Highly selective insertion of arynes into a C(sp)-O(sp3) σ Bond

Article abstract of DOI:10.1021/ol103001k

Arynes react with ethoxyacetylene to afford 2-ethoxyethynylaryl derivatives through a highly chemo-and regioselective formal insertion of the aryne into the C(sp)-O(sp³) bond of the alkyne. Computational studies suggest that the reaction does n

Full text of DOI:10.1021/ol103001k

ORGANIC
LETTERS
2011
Vol. 13, No. 5
960–963
Highly Selective Insertion of Arynes into a
C(sp)-O(sp3) σ Bond
†
Krzysztof Z. Ła-czkowski, Diego Garcıa, Diego Pena,* Agustın Cobas, Dolores Perez,
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and Enrique Guitian*
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Departamento de Quımica Organica and Centro Singular de Investigacion en Quımica
Bioloxica e Materiais Moleculares, Universidade de Santiago de Compostela,
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15782 Santiago de Compostela, Spain
diego.pena@usc.es; enrique.guitian@usc.es
Received December 10, 2010
ABSTRACT
Arynes react with ethoxyacetylene to afford 2-ethoxyethynylaryl derivatives through a highly chemo- and regioselective formal insertion of the
aryne into the C(sp)-O(sp3) bond of the alkyne. Computational studies suggest that the reaction does not proceed through a mechanism initiated
by the nucleophilic addition of the oxygen atom to the aryne as previously proposed but by the addition of the triple bond of the alkyne to the aryne.
In the past decade, aryne chemistry has undergone an
unprecedent revival.1 This is mainly due to the efficient use
of a method to generate benzyne by fluoride-induced
Scheme 1. Insertion of Benzyne into Ethoxyacetylene
β-elimination of o-(trimethylsilyl)phenyl triflate (1a,
Scheme 1), which was first described by Kobayashi and
co-workers.2 The generation of arynes under mild reaction
conditions from commercially available or easily prepared
precursors,3 and the compatibility of this method with
metal catalysis,4 led to the development of a highly diverse
of new C-C bond-forming processes.5 In particular, an
increasingly developed group of transformations involve
† Present address: Faculty of Pharmacy, Nicolaus Copernicus University, 9
M. Curie Sklodowska Street, 85-094 Bydgoszcz, Poland.
(1) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Aca-
demic Press: New York, 1967. (b) Pellissier, H.; Santelli, M. Tetrahedron
aryne insertion into σbonds.6 These are interesting reactions
from a synthetic point of view, as they allow the one-pot
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2003, 59, 701. (c) Pena, D.; Perez, D.; Guitian, E. Heterocycles 2007, 74,
89. (d) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 215.
(2) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
(5) For some recent examples, see: (a) Bhuvaneswary, S.; Jeganmohan,
M.; Cheng, C.-H. Chem. Commun. 2008, 5013. (b) Xie, C.; Liu, L.;
Zhang, Y.; Xu, P. Org. Lett. 2008, 10, 2393. (c) Jeganmohan, M.;
Bhuvaneswari, S.; Cheng, C.-H. Angew. Chem., Int. Ed. 2008, 47, 1.
(d) Hsieh, J.-C.; Cheng, C.-H. Chem. Commun. 2008, 2992. (e) Xie, C.;
Zhang, Y.; Yang, Y. Chem. Commun. 2008, 4810. (f) Worlikar, S. A.;
Larock, R. C. Org. Lett. 2009, 11, 2413. (g) Qiu, Z.; Xie, Z. Angew.
Chem., Int. Ed. 2009, 48, 5729. (h) Yoshida, H.; Morishita, T.; Nakata,
H.; Ohshita, J. Org. Lett. 2009, 11, 373.
(3) For example, benzyne precursor 1a is a commercially available
compound which can be easily obtained in high yield from o-bromo-
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phenol by a one-pot procedure. See: Pena, D.; Cobas, A.; Perez, D.;
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Guitian, E. Synthesis 2002, 1454.
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(4) (a) Pena, D.; Escudero, S.; Perez, D.; Guitian, E.; Castedo, L.
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Angew. Chem., Int. Ed. 1998, 37, 2659. (b) Pena, D.; Perez, D.; Guitian,
E.; Castedo, L. J. Am. Chem. Soc. 1999, 121, 5827. (c) Guitian, E.; Perez,
D.; Pena, D. In Topics in Organometallic Chemistry; Tsuji, J., Ed.;
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(6) Pena, D.; Perez, D.; Guitian, E. Angew. Chem., Int. Ed. 2006, 45,
3579.
Springer-Verlag: Weinheim, 2005; Vol. 14, pp 109-146.
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10.1021/ol103001k
Published on Web 02/03/2011
2011 American Chemical Society

