Palladium-catalyzed chemoselective allylic substitution, suzuki-miyaura cross-coupling, and allene formation of bifunctional 2-B(pin)-substituted allylic acetate derivatives

Article abstract of DOI:10.1002/chem.201402353

A formidable challenge at the forefront of organic synthesis is the control of chemoselectivity to enable the selective formation of diverse structural motifs from a readily available substrate class. Presented herein is a detailed study of chemoselectivity with palladium-based phosphane catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts, and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki-Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity. Studies on the chemoselectivity of Pd catalysts in their reactivity with boron-bearing allylic acetate derivatives led to the development of diverse and practical reactions with potential utility in synthetic organic chemistry.

Full text of DOI:10.1002/chem.201402353

DOI: 10.1002/chem.201402353
Full Paper
&
Synthetic Methods
Palladium-Catalyzed Chemoselective Allylic Substitution, Suzuki–
Miyaura Cross-Coupling, and Allene Formation of Bifunctional
2-B(pin)-Substituted Allylic Acetate Derivatives**
Byeong-Seon Kim, Mahmud M. Hussain, Nusrah Hussain, and Patrick J. Walsh*[a]
Abstract: A formidable challenge at the forefront of organic
synthesis is the control of chemoselectivity to enable the se-
lective formation of diverse structural motifs from a readily
available substrate class. Presented herein is a detailed study
of chemoselectivity with palladium-based phosphane cata-
lysts and readily available 2-B(pin)-substituted allylic ace-
tates, benzoates, and carbonates. Depending on the choice
of reagents, catalysts, and reaction conditions, 2-B(pin)-sub-
stituted allylic acetates and derivatives can be steered into
one of three reaction manifolds: allylic substitution, Suzuki–
Miyaura cross-coupling, or elimination to form allenes, all
with excellent chemoselectivity. Studies on the chemoselec-
tivity of Pd catalysts in their reactivity with boron-bearing al-
lylic acetate derivatives led to the development of diverse
and practical reactions with potential utility in synthetic or-
ganic chemistry.
Introduction
One of the most significant impediments to the efficient syn-
thesis of complex natural and non-natural products is the low
level of chemoselectivity exhibited by many reagents and cata-
lysts.[1,2] To compensate for poor chemoselectivity, synthetic or-
ganic chemists have been forced to design and implement
elaborate protecting-group strategies in their construction of
complex natural products.[3]
Although considerable effort has been devoted to under-
standing chemoselectivity with classical reagents, fewer studies
have focused on chemoselectivity with transition-metal cata-
lysts. Given the increasing importance of transition-metal-cata-
lyzed reactions in organic synthesis,[4] we set out to optimize
and control catalyst chemoselectivity in some of the most syn-
thetically valuable transition-metal-catalyzed reactions, namely,
the Tsuji–Trost allylic substitution[5–9] and Suzuki–Miyaura cross-
coupling reactions.[10,11] Palladium–phosphane complexes cata-
lyze both reactions, even though the mechanistic pathways
are distinct (Figure 1). Allylic substitutions begin with coordina-
tion of the substrate to a palladium(0) center to form a p com-
plex (Figure 1, right-hand cycle). Backside attack by the palladi-
um atom on the carbon atom bearing the leaving group in an
oxidative ionization generates a p-allyl–palladium complex. Ex-
ternal nucleophilic addition to the p-allyl–palladium complex
Figure 1. Catalytic cycles of the Tsuji–Trost allylic substitution (right) and
Suzuki–Miyaura cross-coupling reaction (left).
followed by liberation of the product regenerates the palladi-
um(0) center. In contrast, the palladium(0) center undergoes
oxidative addition in the Suzuki–Miyaura cross-coupling with
an aryl halide to form the palladium(II)–aryl halide intermediate
(Figure 1, left-hand cycle).[12] Transmetallation with boronic acid
derivatives and bases provides the second PdÀC bond.[13] Re-
ductive elimination forms the CÀC bond of the product and re-
generates the palladium(0) center. More broadly speaking, the
palladium atom does not come into contact with the leaving
group or nucleophile in the allylic substitution,[14] whereas the
palladium center directly interacts with both coupling partners
in the Suzuki–Miyaura cross-coupling. The common denomina-
tor in these reactions is the ability of the same palladium cata-
lyst to promote both processes.
[a] B.-S. Kim, Dr. M. M. Hussain, N. Hussain, Prof. Dr. P. J. Walsh
P. Roy and Diana T. Vagelos Laboratories
Department of Chemistry, University of Pennsylvania
231 S. 34th Street, Philadelphia, PA 19104-6323 (USA)
Fax: (+1)12155736743
E-mail: pwalsh@sas.upenn.edu
With this backdrop, we asked a fundamental question:
Could the chemoselectivity of a palladium–phosphane-based
catalyst toward an allylic acetate, an aryl halide, and a vinyl
[**] B(pin)=4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402353.
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boronate ester be controlled by careful choice of reagents and
conditions? This report answers this question and introduces
a third orthogonal reaction pathway of 2-B(pin)-substituted
(B(pin)=4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) allylic ace-
tates that generates allenes with excellent chemoselectivity.
Based on the highly chemoselective reactions developed
herein, 2-B(pin)-substituted allylic acetate derivatives are useful
“linchpins” that can be utilized for the preparation of an array
of small molecules, including functionalized allylic amines and
malonates, a-amino ketones, trisubstituted allylic esters and
carbonates, and 1,3-disubstituted allenes. A portion of this
work related to allylic substitution has been reported previous-
ly.[15] Herein, we disclose the scope of the Suzuki–Miyaura
cross-coupling and allene formation.
Scheme 1. One-pot synthesis of 2-B(pin)-substituted allylic acetates. Cy=cy-
clohexyl.
stituent. The partially occupied p orbital of the B(pin) boron
center dramatically raises the barrier to transmetalation and
the vinylÀBCy2 bond undergoes selective B to Zn transmetala-
tion at À788C to generate the heterobimetallic intermediate.
The addition of the ZnÀC bond to an aldehyde and quenching
the resulting alkoxide with acetic anhydride provided 2-B(pin)-
substituted (E)-allylic acetate 1 in 52–85% yield (Scheme 1).
The reaction worked well with linear and branched aliphatic al-
dehydes (67–85% yield). Likewise, benzaldehyde and its deriva-
tives with electron-withdrawing or electron-donating substitu-
ents proved to be good reaction partners (52–78% yield). Cin-
namaldehyde gave 60% yield of the rearranged dienyl product
formed on isomerization of the acetate moiety (see the Sup-
porting Information). Alkynyldioxaborolanes can be derived
from either aliphatic, aromatic, or functionalized alkynes (R2 =
nBu, (CH2)4Cl, Ph). The scalability of this method was demon-
strated in the synthesis of 2-B(pin)-substituted allylic acetates
in gram quantities, thus positioning us to explore their reactivi-
ty and chemoselectivity with palladium–phosphane-based
catalysts.
