Transition-metal-free α-arylation of β-keto amides via an interrupted insertion reaction of arynes

Article abstract of DOI:10.1021/ol302180v

Direct α-arylation reactions of secondary β-keto amides with arynes, generated by fluoride-induced elimination of ortho-silyl aryltriflates, are described. The transformation proceeds via an interrupted insertion reaction of arynes and leads to densely functionalized aromatic compounds exhibiting a chiral 'all carbon' quaternary center under transition-metal-free conditions. An organocatalytic asymmetric version of the reaction also proved possible, affording the proof of concept that arynes can be involved in enantioselective transformations.

Full text of DOI:10.1021/ol302180v

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4686–4689
Transition-Metal-Free r‑Arylation
of β‑Keto Amides via an Interrupted
Insertion Reaction of Arynes
Kishor Mohanan, Yoann Coquerel,* and Jean Rodriguez*
ꢀ
Aix-Marseille Universite, CNRS, iSm2 UMR 7313,
Service 531, 13397 Marseille cedex 20, France
yoann.coquerel@univ-amu.fr; jean.rodriguez@univ-amu.fr
Received August 5, 2012
ABSTRACT
Direct r-arylation reactions of secondary β-keto amides with arynes, generated by fluoride-induced elimination of ortho-silyl aryltriflates, are
described. The transformation proceeds via an interrupted insertion reaction of arynes and leads to densely functionalized aromatic compounds
exhibiting a chiral ‘all carbon’ quaternary center under transition-metal-free conditions. An organocatalytic asymmetric version of the reaction
also proved possible, affording the proof of concept that arynes can be involved in enantioselective transformations.
Functionalized aromatic compounds are ubiquitous in
drugs and biologically active natural products. The synthe-
sis of functionalized aromatic compounds can traditionally
be realized through FriedelꢀCrafts alkylation reactions with
electron-rich substrates.1 In the past two decades, a
complementary approach has been developed with the
R-arylation of carbonyl compounds, most often relying
on efficient transition-metal catalysts.2 More recently,
several useful metal-free equally efficient organocatalytic
systems have also been developed for these transfor-
mations.3 Noncatalyzed nucleophilic additions of enolates
(or synthetic equivalents) to electrophilic Bi(V),4aꢀc Pb-
(IV),4d,e and I(III)4f,g aromatic derivatives have also suc-
cessfully been examined, and recently, the Maulide group
reported an interesting sulfoxide mediated R-arylation of
carbonyl compounds.5
In 2005, the Stoltz group reported their postulate that
arynes,6 gently generated from ortho-silyl aryltriflates 1 in
(4) For selected applications, see: (a) Ooi, T.; Goto, R.; Maruoka, K.
J. Am. Chem. Soc. 2003, 125, 10494. (b) Matano, Y.; Imahori, H. J. Org.
Chem. 2004, 69, 5505. (c) Koech, P. K.; Krische, M. J. J. Am. Chem. Soc.
2004, 126, 5350. (d) Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001.
(e) Xia, J.; Brown, L. E.; Konopelski, J. P. J. Org. Chem. 2007, 72, 6885.
(f) Eastman, K.; Baran, P. S. Tetrahedron 2009, 65, 3149. (g) Norrby,
P.-O.; Petersen, T. B.; Bielawski, M.; Olofsson, B. Chem.;Eur. J 2010,
16, 8251.
(1) (a) Olah, G. A. FriedelꢀCrafts Chemistry; Wiley: New York, 1973.
(b) Metivier, P. In FriedelꢀCrafts Reaction; Sheldon, R. A., Bekkum, H.,
Eds.; Wiley-VCH: New York, 2001; pp 161ꢀ172.
(2) Reviews: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003,
36, 234. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. (c)
Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49,
676. For recent work, see: Huang, Z.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2012, 51, 1028.
(5) Huang, X.; Maulide, N. J. Am. Chem. Soc. 2011, 133, 8510.
(6) Reviews: (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes;
Academic Press: New York, 1967. (b) Gilchrist, T. L. In The Chemistry of
Functional Groups, Supplement C2; Patai, S., Rappoport, Z., Eds.; Wiley:
Chichester, U.K., 1983; Chapter 11. (c) Hart, H. In The Chemistry of Triple-
Bonded Functional Groups, Supplement C2; Patai, S., Ed.; Wiley:
Chichester, U.K., 1994; Chapter 18. (d) Wenk, H. H.; Winkler, M.; Sander,
W. Angew. Chem., Int. Ed. 2003, 42, 502. (e) Pellissier, H.; Santelli, M.
(3) (a) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 3670. (b) Kobbelgaard, S.; Bella, M.; Jørgensen, K. A.
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J. Org. Chem. 2006, 71, 4980. (c) Aleman, J.; Richter, B.; Jørgensen,
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K. A. Angew. Chem., Int. Ed. 2007, 46, 5515. (d) Aleman, J.; Cabrera, S.;
Maerten, E.; Overgaard, J.; Jørgensen, K. A. Angew. Chem., Int. Ed.
€
2007, 46, 5520. (e) Nicolaou, K. C.; Reingruber, R.; Sarlah, D.; Brase, S.
J. Am. Chem. Soc. 2009, 131, 2086. Corrigendum: J. Am. Chem. Soc.
2009, 131, 6640. (f) Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2009, 131, 11640. (g) Um, J. M.; Gutierrez, O.;
Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc.
2010, 132, 6001. (h) Jensen, K. L.; Franke, P. T.; Nielsen, L. T.; Daasbjerg,
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Tetrahedron 2003, 59, 701. (f) Guitian, E.; Perez, D.; Pena, D. Top.
~
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Organomet. Chem 2005, 14, 109. (g) Pena, D.; Perez, D.; Guitian, E.
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T. A. Chem. Soc. Rev. 2012, 41, 3140.
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K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2010, 49, 129. (i) Pruger, B.;
Hofmeister, G. E.; Jacobsen, C. B.; Alberg, D. G.; Nielsen, M.; Jørgensen,
K. A. Chem.;Eur. J. 2010, 16, 3783.
(7) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
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r
10.1021/ol302180v
Published on Web 08/28/2012
2012 American Chemical Society

