Allylic C-H alkylation of unactivated α-olefins: Serial ligand catalysis resumed

Article abstract of DOI:10.1002/anie.201101654

A delicate interplay of several kinetically labile ligands is required for reactions that proceed through serial ligand catalysis mechanisms. An investigation of the disruption of this balance has enabled the development of a method for the intermolecular

Full text of DOI:10.1002/anie.201101654

Communications
DOI: 10.1002/anie.201101654
ꢀ
C H Alkylation
ꢀ
Allylic C H Alkylation of Unactivated a-Olefins: Serial Ligand
Catalysis Resumed**
Andrew J. Young and M. Christina White*
ꢀ
The palladium(0)-catalyzed alkylation reaction of allylic
oxygenates has found extensive use in organic synthesis.[1]
Recent efforts, however, have focused on the development of
a quinone. In the previously reported C H alkylation of
allylarenes we found that the complex formed by Pd(OAc)2
and DMSO was sufficiently active to cleave the doubly
[11]
ꢀ
ꢀ
catalytic methods to replace allylic C H bonds directly with
activated allylic/benzylic C H bond
in the absence of
bis(sulfoxide) ligands, thus obviating the requirement for a
[2]
ꢀ
ꢀ
C C bonds. The selective alkylation of normally inert C H
bonds presents exciting opportunities for the development of
novel methods and streamlined syntheses of complex mole-
SLC mechanism.[2a]
In support of the hypothesis that unactivated a-olefins
may be alkylated by SLC, stoichiometric studies showed that
allylic C H cleavage of these substrates was effected by
palladium(II)/phenyl bis(sulfoxide) catalyst 1 to afford p-
allylPd, trapped as chloride dimer 7, in good yields (78%,
Scheme 1). Significantly, although benzoylnitromethane
cules.[3] Despite significant advances in C H alkylation, to
date no method has been reported for the intermolecular
ꢀ
ꢀ
ꢀ
allylic C H alkylation of unactivated a-olefins.
ꢀ
Intermolecular palladium(II)-catalyzed allylic C H alky-
lation reactions using our Pd(OAc)2/bis(sulfoxide) catalysts 1
and 2[4] have previously been reported by our research group
and others.[2a,b] Despite the use of various reaction conditions
(DMSO versus no DMSO) and nucleophiles (methyl nitro-
acetate versus benzoylacetone 13) it was observed that both
intermolecular reactions had substrate scopes limited to
activated, allylarene structures.[5] We were intrigued by the
mechanistic underpinnings of this deficiency, particularly in
light of the broad a-olefin scope demonstrated for intermo-
ꢀ
lecular and intramolecular allylic C H esterification and
amination reactions catalyzed by 1.[6,7] Herein we report a
mechanistic study that points to competitive ligand binding as
the underlying cause for the limited substrate scope observed.
Significantly, this mechanistic insight has led to the develop-
ꢀ
ment of the first intermolecular allylic C H alkylation
reaction of unactivated a-olefins.
ꢀ
Scheme 1. Stoichiometric allylic C H alkylation. L/B=linear/branched
product ratio.
ꢀ
We postulated that the allylic C H alkylation of unac-
tivated a-olefins may be achieved by a serial ligand catalysis[8]
mechanism (SLC).[9] Under this scenario, multiple kinetically
labile ligands with different electronic properties reversibly
coordinate to the metal center and mediate individual steps of
the cycle.[10] Specifically, a SLC mechanism for palladium-
ꢀ
nucleophile 9 was present during this C H cleavage step, no
functionalization was observed in the absence of DMSO.
Functionalization of p-allylPd 8 proceeded smoothly in the
presence of a superstoichiometric amount of DMSO to yield
allylic alkylation product 11 (71%, Scheme 1).[12] However,
the efficiency of the stoichiometric reactions that comprise
the proposed catalytic cycle significantly contrasted with the
result of the catalytic reaction. Under optimized conditions
where both phenyl bis(sulfoxide) and DMSO ligands were
present, the product could only be obtained in 25% yield,
leaving substrate, nucleophile, and quinone (Table 1, entry 2).
A more detailed analysis of the kinetic profile of the reaction
showed that catalyst 1 lost nearly all its activity between 12
and 24 h (Figure 1, red square). Collectively, these results
imply that the catalyst becomes prematurely deactivated.[13]
We hypothesized that under a SLC reaction mechanism,
an overly competitive ligand may disrupt the ligand-exchange
processes necessary for efficient catalysis with challenging
unactivated a-olefin substrates. Specifically, DMSO, the
ligand required for functionalization, might be interfering at
high concentrations with reassociation of the bis(sulfoxide)
ꢀ
catalyzed allylic C H alkylation may proceed as follows:
1) catalytic palladium(II)/bis(sulfoxide)-promoted C H
cleavage to furnish a p-allylPd intermediate, 2) stoichiometric
DMSO-promoted functionalization through ionization of the
p-allylPd intermediate, and 3) re-oxidation of Pd0 to PdII with
ꢀ
[*] A. J. Young, Prof. M. C. White
Department of Chemistry, Roger Adams Laboratory
University of Illinois, Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
E-mail: white@scs.illinois.edu
Homepage: http://www.scs.illinois.edu/white
[**] M.C.W. thanks the NSF (CAREER CHE-0548173) for financial
support and Amgen for generous gifts. We thank Sigma–Aldrich for
a gift of catalyst 1. A.J.Y. gratefully acknowledges an award from
Sigma–Aldrich. G. T. Rice confirmed entry 5, Table 2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101654.
6824
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Angew. Chem. Int. Ed. 2011, 50, 6824 –6827

