Aromatic substituent effects in palladium-catalyzed intramolecular olefin oxyarylation reactions

Article abstract of DOI:10.1016/j.tetlet.2020.151674

The effect of electron-donating groups on the palladium-catalyzed intramolecular oxyarylation reaction was studied. In the case of activation at the ortho-position, the reaction favors the formation of a tricyclic lactone via C–H insertion. However, when

Full text of DOI:10.1016/j.tetlet.2020.151674

Tetrahedron Letters 61 (2020) 151674
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aromatic substituent effects in palladium-catalyzed intramolecular
olefin oxyarylation reactions
⇑
Mark C. Maust, Zacary L. Croft, Mackenzie W. Sullivan, Ross L. Dove, Emily E. Hardy, W.E. Brenzovich Jr.
Roanoke College, 221 College Lane, Salem 24153, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The effect of electron-donating groups on the palladium-catalyzed intramolecular oxyarylation reaction
was studied. In the case of activation at the ortho-position, the reaction favors the formation of a tricyclic
lactone via CAH insertion. However, when the ipso-position is activated, the major product is instead a
Received 21 December 2019
Revised 10 January 2020
Accepted 23 January 2020
Available online 30 January 2020
novel
a,b-unsaturated lactone formed by way of a stabilized phenonium intermediate followed by
elimination.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Olefin difunctionalization
Oxidative
Cyclization
Palladium-catalysis revolutionized the field of organic synthesis
by facilitating the predictable formation of carbon-carbon and
carbon-heteroatom bonds [1,2]. Aside from the standard direct cou-
pling of organohalides and organometallic species, palladium-cat-
alyzed olefin difunctionalizations have emerged as an adaptable
and useful synthetic transformation, specifically for the formation
of heterocycles [3,4]. More recently, several groups have investi-
gated the use of high oxidation state palladium(IV) salts, which are
unlikely to undergo b-hydride elimination, preventing competing
Wacker oxidation [5]. The required use of a strong oxidizing agent
limits the formation of highly sensitive Pd(0) species, meaning that
these reactions typically can be run with no special precautions to
exclude water or oxygen [5f]. Multiple variations of high-oxidation
state palladium-catalyzed olefin difunctionalizations have since
been reported, including both inter- and intramolecular variants
[6,7].
In 2009, Michael and coworkers reported an interesting palla-
dium-catalyzed intermolecular aminoarylation of an olefin utiliz-
ing N-fluorobenzenesulfonimide (NFSI) as an external oxidant [8].
The reaction was highly regiospecific with regards to the addition
site on the aromatic ring. Mechanistic studies suggested that the
reaction occurs by an initial aminopalladation followed by a CAH
insertion through a highly electrophilic alkylpalladium intermedi-
ate [9]. Palladium(IV) has been found to undergo CAH insertion via
an electrophilic aromatic substitution mechanism, supporting the
observed regiochemical outcomes [10]. Stephenson and coworkers
elaborated on these finding in 2011 while exploring the synthesis
of the platensimycin core, demonstrating that electron-rich aro-
matic rings can directly displace the alkylpalladium, forming a ser-
ies of interesting dearomatized products in an intramolecular
fashion [11].
Our research program is aimed at further exploring the scope of
palladium-catalyzed heteroarylations in an effort to synthesize
highly constrained ring systems. In addition, we hoped to expand
the scope of the heteroarylation reaction to the formation of
lactones. As such, we were delighted to find that treatment of
2,2-diphenylpent-4-enoic acid (1a) with catalytic palladium(II) tri-
fluoroacetate and two equivalents of the oxidant Selectfluor leads
to moderate yields of the tricyclic lactone 2a, as shown in Scheme 1.
Mass balance for our early reactions was relatively poor, and the
product was initially difficult to characterize due to slow rotation
of the exocyclic aromatic ring due to steric congestion around
the quaternary center.
In an effort to increase the chemical yield, we sought to utilize
the previously reported increased reactivity of electron-rich aro-
matic systems [8,11]. By increasing the electron density, we hoped
to further favor the desired addition of the aromatic ring. Some-
what surprisingly, when substrate 1b containing a strongly donat-
ing methoxy group in the para-position was submitted to the
reaction, only trace formation of a tricyclic lactone 2 was observed.
Instead, novel a,b-unsaturated lactone 3b was formed as the major
product in 49% yield. The structure of 3b, where an aryl group has
been transferred from C2 to C5 of the pent-4-enoic acid structure
with a concurrent b-hydrogen elimination, was proposed following
⇑
Corresponding author.
E-mail address: brenzovich@roanoke.edu (W.E. Brenzovich Jr.).
https://doi.org/10.1016/j.tetlet.2020.151674
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
M.C. Maust et al. / Tetrahedron Letters 61 (2020) 151674
and oxidation of carboxylic acid 1 would form lactone 4. Reaction
by the ortho position (red) of the aromatic ring via CAH insertion as
proposed by Michael and coworkers [9], would produce the origi-
nally observed tricyclic compound
elimination.
2
following reductive
To explain the formation of 3, we propose a reductive displace-
ment by the nucleophilic ipso position of the arene to form pheno-
nium ion 6, stabilized by the donating methoxy group. Baekvall
and coworkers have previously studied the highly reactive pheno-
nium ion formed by the direct displacement of an alkyl palladium
species [13]. Subsequently, several groups have utilized the highly
electrophilic palladium(IV) to form a series of interesting dearom-
atized products [11,14]. In 6, the phenonium ion is anti-coplanar
with the indicated bridge proton facilitating facile b-elimination
to form
a,b-unsaturated lactone (3) driven by the restoration of
aromaticity. All attempts to observe or isolate the proposed inter-
mediates were unsuccessful.
To further explore the nature of this novel reaction, we began a
series of experiments to determine the optimal conditions for the
intramolecular aryl-transfer. As shown in Table 1, the choice of
external oxidant proved crucial. Reduction in the stoichiometric
quantity of Selectfluor to 1.2 equivalents significantly increased
reaction yield, likely by reducing the prevalence of competing side
reactions. N-Fluorobenzenesulfonimide (NFSI), a fluorine based
oxidant used successfully in related aminoarylations [7], effects
the aryl transfer product, albeit at a reduced yield relative to
Selectfluor. Hypervalent iodine oxidants, such as PhI(OAc)2 and
PhI(O2CCF3)2, suffered from competing dioxygenation of the olefin
and reduced yields overall.
Scheme 1. Diverging reactivity of the palladium-catalyzed intramolecular oxyary-
lation reaction.
The reaction is exceptionally fast with total consumption of
starting material observed by NMR and TLC after only 5 min (entry
7). A reaction time of one hour proved optimal, ensuring complete
reaction while minimizing potential decomposition (entry 6).
While all attempted palladium sources produced similar yields,
the non-nucleophilic counterions of Pd(TFA)2 were ideal in reduc-
ing competing side reactions that complicated purification
observed with other catalysts. Additives, such as radical inhibitors
or drying agents had little effect on reaction yields. Full details of
the reaction optimization can be found in the Supplementary
Material.
Fig. 1. Projection of 3b. Carbon atoms shown in grey, oxygen in red, and hydrogen
in white.
extensive NMR analysis and confirmed by X-ray crystallography,
shown in Fig. 1 [12].
Intrigued by this divergence in reactivity, we set about to for-
mulate a mechanistic hypothesis (Scheme 2). Based on literature
precedent [6,11], we propose than an initial carboxypalladation
With optimized conditions in hand, we sought to further under-
stand the impact of electronic effects on the formation of 2 and 3,
Scheme 2. Proposed mechanism for the formation of 2 and 3.

