Epoxides as Alkylating Reagents for the Catellani Reaction

Article abstract of DOI:10.1002/anie.201800573

We report a cooperative catalytic system comprising a Pd^II complex, XPhos, and the potassium salt of 5-norbornene-2-carboxylic acid that enables the use of epoxides as alkylating reagents in the Catellani reaction, thereby expanding the existing paradigm of this powerful transformation. 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 a wide variety of readily available functionalized aryl iodides and epoxides, as well as terminating olefins. The resulting products undergo facile oxa-Michael addition to furnish ubiquitous isochroman scaffolds.

Full text of DOI:10.1002/anie.201800573

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Accepted Article
Title: Epoxides as Alkylating Reagents for the Catellani Reaction
Authors: Qianghui Zhou, Hong Gang Cheng, Chenggui Wu, Han
Chen, Ruiming Chen, Guangyin Qian, Zhi Geng, Qiang Wei,
Yuanyuan Xia, Jingyang Zhang, and Yuming Zhang
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Epoxides as Alkylating Reagents for the Catellani Reaction
Hong-Gang Cheng, Chenggui Wu, Han Chen†, Ruiming Chen†, Guangyin Qian, Zhi Geng, Qiang Wei,
Yuanyuan Xia, Jingyang Zhang, Yuming Zhang and Qianghui Zhou*
functionalization step are quite limited, these include alkyl
Abstract: We report a cooperative catalytic system comprising a
Pd(II) complex, XPhos, and the potassium salt of 5-norbornene-
2-carboxylic acid that enables the use of epoxides as alkylating
reagents in the Catellani reaction, thereby expanding the existing
paradigm of this powerful transformation. The potassium salt of
inexpensive 5-norbornene-2-carboxylic acid acts as both
mediator and base in the process. This mild, chemo-selective,
scalable, and atom-economic protocol is compatible with a wide
variety of readily available functionalized aryl iodides, epoxides as
well as terminating olefins. In addition, the resulting products can
be subjected to facile oxa-Michael addition to furnish ubiquitous
isochroman scaffolds.
3e]
halides,[2,
aryl halides,[4] azirines,[5] O-benzoylhydroxyl-
amines,[3c] and various carboxylic acid derivatives[3g-i,l,m] (Figure
1a). To the best of our knowledege, the use of epoxides as the
electrophilic reagents in Pd/NBE catalysis has not been
reported.[6] The recent innovative research from Kanai and Yu
groups[7] inspired us to pursue epoxide as an alkylating reagent in
this field. We envisioned that by using widely available epoxides
2 as alkylating reagents and electron-deficient olefins 3 as
terminating reagents, versatile products 4 can be readily afforded,
allowing rapid access to isochroman scaffolds via a subsequent
oxa-Michael addition[8] (Figure 1b). The salient features of the
strategy include its broad substrate scope and its high atom
economy[9]–since epoxide can be incorporated into the product in
its entirety, without incurring any sacrificial groups. In addition, the
resulting isochroman substructure exists in many bioactive
natural products and therapeutic agents (e.g., penicitrinol F,[10]
mevashuntin,[11] dopamine D4 receptor antagonist U-101387,[12]
and 5-HT1D agonist PNU-109291[13] etc.) (Figure 1c). Hence, our
proposed epoxide involved Catellani/oxa-Michael sequence will
offer a novel and convergent synthetic strategy to access these
complex targets or analogs thereof.
