Palladium-catalyzed allylic substitution with (η6-Arene- CH2Z)Cr(CO)3-based nucleophiles

Article abstract of DOI:10.1021/ja208935u

Although the palladium-catalyzed Tsuji-Trost allylic substitution reaction has been intensively studied, there is a lack of general methods to employ simple benzylic nucleophiles. Such a method would facilitate access to "α-2-propenyl benzyl" motifs, which are common structural motifs in bioactive compounds and natural products. We report herein the palladium-catalyzed allylation reaction of toluene-derived pronucleophiles activated by tricarbonylchromium. A variety of cyclic and acyclic allylic electrophiles can be employed with in situ generated (η⁶-C ₆H₅CHLiR)Cr(CO)₃ nucleophiles. Catalyst identification was performed by high throughput experimentation (HTE) and led to the Xantphos/palladium hit, which proved to be a general catalyst for this class of reactions. In addition to η⁶-toluene complexes, benzyl amine and ether derivatives (η⁶-C₆H₅CH ₂Z)Cr(CO)₃ (Z = NR₂, OR) are also viable pronucleophiles, allowing C-C bond-formation α to heteroatoms with excellent yields. Finally, a tandem allylic substitution/demetalation procedure is described that affords the corresponding metal-free allylic substitution products. This method will be a valuable complement to the existing arsenal of nucleophiles with applications in allylic substitution reactions.

Full text of DOI:10.1021/ja208935u

ARTICLE
pubs.acs.org/JACS
Palladium-Catalyzed Allylic Substitution with (η6-AreneꢀCH2Z)Cr(CO)3-
Based Nucleophiles
Jiadi Zhang,† Corneliu Stanciu,†,‡ Beibei Wang,† Mahmud M. Hussain,† Chao-Shan Da,†,§ Patrick J. Carroll,†
Spencer D. Dreher,‡ and Patrick J. Walsh*,†
†Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
‡Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
§Institute of Biochemistry & Molecular Biology, School of Life Sciences, Lanzhou University, Southern Tianshui Road 222,
Lanzhou 730000, China
S Supporting Information
b
ABSTRACT: Although the palladium-catalyzed TsujiꢀTrost allylic substitu-
tion reaction has been intensively studied, there is a lack of general methods to
employ simple benzylic nucleophiles. Such a method would facilitate access to
“α-2-propenyl benzyl” motifs, which are common structural motifs in bioactive
compounds and natural products. We report herein the palladium-catalyzed
allylation reaction of toluene-derived pronucleophiles activated by tricarbonyl-
chromium. A variety of cyclic and acyclic allylic electrophiles can be employed
with in situ generated (η6-C6H5CHLiR)Cr(CO)3 nucleophiles. Catalyst iden-
tification was performed by high throughput experimentation (HTE) and led to the Xantphos/palladium hit, which proved to be a general
catalyst for this class of reactions. In addition to η6-toluene complexes, benzyl amine and ether derivatives (η6-C6H5CH2Z)Cr(CO)3 (Z =
NR2, OR) are also viable pronucleophiles, allowing CꢀC bond-formation α to heteroatoms with excellent yields. Finally, a tandem allylic
substitution/demetalation procedure is described that affords the corresponding metal-free allylic substitution products. This method will be
a valuable complement to the existing arsenal of nucleophiles with applications in allylic substitution reactions.
2-methylpyridines (Scheme 1A).4 The sp3-hybridized CꢀH’s of
1. INTRODUCTION
2-methylpyridine have a pKa of 34,5 and therefore its conjugate
The formation of carbonꢀcarbon bonds represents one of the
base is classified as hard. To moderate the reactivity of the
conjugate base, the pyridine nitrogen was coordinated to BF3.