the presence of an excess of nucleophilic fluoride ions,7
could serve as R-arylation reagents for β-keto esters
2 (R1 = alkyl, EWG = CO2R3). Unexpectedly, their studies
have actually shown that benzyne (4a, and other arynes 4)
reacts with β-keto esters to givethe acyl-alkylation product
3 resulting from a net insertion of a benzene into the
R,β-CꢀC bond of the activated carbonyl compound 2
(Scheme 1, top).8 This valuable reaction was presumed to
proceed via an initial nucleophilic addition of the enolate
derived from 2 to benzyne (4a) to give the intermediate aryl
anion 5. In the absence of a proton source, 5 rearranges
via a formal [2 þ 2] cycloaddition/fragmentation sequence
to give 3. Since, the method has been generalized to many
activated carbonyl compounds 2, including 1,3-diesters,
1,3-diketones,9a β-keto cyanides,9b β-keto sulfones,9c
β-keto phophonates,9d cyanomethyl diphenylphosphine
oxide,9e malonitrile, and p-toluenesulfonyl acetonitrile9f
(Scheme 1, top). Only in a few cases, minor amounts of
the R-arylation product could be detected in these reactions.
acidic protons: the CꢀH proton at the R-position and the
NꢀH proton of the secondary amide group. Capitalizing
on Stoltz’s original idea, we surmised that this particular
class of substrates would actually be suitable for an
efficient net R-arylation reaction. This plan relied on the
rapid transfer of the secondary amide NꢀH proton to the
transient intermediate aryl anion 5, thereby interrupting
the normal insertion reaction of arynes with 1,3-dicarbo-
nyls and analogs (Scheme 1, bottom). Related intramo-
lecular proton transfers were postulated in the C-arylation of
β-enamino esters and ketones with arynes.13 Very recently,
the Mhaske group independently reported the R-arylation
of malonamide esters with arynes,14 and this article has
triggered the report of our own results in this field.
We report herein direct R-arylation reactions of rationally
designed secondary β-keto amides with arynes generated
by fluoride-induced elimination of ortho-silyl aryltriflates.
The transformation leads to densely functionalized aromatic
compounds exhibiting a chiral ‘all carbon’ quaternary center
under transition-metal-free conditions. Importantly, the
proof of concept for such an asymmetric organocatalytic
direct arylation has been obtained, which represents the
first enantioselective reaction with an aryne.
Scheme 1. Reactions of 1,3-Dicarbonyls with Arynes: State of
the Art and Novelty
Based on our background, we presumed that N-aryl
secondary β-keto amides would be the most suitable
substrates for our objective because of the significantly
higher acidity of their NꢀH protons when compared
to N-alkyl secondary β-keto amides.12 Our first attempt
involved the reaction of the simple N-phenyl secon-
dary β-keto amide 6a, using the KF/18-crown-6 sys-
tem in THF for the generation of benzyne (4a) from
2-(trimethylsilyl)phenyl triflate (1a). Rewardingly, the
(9) (a) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3292. (b) Yoshida, H.; Watanabe, M.; Ohshita, J.;
Kunai, A. Tetrahedron Lett. 2005, 46, 6729. (c) Huang, X.; Xue, J.
J. Org. Chem. 2007, 72, 3965. (d) Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Li, J.-H.
J. Org. Chem. 2009, 74, 5691. (e) Yoshida, H.; Watanabe, M.; Ohshita,
J.; Kunai, A. Chem. Lett. 2005, 34, 1538. (f) Yoshida, H.; Watanabe, M.;
Morishita, T.; Ohshita, J.; Kunai, A. Chem. Commun. 2007, 1505. In the
latter paper, the proposed mechanism proceeds through an aryne
insertion reaction followed by an R-arylation of the resulting benzylic
anion. In light of our results, and considering the relatively high acidity
of malonitrile R-protons (pKa DMSO = 11.0), an alternative mechanism
involving first an R-arylation and then an aryne insertion reaction
appears also plausible. For an account, see: (g) Yoshida, H.; Takaki, K.
Synlett 2012, 1725.
(10) Reviews: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b)
Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488. (c)
Bella, M.; Gasperi, T. Synthesis 2009, 1583. (d) Das, J. P.; Marek, I.
Chem. Commun. 2011, 47, 4593. For recent realizations from our
laboratory, see: (e) Boddaert, T.; Coquerel, Y.; Rodriguez, J. Adv.
Synth. Catal. 2009, 351, 1744. Corrigendum: Adv. Synth. Catal. 2009,
351, 2541. (f) Presset, M.; Coquerel, Y.; Rodriguez, J. Org. Lett. 2010,
12, 4212. (g) Boddaert, T.; Coquerel, Y.; Rodriguez, J. Chem.;Eur. J.
2011, 17, 2048. (h) Boddaert, T.; Coquerel, Y.; Rodriguez, J. Chem.;Eur.
J. 2011, 17, 2266. (i) Presset, M.; Mohanan, K.; Hamann, K.; Coquerel, Y.;
Rodriguez, J. Org. Lett. 2011, 13, 4124. (j) Boddaert, T.; Coquerel, Y.;
Rodriguez, J. Eur. J. Org. Chem. 2011, 5061.
Our research program on the stereocontrolled creation
of chiral ‘all carbon’ quaternary centers10 has recently
allowed the identification of secondary β-keto amides 611
as a very promising class of pronucleophiles.12 The parti-
cularity of these substrates is that they exhibit two distinct
(11) 6aꢀr were prepared by the technology described in: (a) Presset,
M.; Mailhol, D.; Coquerel, Y.; Rodriguez, J. Synthesis 2011, 2549. (b)
Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009, 74, 415.
ꢀ
(12) Sanchez Duque, M. M.; Basle, O.; Isambert, N.; Gaudel-Siri, A.;
ꢀ
Genisson, Y.; Plaquevent, J.-C.; Rodriguez, J.; Constantieux, T. Org.
Lett. 2011, 13, 3296.
(13) Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029.
(14) Dhokale, R. A.; Thakare, P. R.; Mhaske, S. B. Org. Lett. 2012,
14, 3994. Regio- and enantioselectivity issues were not examined.
(8) (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
5340. (b) Ebner, D. C.; Tambar, U. K.; Stoltz, B. M. Org. Synth. 2009,
86, 161.
Org. Lett., Vol. 14, No. 17, 2012
4687