Our efforts commenced with a model reaction using readily
available 2-iodotoluene (1a), 2-(phenoxymethyl)oxirane (2a) and
ethyl acrylate (3a) (Table 1). After extensive survey of the reaction
parameters,[14] the optimal conditions was identified to be:
Pd(OAc)2 as the catalyst (2.5 mol%), XPhos[15] as the ligand (6
mol%), the patassium salt of inexpensive 5-norbornene-2-
carboxylic acid as the mediator (N2, 50 mol%),[16] NMP as the
solvent, wherein the desired product 4a was afforded in an
excellent yield (92% yield) at 60 oC (entry 1). Control experiments
were subsequently conducted to understand the role of each
component.[17] In the absence of either Pd catalyst or mediator,
no desired product 4a was observed (entries 2-3). The polarity of
The Catellani-type reaction is a powerful strategy that allows
the expeditious synthesis of highly substituted arenes.[1] It utilizes
synergistic interplay of palladium and 2-norbornene (NBE)
catalysis to facilitate sequential ortho C–H functionalization and
ipso termination of aryl iodides. Seminal work by the group of
Catellani,[2] followed by Lautens[1c,e] and others[3] have
significantly enriched this chemistry. Recent efforts in this area
have expanded the scope of terminating reagents substantially as
a gamut of functionalities can be appended at the ipso-position.[1g,
h] In contrast, the electrophilic reagents developed for ortho C–H
Table 1. Optimization of reaction conditions[a]
.
Entry
Change from the standard condition
Yield [%][b]
1
2
none
92 (91)[c]
no Pd(OAc)2
0
0
3
no N2
Figure 1. Palladium-catalyzed Catellani reaction of aryl iodides
4
toluene instead of NMP
PPh3 instead of XPhos
N1 + CsOAc instead of N2
0
[*]
Dr. H.-G. Cheng, C. Wu, H. Chen, R. Chen, G. Qian, Z. Geng, Q. Wei,
Y. Xia, J. Zhang, Y. Zhang, Prof. Dr. Q. Zhou
College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, 430072 (China)
5
83
92
6[d]
E-mail: qhzhou@whu.edu.cn
Homepage: http://qhzhou.whu.edu.cn/
Prof. Dr. Q. Zhou
The Institute for Advanced Studies, Wuhan University, Wuhan,
430072 (China)
These authors contributed equally to this work.
Supplementary information for this article is given via a link at the end
of the document.
[a]All reactions were performed on 0.2 mmol scale. [b]GC yield with biphenyl
as an internal standard. [c] Isolated yield in parentheses. [d] 3.0 equiv. of
NBE and 0.5 equiv. of CsOAc were applied. NMP: N-methyl-2-pyrrolidinone.
[†]
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Table 2. Scope with respect to aryl iodides and olefins[a]
.
reaction solvent proved to be essential as the switching of NMP
to toluene led to no product formation (entry 4). The use of less
bulky ligand PPh3 resulted in a lower yield (entry 5). A combination
of NBE (3.0 equiv.) and CsOAc (0.5 equiv.) instead of N2 afforded
a similar result as entry 1 (entry 6), indicative of N2’s dual
functionality (as mediator and base). It is worth mentioning that
the use of N2 in lieu of NBE and base is advantageous not only
from a reaction economy vantage point; it also confers the
process added operational simplicity[18] as the potassium salt can
be readily removed by an aqueous extraction.
With the above optimal conditions identified, we then
examined the scope of aryl iodides (Table 2a). Gratifyingly, aryl
iodides containing electron-donating and -withdrawing groups all
proved to be competent substrates, providing the desired
products in 55-95% yields. The reaction system also exhibited
high chemo-selectivity: various functional groups were tolerated,
including benzyloxy (4e, 4o and 4p), methoxy (4n), fluoride (4c
and 4h), chloride (4d),[19] bromide (4i),[19] methyl ester (4f, 4j,
and 4o), and amide (4k), providing handles for further product
diversifications. Notably, bicyclic aryliodides (4l and 4m),
heteroaryl iodide (4n), and densely functionalized aryl iodides (4o
and 4p) were suitable substrates. Interestingly, simple phenyl
iodide reacted to afford the bis-alkylated product (4q) as 1:1
diastereomers in 76% yield.