M.C. Maust et al. / Tetrahedron Letters 61 (2020) 151674
3
Table 1
shown in Table 2. The pendant alkyl group on the phenolic oxygen
had little effect on product formation (1b–e), producing almost
Optimization of the formation of 3b.
exclusively the
a,b-unsaturated lactone 3 in reasonable yields.
Yields are slightly reduced for the t-butoxy substrate (3e), possibly
due to the labile nature of the t-butyl ethers under cationic condi-
tions. Though peaks consistent with the presence of tricyclic lac-
tones (2b–e) could be observed in the baseline of crude 1H NMR,
we were unable to successfully isolate or purify the species.
Attempts to perform the reaction on a phenolic substrate, such
as 1f where R = H, resulted only in decomposition of the starting
material.
From our mechanistic hypothesis, we predicted that increasing
the electron density at the position ortho to the ring attachment
would increase the relative formation of the tricyclic lactone.
Indeed, the incorporation of additional electron-donating groups
(1g–k) in the meta-position of the aromatic ring increased the pref-
erence for the tricyclic lactone 2. In fact, as the donating capability
of the group was increased to a methoxy group (1l), the tricyclic
product was formed exclusively. We conclude that the specific
reaction pathway is determined by the relative degree of activation
of the ortho-carbon (to form 2) and the ipso-carbon (to form 3).
We next explored a variety of other substitution patterns to bet-
ter understand the factors that bias the ratio of 2 and 3 (Table 3). In
general, the reaction appears to follow the selectivity observed in a
standard electrophilic aromatic substitution reaction, with addi-
tion occurring preferentially at the most electron-rich site on the
aromatic ring. In the absence of an oxygen substituent, alkyl
groups can be used to direct the reaction (1m–o), though product
Entry
Oxidant
Time
Yieldb (%)
1
2
3
4
5
6
7
Selectfluor
N-Fluorobenzenesulfonimide
PhI(OAc)2
PhI(O2CCF3)2
PhI = O
Selectfluor
12 h
12 h
12 h
12 h
12 h
1 h
59
37
6
13
8
84 (82)c
Selectfluor
5 min
78
aReaction conditions: 1b (0.2 mmol), Selectfluor (0.24 mmol), and Pd(TFA)2
(0.01 mmol) were combined in 1.0 mL of acetonitrile and stirred for the indicated
amount of time at room temperature.
bYield by 1H NMR versus 1,3-dinitrobenzene as internal standard.
cIsolated yield.
Table 2
Substrate Scope.
aReaction conditions: 1 (0.5 mmol), Selectfluor (0.6 mmol), and Pd(TFA)2 (0.025 mmol) were combined in 2.0 mL of acetonitrile and stirred for 1 h at
room temperature.
bRatio determined by crude 1H NMR analysis.
cIsolated yield.