most fundamental and well-studied processes in organic synth-
esis. Nonetheless, the efficient catalytic generation of CꢀC
The resulting BF3-bound complex was deprotonated and em-
bonds between sp3-hybridized carbons remains challenging.1
ployed in palladium-catalyzed asymmetric allylic substitution
Although palladium-catalyzed cross-coupling reactions have re-
ceived significant recent attention, an alternative approach to
with excellent enantio- and diastereoselectivity. Interestingly,
no such activation was necessary with more activated benzylic
such CꢀC bond-formations is the palladium-catalyzed Tsujiꢀ
CꢀH’s, such as those of methylated pyrazine (Scheme 1B),
Trost allylic substitution reaction. This reaction has been intensively
pyrimidine, pyridazine, quinoxaline, and benzoimidazole
studied, because it provides a variety of efficient and atom-economic-
pronucleophiles.4c
al methods for synthesis of natural products and bioactive targets.2
Despite the elegance and medicinal relevance of Trost’s
synthesis of enantioenriched pyridine derivatives, an approach
Although a broad array of stabilized or “soft” nucleophiles
(those derived from conjugate acids with pKa < 25) has been
explored, palladium-catalyzed allylic alkylations with “hard”
to activation of weakly acidic benzylic CꢀH’s for use in allylic
substitution reactions is needed. Toluene, for example, with a pKa
nucleophiles (derived from conjugate acids with pKa > 25) have
of 44 ( 1,6 is very weakly acidic, and the conjugate base of
received considerably less attention. “Hard” nucleophiles used in
toluene has not been used in palladium-catalyzed allylic substitu-
palladium-catalyzed allylic alkylations are largely organometallic
tion reactions (Scheme 1C).7ꢀ9 Yet hundreds of bioactive
compounds such as alkyllithium and Grignard reagents.3 Their
compounds and natural products contain the “α-2-propenyl
high reactivity and limited functional group tolerance, however,
render the use of these hard nucleophiles in allylic substitution
less attractive. One strategy to develop allylic substitution reac-
tions with nucleophiles that are traditionally considered hard is to
benzyl” motif (Figure 1), with applications ranging from medic-
inal agents for hyperkalemia,10 Alzheimer’s,11 and urinary tract
diseases,12 to cosmetics,13 antibiotics,14 and phytoncides.15
“soften” them by addition of an activating agent to acidify the
conjugate acid. Recent advances based on this strategy were
reported by Trost and co-workers with nucleophiles derived from
Received: September 22, 2011
Published: November 02, 2011
r
2011 American Chemical Society
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Scheme 1. Palladium-Catalyzed Benzylic Allylations
Figure 1. Selected bioactive compounds and natural products contain-
ing the “α-2-propenyl benzyl” motif.
To broaden the scope of useful nucleophiles for the palladium-
catalyzed TsujiꢀTrost reaction, we set out to develop the applica-
tion of toluene derivatives as precursors to benzylic nucleophiles.
To achieve this goal, conditions to deprotonate toluene derivatives
that are compatible with the catalyst, reagents, and products in the
allylic substitution reaction would be necessary. It is known that
η6-coordination of arenes to metals activates the benzylic CꢀH’s
toward deprotonation.16,17 We hypothesized that η6-arene com-
plexes could be reversibly deprotonated18 under palladium-
catalyzed allylic substitution reaction conditions and would serve
as surrogates for hard benzylic organometallic reagents. Herein
we report the successful application of (η6-C6H5CH2R)Cr(CO)3
complexes as nucleophile precursors in allylic substitution reac-
tions (Scheme 1C). This method enables the synthesis of a variety
of valuable aryl-containing compounds that would be otherwise
difficult to access.
we initially examined the allylic substitution reaction with the
same catalyst and base. Combination of the toluene complex (η6-
C6H5CH3)Cr(CO)3 (1a) with tert-butyl cyclohex-2-enyl carbo-
nate (2a) as the electrophilic partner, LiN(SiMe3)2 to reversibly
deprotonate the toluene complex, and THF solvent was per-
formed. Heating the reaction mixture to 60 °C in THF resulted
in only trace amounts of product after 12 h (Table 1, entry 1). We
then turned to microscale high-throughput experimentation
(HTE) techniques20 to identify an initial catalyst lead. Using
12 diverse phosphine ligands, 4 palladium precursors, and 4 bases
(see Supporting Information for details) revealed that the
combination of 10 mol % Cl2Pd(COD) and Xantphos with
3 equiv of LiN(SiMe3)2 in THF at 60 °C was the most promising
combination of those examined for conversion of 1a to the
corresponding allylation product 3a. Translation of this lead to
laboratory scale under the same conditions afforded 3a in 39%
yield (Table 1, entry 2). Decreasing the reaction temperature
from 60 °C to ambient temperature and further to 0 °C indicated
that conducting the reaction above or below ambient tempera-
ture proved deleterious to the yield (Table 1, entries 2ꢀ4).