Next, we proceeded to examine the scope of olefins 3. As
shown in Table 2b, an array of mono-substituted olefins with
electron-withdrawing groups are suitable substrates (4a'-e'),
providing the desired product in excellent yield. Notably,
acrylonitrile afforded the product 4c' as a mixture of geometrical
isomers in 90% yield (E:Z = 1.2:1). When vinylphenylsulfone was
used, in situ intramolecular oxa-Michael addition was observed.
The reaction gave the desired product 4e'[20] in 57% yield,
together with the cyclized product 5e' (cis) and 5e'' [20] (trans) in
23% and 11% yields, respectively.[21] In addition, the 1,1-di-
[a] All reactions were performed on 0.4 mmol scale. Isolated yields are
reported. [b] Enantiopure 2a was applied. [c] With 10 mol% of Pd(OAc)2, and
24 mol% of XPhos. [d] With 5 mol% of Pd(OAc)2, and 12 mol% of XPhos.
substituted electron-deficient olefin, benzyl methacrylate
exihibited lower reactivity during this process, delivering the
product 4f' in 65% yield, wherein the olefin was formed through
the final β–H elimination at the methyl group instead of the benylic
position. Interestingly, simple styrene also worked to afford the
products 4g' in moderate yield.
Table 3. Scope with respect to epoxides [a]
.
[a] All reactions were performed on 0.4 mmol scale. Isolated yields are reported. [b] 4.0 equiv. of ethylene oxide were applied. [c] With 5 mol% of Pd(OAc)2,
and 12 mol% of XPhos. [d] slow addition of epoxide via a syringe pump. [e] 1.0 equiv. of N2 was applied. [f] With 10 mol% of Pd(OAc)2, and 24 mol% of XPhos.
[g] one-pot yield.
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To further illustrate the synthetic utility of this protocol, the
scope of epoxides 2 was examined (Table 3).[22] Alkylation with
simple ethylene oxide, propylene oxide, as well as other 2-
alkyloxiranes with long aliphatic chain gave the desired products
4a''-e'' in good to excellent yields (67-96%). Epoxides containing
a variously protected 3-hydroxyl group also gave excellent yields
(4f''-h'', and 4j''). It is noteworthy that a free 3-hydroxyl group was
tolerated, affording a versatile synthon 4i'' in 91% yield. Further
exploration demonstrated that β-protected amino group was also
compatible with this protocol (4k''). When enantiopure epoxides
were used, the reaction proceeded with stereo-retention,
affording the corresponding chiral products (4b'', 4c'', 4f'', 4g'',
yield (1.44 g) in a 8.0 mmol scale experiment. It is noteworthy that
the concentration of the gram scale experiment was as high as
0.5 M – the compatibility with high concentrations is yet another
attractive feature of the method.
The Catellani products 4 and isochroman derivatives 5 are
useful intermediates in a number of synthetic applications. For
example, 5q'' reacts with commercially available amine 6 under
reductive amination condition[24] to afford a methylated analog of
D4 agonist U-101387 in good yield (Scheme 1b). Debenzylation
of 5s'' using Pd/C under 1 atm H2 followed by an acid promoted
lactonization[25] affords polycyclic intermediate 8 in 59% yield (2
steps), which possesses the core structure of penicitrinol F
and 4k'') with ≥99% ee. Encouraged by the stereochemical fidelity, (Scheme 1c). Efforts are underway to utilize this method in the
chiral epoxides derived from several complex natural products
(4l''-n'') (See SI for preparations) were examined in this
transformation, wherein the desired products were obtained in 89-
94% yields, along with complete chemo-selectivity over free
hydroxyl, ketone, lactone, and ester function groups (Table 3b). It
was then surmized that tethering the epoxide and olefin into a
single bifunctional reagent will enable sequential alkylation and
intramolecular termination, providing a unique way to construct
macrocycles.[3l,23] Two of such bifunctional reagents were
prepared, whereupon their reactions with aryl iodide 1k afforded
the 13 and 14-membered macrolactone 4o'' and 4p'' in 56% and
42% yields respectively, offering a stunning testment to the
versatility of this methodology (Table 3c). Further exploration
revealed feedstock acrolein is also an effective termination
reagent, provide products 4q'' and 4r'' in moderate yield,
alongside in situ oxa-Michael adduct 5q'' and 5r''. In contrast,
switching the Michael acceptor to benzyl acrylate, uncyclized 4s''
was obtained as the sole product in 90% yield, which was fully
converted to cyclized product 5s'' by treatment with Cs2CO3 in
heated acetonitrile. Based on the above oberservations, a “one-
pot” precedure was developed: following the completion of the
Catellani reaction, Cs2CO3 was added directly to the reaction
mixture to afford cyclized product 5s'' exclusively in 65% yield
(Table 3d).