reaction provided, after hydrolysis, the expected R-aryla-
tion product 7a in 82% yield (Table 1, entry 1). The scope
of the reaction was then evaluated under these fine condi-
tions with a variety of secondary β-keto amides 6bꢀr, and
as can be seen from Table 1, the reaction was found to be
very general, allowing for the efficient R-arylation of a
number of secondary β-keto amides 6. The reaction was
not significantly influenced by the nature of the amide,
tolerating various cyclic and acyclic substrates, with the R3
aryl group nicely allowing electron-withdrawing (e.g., en-
tries 4, 5, and 8), -neutral (e.g., entries 1, 2, and 11), and
-donor substituents (e.g., entries 10 and 13), amenable to
further selective chemical manipulation. The structure
of the R-arylation product 7b was secured by X-ray
diffraction analysis (Figure 1). However, when the
reaction was performed with the N-alkyl secondary
β-keto amides 6q,r (entries 17 and 18), somewhat lower
yields of the R-arylation products were observed. Espe-
cially, in the reaction of 6r, bearing an electron-donor
tert-butyl substituent, the benzene insertion side-
product 3r was obtained in 36% yield together with the
expected R-arylation product 7r (entry 18; see Support-
ing Information). This limit of reactivity is presumed to
reflect the lower acidity of the NꢀH proton in this
substrate,12 resulting in a less efficient interruption of
the insertion reaction.
Figure 1. Structure of 7b by X-ray diffraction analysis. Ellip-
soids are drawn at the 50% probability level, and hydrogen
˚
atoms are represented as fixed-size spheres of radius 0.15 A. See
Supporting Information for details.
naphthalen-2-yl triflate (1b).15 The illustrative reaction
of 6f with 1b pleasingly afforded the expected R-aryla-
tion product 7s in high yield and with excellent regio-
selectivity (the other regioisomer was not detected,
Scheme 2).
Scheme 2. Regioselective R-Arylation
Table 1. Arylation of Secondary β-Keto Amides with Benzyne
entry
6
R1, R2
R3
7, yielda
Finally, we briefly tested the possibility of performing
the above-described R-arylation reactions in the asym-
metric series. For our early trials, we selected the bifunc-
tional N-aryl thiourea/tertiary amine catalyst 8 described
by Takemoto,16 a catalyst that operates via noncovalent
interactions. In the model reaction of 1a with 6d using the
previously developed conditions in the presence of 10 mol %
of the organocatalyst 8, the product 7d was obtained in
good yield but without any detectable enantioselectivity
(Table 2, entry 1), and a similar result was obtained at
lower temperature (entry 2). However, using cesium fluo-
ride or tetra-n-butyl ammonium fluoride as the fluoride
anion source, some encouraging enantioselectivities
could be observed in the R-arylation reaction of 6d
(entries 3 and 4, respectively). These preliminary results
importantly demonstrate that, for the first time, asym-
metric reactions of arynes are possible.
1
6a
6b
6c
6d
6e
6f
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
(CH2)3
C6H5
4-H3C-C6H4
7a, 82%
7b, 78%
2
3
2,4,6-(H3C)3-C6H2 7c, 90%
4
4-O2N-C6H4
4-F3C-C6H4
4-Br-C6H4
2-Br-C6H4
4-F-C6H4
7d, 92%
7e, 80%
7f, 95%
7g, 78%
7h, 88%
7i, 74%
7j, 83%
7k, 87%
7l, 92%
7m, 82%
7n, 82%
7o, 74%
7p, 92%
7q, 68%
7r, 32%b
5
6
7
6g
6h
6i
8
9
2-I-C6H4
10
11
12
13
14
15
16
17
18
6j
2-H3CO-C6H4
2-naphthyl
4-Br-C6H4
3,5-(H3CO)2-C6H3
4-Br-C6H4
4-F-C6H4
6k
6l
6m
6n
6o
6p
6q
6r
(CH2)3
(CH2)4
CH3, CH3
CH3, CH3
4-Br-C6H4
allyl
CH2C(CH3)2CH2
CH2C(CH3)2CH2
t-Bu
a Isolated pure productobtained after chromatographic purification.
b In that case, 36% of the benzene insertion side-product 3r were
additionally isolated.
(15) For regioselectivity studies with arynes, see: (a)Cheong,P. H.-Y.;
Paton, R. S.; Bronner, S. M.; Im, G.-Y. J.; Garg, N. K.; Houk, K. N. J. Am.
Chem. Soc. 2010, 132, 1267. (b) Tadross, P. M.; Gilmore, C. D.; Bugga, P.;
Virgil, S. C.; Stoltz, B. M. Org. Lett. 2010, 12, 1224.
(16) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672.
Also, the regioselectivity issue of the reaction was exam-
ined with 1,2-naphthalyne generated from 1-trimethylsilyl
4688
Org. Lett., Vol. 14, No. 17, 2012

