Cationic palladium(II)-catalyzed highly enantioselective tandem reactions of orf/70-boronate-substituted cinnamic ketones and internal alkynes: A convenient synthesis of optically active indenes

Article abstract of DOI:10.1021/ol9001015

Cationic palladium(II)-catalyzed tandem reactions of ortho-boronate- substituted cinnamic ketones and internal alkynes to yield optically active indenes were developed in high yields and good enantioselectivities.

Full text of DOI:10.1021/ol9001015

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1405-1408
Cationic Palladium(II)-Catalyzed Highly
Enantioselective Tandem Reactions of
ortho-Boronate-Substituted Cinnamic
Ketones and Internal Alkynes: A
Convenient Synthesis of Optically
Active Indenes
Feng Zhou, Miao Yang, and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 345 Lingling Road, Shanghai 200032, China
xylu@mail.sioc.ac.cn
Received January 16, 2009
ABSTRACT
Cationic palladium(II)-catalyzed tandem reactions of ortho-boronate-substituted cinnamic ketones and internal alkynes to yield optically active
indenes were developed in high yields and good enantioselectivities.
Indenes, especially the multiply substituted indenes, have
been attractive as drug candidates possessing biological
activities,1 functional materials,2 and metallocene complexes
utilized in catalyzing olefin polymerization.3 Although many
methods related to the synthesis of indenes were reported,4
most of them are only useful in synthesizing simple indenes.
In view of synthetically useful methods, tandem cyclization
reactions catalyzed by transition metals have been proven
highly useful, especially when the highly substituted indene
derivatives and their yields are concerned.1b,5
(1) (a) Clegg, N. J.; Paruthiyil, S.; Leitman, D. C.; Scanlan, T. S. J. Med.
Chem. 2005, 48, 5989. (b) Lautens, M.; Marquardt, T. J. Org. Chem. 2004,
69, 4607. (c) Korte, A.; Legros, J.; Bolm, C. Synlett 2004, 13, 2397. (d)
Maguire, A. R.; Papot, S.; Ford, A.; Touhey, S.; O’Connor, R.; Clynes, M.
Synlett 2001, 1, 41. (e) Gao, H.; Katzenellenbogen, J. A.; Garg, R.; Hansch,
C. Chem. ReV. 1999, 99, 723. (f) Senanayake, C. H.; Roberts, F. E.;
DiMichele, L. M.; Ryan, K. M.; Liu, J.; Fredenburgh, L. E.; Foster, B. S.;
Douglas, A. W.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron
Lett. 1995, 36, 3993. (g) Shanmugam, P.; Rajasingh, P. Chem. Lett. 2005,
34, 1494.
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2000, 65, 6739. (b) Barbera´, J.; Rakitin, O. A.; Ros, M. B.; Torroba, T.
Angew. Chem., Int. Ed. 1998, 37, 296. (c) Akbulut, U.; Khurshid, A.;
Hacioglu, B.; Toppare, L. Polymer 1990, 31, 1343.
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3201. (b) Zargarian, D. Coord. Chem. ReV. 2002, 233, 157. (c) Alt, H. G.;
Ko¨ppl, A. Chem. ReV. 2000, 100, 1205. (d) Cadierno, V.; D´ıez, J.; Gamasa,
M. P.; Gimeno, J.; Lastra, E. Coord. Chem. ReV. 1999, 193, 147.
10.1021/ol9001015 CCC: $40.75
Published on Web 02/25/2009
2009 American Chemical Society