Results and Discussion
The application of multifunctional substrates in tandem reac-
tions enables the rapid construction of diverse chemical arrays.
Key to the success of such strategies is the ability to control
chemoselectivity by controlling the relative rate of the process-
es that lead into different reaction manifolds. In this study, we
have embedded a vinyl boronate ester in an allylic acetate
with the goal of controlling the chemoselectivity between pal-
ladium-catalyzed Tsuji–Trost allylic substitution, Suzuki–Miyaura
cross-coupling, and allene-forming reactions (Figure 2). Given
that the same palladium catalysts promote allylic substitution,
cross-coupling, and allene-formation reactions, we focused on
reaction conditions and reagents to control the chemoselectiv-
ity.
Allylic substitution of 2-B(pin)-substituted allylic acetates:
controlling the chemoselectivity
At the outset of our studies, we were concerned about the
ability of 2-B(pin)-substituted allylic acetates to successfully un-
dergo the Tsuji–Trost allylic substitution. Although most acyclic
allylic acetate substrates are mono- or disubstituted,[7] thus
leading to mono or 1,3-disubstituted p-allyl intermediates, the
reactivity of 1,2,3-trisubstituted allylic derivatives toward allylic
ionization with palladium catalysts has been relatively unex-
plored.[27–29] A few examples of allylic acetate derivatives con-
taining a boron atom at the 2 position[30,31] have been used in
transition-metal-catalyzed allylic substitution reactions,[31] al-
though some examples of 3-boron-substituted analogues have
been generated or proposed as intermediates.[32–44] Despite the
lack of clear precedent, the conjugate base of dimethylmalo-
nate and several primary and secondary amines participated in
allylic substitution. For example, 2-B(pin)-substituted allylic ace-
tate 1a underwent substitution with sodium dimethylmalonate
(Table 1, entry 1) to furnish the 2-B(pin)-substituted allylic alky-
lation product 2a in 81% yield. Morpholine, N-methylbenzyla-
mine, and piperidine were good substrates that afforded 2-
B(pin)-substituted allylic amines 2b–d in 79–83% yield
(Table 1, entries 2–4). Benzyl amine, used as the representative
primary amine, also underwent a single allylic substitution to
produce 2e in 65% yield (Table 1, entry 5). The unsymmetrical
dialkyl substrate 1c underwent substitution with morpholine
Figure 2. Potential reactions of 2-B(pin)-substituted allylic esters.
Synthesis of 2-B(pin)-substituted allylic acetates
A crucial step toward the development of new synthetic meth-
ods is the introduction of reliable and scalable procedures to
prepare the substrates. By using our stereodefined 1-alkenyl-
1,1-heterobimetallic reagents, the 2-B(pin)-substituted allylic
acetates were easily prepared in one pot from readily available
alkynyldioxaborolanes (Scheme 1).[15–19] Thus, hydroboration of
air-stable alkynyldioxaborolanes with dicyclohexylborane gen-
erates 1-alkenyl-1,1-diboro intermediates as the only observa-
1
ble regioisomer (as determined by H NMR spectroscopic anal-
ysis).[20–26] Although neither BÀC bond is very nucleophilic, the
boron centers are electronically quite different due to reso-
nance donation from the pinacolato group of the B(pin) sub-
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catalyzed by [{Pd(allyl)Cl}2] and PPh3 (1:4) with nucleo-
philic attack at the less-hindered position of the p-
allyl unit with excellent regioselectivity (>20:1;
Table 1, entry 6). Isomeric 2-B(pin)-substituted allylic
acetates 1d and 1 f each underwent reaction with
morpholine and NaCH(CO2Me)2 by using a catalyst
generated from Pd(OAc)2 and PPh3 (10 and 20 mol%,
respectively) to afford the same regioisomer of the al-
lylic substitution products 2g and 2h with a regiose-
lectivity of ꢀ10:1 (Table 1, entries 7–10). The styryl de-
rivative 1d was less reactive than 1 f toward the same
palladium catalyst, thus resulting in lower yields of
the substitution products 2g and 2h (Table 1, en-
tries 7–10; 45 vs. 80% and 51 vs. 79%, respectively).
In contrast to most p-allyl–palladium complexes with
a single aryl group at the terminus, allylic substitution
took place at the benzylic position in each case. The
reversal in regioselectivity is due to formation of the
anti aryl p-allyl isomer, which exhibits enhanced reac-
tivity at the benzylic position, as outlined in our relat-
ed study.[19] Analogous reactions with electron-with-
drawing or electron-donating substituents on the aryl
groups (1g–j) provided the benzylic substitution
products 2i–l in 75–92% yield of the isolated product
with a regioselectivity of >10:1 (Table 1, entries 11–
14). The unique regioselectivity observed with aryl-
substituted substrates enables the synthesis of ben-
zylic amines, which are common structural motifs in
medicinal chemistry.[45]
Table 1. Palladium-catalyzed allylic substitution of 2-B(pin)-substituted allylic ace-
tates.
Entry Acetate
Nucleophile
Product
Yield
[%][a]
1
1a NaCH(CO2Me)2
2a 81[b]
2
1a
2b 83[b]
3
4
5
1a HNMeBn
2c 80[b]
2d 79[b]
2e 65[b]
1a
1a BnNH2
6
7
8
1c
1d
1 f
2 f 60[b,d]
2g 45[c–e]
2g 80[c,d]
Development of tandem reactions initiated with
allylic substitution
Tandem reactions are important in streamlining or-
ganic synthesis, thus enabling a rapid increase in mo-
lecular complexity while minimizing synthetic and iso-
lation steps.[46–51] We, therefore, undertook develop-
ment of tandem processes with 2-B(pin) allylic ace-
tates that began with allylic substitutions and is fol-
lowed by reactions of the vinyl boronate ester.[52]
9
1d NaCH(CO2Me)2
1 f NaCH(CO2Me)2
2h 51[b,d]
2h 79[b,d]
10
Tandem allylic substitution/oxidation sequences
One of the most utilized transformations of the BÀC
bond is its oxidation. In the case of vinyl boronate
esters, the oxidation products are ketones and allylic
substitution/oxidation will lead to a-functionalized ke-
tones. For the tandem allylic substitution/oxidation
process, the allylic substitution was performed as out-
lined in Table 1.
