Stereochemical and mechanistic investigations of a palladium-catalyzed annulation of secondary alkyl iodides

Article abstract of DOI:10.1002/anie.200603888

(Chemical Equation Presented) Inversion versus retention: A palladium-catalyzed annulation with enantioenriched secondary alkyl iodides gives mechanistic insight into the stereochemistry of this C-H bond functionalization reaction (see scheme) involving a

Full text of DOI:10.1002/anie.200603888

Angewandte
Chemie
DOI: 10.1002/anie.200603888
À
C H Functionalization
Stereochemical and Mechanistic Investigations of a Palladium-
Catalyzed Annulation of Secondary Alkyl Iodides**
Alena Rudolph, Nils Rackelmann, and Mark Lautens*
Transition-metal-catalyzed reactions are widely used as
valuable tools for carbon–carbon bond formation.[1] Whereas
palladium and nickel have classically occupied a central role
tion of secondary alkyl halides prior to the mechanistic
studies. By using racemic alkyl iodides[6] 1–3, the annulation
to form 5- and 6-membered ring systems proceeded in
moderate to good yields (Scheme 1).
À
in the synthesis of Csp2 Csp2 bonds, the use of these transition
metals in coupling reactions of b-hydrogen-containing sub-
strates remains a challenge. b-Hydride elimination and
hydrodehalogenation are significant problems particularly
with secondary alkyl halides and sulfonates, in spite of recent
progress in this area.[2]
We previously reported the synthesis of functionalized
fused aromatic carbo- and heterocycles[3] by using primary
alkyl halides under modified Catellani conditions.[4] A key
extension of our methodology would be the use of secondary
alkyl halides in an intramolecular fashion. Catellani and
Cugini have previously reported a Pd-catalyzed intermolec-
ular cross-coupling reaction with the use of isopropyl iodide,
which proceeded with 31% conversion.[4d] The use of
enantioenriched secondary halides should provide further
insight into the reaction mechanism, as it is not known
whether this reaction proceeds with overall retention or
inversion of stereochemistry. Furthermore there are very few
reports on the stereochemical outcome of reactions that
undergo oxidative addition from a PdII to a PdIV intermedi-
ate,[5] which was suggested as a mechanistic pathway for this
reaction. Herein, we report our findings on the stereochem-
ical outcome of this Pd-catalyzed annulation reaction, which
Scheme 1. Palladium-catalyzed synthesis of fused aromatic bicyclic
systems. Ts=toluene-4-sulfonyl, DME=1,2-dimethoxyethane. [a] Yields
of isolated products. [b] Reaction run with the use of Pd(OAc)2
(20 mol%), PPh3 (44 mol%), norbornene (5 equiv), and Cs2CO3
(3 equiv) in DME (0.1m) for 12 min, at 1808C.
We also examined a route to fused tricyclic ring systems
through a tandem intramolecular ortho alkylation Heck
reaction sequence. Formation of both oxygen- and nitrogen-
containing 6,5,6- and 6,6,6-membered systems (Table 1,
entries 1–4) proceeded in good yield.[7]
Table 1: Palladium-catalyzed synthesis of fused aromatic tricyclic ring
systems.
À
includes a C H functionalization step and oxidative addition
of unactivated enantioenriched secondary alkyl iodides.
Historically, good yields for intermolecular cross-coupling
reactions with secondary alkyl halides were only obtained by
using Ni or Fe complexes.[2d–g,i–k,m–q,u,v] Of these, few examples
employ enantiopure substrates.[2k,o] We needed to develop
suitable conditions for the intramolecular Pd-catalyzed reac-
[*] A. Rudolph, Dr. N. Rackelmann, Prof. Dr. M. Lautens
Davenport Chemistry Laboratories
Department of Chemistry
Entry
Substrate
Product
Ratio
5:1
–
–
–
Yield [%][a]
1[b]
2[b]
3[f]
4[f]
7
8
9
11a + 11b
12a + 12b
13a
78[c]
74[e]
68
University of Toronto
80 St. George Street, Toronto, ON, M5S3H6 (Canada)
Fax: (+1)416-946-8185
[d]
10
14a
62
E-mail: mlautens@chem.utoronto.ca
[**] This work is supported by NSERC (Canada), Merck Frosst (IRC),
and the University of Toronto. A.R. thanks NSERC for financial
support in the form of a postgraduate scholarship. N.R. thanks the
Deutsche Forschungsgemeinschaft (DFG) for support in the form
of a postdoctoral fellowship. We also thank E. N. Jacobsen (Harvard
University) and B. Mariampillai (University of Toronto) for helpful
discussions, Dr. A. Lough for X-ray analysis, Dr. T. Burrow for NMR
assistance, and Dr. A. Young for MS analysis.
[a] Yields of isolated products. [b] Reaction run by using Pd(OAc)2
(15 mol%), PPh3 (33 mol%), norbornene (7 equiv), and Cs2CO3