Combination of 1 equiv of the stronger bases LDA or n-BuLi
with 3 equiv of LiN(SiMe3)2 to favor deprotonation of 1a
resulted in poor yields (Table 1, entries 5 and 6).
A key variable in optimizing organolithium reactions is the
degree of aggregation.21 To reduce the degree of aggregation, a
single equiv of NEt3 was added in combination with 3 equiv of
LiN(SiMe3)2. With this mixture, 3a was formed in >95% yield
(Table 1, entry 7). Under these conditions, catalyst loading could
be reduced to 5 mol % (Table 1, entry 8). Switching the allylic
partner from the carbonate 2a to the pivalate 2b also resulted in
excellent isolated yield (96%, Table 1, entry 9). The structure of
3a was determined by X-ray diffraction (see Supporting In-
formation) and is consistent with allylic substitution outlined in
Table 1. Using these optimized conditions, we then examined
various (η6-C6H5CH2R)Cr(CO)3 complexes as nucleophile
precursors.
2. RESULTS AND DISCUSSION
We recently disclosed the palladiumꢀtriphenylphosphine-catalyzed
cross-coupling of aryl bromides and (η6-C6H5CH2R)Cr(CO)3
complexes in the presence of LiN(SiMe3)2 to afford a broad range of
di- and triarylmethanes (eq 1).18 The Cr(CO)3 fragment is easily
installed simply by refluxing the arene with Cr(CO)6. After the
coupling reaction, decomplexation of the chromium moiety is per-
formed by exposure of the solution of the chromium arene complex
to room light and air. On the basis of this study, we hypothesized that
(η6-C6H5CH2R)Cr(CO)3 complexes might be suitable substrates in
palladium-catalyzed allylic substitution reactions.
2.1. Development and Optimization of Palladium-
Catalyzed Allylic Substitution with (η6-C6H5CH3)Cr(CO)3.
Given that the cross-coupling of (η6-C6H5CH3)Cr(CO)3 with
aryl bromides was successfully catalyzed by palladiumꢀtriphenyl-
phosphine complexes, which also catalyze allylic substitutions,19
2.2. Scope of Nucleophiles in Palladium-Catalyzed Allylic
Substitution Reactions. Employing the optimized conditions
with the pivalate ester 2b (Table 1, entry 9), we evaluated the
scope of the (η6-ArꢀCH2R)Cr(CO)3 pronucleophiles in the
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Table 1. Optimization of Allylic Substitution with 1aa
entry
PG
mol %
ligand
PPh3
base
temp (°C)
yieldb (%)
1
2
3
4
5
6
7
8
9
Boc (2a)
Boc
10
10
10
10
10
10
10
5
LiN(SiMe3)2
60
60
rt
0
trace
39
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
LiN(SiMe3)2
Boc
LiN(SiMe3)2
72
Boc
LiN(SiMe3)2
39
Boc
LiN(SiMe3)2/LDAd
LiN(SiMe3)2/nBuLid
rt
rt
rt
rt
rt
29
Boc
<10
>95
88c
96c
e
Boc
LiN(SiMe3)2/NEt3
e
Boc
LiN(SiMe3)2/NEt3
e
Piv (2b)
5
LiN(SiMe3)2/NEt3
a Reactions conducted on a 0.1 mmol scale using 1 equiv of 1a and 2 equiv of 2 at 0.1 M. b Yield determined by 1H NMR spectroscopy of the crude
reaction mixture. c Isolated yield after chromatographic purification. d Mixed bases of 3 equiv of LiN(SiMe3)2 and 1 equiv of LDA (or nBuLi). e Amine
additive (1 equiv) treated with 3 equiv of LiN(SiMe3)2.
allylic substitution reaction (Table 2). In addition to the toluene
complex (entry 1), use of (η6-ArCH2R)Cr(CO)3 complexes
bearing various substituents on the η6-arene were well tolerated.
