Mechanistic switch via subtle ligand modulation: Palladium-catalyzed synthesis of α,β-substituted styrenes via C-H bond functionalization

Article abstract of DOI:10.1002/adsc.201100140

A new catalyst system able to efficiently perform the synthesis of styrenes via C-H bond functionalization and a subtle ligand modification are described. The high level of activity achieved allows for the synthesis of highly functionalized α,β-substituted styrenes, even the elusive E-configured trisubstituted olefins, in a regio- and stereoselective manner. Mechanistic experiments allowed for the identification of the corresponding synthetic intermediates.

Full text of DOI:10.1002/adsc.201100140

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DOI: 10.1002/adsc.201100140
Mechanistic Switch via Subtle Ligand Modulation: Palladium-
À
Catalyzed Synthesis of a,b-Substituted Styrenes via C H Bond
Functionalization
Areli Flores-Gaspara and Ruben Martina,*
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Paꢀsos Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-977-920-823; e-mail: rmartinromo@iciq.es
Received: February 25, 2011; Published online: May 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.2001100140.
Abstract: A new catalyst system able to efficiently
À
perform the synthesis of styrenes via C H bond
functionalization and a subtle ligand modification
are described. The high level of activity achieved
allows for the synthesis of highly functionalized a,b-
substituted styrenes, even the elusive E-configured
trisubstituted olefins, in a regio- and stereoselective
manner. Mechanistic experiments allowed for the
identification of the corresponding synthetic inter-
mediates.
À
Keywords: aryl halides; catalyst design; C H acti-
vation; palladium; P ligands
Scheme 1. Mechanistic switch in Pd-catalyzed intramolecular
acylation of aryl bromides.
Metal-catalyzed reactions have arguably expanded
the organic chemistꢁs arsenal, allowing the develop-
ment of innovative tactics for the construction of guingly, this method did not lead to BCB, but rather
complex structures in few synthetic steps.[1] Critical to styrenes.[7] Despite the inherent interest of the
for achieving high levels of reactivity, efficiency, prac- latter method, however, this procedure resulted in
ticality and reliability has been the use of ancillary li- low yields, and seemed to be limited to unfunctional-
gands capable of modulating the properties of the cat- ized aryl iodides at relatively high catalyst loadings.
alytic species of such reactions.[2] Indeed, in recent Additionally, only a single example using an aryl bro-
years a myriad of operationally simple and highly effi- mide was reported. In view of the importance of a,b-
cient transformations has been described in the litera- substituted styrene derivatives as synthetic intermedi-
ture in this regard.[2] Particularly intriguing are recent ates in organic synthesis,[8] we wish to report herein
metal-catalyzed strategies for generating multiple the development of a general and highly efficient
compounds from common building blocks as a result method for preparing related compounds when em-
of a subtle modulation of the active catalyst.[3]
ploying aryl bromides as substrates.[9] We demonstrate
As part of our studies in the field of inert bond that subtle changes on the ancillary ligand lead to a
functionalization,[4] we have recently found that ben- dramatic mechanistic switch, resulting in the discov-
À
zocyclobutenones (BCB) could be prepared via Pd- ery of a C H bond functionalization manifold capable
catalyzed intramolecular acylation of a-aryl aldehydes of converting a-aryl aldehydes into BCB or a,b-sub-
À
via C H bond-activation (Scheme 1, upper path- stituted styrenes at will, depending on the judicious
way).[4b,5] In 2009, as part of their pioneering work on choice of the ligand employed.
Pd-catalyzed migrations,[6] the Larock group reported
We started our work by studying the reactivity of
a related procedure using aldehydes of type 1;[7] intri- our model substrate 1a (Figure 1) with several Pd pre-
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Figure 1. Screening of reaction conditions.[a–d] [a] 1a (0.50 mmol), Pd
ACHTUGNNRTE(NUG OAc)2 (2 mol%), L (3 mol%), Cs2CO3 (1.30 equiv.), diox-
[c] [d]
[b]
ane (0.50M) at 1108C. GC yields using dodecane as internal standard. L6*=L6 was used in toluene as the solvent.
