Cationic Pd(II)-catalyzed highly enantioselective arylative cyclization of alkyne-tethered enals or enones initiated by carbopalladation of alkynes with arylboronic acids

Article abstract of DOI:10.1021/ol3003546

Cationic Pd(II)-catalyzed enantioselective arylative cyclization of alkyne-tethered enals or enones initiated by carbopalladation of alkynes was developed without the necessity of a redox system.

Full text of DOI:10.1021/ol3003546

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1756–1759
Cationic Pd(II)-Catalyzed Highly
Enantioselective Arylative Cyclization of
Alkyne-Tethered Enals or Enones Initiated
by Carbopalladation of Alkynes with
Arylboronic Acids
Kun Shen, Xiuling Han,* and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
xlhan@mail.sioc.ac.cn; xylu@mail.sioc.ac.cn
Received February 13, 2012
ABSTRACT
Cationic Pd(II)-catalyzed enantioselective arylative cyclization of alkyne-tethered enals or enones initiated by carbopalladation of alkynes was
developed without the necessity of a redox system.
Transition-metal-catalyzedtandem reactions are power-
ful methods for the construction of structurally complex
frameworks from relatively simple materials and have
attracted great scientific interest from chemists.1,2 Orga-
noboroniccompoundshavebeen widely used intransition-
metal-catalyzed transformations to construct carbonꢀ
carbon bonds because of their nontoxicity, commercial
availability, and stability, especially in the area of multiple
carbonꢀcarbon bond-forming tandem reactions.3,4
Recently, our group has developed a variety of tandem
reactions involving ortho-functionalized boronic esters or
acids with internal alkynes or allenes catalyzed by cationic
Pd(II) complexes.5 Cationic Pd(II)-catalyzed arylative
cyclization of alkyne-tethered aldehydes or ketones have
also been reported.6 In these reactions, vinylpalladium inter-
mediates were generated by carbopalladation of alkynes
followed by subsequent transformations. Compared with
neutral Pd(II) species, cationic Pd(II) catalysts make the
addition of aryl- or vinylpalladium to carbonꢀheteroatom
multiple bonds or electron-deficient carbonꢀcarbon dou-
ble bonds more facile because of their vacant coordination
sites and stronger Lewis acidity.7 In these reactions, the
(1) For reviews, see: (a) Guo, H. C.; Ma, J. Angew. Chem., Int. Ed.
2006, 45, 354. (b) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
Chem. Rev. 2005, 105, 1001. (c) Montgomery, J. Angew. Chem., Int. Ed.
2004, 43, 3890. (d) Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999,
ꢀ
576, 65. (e) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.; Liu, F. Chem.
Rev. 1996, 96, 365. (f) Tietze, L. F. Chem. Rev. 1996, 96, 115. (g)
ꢀ
Heumann, A.; Reglier, M. Tetrahedron 1996, 52, 9289. (h) Trost,
B. M. Science 1991, 254, 1471.
(5) (a) Liu, G.; Lu, X. Adv. Synth. Catal. 2007, 349, 2247. (b) Yang,
M.; Zhang, X.; Lu, X. Org. Lett. 2007, 9, 5153. (c) Zhou, F.; Yang, M.;
Lu, X. Org. Lett. 2009, 11, 1405. (d) Yu, X.; Lu, X. Org. Lett. 2009, 11,
4366.
ꢀ
(2) (a) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (b)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134.
(3) (a) Hall, D. G., Ed. Boronic Acids: Preparation and Applications in
Organic Synthesis and Medicine; Wiley-VCH: Weinheim, 2005. (b) Suzuki,
A. Organoboranes in Organic Synthesis; Hokkaido University: Sapporo,
2004. (c) Matteson, D. S. Stereodirected Synthesis with Organoboranes;
Springer-Verlag: Berlin, 1995. (d) Brown, H. C. Organic Syntheses via
Boranes; Wiley-Interscience: New York, 1975.