Although the p-isopropyl-substituted arene was a good substrate
(entry 2, 89% yield), p-methylanisole gave only trace product. In
contrast, the meta isomer underwent allylation in 80% yield
(entry 3). The difference between these isomeric substrates is
likely due to the decreased acidity of the benzylic CꢀH bonds
para to the methoxy. Aryl substituents on the η6-arene were good
substrates. To highlight the increase in reactivity of (η6-tolyl)Cr-
(CO)3 compared with an unactivated tolyl group, the 4,40-
dimethylbiphenyl complex was employed. This substrate under-
went allylation exclusively at the chromium-activated position
(entry 4, 90% yield). Although the Cr(CO)3 moiety is known to
“walk” between neighboring arenes at high temperature,22 only
the monoallylation product was observed under our conditions,
indicating that walking did not occur. Heteroaryl substrates
containing 2-pyridyl, 2-thiophenyl, and N-pyrrolyl groups at-
tached to the η6-tolyl group proved to be good substrates
(entries 5ꢀ7, 74ꢀ80% yield). Heteroaromatic compounds are
well-known for their utility in medicinal chemistry.
With the (η6-toluene)Cr(CO)3 and 3-methoxy analogue, the
allylic substitution was performed to generate the new arene
complex, as outlined in eq 2. The reaction mixture was then
exposed to light and air by removing the septum and placing the
reaction vessel on a stir plate on the windowsill (eq 2). After the
mixture was stirred for 3ꢀ6 h under light and air, the demetalated
products were isolated in 92% (30a) and 73% (30c) yield.
2.3. Scope of Electrophiles in Palladium-Catalyzed Allyla-
tion Reactions with Arene Nucleophiles. We next studied the
impact of the leaving group on the allylic substitution. Varying
the leaving group on 2-cyclohexen-1-ol from Boc (2a) to pivalate
(2b) and benzoate esters (2c) resulted in 87ꢀ96% isolated yields
of the allylation product 3a (Table 3, entries 1ꢀ3). Although the
pivalate ester resulted in the highest yield, these results indicate that
the reaction with this substrate class is tolerant of the nature of the
leaving group. The reaction of 1a with 2c in the absence of Cl2Pd-
(COD)/Xantphos was performed as a control experiment. Instead
of formation of the allylic substitution product 3a, PhCOCH2ꢀ(η6-
C6H5)Cr(CO)3 was isolated in 98% yield as the exclusive product,
which was formed from nucleophilic addition to the carbonyl group
of 2c (eq 3). This result indicates that palladiumꢀXantphos-based
catalyst changes the chemoselectivity of the reaction from carbonyl
addition to allylic substitution.
Notably, (η6-p-chlorotoluene)Cr(CO)3 complex participated
in the allylic substitution to furnish the product in 45% yield
(entry 8). Surprisingly, no products derived from ArꢀCl oxida-
tive addition of (η6-p-chlorotoluene)Cr(CO)3 by palladium
were observed, although η6-coordination is known to facilitate
oxidative addition of chloroarene complexes.23 The chloro-
substituted biphenyl derivative underwent allylic substitution
to give the chloro-containing product in 71% yield (entry 9).
The (η6-arene)Cr(CO)3 allylicsubstitutionproduct inTable2
could be used in a variety of subsequent transformations
facilitated by the chromium.17 However, the chromium-free
complexes are often the desired products. Arene complexes of
the type (η6-arene)Cr(CO)3 can be decomplexed simply by
exposure to light and air to afford the corresponding arenes.
To demonstrate the synthetic utility of this chemistry, a tan-
dem allylic substitution/demetalation procedure was examined.
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Table 2. Scope of Nucleophiles in Allylic Substitution
Reactionsa
Table 3. Scope of Electrophiles in Allylic Substitution
Reactionsa
a Reactions conducted on a 0.1 mmol scale using 1 equiv of 1, an excess
of LiN(SiMe3)2 and 2 at 0.1 M. (see Supporting Information for details).
b Isolated yield after chromatographic purification. c PMDTA was added
as an amine additive in place of NEt3. d Ratio of linear:branched (L:B)
was determined by 1H NMR of the crude reaction mixture. e The
regioisomers were separable by silica gel chromatography.
(1k) and diphenylmethane (1l) were reacted with 2d, the
monoallylation products were obtained in 86% (4kd) and 91%
(4ld) yields (entries 5 and 6, respectively).