(5 equiv) in DME (0.03m) for 5 min, under thermal conditions at
1808C. [c] Product obtained in 82% yield, 2:1 mixture of 11a:11b when
reaction was run at 1808C for 7 min in the microwave. [d] Relative ratio
could not be determined as 12b was only observed in trace amounts. See
the Supporting Information. [e] Yield of 12a only. [f] Reaction run by
using Pd(OAc)2 (20 mol%), PPh3 (44 mol%), norbornene (7 equiv), and
Cs2CO3 (3 equiv) in DME (0.03m) for 12 min, under thermal conditions
at 1508C.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
We anticipate that the annulation of secondary alkyl
iodides follows the same reaction mechanism (Scheme 2) as
that proposed for the corresponding reaction of primary alkyl
halides.[3h] The reaction begins with oxidative addition of Pd0
to the aryl iodide bond to give intermediate A. Carbopalla-
dation of norbornene provides B, followed by functionaliza-
À
tion of the C H aryl bond to give palladacycle C. Oxidative
addition of the intramolecular secondary alkyl iodide leads to
PdIV intermediate D. Reductive elimination forms the first C
C bond (E). Extrusion of norbornene (F) followed by a Heck
reaction (G) forms the desired product (H).
À
With a viable route to produce various annulated
products, we prepared enantioenriched substrates to deter-
mine the fate of the stereochemical information during the
reaction. For the annulation of substrates (S)-7 and (R)-1,[8]
the corresponding bicyclic and tricyclic products[9] were
obtained with almost no loss of stereochemical information
(Scheme 3a,b). For the annulation of (R)-3, a decrease in the
ee value for product (R)-6 was observed. To the best of our
knowledge, these are the first examples that successfully
utilize enantioenriched secondary alkyl iodides in a cross-
coupling reaction with Pd as a catalyst.
Scheme 3. Synthesis of enantioenriched bi- and tricyclic products.
Our next goal was to determine whether the reaction
proceeds with overall retention or inversion of configuration.
X-ray structures of (R)-3 (Figure 1a) and (R)-15 (Scheme 4
and Figure 1b)[10] were obtained, which revealed that the
annulation reaction proceeded with overall inversion of
configuration. We believe that this conclusion may be
generalized to both nitrogen- and oxygen-containing systems
(Scheme 3) on the basis of our results in Scheme 3a.[11]
Previous investigations of transmetalation[12] to PdII and
cross-coupling reactions[13] with Pd0/PdII systems have shown
that the stereochemistry (overall inversion or retention) may
depend on the substrate class[12a] and/or the reaction con-
ditions.[12e] With regard to this reaction, if reductive elimi-
nation from the PdIV species of the Pd-catalyzed annulation
proceeds with retention of configuration,[14] then we propose
that the inversion of stereochemistry in this reaction likely
occurs during the oxidative addition[15] of the secondary alkyl
iodide to PdII to form the PdIV intermediate.
In summary, we have shown that secondary alkyl iodides
can be successfully applied to this tandem palladium-cata-
À
lyzed coupling reaction, which proceeds by a C H function-
alization pathway. Tricyclic products can be formed with the
use of a secondary iodide and a Heck acceptor tethered to an
oxygen or nitrogen atom. The reaction can
also be applied to enantioenriched sub-
strates, which gives the corresponding prod-
ucts with minimal loss of stereochemical
information. The first successful application
of enantioenriched secondary iodides to a
palladium-catalyzed process allows the
straightforward synthesis of complex and
enantioenriched fused ring systems. Further-
more, the use of enantioenriched substrates
has given us insight into the mechanism,
which suggests that the reaction proceeds
with overall inversion of configuration via a
PdIV intermediate. Development of this
reaction for the preparation of a broader
range of products is currently underway.
Received: September 21, 2006
Published online: January 15, 2007
À
Keywords: C H activation · cross-coupling ·
palladium · polycyclic heterocycles
.
Scheme 2. Proposed reaction mechanism.
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Scheme 4. Conversion of (R)-6 into (R)-15. DIBAL-H=diisobutylalumi-
num hydride.
[7] The regiochemistry of the double bond isomers was determined
by COSY, HSQC, and 1D ROESY NMR spectroscopy.
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preparation. See the Supporting Information for details.
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