L9 was used following the conditions reported in ref.[7]
catalysts, ligands, bases, solvents and temperatures. As strategic advantage, suggesting that subtle differences
expected,[4b] the use of either L1 or L2 afforded exclu- on the ligand backbone lead to a dramatic switch on
sively benzocyclobutenone 2a, thus indicating that selectivity.[3,11] After some experimentation,[12] we
electronic factors on the phosphine binaphthyl back- found that L6 in toluene provided the best results.[13]
bone do not play a critical role. As a result, we hy- At present we believe that ligands of type L6 might
pothesized that the naphthyl moiety could exert an in- act as a monodentate or hemilabile ligands. Although
fluence on the reaction outcome. Thus, we wondered in lower yields, the ability of PCy3 (L7) or PACHTUNGTRENNUNG(t-Bu)3
whether a more flexible bisphosphine backbone with (L8) to selectively furnish 3a clearly supports this
a similar bite angle[10] would have a deleterious effect working hypothesis. Gratifyingly, the formation of 3a
on both reactivity and/or selectivity. Gratifyingly, this could also be accomplished at only 0.5–1 mol% cata-
was indeed the case, as structurally related L3 and L4 lyst loading; note, however, that in this particular
had a different chemical behaviour; thus, while L3 af- case, longer reaction times were generally required.[12]
forded mixtures of both 2a and 3a, the use of a more In order to put these results into perspective, we per-
electron-rich ligand L4 gave access to 3a, with no 2a formed a control experiment with the conditions pre-
being detected by NMR spectroscopy of the crude re- viously described by Larock (Figure 1, L9);[7] only
action mixture.
19% yield was formed in this case, thus indicating the
These results provide us with a unique opportunity superior activity of the catalyst system based upon
to turn the flexibility exerted by these ligands into a L6.
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Mechanistic Switch via Subtle Ligand Modulation: Palladium-Catalyzed Synthesis of a,b-Substituted Styrenes
Table 1. Scope for the synthesis of a-styrene derivatives.[a,b]
Encouraged by our initial findings, we sought to ex-
amine the preparative scope of this reaction. As
become apparent from the results compiled in
Table 1, a host of electron-deficient and electron-do-
nating aryl bromides with different substitution pat-
terns reacted with good to excellent yields. An illus-
trative example is the preparation of 3b and 3f in
93% and 91% yield, indicating that electronic factors
do not play a prominent role in this reaction Notably,
the method showed a strong preference for the cou-
pling of aryl bromides as aryl chlorides (3c) and aryl
fluorides (3e) remained inert. Furthermore, the pres-
ence of ortho substituents did not hinder the reaction,
as 3i and 3j could be efficiently prepared in 80%
yield, respectively. Particularly noteworthy is the che-
moselectivity profile of our method as substrates con-
taining nitro groups (3f), nitriles (3k), aldehydes (3l),
esters (3m) and ketones (3n) were perfectly accom-
modated. Interestingly, our protocol was also amena-
ble for the synthesis of silyl enol ethers (3o).
As highlighted in a recent review, the preparation
of configurationally pure trisubstituted olefins in a
regio- and diastereoselective manner, particularly
with substituents possessing similar electronic or
steric environments is still considered a great synthet-
ic challenge.[14] Indeed, classic Wittig-type olefina-
tions[15] or alkyne hydroarylation[16] are still ineffective
in terms of regio- and diastereoselectivity. Similarly,
the use of metal-catalyzed cross-coupling reactions is
still problematic when preparing geometrically de-
fined alkenyl metal (halide) species having similar
substituents over the alkene backbone.[14,17] Remarka-
bly, our new protocol based upon L6 allows for the
preparation of trisubstituted olefins in high yields
with total regiocontrol and diastereoselectivities up to
22.2:1, hence providing a rapid and modular access to
a variety of E-configured olefins (Table 2; 3p, 3q, 3r
and 3s). Importantly, even unprotected phenols (3s)
were tolerated. This example illustrates that nucleo-
philic attack of OH to the palladium(II) intermediates
within the catalytic cycle does not compete with the
efficacy of this reaction.
Entry Product
Rn
Yield [%][b]
1
2
3
R1 =R2 =H
77% (3a)
R1 =OMe; R2 =H 93% (3b)
R1 =H; R2 =Cl
65% (3c)
4
5
6
R1 =R2 =H
88% (3d)
52% (3e)
R1 =F; R2 =H
R1 =NO2; R2 =H 91% (3f)
7
60% (3g)
8
9
R1 =H
66% (3h)
80% (3i)
R1 =OMe
10
11
80% (3j)
70% (3k)
12
61% (3l)
13
14
90% (3m)
75% (3n)
68% (3o)
The data summarized above advocate the notion
that both BCB 2 and a,b-styrenes 3 might share
common synthetic pathways. As a result, we next
turned our attention to unravel the mechanistic di-
chotomy when using ligands of type L6. We recently
proposed that BCB (2) could derive from Pd(IV)[18]
intermediates II[19] and III, respectively (mechanism
A, Scheme 2);[4b] accordingly, there are in principle
two conceivable mechanisms for the preparation of
a,b-styrene derivatives: (a) reductive elimination of II
via 1,4-palladium migration[6] affording an acylpalla-
dium(II) intermediate (IV) followed by CO extrusion
and a final reductive elimination (mechanism B,
Scheme 2) or (b) CO extrusion from III leading to VI
followed by b-hydride elimination and a final reduc-
15
[a]
Aryl bromide (0.50 mmol), PdACTHNUTRGNENUG(OAc)2 (2 mol%), L6
(3 mol%), Cs2CO3 (1.30 equiv.), toluene (0.50M) at
1108C.