With unsymmetrical linear electrophiles derived from Boc-
protected cinnamyl alcohol (2e), full consumption of (η6-PhEt)-
Cr(CO)3 (1k) was observed. It is well-known that π-allyl-
palladium complexes formed from cinnamyl alcohol derivatives
tend to react with carbon-based nucleophiles at the unsubstituted
terminus of the π-allyl group for both steric and electronic
reasons.16b Surprisingly, however, the allylation product was
obtained as a mixture of regioisomers at ambient temperature
with a linear:branched ratio (L:B) of 77:23 (as determined by 1H
NMR of the crude reaction mixture, entry 7). Regioselectivity in
palladium-catalyzed allylic substitution reactions can be influ-
enced by the nature of the ligands,24 solvent, and counterion.25
For the purpose of comparison, we employed the stabilized
nucleophile derived from dimethyl malonate under the same
reaction conditions with the Xantphos-based palladium catalyst
(eq 4). In this case, the linear product was obtained with excellent
regioselectivity (linear:branched >20:1, 85% yield).26 We hy-
pothesize that the reduced regioselectivity with the nucleophile
generated from (η6-ethylbenzene)Cr(CO)3 is a result of the high
a Reactions conducted on a 0.1 mmol scale using 1 equiv of 1 and 2 equiv
of 2b at 0.1 M. b Isolated yield after chromatographic purification.
c Reaction time was 1.5 h.
We next examined acyclic electrophiles as partners in the
allylic substitution. The Boc derivative of allyl alcohol, 2d, reacted
with various (η6-arene)Cr(CO)3 complexes to yield substitution
products (Table 3, entries 4ꢀ6). Reaction of the (η6-toluene)
Cr(CO)3 complex with BocOCH2CHdCH2 (2d) resulted in
formation of the diallylation product 4ad (81% yield) when
1 equiv of 1a was treated with 6 equiv of LiN(SiMe3)2, 4 equiv of
the allylic substrate (2d), and 2 equiv of N,N,N0,N00,N00-penta-
methyldiethylenetriamine (PMDTA) as additive in place of NEt3.
When (η6-arene)Cr(CO)3 complexes derived from ethylbenzene
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reactivity of the Cr(CO)3-stabilized organolithium, which led to
lower selectivity. We therefore conducted the reaction at 0 °C
and observed an increase in the linear:branched ratio to 85:15
(Table 3, entry 8). The linear product was separated from the
branched by column chromatography and isolated in 75% yield.
Table 4. Tandem Synthesis of Diphenylmethane Derivativesa
2.4. Tandem Allylation/Demetalation with Diphenyl-
methane Derivatives. Diarylmethane derivatives are attract-
ing considerable attention due to their growing importance in
pharmaceutical development,27 dye precursors,28 and applica-
tions in materials science.29 Given the utility of these compounds,
we investigated palladium-catalyzed allylic substitutions with
(η6-C6H5CH2Ph)Cr(CO)3 (1l) with a variety of cyclic and
acyclic allylic partners. The reaction mixtures were then exposed
to light and air to afford metal-free diphenylmethane derivatives
in a one-pot tandem fashion (Table 4).
We initiated our study employing the cyclohex-2-enyl pivalate
2b. The allylic substitution was performed in THF with 1 equiv of
(η6-C6H5CH2Ph)Cr(CO)3 (1l), 2 equiv of pivalate 2b, and
3 equiv of LiN(SiMe3)2 (entry 1). When the allylic substitution
was complete, as judged by TLC, the flask was opened to air and
placed on a stir plate on the windowsill to expose the reaction
mixture to sunlight. A green precipitate formed during the
demetalation as the chromium was oxidized. Thereaction mixture
was then filtered through a pad of MgSO4 and silica, concentrated
in vacuo, and loaded directly onto a silica gel column. The metal-
free product 5lb was isolated as clear oil in 96% yield after column
chromatography. The reaction of tert-butyl cyclopent-2-enyl
carbonate (2g) was performed under similar conditions and
provided the substitution product in 89% yield (5lg, entry 2).
