Intramolecular Pd-Catalyzed Formal anti-Carboalkoxylation of Alkynes: Access to Tetrasubstituted Enol Ethers

Article abstract of DOI:10.1002/chem.201803721

An intramolecular Pd-catalyzed formal anti-carboalkoxylation reaction is presented that provides access to tetrasubstituted enol ethers. The key to success is a cascade consisting of a formal anti-carbopalladation of a carbon–carbon triple bond followed by a nucleophilic attack of a hydroxy group at the emerging vinyl organopalladium species. The desired transformation proceeded smoothly with primary, secondary, and tertiary alcohols, and even with phenols. Depending on the substitution pattern of the enol ethers, a further Tsuji–Trost-type step may occur resulting in oligocyclic ketals.

Full text of DOI:10.1002/chem.201803721

A Journal of
Accepted Article
Title: Intramolecular Pd-Catalyzed Formal anti-Carboalkoxylation of
Alkynes: Access to Tetrasubstituted Enol Ethers
Authors: Daniel B. Werz, Peter G. Jones, and Theresa Schitter
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To be cited as: Chem. Eur. J. 10.1002/chem.201803721
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10.1002/chem.201803721
Chemistry - A European Journal
COMMUNICATION
Intramolecular Pd-Catalyzed Formal anti-Carboalkoxylation of
Alkynes: Access to Tetrasubstituted Enol Ethers
Theresa Schitter,[a] Peter G. Jones,[b] and Daniel B. Werz*[a]
Abstract: An intramolecular Pd-catalyzed formal anti-carbo-
alkoxylation reaction is presented that provides access to tetra-
substituted enol ethers. The key to success is a cascade consisting of
a formal anti-carbopalladation of a carbon‒carbon triple bond followed
by a nucleophilic attack of a hydroxy group at the emerging vinyl
organopalladium species. The desired transformation proceeded
smoothly with primary, secondary, and tertiary alcohols, and even with
phenols. Depending on the substitution pattern of the enol ethers, a
further Tsuji‒Trost-type step may occur resulting in oligocyclic ketals.
Pd species was intercepted by nucleophilic carbon moieties such
as olefins,[15] or stannylated arenes.[16] However, the use of
nucleophilic heteroatomic species such as hydroxy units[17] would
allow a facile generation of tetrasubstituted enol ethers starting
from internal alkynes. Coupling partners would be a C-Br bond for
the first side of the triple bond and aliphatic alcohols or phenols
for the opposite side, leading to HBr as the only side product.
To test our notion, we chose alcohol 1a as model substrate to
optimize the reaction conditions for the anticipated cascade. As
starting point, the reaction was carried out with PdCl2(PhCN)2 as
catalyst for 2 h. Whereas monodentate ligands such as PPh3 or
XPhos gave either no or only low yields of the desired product 2a
(Table 1, entries 1-3) Fu’ s salt[18] delivering the sterically
encumbered tris-tert-butylphosphine afforded 2a in moderate to
good yields (entries 4-9). Further optimization revealed NEt3 as
most suitable base. The yield was improved still more by
increasing the temperature from 100 °C to 120 °C (entry 5). A
change of the polar aprotic solvent from DMF to DMA resulted in
a slight decrease of product formation (entry 9).
Dicarbofunctionalizations of internal alkynes by the addition of
two carbon moieties to a carbon‒carbon triple bond have paved
the way to numerous products with embedded tetrasubstituted
alkene units. For this purpose, several transition-metal-catalyzed
approaches have been developed; in particular, Pd catalysis has
proved
a very powerful method. Initially, carbopalladation
reactions of alkynes were integrated in cascades (domino
processes)[1] leading to steroid derivatives and highly substituted
arenes.[2,3] Recently, novel domino processes with one or several
carbopalladations as key reactions have been designed affording
highly complex natural products or natural product analogs,[4] and
also other more specific targets such as spirocycles,[5]
(oligo)cyclic compounds,[6] dibenzopentafulvalenes,[7] helical
oligoenes,[8] fenestranes,[9] persubstituted cyclooctatetraenes,[10]
and molecular switches.[11] Since the emerging organopalladium
species, which is formed at the beginning of such a cascade,
commonly attacks the carbon‒carbon triple bond in a syn-fashion,
both residues are located at the same side of the newly generated
double bond.[12]
Recently, we designed a process that led to a formal anti-
dicarbofunctionalization of a triple bond.[13,14] The key step is the
cis-trans-isomerization in the coordination sphere of a 14 VE Pd
species, which allows a continuation of the cascade on the
opposite side of the emerging double bond.[13] It is important to
use a substituent at the triple bond that does not allow β-hydride
elimination, since this pathway is faster than the internal
isomerization. In all previous reports, the reactive anti-configured
Table 1. Optimization of the reaction conditions.[a]
Entry
Ligand
PPh3
PPh3
Base
NEt3
NEt3
NEt3
NEt3
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
T [°C]
100
120
120
100
120
120
120
120
120
Yield 2a [%]
1
2
3
4
5
6
7
8
9
-
38
24
65
88
70
35
60
73
XPhos
[tBu3PH][BF4]
[tBu3PH][BF4]
[tBu3PH][BF4]
[tBu3PH][BF4]
[tBu3PH][BF4]
[tBu3PH][BF4]
NEt3
K2CO3
K3PO4
DIPEA
NEt3
[a]
Reaction conditions: 1 (100 µmol), solvent (3.0 mL); yields represent
isolated products; DIPEA = N,N-Diisopropylethylamine; DMA = Dimethyl-
acetamide; DMF = Dimethylformamide.