(4) For reviews on Rh(I)-catalyzed tandem reactions using organo-
boronic reagents, see: (a) Youn, S. W. Eur. J. Org. Chem. 2009, 2597. (b)
Miura, T.; Murakami, M. Chem. Commun. 2007, 217.
(6) (a) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9, 2947. (b)
Han, X.; Lu, X. Org. Lett. 2010, 12, 108.
(7) (a) Yamamoto, A. J. Organomet. Chem. 1995, 500, 337. (b)
Coates, G. W. Chem. Rev. 2000, 100, 1223. (c) Widenhoefer, R. A.
Acc. Chem. Res. 2002, 35, 905. (d) Sodeoka, M.; Hamashima, Y. Bull.
Chem. Soc. Jpn. 2005, 78, 941. (e) Mikami, K.; Hatano, M.; Akiyama, K.
Top. Organomet. Chem. 2005, 14, 279. (f) Nishikata, T.; Yamamoto, Y.;
Miyaura, N. Angew. Chem., Int. Ed. 2003, 42, 2768. (g) Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Organometallics 2004, 23, 4317.
r
10.1021/ol3003546
Published on Web 03/26/2012
2012 American Chemical Society

Pd(II) species was regenerated to complete the catalytic
cycle without the necessity of a redox system.
3aa was isolated in a very low yield (Table 1, entry 8). The
yield of the product decreased as the temperature was
lowered to 60 °C (Table 1, entry 9). On the basis of the
above investigation, the optimal conditions for this tan-
dem reaction were as follows: 1a (0.2 mmol), phenylboro-
nic acid 2a (0.5 mmol, 2.5 equiv), [Pd(dppp)(H2O)2](BF4)2
(3 mol %), and NaOH (0.06 mmol, 0.3 equiv) in toluene/
H2O (2 mL/0.2 mL) at 80 °C.
In our previous work, we reported Pd(II)-catalyzed
intramolecular alkyne-R,β-unsaturated carbonyl coupling
initiated by halopalladation or acetoxypalladation of
alkynes8 (Scheme 1). In the course of these reactions,
halopalladation or acetoxypalladation of alkynes gives
vinyl-palladium intermediate, which undergoes intramo-
lecular carbonꢀcarbon double bond insertion followed by
protonolysis of the newly formed CꢀPd bond to produce
the product and regenerate the Pd(II) catalytic species. In
these reactions, the use of excess halide ion or 2,20-bipyr-
idine ligand played a crucial role in inhibiting β-H elimina-
tion side reactions.9 It is worth noting that β-H elimination
side reactions were inhibited by using cationic Pd(II) as
catalysts in our tandem reaction of ortho-boronate-sub-
stituted cinnamic ketones with alkynes5c and the conjugate
addition reaction of arylboronic acids with enones re-
ported by Miyaura.7f,g We are wondering if this enyne
cyclization reaction is still possible when the reaction is
initiated bycarbopalladation of alkynes underthe catalysis
of cationic Pd(II) species.10
Table 1. Optimization of Reaction Conditionsa
temp (°C)/ yieldb
entry
catalyst
solvent
time (h)
(%)
1c Pd(CF3COO)2 þ dppp toluene/H2O
80/12
80/6
43
38
40
58
15
67
79
20
70
2
3
4
5
[Pd(dppp)(H2O)2](OTf)2 toluene/H2O
[Pd(dppe)(H2O)2](OTf)2 toluene/H2O
[Pd(dppp)(H2O)2](BF4)2 toluene/H2O
[Pd(dppp)(H2O)2](BF4)2 toluene
80/6
80/5
80/12
80/3
6d [Pd(dppp)(H2O)2](BF4)2 toluene/H2O
7e [Pd(dppp)(H2O)2](BF4)2 toluene/H2O
8e [Pd(dppp)(H2O)2](BF4)2 dioxane/H2O
9e [Pd(dppp)(H2O)2](BF4)2 toluene/H2O
80/0.5
80/5
Scheme 1. Intramolecular Alkyne R,β-Unsaturated Carbonyl
Coupling
60/1
a Conditions: reactions were performed with 1a (0.20 mmol), 2a (0.50
mmol, 2.5 equiv), and catalyst (3 mol %) in toluene/H2O (2 mL/0.2 mL),
unless otherwise noted. b Isolated yield. c Pd(CF3COO)2 (5 mol %), dppp
(6 mol %). d KF (2 equiv) was added. e NaOH (0.3 equiv) was added.