arynes has been developed that leads to densely function-
alized chiral ‘all carbon’ quaternary centers. From a
mechanistic point of view, this reaction interrupts the
normal insertion reactivity of arynes with 1,3-dicarbo-
nyls, likely due to the acidic properties of the NꢀH
protons of secondary β-keto amides. Unprecedentedly,
a highly regioselective version of the reaction proved
possible with a nonsymmetrical aryne, and impor-
tantly, the feasibility of an organocatalytic asymmetric
version could be evidenced with a bifunctional thiourea/
tertiary amine catalyst. The reactivity of arynes described
herein opens up new opportunities for their applications
in organic synthesis, and further studies on this exciting
reaction are ongoing in our laboratory.
Table 2. Enantioselective Organocatalytic R-Arylation
entry
fluoride source
temp
yielda
ee 7db
Acknowledgment. We are grateful to Dr. M. Giorgi
1
2
3
4
KF, 18-crown-6rt
KF, 18-crown-6
CsF
rt
92%
82%
85%
76%
0%
0 °C
rt
0%
ꢀ
(Aix-Marseille Universite) for X-ray diffraction analysis
of 7b. Financial support from Aix-Marseille Universite
12%
21%
ꢀ
TBAF
rt
and the CNRS is gratefully acknowledged.
a Isolated pure productobtained after chromatographic purification.
b Determined by HPLC on chiral stationary phase from the enantio-
meric ratio.
Supporting Information Available. full experimental
details, CIF for 7b, and characterization data for all
compounds.This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, a transition-metal-free direct and practi-
cal R-arylation reaction of secondary β-keto amides with
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4689