Palladium-catalyzed carbohalogenation: Bromide to iodide exchange and domino processes

Article abstract of DOI:10.1021/ja206099t

Aryl bromides have been used to prepare a variety of nitrogen- and oxygen-containing heterocycles featuring new carbon-carbon and carbon-iodine bonds. This palladium-catalyzed carbohalogenation requires potassium iodide for the reaction to proceed in high yields. Additionally, the first examples of domino carbohalogenation reactions have been demonstrated using both aryl iodide and aryl bromide starting materials. Complex products with multiple rings and stereogenic centers are generated in excellent yields with moderate to excellent diastereoselectivities.

Full text of DOI:10.1021/ja206099t

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pubs.acs.org/JACS
Palladium-Catalyzed Carbohalogenation: Bromide to Iodide
Exchange and Domino Processes
Stephen G. Newman, Jennifer K. Howell, Norman Nicolaus, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario,
Canada M5S 3H6
S Supporting Information
b
Scheme 1. Studies of Palladium-Catalyzed
Carbohalogenation and Halogen Exchange
ABSTRACT: Aryl bromides have been used to prepare a
variety of nitrogen- and oxygen-containing heterocycles
featuring new carbonÀcarbon and carbonÀiodine bonds.
This palladium-catalyzed carbohalogenation requires potas-
sium iodide for the reaction to proceed in high yields.
Additionally, the first examples of domino carbohalogena-
tion reactions have been demonstrated using both aryl
iodide and aryl bromide starting materials. Complex pro-
ducts with multiple rings and stereogenic centers are
generated in excellent yields with moderate to excellent
diastereoselectivities.
alladium-catalyzed coupling reactions are among the most
P
important methods available for forming carbonÀcarbon
bonds.1 Well-established transformations such as the SuzukiÀ
Miyaura and MizorokiÀHeck reactions remain of great impor-
tance, with recent advances in palladium catalysis focusing on
improving efficiency, reducing waste, and introducing new modes of
reactivity. For example, direct arylation reactions have become a
remarkable method for CÀC bond formation by allowing the use
of unfunctionalized substrates.2 Toward the goal of developing
more efficient palladium-catalyzed carbonÀcarbon bond-form-
ing reactions, we recently demonstrated that reversible oxidative
addition into carbonÀhalogen bonds can lead to selective coupl-
ing of polyhalogenated substrates,3 and we developed a carboio-
dination reaction of aryl iodides (Scheme 1).4 Tong and co-workers
have shown that vinyl iodides can also undergo carbohalogena-
tion reactions, with catalyst loading, ligand, and reaction tempera-
ture being noteworthy differences between these complementary
procedures.5 These reactions form a new carbonÀcarbon bond
and a new carbonÀiodine bond, generating no stoichiometric
waste in the process. The reaction is proposed to occur through
oxidative addition of the aryl iodide to Pd(0), carbopalladation of
the alkene, and carbonÀhalogen reductive elimination. Reduc-
tive elimination of carbonÀhalogen bonds from Pd(II) has only
recently been recognized as a catalytically viable elementary step
in catalysis and is opening up many new pathways in palladium-
catalyzed transformations.6,7
developing domino reactions with polyunsaturated substrates.
Herein we report our findings on how aryl bromides can be used
in the carboiodination reaction and how polyunsaturated alkenes
can be used to form polycyclic alkyl iodides containing multiple
stereogenic centers. Finally, these two concepts have been united
to allow domino reactions to occur starting from aryl bromides.