11
1g
2i 75[c,d]
12
13
1g CH2(CO2Me)2
1h CH2(CO2Me)2
2j 90[c,d,f]
2k 92[c,d,f]
After the allylic substitution, the crude reaction mix-
ture was treated with alkaline hydrogen peroxide to
oxidize the BÀC bond. When NaCH(CO2Me)2 was em-
ployed as the nucleophile in the substitution, subse-
quent oxidation generated the substituted ketone 3a
in 85% yield in this one-pot procedure (Table 2,
entry 1). Secondary amines performed well in the
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and represents an umpolung ketone (Scheme 2).[55–59]
a-Substituted ketones are difficult to synthesize by
using standard p-allyl chemistry. Trost and Gowland
demonstrated that 2-alkoxy allylic acetates underwent
allylic substitution to afford enol ethers that were hy-
drolyzed to afford ketones (Scheme 3A).[55] Organ
et al. performed similar chemistry with allylic phenox-
ides (Scheme 3B).[59]
Table 1. (Continued)
Entry Acetate
Nucleophile
Product
Yield
[%][a]
Enantioenriched allylic amines are valuable synthet-
ic intermediates and are common in natural products
and compounds with biological activity.[45,60] One pos-
sible approach to access such compounds is through
allylic substitution of enantioenriched 2-B(pin)-substi-
tuted allylic acetates. With this approach in mind, 2-
14
1j CH2(CO2Me)2
2l 80[c,d,f]
[a] Yield of the isolated and purified products. [b] [{Pd(allyl)Cl}2]. [c] Pd(OAc)2. [d] Re-
gioselectivities were ꢀ10:1 (except for entry 6) and were determined by 1H NMR
spectroscopic analysis of unpurified reaction mixtures. [e] Recovered starting materi-
al=30%. [f] Bis(trimethylsilyl)acetamide and catalytic KOAc were used.
Table 2. One-pot synthesis of a-substituted ketones through tandem al-
lylic substitution/oxidation.
Scheme 2. 2-B(pin)-substituted allylic substitution products as synthons for
a-electrophilic carbonyl substrates.
B(pin)-substituted allylic acetate 1 f of 80% ee was prepared
using the Sharpless–Katsuki kinetic resolution[61] of 2-B(pin) al-
lylic alcohol 4a[16] and subsequent acetylation with acetic an-
hydride (Scheme 4).[15] We then conducted an allylic substitu-
tion of 1 f and morpholine to form 2-B(pin)-substituted benzyl-
amine 2b in 82% yield without loss of enantiomeric excess
(Scheme 5). A tandem allylic substitution/BÀC bond oxidation
with NaBO3·H2O generated the a-amino ketone with 77% ee in
80% yield (Scheme 5). Unfortunately, by employing alkaline
H2O2 in place of NaBO3·H2O for the oxidation led to racemiza-
tion of the amino ketone product.
Entry
1
Allyl
acetate
a-Substituted ketones
Yield
[%][a]
1a
1a
3a
3b
85
82
2
3
4
1a
1a
3c
81
75
Tandem allylic substitution/Suzuki–Miyaura cross-coupling
3d
Allylic amines are present in molecules with diverse pharmaco-
logical properties, such as Acrivastine (Semprex),[45,62] Flunari-
zine (Sibelium, Ca-channel blocker),[63,64] and several g-amino-
butyric acid (GABA) uptake inhibitors.[65] In the synthesis of al-
lylic amines, it is usually important that the geometry about
the C=C bond can be controlled to provide a single product.
With that aim in mind, we sought to achieve a one-pot allylic
substitution/Suzuki–Miyaura cross-coupling reaction of 2-
B(pin)-substituted allylic acetates. As alluded to in Figure 1, it is
conceivable that the allylic substitution and Suzuki–Miyaura
cross-coupling could be catalyzed with the same palladium
source. One of the key factors to turn on the Suzuki–Miyaura
cross-coupling will be the activation of the BÀC bond, initiated
by hydrolysis to the boronic acid group. It is noteworthy that
a successful allylic substitution/cross-coupling sequence ena-
bles the synthesis of a variety of 2-arylated allylic amines and
malonates from easily accessible 2-B(pin)-substituted allylic
acetates, aryl halides, amines, and malonates. The allylic substi-
tution of 2-B(pin) allylic acetate 1a and morpholine was per-
formed following the conditions given in entry 8 of Table 1.
5
6
1 f
1 f
3e
3e
65
78[b]
[a] Yield of the isolated and purified products. [b]Allylic substitution car-
ried out with Pd(OAc)2 (5 mol%) and PPh3 (10 mol%) at room tempera-
ture and oxidation carried out with NaBO3·H2O (3 equiv) in THF/H2O (1:1)
at room temperature.
tandem allylic substitution/oxidation sequence to form a-
amino ketones 3b–e in 65–82% yield (Table 2, entries 2–5).
Both aliphatic (Table 2, entries 1–4) and 1-phenyl-2-B(pin)-sub-
stituted allylic acetates (Table 2, entries 5 and 6) were good
substrates for the tandem process. A milder oxidation with
NaBO3·H2O[53,54] resulted in an increased yield of 3e (Table 2,
entry 5 vs. 6).
It is noteworthy that the tandem allylic substitution/oxida-
tion sequence is equivalent to an a-carbonyl cation synthon
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Scheme 3. Trost’s (A) and Organ’s (B) approach to access ketone surrogates via allylic substitution reaction of 2-alkoxy substituted allylic acetates and phenox-
ides.
tries 9 and 10). Importantly, in all cases, the geometry of the
double bond was maintained.
Related palladium-catalyzed tandem reactions have been re-
ported by the groups of Kazmaier and Pucheault. Kazmaier
and co-workers established one-pot allylic amination/Stille cou-
plings of b-stannylated allylic carbonates to provide allylic
amine derivatives (Scheme 6A).[66,67] This approach provides
disubstituted allylic amines and is complementary to the
chemistry shown in Table 3, which generates trisubstituted
Scheme 4. Kinetic resolution of 2-B(pin)-substituted allylic alcohol 4 to pre-
pare enantioenriched 2-B(pin)-substituted allylic acetate 1 f. DIPT=N,N-diiso-
propyltryptamine, TBHP=tert-butyl hydroperoxide.
Scheme 6. A) One-pot allylic amination/Stille coupling reaction developed
by Kazmaier and co-workers. B) Tandem Tsuji–Trost allylic substitution/
Suzuki–Miyaura cross-coupling reaction developed by Pucheault and co-
workers.
Scheme 5. Allylic substitution of enantioenriched 1 f with morpholine fol-
lowed by oxidation with sodium perborate.
After completion of the substitution, as judged by TLC analysis,
the reaction mixture was diluted with THF/water (10:1, v/v)
and then Cs2CO3, and aryl halide were added to the reaction
mixture, which was heated (Table 3). After workup, the 2-arylat-
ed trisubstituted allylic amine derivatives 5a–c were isolated in
52–70% yield (Table 3, entries 1–3), including the 3-pyridyl de-
rivative. Likewise, unsymmetrical 2-B(pin)-substituted allylic
acetate 1 f underwent the tandem allylic substitution with
morpholine/cross-coupling to yield trisubstituted benzylic
amines 5d–f in 50–70% yield (Table 3, entries 4–7). Aryl bro-
mide coupling partners with electron-donating or electron-
withdrawing substituents were well tolerated. Iodobenzene
gave a lower yield than the aryl bromides (Table 3, entries 4
and 5). Tandem Suzuki–Miyaura cross-coupling of the allylic
substitution product 2h with sodium malonate failed with io-
dobenzene, leading to recovery of the allylic substitution prod-
uct 2h (43% yield; Table 3, entry 8). In contrast, 1 f and 1h un-
derwent tandem allylic substitution with NaCH(CO2Me)2/cross-
coupling with bromobenzene in 51 and 61% yield (Table 3, en-
products. After our initial report,[15] Pucheault and co-workers
followed with a tandem palladium-catalyzed Tsuji–Trost allylic
substitution/Suzuki–Miyaura cross-coupling of g-borylated allyl-
ic acetates (Scheme 6B).[42] This reaction provides traditional al-
lylic substitution products that can be generated in an efficient
tandem fashion. With respect to the synthesis of compound li-
braries, our approach furnishes 1,2,3-trisubstituted allyl prod-
ucts, which contain an additional point of diversity over those
in Scheme 6. To expand the synthetic utility of 2-B(pin)-substi-
tuted allylic ester derivatives further, we set out to reverse the
chemoselectivity by performing the Suzuki–Miyaura cross-cou-
pling in the presence of the allylic ester derivatives.