Acyclic allylic alcohol derivatives were also good substrates in
the allylic substitution/demetalation tandem reaction. Use of the
Boc derivative of the parent allyl alcohol (2d) resulted in
isolation of the substitution product in 91% yield (5ld, entry
3). Note that the reaction of diphenylmethane [Cr(CO)3-free]
with allylic partners did not give substitution products, under-
scoring the necessity of the activating Cr(CO)3 agent. trans-1,3-
Diphenylallyl acetate (2f) underwent the allylic substitution/
demetalation to give 5lf in 96% isolated yield (entry 4). Reaction
of 1l with a bifunctional substrate, cis-1,4-diacetoxy-2-butene
(2h), gave 77% isolated yield (88% per CꢀC bond formation) of
the diallylation product 5lh as an E/Z ratio of 1:2 (entry 5).30
Evaluation of π-geranylpalladium complex was motivated by
the recent isolation of several α-geranylated toluene derivatives.31
Furthermore, α-geranylated toluene derivatives have shown
interesting bioactive properties32 and are key intermediates in
total synthesis of antibiotics.33 Addition of the organolithium
derived from (η6-C6H5CH2Ph)Cr(CO)3 (1l) to tert-butyl ger-
anyl carbonate complex 2i exhibited good regioselectivity (L:B =
78:22) and good isolated yield of the linear product 5li (73%
yield, entry 6). The carbonꢀcarbon double bond of the products
in Table 4 will facilitate subsequent functionalizations to afford a
variety of diphenylmethane derivatives.
a Reactions conducted on a 0.1 mmol scale using 1 equiv of 1l, an excess
of LiN(SiMe3)2 and 2 at 0.1 M (see Supporting Information for details).
b Isolated yield after chromatographic purification. c Ratio of linear:
1
branched (L:B) was determined by H NMR of the crude reaction
mixture. The regioisomers were separable by silica gel chromatography.
d [Pd(allyl)Cl]2/1,3-bis(diphenylphosphino)propane (DPPP) was used
as catalyst in place of Pd(COD)Cl2/Xantphos.
synthesis of bioactive compounds. We therefore examined reac-
tions of benzyl ether and amine substrates (η6-C6H5CH2Z)Cr-
(CO)3 (Z = OR, NR2). Benzylamines often direct metalation to
the ortho position34 as do activated (η6-C6H5CH2Z)Cr(CO)3
complexes in the presence of strong organolithium bases (Z =
NR2). Interestingly, under the reversible deprotonation condi-
tions employed herein, (η6-C6H5ꢀCH2Z)Cr(CO)3 complexes
exhibit orthogonal chemoselectivity with metalation taking place
at the benzylic CꢀH’s. As illustrated in eq 5, the (η6-
C6H5CH2Z)Cr(CO)3 benzyl ether (1o) and amines (1p, 1q)
are excellent substrates for the allylic substitution reaction with
allyl tert-butyl carbonate 2d, giving products in high yields
(90ꢀ97%).
2.5. Allylation with Benzyl Amine and Ether Derivatives.
Stereogenic centers α to heteroatoms are important in the
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The scalability of this method was demonstrated by a tandem
allylic substitution/demetalation reaction of benzyl morpholine
(1q) on a 3 mmol scale, which afforded the metal-free organic
product in 89% yield (eq 6).
Scheme 3. Allylic Substitution with Retention of
Configuration
“soft” undergo external attack on the π-allyl ligand35 and the net
process of the allylic substitution is stereoretentive (via double
inversion). In contrast, “hard” nucleophiles undergo addition to
the metal center of the π-allyl complex (i.e., transmetalation)
followed by reductive elimination to form the new CꢀC bond.36
This latter mechanism results in an overall inversion of config-
uration in the allylic substitution.
To determine whether the conjugate bases of the (η6-arene)-
Cr(CO)3 complexes behave as “soft” or “hard” nucleophiles in
the palladium-catalyzed allylic substitution, (η6-toluene)Cr-
(CO)3 complex 1a was reacted with the cis-disubstituted stereo-
chemical probe 2j (Scheme 3). In the allylic substitution with 2j
the product cis-6 was obtained in 63% isolated yield as a single
diastereomer, as determined by comparison of the splitting
2.6. Allylation at Multiple Benzylic Sites. Having demon-
strated that diallylation could occur on a single benzylic methyl
group (Table 3, entry 4), we explored the possibility of activation
of multiple benzylic positions in (η6-arene)Cr(CO)3 complexes
of p-xylene and tetralin (Scheme 2). Subjecting (η6-p-xylene)Cr-
(CO)3 (1m) to allylation conditions with a sterically hindered
allylic partner, cyclohex-2-enyl mesitoate (2k), furnished the
diallylation product 7 in 78% isolated yield.