The reaction scope with a variety of arylboronic acids
and alkyne-tethered enals or enones is summarized in
Table 2. Generally, the reaction worked well with both
electron-rich and electron-deficient arylboronic acids to
give the corresponding products in moderate to good
yields. However, aryboronic acids with electron-donating
groups gave higher yields than those with electron-
withdrawing groups (Table 2, entries 1ꢀ9). Arylboronic
acids with halogen substituents, which offered opportu-
nities for further transformations of the products, were
compatible in this reaction (Table 2, entries 6 and 7).
β-Naphthylboronic acid 2j provided the highest yield in
this reaction (Table 2, entry 10).
Enals bearing other substituted alkynes were treated
with phenylboronic acid. Slightly lower yields were ob-
tained with 1b (R = n-Pr) and 1c (R = Ph) than with
1a (R = Me) (Table 2, entries 1, 11, and 12). While alkyne-
tethered enones 1d and 1e worked well in this reaction
(Table 2, entries 13 and 14), the reaction of alkyne-tethered
enoate 1f did not occur (Table 2, entry 15). Five-membered
heterocycles could also be synthesized using this method
(Table 2, entries 16 and 17). The stereochemistry of the
exocyclic double bond in the products was assigned as the
E configuration as confirmed by the X-ray crystallography
of 2,4-dinitrophenylhydrazone derivative of 3af.
In our initial study, alkyne-tethered enal 1a was used as
the model substrate in combination with PhB(OH)2 to
examine the effect of various cationic palladium catalysts.
When Pd(CF3COO)2/dppp and [Pd(dppp)(H2O)2](OTf)2
were used ascatalysts, the reaction provided3a in 43% and
38% yields, respectively (Table 1, entries 1 and 2). A
similar result was obtained when the reaction was cata-
lyzed by [Pd(dppe)(H2O)2](OTf)2 (40% yield, Table 1,
entry 3). However, the reaction afforded 3aa in a higher
yield with [Pd(dppp)(H2O)2](BF4)2 as the catalyst (58%
yield, Table 1, entry 4). By using toluene in the absence of
H2O as solvent, 3aa was isolated only in 15% yield
(Table 1, entry 5). Several kinds of additives were used to
accelerate the transmetalation step. The good yields were
achieved when 2 equiv of KF or 0.3 equiv of NaOH were
added to the reaction (Table 1, entries 6 and 7). Never-
theless, when the reaction was performed in dioxane/H2O,
(8) (a) Wang, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 5213. (b) Xie, X.;
Lu, X. Synlett 2000, 707. (c) Zhao, L.; Lu, X.; Xu, W. J. Org. Chem.
2005, 70, 4059.
(9) Lu, X. Top. Catal. 2005, 35, 73.
(10) For rhodium(I)-catalyzed this type of arylative cyclization, see:
Shintani, R.; Tazuhiro, A.; Okamoto, K.; Hayashi., T. Angew. Chem.,
Int. Ed. 2005, 44, 3909.
Org. Lett., Vol. 14, No. 7, 2012
1757

Table 2. Cationic Pd(II)-Catalyzed Arylative Cyclization of
Alkyne-Tethered Enals or Enonesa
Scheme 2. Arylative Cyclization of 1i with 2a
the enantioselectivity (Table 3). High enantioselectivities
were obtained by using bisphosphine ligands withbiphenyl
or binaphthyl motifs (Table 3, entries 1ꢀ7), and the best
result (66% yield, 93% ee) was achieved with (S)-SEG-
PHOS (Table 3, entry 6). Elevating the reaction tempera-
ture to 40 °C resulted in a decreased enantioselectivity
(Table 3, entry 8). When the reaction was performed in the
absence of water, both the yield and the enantioselectivity
Table 3. Optimization of the Asymmetric Arylative Cyclizationa
a The reaction was carried out with 1 (0.2 mmol) and 2 (0.5 mmol) in
toluene/H2O (2 mL/0.2 mL) in the presence of [Pd(dppp)(H2O)2](BF4)2
(3 mol %) and NaOH (0.3 equiv) at 80 °C, unless otherwise noted.
b Isolated yield. c The reaction was performed at 60 °C.
From the literature, it is known that γ-butyrolactone
frameworks widely exist in some natural products and
bioactive molecules.11 We then wondered whether our new
method was suitable for the synthesis of these compounds
from the easily available acyclic allylic 2-alkynoate pre-
cursors. However, when substrates 1i and 2a were con-
ducted under the standard reaction conditions, the desired
product 3ia was obtained in 41% yield together with
another uncyclized product 3ia0 (48%) (Scheme 2). The
stereochemistry of the newly formed double bond in
products 3ia and 3ia0 was assigned as the (E)-configuration
on the basis of the lower field chemical shift of the methyl
group resulting from the deshielding effect of the same side
entry
ligand
solvent
yieldb (%) eec (%)
1
(S,S)-BDPP
dioxane/H2O
58
52
48
36
58
66
65
61
28
0
3
53
92
73
85
93
93
79
74
2
(S,S)-CHIRAPHOS dioxane/H2O
3
(R)-BINAP
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane
4
(R)-Tol-BINAP
(R)-SYNPHOS
(S)-SEGPHOS
(S)-S1
5
6
7
8d
9
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
10
11
12
13
14e
15e,f
16g
17h
MeOH
THF/H2O
52
64
40
24
70
trace
40
35
76
93
30
5
1
carbonyl group in H NMR spectra and compared with
the data in the literature.12
Subsequently, the asymmetric version of this cyclization
reaction was studied. Various chiral ligands, solvents, and
palladium species were screened to improve the yield and
toluene/H2O
DCE/H2O
dioxane/H2O
toluene/H2O
dioxane/H2O
dioxane/H2O
46
a Conditions: reactions were performed with 1a (0.10 mmol), 2a (0.15
mmol), Pd(CH3CN)4(BF4)2 (5 mol %), ligand (6 mol %) in dioxane/
H2O (1 mL/0.1 mL) at room temperature for 2 days, unless otherwise
noted. b Isolated yield. c Determined by HPLC analysis. d The reaction
was performed at 40 °C for 1 day. e NaOH (0.03 mmol, 0.3 equiv) was
added. f The reaction was performed for 6 h. g Pd(CF3COO)2 (5 mol %)
was used. h Pd(OAc)2 (5 mol %) was used.
(11) (a) Fischer, N. H.; Olivier, E. J.; Fischer, H. D. Fortschr. Chem.
Org. Naturst. 1979, 38, 47. (b) Devon, T. K.; Scott, A. I. In Handbook of
Naturally Occurring Compounds; Academic Press: New York, 1975; Vol. 1.
(12) (a) Torabi, H.; Evans, R. L.; Stavely, H. E. J. Org. Chem. 1969,
34, 3792. (b) Minami, T.; Niki, I.; Agawa, T. J. Org. Chem. 1974, 39,
3236. (c) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245. (d) Ma, S.; Zhu, G.;
Lu, X. J. Org. Chem. 1993, 58, 3692. (e) Xie, X.; Lu, X. Tetrahedron Lett.
1999, 40, 8415.
1758
Org. Lett., Vol. 14, No. 7, 2012

were sharply reduced (Table 3, entry 9). Other solvents
were also tested (Table 3, entries 10ꢀ13). No desired
product was observed in MeOH (Table 3, entry 10), and
the ee value decreased in THF/H2O or toluene/H2O
(Table 3, entries 11 and 12). A high ee value was also
achieved in DCE/H2O, while the yield was low (Table 3,
entry 13). The ee value was sharply reduced when 0.3 equiv
of NaOH was used as an additive (Table 3, entries 14 and 15).
Pd(CF3COO)2 could not catalyze the reaction efficiently
(Table 3, entry 16), and neutral palladium species Pd(OAc)2
gave low yield and ee (Table 3, entry 17).
Under optimized conditions as shown in Table 3, entry 6,
a variety of enyne substrates and arylboronic acids were
subjected to asymmetric arylative cyclization (Table 4). The
reactions furnished in high enantioselecivities with moderate
yields which were probably due to the competive conjugate
addition side reactions.7f,g Again, the β-naphthylboronic
acid 2j gave the highest yield with 97% ee (Table 4, entry 8).
Carbopalladation of the substrate affords vinylpalladium
intermediate C. Subsequent carbonꢀcarbon double bond
insertion gives intermediate D. The protonolysis of the
newly formed CꢀPd bond generates the product and
regenerates the Pd(II) species A. While Pd(0) catalyst has
been reported to be effective in this kind of arylative
cyclization reaction through a cyclometalation pathway
involving Pd(II)/Pd(0) catalytic cycle,14 Pd(II) catalytic
cycle is a plausible mechanism for this cationic Pd(II)
catalyzed transformations based on the following results:
(1) Halogen-substituted phenylboronic acids can be used as
the substrates for this reaction (Table 2, entries 6 and 7). (2)
Allylic esters can be used as the substrates for this reaction
(Scheme 2). Both the arylꢀhalogen bond and the allylic
ester group will be cleaved first in the presence of Pd(0).
Scheme 3. Proposed Mechanism for the Tandem Reaction
Table 4. Asymmetric Arylative Cyclization Reaction of Alkyne-
Tethered Enals Catalyzed by Pd(CH3CN)4(BF4)2/(S)-SEG-
PHOS Systema
entry
substrate
product
yieldb (%)
eec (%)
1
2
1a, 2a
1a, 2b
1a, 2c
1a, 2d
1a, 2e
1a, 2f
1a, 2i
1a, 2j
1b, 2a
1d, 2a
1e, 2a
3aa
3ab
3ac
3ad
3ae
3af
66
61
65
61
68
57
64
70
52
67
65
93 (ꢀ)
93 (ꢀ)
93 (ꢀ)
92 (ꢀ)
85 (ꢀ)
95 (ꢀ)
94 (ꢀ)
97 (ꢀ)
80 (ꢀ)
93 (ꢀ)
92 (ꢀ)
3
4
5
6
In conclusion, a cationic Pd(II)-catalyzed enantioselective
arylative cyclization of alkyne-tethered enals or enones
initiated by carbopalladation of alkynes was developed. This
newly developed tandem reaction proceeds through a Pd(II)
catalytic cycle without the necessity of a redox system.
7
3ai
8
3aj
9
3ba
3da
3ea
10
11
a The reaction was carried out with 1 (0.1 mmol) and 2 (0.15 mmol) in
dioxane/H2O (1 mL/0.1 mL) in the presence of Pd(CH3CN)4(BF4)2 (5mol%)
and (S)-SEGPHOS (6 mol %) at room temperature for 2ꢀ3 days, unless
otherwise noted. b Isolated yield. c Determined by HPLC analysis.
Acknowledgment. We thank the National Basic Re-
search Program of China (2011CB808706), National Nat-
uralScience FoundationofChina (20872158), and Chinese
Academy of Sciences for financial support.
A possible mechanism of this tandem reaction is shown
in Scheme 3. The Pd hydroxo complex A is supposed to be
the active catalytic species.13 Arylpalladium species B is
formed by transmetalation of A with arylboronic acids.
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999,
121, 5450. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c)
Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 2002, 124, 5052. (d) Stang, P. J.; Cao, D. H.; Poulter, G. T.; Arif,
A. M. Organometallics 1995, 14, 1110.
(14) Tsukamoto, H.; Suzuki, T.; Uchiyama, Y.; Kondo, Y. Tetra-
hedron Lett. 2008, 49, 4174.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1759