Chemoselective Suzuki–Miyaura cross-coupling in the
presence of allylic leaving groups
As demonstrated in Tables 1–3, allylic substitutions of 2-B(pin)-
substituted allylic acetates proceed readily despite the large
size of the B(pin) group. We asked the question whether the
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Precedents for the oxidative addition of aryl
halides in the presence of allylic acetates
Table 3. Tandem allylic substitution/Suzuki–Miyaura cross-coupling of 2-B(pin)-substituted
allylic acetates.
The chemoselectivity of palladium-based cata-
lysts has been investigated by several
groups.[73–76] Lautens et al. developed a reductive
coupling of allylic acetates that involves b-OAc
elimination (Scheme 7A).[77,78] Jiao and co-work-
ers demonstrated a complementary Heck reac-
tion of allylic acetates that undergo traditional b-
hydride elimination rather than b-acetate elimina-
tion (Scheme 7B).[79] Genet and co-workers con-
ducted a chemoselective Suzuki–Miyaura cross-
coupling reaction of g-borylated allylic acetates
with activated alkenyl iodides (Scheme 7C).[80] Ko-
Entry Allyl acetate
NuÀ/NuH
Ar-X
Product
Yield
[%][a]
4-Me-
C6H4-
Br
1
2
3
1a
1a
1a
5a 70
4-
MeO-
C6H4-
Br
3-
C5H3N-
Br
5b 65
5c 52
ˇ
´
covsky and co-workers investigated a Suzuki–
Miyaura cross-coupling reaction of simple g-bory-
lated allylic carbonates with aryl iodides
(Scheme 7D).[39] The cross-coupling products
were isolated in low-to-moderate yields (32%
average yield for 15 substrates), and the reac-
tions failed with aryl bromides. Although the
conditions and catalysts used in Scheme 7A–D
are different, the trend suggests that an oxidative
addition of sp2 CÀI bonds is faster than ionization
of allylic acetates, but the increased reactivity of
carbonates results in low cross-coupling yields
(Scheme 7D).
4
5
1 f
1 f
Ph-I
5d 50
5d 70
Ph-Br
4-
MeO-
C6H4-
Br
4-O2N-
C6H4-
Br
6
1 f
5e 69
7
8
1 f
5 f 59
[b]
1 f NaCH(CO2Me)2 Ph-I
–
In the case of aryl bromides, Trost, Malhotra,
and Chan recently found that tert-butoxycarbonyl
(Boc)-activated allylic alcohols undergo allylic
substitution in the presence of an aryl bromide
(Scheme 7E).[81] Interestingly, Organ et al. demon-
strated that the same palladium catalyst can be
used to selectively afford either the allylic substi-
tution or vinylic cross-coupling products from
9
1 f NaCH(CO2Me)2 Ph-Br
5g 51
10
1h NaCH(CO2Me)2 Ph-Br
5h 61
[a] Yield of the isolated and purified products. [b] No cross-coupling product was observed,
but 43% of 2h was isolated.
polyfunctionalized
olefin
building
blocks
(Scheme 7F).[59,72] Due to the diverse substrates,
catalysts, and conditions employed in Scheme 7,
only a fragmented picture of the reactivity land-
Suzuki–Miyaura cross-coupling reaction could be conducted in
the presence of the allylic ester derivatives. The determining
factor that controls the bifurcation between the two reaction
manifolds is the relative rate of oxidative ionization of the allyl-
ic ester versus the oxidative addition of the aryl halide (Fig-
ures 1 and 2). Although there have been many studies on the
oxidative addition of aryl and vinyl halides and numerous in-
vestigations into the oxidative ionization of allylic acetates,[12,14]
very few studies compare the relative rates of these two pro-
cesses.[68–71] As pointed out by Organ et al.,[59,72] in cases in
which a comparison was made, the substrates employed were
frequently biased by either steric effects or conformational re-
strictions that disfavor the proper orbital alignment needed for
the allylic ionization to proceed.
scape is provided. A systematic study is necessary to map the
relative reactivity of aryl halides in the Suzuki–Miyaura cross-
coupling in the presence of allylic ester derivatives of varying
reactivity.
Development of orthogonal reaction conditions for the
palladium-catalyzed allylic substitution and Suzuki–Miyaura
cross-coupling
To favor the Suzuki–Miyaura cross-coupling manifold, the palla-
dium(0) form of the catalyst would need to be rapidly cap-
tured by the aryl halide. It is well known that the relative rate
of oxidative addition of a homologous series of aryl halides is
Ar-I>Ar-Br>Ar-Cl.[12,13] We envisioned that an aryl iodide
would rapidly undergo oxidative addition to a Pd0 center to
generate a PdII–aryl iodide intermediate, which is unreactive
toward oxidative ionization of the allylic acetate (Figure 1). To
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Optimization of Suzuki–Miyaura cross-coupling of 2-B(pin)-
substituted allylic acetates
Lowering the catalyst loading from 15 (Scheme 8 and Table 4,
entry 1) to 10 mol% Pd resulted in decreased yield of the
cross-coupled product 6a (Table 4, entry 2). To optimize the
coupling, different phosphane ligands were employed. The
bulky P(o-Tol)3 led to formation of the product in only 20%
yield (Table 4, entry 3). Bidentate phosphane ligands gave poor
yields of the arylated allylic acetates (27–62% yield; Table 4,
entries 4–6). Subjecting the di-n-butyl allylic acetate 1a to vari-
ous Pd precursors showed that Pd(OAc)2/P(tBu)3, [Pd(PPh3)4],
and [PdCl2(PPh3)2]/PPh3 all formed suitable catalysts for the
chemoselective activation of iodobenzene versus oxidative ion-
ization of the allylic acetate (Table 4, entries 7–9). Several bases
were screened (i.e., Cs2CO3, CsF, and K3PO4), of which Cs2CO3
gave the highest yield (Table 4, entries 10–12). When toluene
was used in place of THF or dioxane, the catalyst loading
could be lowered to 5 mol% with shorter reaction times and
up to 96% yield (Table 4, entries 13–16). Further decreasing
the catalyst loading, however, led to incomplete reactions and
lower yields. A 1:3 ratio of Pd(OAc)2 to PPh3 was optimal for
catalyst formation (95–96% yield; Table 4, entries 13 and 14)
and suitable for evaluation of the scope of the cross-coupling
reaction.