1
patterns and coupling constants with related products by H
NMR spectroscopy (see Supporting Information for details).
Formation of cis-6 indicates that the reaction occurs predomi-
nantly via external attack of the “soft” conjugate base derived
from (η6-toluene)Cr(CO)3 on the palladium-bound π-allyl ligand.
The observed double inversion is consistent with the ability of the
Cr(CO)3 moiety to stabilize benzyl anions by delocalization of the
negative charge onto the chromium to “soften” the nucleophilicity of
the organolithium.16,17
Scheme 2. Allylation at Multiple Benzylic Sites
3. SUMMARY AND OUTLOOK
We have developed the first general method for palladium-
catalyzed allylic substitution with the conjugate bases of toluene
derivatives. Key to the success of our method is the activation of
the arene’s benzylic CꢀH’s by η6-coordination to tricarbonyl-
chromium. Also very important was the HTE approach to identify
the Xantphos/Pd(COD)Cl2 combination as an excellent catalyst
for this allylic substitution reaction. Mechanistic studies indicate that
(η6-toluene)Cr(CO)3 derivatives behave as “soft” or stabilized
nucleophiles. They attack the palladium π-allyl complex externally,
leading to a net double inversion in the allylic substitution. The (η6-
arene)Cr(CO)3 derivatives are reversibly deprotonated by LiN-
(SiMe3)2 under mild conditions, allowing for the in situ generation
of the nucleophilic organolithium intermediates.
The synthetic significance of this method is that it enables the
application of a variety of benzylic nucleophiles in palladium-
catalyzed allylic substitution reactions and provides access to
allylation products that are otherwise difficult to prepare. The
method is general in that a range of nucleophiles, derived from
(η6-arene)Cr(CO)3 complexes, can be readily employed with
structurally diverse allylic alcohol derivatives bearing OAc, OBz,
OBoc, or OPiv leaving groups. A tandem allylic substitution/
demetalation procedure has been developed for the one-pot
synthesis of diarylmethane derivatives, which are increasing in
their importance. We believe this method will be a valuable
complement to the existing arsenal of nucleophiles with applica-
tions in allylic substitution reactions. Identification of catalysts for
In the case of (η6-tetralin)Cr(CO)3 (1n), we were somewhat
concerned that after the first allylation, the newly formed
2-propenyl moiety would hinder deprotonation of the second
benzylic center by the bulky base, LiN(SiMe3)2. As shown in
Scheme 2, however, the double allylation proceeded smoothly at
ambient temperature and the cis-diallylation product 9 was
isolated in 76% yield.17,18 Presumably this approach could be
coupled with ring closing metathesis to afford bicyclic scaffolds.
2.7. Internal vs External Attack of (η6-ArCH2Li)Cr(CO)3 on
π-Allyl Palladium Intermediate. One significant difference be-
tween “hard” and “soft” nucleophiles in allylic substitution reactions
is their distinct mechanistic pathways. Nucleophiles classified as
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asymmetric palladium-catalyzed allylic substitution reactions is
underway.37
two drops of H2O and diluted with 10ꢀ20 mL of diethyl ether, and the
solution was exposed to sunlight by placing it on the windowsill and
stirring for 3ꢀ6 h. The demetalation step was monitored until TLC
showed complete consumption of the (η6-arene)Cr(CO)3 product. During
this time, a green precipitate formed as the chromium was oxidized. The
reaction mixture was then filtered through a pad of MgSO4 and silica,
concentrated in vacuo, and loaded directly onto a silica gel column. After
demetallation, the crude material was purified by flash chromatography
on silica gel (eluted with hexanes to EtOAc/hexanes = 5:95).
4. EXPERIMENTAL SECTION
Representative procedures are described herein. Full experimental
details and characterization of all compounds are provided in the Supporting
Information.