4
M.C. Maust et al. / Tetrahedron Letters 61 (2020) 151674
Table 3
Substrate Scope.
aReaction conditions: 1 (0.5 mmol), Selectfluor (0.6 mmol), and Pd(TFA)2 (0.025 mmol) were combined in 2.0 mL of acetonitrile and stirred for 1 h
at room temperature.
bRatio determined by crude 1H NMR analysis.
cIsolated yield.
dIsolated as a mixture of stable rotational isomers.
eYield determined by 1H NMR analysis.
mixtures are generally formed. In cases of relatively equal activa-
tion between the two sites (1m), the tricyclic lactone 2m is the
preferred product by a significant margin. The reaction is generally
tolerant of groups in the ortho-position (1n–q,s); however, this
generally results in reduced yields and a slight increase in prefer-
ence for the formation of the tricyclic product. The decreased reac-
tivity is likely due to the increased steric demand around the
reacting ipso carbon.
As a note, purification and characterization of the tricyclic lac-
tones (2) was complicated by the previously observed restricted
rotation of the exocyclic aromatic ring. Though the 13C NMR spec-
tra of the compounds exhibit complete coalescence at room tem-
perature, elevated temperature was required to resolve peaks in
the 1H NMR. Compounds with substitution ortho to the ring junc-
tion (2n,o,q) exhibited locked rotation of the exocyclic aromatic
ring and formed as stable and isolable mixtures of rotational
isomers.
electron-donating groups on the ring supports our proposed
mechanism, indicating that the relative nucleophilic activation of
the ipso- and ortho-positions determines the product ratio. Further
work to explore our mechanistic hypothesis in more detail is
ongoing.
Despite the moderate yields, we have discovered and elabo-
rated on an interesting and novel rearrangement catalyzed by high
oxidation state palladium. The extreme sensitivity to the position
and nature of the functional groups on the aromatic ring may limit
the synthetic utility; however, it does provide an interesting model
for additional research in the field of high oxidation state palla-
dium-catalysis. It provides additional evidence for the highly elec-
trophilic nature of alkyl palladium(IV) intermediates. Further study
into the mechanism and intermediates has the potential to lead to
the development of new and interesting transformations.
Declaration of Competing Interest
While the substrate scope for the aryl-transfer reaction is rela-
tively limited due to restrictions on the aromatic rings, the reaction
provides interesting insight into high-oxidation state palladium
reactions. The substrate scope with respect to the influence of
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.