Substrate scope of Suzuki–Miyaura cross-coupling of 2-
B(pin)-substituted allylic acetates with aryl iodides
Scheme 7. Precedents for the oxidative addition of aryl halides in the pres-
ence of allylic acetates (see the text for discussion; dba=dibenzylideneace-
tone).
To determine the substrate scope for the Suzuki–Miyaura
cross-coupling of 2-B(pin)-substituted allylic acetates, we decid-
ed to vary the allylic acetate (R1 and R2) and the coupling part-
ner (ArÀI). Aliphatic 2-B(pin)-substituted allylic acetate 1a
cleanly provided the arylated allylic acetates 6a–c in good-to-
excellent yields with several aryl iodides bearing electron-with-
drawing or electron-donating groups (60–96% yield; Table 5,
entries 1–3). a-Branching is tolerated in the allylic acetate, as
shown from the reaction of the allylic acetate 1b with iodo-
benzene (67% yield; Table 5, entry 4). The styryl-derived allylic
acetate 1d gave 92–99% yield of the cross-coupled products
6e and 6 f (Table 5, entries 5 and 6). The isomeric allylic acetate
1 f gave the Suzuki–Miyaura cross-coupled products 6g and
6h in 70–75% yield (Table 5, entries 7 and 8). The isomeric
pairs in entries 5 and 7 and entries 6 and 8 (Table 5) each un-
dergo Suzuki–Miyaura cross-coupling with no scrambling of
the acetate position. These results indicate that the oxidative
ionization of the acetate unit is not reversible or does not dis-
rupt a tight ion pair under these conditions.[14]
explore the possibility of conducting the Suzuki–Miyaura cross-
coupling of 2-B(pin)-substituted allylic acetates, the di-n-butyl
substrate 1a was combined with iodobenzene, Pd(OAc)2
(15 mol%), PPh3 (30 mol%), and Cs2CO3 (3 equiv) in a THF/
water reaction mixture (10:1; Scheme 8). A clean reaction oc-
Scheme 8. Suzuki–Miyaura cross-coupling of 2-B(pin)-substituted allylic ace-
tate 1a.
curred at 708C to generate 2-aryl-substituted allylic acetate 6a
in 90% yield of the isolated product. The cross-coupling was
incomplete and gave diminished yields at lower catalyst load-
ing. We set out to optimize the Suzuki–Miyaura cross-coupling
reaction of 2-B(pin)-substituted allylic acetates to lower the
catalyst loading, increase the yields, and develop a broad sub-
strate scope (Scheme 8).
Scheme 9. Gram-scale Suzuki–Miyaura cross-coupling reaction of 1e.
Chem. Eur. J. 2014, 20, 11726 – 11739
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provide the arylated allylic acetates 6a–c, 6j, and 6k
in moderate-to-excellent yields (54–91% yield;
Table 6, entries 1–5). a-Branching is tolerated, as
shown in the reaction of the allylic acetate 1b with
bromobenzene (87% yield; Table 6, entry 6). The
styryl-derived allylic acetate 1d gave an excellent
yield of the cross-coupled product 6 f with 1-bromo-
4-nitrobenzene (90% yield; Table 6, entry 7).
Table 4. Optimization of Pd-catalyzed Suzuki–Miyaura cross-coupling of 2-B(pin)-sub-
stituted allylic acetate 1a.
Entry Pd/ligand[a]
Base[b]
Solvent[c] Conc.
t
Yield
[m][d]
[h] [%][e]
With the isomeric allylic acetate 1 f, the Suzuki–
Miyaura cross-coupled product 6h was obtained in
80% yield (Table 6, entry 8) with no observed scram-
bling of the acetate position. Heteroaryl bromides
such as 2- or 3-bromothiophene underwent cross-
coupling with 1a in 74–82% yield (Table 6, entries 9
and 10). Having demonstrated that aryl iodides and
bromides undergo oxidative addition faster than 2-
B(pin)-substituted allylic acetates undergo oxidative
ionization under these conditions, we wanted to de-
termine whether this trend would continue to hold
with more reactive allylic substrates.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(OAc)2/PPh3 (15 mol%, 1:2)
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 THF
0.022 24 90[f]
0.022 48 62
0.022 48 20
0.022 48 32
0.022 48 27
0.022 48 62
0.022 48 80
0.022 36 87
Pd(OAc)2/PPh3 (10 mol%, 1:2)
Pd(OAc)2/P(o-Tol)3 (10 mol%, 1:2)
Pd(OAc)2/DPPP (10 mol%, 1:1)
Pd(OAc)2/DPPE (10 mol%, 1:1)
Pd(OAc)2/DPPF (10 mol%, 1:1)
Pd(OAc)2/P(tBu)3 (10 mol%, 1:1)
[Pd(PPh3)4] (10 mol%)
[PdCl2(PPh3)2]/PPh3 (10 mol%, 1:1) Cs2CO3 THF
[PdCl2(PPh3)2]/PPh3 (10 mol%, 1:1) Cs2CO3 dioxane
[PdCl2(PPh3)2]/PPh3 (10 mol%, 1:1) CsF
[PdCl2(PPh3)2]/PPh3 (10 mol%, 1:1) K3PO4
0.08
0.08
0.08
0.08
0.17
0.17
0.17
0.17
24 71
18 61
18 25
24 52
dioxane
toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Pd(OAc)2/PPh3 (10 mol%, 1:3)
Pd(OAc)2/PPh3 (5 mol%, 1:3)
[PdCl2(PPh3)2]/PPh3 (5 mol%, 1:1)
[Pd(PPh3)4] (10 mol%)
4
96[f]
18 95[f,g]
18 93[f,g]
18 96[f,g]
Substrate scope of Suzuki–Miyaura cross-coupling
of 2-B(pin)-substituted allylic benzoates and
carbonates
[a] The mol% of Pd is given with the molar ratio of Pd/phosphane in parenthesis.
[b] Three equivalents of base and iodobenzene were used unless otherwise noted.
[c] Solvent/H2O=10:1. [d] Ratio of 1a (mmol)/solvent (mL). [e] Yield was determined
by integration of the 1H NMR spectra of the crude reaction mixture with 1,4-dimethox-
ybenzene as an internal standard. [f] Yield of the isolated and purified products.
[g] Two equivalents of Cs2CO3 and iodobenzene were used. DPPE=1,2-bis(diphenyl-
phosphino)ethane, DPPF=1,1’-bis(diphenylphosphino)ferrocene, DPPP=1,3-bis(di-
phenylphosphino)propane.
