Olefin-Directed Palladium-Catalyzed Regio- and Stereoselective Oxidative Arylation of Allenes

Article abstract of DOI:10.1002/anie.201502924

An olefin-directed palladium-catalyzed oxidative regio- and stereoselective arylation of allenes to afford 1,3,6-trienes has been established. A number of functionalized allenes, including 2,3- and 3,4-dienoates and 3,4-dienol derivatives, have been inves

Full text of DOI:10.1002/anie.201502924

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201502924
German Edition: DOI: 10.1002/ange.201502924
Allene Arylation
Olefin-Directed Palladium-Catalyzed Regio- and Stereoselective
Oxidative Arylation of Allenes**
Can Zhu, Bin Yang, Tuo Jiang, and Jan-E. Bäckvall*
Abstract: An olefin-directed palladium-catalyzed oxidative
regio- and stereoselective arylation of allenes to afford 1,3,6-
trienes has been established. A number of functionalized
allenes, including 2,3- and 3,4-dienoates and 3,4-dienol deriv-
atives, have been investigated and found to undergo the olefin-
directed allene arylation. The olefin moiety has been proven to
be a crucial element for the arylating transformation.
A
llenes, a class of compounds with the interesting and
special substructure of two cumulative carbon–carbon double
[1]
bonds, have been demonstrated as powerful building blocks
for the construction of complicated natural products, as well
[
2,3]
as pharmacologically active compounds.
Therefore, much
attention has been focused on transition-metal-catalyzed
cyclizations of functionalized allenes, especially those cata-
lyzed by palladium. The Pd -promoted reactions of allenes
with a nucleophilic functionality, mostly an N- or O-contain-
ing functional group, would produce cyclic intermediates Int-
Scheme 1. a) Traditional Pd-catalyzed cyclization of functionalized
allenes. b) Envisioned Pd-catalyzed cyclization of enallenes with an
external nucleophile. c) Observed approach of olefin-directed Pd-cata-
lyzed oxidative arylation of allenes. FG=functional group. Nu=nu-
cleophilic unit.
[4]
II
1
or Int-1’ (Scheme 1a). A subsequent cross-coupling reaction
would lead to product A or A’ respectively. However, the
utilization of a p-bond-containing group as a nucleophile for
[
5]
such cyclizations is highly limited. On this basis, we
envisioned that enallene (1, FG = vinyl) may undergo annu-
II
lation under the catalysis of Pd to provide cyclized product B
by reaction with an external nucleophile via Int-2 (Scheme
Scheme 2. Pd-catalyzed oxidative phenylation of allene 1a. BQ=1,4-
1
b).
Based on this concept, we initially chose a readily
benzoquinone.
[6]
accessible 2,3-dienoate as the standard substrate. When
allyl-substituted 2,3-dienoate 1a was treated with Pd(OAc)2
(
5 mol%), PhB(OH) (1.3 equiv), and BQ (1.1 equiv) in the
2
presence of NaOAc (1.2 equiv) in THF at 508C for 23 h, the
envisioned product 4a was not observed (Scheme 2). Surpris-
[
*] Dr. C. Zhu, B. Yang, Dr. T. Jiang, Prof. Dr. J.-E. Bäckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
1
0691 Stockholm (Sweden)
E-mail: jeb@organ.su.se
**] Financial support from the European Research Council (ERC AdG
47014), The Swedish Research Council, The Berzelii Center
[
Scheme 3. Investigation of different substituents on allenes for the Pd-
catalyzed oxidative allene-arylation. [a] Yield determined by H NMR
analysis using anisole as the internal standard.
2
1
EXSELENT, and the Knut and Alice Wallenberg Foundation is
gratefully acknowledged. We thank Maoping Pu and Timofei
Privalov for fruitful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502924.
ingly, instead the phenylated triene product (E)-3aa was
obtained in 74% yield as a single stereoisomer (Scheme 2, cf.
Scheme 1c). The stereochemistry was determined by NOE
measurements. It should be noted that the reaction worked
even better without NaOAc, producing (E)-3aa in 83% yield
as shown in Scheme 3. The exclusive stereoselectivity for the
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E isomer in this allene arylation indicates coordination of the
olefin group during the reaction.
acid led to a notable decrease in yield probably due to steric
effects (Table 1, entry 3). For a series of electron-deficient
.
