Intramolecular heck reactions of unactivated alkyl halides

Article abstract of DOI:10.1021/ja075245r

A method has been developed for achieving palladium-catalyzed intramolecular Heck reactions of unactivated, β-hydrogen-containing alkyl bromides and chlorides. The data from a stereochemical investigation are consistent with carbon-carbon bond formation via an alkylpalladium, rather than a radical, intermediate. Copyright

Full text of DOI:10.1021/ja075245r

Published on Web 08/24/2007
Intramolecular Heck Reactions of Unactivated Alkyl Halides
Luke Firmansjah and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139
Received July 13, 2007; E-mail: gcf@mit.edu
The palladium-catalyzed Heck reaction of olefins with aryl and
Vinyl halides and sulfonates has been developed into a method of
broad scope that has found application throughout organic chemistry
1
and related disciplines. In contrast, there have been only isolated
reports of corresponding couplings of alkyl electrophiles, in
particular, unactivated substrates that bear â hydrogens.2 It is
worth noting that metals other than palladium can catalyze certain
Heck-like reactions of alkyl halides with olefins; in these examples,
the carbon-carbon bond-forming step generally involves a radical,
-4
5-7
rather than a metal-mediated, process.
An expansion in the scope of palladium-catalyzed Heck couplings
to include alkylations, in addition to arylations and vinylations,
would significantly enhance the utility of this powerful transforma-
tion. Upon examination of the mechanism of the Heck reaction, it
becomes clear that a key challenge in developing an “alkyl-Heck”
coupling is to control the rate of â-hydride elimination relative to
insertion (Figure 1). For the classic Heck reaction of an aryl or
vinyl electrophile (R ) aryl, vinyl), the situation is comparatively
straightforward: facile â-hydride elimination is generally desirable.
Since A is not prone to â-hydride elimination, if B proceeds faster
to C than to D, efficient Heck arylation can be achieved.8
Figure 1. Outline of the catalytic cycle for the Heck reaction.
Table 1. An Alkyl-Heck Reaction of an Unactivated Electrophile:
Influence of Reaction Parameters
In the case of an alkyl-Heck reaction (Figure 1, R ) alkyl), if
â-hydride elimination is extremely facile, then A may not proceed
to B. Thus, for a successful alkyl-Heck coupling, alkylpalladium
species A and B should have opposite reactivity profiles: A should
be prone to insert, rather than â-hydride eliminate, and B should
prefer to â-hydride eliminate, instead of inserting.
Because dictating this pattern of reactivity is likely to be a diffi-
cult challenge, we decided to pursue a more viable initial objective,
namely, the development of an intramolecular alkyl-Heck reaction.
Such a process relies upon A undergoing intramolecular insertion
of a pendant olefin more rapidly than â-hydride elimination, and
then B undergoing â-hydride elimination faster than intermolecular
insertion. In this report, we establish that a palladium/N-heterocyclic
carbene catalyst displays the desired reactivity profile, furnishing
an effective method for achieving alkyl-Heck reactions (eq 1).
entry
variation from the “standard” conditions
yield of Aa
yield of Ba
1
2
3
4
5
6
7
8
9
none
IMes‚HBF
SIPr‚HBF
P(t-Bu) Me, instead of SIMes‚HBF
PCy , instead of SIMes‚HBF /KOt-Bu
80
13
27
43
53
44
<2
<2
37
46
6
5
4
, instead of SIMes‚HBF
, instead of SIMes‚HBF
4
4
4
20
52
23
50
2
<2
8
15
2
4
/KOt-Bu
3
4
Pd (dba) , instead of Pd (MeO-dba)
2
3
2
3
no SIMes‚HBF
no Pd (MeO-dba)
PO , instead of Cs
NMP, instead of CH
4
2
3
K
3
4
2
CO
3
CN
10
3
a
Determined through analysis by GC (average of two experiments).
couplings of aryl electrophiles, the MeO-dba adduct provides a
superior result to dba (entry 6).1
Pd (MeO-dba)
, there is essentially no reaction (entries 7 and 8),13
and the other Brønsted bases and solvents that we have examined
1,12
In the absence of SIMes or
2
3
1
4
furnish a less efficient process (e.g., entries 9 and 10).