To delineate further how differences in the substrate
reactivity impact the reaction outcome, we turned
our attention to increasing the reactivity of the allylic
moiety by using more active leaving groups. Allylic
benzoates and carbonates are known to be more re-
active in allylic substitutions than acetates, with car-
To demonstrate scalability of the Suzuki–Miyaura cross-cou-
pling 2-B(pin)-substituted allylic acetates, 1e was subjected to
cross-coupling conditions on a scale of 5 mmol to give
1.3 grams of the 2-arylated allylic acetate 6i in 80% isolated
yield (Scheme 9). Given that aryl iodides react faster with palla-
dium(0) than allylic acetates, we next examined less reactive
aryl bromides.
bonates up to 200 times more reactive than acetates.[14] We,
therefore, prepared several 2-B(pin)-substituted allylic ben-
zoates and carbonates from the parent di-n-butyl-2-B(pin)-sub-
stituted allylic alcohol (see the Supporting Information). The 2-
B(pin)-substituted allylic benzoates and carbonates were sub-
jected to the optimal cross-coupling reaction conditions given
in entry 13 of Table 4 with aryl iodides and bromides. 2-B(pin)-
substituted allylic benzoate 7a underwent cross-coupling with
iodobenzene to furnish 2-aryl substituted allylic benzoate 9a
in 96% yield (Table 7, entry 1). Bromobenzene, on the other
hand, resulted in low yield of the cross-coupled product 9a
(38%), with multiple byproducts (Table 7, entry 2). The palladi-
um catalyst likely activates the allylic benzoate in the presence
of the less reactive bromobenzene. Electron-deficient aryl hal-
ides are known to undergo oxidative addition more rapidly
than analogous electron-rich aryl halides.[82–85] With 4-trifluoro-
methylbromobenzene and allylic benzoate 7a the cross-cou-
pled product 9b was isolated in 76% yield (Table 7, entry 3).
The 2-B(pin)-substituted allylic carbonates 8a and 8b under-
went cross-coupling with both aryl iodides and electron-defi-
cient bromides to furnish the 2-arylated allylic carbonates 9c–f
in 57–91% yield (Table 7, entries 4–8). These results demon-
strate that the palladium catalyst preferentially oxidatively
adds aryl iodides and bromides over 1,3-dialkyl-substituted 2-
B(pin) allylic benzoates and carbonates. However, the more re-
active 1-phenyl-2-B(pin)-substituted allylic benzoate 7b and
Substrate scope of Suzuki–Miyaura cross-coupling of 2-
B(pin)-substituted allylic acetates with aryl bromides
We are aware of one study that compared the relative reactivi-
ty of sp2 CÀBr bonds versus allylic acetates with palladium cat-
alysts. Organ et al. demonstrated that the preference of the
palladium center was dependent on the nucleophile
(Scheme 7F).[72]
Subjecting the 2-B(pin)-substituted allylic acetates to the
Suzuki–Miyaura conditions employed in entry 13 of Table 4
with various aryl and heteroaryl bromides resulted in chemose-
lective activation of the aryl bromides over the allylic acetates.
The substituents on the allylic acetate (R1 and R2) and the aryl
bromide coupling partners (ArÀBr) were varied to determine
the scope of the chemoselective cross-coupling (Table 6). 2-
B(pin)-substituted aliphatic allylic acetate 1a underwent cross-
coupling with aryl bromides bearing electron-withdrawing or
electron-donating groups with para and ortho substitution to
Chem. Eur. J. 2014, 20, 11726 – 11739
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Table 5. Chemoselective Suzuki–Miyaura cross-coupling of 2-B(pin)-sub-
Table 6. Chemoselective Suzuki–Miyaura cross-coupling of 2-B(pin)-sub-
stituted allylic acetates with aryl iodides.
stituted allylic acetates with aryl bromides.
Entry
Acetate
Ar-I
Ph-I
Product
Yield
[%][a]
Entry
Acetate
Ar-Br
Ph-Br
Product
Yield
[%][a]
1
1a
6a
6b
96
60
1
1a
6a
6b
73
54
2
3
1a
1a
4-MeO-C6H4-I
4-O2N-C6H4-I
2
3
4
1a
1a
1a
4-MeO-C6H4-Br
4-O2N-C6H4-Br
4-F3C-C6H4-Br
6c
6j
91
85
6c
92
4
5
1b
1d
Ph-I
Ph-I
6d
6e
67
99
5
6
1a
1b
2-MeO-C6H4-Br
6k
6d
80
87
6
7
8
1d
1 f
1 f
4-O2N-C6H4-I
6 f
92
Ph-Br
Ph-I
6g
6h
70[b]
7
8
1d
4-O2N-C6H4-Br
4-O2N-C6H4-Br
6 f
90
4-O2N-C6H4-I
75[b]
1 f
6h
80[b]
[a] Yield of the isolated and purified products. [b] The reaction was con-
ducted at 758C in THF/H2O (10:1).
9
1a
1a
6l
74
82
carbonate 8c decomposed, and no cross-coupling product
was observed (Table 7, entries 9 and 10).
10
6m
Chemoselective allene formation from 2-B(pin)-substituted
allylic acetates, benzoates, and carbonates
[a] Yield of the isolated and purified products. [b] The reaction was con-
ducted at 758C in THF/H2O (10:1).
The efficiency of Suzuki–Miyaura cross-coupling of 2-B(pin)-
substituted allylic substrates is related to the ability of the allyl-
ic leaving group to ionize under palladium catalysis (Table 7).
Reactive substrates toward allylic ionization, such as benzoate,
carbonates, or substrates with benzylic acetates (Table 7, en-
tries 9 and 10) tended to yield less cross-coupling products
1
and more decomposition products. H NMR spectroscopic anal-
Chem. Eur. J. 2014, 20, 11726 – 11739
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Precedents for a catalytic 1,2-elimination to form allenes
Table 7. Chemoselective Suzuki–Miyaura cross-coupling of 2-B(pin)-sub-
stituted allyl benzoates and carbonates.
Tanaka and co-workers reported the conversion of 2-bromo al-
lylic mesylate derivatives into allenes with a catalytic amount
of palladium and 2 equivalents of diethylzinc as a reducing
agent (Scheme 10A).[94] More recently, Kazmaier and co-work-
ers demonstrated that b-stannylated allylic acetates or phenox-
ides undergo 1,2-elimination reactions to provide Pd–allene in-
termediates, from which terminal allenes were isolated
(Scheme 10B).[95,96] An advantage of our 2-B(pin)-substituted al-
lylic acetates is that they do not require stoichiometric reduc-
ing agents or highly reactive mesylates and they provide 1,3-
disubstituted internal allenes.
Entry 2-B(pin)-substituted
allyls
Ar-Br
Product
Yield
[%][a]
1
2
7a
7a
Ph-I
Ph-Br
9a 96
9a 38
3
4
7a
8a
4-F3C-C6H4-Br
9b 76
Ph-I
9c 91
5
6
8a
8a
4-NO2-C6H4-I
4-NO2-C6H4-Br
9d 78
9d 75
Scheme 10. A) Palladium-catalyzed elimination reaction with diethylzinc de-
veloped by Tanaka and co-workers. B) 2-Sn(nBu)3 elimination of 2-stannylat-
ed allylic acetates and phenoxides to form terminal allenes developed by
Kazmaier and co-workers.
