Palladium-catalyzed oxidative carbocyclization/arylation of enallenes

Article abstract of DOI:10.1021/ol202451f

A stereoselective palladium-catalyzed oxidative carbocyclization/arylation of enallenes is described. The reaction shows wide tolerance toward highly functionalized arylboronic acids and results in a cis addition of two carbon moieties to an olefin in goo

Full text of DOI:10.1021/ol202451f

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5838–5841
Palladium-Catalyzed Oxidative
Carbocyclization/Arylation of Enallenes
˚
Tuo Jiang, Andreas K. A. Persson, and Jan-E. Backvall*
€
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-10691, Stockholm, Sweden
jeb@organ.su.se
Received September 9, 2011
ABSTRACT
A stereoselective palladium-catalyzed oxidative carbocyclization/arylation of enallenes is described. The reaction shows wide tolerance toward
highly functionalized arylboronic acids and results in a cis addition of two carbon moieties to an olefin in good to excellent yields.
Carbocyclization reactions are considered as some ofthe
most important chemical transformations since tremen-
dous amounts of naturally occurring products bear such a
carbocyclic backbone.1 Despite the rich development of
transition-metal-catalyzed carbocyclizations,2,3 there is
still a demand for novel methods with high regio- and
stereoselectivity. Our research group has previously re-
ported on the utilization of allenes as carbon nucleophiles
in palladium-catalyzed carbocyclizations under oxidative
conditions.4À6 For both enallenes4 and diene-allenes,5 new
carbonÀcarbon bonds were formed selectively and effi-
ciently using stoichiometric amounts of BQ (p-benzoq-
uinone) as the terminal oxidant. In a few cases, BQ could
be successfully replaced by an aerobic biomimetic reoxida-
tion system making the chemical process more environ-
mentally benign.4e,6
(1) Selected reviews involving carbocyclization reactions, see:
(a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem.
€
Rev. 2007, 107, 5318. (b) Muller, T. J. J. Top. Organomet. Chem. 2006,
19, 249. (c) Mikami, K.; Hatano, M.; Akiyama, K. Top. Organomet.
Chem. 2005, 14, 279. (d) Negishi, E.; Wang, G.; Zhu, G. Top. Organomet.
Chem. 2006, 19, 1.
(2) For palladium-catalyzed carbocyclization reactions, see: (a) Negishi,
E.; Meijere, A. Handbook of Organopalladium Chemistry for Organic
Synthesis; Wiley-Interscience: New York, 2002. (b) Pei, T.; Wang, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 648. (c) Ferreira, E. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578.
Organoboron reagents have been widely used by the
chemical community to seletively facilitate the forma-
tion of new carbonÀcarbon bonds. Among those elegant
(3) For the recent examples of palladium-catalyzed carbocyclization
in natural product syntheses, see: (a) Baran, P. S.; Corey, E. J. J. Am.
Chem. Soc. 2002, 124, 7904. (b) Garg, N. K.; Caspi, D. D.; Stoltz, B. M.
J. Am. Chem. Soc. 2004, 126, 9552. (c) Corkey, B. K.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 2764. (d) Nakanishi, M.; Mori, M. Angew. Chem.,
Int. Ed. 2002, 41, 1934.
(7) (a) Hoffmann, R. W.; Herold, T. Angew. Chem., Int. Ed. 1978, 17,
768. (b) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(c) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186. (d) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(8) (a) Suzuki, A.; Miyaura, N. Chem. Rev. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147. (c) Miyaura, N. Top. Curr.
Chem. 2002, 219, 11. (d) Miyara, N. Metal-Catalyzed Cross-Coupling
Reactions of Organoboron Compounds with Organic Halides. In
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, 2004; pp 41À123.
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(4) (a) Franzen, J.; Lofstedt, J.; Dorange, I.; Backvall, J.-E. J. Am.
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Chem. Soc. 2002, 124, 11246. (b) Franzen, J.; Backvall, J.-E. J. Am.
Chem. Soc. 2003, 125, 6056. (c) Franzen, J.; Lofstedt, J.; Falk, J.;
Backvall, J.-E. J. Am. Chem. Soc. 2003, 125, 14140. (d) Narhi, K.;
Franzen, J.; Backvall, J.-E. Chem.;Eur. J. 2005, 11, 6937. (e) Persson,
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A. K. A.; Backvall, J.-E. Angew. Chem., Int. Ed. 2010, 49, 4624.
(9) For oxidative Heck reacion, see: (a) Karimi, B.; Behzadnia, H.;
Elhamifar, D.; Akhavan, P. F.; Esfahani, F. K.; Zamani, A. Synthesis
2010, 9, 1399. (b) Cho, C. S.; Uemura, S. J. Organomet. Chem. 1994, 465,
85. (c) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y.
Science 2000, 287, 1992. (d) Werner, E. W.; Sigman, M. S. J. Am. Chem.
Soc. 2010, 132, 13981. (e) Liu, Y.; Li, D.; Park, C.-M. Angew. Chem., Int.
Ed. 2011, 50, 7333. (f) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem.
Soc. 2009, 131, 5072. (g) For a recent review on palladium-catalyzed
alkene functionalization, see: McDonald, R. I.; Liu, G.; Stahl, S. S.
Chem. Rev. 2011, 111, 2981.
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10.1021/ol202451f
Published on Web 10/03/2011
2011 American Chemical Society