[b]
Isolated yields, average of at least two runs.
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Table 2. Scope for the synthesis of a-styrene derivatives in a
tive elimination from an intermediate of type VII. At
present we cannot rule out intermediates VIII or IX
via concerted metalation-deprotonation mechanisms
promoted by carbonate bases.[20]
regio- and diastereoselective manner.[a,b]
Although acylpalladium species have been postulat-
ed by Larock,[6] their prominent role for the synthesis
of a-styrenes 3 still needs to be clarified.[7] As a
result, we decide to gather indirect evidence through
deuterium-labelling experiments (Scheme 3). If a
mechanism via VI would be operating, we hypothe-
sized that the reaction of 1d-D would result in a loss
of the deuterium label; on the contrary, in mechanism
B, the deuterium label would be transferred to the
aryl moiety. Experimentally, we found that the reac-
tion of 1d-D gave styrene 3d-D as the only product in
85% isolated yield (Scheme 3). Notably, 1d-D4 exclu-
sively afforded 3d-D3, thus suggesting that only the
hydrogen (or deuterium) from the aldehyde motif mi-
grated to the aryl backbone.[21] While these experi-
ments might not be taken as a definitive proof, we be-
lieve they provide a strong evidence for mechanism B
(Scheme 3).
Additionally, we hypothesized that acylpalladium
intermediate IV (or IX) could be trapped by addition
of nucleophiles in the reaction mixture. Gratifyngly,
the reaction of 1a in the presence of CH3OH,
CD3OD, n-BuOH or pyridinylmethanol at 608C af-
forded the corresponding esters 4a, 4a-D3, 4b and 4c
in good yields, respectively;[22] not even traces of sty-
rene 3a were identified in the crude reaction mixtures.
We believe these experiments additionally support
Entry
1
Product
Yield [%][b]
71% (3p), 16.5:1 (E:Z)
2
3
92% (3q), 22.2:1 (E:Z)
87% (3r), 10:1 (E:Z)
74% (3s),[c] 14.3:1 (E:Z)
4
[a]
As for Table 1.
Isolated yields, average of at least two runs.
Cs2CO3 (2.60 equiv.) was used.
[b]
[c]
Scheme 2. Possible mechanistic scenarios.
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Mechanistic Switch via Subtle Ligand Modulation: Palladium-Catalyzed Synthesis of a,b-Substituted Styrenes
Scheme 3. Mechanistic considerations.
the intermediacy of acylpalladium intermediates of Acknowledgements
type IV (or IX).
We thank the ICIQ Foundation, Consolider Ingenio 2010
In summary, we have found that a subtle modifica-
tion on the phosphine ligand backbone leads to a new
mechanistic manifold for the preparation of configu-
(CSD2006-0003) and MICINN (CTQ2009-13840) for finan-
cial support. Dr. Arkaitz Correa is gratefully acknowledged
for preliminary results. Johnson Matthey, Umicore and
Nippon Chemical Industrial are acknowledged for gifts of
metal and ligand sources. R.M. and A.-F.G. thank MICINN
for a RyC predoctoral fellowship (FPU).
À
rationally pure a,b-substituted styrenes via C H
bond-functionalization. This procedure is distinguish-
ed by its excellent chemoselectivity and wide scope.
Further investigations to investigate the preparative
scope of related reactions as well as the isolation of
the reaction intermediates are currently underway in
our laboratories.
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An oven-dried screw-cap test tube containing a stirring bar
was charged with PdACHTNUTRGNE(NUG OAc)2 (2.3 mg, 2.0 mol%), 1,3-dicyclo-
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1
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(s, 1H), 5.18 (d, J=1.4 Hz, 1H), 2.25 (s, 3H); 13C NMR
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À
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