In our initial report on carbohalogenation, only aryl iodide
starting materials were effective substrates. Aryl iodides are the
most reactive of the aryl halides toward oxidative addition9 and
thus are very useful starting materials. Unfortunately, they are the
least desirable from the standpoint of cost and availability. Thus,
intense effort has been devoted to improving the scope of these
coupling reactions, and a wide range of halides and pseudohalides
can now be used.10
To increase the usefulness of our methodology, we explored
carbohalogenation using aryl bromides. Despite screening a
range of conditions and ligands, we could not obtain synthetically
useful quantities of carbobromination products. Given the pre-
cedent that similar aryl bromides react with a wide range of Pd(0)
catalysts,11 we hypothesized that the oxidative addition and
carbopalladation steps of the carbohalogenation were occurring
but that the novel alkyl halide reductive elimination may be less
To further the utility of the carbohalogenation reaction, we
explored two new directions. Inspired by the work of Buchwald
and co-workers on aromatic halogen exchange reactions,6e,8
we sought relief from the constraint of using more expensive aryl
iodide starting materials by pursuing the reactivity of aryl
bromides in the presence of iodide sources. Second, we were
interested in increasing the complexity of the products by
Received: July 1, 2011
Published: September 06, 2011
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2011 American Chemical Society
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Scheme 2. Optimization of the Bromide to Iodide Exchange
Table 1. Scope of Palladium-Catalyzed Halogen-Exchange
Carboiodinationa
efficient with bromides than it is with iodides. Buchwald and co-
workers previously showed that aromatic halogen and pseudo-
halogen exchange can occur through the use of copper8 and
palladium6e catalysis. We hypothesized that the addition of a
stoichiometric amount of iodide may displace the bromide and
allow reductive elimination and catalyst turnover to take place
(Scheme 2). Indeed, upon treatment of aryl bromide 1a with
12
catalytic Pd(Q-Phos)2 and 3 equiv of lithium iodide, alkyl
iodide 2a was formed in 28% yield. Different iodide sources were
tested, and KI was found to be superior at facilitating this tran-
sformation.13 Interestingly, the addition of crown ether to increase
the nucleophilicity of the iodide or the use of soluble TBAI com-
pletely inhibited the reaction, suggesting that the concentration
of iodide in solution is an important variable.
Ultimately, running the reaction under higher dilution with 2
equiv of potassium iodide allowed us to isolate aryl iodide 2a in
95% yield. Screening of other solvents, catalysts, and tempera-
tures did not lead to improved reactivity. With these optimized
conditions, the scope of the bromide to iodide exchange was
further explored (Table 1) by preparing a number of useful func-
tionalized dihydrobenzofurans (entries 1À5) and indolines
(entries 6À8) and an isochroman (entry 9).14
Concurrent with the development of our halogen exchange
process, we sought to use polyunsaturated aryl iodides to form
complex polycyclic products containing multiple stereogenic cen-
ters. Transition-metal-catalyzed domino reactions have found im-
mense use in the synthesis of polycyclic carbo- and heterocycles.15
Palladium-catalyzed “zipper”-type transformations, which involve
oxidative addition, multiple carbopalladations, and a terminating
event, are particularly effective at constructing complex ring systems
from simple starting materials.16 The extension of our methodology
to domino substrates was nontrivial, as carbopalladation and reduc-
tive elimination are competing intramolecular processes that could
lead to monocyclization as well as domino cyclization products.
We chose as our test substrate amide 3, which upon cyclization
could provide either monocyclization product 4 or domino carbo-
halogenation product 5 (Scheme 3). Utilizing our typical reaction
conditions, we observed the domino cyclization product in 91%
yield as a 5:1 mixture of diastereomers, and no monocyclization
product was observed. The stereochemistry of the major product
was confirmed to be 5a by single X-ray crystallography. A variety of
other ligands were screened, but none were found to be more
effective than Q-Phos. The reaction conditions developed by Tong
and co-workers5 were also tried, but only trace amounts of the
domino carboiodination product were detected.17
a Reaction conditions: Substrate 1 (0.1 mmol), KI (0.2 mmol),
Pd(Q-Phos)2 (5 or 7.5 mol %), 0.05 M in toluene, 100 °C for 16 h.
in 68% yield as a single diastereomer, the relative stereochemistry
was established by nuclear Overhauser effect (NOE) analysis.
Next, in an attempt to form spirocyclic products, compound 8
was employed in the cyclization, providing 9 in 96% yield and 3:1
dr; again, the stereochemistry was established by NOE analysis.
The phenolic backbone was changed to quinoline 10, which
provided spirocycle 11 in 90% yield and 2:1 dr, and the
stereochemistry was confirmed by single-crystal X-ray analysis.