We next investigated how the olefin group in the substrate
influenced the outcome of the reaction (Scheme 3). To
demonstrate the necessity of the allyl group, we examined
the reactivity of allenes with different substituents: 2,3-
dienoates with a propyl substituent (1ab), hydrogen (1ac), or
methyl group (1ad) all failed to undergo the arylating
transformation, indicating that the olefin group of 1a is an
arylboronic acids, LiOAc 2H O (50 mol%) was required as
2
an additive to ensure an efficient transformation: halogenated
arenes proved to be compatible with the reaction conditions
(Table 1, entries 7 and 8). Other electron-withdrawing sub-
stituents, such as 3-NO , 4-NO , 4-formyl, and 4-acetyl could
2
2
be present in the aryl unit, leading to the corresponding
trienes in good yields (Table 1, entries 9–12). Finally, it is
worth noting that 2-naphthylboronic acid also works well,
affording 3am in 71% yield (Table 1, entry 13).
[
7,8]
indispensable assisting/directing group
for the allene
arylation. Coordination of the C=C bond during the reaction
would account for the high stereoselectivity for the E isomer
We further investigated the oxidative allene arylation
using different allenes (Scheme 4). The reaction of substrates
(
Scheme 1c).
With these inspiring results in hand, we set out to optimize
the reaction conditions (for details, see the Supporting
Information). Solvent screening showed that acetone was
the best solvent for this transformation, improving the yield
1
further to 91% (yield determined by H NMR analysis using
anisole as the internal standard). Other solvents such as 1,4-
dioxane, 1,2-dichloroethane, and toluene also gave good
yields. Catalyst screening showed that Pd(TFA) (TFA = tri-
2
fluoroacetate) produced the corresponding triene in only
4
0% yield, while [Pd(PPh ) Cl ] and [Pd(CH CN) Cl ] failed
3 2 2 3 2 2
to promote the transformation. We were pleased to obtain
E)-3aa in 90% yield (87% yield of isolated product) with
(
a catalyst loading of 1 mol%. Both Pd(OAc) and BQ are
2
required for the reaction to occur. Finally, 508C was found to
be the best temperature for this reaction.
Under the optimal conditions, we next examined the
scope of arylboronic acids in the reaction with 2,3-dienoate
1
a. Arylboronic acids bearing electron-donating substituents
such as 3-Me, 2-MeO, 3-MeO, and 4-MeO all reacted well and
produced the corresponding trienes in good yields (Table 1,
entries 2 and 4–6), while the para-tBu-substituted arylboronic
Scheme 4. Scope of allenes for the olefin-directed Pd-catalyzed oxida-
.
[
a]
tive arylation. [a] LiOAc 2H
2
O (50 mol%) was added to the reaction.
Table 1: Scope of functionalized arylboronic acids.
with phenyl or two methyl substituents on the olefin moiety
worked well, producing 3b and 3c in 78 and 75% yield,
respectively. Furthermore, cycloalkylidene allenes could also
be employed, affording products 3d, 3e, and 3e’ in excellent
yields. To demonstrate the broad scope of allenes in our
olefin-directed arylation reaction, we chose more general
[
b]
Entry
Ar
t [h]
Yield of 3 [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
Ph
3-Me-C H
4-tBu-C H
2-MeO-C H
3-MeO-C H
4-MeO-C H
3-Br-C H
4-F-C H
3-O N-C H
4
4-O N-C H
2 6 4
4-formyl-C H
4-acetyl-C H
21
18
16
21
20
16
14
17
21
17
15
16
17
87 (3aa)
94 (3ab)
64 (3ac)
76 (3ad)
77 (3ae)
80 (3af)
82 (3ag)
90 (3ah)
91 (3ai)
80 (3aj)
70 (3ak)
85 (3al)
71 (3am)
6
4
3
6
4
allene-containing structures: 3,4-dienoate 1g (R =
6
4
4
4
[9]
CH CO Et) also showed excellent reactivity. It is worth
2
2
6
3
noting that the reaction of 3,4-dienol 1h (R = CH CH OH),
2
2
6
[
[
[
c]
an allene containing a free OH group, produced triene 3h
instead of proceeding via oxypalladation as shown in Sche-
me 1a. The corresponding yield is lower probably due to the
instability of the starting material and possible reaction with
6
4
c]
6
4
c,d]
2
6
[
[
[
[
c]
c]
c]
c]
0
1
2
3
6
4
[10]
the OH group. Surprisingly, benzyl and tosyl groups could
6
4
be introduced to improve the corresponding yield signifi-
cantly as shown by the formation of 3i and 3j in 93 and 80%
yield, respectively. Finally, it is interesting to note that 54%
yield of 3k could be still obtained using a trisubstituted allene
2-naphthyl
[
(
a] The reaction was conducted at 508C in acetone (1 mL) with 1a
0.2 mmol), arylboronic acid 2 (1.3 equiv), and BQ (1.1 equiv) in the
presence of Pd(OAc) (1 mol%). [b] Yield of isolated product after
2
3
[11]
.
