Ruthenium-catalyzed hydroarylations of methylenecyclopropanes: Mild C-H bond functionalizations with conservation of cyclopropane rings

Article abstract of DOI:10.1021/ol8011875

(Chemical Equation Presented) Ring conservation was observed in the first catalytic intermolecular hydroarylation of methylenecyclopropanes via C-H bond functionalization, a remarkable reactivity mode for a transformation proceeding through (cyclopropylcarbinyl)metal intermediates.

Full text of DOI:10.1021/ol8011875

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3409-3412
Ruthenium-Catalyzed Hydroarylations of
Methylenecyclopropanes: Mild C-H
Bond Functionalizations with
Conservation of Cyclopropane Rings
Sergei I. Kozhushkov,† Dmitry S. Yufit,‡ and Lutz Ackermann*,†
Institut fu¨r Organische and Biomolekulare Chemie der Georg-August-UniVersita¨t
Go¨ttingen, Tammannstrasse 2, 37077 Go¨ttingen, Germany, and Department of
Chemistry, UniVersity of Durham, South Road, Durham DH1 3LE, U.K.
lutz.ackermann@chemie.uni-goettingen.de
Received May 28, 2008
ABSTRACT
Ring conservation was observed in the first catalytic intermolecular hydroarylation of methylenecyclopropanes via C-H bond functionalization,
a remarkable reactivity mode for a transformation proceeding through (cyclopropylcarbinyl)metal intermediates.
Transition-metal-catalyzed additions of arenes to C-C
multiple bonds, hydroarylation reactions, have received
considerable attention as an ecologically and economically
benign approach to the direct functionalization1 of aromatic
C-H bonds. Consequently, a number of valuable protocols
for intermolecular hydroarylations of alkenes, alkynes, and
allenes have been developed,2 with ruthenium-catalyzed3
directed4 C-H bond functionalizations being among the most
powerful strategies.5,6
development of efficient synthetic methodologies. In par-
ticular, (transition) metals were found useful for the conver-
sion of these highly strained starting materials.8 Notably,
(2) (a) Dyker, G., Ed. Handbook of C-H Transformations; Wiley-VCH:
Weinheim, 2005. (b) Bandini, M.; Emer, E.; Tommasi, S.; Umani-Ronchi,
A. Eur. J. Org. Chem. 2006, 3527–3544. (c) Nevado, C.; Echavarren, A. M.
Synthesis 2005, 167–182. (d) Liu, C.; Bender, C. F.; Han, X.; Widenhoefer,
R. A. Chem. Commun. 2007, 3607–3618. (e) Kakiuchi, F.; Chatani, N. AdV.
Synth. Catal. 2003, 345, 1077–1101. (f) Jia, C.; Kitamura, T.; Fujiwara, Y.
Acc. Chem. Res. 2001, 34, 633–639, and references cited therein.
(3) Selected related intermolecular hydroarylations catalyzed by metals
other than ruthenium: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2008, 130, 3645–3651. (b) Nakao, Y.; Kanyiva, K. S.;
Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448–2449. (c) Lewis, J. C.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332–5333.
(d) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362–5367.
(e) Oxgaard, J.; Periana, R. A.; Goddard, W. A., III. J. Am. Chem. Soc.
2004, 126, 11658–11665. (f) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem.
2003, 3485–3496. (g) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1992–1995. (h) Jun, C.-H.; Hong, J.-B.;
Kim, Y.-H.; Chung, K.-Y. Angew. Chem., Int. Ed. 2000, 39, 3440–3442.
(i) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616–6623.
(4) Kakiuchi, F. Top. Organomet. Chem. 2007, 24, 1–33.
The chemistry of highly strained methylenecyclopropanes7
is attractive because their enhanced reactivities allow to probe
fundamental concepts in organic chemistry and enable the
† Georg-August-Universita¨t Go¨ttingen.
‡ University of Durham.
(1) Recent reviews on C-H bond functionalizations, see: (a) Ackermann,
L. Top. Organomet. Chem 2007, 24, 35–60. (b) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174–238. (c) Stuart, D. R.; Fagnou, K.
Aldrichim. Acta 2007, 40, 35–41. (d) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. ReV. 2007, 36, 1173–1193. (e) Ackermann, L. Synlett 2007, 507–526.
(f) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205. (g) Catellani, M.;
Motti, E.; Della Ca’, N.; Ferraccioli, R. Eur. J. Org. Chem. 2007, 4153–
4165. (h) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.;
Lazareva, A. Synlett 2006, 20, 3382–3388. (i) Yu, J.-Q.; Giri, R.; Chen, X.
Org. Biomol. Chem. 2006, 4, 4041–4047.
(5) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529–531. (b) Kakiuchi, F.;
Murai, S. Acc. Chem. Res. 2002, 35, 826–834. (c) Kakiuchi, F.; Chatani,
N. In Ruthenium in Organic Synthesis; Murahashi, S.-I., Ed.; Wiley-VCH:
Weinheim, 2004; pp 219-255, and references cited therein.
10.1021/ol8011875 CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