ꢀ
Table 1: Effect of additives on the allylic C H alkylation reaction.
Entry[a] Catalyst
Additive
–
Yield (L+B) [%][b] L/B[b]
ꢀ
Scheme 2. Effect of additives on the allylic C H esterification reaction.
BQ=benzoquinone.
1
2
3
4
5
6
7
8
9
10
R=Ph 1
1
1
R=Bn 2
2
2
Pd(OAc)2 DMSO (30 vol%)
R=nPr 3
R=Cy 4
<5
–
DMSO (30 vol%)[c] 25
12:1
–
13 (1 equiv)
–
DMSO (30 vol%)
13 (1 equiv)
<5
be stronger s-donor ligands than aryl bis(sulfoxides). We
reasoned that alkyl bis(sulfoxide) ligands may be better able
to compete with high concentrations of DMSO for binding to
the palladium center. This strategy was inspired by the
observation that the sluggish reaction of (phenylsulfonyl)ni-
tromethane nucleophile with allylbenzene required the use of
the Pd(OAc)2/benzyl bis(sulfoxide) catalyst 2 to reach full
conversion,[2a] which implies that 2 remained active in solution
for a longer period of time than 1. We were gratified to find
that alkyl ligands did in fact generate more active catalysts,
thereby providing conditions for the first intermolecular
alkylation of unactivated a-olefins (Table 1, entries 5, 8–10).
While catalyst activity is influenced by steric factors (R = tBu;
Table 1, entry 10), it is clear that the electronic effect of
replacing aryl with alkyl substituents is primarily responsible
for the improved reactivity (compare R = Ph, R = Cy,
entries 2 and 9). Notably, catalyst 2 was also relatively
insensitive to DMSO in the allylic esterification reaction
(see the Supporting Information).
<5
59
<5
6
–
12:1
–
–
DMSO (30 vol%)
DMSO (30 vol%)
62
57
40
11:1
12:1
10:1
R=tBu 5 DMSO (30 vol%)
[a] 6 (1 equiv), 9 (4 equiv), catalyst (0.10 equiv), 2,6-dimethylbenzoqui-
none (1.1 equiv), 1,2-dichloroethane (0.67m), 458C, 72 h. [b] Deter-
mined by 1H NMR analysis of the crude product. [c] 30 vol%=6.3 equiv.
B=branched, L=linear, Bn=benzyl, Cy=cyclohexyl.
We endeavored to further elucidate the interplay between
the two sulfoxide ligands.[14] Consistent with the hypothesis
ꢀ
that allylic C H alkylation of unactivated substrates proceeds
through a SLC mechanism, the omission of either sulfoxide
ligand dramatically reduces the reactivity (no DMSO, 59!
< 5%; no bis(sulfoxide), 59!6%; Table 1, entries 4 and 7).
Stoichiometric studies demonstrated that catalyst 1 had rates
Figure 1. Comparison of the allylic alkylation reaction catalyzed by 1
(red square) or 2 (blue diamond), and DMSO.
ꢀ
comparable to or faster than 2 for the C H cleavage and
functionalization steps (see the Supporting Information).
However, in contrast to 1, catalyst 2 is active in solution for an
