Pd(II)/Bronsted acid catalyzed enantioselective allylic C-H activation for the synthesis of spirocyclic rings

Article abstract of DOI:10.1021/ja2102407

A Pd(II)/Bronsted acid catalyzed migratory ring expansion for the synthesis of indene derivatives possessing a stereogenic spirocyclic carbon center was developed. This transformation is believed to mechanistically proceed via enantioselective allylic C-H activation with concomitant semipinacol ring expansion to the nascent π-allylpalladium species. Enantioselectivities as high as 98% ee were attainable.

Full text of DOI:10.1021/ja2102407

Communication
pubs.acs.org/JACS
Pd(II)/Brønsted Acid Catalyzed Enantioselective Allylic C−H
Activation for the Synthesis of Spirocyclic Rings
Zhuo Chai and Trevor J. Rainey*
Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States
S
* Supporting Information
asymmetric Pd(II)/Brønsted acid cocatalyzed semipinacol
rearrangement via direct allylic C−H activation.
ABSTRACT: A Pd(II)/Brønsted acid catalyzed migratory
ring expansion for the synthesis of indene derivatives pos-
sessing a stereogenic spirocyclic carbon center was developed.
This transformation is believed to mechanistically proceed via
enantioselective allylic C−H activation with concomitant
semipinacol ring expansion to the nascent π-allylpalladium
species. Enantioselectivities as high as 98% ee were attainable.
In our initial efforts to transform substrate 2a to the desired
product 3a (Table 1), several neutral and cationic Pd(II)
a
Table 1. Screen of Reaction Conditions
he Pd(II)-catalyzed allylic C−H activation of alkenes with
b
T
subsequent nucleophilic attack on the resulting π-allyl Pd
complex constitutes an efficient and atom-economical method
for the construction of C−C, C−N, and C−O bonds.1 While
previous work in this has focused predominantly on internal
alkenes,1c significant progress has recently been made by
White’s group2 and others3 on the allylic oxidation, amination,
and alkylation of terminal alkenes. Despite these advances, the
development of enantioselective reactions has met with limited
success. Although chiral Pd(II) catalysts have been used for the
asymmetric allylic acetoxylation of cyclohexene,4 and more
recently a chiral Lewis acid strategy was employed by White
et al. to induce the same reaction of terminal alkenes,2e enan-
tioselectivity in both cases remained modest (≤65% ee).
Moreover, there is no report of asymmetric Pd(II)-catalyzed
direct allylic amination or alkylation of alkenes.
entry
ligand
oxidant
conv. (%)
yield (%)
% ee
1
2
3
1a
1b
1c
1d
1e
1f
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
NQ
O2
<10
<10
>90
>95
<10
58
n.d.
n.d.
62
73
n.d.
42
45
46
0
n.d.
n.d.
0
c
4
0
5
6
7
8
9
n.d.
70
34
77
_
1g
1h
1i
88
70
0
d
10
1j
43
22
43
49
60
0
0
e
11
1h
1h
1h
1h
1h
1h
1h
1h
1h
66
76
75
63
-
f
12
77
g
13
83
14
<5
36
h
Chiral spirocyclic indenes and indanes represent a structural
motif present in biologically active natural products such as
fredericamycin A, an antitumor compound with antibiotic
properties,5 and acutumine, an alkaloid possessing antiamnesic
and selective T-cell cytotoxicity.6 Additionally, their rigid struc-
tures make them an ideal platform for the development of
chiral ligands such as the Spinol-based ligands, which have been
applied successfully for various reactions7 (Figure 1). At present
15
20
14
52
49
67
75
28
77
77
75
i
16
j
MnO2
BQ
BQ
BQ
30
17
84
jk
,
18
19
74
jl
,
89
a
Reactions were run on a 0.1 mmol scale in 1.0 mL of toluene. Conversions
were based on recovered starting material, and isolated yields were reported.
Determined by chiral HPLC. At 45 °C. At 21 °C. At 50 °C.
PhCF3 as solvent. PhCl as solvent. 10 mol % of BQ with an oxygen
balloon. 20 mol % of BQ with 1 equiv of MnO2. 10 mol % of
b
c
d
e
f
g
h
i
j
k
Pd(OAc)2 and 20 mol % of 1h in 2.0 mL of solvent. 1.0 equiv of BQ
l
was used. In PhCF3 at 55 °C.
complexes along with various chiral oxazoline ligands were
screened (see Supporting Information). Given the disappoint-
ing results obtained in this preliminary study, we sought out
potentially more reactive complexes and specifically were intri-
gued with the possibility of using chiral Brønsted acids in
combination with a Pd(II) precatalyst.9 Early in 1990, a report
Figure 1. Representative spirocyclic compounds.
the catalytic-enantioselective construction of such quaternary
spirocyclic carbon centers remains challenging.8 Herein we
report a procedure for their construction based on a novel
Received: January 28, 2011
Published: February 7, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
described the use of BINOL-derived phosphoric acid 1a as a
ligand in PdCl2 catalyzed asymmetric hydrocarboxylation of
two vinyl arenes.10 Surprisingly, no further work has been reported
in exploiting the potential of these additives in other Pd(II)-
catalyzed oxidative reactions. With their attenuation of reactivity,
inertness to oxidative conditions, and recent successful combined
uses with metal salts in various reactions,11 the use of chiral
phosphoric acids in the realm of Pd(II) chemistry has unrealized
potential (Figure 2).
Table 2. Scope of the Semipinacol Rearrangement Reaction
Figure 2. Chiral Brønsted acids evaluated in this study.
Consistent with our above expectation, the addition of
phosphoric acids had a dramatic effect on the reactivity of
Pd(II) complexes and, furthermore, gave the desired product in
good yields. After some experimentation, Pd(OAc)2 was iden-
tified as the metal catalyst of choice. Screening of a series of
BINOL-derived Brønsted acids then furnished optimal results
(Table 1, entries 1−10).12 In the absence of either Pd(OAc)2 or
the Brønsted acid, essentially no conversion of the starting material
