Exploiting the divergent reactivity of aryl-palladium intermediates for the rapid assembly of fluorene and phenanthrene derivatives

Article abstract of DOI:10.1002/anie.200805780

They all fall down: The value of domino processes can be greatly enhanced when the possibility exists for one to selectively diverge from a common intermediate. In preliminary studies the dual reactivity of aryl-palladium intermediates is exploited. A div

Full text of DOI:10.1002/anie.200805780

Angewandte
Chemie
DOI: 10.1002/anie.200805780
Domino Reactions
Exploiting the Divergent Reactivity of Aryl–Palladium Intermediates
for the Rapid Assembly of Fluorene and Phenanthrene Derivatives**
Ya-Bin Zhao, Brian Mariampillai, David A. Candito, Benoꢀt Laleu, Mengzhou Li, and
Mark Lautens*
Domino reactions have attracted significant attention in the
synthetic community because of their ability to create
complex and diverse scaffolds in an efficient manner.[1] The
value of domino processes can be greatly enhanced when
divergence from a common intermediate is possible. In order
for this strategy to be of synthetic utility, the reactivity of the
intermediate must be controlled to provide one of two
products selectively.
Palladium intermediates provide an avenue by which this
strategy can be realized. It has been well established that
palladium intermediates possess electrophilic character; how-
ever, it has recently been demonstrated that nucleophilic
behavior is also possible.[2–4] Herein we report our preliminary
studies on a strategy in which the dual reactivity of aryl–
palladium intermediates is exploited (Scheme 1). After a
À
sequence of norbornene mediated C H activation and
subsequent ortho-arylation the resulting aryl–palladium inter-
Scheme 1. The synthetic strategy.
mediate can go on to provide the product of a-arylation or
addition onto the carbonyl functionality.[3–6] Subtle variation
of the reaction conditions could alter the reactivity of this
intermediate to favor either product selectively, demonstrat-
ing the balance that exists between the dual character of aryl–
palladium intermediates.[7] By employing this strategy, a
diverse array of fluorene and phenanthrene derivatives were
synthesized. These compounds are known for their biological
activity and applications in materials chemistry.[8] Thus, the
development of efficient, diversity-oriented strategies for
their synthesis is a useful endeavor.
optimized conditions for cyanation afforded 1 as the major
product (Table 1, entry 1).
Encouraged by this result, an optimization was under-
taken and it was found that the presence of water was critical
to obtaining high yields of the desired product. In the absence
of water a mixture of products arising from both the carbonyl
addition and a-arylation was always obtained. A variety of
aryl chlorides can be used in the reaction, affording the 9H-
fluoren-9-ol derivatives in moderate to good yields, and aryl
bromides afford similar results (Table 1).
The sequence of domino ortho-arylation and subsequent
addition to a carbonyl group was discovered serendipitously
during our investigation into a sequence of domino ortho-
functionalization and subsequent cyanation.[9] The reaction of
2’-chloroacteophenone and 1-iodonaphthalene under the
The observation of a-arylated products prompted us to
explore this alternate mode of reactivity for the aryl–
palladium intermediate. In acetonitrile, under anhydrous
conditions, it was possible to obtain the phenanthren-9-ol
products in moderate to good yield (Table 2). These subtle
variations of the reaction conditions had a profound influence
on the outcome of the reaction.[7]
Our success with the addition of aryl–palladium inter-
mediates to ketones encouraged us to explore addition to
other carbonyl-containing functionalities including esters,
which are generally considered to be unreactive in the
presence of palladium. Recently, Solꢀ and Serrano reported
the intramolecular addition of a PdII species to aliphatic
esters.[7] They found that an ortho-nitrogen atom was needed
to activate the metal center and facilitate addition to the ester
functionality via an azapalladacycle intermediate.
[*] Y.-B. Zhao, Dr. B. Mariampillai, D. A. Candito, B. Laleu, M. Li,
Prof. M. Lautens
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, ON M5S3H6 (Canada)
Fax: (+1)416-946-8185
E-mail: mlautens@chem.utoronto.ca
[**] We thank the Natural Sciences and Engineering Research Council
(NSERC), the Merck Frosst Centre for Therapeutic Research, and
the University of Toronto for financial support. B.M. thanks the
Government of Ontario for a schloraship. Y.-B.Z. thanks the
Government of China for a National Graduate Student Program of
Building World-Class Universities Grant. D.C. thanks NSERC for a
PGS M scholarship. B.L. thanks the Swiss National Science
Foundation for a postdoctoral fellowship.
