Allylie substitution versus Suzuki cross-coupling: Capitalizing on chemoselectivity with bifunctional substrates

Article abstract of DOI:10.1002/anie.200905399

One catalyst, two reactions-a tale of chemoselectivity: Given the choice between an allylic acetate and a vinylboronate ester, palladium preferentially reacts with the allylic acetate to give the allylic substitution product. In the presence of an aryl bromide and base, Suzuki cross-coupling subsequently ensues to afford allylic amines (see scheme; pin = pinacol, THF = tetrahydrofuran). Chemical equation representation

Full text of DOI:10.1002/anie.200905399

Communications
DOI: 10.1002/anie.200905399
Chemoselectivity
Allylic Substitution versus Suzuki Cross-Coupling: Capitalizing on
Chemoselectivity with Bifunctional Substrates**
Mahmud M. Hussain and Patrick J. Walsh*
In memory of Keith Fagnou
Table 1: One-pot synthesis of B(pin)-substituted allylic acetates.[a]
The greatest challenge in the synthesis of complex molecules
has been, and continues to be, chemoselectivity.[1–3] Highly
chemoselective reactions obviate the need for elaborate
protecting-group strategies and maximize synthetic efficiency.
To achieve high levels of chemoselectivity, chemists are
increasingly employing transition-metal catalysts, with palla-
dium being favored.[4,5] Two of the most important and
frequently applied palladium-catalyzed reactions are the
Suzuki cross-coupling[6,7] and the Tsuji–Trost allylic substitu-
tion.[4,8–10] We envisaged, therefore, that bifunctional reagents
that possess both allylic acetate and a vinylboronate ester
groups would combine the utility of these powerful reactions.
The possibility of employing such reagents, however, hinges
on chemoselectivity, because both the Suzuki and the Tsuji–
Trost reactions are catalyzed by palladium phosphine com-
plexes. In this study, we have embedded vinylboronate ester
moieties within allylic acetate derivatives. Herein, we disclose
the chemoselective reactions of B(pin)-substituted allylic
acetates in tandem allylic substitution/Suzuki cross-coupling
and allylic substitution/oxidation reactions to provide rapid
access to valuable trisubstituted allylic amines, 1,4-dicarbonyl
compounds, and a-amino ketones.
Entry
R
R’
Product
Yield [%][b]
1
2
3
4
5
6
7
nBu
Ph
nBu
4-FC6H4
4-CF3C6H4
4-OMeC6H4
Cy
nBu
nBu
Ph
nBu
nBu
nBu
nBu
1a
1b
1c
1d
1e
1 f
1g
82
75
67
73
78
52
85
[a] See the Supporting Information for details. [b] Yield of isolated and
purified product. Cy=cyclohexyl, pin=pinacol.
activation of the allylic acetate versus transmetalation of the
B C bond, which is a key step in Suzuki cross-coupling[6] and
À
base-free oxidative Heck reactions.[13,14] A second concern
was that the bulky B(pin) group would retard or inhibit
oxidative ionization of the allylic acetate by the Pd0 catalyst. It
is known that 2-substituted allylic acetates and allylic halides
exhibit decreased reactivity.[15,16]
For any synthetic method to be useful, the substrates must
be readily accessible. The B(pin)-substituted allylic acetates
were prepared in one pot using our stereodefined 1-alkenyl-
1,1-heterobimetallic reagents (Table 1).[11,12] Thus, hydrobo-
ration of air-stable alkynyldioxaborolanes with dicyclohex-
ylborane and selective B to Zn transmetalation of the vinyl–
BCy2 moiety generates the heterobimetallic intermediate.
Subjecting the bis(n-butyl) allylic acetate (1a) to various
palladium sources with either NaCH(CO2Me)2 or morpholine
indicated that [{(h3-C3H5)PdCl}2] and PPh3 formed a suitable
catalyst (see the Supporting Information for details). When
1a was combined with [{(h3-C3H5)PdCl}2] (5 mol%), PPh3
(20 mol%), and NaCH(CO2Me)2 in THF, the allylic substi-
tution product was obtained in 81% yield after 10 h at 408C
(Table 2, entry 1). Importantly, the vinyl boronate ester group
remained intact.