M.C. Maust et al. / Tetrahedron Letters 61 (2020) 151674
[5] (a) J.J. Topczewski, M.S. Sanford, Chem. Sci. 6 (2015) 70–76;
5
Acknowledgments
(b) K.J. Bonney, F. Schoenebeck, Chem. Soc. Rev. 43 (2014) 6609–6638;
(c) A.J. Hickman, M.S. Sanford, Nature 484 (2012) 177–185;
(d) P. Sehnal, R.J.K. Taylor, I.J.S. Fairlamb, Chem. Rev. 110 (2010) 824–889;
(e) L. Xu, B. Li, Z. Yang, Z. Shi, Chem. Soc. Rev. 39 (2010) 712–733;
(f) K. Muñiz, Angew. Chem., Int. Ed. 48 (2009) 9412–9423;
(g) A.J. Canty, Acc. Chem. Res. 25 (1992) 83–90.
Acknowledgement is made to the donors of the American
Chemical Society Petroleum Research Fund (53776-UNI1) for par-
tial support of this research.
[6] (a) For reviews of palladium(IV)-catalyzed oxidative difunctionalization
reactions: G. Broggini, T. Borelli, S. Giofré, A. Mazza Synthesis 49 (2017)
2803–2818;
Appendix A. Supplementary data
(b) G. Yin, X. Mu, G. Liu, Acc. Chem. Res. 49 (2016) 2413–2423.
[7] (a) D.N. Garad, S.B. Mhaske, Org. Lett. 18 (2016) 3862–3865;
(b) R. Jana, T.P. Pathak, K.H. Jensen, M.S. Sigman, Org. Lett. 14 (2012) 4074–
4077;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151674.
(c) P.A. Sibbald, F.E. Michael, Org. Lett. 11 (2009) 1147–1149;
(d) A. Wang, H. Jiang, H. Chen, J. Am. Chem. Soc. 131 (2009) 3846–3847;
(e) K. Muñiz, C.H. Hoevelmann, J. Streuff, J. Am. Chem. Soc. 130 (2008) 763–
773;
(f) D. Kalyani, M.S. Sanford, J. Am. Chem. Soc. 130 (2008) 2150–2151;
(g) Y. Li, D. Song, V.M. Dong, J. Am. Chem. Soc. 130 (2008) 2962–2963;
(h) L.V. Desai, M.S. Sanford, Angew. Chem. Int. Ed. 46 (2007) 5737–5740;
(i) G. Liu, S.S. Stahl, J. Am. Chem. Soc. 128 (2006) 7179–7181;
(j) J. Streuff, C.H. Hoevelmann, M. Nieger, K. Muñiz, J. Am. Chem. Soc. 127
(2005) 14586–14587;
References
[1] (a) X.F. Wu, P. Anbarasan, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 49
(2010) 9047–9050;
(b) C.C.C. Johansson-Seechurn, M.O. Kitching, T.J. Colacot, V. Snieckus, Angew.
Chem. Int. Ed. 51 (2012) 5062–5085.
[2] K.C. Nicolaou, P.G. Bulger, D. Sarlah, For the importance of palladium catalysis
to organic synthesis, Angew. Chem. Int. Ed. 44 (2005) 4442–4489.
[3] For a recent review on palladium-catalyzed difunctionalizations: H. Jiang, M.
Hu, W. Wu ChemSusChem 12 (2019) 2911–2935.
[4] (a) J.K. Kirsch, J.L. Manske, J.P. Wolfe, J. Org. Chem. 83 (2018) 13568–13573;
(b) J.R. Boothe, Y. Shen, J.P. Wolfe, J. Org. Chem. 82 (2017) 2777–2786;
(c) L. Ye, K.-Y. Lo, Q. Gu, D. Yang, Org. Lett. 19 (2017) 308–311;
(d) L. Li, X. Zhou, B. Yu, H. Huang, Org. Lett. 19 (2017) 4600–4603;
(e) J. Mikesell, M.D. Mosher, Tetrahedron Lett. 57 (2016) 1011–1013;
(f) G. Albarghouti, R. Kotikalapudi, D. Lankri, V. Valerio, D. Tsvelikhovsky,
Chem. Commun. 52 (2016) 3095–3098;
(k) E.J. Alexanian, C. Lee, E.J. Sorensen, J. Am. Chem. Soc. 127 (2005) 7690–
7691.
[8] C.F. Rosewall, P.A. Sibbald, D.V. Liskin, F.E. Michael, J. Am. Chem. Soc. 131
(2009) 9488–9489.
[9] P.A. Sibbald, C.F. Rosewall, R.D. Swartz, F.E. Michael, J. Am. Chem. Soc. 131
(2009) 15945–15952.
[10] A.J. Canty, A. Ariafard, B.F. Yates, M.S. Sanford, Organometallics 34 (2015)
1085–1090.
[11] B.S. Matsuura, A.G. Condie, I.A. McBee, R.C. Buff, G.J. Karahalis, C.R.J.
Stephenson, Org. Lett. 13 (2011) 6320–6323.
[12] Full details on the crystal structure can be found in the Supplementary
Material.
[13] J.E. Baeckvall, R.E. Nordberg, J. Am. Chem. Soc. 102 (1980) 393–395.
[14] Z. Wu, D. Wang, Y. Liu, L. Huan, C. Zhu, J. Am. Chem. Soc. 139 (2017) 1388–
1391.
(g) G. Broggini, V. Berbera, E.M. Beccalli, U. Chiacchio, A. Fasana, S. Galli, S.
Gazzola, Adv. Synth. Catal. 355 (2013) 1640–1648;
(h) J.F.M. Hewitt, L. Williams, P. Aggarwal, C.D. Smith, D.J. France, Chem. Sci. 4
(2013) 3538–3543;
(i) T.A. Doroski, M.R. Cox, J.B. Morgan, Tetrahedron Lett. 50 (2009) 5162–5164;
(j) M.B. Hay, J.P. Wolfe, Tetrahedron Lett. 47 (2006) 2793–2796;
(k) J.P. Wolfe, M.A. Rossi, J. Am. Chem. Soc. 126 (2004) 1620–1621;
(l) J.E. Baeckvall, E.E. Bjoerkman, S.E. Bystroem, A. Cavallo, Tetrahedron Lett. 23
(1982) 943–946.