ortho-difunctionalization of aromatic rings. Aryne inser-
tion into B-B,7 Se-Se,8 C-C,9 C-N (amides),10 CdO
(amides),11 CO-Cl (acid chlorides),12 and C-Br
(bromoalkynes)13 bonds have been recently described.
To the best of our knowledge, only two examples of the
insertion of arynes into C-O σ bonds have been reported
to date: the reaction of benzyne, generated by Kobayashi’s
method,2 with styrene oxide,14 and the unexpected inser-
tion of benzyne, generated by decomposition of benzene-
diazonium 2-carboxylate, into a C-O bond of ethoxy-
acetylene, as reported by Stiles et al. in 1962.15 We thought
that the latter approach could be developed into a useful
synthesis of o-alkoxyarylacetylenes,16 which are currently
obtained by a multistep synthesis involving o-halogenation
of the corresponding phenols, followed by Williamson
alkylation and Sonogashira coupling. We report here
the selective ethoxyethynylation of arynes generated by
Kobayashi’s method and the computational mechanistic
study of this intriguing transformation.
Table 1. Insertion of Arynes into Ethoxyacetylenea
The generation of benzyne (2a) by treatment of triflate
1a3 with CsF at room temperature in the presence of
ethoxyacetylene afforded 1-ethoxy-2-ethynylbenzene (3a,
Scheme 1), resulting from the formal insertion of 2a into
the C(sp)-O(sp3) bond of the alkyne. Notably, the other
possible isomer 3a0, from the insertion into the C(sp3)-
O(sp3) bond, was not detected in the reaction mixture. This
result confirmed the surprising observation reported by
Stiles et al.15
This formal insertion reaction was applied to other
substituted or polycyclic arynes (Table 1). Moderate to
good yields of the corresponding C-O insertion products
3b (73% yield, entry 2) and 3c (67%, entry 3) were
obtained. Entries 4-6 concern the generation of asym-
metric arynes and therefore the possible formation of
mixtures of regioisomeric products. For example, the
reaction of 3-methoxybenzyne, the aryne generated from
triflate 1d (entry 4), could afford compounds 3d and 3d0.
However, this insertion took place with complete regios-
electivity, affording only isomer 3d in 54% yield. The
structure of the product was established as 3d by NMR
spectroscopy and was confirmed by comparison with a
sample obtained by an independent synthesis, as shown in
a Reactions were performed using 2 equiv of ethoxyacetylene and 2
equiv of CsF in MeCN at room temperature for 12 h.
Scheme 2. The tert-butylamine-promoted ortho-bromina-
tion of phenol 4,17 followed by alkylation with ethyl
bromide, led to compound 5in a reasonable yield. Palladium-
catalyzed cross coupling of this compound with triisopro-
pylsilylacetylene under Sonogashira conditions afforded
alkyne 6 in 80% yield. Remarkably, among all the phos-
phine ligands tested in this reaction, XPhos proved to be
superior.18 Finally, deprotection of the alkyne with fluor-
ide afforded 3d, which was identical to the product of the
reaction of 3-methoxybenzyne with ethoxyacetylene (entry
4, Table 1).
(7) Yoshida, H.; Okada, K.; Kawashima, S.; Tanino, K.; Ohshita, J.
Chem. Commun. 2010, 46, 1763.
(8) Toledo, F. T.; Marques, H.; Comasseto, J. V.; Raminelli, C.
Tetrahedron Lett. 2007, 48, 8125.
(9) (a) Liu, Y. -L.; Liang, Y.; Pi, S. -F.; Li, J. -H. J. Org. Chem. 2009,
74, 5691. (b) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul,
Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745.
(c) Huang, X.; Xue, J. J. Org. Chem. 2007, 72, 3965. (d) Yoshida, H.;
Kishida, T.; Watanabe, M.; Ohshita, J. Chem. Commun. 2008, 5963. (e)
Yoshida, H.; Morishita, T.; Ohshita, J. Chem. Lett. 2010, 39, 508.
(10) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168.
(11) Yoshioka, E.; Kohtani, S.; Miyabe, H. Org. Lett. 2010, 12, 1956.
(12) Yoshida, H.; Mimura, Y.; Ohshita, J.; Kunai, A. Chem. Com-
mun. 2007, 2405.
Moderate regioselectivity was observed in the reaction
of 1,2-naphthyne (entry 5) with ethoxyacetylene, in favor
of 3e (ratio 3e:3e0 = 7:3).19,20 By contrast, the reaction of
4-methylbenzyne, generated from triflate 1f (entry 6),
(13) Morishita, T.; Yoshida, H.; Ohshita, J. Chem. Commun. 2010,
640.
(17) Ishizaki, M.; Ozaki, K.; Kanematsu, A.; Isoda, T.; Hoshino, O.
J. Org. Chem. 1993, 58, 3877.
(18) XPhos: 2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
See: Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
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(14) Beltran-Rodil, S.; Pena, D.; Guitian, E. Synlett 2007, 1308.
(15) Stiles, M.; Burkhardt, U.; Haag, A. J. Org. Chem. 1962, 27, 4715.
(16) Arylacetylenes are very useful moieties for various synthetic
procedures such as azide-alkyne Huisgen cycloaddition, Sonogashira
coupling, or poly(aryl acetylene) synthesis.
(19) The structures of both regioisomers were confirmed by compar-
ison with a sample of 3e0 obtained by an independent synthesis.
Org. Lett., Vol. 13, No. 5, 2011
961