With our optimized method, we can generate an array of five-
membered rings via palladium-catalyzed intramolecular alkyl-Heck
reactions of â-hydrogen-containing, unactivated alkyl bromides
(Table 2). Cyclizations of a variety of substrates in which there is
an aromatic group in the homoallylic position proceed smoothly
with comparable efficiency (entries 1-4). A heteroaromatic sub-
stituent is also tolerated (entry 5). Of course, the method is
applicable to compounds that bear groups other than aromatic rings
(entries 6-8). A substrate that is more hindered with respect to
oxidative addition undergoes alkyl-Heck cyclization in fairly good
yield (entry 8), although the reaction is less facile. Finally, indane
derivatives can be accessed through this procedure (entry 9).
We were pleased to determine that Pd/SIMes catalyzes not only
alkyl-Heck reactions of unactivated, â-hydrogen-containing alkyl
On the basis of earlier studies of palladium-catalyzed cross-
couplings of unactivated primary alkyl electrophiles, we focused
9
our catalyst-development efforts on the use of carbene and trialkyl-
phosphine ligands (e.g., Table 1, entries 1-5). In comparison with
the best ligand that we have discovered to date for the alkyl-Heck
reaction (SIMes; entry 1), other carbenes (entries 2 and 3)10 as well
as phosphines (entries 4 and 5) are less effective. The choice of
palladium complex is important: as observed with certain cross-
15
11340
9
J. AM. CHEM. SOC. 2007, 129, 11340-11341
10.1021/ja075245r CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Alkyl-Heck Reactions of Unactivated Alkyl Bromides
a stereochemical investigation are consistent with carbon-carbon
bond formation via an alkylpalladium, rather than a radical,
intermediate. Additional synthetic and mechanistic studies of this
and related processes are underway.
Acknowledgment. Primary funding has been provided by the
NIH (NIGMS, Grant R01-GM62871), and supplementary support
has been furnished by Merck Research Laboratories, Novartis,
Boehringer Ingelheim, and Johnson Matthey. Dr. Jeff Simpson is
acknowledged for assisting with deuterium-NMR studies.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(
1) For a review of the Heck reaction, see: Br a¨ se, S.; de Meijere, A. In Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: New York, 2004; Chapter 5.
(
2) For examples of palladium-catalyzed Heck reactions of actiVated alkyl
halides that lack â hydrogens, see: (a) benzylic electrophiles: Heck, R.
F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320-2322. Wu, G.-z.;
Lamaty, F.; Negishi, E.-i. J. Org. Chem. 1989, 54, 2507-2508. Pan, Y.;
Zhang, Z.; Hu, H. Synth. Commun. 1992, 22, 2019-2029. Pan, Y.; Zhang,
Z.; Hu, H. Synthesis 1995, 245-247. Kumar, P. Org. Prep. Proc. Int.
1997, 29, 477-480. Wang, L.; Pan, Y.; Jiang, X.; Hu, H. Tetrahedron
Lett. 2000, 41, 725-727. Higuchi, K.; Sawada, K.; Nambu, H.; Shogaki,
T.; Kita, Y. Org. Lett. 2003, 5, 3703-3704. Narahashi, H.; Yamamoto,
A.; Shimizu, I. Chem. Lett. 2004, 348-349. (b) R-halocarbonyls: Mori,
M.; Oda, I.; Ban, Y. Tetrahedron Lett. 1982, 23, 5315-5318. Glorius, F.
Tetrahedron Lett. 2003, 44, 5751-5754.
a
Isolated yield (average of two experiments). b Base used: K3PO4. Purity
of product: 95%. The value in parentheses is the yield according to GC
analysis (the product is slightly volatile).
Table 3. Alkyl-Heck Reactions of Unactivated Alkyl Chlorides
(3) For leading references to related reactions of allylic electrophiles, see:
Oppolzer, W. Angew. Chem., Int. Ed. 1989, 28, 38-52.
(
4) For examples of palladium-catalyzed Heck reactions of an unactivated
alkyl halide that is not prone to â-hydride elimination (1-bromoadaman-
tane), see: Br a¨ se, S.; Waegell, B.; de Meijere, A. Synthesis 1998, 148-
152.