these transformations proceeded almost exclusively via
opening of at least one cyclopropane ring.9 Herein, we report
on the development of unprecedented intermolecular10 hy-
droarylations of methylenecyclopropanes through C-H bond
functionalizations, surprisingly occurring with conservation
of all cyclopropane rings.
Table 1. Ruthenium-Catalyzed Hydroarylation of 2a
At the outset of our studies, we tested ruthenium-
catalyzed11 hydroarylations of methylenecyclopropane 2,
employing [RuCl2(cod)]n as precatalyst12 modified with a
representative set of commonly used ligands (Figure 1). Due
entry
L
1a (%)
3a (%)
1
2
3
4
5
6
7
8
9
PPh3 (4)
rac-BINAP (5)
dppf (6)
PCy3 (7)
8
9
10
11
11
97
97
96
96
95
80
53
39
40
<5
<5
17
46
53
54b
a Reaction conditions: 1a (1-2 mmol), 2 (3 equiv), [RuCl2(cod)]n (5
mol %), L (10 mol %), 1,4-dioxane (3 mL), 120 °C, 48 h; cod )
cis-1,4-cyclooctadiene. b NMP (3 mL) as solvent.
Figure 1. Ligands employed for catalytic hydroarylations.
to cyclopropane ring-opening, triaryl phosphines 4-6 pro-
vided rather unsatisfactory results (Table 1, entries 1-3).13
On the contrary, more selective catalysis was achieved
with electron-rich phosphines 7-10 (entries 4-7), with
monophosphine biphenyl ligand 1114 providing superior
results (entries 8 and 9). Remarkably, the anti-Markovnikov
addition of arene 1a occurred with complete conservation
of the three-membered ring, yielding cyclopropane derivate
3a highly selectively.
The optimized catalyst enabled an efficient C-H bond
functionalization of pyridine 1b as well, giving rise to desired
product 3b with excellent chemo- and regioselectivity
(Scheme 1).
(6) Selected additional ruthenium-catalyzed hydroarylations: (a) Foley,
N. A.; Lail, M.; Lee, J. P.; Gunnoe, T. B.; Cundari, T. R.; Petersen, J. L.
J. Am. Chem. Soc. 2007, 129, 6765–6781. (b) Martinez, R.; Chevalier, R.;
Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2006, 45, 8232–8235. (c)
Grellier, M.; Vendier, L.; Chaudret, B.; Albinati, A.; Rizzato, S.; Mason,
S.; Sabo-Etienne, S. J. Am. Chem. Soc. 2005, 127, 17592–17593. (d) Busch,
S.; Leitner, W. AdV. Synth. Catal. 2001, 343, 192–196. (e) Lewis, L. N.;
Smith, J. F. J. Am. Chem. Soc. 1986, 108, 2728–2735, and references cited
therein.
(7) (a) de Meijere, A.; Kozhushkov, S. I.; Schill, H. Chem. ReV. 2006,
106, 4926–4996. (b) Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589–636.
(8) Reviews on metal-promoted reactions of methylenecyclopropanes:
(a) Binger, P.; Schmidt, T. In Houben-Weyl; de Meijere, A., Ed.; Thieme:
Stuttgart, 1997; Vol. E17c, pp 2217-2294. (b) Nakamura, I.; Yamamoto,
Y. AdV. Synth. Catal. 2002, 344, 111–129. (c) Rubin, M.; Rubina, M.;
Gevorgyan, V. Chem. ReV. 2007, 107, 3117–3179.
Scheme 1
.
Ruthenium-Catalyzed Hydroarylation with Pyridine
1b
(9) Only a few catalytic reactions were thus far reported, not resulting
in an opening of at least one cyclopropane ring: (a) Takeuchi, D.; Anada,
K.; Osakada, K. Angew. Chem., Int. Ed. 2004, 43, 1233–1235. (b) Pohlmann,
T.; de Meijere, A. Org. Lett. 2000, 2, 3877–3879. (c) Tian, G.-Q.; Shi, M.
Org. Lett. 2007, 9, 4917–4920. (d) Shao, L.-X.; Ming-Hui Qi, M.-H.; Shi,
M. Tetrahedron Lett. 2008, 49, 165–168.
(10) A recent elegant intramolecular rhodium-catalyzed C-H bond
activation with alkylidenecyclopropanes also resulted in ring opening of
the cyclopropane moiety: A¨ıssa, C.; Fu¨rstner, A. J. Am. Chem. Soc. 2007,
129, 14836–14837.
Therefore, we set out to probe the more challenging
hydroarylation of bicyclopropylidene (12)15 with pyridine
derivatives 1a and 1b (Scheme 2). Under the optimized
(11) Selected reports from our laboratories on ruthenium-catalyzed C-H
bond functionalizations: (a) Ackermann, L.; Vicente, R.; Althammer, A.
Org. Lett. 2008, 2299–2302. (b) Ackermann, L.; Althammer, A.; Born, R.
Synlett 2007, 2833–2836. (c) Ackermann, L.; Born, R.; Alvarez-Bercedo,
P. Angew. Chem., Int Ed. 2007, 46, 6364–6367. (d) Ackermann, L.;
Althammer, A.; Born, R. Angew. Chem., Int. Ed. 2006, 45, 2619–2622. (e)
Ackermann, L. Org. Lett. 2005, 7, 3123–3125.
Scheme 2
.
Ruthenium-Catalyzed Hydroarylation of
Bicyclopropylidene 12
(12) Under otherwise identical reaction conditions, catalytic amounts
of [RhCl(cod)]2 and PPh3 yielded quantitative ring opening of 2, along with
its polymerization, even at 50 °C reaction temperature.
(13) Here, only undesired by-products due to Diels-Alder [4 + 2]
cycloadditions of 2-phenylbuta-1,4-diene were obtained (see the Supporting
Information).
(14) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, Buchwald,
A. S. J. Am. Chem. Soc. 2003, 125, 6653–6655.
(15) de Meijere, A.; Kozhushkov, S. I.; Khlebnikov, A. F. Top. Curr.
Chem. 2000, 207, 89–147.
3410
Org. Lett., Vol. 10, No. 16, 2008