The preparation of 11 also demonstrates an expansion in
functional group tolerance, being the first example of an
To evaluate the domino carbohalogenation reaction further,
diene 6 was subjected to the reaction conditions (Scheme 4), and
[6.5.0] bicycle 7 containing three stereogenic centers was formed
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Scheme 3. Domino Synthesis of Polycyclic Alkyl Iodides
Scheme 6. Domino Cyclization Using an Aryl Bromide
Scheme 7. Preliminary Enantioselective Results
Scheme 4. Complex Molecule Synthesis via
Carbohalogenation
lacks the ThorpeÀIngold effect found in 8, was subjected to
the reaction conditions and provided monocyclized product
14 in 60% yield (Scheme 5). No evidence of domino cycliza-
tion arising from carbopalladation of intermediate 13 was
observed. While further studies are necessary to make defini-
tive conclusions about the rates of cyclization and reductive
elimination, this experiment gives significant insight into the
relative rates and practical information on potential synthetic
applications of our methodology.
These two processes could ultimately be combined in an
efficient halogen-exchange domino reaction. Substrate 15, the
bromide analogue of 3, was prepared (Scheme 6). Utilizing our
standard halogen exchange conditions, we observed cyclization
to 5 in 89% yield and 3:1 dr.18
Lastly, in the interest of developing an enantioselective variant
of this process, we explored a variety of chiral ligands.
Preliminary results using the ligands Josiphos and Walphos
were promising (Scheme 7). Cyclized iodide 2a could be
obtained in up 14% yield and 94% ee using Josiphos. Domino
product 5a could also be obtained in 65% yield, 2:1 dr, and
40% ee using Walphos. Further studies into this enantiose-
lective process are underway.
Scheme 5. Interrupted Domino Reaction
In conclusion, we have demonstrated the first example of
cyclization of aryl bromides in the presence of an iodide source to
generate alkyl iodide products in excellent yields. In addition,
polyunsaturated aryl iodide substrates are amenable to dom-
ino carbohalogenation reactions yielding complex bicyclic
alkyl iodides containing multiple stereogenic centers in high
yields with good diastereoselectivities. These concepts can be
merged to allow polyunsaturated aryl bromide substrates to
participate in domino chemistry, generating bicyclic alkyl
iodide products. Finally, preliminary studies of asymmetric
carboiodination have given promising results. These modifi-
cations significantly broaden the range of substrates that can
be utilized for carbohalogenation.
aromatic nitrogen-containing heterocycle undergoing cycliza-
tion. In substrates 3, 6, 8, and 10, only the domino cyclization
products were ever observed.
We hypothesized that if carbopalladation of the monocyclized
intermediate were slowed, the reductive elimination to the
monounsaturated product could be observed. Ether 12, which
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’ ASSOCIATED CONTENT
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S
Supporting Information. Experimental procedures,
b
spectral data for all new compounds, and crystallographic data
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
(13) Aryl chlorides gave much lower conversions under these
reaction conditions. Aryl triflates gave no conversion.
Corresponding Author
mlautens@chem.utoronto.ca
(14) Substitution of the iodide using the nucleophilic species
cyanide, thiophenolate, azide, and water was surprisingly efficient. See
the Supporting Information for further details.
’ ACKNOWLEDGMENT
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the University of Toronto for
financial support. Merck-Frosst Canada is thanked for an In-
dustrial Research Chair. S.G.N. and J.K.H. thank NSERC for
postgraduate scholarships (CGS-D and CGS-M). N.N. thanks
the German Academic Exchange Service (DAAD) for postdoc-
toral funding. Margot Lautens isthanked for aiding inthe synthesis
of starting materials. We thank Johnson Matthey Catalysis and
Chiral Technologies for donating palladium catalysts, including
Pd(Q-Phos)2, Solvias AG for donating phosphine ligands, and
Alan J. Lough (Chemistry Department, University of Toronto) for
obtaining the crystal structures of 5a and 11.
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(17) For further details on ligand screens, see the Supporting
Information.
(18) Subjection of 3 to cyclization in the presence of KI at 0.05 M in
toluene also gave 5 in 3:1 dr.
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