extended period of time (Figure 1, blue diamond). These
results are consistent with our hypothesis of gradual catalyst
deactivation in the presence of DMSO as a result of
competitive ligand binding effects, with 2 demonstrating
better stability to DMSO than 1.
Having developed conditions suitable for the allylic
alkylation of unactivated a-olefins, we proceeded to examine
the substrate scope of the method. In all cases the reaction
proceeds with high regioselectivity and excellent E/Z selec-
tivity (> 20:1). The alkylation is tolerant of a variety of
functionality at the homoallylic position, including carbon,
oxygen, and nitrogen (Table 2, entries 2, 3, and 5–8). Under
these reaction conditions, proximal stereogenic centers are
not racemized. Similarly, a potentially epimerizable a-car-
bonyl stereocenter retains its configuration, thus illustrating
how this method is orthogonal to traditional carbanion-based
ligand (present at only 10 mol%) with palladium to form
ꢀ
complex 1, which is needed for C H cleavage. In the case of a
ꢀ
previously reported allylic C H alkylation in which no
DMSO was used,[2b] analogous inhibition may have resulted
from the use of stoichiometric quantities of benzoylacetone
nucleophile 13, a well-known ligand for palladium. Under
these conditions, unactivated a-olefins were reported to
afford Wacker products;[2b] this reactivity is characteristic of
Pd(OAc)2 in the absence of a bis(sulfoxide) ligand.[4]
To investigate the proposed competitive inhibition of 1 by
DMSO and benzoylacetone 13 during SLC we evaluated the
ꢀ
ability of these ligands to disrupt the allylic C H esterification
reaction. This transformation is known to proceed through a
SLC mechanism wherein palladium(II)/bis(sulfoxide) 1 medi-
ꢀ
ates allylic C H cleavage, and the benzoquinone ligand
[8]
ꢀ
promotes C O bond formation. Consistent with these
ligands being able to disrupt a SLC catalytic cycle, the
ꢀ
addition of just one equivalent of DMSO or 13 to the allylic
C C bond-forming reactions (Table 2, entry 4). A trisubsti-
ꢀ
C H esterification results in drastically reduced reactivity
tuted olefin is tolerated under the reaction conditions, thus
demonstrating the chemoselectivity of the catalyst for termi-
nal olefins (Table 2, entry 3). Notably, even an unprotected
secondary alcohol is stable to the oxidative conditions
(DMSO, 79!21%; 13, 79!6%; Scheme 2).
To address the problem of competitive ligand binding
effects we investigated alkyl bis(sulfoxide) ligands that would
Angew. Chem. Int. Ed. 2011, 50, 6824 –6827
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6825

