Palladium-catalyzed oxidative diarylating carbocyclization of enynes

Article abstract of DOI:10.1021/ol301551x

A mild and efficient palladium-catalyzed oxidative diarylating carbocyclization of enynes is described. The reaction tolerates a range of functionalized arylboronic acids to give diarylated products in good yields. Control experiments suggest that the reaction starts with an arylpalladation of the alkyne, followed by carbocyclization, transmetalation, and reductive elimination to afford the diarylated product.

Full text of DOI:10.1021/ol301551x

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3538–3541
Palladium-Catalyzed Oxidative Diarylating
Carbocyclization of Enynes
€
Min Jiang, Tuo Jiang, and Jan-E. Backvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received June 5, 2012
ABSTRACT
A mild and efficient palladium-catalyzed oxidative diarylating carbocyclization of enynes is described. The reaction tolerates a range of
functionalized arylboronic acids to give diarylated products in good yields. Control experiments suggest that the reaction starts with an
arylpalladation of the alkyne, followed by carbocyclization, transmetalation, and reductive elimination to afford the diarylated product.
Cyclic structures constitute the backbone of a large
number of natural products, and therefore, efficient meth-
ods for the construction of cyclic structures from simple
acyclic building blocks are of current interest. In the past
several decades, transition-metal-catalyzed cyclization re-
actions of enynes1 have emerged as highly useful tools for
the synthesis of functionalized cyclic and heterocyclic
compounds.2,3 Various transition-metal catalysts, such as
Pd,4 Pt,5 and Au,6 have been studied extensively. Gener-
ally, complexation of the π-electrons of the enyne with a
transition-metal catalyst allows the activation of either
alkene or alkyne or both simultaneously. Regarding the
relative reactivity of the unsaturated subunits, three dif-
ferent mechanisms involving a cyclometalation inter-
mediate,7 a π-allyl complex,8 or a vinylÀmetal complex9
have been proposed. Recently, the synthesis of cyclopro-
panes via metal-catalyzed reactions of enynes has also been
reported.10
So far, palladium has played a pivotal role in the
development of metal-catalyzed cycloisomerization reac-
tions of 1,n-enynes.4,7aÀc,8a,b,9a,b However, there are only a
few reports describing the arylation of alkynes with Pd(II)
(1) For reviews on cyclizations of enynes, see: (a) Marco-Contelles,
ꢀ
(7) (a) Trost, B. M.; Romero, D. L.; Rise, F. J. Am. Chem. Soc. 1994,
116, 4268. (b) Canty, A. J. Acc. Chem. Res. 1992, 25, 83. (c) Beller, M.;
ꢀ~
J.; Soriano, E. Chem.;Eur. J. 2007, 13, 1350. (b) Jimenez-Nunez, E.;
Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (c) Michelet, V.; Toullec,
~
Fischer, H.; Hermann, W. A.; Ofele, K.; Brossmer, C. Angew. Chem.,
^
P. Y.; Genet, J. P. Angew. Chem., Int. Ed. 2008, 47, 4268.
Int. Ed. 1995, 34, 1848. (d) Buisine, O.; Aubert, C.; Malacria, M.
Chem.;Eur. J. 2001, 7, 3517.
(8) (a) Oppolzer, W. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Elsevier: Oxford,
1991; Vol. 5, p 29. (b) Trost, B. M.; Luengo, J. I. J. Am. Chem. Soc.
1988, 110, 8239. (c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999,
121, 9728.
(9) (a) Trost, B. M.; Pedregal, C. J. Am. Chem. Soc. 1992, 114, 7292.
(b) Trost, B. M.; Tour, J. M. J. Am. Chem. Soc. 1987, 109, 5268.
(c) Nishida, M.; Adachi, N.; Onozuka, K.; Matsumura, H.; Mori, M.
J. Org. Chem. 1998, 63, 9158.
(2) (a) Ni, Y.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 11162.
(b) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem.
€
Soc. 2005, 127, 6178. (c) Furstner, A.; Davies, P. W.; Gress, T. J. Am.
Chem. Soc. 2005, 127, 8244.
€
(3) (a) Furstner, A.; Hannen, P. Chem. Commun. 2004, 2546.
(b) Nevado, C.; Ferrer, C.; Echavarren, A. M. Org. Lett. 2004, 6, 3191. (c)
Lee, S. I.; Kim, S. M.; Choi, M. R.; Kim, S. Y.; Chung, Y. K.; Han, W.-S.;
Kang, S. O. J. Org. Chem. 2006, 71, 9366.