7
8
8a
8b
4-CF3-C6H4-Br
9e 57
Optimization of allene formation
Ph-I
9 f 83
We set out to screen a variety of palladium precursors and li-
gands to identify catalysts that would favor allene formation
from 1-phenyl-2-B(pin)-substituted allylic acetate 1 f. Subject-
ing 1 f to catalytic [Pd(PPh3)4] in THF/H2O (5:1) at 608C resulted
in 20% consumption of 1 f with no allene formation, as deter-
[b]
9
7b
8c
Ph-I
Ph-I
–
1
mined by H NMR spectroscopic analysis (Table 8, entry 1). The
[b]
10
–
use of stoichiometric [Pd(PPh3)4] yielded allene 10a in only 4%
yield, with mostly decomposition products (Table 8, entry 2).
We next examined bases, which dramatically changed the out-
come of the reaction. The addition of one equivalent of Cs2CO3
and 1 mol% [Pd(PPh3)4] led to allene formation in 87% yield,
whereas Cs2CO3 alone exhibited no reactivity (Table 8, entries 3
and 4). Other palladium sources and phosphanes were exam-
ined (Table 8, entries 5–9) under the conditions given in
entry 3 of Table 8. Both Pd(OAc)2/2PPh3 and [{Pd(allyl)Cl}2]/
4PPh3 formed suitable catalysts for allene formation (73 and
80% yield; Table 8, entries 5 and 6, respectively). Some diene
products (<5%) were also produced. The reaction with [{Pd-
(allyl)Cl}2] and DPPE (4 equiv) did not reach completion within
1.5 hours (72 and 10% yield of 10a and starting-material 1 f,
respectively; Table 8, entry 7). Precatalyst [{Pd(allyl)Cl}2]/PCy3
(3 equiv) resulted in 93% yield (Table 8, entry 8). Finally, [{Pd-
(allyl)Cl}2]/CyJohnPhos (3 equiv) and Cs2CO3 (1 equiv) at 608C
resulted in 99% assay yield of the allene product 10a (Table 8,
entry 9). Screening the Buchwald phosphane ligands SPhos,
[a] Yield of the isolated and purified products. [b] Starting materials de-
composed. LG=leaving group.
ysis of unpurified reaction mixtures suggested that decom-
posed products included allenes and dienes. We hypothesized
that the diene products were generated from the allene
through palladium-catalyzed isomerization or carbopalladation
reactions.[86] If this hypothesis is correct, a third manifold of re-
activity might be tapped to afford an additional family of prod-
ucts from 2-B(pin)-substituted allylic ester derivatives. We,
therefore, set out to identify catalysts to promote the chemo-
selective elimination of 2-B(pin)-substituted allylic substrates to
provide internal allenes, which are important synthetic inter-
mediates and common in natural products.[87–93]
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Table 8. Optimization of allene formation from 2-B(pin)-substituted allylic
acetate 1 f.
Table 9. Allene formation from 2-B(pin)-substituted allylic acetates, ben-
zoates, and carbonates.
Entry [Pd]
Ligand ([mol%]) Base ([equiv])
t [h] Yield [%][b]
Entry Substrate
Product
Yield
[%][a]
1 f[c] 10a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
15
[Pd(PPh3)4]
–
–
–
–
–
–
1.5 80
0
4
[Pd(PPh3)4][d]
[Pd(PPh3)4]
–
1.5
1.5
0
0
1
2
1 f
1i
10a 90
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
87
<2
73
80
72
93
99
7
94
85
19
41
76
90
1.5 95
Pd(OAc)2
PPh3 (2)
1.5
1.5
0
0
10b 92
10c 87
10d 92
[{Pd(allyl)Cl}2] PPh3 (2)
[{Pd(allyl)Cl}2] DPPE (2)
[{Pd(allyl)Cl}2] PCy3 (1.5)
[{Pd(allyl)Cl}2] CyJohnPhos (1.5) Cs2CO33 (1)
[{Pd(allyl)Cl}2] CyJohnPhos (1.5)
[{Pd(allyl)Cl}2] CyJohnPhos (1.5) Cs2CO3 (0.5)
[{Pd(allyl)Cl}2] CyJohnPhos (1.5) Cs2CO3 (3)
[{Pd(allyl)Cl}2] CyJohnPhos (1.5) NaOAc·3H2O (3) 1.0 78
1.5 12
1.0
1.0
0
0
3
4
1h
1k
–
1.0 90
1.0
1.0 15
0
[{Pd(allyl)Cl}2] CyJohnPhos (1.5) K2CO3 (3)
[{Pd(allyl)Cl}2] CyJohnPhos (1.5) NaHCO3 (3)
[{Pd(allyl)Cl}2] CyJohnPhos (1.5) NaHCO3 (1)
1.0 59
1.0
1.0
0
0
5
6
1m
1a
7a
7c
10e 55
[a] Reactions were conducted at 0.17m concentration on scale of
0.04 mmol. [b] Yield was determined by integration of the 1H NMR spec-
tra of the crude reaction mixture with 1,4-dimethoxybenzene as an inter-
nal standard. [c] Recovered 1 f. [d] One equivalent of [Pd(PPh3)4]. CyJohn-
Phos=2-(dicyclohexylphosphino)biphenyl.
[b]
10 f
–
7
10 f 53
10g 79
10 f 85
10g 83
XPhos, DavePhos, and JohnPhos with [{Pd(allyl)Cl}2] resulted in
slower conversion into allenes.[97] In the absence of Cs2CO3 at
608C, [{Pd(allyl)Cl}2]/CyJohnPhos (3 equiv) resulted in the for-
mation of only 7% of allene product 10a and 90% starting-
material 1 f (Table 8, entry 10). Lowering the Cs2CO3 loading to
0.5 equivalents did not affect the reactivity significantly (94%
yield; Table 8, entry 11), and three equivalents of Cs2CO3 ren-
dered the reaction slower (85 and 15% yield of 10a and start-
ing-material 1 f; Table 8, entry 12). Bases such as NaOAc·3H2O,
K2CO3, and NaHCO3 were less effective (Table 8, entries 13–16).
Ultimately, 0.5 mol% [{Pd(allyl)Cl}2], 1.5 mol% CyJohnPhos, and
one equivalent of Cs2CO3 gave the best yield (Table 8, entry 9)
of the conditions examined.
8
9
8a
8d
10
[a] Yield of the isolated and purified products. [b] The starting material
decomposed during the course of the reaction.
and 8). With the dialkyl 2-B(pin)-substituted derivatives, the
greater leaving-group ability of carbonates 8a and 8d resulted
in higher yields of allene products 10 f and 10g (85 and 83%
yield; Table 9, entries 9 and 10). The results given in Tables 8
and 9 indicate that the proper choice of catalyst, substrates,
and conditions enable the facile generation of allenes from 2-
B(pin)-substituted allylic esters and carbonates.