By employing similar reaction conditions, secondary
amines participated in the allylic substitution and provided
B(pin)-substituted allylic amines in 79–83% yield (Table 2,
entries 2–4). The primary amine, benzyl amine, also under-
went allylic substitution (65% yield; Table 2, entry 5). The
reaction of B(pin)-substituted allylic acetates 1b and 1c with
NaCH(CO2Me)2 or morpholine gave unexpected regioselec-
tivity (ꢀ 10:1) derived from attack at the benzylic position
(45–80% yield; Table 2, entries 6–9). Compound 1c was less
reactive than 1b in the allylic substitution reaction. The
reactions worked well with electron-withdrawing or electron-
donating substituents on the aryl group (1d–1 f, > 12:1
regioselectivity; Table 2, entries 10–13). The dialkyl substrate
1g underwent nucleophillic attack at the less hindered
position with > 20:1 regioselectivity (Table 2, entry 14).
À
Addition of the Zn C bond to aldehydes and quenching the
resulting alkoxides with acetic anhydride provided (E)-allylic
acetates 1a–1g in 52–85% yield (Table 1). To demonstrate
the scalability of the reaction, 1a–1c were prepare in gram
quantities.
At the outset of our investigation with B(pin)-substituted
allylic acetates, we were concerned about the chemoselective
[*] M. M. Hussain, Prof. P. J. Walsh
Department of Chemistry
University of Pennsylvania
231 S. 34th St, Philadelphia, PA 19104 (USA)
Fax: (+1)215-573-6743
E-mail: pwalsh@sas.upenn.edu
Homepage: http://titanium.chem.upenn.edu/walsh/index.html
[**] This research was supported by the National Institutes of Health,
General Medical Sciences (GM058101), and the National Science
Foundation (CHE-0848467).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905399.
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Chemie
Table 2: Palladium-catalyzed allylic substitution with B(pin)-substituted allylic acetates.[a]
Entry Allylic acetate Nucleophile
Product
Yield Entry Allylic acetate
[%][b]
Nucleophile
Product
Yield
[%][b]
1
2
NaCH(CO2Me)2
81[c]
83[c]
8
9
1b
1c
NaCH(CO2Me)2
NaCH(CO2Me)2
79[c,f]
1a
1a
51[c,f]
3
BnNHMe
80[c] 10
75[d,f]
4
5
1a
1a
79[c] 11
1d
CH2(CO2Me)2
CH2(CO2Me)2
90[d,f,g]
BnNH2
65[c] 12
92[d,f,g]
6
7
80[d,f] 13
CH2(CO2Me)2
80[d,f,g]
45[d,e] 14
60[c,f]
[a] See the Supporting Information for experimental details. [b] Yield of isolated and purified products. [c] [{(h3-C3H5)PdCl}2]. [d] Pd(OAc)2. [e] 30% of
unchanged starting material was recovered. [f] Regioselectivity of ꢀ10:1. [g] N,O-Bis(trimethylsilyl)acetamide (BSA) and catalytic KOAc were used.
Bn=benzyl, morph=morpholine, pip=piperidine THF=tetrahydrofuran.
Table 3: Probing regioselectivity with 2-substituted allylic acetates.
Regioselectivity in the allylic substitution reaction can be
affected by the nature of the ligands and nucleophile.[5]
A
comparison of the reactivity and regioselectivity of B(pin)-
substituted allylic acetates with the parent and 2-methyl
derivatives was therefore performed (Table 3). In contrast to
attack at the benzylic position as shown in Table 2, the parent
compound (R = H; Table 3, entry 1) underwent allylic sub-
stitution with attack distal to the aryl group with high
regioselectivity (9:1). No reaction occurred with the 2-
methyl substrate under our reaction conditions (Table 3,
entry 4). The regioselectivities and reactivities shown in
Table 3 highlight important distinctions between the B(pin)-
substituted allylic acetates and the parent and methyl-
substituted derivatives.
Entry
Ar
R
A/B
Yield [%][a]
1
2
3
4
Ph
Ph
4-CF3C6H4
Ph
H
1:9
85
79
92
n.r.