[a]
Dipl.-Chem. T. Schitter, Prof. Dr. D. B. Werz
Technische Universität Braunschweig
Institute of Organic Chemistry
With the optimized reaction conditions in hand, we examined
the general applicability of this cascade. In these initial stages, we
limited our experiments to the formation of a five-membered ring
as the first step of this domino process. Products 2a–2h were
obtained in yields of 55–98% (Scheme 1). Variation of substi-
tuents at the alkyne (R2) showed that the domino reaction pro-
ceeded smoothly both with a tert-butyl (2a, 2g–2h, 55–88%) and
a silyl-containing group (2b–2f). In the case of silyl groups, both
TMS (2b–2c, 2e, 63–98%) and the more bulky TBDMS group (2d,
Hagenring 30, 38106 Braunschweig (Germany)
E-mail: d.werz@tu-braunschweig.de
Homepage: http://www.werzlab.de
[b]
Prof. Dr. P. G. Jones
Technische Universität Braunschweig
Institute of Inorganic and Analytical Chemistry
Hagenring 30, 38106 Braunschweig (Germany)
Supporting information for this article can be found via a link at the
end of this document.
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2f, 81–84%) afforded the products in good to excellent yields.
Oxygen in the tether was tolerated (2a–2b, 2g–2i). The
transformation proceeded smoothly with different bromoarenes
(2e–2h). Naphthofurane derivative 2g and benzofurane
derivatives 2a, 2b and 2h showed a strong susceptibility to a
formal ene-reaction with oxygen from the air leading to hydro-
peroxides of type 2i (X-ray structure, see Supporting Information).
The driving force of this reaction is the gain of aromaticity leading
to the formation of benzofurans (Scheme 1).
Scheme 2. Scope of the domino reaction with respect to six-membered ring
systems; yields represent isolated products; [a]100 °C.
For domino precursors with an excellent leaving group X (5a–
5d), the domino process continued after the formal anti-carbo-
alkoxylation.
A subsequent Tsuji–Trost-type reaction was
Scheme 1. Scope of the domino reaction with respect to five-membered ring
observed. Phenolates stabilized by electron-withdrawing groups
(5a–5c), but also compound 5d, which is able to eliminate
carboxylate (see catalytic cycle in Scheme 4b), underwent this
further transformation. In all cases, the corresponding ketals 6a–
6d were isolated in good to excellent yields (54–99 %).[19] The
structure of ketal 6a was confirmed by X-ray crystallography.[20] In
contrast to 5d, the corresponding TMS-masked alkyne 5e did not
undergo the domino process including the Tsuji–Trost-type re-
arrangement, most probably because of the β-silyl effect, which
raises the activation barrier of this process (Scheme 3).
systems; yields represent isolated products; [a]100 °C.
The method is also effective for other ring sizes. Thus, various
domino precursors of type 3 with an extended chain connecting
bromoarene and alkyne were synthesized. Application of the
developed conditions afforded the desired products 4a–4m in 35–
97% yield (Scheme 2). Oxygen (4a–4c, 4f–4m) and tosyl-
protected nitrogen (4d and 4e) in the tether were tolerated.
