryl Mesityl Iodonium Triflatesa
a Reaction conditions: arylethynylanilide (0.3 mmol), iodonium salt
(0.36 mmol), Cu(OTf)2 (0.03 mmol), DCE (3 mL) at 50 °C. Percent yields
of isolated product. (a) Molecular structure of the major isomers. Value
refers to the major/minor ratio obtained from the NMR analysis of
freshly prepared samples.18
a Reaction conditions: arylethynyl pivalanilide (0.3 mmol), iodonium
salt (0.36 mmol), Cu(OTf)2 (0.03 mmol), DCE (3 mL) at 50 °C. Percent
yields of isolated product. (a) Molecular structure of the major isomers.
Value refers to the major/minor ratio obtained from the NMR analysis
of freshly prepared samples.18
Exchanging the aryl group in the ethynyl substituent to a
butyl group had no deleterious consequences on reactivity,
and benzoxazine formation took place smoothly to afford
the desired alkyl substituted product 3n in good yield
(74%) as single isomer.
The ring closure and the CÀC bond formation were
also performed with substrates bearing substituents on the
anilide. The presence of halogens on the aromatic ring such
as fluoro- and chloro- groups are well tolerated under the
reaction conditions, and the reaction provides the products
3o and 3p in high yield (70% and 71%). The transforma-
tion also worked with functional groups with different
triflates in the transformation (Scheme 4). Utilizing the
developed conditions, reaction of m- and p-tolyliodonium
triflates with alkynylpivalanilides gave the products 3b, 3c,
3w, and 3x in 35À69% yields. However, ortho-substituted
tolylethynyliodonium salt did not provide benzoxazine
3d.19 Iodonium salts with halogen (F, Cl, Br)-substituted
aromatic rings reacted with similar efficiency and provide
the appropriate products in 38À83% yields. The benzox-
azines were obtained in good yield when ester (3l), acetyl
(3cc), and trifluoromethyl (3dd) groups were present in the
aryl part of the iodonium salt.
(17) Structure and geometry of the major isomer of compound 3j
were determined by single-crystal X-ray diffraction measurements. See
the Supporting Information. We found that the aryl groups originating
from the acetylene derivative were in a cis position to the oxygen of the
oxazine ring.
While NMR studies supported the formation of
a benzoxazine product, unambiguous identification of
(18) Effects of time, temperature, light, and presence of acid on
isomerization have been examined with NMR. For results of prelimin-
ary studies of the isomerization, see the Supporting Information.
(19) It is of note that the deleterious effect of any kind of ortho
substituent on the aryl ring of the iodonium salt was observed in five
additional cases (F, Cl, Br, CF3, COOEt, not shown in Scheme 5).
5656
Org. Lett., Vol. 15, No. 22, 2013

product was achieved through a single-crystal X-ray dif-
fraction study of a benzoxazine derivative (3aa) (Figure 1).
X-ray analysis confirmed that benzoxazine derivatives are
formed through 6-exo-dig ring closure and subsequent
CÀC bond formation on the exo double bond.
intermediate (4). We suppose that this highly electrophilic
Cu(III) species coordinates to the triple bond from the
outer sphere and induces the ring closure.The lone pair
of the amide nitrogen serves as the electron source, and
the oxygen attacks to the sp carbon atom next to the aro-
matic ring of the anilide. With the lost of triflate anion
from 5 alkenylcopper intermediate (6) forms, which is able
to undergo reductive elimination providing the CuOTf
catalyst and the benzoxazine product 3.The overall trans-
formation includes 6-exo-dig cyclization which is accom-
panied by the formation of new CÀO and CÀC bonds.
This mechanistic path provides the major geometric iso-
mers formed during the transformation where the aryl
group derived from the arylacetylene is in the cis position
to the oxygen atom of the benzoxazine ring.20
In conclusion, we have developed a new copper-
catalyzed oxidative transformation for the construction
of benzoxazine derivatives from substituted o-ethynylani-
lides and diaryliodonium salts. We determined that the
oxidative transformation includes an unusual 6-endo-dig
cyclization withthe formation of a CÀO bond, followedby
CÀC bond coupling in the exo double bond. The devel-
oped methodology enables the versatile synthesis of a
new class of benzoxazines with high modularity due
to the easily variable functional groups built in through
the reaction sequence. Examination of the isomerization,
detailed mechanistic studies, and the expansion of the
principle of an endo-dig cyclizationÀCÀC bond formation
sequence catalyzed by copper for substrates containing
a triple bond and nucleophilic sites are in progress in our
laboratory.
Figure 1. Molecular structure of compound 3aa. The displace-
ment ellipsoids are drawn at the 50% probability level, and
heteroatoms are shaded.
Scheme 5. Proposed Mechanism for the Formation of the Major
Geometric Isomer
Acknowledgment. This project was supported by the
€
“Lendulet” Research Scholarship of the Hungarian Acad-
emy of Sciences and by OTKA-NKTH (CK 80763). We
also thank Prof. Tim Peelen (Lebanon Valley College) for
proofreading this manuscript.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) Although the products could isomerize during the workup
process, we cannot exclude completely the possibility of the formation
of the minor isomer during the oxidative coupling. We suppose that the
reaction would also take place via the inner sphere coordination of
copper to the triple bond providing the minor geometric isomer or via
vinyl cation formation as has been proposed very recently: see ref 8b.
Regarding a possible mechanism of the transformation,
on the basis of similar copper-catalyzed oxidative cou-
plings, we propose that the reaction starts with the forma-
tion of the Cu(I) species from Cu(OTf)2 (Scheme 5). In the
following step, the Cu(I) catalyst is oxidized by the iodo-
nium salt (2) resulting the formation of ArÀCu(OTf)2
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5657