(R = H), and the stereochemistry was further confirmed
by NOE measurements (for details, see the Supporting
Information).
column chromatography. [c] LiOAc 2H O (50 mol%) was added to the
reaction mixture. [d] Product 3ai was obtained in only 41% yield in the
2
.
absence of LiOAc 2H O.
2
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Scheme 5. Directing-group investigation for the allene arylation.
A C=C bond in the chain has been demonstrated as an
indispensable directing group for the allene arylation reaction
developed, while 2,3-dienoates lacking this double bond
failed to undergo the arylation (see Scheme 3). We subse-
quently examined two other substrates (1l and 1m) with p-
bond-containing groups. Treatment of benzyl-substitued 2,3-
dienoate 1l under the standard conditions of Table 1 failed to
give the desired product, and 1l was recovered in 88% yield
Scheme 6. Proposed mechanism for the olefin-directed Pd-catalyzed
oxidative arylation of allenes. HQ=hydroquinone.
CÀH bond cleavage. Further, transmetalation of Int-4 with
ArB(OH)2 would produce Int-5, which on subsequent
(
Scheme 5). Interestingly, an alkynyl-substituent was found to
work as a directing group for the allene arylation. Thus,
reaction of the alkynyl-substituted 2,3-dienoate 1m afforded
the corresponding dienyne product 3m in 71% yield.
To gain a deeper insight into the reaction mechanism, the
deuterium kinetic isotope effect (KIE) was determined from
reductive elimination would lead to 1,3,6-triene 3 (path a).
II
However, transmetalation of the Pd species with ArB(OH)
via Int-3’ could also occur before allene attack (path b).
2
15]
[
The pathway via Int-4 (path a) seems more likely than that via
II
Int-3’ (path b) considering the fact that the Pd center is more
the reaction of a 1:1 mixture of 1g and [D ]-1g at room
electrophilic in Int-3 than in Int-3’. Furthermore, a pathway
via Int-3’ would not give a large competitive isotope effect
[Eqs. (2) and (3)] unless the transmetalation (Int-3!Int-3’) is
6
temperature for 10 min [Eq. (1)]. The product ratio 3g/[D ]-
5
3
g (ca. 31% conv.) measured was 3.3:1, while the ratio of the
[16]
recovered 1g and [D ]-1g was 1:1.6. From these ratios the
reversible, which seems unlikely.
6
KIE was determined to be k /k = 4.1. Furthermore, parallel
In conclusion, we have developed an efficient olefin-
directed palladium-catalyzed oxidative regio- and stereose-
H
D
kinetic experiments using 1g and [D ]-1g provided an
6
[17]
intermolecular KIE (k /k , from initial rate) value of 4.1
lective
arylation of allenes to afford 1,3,6-trienes. The
H
D
[
12]
[
Eqs. (2) and (3)]. These results indicate that the allenylic
reaction showed a broad substrate scope for the arylboronic
acids and allene substrates. The catalyst loading could be
decreased to as low as 1 mol%, giving products in good to
excellent yields. Mechanistic studies indicate that the allenylic
CÀH bond cleavage is the rate-limiting step. The olefin unit
CÀH bond cleavage is the rate-determining step in the olefin-
directed allene arylation reaction and that the cleavage of the
[
13]
CÀH bond has to occur before any irreversible steps.
Based on the observed kinetic isotope effects, the
stereochemical outcome, and the experiments in Scheme 3,
a possible mechanism for the reaction is proposed in
Scheme 6. Simultaneous coordination of the allyl C=C bond
was proven to be essential to realize the transformation, and
this observation has important mechanistic implications for
our previously developed oxidative carbocyclizations involv-
II
[14]
[18]
II
and the allenic C=C bond of substrate 1 to the Pd center
ing allenes. In these Pd -catalyzed reactions, it has now
II
would generate chelate Int-3, followed by allene attack to
afford vinylpalladium intermediate Int-4 involving allenylic
been confirmed that the allene attack on Pd requires an
additional coordination of an olefin or acetylene. Finally,
because of the regio- and stereoselective formation of multi-
substituted trienes, this method will be useful in synthetic and
materials chemistry. Further studies on the scope, mechanism,
and synthetic application of this reaction are currently under
way in our laboratory.
Keywords: allenes · arylation · directing groups · oxidation ·
palladium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9066–9069
Angew. Chem. 2015, 127, 9194–9197
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