methods, asymmetric allylation7 and SuzukiÀMiyaura
cross-coupling8 are distinguished representatives. In parti-
cular the latter is a major method for carbonÀcarbon bond
formation. Recently, also arylation of olefins via oxidative
Heck procedures has been successfully accomplished by
using arylboronic compounds.9 The advantages of using
organoboron compounds as transmetalation reagents in-
clude their low toxicity,10 the mild reaction conditions
involved, and their commercial accessibility. Arylboronic
acids, for instance, is a family of commercialized boron
compounds with a range of diverse functionalities. These
properties have notably contributed to their extensive use
in palladium-catalyzed arylation via trapping of aryl-,8
alkyl-,11 and allylpalladium12 species. Such procedures
allow for simple and efficient introduction of aryl groups
in a range of substrates.
report a palladium-catalyzed oxidative carbocyclization/
arylation of enallenes.
In preliminary experiments, we applied the same condi-
tions as in the borylation case, treating enallene 1a with 5
mol % of Pd(OAc)2, 1.2 equiv of BQ, and 1 equiv of
PhB(OH)2 in toluene at 40 °C. After 24 h, the reaction
afforded the desired phenylated product 2aa in 53% yield
accompanied by unreacted starting material.14 Trace amounts
of the byproduct 4a, arising from β-hydride elimination of
the alkylpalladium intermediate, was also observed.
Encouraged by this result, we screened a range of
reaction parameters to find a suitable protocol for selective
formation of 2aa. We found that the role of the solvent was
of great importance for a successful reaction: solvents such
as THF, acetone, and 1,4-dioxane promoted the formation
ofthe desiredproduct in good yields.15 Among the solvents
tested, THF was by far the most effective, resulting in the
best selectivity for arylation over β-elimination. The cata-
lytic activity varied with the palladium salts employed:
Pd(OOCCF3)2 showed good activity comparable to Pd-
(OAc)2, whereas other palladium salts [e.g., PdCl2DMSO2
and Pd(acac)2] showed much lower activity. The catalyst
loading could be lowered to 1 mol % without a significant
decrease in yield. Gratifyingly, only trace amounts (2%) of
biphenyl via homocoupling of phenylboronic acids could
be detected in the crude reaction mixture. The amount of p-
benzoquinone (BQ) could be reduced to 1.1 equiv without
a significant loss in yield or selectivity. Increasing the
temperature accelerated the reaction, and 60 °C was found
to be the optimal temperature (Scheme 2). Under these
conditions 2aa was obtained in 83% yield with only 4% of
the β-elimination product 4a.
Scheme 1. Palladium-Catalyzed Oxidative Functionalization of
Enallenesa
a E = CO2Me, BQ = p-benzoquinone, B2pin2 = bis(pinacolato)diboron.
Recently, we reported a palladium-catalyzed oxidative
borylative carbocyclization of enallenes, in which B2pin2
[bis(pinacolato)diboron] served as the borylating reagent
(Scheme 1, upper pathway).13 The proposed mechanism
involves formation of an alkylpalladium intermediate,
followed by transmetalation with B2pin2 and subsequent
reductive elimination to furnish the cyclized alkylborates 3
in high yield. The introduction of a pinacol borane allows
for further chemical transformations, e.g. oxidation and
cross-coupling reactions. As a novel extension of our
enallene chemistry, we attempted to actualize the direct
functionalization of alkylpalladium species using organo-
boron reagents such as arylboronic acids. Herein, we
Scheme 2. Palladium-Catalyzed Oxidative Carbocyclization/
Arylation of Enallenes
The conditions in Scheme 2 were used to investigate the
scope of the palladium-catalyzed oxidative carbocycli-
zation/arylation of enallenes. Both electron-rich and
electron-deficient arylboronic acids were evaluated and
the results are summarized in Table 1.16 Arylboronic
acids bearing electron-donating substituents such as
alkyl- (entries 2 À 4 and 8), alkoxy- (entries 5 À 7) and
(10) Organosilicon reagents have also been widely used due to its low
toxicity, see: (a) Hatanaka, Y.; Hiyama, T. Synlett 1991, 845. (b) Hiyama,
T.; Shirakawa, E. Topp. Curr. Chem. 2002, 219, 61. (c) Denmark, S. E.;
Sweis, R. F. Acc. Chem. Res. 2002, 35, 835. (d) Denmark, S. E.; Sweis, R. F.
Chem. Pharm. Bull. 2002, 50, 1531.
(11) (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417. (b) Oh, C. H.; Sung, H. R.; Park, S. J.; Ahn, K. H. J. Org. Chem.
2002, 67, 7155. (c) Lee, C.-K.; Oh, K. S.; Kim, K. S.; Ahn, K. H. Org.
Lett. 2000, 2, 1213. (d) Trejos, A.; Fardost, A.; Yahiaoui, S.; Larhed, M.
Chem. Commun. 2009, 7587.
(14) Yields were determined by 1H NMR analysis of the crude
mixture using anisole as the internal standard.
(12) (a) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am.
Chem. Soc. 2011, 133, 5784. (b) Liao, L.; Sigman, M. S. J. Am. Chem.
Soc. 2010, 132, 10209. (c) Grigg, R.; Sridharan, V.; Xu, L.-H. J. Chem.
Soc., Chem. Commun. 1995, 1903.
(15) NMR yields for reactions in THF, acetone, and 1,4-dioxane
were greater than 85%. Other solvents (ethyl acetate, toluene, DCM,
DCE, and CH3CN) gave incomplete reactions under the same condi-
tions. For more details, see Supporting Information.
(16) The use of ArBF3K or ArB(pin) does not lead to any trapping
product, and only the β-elimination product was observed.
˚
€
(13) Persson, A. K. A.; Jiang, T.; Johnson, M.; Backvall, J.-E. Angew.
Chem., Int. Ed. 2011, 50, 6155.
Org. Lett., Vol. 13, No. 21, 2011
5839