Communications
ꢀ
Table 2: Scope of the allylic C H alkylation reaction.
entire subunit, we sought to demonstrate how the motif could
be elaborated orthogonally by selectively excising each of the
electron-withdrawing moieties. We discovered that the ben-
zoyl group may be cleaved under very mild conditions to
furnish homoallylic nitroalkane 14 in excellent yield [Eq. (1)].
Alternatively, the nitro group can be removed by a radical
Bu3SnH/AIBN (AIBN = 2,2’-azobisisobutyronitrile) reaction
to provide g,d-unsaturated ketone 16 [Eq. (2)].[18]
Entry
Major product
L/B[b]
Yield L [%][a]
unactivated olefins
1
12:1
56
2
>20:1
>20:1
>20:1
61
3
49[c]
56[c]
4[d]
5[d]
>20:1
63[c]
6
7
>20:1
>20:1
58[c]
53[c]
In summary, this study underscores the delicate balance of
ligand-exchange processes required to realize a SLC mech-
anism, and explores the consequences of competitive ligand
8
>20:1
66[c]
ꢀ
binding. By identifying a C H cleavage ligand that is better
able to compete with the functionalization ligand, we have
activated olefins
ꢀ
developed the first intermolecular allylic C H alkylation
9
10
R=H
Me
11:1
>20:1
73
54
reaction that encompasses unactivated as well as activated a-
olefin substrates. With the further development of general
ꢀ
and selective reactions, we anticipate that C H functionali-
zation will play an increasingly important role in the future of
organic synthesis.
11
12
5:1
63
60
>20:1
Experimental Section
[a] Olefin (1 equiv), 9 (4 equiv), 2 (0.10 equiv), 2,6-dimethylbenzoqui-
none (1.1 equiv), 1,2-bis(benzylsulfinyl)ethane (0.05 equiv), 1,2-
dichloroethane/DMSO (7:3, 0.67m), 458C, 72 h. Average of 2 runs.
Product isolated as a single stereo- and constitutional isomer. E/Z>
20:1. [b] Determined by 1H NMR spectroscopic analysis of the crude
product. [c] d.r.=1:1. [d] Dioxane/DMSO (7:3, 0.67m). Boc=tert-
butoxycarbonyl, Ts=4-toluenesulfonyl.
General procedure for the allylic alkylation (Table 2): A one dram
vial
bis(benzylsulfinyl)ethane](OAc)2 (2; 0.10 equiv, 0.030 mmol,
15.9 mg), 2,6-dimethylbenzoquinone (1.1 equiv, 0.33 mmol,
(4 mL,
borosilicate)
was
charged
with
Pd[1,2-
44.9 mg), benzoylnitromethane (9; 4.0 equiv, 1.20 mmol, 198 mg),
and 1,2-bis(benzylsulfinyl)ethane (0.05 equiv, 0.015 mmol, 4.6 mg).
The olefin (1 equiv, 0.30 mmol) was weighed out in a = dram vial,
1
2
dissolved in 1,2-dichloroethane (0.315 mL), and transferred to the
reaction vial. Dimethylsulfoxide (0.135 mL) and a teflon stir bar were
added sequentially to the reaction vial. No precautions were taken to
exclude air or moisture. The reaction vial was capped and stirred at
458C for 72 h. The vial was cooled to room temperature, and the
reaction mixture was diluted with saturated aqueous NH4Cl (40 mL)
and extracted with ethyl acetate (3 ꢀ 30 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated in vacuo.
Purification by flash chromatography (SiO2, EtOAc/hexanes mix-
tures) provided the pure linear product. In cases where branched
product was observed, it could be readily separated and generally
possessed a higher Rf value than linear product.
ꢀ
(Table 2, entry 6). Strategically, the C H alkylation discon-
nection provides facile entry to products that are often
difficult to access by conventional means (Table 2, entries 5
and 8).[15] Whereas conventional syntheses require tedious
ꢀ
manipulation of oxidized functionality, C H alkylation uses
inert a-olefins which may be installed at any stage by using
versatile, stereoselective allylation methods.[16]
ꢀ
The C H alkylation reaction conditions are also suitable
for allylbenzene substrates and other classes of activated
substrates such as amides and enols, thus providing a general
reaction protocol that encompasses both activated and
unactivated a-olefin substrates (Table 2, entries 9–12). The
Received: March 7, 2011
Published online: June 7, 2011
ꢀ
alkylation of 1-methylallylbenzene is a unique example of C
H activation of a g-branched olefin (Table 2, entry 10).
The a-nitro ketone subunit of the products is a versatile
synthetic handle for which a variety of methods have been
described.[17] As a complement to transformations on the
ꢀ
Keywords: allylic alkylation · C H activation · ligand effects ·
palladium catalysis · sulfoxide ligands
.
6826 www.angewandte.org
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Angew. Chem. Int. Ed. 2011, 50, 6824 –6827

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ꢀ
[9] For discussions of different strategies to promote allylic C H
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[12] Catalytic kinetic studies indicate that reoxidation of Pd0 is not
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ꢀ
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ꢀ
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[14] Palladium/bis(sulfoxide) binding could not be observed directly
by IR, 1H NMR, or UV/Vis spectroscopy. See the Supporting
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[15] For a conventional synthesis of an analogue to Table 2, entry 5,
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ꢀ
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[5] Alkyl-substituted a-olefins were nearly inert under these con-
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ꢀ
[6] Intermolecular C H esterifications of unactivated a-olefins with
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ꢀ
intermolecular C H aminations of unactivated a-olefins with
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