Intramolecular Formal anti-Carbopalladation/Heck Reaction: Facile Domino Access to Carbo- and Heterooligocyclic Dienes

Article abstract of DOI:10.1002/chem.201502327

An intramolecular domino process consisting of a formal anti-carbopalladation followed by Heck reaction is realized. Complex oligo(hetero)cyclic scaffolds are efficiently obtained in one synthetic step from easily obtainable enyne precursors. In contrast to common syn-carbopalladation reactions of alkyne units, the carbopalladation employed here is designed to afford an anti-arrangement of the two new substituents across the emerging double bond. A prerequisite is that the residues next to the alkyne should lack any β-hydrogen atoms. The method paves the way to tri- and tetrasubstituted double-bond systems that have not been accessible by conventional Pd catalysis.

Full text of DOI:10.1002/chem.201502327

DOI: 10.1002/chem.201502327
Communication
&
Organic Synthesis
Intramolecular Formal anti-Carbopalladation/Heck Reaction: Facile
Domino Access to Carbo- and Heterooligocyclic Dienes
[a, b]
[a]
[c]
[a]
Martin Pawliczek,
Bastian Milde, Peter G. Jones, and Daniel B. Werz*
Abstract: An intramolecular domino process consisting of
a formal anti-carbopalladation followed by Heck reaction
is realized. Complex oligo(hetero)cyclic scaffolds are effi-
ciently obtained in one synthetic step from easily obtain-
able enyne precursors. In contrast to common syn-carbo-
palladation reactions of alkyne units, the carbopalladation
employed here is designed to afford an anti-arrangement
of the two new substituents across the emerging double
bond. A prerequisite is that the residues next to the
alkyne should lack any b-hydrogen atoms. The method
paves the way to tri- and tetrasubstituted double-bond
systems that have not been accessible by conventional Pd
catalysis.
Scheme 1. a) Domino sequences consisting of syn-carbopalladation and ter-
minating Heck or Stille reaction, respectively. b) Domino sequence consisting
of formal anti-carbopalladation and terminating Heck reaction.
Domino reactions have become a powerful tool to access mo-
[1]
lecular complexity in a fast and efficient way. Numerous pro-
cesses involving cationic, anionic, radical, pericyclic, photo-
chemical, and transition-metal-catalyzed transformations are
known. Pd-catalyzed domino reactions especially have enjoyed
an astonishing development over the last two decades, lead-
ing to a series of important scaffolds and highly complex mole-
carbon–carbon triple bond from the same side and a further
reaction partner such as the double bond or the stannyl resi-
due is adjacent, a syn-addition to the alkyne results.
Recently, we designed systems that are able to undergo dis-
[1–4]
[5]
cules in just one experimental step.
Besides a combination
tinct formal anti-carbopalladation reactions of alkynes. A pre-
of the Heck reaction with various cross-coupling reactions, car-
bopalladations of alkynes or allenes have been shown to be
promising propagating steps.
requisite is the presence of a residue next to the alkyne that is
[
6]
not capable of performing b-hydride elimination. Additionally,
other reaction partners must not be available in the direct
neighborhood. Mechanistically, by a combination of experi-
ments and quantum chemical calculations, we elucidated the
key step of the formal anti-carbopalladation. It was shown that
the Pd does not activate the p-system in such a way that an
Scheme 1a depicts two examples of a two-step domino pro-
cess. In both cases the carbopalladation follows the oxidative
addition of the catalytically active species in the carbon–halo-
gen bond. In the first case, the cascade is terminated by
a Heck reaction, whereas the second example employs a Stille
cross-coupling. Since the organopalladium species attacks the
[
7]
attack of a nucleophile from the opposite side takes place.
However, after a common syn-attack of the organopalladium
[
8,9]
species, a cis–trans-isomerization
takes place in the coordi-
nation sphere of the Pd since all other energetically more fa-
vored pathways are ruled out. The correct choice of ligand
system is important; bidentate ligands completely shut down
the desired mechanistic pathway. Consistent with this observa-
tion, and in combination with quantum chemical insights, we
postulated a 14 VE Pd species that is able to isomerize the
[
a] M. Pawliczek, B. Milde, Prof. Dr. D. B. Werz
Technische Universität Braunschweig
Institute of Organic Chemistry
Hagenring 30, 38106 Braunschweig (Germany)
E-mail: d.werz@tu-braunschweig.de
[
b] M. Pawliczek
Georg-August-Universität Gçttingen
Institute of Organic and Biomolecular Chemistry
2
double-bond geometry through a h -vinyl palladium transition
[
10]
3
7077 Gçttingen (Germany)
state.