(4) (a) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110,
1636. (b) Trost, B. M.; Trost, M. K. J. Am. Chem. Soc. 1991, 113, 1850.
(c) Mikami, K.; Hatano, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5767.
(5) (a) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organo-
metallics 1996, 15, 901. (b) Trost, B. M.; Chang, V. K. Synthesis 1993,
824.
ꢀ
(10) (a) Barbazanges, M.; Auge, M.; Moussa, J.; Amouri, H.; Aubert,
C.; Desmarets, C.; Fensterbank, L.; Gandon, V.; Malacria, M.; Ollivier,
C. Chem.;Eur. J. 2011, 17, 13789. (b) Tong, X.; Beller, M.; Tse, M. K.
J. Am. Chem. Soc. 2007, 129, 4906. (c) Welbes, L. L.; Lyons, T. W.;
Cychosz, K. A.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 5836.
(11) (a) Zhao, C. X.; Larock, R. C. Org. Lett. 2005, 7, 259. (b) Zhao,
C. X.; Larock, R. C. J. Org. Chem. 2006, 71, 3184. (c) Satoh, T.; Ogino,
S. J.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 2004, 43, 5063.
(d) Shen, K.; Han, X. L.; Lu, X.-Y. Org. Lett. 2012, 14, 1756.
ꢀ
(6) (a) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
~
ꢁ
(b) Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez, E.;
Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M.
Chem.;Eur. J. 2006, 12, 16773.
r
10.1021/ol301551x
Published on Web 06/20/2012
2012 American Chemical Society

as catalyst, which still is a challenge.11 Cardenas and co-
ꢀ
workers reported a Pd(0)-catalyzed borylative cyclization
of 1,6-enynes and enallenes using B2pin2 [bis(pin-
acolato)diboron] as the boron-transfer reagent.12 The
reaction was proposed to proceed via hydropalladation
of the alkyne moiety followed by cyclization via carbopal-
ladation of the alkene and subsequent borylation to afford
homoallylic alkylboronates in moderate tohighyields. The
Pd(0)-catalyzed cyclization of enynes with bimetallic re-
agents has been found to afford cyclized products includ-
ing two functional groups.13
Scheme 1. Palladium-Catalyzed Oxidative Diarylating
Carbocyclization of Enyne
Optimization of the reaction conditions initially focused
on the variation of the palladium catalyst. The catalytic
activity of various palladium(II) species differed, and
PdCl2, PdCl2(PPh3)2, and Pd(acac)2 failed to promote
any arylation resulting in full recovery of the starting
material. Pd(OAc)2 afforded the cyclic diarylated com-
pound 3aa but only as a minor product. Electron-deficient
Pd(OCOCF3)2 proved to be superior to Pd(OAc)2 provid-
ing the diarylated product 3aa in 73% yield together with
8% of 4aa (Scheme 1). The catalyst loading could be
lowered to 1 mol % without any erosion in yield and
stereoselectivity. Other stoichiometric oxidants such as
Our research group has been involved in the develop-
ment of various palladium-catalyzed carbocyclizations un-
der oxidative conditions.14,15 Recently, we reported the
palladium-catalyzed oxidative carbocyclizationÀborylation
and Àarylation of enallenes14f,g and allenynes.14h In the
oxidative carbocyclization/arylation reactions, arylboro-
nic acids were used to readily generate an arylpalladium
species from a Pd(II) catalyst. As an extension of our
oxidative palladium chemistry, we envisioned that the
arylpalladium species formed may undergo arylpallada-
tion of either alkene or alkyne in enynes to generate an
alkyl- or vinylpalladium intermediate. These intermediates
may trigger cyclization reactions leading to an overall
diarylation with novel complexity. Herein, we report a
mild and efficient stereoselective diarylating carbocycliza-
tion of enynes catalyzed by Pd(II) under oxidative condi-
tions to give the corresponding diarylated carbocycles in
good yields.
In our preliminary experiments, O-tethered 1,6-enyne 1a
was treated with 10 mol % of Pd(OAc)2, 3.0 equiv of
phenylboronic acid (2a), and 1.0 equiv of p-benzoquinone
(BQ) in tetrahydrofuran (THF) at room temperature. Full
conversion of 1a was achieved in 16 h, and gratifyingly, the
desired cyclic diarylated product 3aa was isolated in 32%.
