Palladium-catalyzed oxidative arylating carbocyclization of allenynes: Control of selectivity and role of H2O

Article abstract of DOI:10.1002/anie.201404264

Highly selective protocols for the carbocyclization/arylation of allenynes using arylboronic acids are reported. Arylated vinylallenes are obtained with the use of BF₃·Et₂O as an additive, whereas addition of water leads to arylated trienes. These conditions provide the respective products with excellent selectivities (generally >97:3) for a range of boronic acids and different allenynes. It has been revealed that water plays a crucial role for the product distribution.

Full text of DOI:10.1002/anie.201404264

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Angewandte
Communications
DOI: 10.1002/anie.201404264
Homogeneous Catalysis
Palladium-Catalyzed Oxidative Arylating Carbocyclization of
Allenynes: Control of Selectivity and Role of H2O**
Teresa Bartholomeyzik, Javier Mazuela, Robert Pendrill, Youqian Deng,* and Jan-E. Bꢀckvall*
Dedicated to the MPI fꢁr Kohlenforschung on the occasion of its centenary
Abstract: Highly selective protocols for the carbocyclization/
arylation of allenynes using arylboronic acids are reported.
Arylated vinylallenes are obtained with the use of BF3·Et2O as
an additive, whereas addition of water leads to arylated trienes.
These conditions provide the respective products with excellent
selectivities (generally > 97:3) for a range of boronic acids and
different allenynes. It has been revealed that water plays
a crucial role for the product distribution.
P
alladium-catalyzed carbocyclization reactions are powerful
tools for the formation of cyclic systems in an atom-
economical fashion.[1–3] In particular, in natural product
synthesis considerable attention has been directed toward
stereo- and regioselectivity of carbocyclizations,[2] and there is
a continuous demand for new highly selective methods.
During the past decade our group has been studying
palladium-catalyzed carbocyclization reactions under oxida-
tive conditions.[4–7] In many of these examples the construc-
tion of the ring proceeds with high stereoselectivity and is
followed by a regioselective functionalization.[5] However,
more recently we discovered the oxidative carbocyclization of
allenynes under arylating conditions that led to a mixture of
constitutional isomers.[6] Depending on the specific structure
of the allenyne substrate 1 a mixture of phenylated vinyl-
allene 2 and phenylated triene 3 was obtained with Pd(OAc)2
as catalyst and PhB(OH)2 as the arylating agent (Scheme 1).[6]
Under these reaction conditions allenyne 1a afforded an
inseparable mixture of vinylallene 2a and triene 3a in a ratio
of 1:3, whereas 1b reacted under the same conditions to yield
2b and 3b in a ratio of 7.4:1 (Scheme 1). Here we present
protocols that allow the selective formation of either of the
arylated carbocycles 2 or 3.
Scheme 1. Palladium-catalyzed oxidative arylating carbocyclization of
allenynes 1.[6] E=CO2Me, BQ=1,4-benzoquinone.
In the related Pd-catalyzed borylating carbocyclization,
which we previously studied, we were able to obtain full
control of selectivity to give either borylated triene or
borylated vinylallene products by the use of additives.[7]
Keeping these results in mind we started modifying the
original conditions for the arylating carbocyclization
(Scheme 1) in a similar fashion.
Initially we focused on developing a method for the
exclusive formation of vinylallene 2a from 1a, thus reversing
the inherent selectivity for triene 3a. We found that the use of
different acidic additives increased the ratio 2a:3a (Table S1
in the Supporting Information (SI)), and in analogy with the
carbocyclization/borylation reaction the best result was
obtained with Lewis acid BF3·Et2O (10 mol%). The latter
conditions afforded 2a as the sole product in 55% isolated
yield (Table 1, entry 1).
The study of the substrate scope under optimized reaction
conditions (Table 1) illustrates the previous observation that
allenyne substrates with a longer alkyl chain on the alkyne
more easily form vinylallene product 2. When the substituent
on the alkyne was an ethyl or pentyl group the reaction gave
up to 87% yield (Table 1, entries 1–3 vs. 4–7).[8] On the other
hand, the substitution on the allene moiety (dimethyl,
pentamethylene, or methyl ethyl substitution) showed little
influence on the carbocyclization of 1 to 2 (Table 1).