[
c] Prof. Dr. P. G. Jones
In this paper, we merge our design for a formal anti-carbo-
palladation with a terminating Heck reaction in an intramolec-
ular domino sequence (Scheme 1b). From simple, easily acces-
sible enynes, complex oligo(hetero)cyclic scaffolds with a diene
or even a triene moiety are available. Furthermore, we investi-
Technische Universität Braunschweig
Institute of Inorganic and Analytical Chemistry
Hagenring 30, 38106 Braunschweig (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502327.
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Communication
gated the type of residue adjacent to the alkyne that allows
for an anti-carbopalladation.
Enyne 1a was chosen, equipped with an aryl bromide for
oxidative addition as well as a tertiary hydroxy group capping
the alkyne, to serve as model compound to optimize the reac-
tion. Contrary to our intermolecular mechanistic investigations,
we anticipated that aryl iodides would not be necessary for
the intramolecular process. Based on our previous results we
started with a catalytic system consisting of [Pd(PhCN) Cl ] and
2
2
PPh with NEt as the base and 0.55 equivalents of water as ad-
3
3
ditive in DMA (0.025m). After stirring for 16 h at 1008C, full
conversion of the starting material was achieved and the de-
sired oligocyclic domino product 2a was isolated in 68% yield
(
Table 1, entry 1). Afterwards, different ligands were tested,
[
a]
Table 1. Screening of reaction conditions.
Entry
Ligand
PPh
Q-Phos
X-Phos
Solvent
T
Yield [%]
1
2
3
4
5
3
DMA
DMA
DMA
DMA
DMF
DMF
DMF
DMF
DMF
DMF
toluene
100
100
100
100
100
100
100
120
80
68
0
0
Scheme 2. Domino reactions with alkynes capped by tertiary alcohols.
[
[
1
a] Reaction conditions: 1 (100 mmol, 1.00 equiv), [PdCl
tBu PH][BF ] (20 mol%), NEt (5.00 equiv), H O (0.55 equiv), DMF, 1008C,
6 h. [b] 1308C.
2 2
(PhCN) ] (10 mol%),
3
4
3
2
[tBu
[tBu
3
PH][BF
PH][BF
PH][BF
PH][BF
PH][BF
PH][BF
PH][BF
PH][BF
4
]
72
83
74
68
77
69
80
0
3
4
]
[
b]
c]
6
7
8
9
1
[tBu
[tBu
[tBu
[tBu
[tBu
[tBu
3
4
]
]
]
]
]
]
[
3
3
3
3
3
4
4
4
4
4
such as oxygen, sulfur, and nitrogen in the tether, resulting in
yields ranging from 47–75% (2e–h). To achieve full conversion
of the NTs-containing domino precursor 1h, a higher reaction
temperature (1308C) was required. Finally, utilization of a termi-
nal alkene for the final step afforded 2i in 50% yield. The low
yield can be ascribed to a facile double-bond migration of the
exocyclic double bond into the ring system followed by a sub-
sequent ring-opening leading to decomposition.
[
d]
0
100
100
11
[
(
(
a] Reaction conditions: 1a (100 mmol, 1.00 equiv), [PdCl
10 mol%), ligand (20 mol%), NEt (5.00 equiv), H O (0.55 equiv), solvent
4 mL), T, 16 h. [b] DMF (2 mL), [c] DMF (1 mL) [d] no H O added. DMA=
2 2
(PhCN) ]
3
2
2
dimethylacetamide, DMF=dimethylformamide.
In addition, diyne-based domino precursor 3 was prepared.
Instead of the terminating Heck reaction, a reductive oxycarbo-
palladation was anticipated as the final step. The reaction was
successfully conducted. As result, the electron-rich oligocyclic
dienol ether 4 was isolated in 67% yield (Scheme 3).