The major byproduct was identified as the diarylated
alkyne product 4aa in 52% yield (Scheme 1). The stereo-
chemistry of the newly formed double bond in both 3aa
and 4aa was established as Z by NOE experiments.
Cu(OAc)2 2H2O and DDQ were also evaluated, but none
3
of them was successful in forming 3aa. Further examina-
tion of solvent effects revealed that acetone, diethyl ether,
1,2-dichloroethane (DCE), and DMF gave significantly
lower yields, and no reaction was observed with acetoni-
trile or toluene as solvents. An increase of the temperature
to 50 °C had a negative effect on the reaction leading to a
decreased yield of 3aa to 42%. Therefore, the optimal
conditions were set to 1 mol % of Pd(OCOCF3)2, 3 equiv
of phenylboronic acid, and 1 equiv of BQ in THF at room
temperature.
Attempts to use malonate- or N-tethered enynes gave no
reaction, and ester-tethered enyne produced a diene side
product (Figure SI-1 in the Supporting Information),
suggesting that the oxygen tether is crucial for the diarylat-
ing carbocyclization.
Using the optimizedconditions, wefurtherexaminedthe
scope of arylboronic acids 2. A variety of both electron-
deficient and electron-rich arylboronic acids were evalu-
ated, and the results are summarized in Table 1. The
diarylating carbocyclization procedure tolerated a broad
range of functional groups, and the electronic nature of the
arylboronic acids 2 had little influence on the yield of the
reaction. Halide-substituted arylboronic acids reacted well
with enyne 1a to give the corresponding diarylated product
3 in good yields (Table 1, entries 2À6). A bromoaryl
functionality, which is a labile moiety in Pd(0)-catalyzed
cross-coupling reactions, showed good compatibility with
the oxidative palladium conditions (entries 5 and 6). The
use of a bromo substitution allows modification of the
diarylated carbocycles. Electron-rich arylboronic acids
bearing alkyl (entries 7À9), alkoxy (entry 10), or silyl
substitution (entry 11) proceeded well under the optimal
reaction conditions, while a slightly prolonged reaction
time was required to reach full conversion. Additional
olefin functionality was tolerated, and no cross-insertion
~
(12) (a) Pardo-Rodrıguez, V.; Marco-Martınez, J.; Bunuel, E.;
ꢀ
Cardenas, D. J. Org. Lett. 2009, 11, 4548. (b) Marco-Martınez, J.;
~
~
ꢀ
Bunuel, E.; Munoz-Rodrıguez, R.; Cardenas, D. J. Org. Lett. 2008,
ꢀ
~
10, 3619. (c) Marco-Martınez, J.; Lopez-Carrillo, V.; Bunuel, E.;
ꢀ
Simancas, R.; Cardenas, D. J. J. Am. Chem. Soc. 2007, 129, 1874.
(13) (a) Mori, M.; Hirose, T.; Wakamatsu, H.; Imakuni, N.; Sato, Y.
Organometallics 2001, 20, 1907. (b) Sato, Y.; Imakuni, N.; Mori, M. Adv.
Synth. Catal. 2003, 345, 488. (c) Sato, Y.; Imakuni, N.; Hirose, T.;
Wakamatsu, H.; Mori, M. J. Organomet. Chem. 2003, 687, 392.
(d) Onozawa, S.-y; Hatanaka, Y.; Choi, N.; Tanaka, M. Organometal-
lics 1997, 16, 5389.
ꢀ
€
(14) (a) Franzen, J.; Backvall, J.-E. J. Am. Chem. Soc. 2003, 125,
€
€
6056. (b) Piera, J.; Narhi, K.; Backvall, J.-E. Angew. Chem., Int. Ed.
€
2006, 45, 6914. (c) Piera, J.; Persson, A.; Caldentey, X.; Backvall, J.-E.
J. Am. Chem. Soc. 2007, 129, 14120. (d) Johnston, E. V.; Karlsson, E. A.;
Lindberg, S. A.; Akermark, B.; Backvall, J.-E. Chem.;Eur. J. 2009, 15,
˚
€
˚
€
6799. (e) Persson, A. K. A.; Backvall, J.-E. Angew. Chem., Int. Ed. 2010,
˚
49, 4624. Eneallenes: (f) Persson, A. K. A.; Jiang, T.; Johnson, M. T.;
€
Backvall, J.-E. Angew. Chem., Int. Ed. 2011, 50, 6155. (g) Jiang, T.;
˚
€
Persson, A. K. A.; Backvall, J.-E. Org. Lett. 2011, 13, 5838. Allenyne:
˚
(h) Deng, Y.-Q.; Bartholomeyzik, T.; Persson, A. K. A.; Sun, J. L.;
€
Backvall, J.-E. Angew. Chem., Int. Ed. 2012, 51, 2703.