We also studied the influence of the structure of the
boronic acid in the formation of vinylallenes 2 starting from
allenyne 1a (Table 2). In all cases the reaction proceeded in
a highly selective manner independently of the steric and
electronic properties of the arylboronic acid to give products
in isolated yields of up to 72%. Electron-donating alkyl
groups in different positions on the phenyl ring (Table 2,
entries 2–5) were tolerated as well as different electron-
[*] Dipl.-Chem. T. Bartholomeyzik, Dr. J. Mazuela, Dr. R. Pendrill,
Dr. Y. Deng, Prof. Dr. J.-E. Bꢀckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
10691 Stockholm (Sweden)
E-mail: dengyouqian@gmail.com
jeb@organ.su.se
Homepage: http://www.organ.su.se/jeb/index.html
[**] Financial support from the European Research Council (ERC AdG
247014), the Swedish Research Council, the Berzelii Centre
EXSELENT, the Knut and Alice Wallenberg Foundation, and the
Wenner-Gren Foundation (Y.D.) is gratefully acknowledged. We also
thank Tuo Jiang and Abraham Mendoza for valuable discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404264.
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Table 1: Scope of allenynes 1a–g in the formation of vinylallenes 2a–g.[a]
Table 2: Scope of arylboronic acids in the formation of vinylallenes 2.[a]
Entry
1
Substrate
Product
Yield [%][b]
2/3[c]
Entry
Ar
Product
Yield [%][b]
2/3[c]
98:2
1
2
3
4
5
6
7
8
Ph
2a
55
65
64
67
72
46
64
61
69
63
69
66
64
43
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-tBuC6H4
p-vinylC6H4
2-naphthyl
p-CHOC6H4
p-CF3C6H4
m-NO2C6H4
p-BrC6H4
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
2aj
2ak
2al
2am
2an
97:3
99:2
99:1
98:2
98:2
98:2
98:2
98:2
98:2
99:1
98:2
98:2
>99:1
55
98:2
2
3
66
63
>99:1
>99:1
9
10
11
12
13
14[d]
m-BrC6H4
m-MeOC6H4
p-MeOC6H4
[a] The reactions were carried out on a 0.2 mmol scale in 1.0 mL of THF
at 258C. [b] Yield of isolated product. [c] Determined from the crude
1H NMR spectrum. [d] Ca. 5% of remaining 1a was detected in the crude
1H NMR spectrum with anisole as internal standard. E=CO2Me.
4[d]
85
87
77
97:3
98:2
94:6
However a higher catalyst loading and an increased temper-
ature were required.
5
Employing the stronger oxidant tetrafluoro-1,4-benzoqui-
none (tetra-F-BQ) led to further increase in yield of triene
products 3 (see Table S4). Under the optimized conditions in
Table 3 the scope of allenyne substrates in triene formation
was studied.
6[e]
For all substrates with a methyl group on the alkyne,
excellent selectivities for triene products 3 over vinylallene
products 2 were obtained (Table 3, entries 1–3). More impor-
tantly, also allenynes 1e and 1b gave triene products 3e and
3b, respectively, with high selectivity under these reaction
conditions (Table 3, entries 4 and 5).
7
82
>99:1
[a] Unless otherwise stated, all reactions were carried out on a 0.2 mmol
scale in 1.0 mL of THF at 258C. [b] Yield of isolated products.
[c] Determined from the crude 1H NMR spectrum. [d] 0.1 mmol in
0.5 mL of THF. [e] d.r.=1:1. E=CO2Me.
Entries 2 and 6 demonstrate that the reaction proceeds
with a high selectivity for 3 over 2 also for unsymmetrically
substituted allenes and in these cases an inseparable mixture
of isomers is obtained. Owing to the fact that triene formation
is disfavored for a pentamethylene-substituted allene moiety
and that the long alkyl chain favors the vinylallene product,[6]
the selectivity 3g/2g drops to 80:20 for entry 7 (cf. entry 5).
The yield of pure triene product 3g isolated from the crude
reaction mixture was only 40%, because side product 4g was
formed in significant amounts (see Scheme S1). Similarly,
a corresponding side product 4d was formed in the reaction of
cyclohexylidene-substituted 1d, although in smaller amounts.