Because the reaction is not restricted to tertiary alcohols,
a tert-butyl group was applied to mask the alkyne. By employ-
ing this functional group, lower reaction temperatures and
shorter reaction times could be applied to achieve full conver-
sion. In addition, water as the additive had no effect on the
whereby only the sterically encumbered very electron-rich tris-
[11]
(
tert-butyl)phosphine derived from Fu’ s salt
[tBu PH][BF ]
3 4
was able to yield the product in an improved 72% yield (en-
tries 2–4). Furthermore, replacing DMA with DMF increased the
yield to 83% (entry 5). Application of higher concentrations or
different reaction temperatures resulted in lower yields (en-
tries 6–9). Omitting water as the additive reduced the yield
slightly to 80% (entry 10). Finally, apolar toluene was applied
as the solvent; product formation was not observed, underlin-
ing the necessity for polar solvents to achieve the internal cis–
trans-isomerization (entry 11).
With the optimized reaction conditions in hand, we exam-
ined the scope of the reaction (Scheme 2). Additional substitu-
ents on either the initial or the terminating arene unit had no
effect on the outcome of the reaction. Domino products 2b–d
were isolated in 79–85% yields. A tertiary alcohol based on
a cyclopentane was also suitable, yielding the desired product
in 76% yield. Afterwards, we introduced further heteroatoms
Scheme 3. Utilization of diyne 3 for the synthesis of oligocyclic dienol ether
4.
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Scheme 5. Domino reaction with alkynes capped by a TMS group.
Scheme 6. Synthesis of pyridine-based domino products.
(
Scheme 6). To our delight, the intramolecular transformation
Scheme 4. Domino reactions with alkynes capped by tert-butyl groups and
[
13]
ORTEP plot (50% ellipsoid probability) of 6e. [a] Reaction conditions: 5
100 mmol, 1.00 equiv), [PdCl (PhCN) ] (10 mol%), [tBu PH][BF ] (20 mol%),
NEt (5.00 equiv), DMF (4 mL), 808C, 2 h.
proceeded smoothly and the tricyclic domino product 11 was
obtained in 68% yield.
(
2
2
3
4
3
Examining the nature of the employed bromide, we were in-
terested in making use of vinylic bromides. For that purpose,
domino precursors 12a and 12b should serve as model com-
pounds in which the aryl bromide moiety has been exchanged
for a vinylic counterpart (Scheme 7). The reaction proceeded
yields, and was therefore omitted. In all cases with a tert-butyl
group, the domino process proceeded smoothly, forming the
respective products in good yields (Scheme 4). Domino prod-
uct 6a, which is the counterpart of 2a, was obtained in 87%
yield. Further, 6b and 6c, possessing exocyclic 1,1-unsubstitut-
ed double bonds, were isolated in 76 and 81% yields, respec-
tively. The more highly functionalized derivative 6d, containing
a free as well as a TBS-protected alcohol, was obtained in
a yield of 90%, which demonstrates the potential for synthesiz-
ing highly functionalized molecules by this method. Finally, lac-
tone-containing domino products 6e and 6 f were synthesized
in excellent 99 and 94% yield, respectively. The electron-poor
character of the double bond system renders the latter two
compounds more stable than the above-mentioned ones. The
anti-connection of the newly formed double bond in com-
[12,13]
pound 6e was proved by X-ray analysis (Scheme 4).
Scheme 7. Application of vinylic bromides as starting materials.
After successful application of the tert-butyl as an alkyne
cap, we prepared the TMS-masked system 7. Under the reac-
tion conditions for tert-butyl groups, 7 was converted to the
desired domino product in 89% yield (Scheme 5). The attached
TMS group of 8 is rather unstable and can be readily removed;
application of TBAF in THF yielded lactone 9, with a trisubstitut-
ed double bond, in 66% yield. A one-step procedure starting
from domino precursor 7 was also developed, yielding desily-
lated 9 in an improved 72% yield.
In our previous intermolecular studies, the presence of pyr-
idine moieties suppressed the required isomerization process.
To utilize nitrogen-containing heterocycles in the intramolecu-
lar domino process, bromopyridine 10 was examined
smoothly, and the corresponding domino products 13a and
13b were isolated in 75 and 39% yield, respectively. The yield
for compound 13b can be ascribed to the very sensitive
double-bond arrangement across the ring system, which is
generated during the domino process. The shorter tether dem-
onstrates that the formation of five- instead of six-membered
rings is also possible.
