Epoxides as AlkylatingReagents for the Catellani Reaction
Hong-Gang Cheng,Chenggui Wu,Han Chen
,Guangyin Qian, Zhi Geng,
Qiang Wei, Yuanyuan Xia, Jingyang Zhang,Yuming Zhang,and Qianghui Zhou*
Dedicated to Prof.Phil S. Baran and Prof.Dawei Ma
Abstract: We report acooperative catalytic system comprising
complex, XPhos,and the potassium salt of 5-norbor-
nene-2-carboxylic acid that enables the use of epoxides as
alkylating reagents in the Catellani reaction, thereby expanding
the existing paradigm of this powerfultransformation. The
potassium salt of inexpensive 5-norbornene-2-carboxylic acid
acts as both mediator and base in the process.This mild,
chemoselective,scalable,and atom-economical protocol is
compatible with awide variety of readily available function-
alized aryl iodides and epoxides,aswell as terminating olefins.
The resulting products undergo facile oxa-Michael addition to
furnish ubiquitous isochroman scaffolds.
The Catellani-type reaction is apowerful strategy that allows
the expeditious synthesis of highly substituted arenes.
utilizes the synergistic interplay of palladium and 2-norbor-
nene (NBE) catalysis to facilitate sequential ortho-C
functionalization and ipso termination of aryl iodides.Semi-
nal work by the group of Catellani
and later studies by
Lautens and co-workers
enriched this chemistry.Recent efforts in this area have
expanded the range of possible terminating reagents substan-
tially,sothat now agamut of functionalities can be appended
at the ipso position.
In contrast, the electrophilic reagents
developed for the ortho-C
Hfunctionalization step are quite
limited;they include alkyl halides,
and various carboxylic
(Figure 1a). To the best of our knowl-
edge,the use of epoxides as the electrophilic reagents in Pd/
NBE catalysis has not been reported.
research from the Kanai and Yu groups
inspired us to
pursue epoxides as alkylating reagents in this field.
We envisioned that the use of widely available epoxides 2
as alkylating reagents and electron-deficient olefins 3 as
terminating reagents would readily afford versatile products
4,thus allowing rapid access to isochroman scaffolds through
asubsequent oxa-Michael addition
(Figure 1b). Thesalient
features of the strategy include its broad substrate scope and
its high atom economy,
since an epoxide can be incorpo-
rated into the product in its entirety,without the need for any
sacrificial groups.Furthermore,the resulting isochroman
substructure exists in many bioactive natural products and
therapeutic agents (e.g., penicitrinol F,
dopamine D4 receptor antagonist U-101387,
;Figure 1c). Hence,our proposed
Catellani/oxa-Michael sequence involving an epoxide will
offer anovel and convergent synthetic strategy to access these
complex targets or analogues thereof.
Our efforts commenced with amodel reaction of readily
available 2-iodotoluene (1a)with 2-(phenoxymethyl)oxirane
(2a)and ethyl acrylate (3a;Table 1). After an extensive
survey of the reaction parameters,
the optimal conditions
as the catalyst (2.5 mol %), XPhos
the ligand (6 mol%), the potassium salt of inexpensive 5-
norbornene-2-carboxylic acid as the mediator (N
NMP as the solvent] afforded the desired
product 4a in excellent yield (92%yield) at 60 88C(Table 1,
entry 1). Control experiments were subsequently conducted
to understand the role of each component.
In the absence
Figure 1. Palladium-catalyzed Catellani reaction of aryl iodides.
[*] Dr.H.-G. Cheng, C. Wu,H.Chen,
G. Qian, Z. Geng,
Q. Wei, Y. Xia, J. Zhang, Y. Zhang, Prof. Dr.Q.Zhou
College of Chemistry and Molecular Sciences
Wuhan, 430072 (China)
The Institute for Advanced Studies, Wuhan University
Wuhan, 430072 (China)
]These authors contributed equally.
Supportinginformation and the ORCID identification number(s) for
the author(s) of this article can be found under:
3502 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Angew.Chem. 2018, 130,3502 –3506