polar effect of the methoxy group. Therefore, a mechanism
involving path i would probably proceed via intermediate
Id0 (instead of Id) to afford compound 3d0, but this
compound was not detected in the reaction mixture. This
finding prompted us to initiate a computational study on
the mechanistic alternatives of this intriguing transformation.
To study the mechanism of the reaction in detail, DFT
calculations were performed at the B3LYP/6-31þþG(d,p)
level.20 We analyzed three possible reaction pathways for
the reaction of arynes 2a,d and ethoxyacetylene to afford
3a,d (Scheme 3). As previously mentioned,1a path i in-
volves the initial formation of betaine Ia. The aryl carb-
anion could intramolecularly attack the alkyne to give
oxacycle IIa, which would evolve to compound 3a by ring-
opening. However, all our attempts to locate intermediates
Ia and IIa were unsuccessful, since all the starting geome-
tries for these species converged upon optimization to the
starting materials and to compound 3a, respectively.
Therefore, structures Ia and IIa are not minima in the
potential energy surface.
Scheme 2. Alternative Synthesis of Compound 3d
afforded the two possible isometic products 3f and 3f0 in a
1:1 ratio. It is known that a methyl group in this position
has a limited influence on the reactivity of arynes.1 There-
fore, the lack of regioselectivity in this case supports a
mechanism in which the aryne is an intermediate.
Scheme 3. Postulated Mechanistic Pathwaysa
Figure 1. Transition states of pathways shown in Scheme 3.
A concerted pathway involving the one-step insertion of
benzyne (2a) into the C(sp)-O(sp3) bondof the alkyne was
also considered (path ii). Indeed, it was possible to locate a
transition state TS1a (Figure 1) that, as predicted, is very
asynchronous, with a distance for the forming C-O bond
˚
of1.67A, i.e., significantly shorterthanthatcorresponding
˚
to the forming C-C bond (2.4 A). However, this path
a Key: a, R1 = R2 = H; d, R1 = OMe, R2 = H; d’, R1 = H, R2 =
OMe.
showed a significant energy barrier of 25.6 kcal/mol (Figure 2).
A more favorable route was found (path iii), and this
starts with the nucleophilic addition of the triple bond of
ethoxyacetylene to benzyne (2a) through the transition
state TS2a. This step has a very low barrier in terms of
electronic energy (2.6 kcal/mol), while the free energy
barrier increases to 14.2 kcal/mol due to the entropic
contribution associated with a bimolecular reaction
(Figure 2). In transition state TS2a, the alkyne is perpen-
dicular to the benzyne plane, the forming C1-C bond
In a fascinating monograph on aryne chemistry,1a
Hoffmann proposed a mechanism for the reaction of
benzyne with ethoxyacetylene initiated by the nucleophilic
attack of the oxygen atom of the alkyne to the triple bond
of the aryne to give betaine Ia (path i, Scheme 3). Although
this could be the more intuitive mechanism based on
classical aryne chemistry, the initial formation of betaine
I would explain neither the highly selective insertion into the
C(sp)-O(sp3) bond of the alkyne nor the regioselective
formation of compound 3d. In particular, it is known that
the addition of nucleophiles to 3-methoxybenzyne (2d)
proceeds with high regioselectivity to give the meta-sub-
stituted product, which is attributed to the stabilization of
the developing negative chargein the transition state by the
˚
length is 2.24 A, while the distance between the O and C2
˚
atoms is 4.47 A, showing that the formation of this bond
has not started. It is worth noting that an Intrinsic Reac-
tion Coordinates (IRC) calculation starting from TS2a led
to a flat region that corresponds to the zwitterionic struc-
ture IIIa. However, IIIa is not a stationary point and it
evolved to structure IVa upon optimization (vide infra).
The distance between the O and C3 atoms in this structure
(20) See the Supporting Information for details.
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Org. Lett., Vol. 13, No. 5, 2011