[5]
We demonstrated that tertiary alcohols, tert-butyl and TMS-
groups are able to serve as caps for the alkyne moiety. Their
common feature is the absence of any b-hydrogen atoms.
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Scheme 8. Substrates with caps other than tertiary alcohols, tert-butyl
groups or silyl groups, and the corresponding results. Reaction conditions:
1
(
[
4 (100 mmol, 1.00 equiv), [PdCl
20 mol%), NEt (5.00 equiv), DMF (4 mL). [a] 1008C, 16 h. [b] 808C, 12 h.
c] 808C, 1.5 h. [d] 808C, 3 h.
2 2 3 4
(PhCN) ] (10 mol%), [tBu PH][BF ]
3
Scheme 9. Proposed reaction mechanism.
Therefore, we became interested in studying the behavior of
other functional groups lacking b-hydrogen atoms (Scheme 8).
Starting with a terminal alkyne, the reaction led to a complex
product mixture that did not contain the desired compound
al groups, several different alkyne caps, and also vinyl bro-
mides were applied, yielding the corresponding domino prod-
ucts in moderate to excellent yields. Further studies to transfer
the methodology of this domino process to more complex
molecular systems are ongoing and results will be reported in
due course.
15a. The employment of a ketal, on the other hand, was feasi-
ble and the corresponding tricyclic compound 15b was ob-
tained in 62% yield. Further, the transformation with alkynes
capped by another alkyne or divalent sulfur was successful,
yielding 15c and 15d in 35 and 56% yield, respectively. To our
surprise, when esters or phenyl-substituted alkyne systems
were applied, which are known to facilitate isomerization by
Experimental Section
General procedure for the domino reaction
[
9]
A solution of enyne (100 mmol, 1.0 equiv) in DMF (4 mL) was de-
gassed with argon for 20 min. Afterwards, NEt3 (500 mmol,
charge separation, the corresponding domino products 15e
and 15 f were not observed.
5
1
.0 equiv), water (111 mmol, 1.1 equiv), [PdCl (PhCN) ] (10.0 mmol,
2 2
Based on our previous computational and experimental re-
sults, we propose the following mechanistic scenario
0 mol%), and [tBu PH][BF ] (20.0 mmol, 20 mol%) were added and
3
4
the reaction mixture was pre-stirred for 30 min at room tempera-
ture in a sealed flask. Subsequently, the reaction was heated for
16 h at 1008C and cooled back to room temperature. The reaction
[
5]
0
(
Scheme 9). Oxidative addition of Pd forms intermediate A,
which subsequently undergoes carbopalladation of the adja-
II
was diluted with sat. NH Cl solution and extracted with EtOAc,
cent triple bond. Afterwards, the 14 VE Pd -complex B isomer-
4
2
washed with brine, and dried over Na SO . The solvent was re-
2
4
izes by double-bond rotation by an h -vinyl transition state
moved in vacuo and the residue was purified by column chroma-
tography on silica gel.
TS(C) to intermediate D, containing the observed anti-connec-
tion across the resulting double bond. The isomerized double-
bond geometry of D enables a final Heck reaction to take
place and to complete the domino process. As result, product Acknowledgements
0
6
b is released and the Pd catalyst is regenerated for the next
cycle.
In summary, we have developed an intramolecular domino
This research was supported by the German Research Founda-
tion (DFG, Emmy Noether and Heisenberg Fellowships to
D.B.W. and WE2932/7-1) and by the Fonds der Chemischen In-
dustrie (Ph.D. Fellowship to M.P. and Dozentenstipendium to
D.B.W.). We thank A. Reding and S. Mende for preparative as-
sistance.
process containing a formal anti-carbopalladation as key step
for the synthesis of oligo(hetero)cyclic scaffolds. The sequence
is terminated by a Heck reaction. During the transformation
two new carbon–carbon bonds are formed in an anti-fashion
across the generated double bond, associated with isomeriza-
II
tion of an intermediary 14 VE Pd species. A variety of function-
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2
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Keywords: carbopalladation · domino reaction · heterocycles ·
Heck reaction · palladium
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Published online on July 31, 2015
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