B(pin)
B(pin)
CH3
>10:1
20:1
–
n.r.=no reaction.
To develop the full potential of our bifunctional sub-
strates, we performed tandem processes beginning with allylic
substitution and subsequent reactions of the vinyl boronate
ester.[17] As illustrated in Table 4, the palladium-catalyzed
allylic substitution was performed as in Table 2. The reaction
mixture was then treated with alkaline hydrogen peroxide to
oxidize the vinyl boronate ester. The resulting a-amino
ketones were isolated in 65–85% yield in this one-pot
procedure (Table 4, entries 1–5). A milder oxidation with
NaBO3·H2O resulted in an increased yield (compare Table 4,
entries 5 and 6). Notably, such products are not easily
prepared by standard p-allyl chemistry. Trost and Gowland
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Communications
Table 4: One-pot synthesis of a-substituted ketones.
Enantioenriched allylic amines are important intermedi-
ates and are found in natural products.[19] With this in mind,
we conducted the allylic substitution with 1b (of 80% ee) and
morpholine to generate the B(pin)-substituted benzyl amine
2b in 82% yield without loss in enantiomeric excess
(Scheme 2).[20] The one-pot allylic substitution/B C bond
À
Entry
NuÀ/NuH
Allylic acetate
Yield [%][a]
oxidation with NaBO3·H2O furnished the a-amino ketone
with 77% ee in 80% yield.
1
2
3
4
NaCH(CO2Me)2
1a
1a
1a
1a
85
82
81
75
In summary, scalable one-pot syntheses of B(pin)-sub-
stituted allylic acetates 1a–1g are reported. These bifunc-
tional templates are excellent substrates for chemoselective
palladium-catalyzed allylic substitution reactions, despite the
PhCH2NHMe
well-known propensity of PdII to react with B C bonds.
À
Notably, these reactions proceed via boron-substituted p-allyl
palladium intermediates, which have been underutilized in
allylic substitutions[21,22] and related reactions.[23–25] Addition-
ally, the regioselectivity in the allylic substitution is opposite
to that observed with the parent allylic acetate.
5
6
1b
1b
65
78[b,c]
[a] Yield of purified and isolated product. [b] Allylation carried out with
Pd(OAc)2 (5 mol%) and PPh3 (10 mol%) at RT. [c] Oxidation carried out
with 3 equivalents of NaBO3·H2O in THF/H2O (1:1) at RT.
The allylic substitution can be paired with oxidation to
provide valuable a-amino ketones and 1,4-dicarbonyl com-
pounds, which are not accessible by the Tsuji–Trost allylation
have shown that allylic acetates bearing a 2-alkoxy
group undergo allylic substitution reactions to
generate enol ethers. The resulting enol ether
products can be hydrolyzed to ketones.[18]
The observation that palladium-catalyzed
allylic substitutions can be conducted without
interference by the B(pin) substituent hints at the
possibility of achieving a one-pot allylic substitu-
tion/Suzuki cross-coupling reaction. Ideally both
steps can be catalyzed using the same palladium
source. A successful allylic substitution/cross-cou-
pling sequence would, therefore, make possible the
Scheme 2. Allylic substitution of enantioenriched B(pin)-substituted allylic acetate
1b.
synthesis of a variety of 2-arylated allylic amines from B(pin)-
substituted allylic acetates (1), amines, and aryl bromides.
Thus, after the completion of the allylic substitution with
morpholine, the reaction mixture was diluted with THF/water
(10:1), Cs2CO3 and aryl bromide were added, and the reaction
mixture was heated to 758C (Scheme 1). After workup,
arylated trisubstituted allylic amine derivatives were isolated
in 52–70% yield. Importantly, only the E double-bond isomer
was observed.
alone. The allylic substitution can be followed by Suzuki
cross-coupling to afford E-trisubstituted allylic amines with
four points of diversity. The key to the success of this, and
other related processes,[26–33] is the remarkable chemoselec-
tivity exhibited by palladium-based catalysts.
Received: September 25, 2009
Revised: December 25, 2009
Published online: February 4, 2010
Keywords: allylic substitution ·
.
bifunctional substrates · chemoselectivity ·
cross-coupling · tandem reactions
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