(15) For work by others on oxidative CÀC bond-forming reactions,
see: (a) Jensen, T.; Fristrup, P. Chem.;Eur. J. 2009, 15, 9632. (b) Liao,
L.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 10209. (c) Werner, E. W.;
Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 13981.
Org. Lett., Vol. 14, No. 13, 2012
3539

was observed (entry 12). Heteroarylboronic acids (entries
13 and 14) and (E)-styrylboronic acid (entry 15) worked
well and afforded the corresponding diarylatedproducts in
good yields. Each product was obtained as a single
diastereomer.
Table 2. Palladium-Catalyzed Oxidative Diarylating
Carbocyclization of Enynes
Table 1. Scope of Functionalized Arylboronic Acids
entrya
ArB(OH)2, Ar
product
yieldb (%)
1
2
2a, C6H5
3aa
3ab
3ac
3ad
3ae
3af
73
70
71
65
64
66
75
72
77
81
65
76
81
77
71
2b, 4-FC6H4
2c, 4-ClC6H4
2d, 3,4À2ClC6H3
2e, 2-BrC6H4
2f, 4-BrC6H4
2g, 4-MeC6H4
2h, 3-MeC6H4
2i, 4-tBuC6H4
2j, 3-MeOC6H4
2k, 4-TMSC6H4
2l, 4-vinylC6H4
2m, 2-furyl
3
4
5
6
7c
8c
9c
10c
11
12
13
14
15
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
2n, 3-furyl
2o, E-styryl
a Reaction conditions: 1a (0.2 mmol), Pd(OCOCF3)2 (0.002 mmol),
BQ (0.2 mmol), and arylboronic acid 2 (0.6 mmol) in THF (2.0 mL) at
room temperature for 16 h. b Isolated yields. c The reaction time was 24 h.
The reactions of enynes 1aÀg in the diarylating carbo-
cyclization are summarized in Table 2. 1,6-Enyne 1a
afforded diarylated products in good yields (Table 2, en-
tries 1À3). When a terminal substituent of the alkyne was
introduced, the reaction was slower and required an
increase of the temperature to 50 °C. Under these condi-
tions, the desired diarylated products 3bm and 3cm were
isolated in 87% and 51% yield, respectively (entries 4 and
5). Additional dimethyl substitution at the propargyl
position had minor influence on the reaction outcome
and the diarylated products 3dn and 3do were obtained
in 68 and 53% yield, respectively (entries 6 and 7). The
diarylating carbocyclization process of nonsubstituted
enyne 1e also gave the desired product 3el at 50 °C (entry 8).
1,7-Enyne 1f showed lower activity under the optimal
conditions, which may be attributed to the less favored
coordination. By increasing the catalyst loading to 3 mol
%, the reaction of enyne 1f at 50 °C with boronic acids 2a
a Reaction conditions: 1 (0.2 mmol), Pd(OCOCF3)2 (0.002 mmol),
BQ (0.2 mmol), and arylboronic acid 2 (0.6 mmol) in THF (2.0 mL) at
room temperature for 16 h. b Isolated yields. c 3 mol % of Pd(OCOCF3)2
was used at 50 °C for 8 h.
and 2l gave the corresponding six-membered ring products
3fa and 3fl in 73% and 68% yield, respectively (entries 9
and 10). E- and Z-enyne isomers 1a and 1g afforded
diastereoisomers 3af and 3gf, respectively (entries 11 and
12). The 1H NMR spectra of 3af and 3gf are in accordance
with the stereochemistry assigned.16 Reaction of 2-cyclo-
hexenyl propargyl ether was unsuccessful and no carbocy-
clization product was formed (see the Supporting Infor-
mation).
By altering the terminal substituent on the alkene to an
alkyl group, a different product was obtained which arose
from a β-elimination in the final step. In the presence of
β-hydrogens, β-elimination is apparently favored over
transmetalationÀreductive elimination and enyne 1h af-
forded diene 5 in 56% yield (Scheme 2).
(16) The stereochemical assignment of 3af and 3gf from the mechan-
ism in Scheme 3 is in accord with δHa occurring at a lower field (higher
shift) in 3af than in 3gf due to the closeness to the p-bromophenyl group.