4.1. General Methods. All reactions were performed under
nitrogen using oven-dried glassware and standard Schlenk or vacuum
line techniques. Air- and moisture sensitive solutions were handled
under nitrogen and transferred via syringe. THF was freshly distilled
from Na/benzophenone ketyl under nitrogen. Unless otherwise stated,
reagents were commercially available and used as purchased without
further purification. Chemicals were obtained from Sigma-Aldrich or
Acros, and solvents were purchased from Fisher Scientific. The progress
of reactions was monitored by thin-layer chromatography using Whatman
Partisil K6F 250 μm precoated 60 Å silica gel plates and visualized by
short-wave ultraviolet light as well as by treatment with ceric ammonium
molybdate (CAM) stain. Silica gel (230ꢀ400 mesh, Silicycle) was used for
’ ASSOCIATED CONTENT
S
Supporting Information. Procedures, full characteriza-
b
tion of new compounds, and crystallographic data for 3a. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
pwalsh@sas.upenn.edu
1
flash chromatography. The H NMR and 13C{1H} NMR spectra were
obtained using a Br€uker AM-500 Fourier-transform NMR spectrometer at
500 and 125 MHz, respectively. Chemical shifts are reported in units of parts
per million (ppm) downfield from tetramethylsilane (TMS), and all
coupling constants are reported in hertz. The infrared spectra were obtained
on KBr plates using a Perkin-Elmer Spectrum 100 Series FTIR spectro-
meter. The masses of chromium-complexes were recorded with electro-
spray + (ES+) HRMS methods, and [M]+ or [M ꢀ (CO)3]+ (unless
otherwise stated) was confirmed by the presence of the characteristic
chromium isotope pattern. Chromium-decomplexed masses were re-
corded with chemical ionization + (CI+) HRMS methods.
’ ACKNOWLEDGMENT
We thank the NSF (CHE-0848467 and 0848460) for partial
support of this research. We also thank the NIH for the purchase
of a Waters LCTOF-Xe Premier ESI mass spectrometer (grant
no. 1S10RR23444-1) and NSF for an X-ray diffractometer (CHE-
0840438).
’ REFERENCES
4.2. Cautionary Note. Care should be taken to avoid direct
exposure of reaction mixtures to bright light, as arene tricarbonylchro-
mium complexes can decompose in solution under bright light and air.
4.3. General Procedure A. Synthesis of (η6-Toluene)Cr-
(CO)3 Derivatives. A solution of Cr(CO)6 (1.10 g, 5.0 mmol), arene
(1.2ꢀ5 equiv), and THF (3 mL) in 1,4-dioxane (8 mL) was heated
under reflux (oil bath temp = 120 °C) under a nitrogen atmosphere for
3ꢀ5 days. The yellowꢀorange solution was allowed to cool, and
completion of the reaction was verified by the absence of solid Cr(CO)6
on the sides of the flask (from sublimation) after refluxing subsided. After
cooling to rt, the solution was filtered through Celite and then evaporated
under reduced pressure. The yellow product was either recrystallized
from diethyl ether and hexanes or purified by column chromatography
eluting with EtOAc/hexanes.
4.4. General Procedure B. Pd-Catalyzed Allylic Substitu-
tion with (η6-Arene-CH2Z)Cr(CO)3-Based Nucleophiles. An
oven-dried reaction vial equipped with a stir bar was charged with (η6-
arene-CH2Z)Cr(CO)3 (0.10 mmol). To the reaction vial was added
LiN(SiMe3)2 (50.2 mg, 0.30 mmol, 3 equiv) under a nitrogen atmo-
sphere followed by 0.5 mL of dry THF, and the reaction mixture was
stirred for 5 min. A solution of Pd(COD)Cl2 (1.43 mg, 0.0050 mmol)
and Xantphos (4.34 mg, 0.0075 mmol) in 0.5 mL of THF was taken up
by syringe and added to the reaction vial. After stirring for 5 min, the
allylic electrophile (0.2 mmol, 2 equiv) was added to the reaction
followed by NEt3 (14 μL, 0.1 mmol, 1 equiv). The reaction mixture was
stirred for 12 h at rt. The reaction mixture was quenched with two drops
of H2O, diluted with 3 mL of ethyl acetate, and filtered over a pad of
MgSO4 and silica. The pad was rinsed with additional ethyl acetate, and
the solution was concentrated in vacuo. The crude material was loaded
onto a silica gel column and purified by flash chromatography.
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