Unlike allenynes with a longer alkyl chain on the alkyne
(1b, 1e–1g) substrate 1a does not require the use of
tetrafluoro-1,4-benzoquinone. When instead BQ (1.1 equiv),
phenyl boroxine (0.43 equiv), Pd(OAc)2 (1 mol%) and H2O
(5.0 equiv) were used in dioxane at 808C, triene 3a was
obtained in 78% yield with excellent selectivity 3a/2a
(Table 4, entry 1). The reaction was run with a range of
substituted boroxines[10] to give triene 3 in good yield with
withdrawing functionalities (Table 2, entries 8–10). A syn-
thetically useful bromo substituent in the para- or meta-
position was found to be compatible with the reaction
conditions (Table 2, entries 11 and 12).[9]
To reverse the selectivity to give trienes 3 in the oxidative
carbocyclization of allenynes 1, we studied the effect of
various additives and found that H2O most efficiently
promoted the formation of triene products 3 (see SI).
Commercially available arylboronic acids consist of variable
mixtures of the boronic acid and the boroxine. In order to
ensure reproducibility we therefore decided to use phenyl
boroxine.[10]
In our optimization study the use of dioxane instead of
THF as solvent increased the relative amount of products 3.
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Table 3: Scope of allenynes 1a–g in the formation of trienes 3a–g.[a]
Table 4: Scope of aryl boroxines in the formation of trienes 3.[a]
Entry
Ar
Product
Yield [%][b]
3/2[c]
Entry Substrate
Product
Yield [%][b] Selectivity
3/2[c]
1
2
3
4
5
6
7
8
Ph
3a
78
77
76
75
65
80
83
84
85
61
76
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
p-MeC6H4
m-MeC6H4
p-tBuC6H4
2-naphthyl
p-CHOC6H4
p-CF3C6H4
m-NO2C6H4
p-BrC6H4
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
1[d]
72
68
>99:1
>99:1
2[e]
9
10
11
m-MeOC6H4
p-MeOC6H4
3aj
3ak
[a] The reactions were carried out on a 0.2 mmol scale in 2 mL of
dioxane. [b] Yield of isolated product. [c] Determined from the crude
1H NMR spectrum. E=CO2Me.
3
73
>99:1
high selectivity (Table 4, entries 2–11). Boroxines with an
electron-withdrawing substituent (Table 4, entries 6–9) pro-
vided slightly better results (80–85% yield) than electron-rich
boroxines.[11,12] The cis-configuration of the tetrasubstituted
4
65
66
>99:1
À
C C double bond in these triene products was confirmed by
X-ray diffraction studies of 3ak.[13]
5[d]
94:6
The ability of added H2O to selectively promote the
formation of triene 3 suggests an interesting influence of the
water content on the reaction mechanism. To the best of our
knowledge there is no reported case of a palladium-catalyzed
reaction involving boronic acids, in which H2O as an additive
influences the selectivity between reaction products.[14] We
investigated the reaction of allenyne 1a in dioxane with
different amounts of added H2O (Table 5). With no added
H2O the selectivity between products 2a and 3a was poor
(Table 5, entry 1), but with addition of ꢀ 0.5 equiv of H2O,
6
74
>98:2
Table 5: Effect of H2O on the product ratio (2a/3a).[a,b]
40
80:20
7
33[f]
Entry
H2O (equiv)
2a [%]
3a [%]
2a/3a[c]
5 [%]
[a] Unless otherwise stated, the reactions were carried out on a 0.2 mmol
scale in 2.0 mL of dioxane at 608C for 20 h (entries 1, 3–4) or 24 h
(entries 2, 5–7). [b] Yield of isolated product. [c] Determined from the
crude 1H NMR. [d] Ca. 5% of remaining 1 was detected in the crude
1H NMR spectrum with anisole as internal standard. [e] Reaction was
performed using 0.15 mmol 1c in 1.5 mL of dioxane. [f] Yield determined
1
2
3
4
5
6
–
16
–
–
–
–
39
64
65
74
78
74
29:71
<1:99
<1:99
<1:99
<1:99
<1:99
3
15
18
14
7
0.5
1.0
3.0
5.0
10.0
1
from crude H NMR spectrum with anisole as internal standard.
–
3
E=CO2Me.
[a] The reactions were carried out on a 0.1 mmol scale in 1.0 mL of
dioxane at 808C. [b] Yields were determined from the 1H NMR spectrum
1
with anisole as internal standard. [c] Determined from the H NMR
spectrum. E=CO2Me.
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2010, 12, 3784; f) X. Sui, R. Zhu, G. Li, X. Ma, Z. Gu, J. Am.
Chem. Soc. 2013, 135, 9318.
triene 3a was the only cyclization product. However, signifi-
cant amounts of uncyclized arylated side product 5 were
formed as a side product with 0.5–3.0 equiv (Table 5,
entries 2–4). Both 3a and 5 are likely to arise from
a common pathway through allene attack on PdII via allylic
[3] For selected recent oxidative carbocyclization reactions by other
groups, see: a) K.-T. Yip, D. Yang, Org. Lett. 2011, 13, 2134;
b) B. S. Matsuura, A. G. Condie, R. C. Buff, G. J. Karahalis,
C. R. J. Stephenson, Org. Lett. 2011, 13, 6320; c) T. Wu, X. Mu,
G. Liu, Angew. Chem. 2011, 123, 12786; Angew. Chem. Int. Ed.
2011, 50, 12578; d) X. Mu, T. Wu, H. Wang, Y. Guo, G. Liu, J.
Am. Chem. Soc. 2012, 134, 878; e) R. Zhu, S. L. Buchwald,
Angew. Chem. 2012, 124, 1962; Angew. Chem. Int. Ed. 2012, 51,
1926; f) Y. Wei, I. Deb, N. Yoshikai, J. Am. Chem. Soc. 2012, 134,
9098.
À
C H cleavage (see Scheme S2). An increase of H2O to
5.0 equiv resulted in inhibition of side product 5 in favor of an
elevated yield of 3a, which reached 78% with 5.0 equiv of
H2O as the best conditions (Table 5, entry 5).
We also studied how the equilibrium between phenyl
boroxine and phenylboronic acids varied with the H2O
concentration in deuterated dioxane. We found that hydrol-
ysis of boroxine is complete at a H2O concentration corre-
sponding to ca. 3.0 equiv of H2O in Table 5. This indicates that
H2O not only plays the role of hydrolyzing the boroxine, but it
also suppresses the formation of 5.
The mechanisms for formation of 2 and 3, respectively,
most likely follow the corresponding mechanisms for the
analogous borylating carbocyclization reactions of alle-
nynes.[7,15]
In summary, control of selectivity was achieved in the
palladium-catalyzed oxidative arylating carbocyclization of
alkyl-substituted allenynes under mild reaction conditions.
With BF3·Et2O as an additive (10 mol%) arylated vinyl-
allenes were selectively formed. Addition of H2O (5.0 equiv)
resulted in selective formation of arylated trienes. In both of
these procedures, a wide range of arylboronic acids and
boroxines with functional groups are tolerated. The detailed
mechanism regarding the roles of BF3·Et2O and H2O is not
clear at present. Further studies on the mechanism by DFT
calculations are underway.
[4] a) J. Piera, K. Nꢃrhi, J.-E. Bꢃckvall, Angew. Chem. 2006, 118,
7068; Angew. Chem. Int. Ed. 2006, 45, 6914; b) J. Franzꢀn, J.-E.
Bꢃckvall, J. Am. Chem. Soc. 2003, 125, 6056.
[5] For allene substrates, see: a) Y. Deng, J.-E. Bꢃckvall, Angew.
Chem. 2013, 125, 3299; Angew. Chem. Int. Ed. 2013, 52, 3217;
b) A. K. ꢂ. Persson, T. Jiang, M. T. Johnson, J.-E. Bꢃckvall,
Angew. Chem. 2011, 123, 6279; Angew. Chem. Int. Ed. 2011, 50,
6155; c) T. Jiang, A. K. ꢂ. Persson, J.-E. Bꢃckvall, Org. Lett.
2011, 13, 5838; d) A. K. ꢂ. Persson, J.-E. Bꢃckvall, Angew.
Chem. 2010, 122, 4728; Angew. Chem. Int. Ed. 2010, 49, 4624;
e) J. Piera, A. Persson, X. Caldentey, J.-E. Bꢃckvall, J. Am.
Chem. Soc. 2007, 129, 14120; f) J. Lçfstedt, K. Nꢃrhi, I. Dorange,
J.-E. Bꢃckvall, J. Org. Chem. 2003, 68, 7243; g) C. M. R. Volla, J.-
E. Bꢃckvall, Angew. Chem. 2013, 125, 14459; Angew. Chem. Int.
Ed. 2013, 52, 14209; for other unsaturated substrates, see: h) M.
Jiang, T. Jiang, J.-E. Bꢃckvall, Org. Lett. 2012, 14, 3538; i) M.
Jiang, J.-E. Bꢃckvall, Chem. Eur. J. 2013, 19, 6571.
[6] Y. Deng, T. Bartholomeyzik, A. K. ꢂ. Persson, J. Sun, J.-E.
Bꢃckvall, Angew. Chem. 2012, 124, 2757; Angew. Chem. Int. Ed.
2012, 51, 2703.
[7] Y. Deng, T. Bartholomeyzik, J.-E. Bꢃckvall, Angew. Chem. 2013,
125, 6403; Angew. Chem. Int. Ed. 2013, 52, 6283.
[8] With an isopropyl-substituent the corresponding vinylallene 2
was also formed. Due to low conversion ( ꢁ 20%) we could not
isolate it from the starting allenyne.
Received: April 12, 2014
Published online: June 30, 2014
[9] ortho-Bromophenylboronic acid did not work, probably due to
=
steric effects. A vinylboronic acid (trans-PhCH CHB(OH)2)
provided not more than 20% (NMR yield) of the corresponding
product 2.
[10] For the preparation of aryl boroxines, see: S. K. Alamsetti,
A. K. ꢂ. Persson, T. Jiang, J.-E. Bꢃckvall, Angew. Chem. 2013,
125, 13990; Angew. Chem. Int. Ed. 2013, 52, 13745.
Keywords: allenes · boronic acids · cyclization · oxidation ·
palladium
.
=
[11] Vinylboronic acid (trans-PhCH CHB(OH)2) gave the corre-
[1] For selected reviews involving palladium-catalyzed carbocycli-
zation reactions, see: a) I. Ojima, M. Tzamarioudaki, Z. Li, R. J.
Donovan, Chem. Rev. 1996, 96, 635; b) E. M. Beccalli, G.
Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 2007, 107,
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A. Simonneau, Chem. Rev. 2011, 111, 1954; e) C. S. Yeung, V. M.
Dong, Chem. Rev. 2011, 111, 1215; f) Y. Deng, A. K. ꢂ. Persson,
J.-E. Bꢃckvall, Chem. Eur. J. 2012, 18, 11498; g) T. Lechel, F.
Pfrengle, H.-U. Reissig, R. Zimmer, ChemCatChem 2013, 5,
2100.
[2] For selected examples in natural product syntheses, see: a) M.
Nakanishi, M. Mori, Angew. Chem. 2002, 114, 2014; Angew.
Chem. Int. Ed. 2002, 41, 1934; b) P. S. Baran, E. J. Corey, J. Am.
Chem. Soc. 2002, 124, 7904; c) N. K. Garg, D. D. Caspi, B. M.
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sponding triene 3al in 47% NMR yield (see SI).
[12] No conversion was observed when alkylboronic acids were used
under conditions to form vinylallenes 2 or trienes 3.
[13] See the Supporting Information for the crystal data of 3ak.
[14] Boronic Acids: Preparation and Applications in Organic Syn-
thesis and Medicine (Ed.: D. G. Hall), Wiley-VCH, Weinheim,
2005.
[15] The formation of 3 is proposed to occur through allene attack on
PdII and allylic C H cleavage (Scheme S2). Formation of 2
À
would in analogy with the borylating carbocyclization of
allenyne 1 occur via alkyne attack on PdII and propargylic
À
C H cleavage. Support for the latter mechanism was provided
by a preliminary competitive isotope experiment in which a 1:1
mixture of 1b and [D2]-1b (dideuterated at the propargylic
position; a in pentyl group) afforded 2b and [D1]-2b in a ratio of
3.9:1 at ca. 30% conversion (which gives kH/kD ꢁ 5).
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