Control experiments showed that the diarylating carbo-
cyclization does not occur with the corresponding 1,6-
dienes under the reaction conditions used in Table 2. When
3540
Org. Lett., Vol. 14, No. 13, 2012

configuration to give diarylated product 3. The released
Pd(0) is reoxidized to Pd(II) by the coordinated BQ.18
When R2 is an alkyl group, rapid β-hydride elimination
would be favored to produce alkene 5. The formation of
the undesired acyclic side product 4 is attributed to a slow
carbocyclization where competing transmetalation of the
vinylpalladium intermediate A to give intermediate C
occurs. Subsequent reductive elimination from intermedi-
ate C would give the acyclic diarylated product 4.19
In the proposed mechanism, the enyne coordinates to
the metal in an ArPdX species. When the tether is a carbon
or nitrogen atom, formation of the corresponding inter-
mediate A may be less favored in accordance with the
aboveexperiments. Comparison of the1H NMR spectra of
1,6-enynes 1e, I, II, and III shows that there are differences
in chemical shift of the alkynyl proton: 2.42 ppm (1e), 2.02
ppm (I), 2.02 ppm (II) and 2.90 ppm (III) (Figure 1). We
argue that the induction effect from the propargyl oxygen
contributes to the activation of the alkyne moiety while a
carbon or a nitrogen atom in the tether does not. Also,
ester-tethered enyne III gave a fast reaction of the alkyne;
however, in this case fast protonolysis of the arylpallada-
tion intermediate corresponding to A occurs. Trost has
also suggested that the electronic effects of substituents on
the tether between both unsaturated moieties would con-
siderably influence the rate and regioselectivity of the
cycloisomerizations of enynes.20
Scheme 2. Reaction of 1h with Substituted Alkyl Group
the 1,6-diene corresponding to 1a was employed as the
substrate, no reaction was observed (see the Supporting
Information). Apparently, the alkynyl group is essential
for the palladium-catalyzed oxidative diarylating carbocy-
clization, which indicates that the reaction is initiated by an
arylpalladation of the alkyne. Another control experiment
monitored by 1H NMR showed that fast arylpalladation
of 1-benzyloxymethyl-1-butyne takes place at 25 °C on
reaction with PhB(OH)2/PdOCOCF3 (1:1) (see Support-
ing Information).
Scheme 3. Proposed Mechanism for Pd-Catalyzed Oxidative
Diarylating Carbocyclization of Enynes
Figure 1. Shift of the alkynyl proton in enynes 1e and IÀIII.
On the basis of the above experimental results, a plau-
sible reaction pathway is proposed in Scheme 3. Fast
transmetalation between the arylboronic acid and the
Pd(II) catalyst generates an ArPdX species,17 which adds
to the alkyne in a syn-arylpalladation. The vinylpalladium
intermediate A9 formed subsequently undergoes a carbo-
cyclization where the alkene inserts into the vinylÀPd
bond to give intermediate B.4 When R2 = H or phenyl,
transmetalation of cyclic intermediate B with a second
arylboronic acid occurs. Reductive elimination is acceler-
ated by coordination of BQ18 and occurs with retention of
In summary, we have developed a mild and efficient Pd-
catalyzed oxidative diarylating carbocyclization of enynes
using arylboronic acids with stereoselective formation of
tetrahydrofurans and tetrahydropyranes. Formally it oc-
curs with cis-addition to the alkyne and olefin with double
assembly of various aryl functionalities. Further studies
regarding the scope, mechanism, and synthetic application
of this reaction are currently underway in our laboratory.
Acknowledgment. Financial support from the European
Research Council (ERC AdG247014) and the Swedish
Research Council is gratefully acknowledged.
(17) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083.
(18) For BQ acting as ligand and oxidant for palladium, see ref 14
€
and: (a) Backvall, J.-E.; Nordberg, R. E.; Wilhelm, D. J. Am. Chem. Soc.
1985, 107, 6892. (b) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 78. (c) Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 9651.
(19) The use of 1a deuterated on the alkyne (1a-d1) showed that the
diarylative carbocyclization occurs without loss of deuterium (see the
Supporting Information).
Supporting Information Available. Description of ex-
perimental procedures and full characterization of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) Trost, B. M.; Lautens, M.; Chan, C.; Jebaratnam, D. J.; Mueller,
T. J. Am. Chem. Soc. 1991, 113, 636.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3541