preparation of various natural products and potential therapeutics.
In summary, we have developed a cooperative catalytic
system comprising a Pd(II) complex, XPhos and potassium salt of
5-norbornene-2-carboxylic acid that enables the use of epoxides
as alkylating reagents in the Catellani reaction, thereby expanding
the existing paradigm of this powerful transformation. Control
experiment revealed that the potassium salt of inexpensive 5-
norbornene-2-carboxylic acid acts as both mediator and base.
This mild, chemo-selective, scalable, and atom-economical
protocol is compatible with
a range of readily available
functionalized aryl iodides, epoxides as well as terminating olefins.
The products of the reaction are poised to undergo oxa-Michael
reactions, allowing expedient access to valuable isochroman
scaffolds. Total syntheses of complex natural products invoking
this method as the key step are currently ongoing in our laboratory,
and will be reported in due course.
Acknowledgements
We are grateful to National “1000-Youth Talents Plan”, the
Innovation Team Program of Wuhan University (Program No.
2042017kf0232) and start-up funding from Wuhan University for
financial support. We thank Dr. Qi Liu, Prof. Hengjiang Cong
(Wuhan University) and Prof. Fangfang Pan (Central China
Normal University) for X-ray analysis, Prof. Dawei Ma (Shanghai
Institute of Organic Chemistry, China) and Prof. Phil S. Baran (the
Scripps Research Institute, US) for helpful discussions, Dr. Han-
Qing Dong (Arvinas Inc., US) and Dr. Ming Yan (the Scripps
Research Institute, US) for assistance with the preparation of the
manuscript.
The idenfication of feedstock ethylene oxide and acrolein as
effective substrates prompted us to further investigate the
practicality of this protocol on larger scales (Scheme 1a). With
only 1.0 mol% Pd(OAc)2 and 2.4 mol% XPhos, the isochroman
derivative 5a'' was furnished through the “one-pot” protocol in 77%
Keywords: Catellani reaction • norbornene • cooperative
catalysis • epoxide • oxa-Michael addition • isochroman
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Scheme 1. Scale-up experiments and synthetic applications
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[17] Control experiments regarding the prelimianry mechanism study were
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see: Ref. [1c], [1g] and [3g]
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Hong-Gang Cheng, Chenggui Wu, Han
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Zhi Geng, Qiang Wei, Yuanyuan Xia,
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Qianghui Zhou*
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Epoxides as Alkylating Reagents for
the Catellani Reaction
A cooperative catalytic system comprising a Pd(II) complex, XPhos and potassium
salt of 5-norbornene-2-carboxylic acid to promote the cleavage of C–O bond of
epoxides for C–H alkylation was developed, thereby enabling these versatile building
blocks to serve as alkylating reagents in the Catellani reaction. The potassium salt of
inexpensive 5-norbornene-2-carboxylic acid serves dual purposes as mediator and
base in the process. The salient features of the reaction include its broad substrate
scope (with respect to aryl iodides, epoxides and terminating olefins) and its high
atom economy. In addition, the resulting products can be subjected to oxa-Michael
addition to furnish valuable isochroman scaffolds.
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