Figure 3. Resonance forms IVa,d,d0 and Va,d,d0.
which leads to intermediate IVd, is located only 0.4 kcal/mol
above IIId, reflecting how flat this region of the potential
energy surface is. This explains the difficulty in finding the
minima IIIa and TS3a for the reaction of ethoxyacetylene
with benzyne (2a), as mentioned previously. However,
with the 6-31þþG(d,p) basis set IIId and TS3d are not
stationary points and TS2d leads directly to IVd. Finally, a
facile simultaneous 1,2-hydrogen migration and ring-
opening would lead to the final compound 2d with an
electronic barrier of 6.4 kcal/mol.
Figure 2. Calculated energetic diagram for paths ii and iii.
In conclusion, the synthesis of 2-ethoxyethynylaryl deri-
vatives was performed by a highly chemo- and regioselective
insertion of arynes into the C(sp)-O(sp3) bond of ethoxy-
acetylene. This reaction proceeded under mild conditions
and in the absence of metal catalysis. The computational
study of this intriguing transformation suggests an unex-
pected mechanism which explains the observed selectivity.
˚
is2.3 A (Figure3), suggesting animportant contribution of
the resonance form corresponding to the free carbene Va in
the structure of this intermediate. Finally, IVa would
evolve through simultaneous 1,2-hydrogen migration
and ring-opening to afford 3a in a process with an energy
barrier of 4.3 kcal/mol.
The computational study of the reaction of 3-methoxy-
benzyne (2d) with ethoxyacetylene (entry 4, Table 1)
afforded similar results. In this case, for the first step of
path iii two possible transition states were located: TS2d,
which would lead to the experimentally isolated product
3d, and TS2d0, which would evolve to regioisomer 3d0 (not
isolated experimentally). Notably, the energetic barrier
corresponding to TS2d0 is 2.8 kcal/mol higher than the
barrier to TS2d, which explains the observed regioselec-
tivity, and both are much lower than the barrier for the
concerted reaction via TS1d,d0 (path ii). It should be
mentioned that B3LYP/6-31G(d) calculations showed
that in the case of TS2d, the transition state progresses to
the formation of the zwitterion IIId. Remarkably, TS3d,
Acknowledgment. Financial support from the Spanish
Ministry of Science and Innovation (MICINN, CTQ2010-
18208)) and the Xunta de Galicia (10PXIB2200222PR) is
gratefully acknowledged. Generous allocation of computer
time was kindly provided by the Centro de Supercompu-
ꢀ
tacion de Galicia (CESGA).
Supporting Information Available. Experimental, spec-
troscopic, and computational data. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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