was observed under the otherwise same reaction conditions.13 It was
found that phosphoric acid 1d with the electron-withdrawing
CF3 substituents, which is supposed to be relatively more
acidic, displayed the best catalytic efficiency even at a lower
temperature (entry 4) while the sterically hindered 1h gave the
highest enantioselectivity (entry 8). In view of this result, we
prepared Brønsted acids 1i and 1j with the same skeleton as
that of 1i but with increased acidity14 with the expectation of
obtaining both good enantioselectivity and conversion. With 1i,
however, no reaction took place, probably due to the strong
coordination capacity of the thiol group (entry 9). Catalyst 1j
displayed exceptionally high reactivity albeit with no enan-
tioselectivity: racemic product 3a was obtained even when the
reaction was run at room temperature (entry 10). Lowering of
the reaction temperature to minimize the formation of Pd black
resulted in only a slight influence on yield and enantioselectivity
(entry 11). The use of noncoordinating aromatic solvents and
1,4-benzoquinone (BQ) as the oxidant was crucial for this
reaction. Rate acceleration was observed as the polarity of the
solvent increased, but with diminished enantioselectivity
(entries 12−13). It should be noted that when toluene was
used as the solvent, a sharp dependence of the conversion and
yield on the water content of the commercial solvent was also
observed while the enantioselectivity essentially remained
unchanged.15 While the use of 1,4-naphthoquinone (NQ) or
MnO2 as the oxidant were not effective, the use of O2 in the
presence of 10 mol % of BQ led to a sluggish reaction but gave
comparable enantioselectivity (entries 14−16). Doubling the
amount of both catalysts could further improve the conversion
and yield, while decreasing the amount of BQ slightly slowed
down the reaction with little influence on the enantioselectivity
(entries 17−19).
a
0.1 mmol scale, Pd(OAc)2 (10 mol %), 1h (20 mol %), BQ (2.0
b
equiv), in PhCF3 (2.0 mL) at 55 °C for 72 h. Isolated yields.
Numbers in parentheses are conversions based on recovered starting
c
d
e
material. Determined by 1H NMR analysis. Reaction time: 48 h. In
f
g
PhCH3 at 60 °C for 48 h. In PhCH3 at 50 °C for 72 h. Yield
estimated by H NMR analysis.
1
obtained with moderate to good diastereoselectivity (entries 2−8).
Functionality such as aryl chloride and benzyl ether was well
tolerated. Moreover, substrates with alkyl substituents at this
position gave somewhat better yields than those with aromatic
ones, except for 3g with an additional coordinative oxygen
atom (entry 7). In the case of acid sensitive substrate 2i, which
has two possibilities of bond migration (methylene vs phenyl)
in the semipinacol rearrangement process, only the methylene
migration product 3i was obtained in moderate yield and enan-
tioselectivity (entry 9). This result deserves attention because
of the failure of previous work to induce this type of ring
expansion of related allylic alcohols derived from benzocyclo-
butanones.17 Substrate 2j with a substituted indene ring also
worked well in this reaction (entry 10). The use of related
substrates without the indene structure failed to undergo the
desired reaction.18 We consequently proposed that the reaction
proceeded via allylic C−H activation, with the greater reactivity
(acidity) of indenyl methylene protons accountable for the
substrate specificity. Thus, substrate 2k was expected to give
similar results to that of 2a, so that a common allylic Pd inter-
mediate might be shared by both substrates. However, the
We next examined the scope of this reaction (Table 2).16 For
substrates 2b−2h with a substituent at the 4-position of the
cyclobutane ring, in general, excellent enantioselectivity was
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Journal of the American Chemical Society
Communication
desired reaction hardly took place, probably due to the steric
hindrance of the tertiary C−H bond in 2k (entry 11).
In summary, we have developed an enantioselective
semipinacol rearrangement initiated by Pd(II)-catalyzed direct
allylic C−H activation to give chiral spirocyclic indenes. Our
results indicate that a chiral Brønsted acid strategy could be a
valuable method for the development of asymmetric Pd(II)-
catalyzed oxidative reactions of alkenes through direct allylic
C−H activation. Efforts toward this direction as well as a de-
tailed understanding of the mechanism are currently underway
in our laboratories.
An intermolecular kinetic isotopic effect experiment (KIE)
study with substrate 2a-d2 disclosed a primary kinetic isotopic
effect for this reaction (see Supporting Information for more
details), which is clearly in support of our above hypothesis that
an allylic C−H bond is broken prior to or during the rate-
limiting step (eq 1). In contrast, use of the more reactive cata-
lyst Pd(CH3CN)4(BF4)2 did not result in an observable kinetic
isotope effect (kH/kD = 1.02−1.03). The data in this case are
consistent with a mechanism in which alkene coordination to
the metal center depletes electron density in the alkene through
ligand to metal electron donation; rearrangement followed by
fast β-hydride elimination then furnishes the observed product.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, details on condition screening, and
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
trevor.rainey@chemistry.montana.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from Montana State University is gratefully
acknowledged.
■
REFERENCES
■
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3618
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