Domino products bearing an electron-withdrawing group such as
nitro (4i) and nitrile (4g and 4h) were isolated in good to excellent
yields of 67–97%. Enol ethers with electron-donating groups at
the aromatic moiety (4j–4m) were isolated in yields between
57 and 83%. Furthermore, the cascade also tolerates fluoride as
substituent at the arene; the respective product 4f was accessed
in 94% yield. Further investigations demonstrated that additional
steric bulk (R3 = Me) leading to a quaternary carbon next to the
triple bond did not hamper the domino process. The corres-
ponding products (4k–4m) were isolated in good yields up to 83%
(Scheme 2). The structural identity of two of the generated enol
ethers was also proved by X-ray crystallography (Scheme 2, 4e
and 4g).
Scheme 3. Scope of domino cascade followed by a subsequent Tsuji‒Trost-
type reaction; yields represent isolated products.
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For the transformation described here, our observations are
supportive of a cis-trans-isomerization pathway in the coordi-
nation sphere of Pd (Scheme 4).[13] Oxidative addition of the Pd0
species into the C–Br bond of 1a forms intermediate A, which
directly reacts with the triple bond in a syn-carbopalladation. An
emerging 14 VE species B is able to isomerize via a ƞ2–vinyl
transition state to intermediate C, where the Pd now has the
desired anti-configuration. Base-promoted coordination of the
hydroxy group to the palladium center leads to the formation of
intermediate D. Reductive elimination regenerates the palladium
catalyst and enol ether 2a is formed (Scheme 4a). Trapped
intermediates in a formal anti-carbopalladation/C‒H-activation
cascade corroborate such a mechanistic scenario.[21]
Scheme 5. Termination of the formal anti-carboalkoxylation cascade using
secondary, tertiary and aromatic hydroxy groups; yields represent isolated
products.
The versatility of silyl groups as termini of the alkyne was
demonstrated by several further functionalizations (Scheme 6).
Desilylation of 2c using tetrabutylammonium fluoride afforded the
corresponding trisubstituted enol ether 11 in 87% yield.
Furthermore, 2c was halogenated by using N-iodosuccinimide.
The emerging iodo enol ether is a capricious compound and was
therefore directly subjected to further derivatisation. Stille reaction
with trimethyl(phenyl)tin yielded the phenyl-substituted derivative
12 in 95% yield. Moreover, a Heck reaction afforded diene 13 in
69% yield, while a Suzuki coupling with butylboronic acid provided
the alkyl-substituted product 14 in 63% yield.
Scheme 4. Proposed catalytic cycle.
The subsequent Tsuji‒Trost-reaction is depicted in Scheme 4b.
The Pd0 reacts with the allyl enol ether affording a highly stabilized
Pd-allyl complex E while phenolate is eliminated. After rotation
about the single bond, the phenolate attacks the cationic allyl-
palladium complex in γ-position yielding ketals 6.
The efficacy of the enol ether formation prompted us to
investigate the terminating nucleophilic attack with other types of
hydroxy groups. After having used primary alcohols, the scope
was extended to secondary (7a) and tertiary alcohols (7b and 7c)
yielding the products 8a–8c in good to excellent yields up to 94%
(Scheme 5a). Slightly modified reaction conditions (tris(di-
benzylideneacetone)dipalladium as Pd source and potassium
carbonate as base), without further optimization,[4a] even allowed
the use of a phenol moiety as nucleophile (Scheme 5b).
Scheme 6. Follow-up chemistry.
In conclusion, we outline an efficient formal anti-carbo-
alkoxylation cascade leading to tetrasubstituted enol ethers. The
chemistry is based on a formal anti-carbopalladation being
terminated by the nucleophilic attack of a hydroxy group. Primary,
secondary, tertiary and phenolic alcohols were successfully
utilized. Generated silyl-substituted enol ethers paved the way to
simple derivatizations of the double bond. Further studies of
formal anti-bisfunctionalization processes using other types of
nucleophiles are ongoing in our laboratory.
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We are grateful to the German Research Foundation (DFG, WE
2932/7-1) for funding.
Keywords: alkynes • carbopalladation • formal anti-bis-
functionalization • enol ethers • palladium
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COMMUNICATION
COMMUNICATION
Theresa Schitter, Peter G. Jones, Daniel
B. Werz*
Page No. – Page No.
Intramolecular Pd-Catalyzed Formal
anti-Carbalkoxylation of Alkynes:
Access to Tetrasubstituted Enol
Ethers
Pd as Activator, OH as Terminator: A Pd-catalyzed cascade involving a formal anti-
carbopalladation of internal alkynes was terminated by the nucleophilic attack of a
hydroxy group leading to tetrasubstituted enol ethers. A subsequent Tsuji–Trost-like
rearrangement was observed for products with an excellent leaving group.
This article is protected by copyright. All rights reserved.