(
5) Cobalt-catalyzed coupling of alkyl halides with olefins (radical path-
way): (a) Branchaud, B. P.; Detlefsen, W. D. Tetrahedron Lett. 1991,
3
2, 6273-6276. (b) Affo, W.; Ohmiya, H.; Fujioka, T.; Ikeda, Y.;
Nakamura, T.; Yorimitsu, H.; Oshima, K.; Imamura, Y.; Mizuta, T.;
Miyoshi, K. J. Am. Chem. Soc. 2006, 128, 8068-8077.
(
6) Titanocene-catalyzed coupling of alkyl halides with styrenes (radical
pathway): Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663-
672.
(
7) Nickel-catalyzed coupling of alkyl bromides with styrene (no mechanistic
experiments): Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya,
I. P. J. Organomet. Chem. 1988, 344, 253-259.
8) For the sake of simplicity, this discussion is based on irreversible
elementary steps.
(
a
Isolated yield (average of two experiments).
(
9) For reviews of cross-coupling reactions of alkyl electrophiles, see: (a)
Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-688. (b)
Netherton, M. R.; Fu, G. C. Topics in Organometallic Chemistry:
Palladium in Organic Synthesis; Tsuji, J., Ed.; Springer: New York, 2005.
bromides, but also of the corresponding chlorides (Table 3). Perhaps
not surprisingly, a higher reaction temperature is necessary.16
(
(
(
(
(
10) For a recent review of palladium/carbene-catalyzed reactions, see: Diez-
As indicated above, there have been previous reports of alkyl-
Heck-like processes catalyzed by metals other than palladium. In
these examples, it has generally been postulated that the carbon-
carbon bond-forming step involves a radical, not an alkylmetal,
intermediate,5 which renders these processes mechanistically
distinct from a true alkyl-Heck reaction. To determine if Pd/SIMes-
catalyzed cyclizations also follow a radical pathway, we examined
the reaction of the deuterium-labeled substrate illustrated in eq 2.
In the presence of Pd/SIMes, a single diastereomer is produced,
the stereochemistry of which is consistent with an S
for oxidative addition.17 Thus, our palladium-catalyzed alkyl-Heck
reactions appear to proceed via a pathway distinct from related,
radical-mediated transformations catalyzed by other metals.
Gonzalez, S.; Nolan, S. P. Topics in Organomet. Chem. 2007, 21, 47-
82.
11) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; McGlacken, G. P.; Weissburger,
F.; de Vries, A. H. M.; Schmieder-van de Vondervoort, L. Chem. Eur. J.
2006, 12, 8750-8761.
12) For an overview of the role of dba in palladium-catalyzed coupling
reactions, see: Amatore, C.; Jutand, A. Coord. Chem. ReV. 1998, 178,
511-528.
-7
13) For a transition metal-free, N-heterocyclic carbene-catalyzed Heck-like
reaction of alkyl halides and tosylates, see: Fischer, C.; Smith, S. W.;
Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 1472-1473.
14) For entries 2, 3, 7, 8, 9, and 11 of Table 1, unreacted starting material
accounts for the majority of the mass balance.
N
2 mechanism
(15) Under our standard conditions, the following alkyl-Heck cyclizations were
not successful (<30% yield): (1) reaction of a disubstituted olefin; (2)
formation of a six-membered ring; and, (3) cyclization of an unactivated
secondary alkyl bromide.
16) Under the conditions described for alkyl-Heck cyclizations of alkyl
bromides (Table 2), the reaction of an alkyl chloride (entry 1 of Table 3)
proceeds in <5% yield.
(
(
17) (a) For a discussion of the mechanism of oxidative addition of alkyl halides
to metals such as palladium, see: Stille, J. K.; Lau, K. S. Y. Acc. Chem.
Res. 1977, 10, 434-442. (b) For a more recent example of a palladium-
catalyzed reaction of a primary alkyl iodide that is believed to proceed
through a radical pathway, see: Stadtm u¨ ller, H.; Vaupel, A.; Tucker, C.
E.; St u¨ demann, T.; Knochel, P. Chem. Eur. J. 1996, 2, 1204-1220. (c)
For another example of oxidative addition of an alkyl electrophile to a
palladium/L complex (L ) a bulky, electron-rich ligand (P(t-Bu
2
)Me)))
In summary, we have developed a method for achieving
palladium-catalyzed intramolecular Heck reactions of unactivated,
â-hydrogen-containing alkyl bromides and chlorides. The data from
N
via an S 2 pathway, see: Netherton, M. R.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 3910-3912.
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