Table 1. Optimization of Cationic Palladium
Complex-Catalyzed Tandem Addition of
ortho-Boronate-Substituted Cinnamic Ketones and Interanl
Alkynesa
Table 2. Cationic Palladium Complex-Catalyzed Tandem
Addition of ortho-Boronate-Substituted Cinnamic Ketones and
Internal Alkynesa
entry cat. (mol %)
solvent
MeOH
MeOH
MeOH
temp (°C) time (h) yield (%)b
1
A (3)
A (3)
B (3)
B (3)
B (3)
C (1.5)
D (3)
D (3)
D (3)
D (3)
D (3)
D (3)
50
50
50
50
50
80
80
80
80
80
25
50
48
48
48
48
48
48
48
48
48
48
48
20
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
96
2c
3
4c
5
MeOH
dioxane/H2O
dioxane/H2O
dioxane
dioxane
dioxane
dioxane
dioxane/H2O
dioxane/H2O
entry
1
R4≡ R5
Product
Yield (%)b
6
7
1
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2a
2a
2a
3aa
3ab
3ac
3ad
3ae
3ba
3bb
3bc
3bd
3be
3ca
3da
3ea
3fa
>99
93
78
82
85
>99
>99
57
89
75
8d
9e
10f
11
12
2
3c
4
5c
6
>99
a Reaction conditions: 1a (0.15 mmol), 2a (0.18 mmol). b Isolated yield.
c KF (1.5 equiv) was added. d Ba(OH)2 (1.5 equiv) was added. e K3PO4
(1.5 equiv) was added. f Amberlite IRA-400 (OH) (1.5 equiv) was added.
7
8c
9
10c
11d
12
13
14
NR
>99
>99
81
However, no methods have been reported for the control
of the C-1 stereogenic center. Thus far, the synthesis of
optically active indenes is limited to a few examples.6 An
expedient and promising method for the synthesis of indenes
is the rhodium-catalyzed tandem reactions of ortho-boronate-
substituted cinnamic ketones and alkynes.1b However, much
less attention has been paid to the asymmetric version of
this tandem reaction. Recently, cationic palladium species
has been shown to be highly active catalysts in the arylbo-
ronic acid initiated conjugate addition reaction by Miyaura’s
group7 and in several tandem reactions by our group.8 These
results prompted us to investigate the tandem reactions of
a Reaction conditions: 1 (0.15 mmol), 2 (0.18 mmol), [Pd(dppp)-
(H2O)2](OTf)2 (3 mol %) and dioxane/H2O (10/1), reaction time (24- 48 h).
b Isolated yield. c [Pd(dppp)(H2O)2](OTf)2 (4 mol %). d Reaction temperature
was 80 °C.
ortho-boronate-substituted cinnamic ketones and alkynes
under the catalysis of cationic palladium species. Herein we
report our results of the successful synthesis of the optically
active indenes.
(4) (a) Gassman, P. G.; Ray, J. A.; Wenthold, P. G.; Mickelson, J. W.
J. Org. Chem. 1991, 56, 5143. (b) Becker, C.; McLaughlin, M. Synlett 1991,
642. (c) Prough, J. D.; Alberts, A. W.; Deanna, A. A.; Gilfillian, J. L.;
Huff, J. W.; Smith, R. L.; Wiggins, J. M. J. Med. Chem. 1990, 33, 758. (d)
Singh, G.; Ila, H.; Junjappa, H. Synthesis 1986, 744. (e) Kimiaki, Y.;
Hideyoshi, M.; Akira, S. Bull. Chem. Soc. Jpn. 1986, 59, 3699. (f) Yoshida,
H.; Kato, M.; Ogata, T. J. Org. Chem. 1985, 50, 1145.
First, neutral and cationic palladium complexes with 2,2-
bipyridine (bpy) as ligand were chosen as the catalysts to
examine the tandem reactions of arylboronic ester 1a with
methyl 2-butynoate (2a). No reaction occurred even in the
case using dioxane/H2O as the solvent (Table 1, entries 1-6).
Then reactions of cationic palladium complex [Pd(dppp)-
(H2O)2](OTf)2 (3 mol %) as catalyst in dioxane (2 mL) were
examined. These reactions were also inactive even when
bases, which are believed to facilitate the transmetalation of
arylboronic compounds,7a were added at 80 °C (Table 1,
entries 8-10). When a dioxane/H2O (10/1) solvent mixture
was used instead of dioxane, the coupling product 3aa was
obtained in quantitative yield after 20 h (Table 1, entry 12).
Thus, arylboronic ester (0.15 mmol), alkyne (0.18 mmol),
[Pd(dppp)(H2O)2](OTf)2 (0.0045 mmol, 3 mol %), and
dioxane/H2O (10/1) at 50 °C were chosen as the optimized
conditions.
(5) (a) Zhang, D.; Liu, Z.; Yum, E. K.; Larock, R. C. J. Org. Chem.
2007, 72, 251. (b) Zhang, D.; Yum, E. K.; Liu, Z.; Larock, R. C. Org. Lett.
2005, 7, 4963. (c) Xi, Z.; Guo, R.; Mito, S.; Yan, H.; Kanno, K.; Nakajima,
K.; Takahashi, T. J. Org. Chem. 2003, 68, 1252. (d) Yoshikawa, E.;
Radhakrishnan, K. V.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 7280.
(e) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc.
2006, 128, 202.
(6) Romines, K. R.; Lovasz, K. D.; Mizsak, S. A.; Morris, J. K.; Seest,
E. P.; Han, F.; Tulinsky, J.; Judge, T. M.; Gammill, R. B. J. Org. Chem.
1999, 64, 1733.
(7) (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004,
23, 4317. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem.,
Int. Ed. 2003, 42, 2768.
(8) (a) Yang, M.; Zhang, X.; Lu, X. Org. Lett. 2007, 9, 5131. (b) Song,
J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9, 2947. (c) Liu, G.; Lu, X.
AdV. Synth. Catal. 2007, 349, 2247. (d) Liu, G.; Lu, X. J. Am. Chem. Soc.
2006, 128, 16504.
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Org. Lett., Vol. 11, No. 6, 2009

Table 3. Optimization of Chiral Cationic Palladium Complex-
Catalyzed Tandem Addition of ortho-Boronate-Substituted
Cinnamic Ketones and Internal Alkynesa
Table 4. Chiral Cationic Palladium Complex-Catalyzed
Asymmetric Tandem Addition of ortho-Boronate-Substituted
Cinnamoyl Compounds and Internal Alkynesa
yield ee
entry
cat.
solvent
(%)b (%)c
d
d
1
[Pd((R)-BINAP)(H2O)2] (OTf)2
Pd(OTf)2.2H2O/(R)-BINAP
Pd(TFA)2/(R)-BINAP
[Pd((R)-BINAP)(H2O)2] (OTf)2
Pd(OTf)2.2H2O/(R)-BINAP
Pd(OTf)2.2H2O/(R-BINAP)
Pd(OTf)2.2H2O/(S,S)-BDPP
Pd(OTf)2.2H2O/(S-S1)
Dioxane/H2O NR
Dioxane/H2O NR
Dioxane/H2O NR
CH3NO2/H2O 89
CH3NO2/H2O 96
-
2
-
3
-
4
60
60
76
75
70
91
75
79
-
5
6
THF/H2O
THF/H2O
THF/H2O
THF/H2O
55
92
44
99
7
8
9
Pd(OTf)2.2H2O/(S-S2)
Pd(OTf)2.2H2O/(S-S2)
10
11
12
Dioxane/H2O 85
Pd(OTf)2.2H2O/(R-Tol-BINAP)
Pd(OTf)2.2H2O/(R,R-Me-Duphos) THF/H2O
THF/H2O
89
trace
a Reactions were run in a solvent mixture containing Pd(OTf)2·2H2O (4
mol %), chiral ligands (4.4 mol %), substrate 1a (0.12 mmol) and 2a (0.14
mmol) under nitrogen atmosphere at reflux. The mixture was stirred until
1a disappeared as monitored by TLC. b Isolated yield. c Determined by
HPLC analysis using a Chiralcel OD-H column. d Using isolated complex
as catalyst.
With these results in hand, the scope of the annulation
reaction was investigated. Using 1a as the model substrate,
a series of alkynes were screened. Alkynes with an electron-
withdrawing group on one side (2a, 2b, and 2e) gave
products in excellent yields (Table 2, entries 1-2, and 5).
Alkynes with increasing electron density of the triple bond,
for example, hepta-4-yne (2c) and the bis(methoxymethyl)
substituted alkyne (2d), still gave yields around 80% (Table
2, entries 3-4). Similar reactivity was observed in the
ketones with different substitutents (Table 2, entries 6-10).
When the ketone group in 1a was changed to an ester group
(1c) (Table 2, entry 11), no reaction occurred. The effect of
substituents on the aromatic ring of the boronate-substituted
cinnamic ketones was also examined. The reactions all gave
excellent yields (Table 2, entries 12-14).
Subsquently, the asymmetric version of this tandem
cyclization was studied. For simplifying the operation of the
ligand screening, the cationic palladium species used for
screening were prepared in situ by adding the ligand directly
to the Pd(OTf)2.2H2O without isolation of the palladium
complexes.9 At first, the annulation reaction of 1a with 2a
in dioxane/H2O (10/1) was examined using chiral cationic
palladium complexes as the catalyst. No annulation product
a Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), Pd(OTf)2.2H2O
(4 mol %) and (S)-S2 (4.4 mol %). Reaction time (24-48 h) monitored by
TLC. b Isolated yield. c Determined by HPLC analysis using a Chiralcel
OD, AD, OJ-H column. d 1a (0.12 mmol), 2b (0.14 mmol). e 1a (0.12
mmol), 2d (0.14 mmol). f 1a (0.12 mmol), 2e (0.14 mmol). g 1a (0.12 mmol),
2c (0.24 mmol). h Pd(OTf)2.2H2O (6 mol %) and (S)-S2 (6.6 mol %).
(9) Mikami, K.; Hatano, M.; Akiyama, K. Top. Organomet. Chem 2005,
14, 279 and references therein.
Org. Lett., Vol. 11, No. 6, 2009
1407

situ reaction of Pd(OTf)2.2H2O and the chiral ligand.9,10
A
is believed to be the active catalyst and enables smooth
transmetalation with the substrate 1 to yield a cationic
arylpalladium(II) species B.7a,9,11,12 Next, π-coordination of
the carbon-carbon triple bond to the cationic palladium
center occurs to form C, followed by the regioselective
insertion of the alkyne into the carbon-palladium bond,
affording the vinylpalladium intermediate D (carbopallada-
tion). Then, conjugate addition of the vinylpalladium species
to the cinnamic ketones occurs to yield the product 3. It is
also proposed that the coordinated intermediate D is helpful
to the enantioface discrimination of R, ꢀ-unsaturated ketones,
resulting in high ee values.8 It is also worth mentioning that
this tandem cyclization through transmetalation-alkyne inser-
tion-enantioselective conjugate addition under the chiral
cationic palladium complexes did not afford the Heck-type
coupling products via ꢀ-hydride elimination.13,14
Scheme 1. Proposed Mechanism for the Tandem Annulation
Reaction
In conclusion, we have developed a cationic palladium-
catalyzed enantioselective tandem reaction of ortho-boronate-
substituted cinnamic ketones and internal alkynes. The use
of the cationic palladium complexes as the catalyst is crucial
for the high selectivity of the reaction. This tandem reaction
provided an efficient way for the construction of optically
active, multiply substituted indene derivatives.
was detected (Table 3, entries 1-3). Then a solvent mixture
of CH3NO2/H2O (10/1), THF/H2O (10/1) with (R)- BINAP
as the ligand was applied, and the reactions gave moderate
to excellent yields with moderate to good enantioselectivity
(Table 3, entries 4-6). Finally, THF/H2O (10/1) was chosen
as the solvent. Our investigations then focused on the
examination of different chiral diphosphine ligands, and the
ligand (S)-S2 was found to give the best result (Table 3,
entries 7-11). With the optimization of the solvents and
ligands, Pd(OTf)2.2H2O/(S)-S2 in THF/H2O (10/1) under
reflux conditions was found to be the best reaction conditions
to obtain (+)-3aa in quantitative yield with 91% ee (Table
3, entry 9).
The results of the asymmetric version of this tandem
cyclization reaction are summarized in Table 4. All reactions
took place smoothly under the optimized conditions in good
yields ranging from 55% to 99%. Alkynes with an electron-
withdrawing group on one side (2a, 2b, and 2e) gave
products in good ee (Table 4, 1-2, 4-5, and 7-10) except
for the result of entry 4. Whereas hepta-4-yne (2c) was
subjected to the reaction conditions, the ee declined to a low
value (Table 4, entries 11-12). In the case of bis(methoxym-
ethyl) substituted alkyne (2d), the product with the opposite
sign of optical rotation was obtained (Table 4, entries 3 and
6).
Acknowledgment. Major State Basic Research Program
(2006CB806105). We thank the National Natural Science
Foundation of China (20732005) and Chinese Academy of
Sciences for financial support. We thank Prof. Zhaoguo
Zhang of Shanghai Jiao Tong University for providing the
ligand (S)-S1, (S)-S2.
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.
OL9001015
(10) (a) Phua, P. H.; White, A. J. P.; de Vries, J. G.; Hii, K. K. AdV.
Synth. Catal. 2006, 348, 587. (b) Hamashima, Y.; Hotta, D.; Sodeoka, M.
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A plausible mechanism of this tandem reaction is shown
in Scheme 1. First, the monohydroxo cationic palladium
species A with vacant sites might be formed from the in
Yamamoto, Y.; Gridnev, I. D.; Miyaura, N. Organometallics 2005, 24, 5025
.
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Org. Lett., Vol. 11, No. 6, 2009