Initial attempts to add the aryl–palladium intermediates
to the ester functionality were unsuccessful, presumably
because of reduced reactivity. However, by modifying the
catalyst system and heating the reaction mixture to 1508C in a
microwave reactor, it was possible to achieve the desired
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805780.
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Table 1: Scope of ortho-arylation/ketone addition.[a]
Table 2: Preliminary study of the ortho-arylation/a-arylation.[a]
No. Aryl
iodide
Ketone
Product
Yield
[%][b]
No.
Aryl
iodide
Ketone
Product
Yield
[%][b]
82
1
2
3
7
8
9
70
47
52
1
2
1
2
80[c]
81
86
64
3
4
3
4
[a] All reactions were run under the following conditions: Aryl iodide
(1.0 equiv), aryl chloride (1.5 equiv), Pd(OAc)2 (10 mol%), PPh3
(22 mol%), Cs2CO3 (3.0 equiv), and norbornene (3.0 equiv) in CH3CN
(0.05m) were heated in a sealed tube at 908C for 24 h using an oil bath.
[b] Yield of isolated product.
5
6
5
6
71
65
Table 3: Scope of ortho-arylation/ester addition.[a]
[a] All reactions were run under the following conditions: Aryl iodide
(1.0 equiv), aryl chloride (1.5 equiv), Pd(OAc)2 (10 mol%), PPh3
(22 mol%), Cs2CO3 (3.0 equiv), norbornene (3.0 equiv), and H2O
(48 equiv) in DME (0.05m) were heated in a sealed tube at 908C for
24 h using an oil bath. [b] Yield of the isolated product. [c] 2’-
Bromoacteophenone was used.
No. Aryl
iodide
Ester
Product
Yield
[%][b]
72
1
2
3
10
15[c]
transformation (Table 3). A lower ligand to palladium ratio
was beneficial for this transformation, suggesting that a
coordinatively unsaturated palladium species is needed.
Furthermore, coordination of the ester functionality may
also play a role in the catalytic cycle.[4,7] Under the optimized
conditions a number of 9H-fluoren-9-one derivatives could be
prepared in moderate to good yield. Unfortunately, a
limitation of this protocol is that aryl chlorides failed to
provide the desired product in good yield (Table 3, entry 1).
Preliminary investigations have also been carried out into
the addition of aryl–palladium intermediates to aldehydes.
Subjecting 2-bromobenzaldehyde to the reaction conditions
produced a mixture of 9H-fluoren-9-one and 9H-fluoren-9-ol
products. By omitting water it was possible to obtain an
excellent yield of the 9H-fluoren-9-one (Table 4, entry 1). The
mixture is likely to result from rapid protonation of the
palladium alkoxide formed after the addition process rather
than b-hydride elimination.[3] Several aldehydes were sub-
jected to the reaction conditions affording the 9H-fluoren-9-
one products in good yields (Table 4).
11 88
12 83
4
5
13 46
14 59
[a] All reactions were run under the following conditions: Aryl iodide (1.0 equiv),
aryl bromide (1.0 equiv), Pd(OAc)2 (10 mol%), PCy3HBF4 (10 mol%), Cs2CO3
(1.5 equiv), and norbornene (1.0 equiv) in DME (0.05m) were heated in a sealed
tube at 1508C for 10 min under microwave irradiation. [b] Yield of isolated
product. [c] Methyl-2-chlorobenzoate was used.
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Table 4: Preliminary study of the ortho-arylation/aldehyde addition.[a]
Experimental Section
Typical procedure for additions to ketones: Palladium acetate
(0.1 equiv), triphenylphosphine (0.22 equiv), norbornene
(3.0 equiv), and cesium carbonate (3.0 equiv) were added to a 5 mL
microwave vial (previously dried overnight in an oven at 1208C)
containing a magnetic stir bar. The vial was then sealed and flushed
with argon for 1 min by venting through a needle, after which dry
dimethoxyethane (4 mL) was added and stirring was begun. Argon
was then bubbled through the solvent for 5 min as the remaining
reagents were added. The aryl iodide (1.0 equiv, 0.2 mmol scale), aryl
chloride (1.5 equiv), and water (48 equiv) were added by syringe (if
the aryl iodide or chloride is a solid it was weighed out along with the
other solids prior to sealing the vessel). The resulting mixture was
then stirred at room temperature for 5 min and then placed in a
preheated oil bath at 908C for 24 h. The reaction mixture was then
cooled to room temperature and then diluted with dichloromethane
(5 mL). The mixture was washed with brine (1 ꢁ 10 mL), and the
aqueous phase was extracted with dichloromethane (2 ꢁ 10 mL). The
organic extracts were dried over sodium sulfate and filtered.
Concentration of the solution by rotary evaporation under reduced
pressure gave a residue which was purified by using flash column
chromatography.
No. Aryl
iodide
Aldehyde
Product
Yield
[%][b]
1
2
10
15
93
93
3
16
60
[a] All reactions were run under the following conditions: Aryl iodide
(1.0 equiv), aryl bromide (1.5 equiv), Pd(OAc)2 (10 mol%), PPh3
(22 mol%), Cs2CO3 (3.0 equiv), and norbornene (3.0 equiv) in DME
(0.05m) were heated in a sealed tube at 908C for 24 h using an oil bath.
[b] Yield of isolated product.
Received: November 27, 2008
Published online: January 28, 2009
À
Keywords: annulation · C H activation · domino reactions ·
homogeneous catalysis · palladium
.
Recently, Dai and Lu reported the palladium-catalyzed
diastereoselective addition of arylboronic acids to N-sulfinyl
iminoacetates yielding arylglycine derivatives in good yields
and high diastereoselectivity.[10a] Intrigued by these results, an
attempt was made to react aryl–palladium intermediates with
N-sulfinyl imines [Eq. (1)]. The results demonstrate a proof of
principle and the potential for this transformation to be a
highly selective, synthetically viable process.
[1] L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions in
Organic Synthesis, Wiley, New York, 2006.
[2] a) E. Negishi, A. de Meijere, Handbook of Organopalldium
Chemistry for Organic Synthesis I and II, Wiley-VCH, New
York, 2002; b) J. Tsuji, Palladium Reagents and Catalysts—New
Perspectives for the 21st Century, Wiley, Chichester, 2004.
[3] For the reaction of aryl and vinyl palladium complexes with
aldehydes, see: a) R. C. Larock, M. J. Doty, S. Cacchi, J. Org.
Chem. 1993, 58, 4579 – 4583; b) V. Gevorgyan, L. G. Quan, Y.
Yamamoto, Tetrahedron Lett. 1999, 40, 4089 – 4092; c) L. Zhao,
X. Lu, Angew. Chem. 2002, 114, 4519 – 4521; Angew. Chem. Int.
Ed. 2002, 41, 4343 – 4345; d) J. Vicente, J.-A. Abad, B. Lopez-
Pelaez, E. Martinez-Viviente, Organometallics 2002, 21, 58 – 67;
e) M. Yang, X. Zhang, X. Lu, Org. Lett. 2007, 9, 5131 – 5133.
[4] For the reaction of aryl and vinyl palladium complexes with
ketones, see: a) L. G. Quan, V. Gevorgyan, Y. Yamamoto, J. Am.
Chem. Soc. 1999, 121, 3545 – 3546; b) L. G. Quan, M. Lamrani,
Y. Yamamoto, J. Am. Chem. Soc. 2000, 122, 4827 – 4828; c) D.
Solꢀ, L. Vallverdu, X. Solans, M. Font-Bardia, J. Bonjoch, J. Am.
Chem. Soc. 2003, 125, 1587 – 1594; d) G. Liu, X. Lu, J. Am.
Chem. Soc. 2006, 128, 16504 – 16505; e) J. Song, Q. Shen, F. Xu,
X. Lu, Org. Lett. 2007, 9, 2947 – 2950; G. Liu, X. Lu, Tetrahedron
2008, 64, 7324 – 7330.
[5] For details on the Catellani reaction mechanism, see: a) M.
Catellani, E. Motti, N. Della Caꢂ, R. Ferraccioli, Eur. J. Org.
Chem. 2007, 4153 – 4165; b) D. J. Cꢃrdenas, B. Martin-Matute,
A. M. Echavarren, J. Am. Chem. Soc. 2006, 128, 5033 – 5040;
c) S. Deledda, E. Motti, M. Catellani, Can. J. Chem. 2005, 83,
741 – 747; d) F. Faccini, E. Motti, M. Catellani, J. Am. Chem. Soc.
2004, 126, 78 – 79.
[6] a) D. A. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 234 –
245; b) M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
11108 – 11109; c) H. N. Nguyen, X. Huang, S. L. Buchwald, J.
Am. Chem. Soc. 2003, 125, 11818 – 11819; d) M. S. Viciu, R. A.
Kelly, E. D. Stevens, F. Naud, M. Studer, S. P. Nolan, Org. Lett.
2003, 5, 1479 – 1482; e) M. S. Viciu, R. Germaneau, S. P. Nolan,
In conclusion, the methodology reported allows the rapid
assembly of a number of diverse fluorene and phenanthrene
derivatives. Furthermore, it demonstrates the dual character
of organopalladium complexes and the manner in which this
character can be manipulated by a subtle variation in the
reaction conditions. The exploitation of this dual reactivity
has been demonstrated to be a powerful synthetic tool.
Studies are ongoing to expand the scope and application of
the present methodology, as well as to elucidate the mech-
anistic details of these catalytic processes.
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Communications
Org. Lett. 2002, 4, 4053 – 4056; f) O. Navarro, N. Marion, Y.
Lett. 2002, 12, 2643 – 2646; b) L. Yang et al., Bioorg. Med. Chem.
2006, 14, 3496 – 3501; c) L. Yang, J. K. Feng, Y. Liao, A.-M. Ren,
Opt. Mater. 2007, 29, 642 – 650; d) M. Kimura, S. Kuwano, Y.
Sawaki, H. Fujikawa, K. Noda, Y. Taga, K. Takagi, J. Mater.
Chem. 2005, 15, 2393 – 2398.
Oonishi, R. A. Kelly, S. P. Nolan, J. Org. Chem. 2006, 71, 685 –
692; g) L. Ackermann, J. H. Spatz, C. J. Gschrei, R. Born, A.
Althammer, Angew. Chem. 2006, 118, 7789 – 7792; Angew.
Chem. Int. Ed. 2006, 45, 7627 – 7630; h) G. Chen, F. Kwong,
H. O. Chan, W.-Y. Yu, A. S. C. Chan, Chem. Commun. 2006,
1413 – 1415; i) D. J. Spielvogel, S. L. Buchwald, J. Am. Chem.
Soc. 2002, 124, 3500 – 3501.
[9] B. Mariampillai, J. Alliot, M. Li, M. Lautens, J. Am. Chem. Soc.
2007, 129, 15372 – 15379.
[10] For the addition of palladium intermediates to the imino group,
see: a) H. Dai, X. Lu, Org. Lett. 2007, 9, 3077 – 3080; b) A.
Takeda, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc. 2000, 122,
5662 – 5663; c) H. Ohno, A. Aso, Y. Kadoh, N. Fujii, T. Tanaka,
Angew. Chem. 2007, 119, 6441 – 6444; Angew. Chem. Int. Ed.
2007, 46, 6325 – 6328.
[7] a) D. Solꢀ, O. Serrano, Angew. Chem. 2007, 119, 7408 – 7410;
Angew. Chem. Int. Ed. 2007, 46, 7270 – 7272; b) D. Solꢀ, O.
Serrano, J. Org. Chem. 2008, 73, 2476 – 2479; c) D. Solꢀ, O.
Serrano, J. Org. Chem. 2008, 73, 9372 – 9378.
[8] a) P. C. Ting, J. F. Lee, M. M. Albanese, W. C. Tom, D. M.
Solomon, R. Aslanian, N.-Y. Shih, R. West, Bioorg. Med. Chem.
1852
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