Substrate scope for allene formation from 2-B(pin)-substitut-
ed allylic acetates, benzoates, and carbonates
Subjecting various 1-aryl-2-B(pin)-3-butyl allylic acetates to the
conditions given in entry 9 of Table 8 resulted in the formation
of allene products. For example, aryl substrates bearing elec-
tron-withdrawing or electron-donating groups at the para po-
sition provided excellent yields of allene products 10a–d (87–
92%; Table 9, entries 1–4). The styryl-derived allylic acetate 1l
gave 10e in 55% yield without any noticeable isomerization of
the vinyl group (Table 9, entry 5). Although 1,3-di-n-butyl-2-
B(pin) allylic acetate 1a was not suitable for this transforma-
tion (Table 9, entry 6), benzoate substrates 7a and 7c were
converted into allene products 10 f and 10g in 53 and 79%
yields, respectively, of the isolated products (Table 9, entries 7
Plausible catalytic cycle of the allene-formation reaction and
allene racemization
To rationalize the formation of allylic substitution versus allene
products, a plausible catalytic cycle for allene formation is illus-
trated in Figure 3. Electron-donating ligands, such as PCy3 and
CyJohnPhos, easily lead to p-allyl–palladium intermediates. In
the presence of good nucleophiles, such as malonates or
amines, allylic substitution occurs by addition of the nucleo-
Chem. Eur. J. 2014, 20, 11726 – 11739
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Table 10. Palladium-catalyzed allene-formation reaction of enantioen-
riched 1 f.
Entry
t [min]
Yield [%][a]
ee[b] of 10a [%]
1 f
10a
1
2
3
4
5
6
0
10
20
35
45
60
100
82
50
0
0
0
–
18
50
100
100
100
–
36
29
13
3
0
[a] The yield of conversion was determined by 1H NMR spectroscopic
analysis of aliquots of the unpurified reaction mixture. [b] Enantiomeric
excess of allene 10a was determined by HPLC analysis (see the Support-
ing Information).
Figure 3. Plausible catalytic cycle for allene formation.
phile to the p-allyl–palladium species. In contrast, in the ab-
sence of a suitable nucleophile, the base is proposed to attack
the empty coordination site on the boron atom or hydrolyze
the boronate ester group. Several possible explanations for the
observed dependency on base strength can be considered.
The stronger bases are more likely to promote hydrolysis of
the B(pin) group to a boronic acid group. Also, more reactive
carbonate bases are harder and will be better nucleophiles
toward the boron atom than either bicarbonate or acetate
bases. Finally, elimination of a three-coordinate boron atom
can be envisioned to lead to a palladium–allene p complex
before allene dissociation.
thetic strategy for the rapid generation of molecular complexi-
ty and diversity. The key to the development of such a method-
ology is to tailor the catalyst, reagents, and conditions to
afford chemoselective activation of the substrate. Toward this
goal, we have introduced a new class of bifunctional reagents
that contains vinyl boronate esters embedded within allylic
acetates. The requisite 2-B(pin)-substituted allylic acetates were
synthesized on a gram scale in one-pot procedures from readi-
ly available materials by using the heterobimetallic chemistry
developed in our laboratory.[15–18]
To facilitate applications of our bifunctional substrates,
methods to control the chemoselectivity of their activation is
crucial. The challenge is to employ common palladium–phos-
phane-based catalysts and modulate their activation of 2-
B(pin)-substituted allylic acetates through manipulation of the
reagents, substrates, and conditions. In the case of allylic sub-
stitutions, the reactions were conducted under conditions in
which the B(pin) group was stable to hydrolyze (and palladium
hydroxide intermediates are not likely to be formed),[13,102] thus
inhibiting B to Pd transmetalation. Under such conditions, oxi-
dative ionization of the acetate and nucleophilic addition to
the p-allyl–palladium intermediate were much faster than
transmetalation. In the Suzuki–Miyaura cross-coupling reaction
of 2-B(pin)-substituted allylic acetates, the chemoselectivity of
the Pd0 center is on the order of Ar-I>Ar-Br>allylic acetate.
Once the Pd0 center is converted into PdII by the aryl halide,
ionization of the allylic acetate does not interfere with the
cross-coupling reaction. Under conditions in which the B(pin)
group hydrolyzes to the boronic acid (or palladium hydroxides
can form), transmetalation is also fast. Detailed study of this
system indicates the relative order of reactivity toward the Pd0
center is Ar-I>Ar-Br>allylic carbonate>allylic benzoate>allyl-
ic acetate, with the reactivity of the allylic carbonates ap-
proaching that of aryl bromides. For allylic acetates with the
acetate group in benzylic position, the allylic acetate is more
reactive than aryl bromides in the presence of L2Pd. The obser-
vations outlined herein enabled a complete reversal of chemo-
Optically active allenes are ubiquitous intermediates and tar-
gets for the synthesis of natural products and biologically
active compounds.[98,99] To investigate the possibility of chirality
transfer in the catalytic cycle shown in Figure 3, we performed
the allene-formation reaction with enantioenriched 2-B(pin)-al-
lylic acetate 1 f to generate allene product 10a. The reaction
of 1 f (60% ee) in the presence of the Pd/CyJohnPhos catalyst
afforded the enantioenriched allene 10a with 36% ee in 18%
yield in 10 minutes (Table 10, entry 2). When the reaction
reached completion within 35 minutes, however, a significant
loss of enantiometic excess was observed (Table 10, entries 3
and 4). Finally, allene product 10a was racemized completely
within one hour (Table 10, entry 6). It is noteworthy that B(pin)-
substituted 1 f (60% ee) was not racemized during the course
of the reaction. These results suggest that 2-B(pin)-allylic ace-
tate undergoes stereoselective allene formation, however,
a competing racemization of the allene product in the pres-
ence of the palladium catalyst, probably through hydropallada-
tion, is responsible for the observed loss of enantiomeric
excess over time.[100,101]
Conclusion
The application of multicomponent tandem reactions to mole-
cules bearing more than one reaction site is a powerful syn-
Chem. Eur. J. 2014, 20, 11726 – 11739
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2À
a nucleophile, we hypothesized that hard bases (i.e., CO3
,
HCO3À, and AcOÀ), or the hydroxide ion generated from these
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With the ability to control chemoselectivity, various tandem
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can be paired with the oxidation of vinyl boronates to provide
valuable a-amino ketones and 1,4-dicarbonyl compounds.
Given the high levels of control over the chemoselectivity in
our optimized palladium-catalyzed reactions of 2-B(pin)-substi-
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functional substrates will serve as useful intermediates in
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Keywords: allenes · allylic substitution · chemoselectivity ·
cross-coupling · palladium
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Received: February 25, 2014
Published online on July 30, 2014
Chem. Eur. J. 2014, 20, 11726 – 11739
www.chemeurj.org
11739
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim