Carboxylate assistance for catalyzed hydroarylations of methylenecyclopropanes

Article abstract of DOI:10.1021/ol402037f

Carboxylate assistance enabled efficient and chemoselective ruthenium(II)-catalyzed hydroarylations and hydroalkenylations of highly strained methylenecyclopropanes via C-H bond activation occurring with ring conservation of the cyclopropane moieties.

Full text of DOI:10.1021/ol402037f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Carboxylate Assistance for Catalyzed
Hydroarylations of
Methylenecyclopropanes
Marvin Schinkel,† Jan Wallbaum,† Sergei I. Kozhushkov,† Ilan Marek,‡ and
Lutz Ackermann*,†
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstraße 2, 37077 Gottingen, Germany, and Schulich Faculty of Chemistry,
Technion-Israel Institute of Technology, 32000 Haifa, Israel
Lutz.Ackermann@chemie.uni-goettingen.de
Received July 19, 2013
ABSTRACT
Carboxylate assistance enabled efficient and chemoselective ruthenium(II)-catalyzed hydroarylations and hydroalkenylations of highly strained
methylenecyclopropanes via CꢀH bond activation occurring with ring conservation of the cyclopropane moieties.
The catalyzed functionalization of otherwise unreactive
CꢀH bonds represents an environmentally benign tool
for the formation of CꢀC bonds in a step-economical
fashion.1 Metal-catalyzed additions of arenes onto CꢀC
multiple bonds;hydroarylation reactions2;are particu-
larly attractive due to their perfect atom economy,3 with
notable progress being accomplished with versatile
ruthenium4 catalysts.5 In this context, we recently reported
on the significant rate acceleration caused by carbox-
ylates1a,6 in ruthenium-catalyzed hydroarylations with
†
€
Georg-August-Universitat.
‡ Technion-Israel Institute of Technology.
(1) Selected recent reviews: (a) Ackermann, L. Acc. Chem. Res. 2013,
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2009, 48, 9792–9826 and references cited therein.
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T. B. J. Organomet. Chem. 2011, 696, 305–315. (b) Foley, N. A.; Lee,
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Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993,
366, 529–531. Selected ruthenium-catalyzed hydroarylations: (b)
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R.; Genet, J.-P.; Darses, S. Chem. Commun. 2008, 3855–3857. (d) Foley,
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Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886–896. (c)
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r
10.1021/ol402037f
XXXX American Chemical Society

Scheme 1. Hydroarylations with Disubstituted Arenes 1a
Table 1. Optimization of Ruthenium-Catalyzed
Hydroarylationa
additive
yield
(%)
entry
[Ru]
(amt (mol %))
1
2
3
4
5
6
7
8
9
ꢀ
X-Phos (10)
X-Phos (10)
KOAc (100)
CsOAc (100)
NaOAc (300)
KOAc (100)
KOAc (30)
0
53
55
60
62
76
57
66
66
79
82
97
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl3(H2O)n]
[RuCl3(H2O)n]
[RuCl3(H2O)n]
[RuCl3(H2O)n]
[RuCl3(H2O)n]
[RuCl2(p-cymene)]2
a Reaction conditions: 1 (1.0ꢀ2.0 mmol), 2a (3.0 equiv); (A)
[Ru(MesCO2)2(p-cymene)] (4; 5.0 mol %)/KO2CMes (20 mol %); (B)
[RuCl3(H2O)n] (5.0 mol %)/KOAc (1 equiv); 1,4-dioxane or PhMe
(3.0 mL), 120 °C, 48 h.
KO2CMes (30)
KO2CMes (30)
ꢀ
10 [Ru(MesCO2)2(p-cymene)] (4)
11 [Ru(MesCO2)2(p-cymene)] (4)
KO2CMes (10)
12 [Ru(MesCO2)2(p-cymene)] (4) KO2CMes (20)
a Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), [Ru]
(5 mol %), 1,4-dioxane (3.0 mL), 120 °C, isolated yields. X-Phos =
[dicyclohexyl(20,40,60-triisopropylbiphenyl-2-yl)phosphine].
Scheme 2. Carboxylate-Assisted Hydroarylations with
Disubstituted Pyridinesa
simple nonactivated alkenes.7 In continuation of these
studies, we observed that the efficacy and chemoselectivity
of hydroarylations with highly strained methylenecyclo-
propanes (MCPs)8ꢀ10 can be significantly improved through
carboxylate-assisted ruthenium(II) catalysis, the results of
which we present herein.
At the outset of our studies, we explored representative
ruthenium precursors and additives in the hydroarylation
of 2-phenylmethylenecyclopropane (2a) with 2-phenylpyr-
idine (1a) in 1,4-dioxane at 120 °C (Table 1).
While no reaction occurred in the absence of a ruthenium
catalyst (entry 1), the use of inexpensive KOAc in combina-
tion with [RuCl3(H2O)n] proved highly effective (entries
3ꢀ8) and outperformed the previously used [RuCl2(cod)]n/
X-Phos catalytic system9 (entry 2). However, the well-defined
ruthenium complex [Ru(MesCO2)2(p-cymene)] (4)11 was
a Reaction conditions:
1
(1.0ꢀ2.0 mmol), 2a (3 equiv); (A)
[Ru(MesCO2)2(p-cymene)] (4; 5.0 mol %)/KO2CMes (20 mol %), (B)
[RuCl3(H2O)n] (5.0 mol %)/KOAc (1 equiv); 1,4-dioxane or PhMe
(3.0 mL), 120 °C, 48 h.
(9) (a) Ackermann, L.; Kozhushkov, S. I.; Yufit, D. S. Chem. Eur. J.
2012, 18, 12068–12077. (b) Kozhushkov, S. I.; Yufit, D. S.; Ackermann,
L. Org. Lett. 2008, 10, 3409–3412.
found to be optimal (entries 9 and 10), particularly in the
presence of cocatalytic amounts of KO2CMes (entries 11
and 12).
With two highly selective catalytic systems in hand, we
studied their application to the hydroarylation of methy-
lenecyclopropane 2a through CꢀH bond activation using
2-phenylpyridine derivatives 1 substituted on the aryl
moiety (Scheme 1). Notably, both catalytic systems deliv-
ered the ortho-alkylated arenes 3 in high yields and with
excellent chemoselectivity.
(10) Only few metal-catalyzed reactions of MCPs have thus far been
reported that do not result in the opening of at least one cyclopropane
ring: (a) Ogata, K.; Shimada, D.; Fukuzawa, S.-I. Chem. Eur. J. 2012, 18,
6142–6146. (b) Liu, T.-L.; He, Z.-L.; Tao, H.-Y.; Cai, Y.-P.; Wang, C.-J.
Chem. Commun. 2011, 47, 2616–2618. (c) Fall, Y.; Doucet, H.; Santelli,
M. Tetrahedron 2010, 66, 2181–2188. (d) Shirakura, M.; Suginome, M.
J. Am. Chem. Soc. 2009, 131, 5060–5061. (e) Tian, G. Q.; Shi, M. Org.
Lett. 2007, 9, 4917–4920. (f) Takeuchi, D.; Anada, K.; Osakada, K.
Angew. Chem., Int. Ed. 2004, 43, 1233–1235. (g) Itazaki, M.; Nishihara,
Y.; Osakada, K. J. Org. Chem. 2002, 67, 6889–6895. (h) Pohlmann, T.;
de Meijere, A. Org. Lett. 2000, 2, 3877–3879. See also: (i) Aıssa, C.;
¨
€
Furstner, A. J. Am. Chem. Soc. 2007, 129, 14836–14837.
(11) (a) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548–6551.
(b) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org.
Lett. 2010, 12, 5032–5035.
Furthermore, 2-arylpyridines substituted at the hetero-
aromatic moiety were found to be viable substrates as
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Hydroarylations of Substituted
Methylenecyclopropanes 2a
Scheme 5. Hydroalkenylation with Alkene 5
Scheme 6. Proposed Key Intermediate 7
Experiments with meta-substituted arenes 1 generally
led to preferential alkylation at the less hindered 6-position
(Scheme 4). However, the CꢀH bond functionalization at
substrate 1l with a m-methoxy substituent furnished a
mixture of the minor 6-substituted (3la) and the major
2-substituted (3la0) products. The predominant formation
of the latter can be rationalized in terms of a secondary
chelating effect exerted by the methoxy substituents.
The highly active catalyst 4 also enabled the difficult func-
tionalization of the nonaromatic C(sp2)ꢀHbondinalkene5
to yield the desired hydroalkenylation product 6(Scheme 5).
As to the catalyst working mode, we propose that the
carboxylate ligand improves the chemoselectivity of the
ruthenium catalysts, thereby favoring the formation of
desired products 3/6from the key intermediate 7(Scheme 6).
In summary, we have developed a novel protocol for
challenging ruthenium-catalyzed hydroarylations and hy-
droalkenylations of highly strained methylenecyclopro-
panes 2 via CꢀH activation employing ruthenium
carboxylates as the catalysts. Carboxylate assistance thus
allowed for not only significantly more efficient transfor-
mations but also more selective anti-Markovnikov trans
hydroarylations of substituted methylenecyclopropanes
with retention of the cyclopropane moieties.13
a Reaction conditions:
[Ru(MesCO2)2(p-cymene)] (4) (5.0 mol %)/KO2CMes (20 mol %),
PhMe (3.0 mL), 120 °C, 48 h; isolated yields. b Reaction in 1,4-dioxane.
1
(1.0ꢀ2.0 mmol),
2
(3.0 equiv),
Scheme 4. Hydroarylations with Meta-Substituted Arenes 1
well, thereby delivering the desired products 3faꢀ3ha
(Scheme 2). The synthesis of product 3ia proceeded less
efficiently, likely due to the increased steric interactions
exerted by the 3-methyl substituent.
The ruthenium catalyst [Ru(MesCO2)2(p-cymene)] (4)
was not limited to substrates displaying the substituents on
the phenylpyridines 1 (Schemes 1ꢀ3)12 but was also found
to be applicable to alkyl-substituted methylenecyclopro-
panes 2 as well as methylenespiropentane (2e) (Scheme 3).
In these transformations, the anti-Markovnikov trans hy-
droarylation with retention of the cyclopropane moieties
was significantly improved in comparison with the catalyst
derived from [RuCl2(cod)]n/X-Phos, for which undesired
ring-opening reactions were unfortunately observed.9a
Acknowledgment. Financial support by the Nieder-
sachsen-Technion Research Cooperation Program and
the European Research Council (ERC) under the Eur-
opean Community’s Seventh Framework Program (FP7
2007ꢀ2013) is gratefully acknowledged.
Supporting Information Available. Text, figures, and a
table giving experimental procedures, characterization
data, and 1H and 13C NMR spectra for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Arenes bearing pyrazoles or imines as the directing groups gave
less satisfactory results.
(13) For a recent notable CꢀH bond functionalization with MCPs
partially occurring through ring opening, see: Cui, S.; Zhang, Y.; Wu, Q.
Chem. Sci. 2013, 4, 3421–3426 and references cited therein.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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