silyl-groups (entry 9) reacted well under the standard
conditions and reached full conversion within 4 h. ortho-
Substituted arylboronic acids showed a notable decrease
in yield probably due to the steric effects, resulting in a
less facile transmetalation. Also, additional olefin func-
tionality was tolerated without any notable formation of
aryl-olefin coupling products (entry 10).
The reaction of different acyclic and cyclic enallenes
with phenylboronic acid was also investigated (Table 2).
Notably, this procedure appeared to be most efficient
for enallenes with a terminal alkene, which afforded the
corresponding phenylated product in good yield (Table 2,
entries 1 and 2). For substrates with a substituent on the
terminal position of the alkene we were pleased to find
that utilization of a slight excess of phenylboronic acid
Table 1. Scope of Functionalized Arylboronic Acidsa
Table 2. Scope of Different Enallenesa
entry
aryl group (Ar)
product
time (h)
yieldb (%)
1
C6H5
2aa
2ab
2ac
2ad
2ae
2af
2
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
21
83
79
88
84
61
87
75
82
88
90
90
82
92
73
86
95
86
68
2
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
2-OMe-C6H4
3-OMe-C6H4
4-OMe-C6H4
4-tBu-C6H4
4-TMS-C6H4
4-vinyl-C6H4
4-F-C6H4
3
4
5
6
7
2ag
2ah
2ai
8
9
10
11
12
13
14
15
16
17
18c
2aj
2ak
2al
4-Cl-C6H4
4-Br-C6H4
2am
2an
2ao
2ap
2aq
2ar
4-CF3-C6H4
4-acetyl-C6H4
4-formyl-C6H4
3-NO2-C6H4
4-OH-C6H4
a Reaction conditions: 0.2 mmol 1a, 1 mol % of Pd(OAc)2, 1.1 equiv
of BQ, 1.0 equiv of ArB(OH)2, THF (0.1 mmol/mL), 60 °C. b Isolated
yield after column chromatography. c 1.3 equiv of ArB(OH)2 was used.
Electron-deficient arylboronic acids required slightly
longer reaction time to reach full conversion. para-Halo-
genated aromatics also proved compatible with the reac-
tion conditions (entries 11 À 13) including the bromo-
substituted substrates, which are sensitive coupling partners
in Pd(0)-catalyzed cross-coupling reactions. The remain-
ing bromo functionality serves as a valuable handle for
further modification of the product. Other electron-with-
drawing substituents that are tolerated include trifluoro-
methyl, acetyl, formyl and nitro groups (entries 14 À 17).
Among these, formyl and acetyl groups are of specific
importance since carbonyl-related chemistry might be
implemented subsequently. Interestingly, p-hydroxyphe-
nylboronic acid proved less effective as an excess of the
boronic acid and prolonged reaction time were required
to afford the arylated product in 68% yield (entry 18).
This may be attributed to the change of the overall acidity
or factors involving transmetalation.17
a Reaction conditions: 0.2 mmol of 1, 1 mol % of Pd(OAc)2, 1.1 equiv
of BQ, 1.0 equiv (entries 1À2) or 1.3 equiv (entries 3À6) of PhB(OH)2,
THF (0.1 mmol/mL), 60 °C. b Isolated yield after column chromato-
graphy. c No reaction based on 1H NMR analysis of the crude mixture.
(1.3 equiv) significantly suppressed the formation of the β-
elimination product (entries 3À5, Table 2).18 Cyclic en-
allenes underwent the carbocyclization/arylation sequence
affording the products with stereospecific cis addition of
both the allene and the phenyl to the olefin (entries 4
and 5). The stereochemistry of 2d and 2e was determined
by comparing the coupling constant with analogous com-
pounds from our previous studies.13 It is also worth
mentioning that in these cases we observed side products
(17) The use of vinylboron compounds CH2dC(Ph)B(OH)2 and (E)-
PhCHdCHB(OH)2 gave an incomplete conversion of 47% and 35%
respectively. Alkylboron compounds gave no reaction.
(18) β-Elimination products were formed in <1% yields in the crude
mixtures in entries 3À5 when 1.3 equiv of phenylboronic acid was used.
5840
Org. Lett., Vol. 13, No. 21, 2011

where arylation occurred on the allene moiety. This type of
byproduct is of special interest when considering various
mechanistic pathways (Scheme 3, 6c).
Scheme 3. Mechanistic Proposal
The unsuccessful reaction of 1f shows the limitation of
this reaction; steric hindrance of the allene part has a large
negative effect on the reaction outcome. Some further
modifications were tried to increase the yield of 2c, 2d,
and 2e. Addition of a range of additives such as H2O,
NaOAc, Na2CO3, and DMSO failed in both diminishing
the amount of β-elimination product and improving the
yield of the desired carbocycles.
Mechanistically, we postulate a reaction pathway based
on our previous results.4 Initial coordination between
enallene 1 and Pd(OAc)2 enables allene attack on Pd(II)
generating vinylpalladium intermediate A, the key species
promoting the carbocyclization to B as previously sug-
gested. The undesired β-hydride elimination from alkyl-
palladium species B could be suppressed, and 4 was formed
in <4% and 5 in <1%. Transmetalation of cyclic inter-
mediate B with arylboronic acids, followed by reductive
elimination with retention of configuration, would give the
desired product 2. The released Pd(0) is reoxidized to
Pd(II) by p-benzoquinone. Isolation of product 6c indi-
cates that the carbocyclization/arylation reaction of en-
allenes proceeds via our proposed pathway. We should
point out that formation of the undesired, phenylated
product 6 can be rationalized through other palladium-
catalyzed pathways.19 Also we cannot rule out the possi-
bility of intermediate C triggering carbocyclization or that
a Pd(IV)-type cyclometalation mechanism is in operation.
In summary, we have successfully extended the scope of
our carbocyclization chemistry by introducing a variety of
functionalized aryl groups with the aid of commercially
available arylboronic acids. This extension further
increases the chemical complexity by the formation of
two carbonÀcarbon bonds under oxidative conditions.
Studies leading to a more detailed insight of the reaction
mechanism are underway and will be reported in the near
future.
Acknowledgment. European Research Council (ERC
AdG 247014), The Swedish Research Council, the Berzelius
center EXSELENT, and C. F. Liljevalch J:ors travel grant
are gratefully acknowledged.
Supporting Information Available. Detailed experimen-
tal procedure and product characterization. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(19) Deagostino, A.; Prandi, C.; Tabaso, S.; Venturello, P. Molecules
2010, 15, 2667.
Org. Lett., Vol. 13, No. 21, 2011
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