reaction conditions, these substrates were converted into the
corresponding cis-adducts 13a and 13b, as well as 14,
respectively, in high isolated yields.
Scheme 3. Ruthenium-Catalyzed Hydroarylation of Alkene 2
2
with Pyridine 1a-[D5] (Dinc ) H Incorporation)
incorporation into the cyclopropane moiety of product 3a
was found to be incomplete. Moreover, recovered starting
material revealed a regioselective deuterium-proton ex-
change17 at the ortho-position of pyridine 1a-[D5].
Notably, hydroarylation of bicyclopropylidene (12) with
pyridine 1a-[D5] highlighted a regioselective deuterium-
proton exchange as well, indicating that C-H bond activation
is not rate-limiting (Scheme 4). In these deuterium-proton
Figure 2. Molecular structures of pyridines 13a (top) and 13b
(bottom) in the crystal.16
Scheme 4. Ruthenium-Catalyzed Hydroarylation of Alkene 12
2
with Pyridine 1a-[D5] (Dinc ) H Incorporation)
Importantly, X-ray diffraction analyses of novel products
13a, 13b (Figure 2), and 14 (Figure 3) revealed that all three-
exchange reactions, starting materials 2 and 12, respectively,
served most likely as proton donors.18
Based on our observations, we propose a mechanistic
rationale for ruthenium-catalyzed hydroarylations of meth-
ylelencyclopropanes depicted in Scheme 5. Coordination of
the catalytically competent ruthenium complex 1519,20 ini-
(17) A deuterium-proton exchange was previously observed in hy-
droarylations of simple alkenes: (a) Kakiuchi, F.; Ohtaki, H.; Sonoda, M.;
Chatani, N.; Murai, S. Chem. Lett. 2001, 30, 918–919. (b) Ie, Y.; Chatani,
N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J.
Org. Chem. 2000, 65, 1475–1488.
Figure 3.
Molecular structure of pyridine 14 in the crystal.16
(18) When using DMF-[D7] as solvent, proton-deuterium exchange on
pyridines 1a and 3a was not observed under otherwise identical reaction
conditions.
membered rings remained intact during the C-H bond
functionalization reactions (Supporting Information).16
Since the high selectivity of our novel ruthenium catalyst
enabled C-H bond functionalizations to occur with retention
of cyclopropane moieties, we became interested in testing
its working mode. Thus, we subjected deuterium labeled
pyridine 1a-[D5] to the reaction conditions for the hydroary-
lation of alkene 2 (Scheme 3). Interestingly, deuterium
(19) The high selectivity obtained with monophosphine biphenyl ligand
11 is likely due to formation of arene-tethered ruthenium phosphine
complexes. For the use of comparable phosphines in ruthenium catalysis,
see: (a) Aikawa, K.; Kaito, I.; Mikami, K. Chem. Lett. 2007, 36, 1482–
1483. (b) Faller, J. W.; Fontaine, P. P. Organometallics 2007, 26, 1738–
1743, and references cited therein
(20) The corresponding arene-tethered ruthenium phosphine complex
.
derived from ligand 11 was isolated and unambigiously characterized:
Kozhushkov, S. I.; Yufit, D. S.; Ackermann, L. Unpublished results
.
(21) (a) Wendisch, D. In Houben-Weyl; Thieme: Stuttgart, 1971; Vol.
4/3, pp 399-405. (b) Dyker, G. Angew. Chem., Int. Ed. Engl. 1995, 34,
2223–2224. (c) Nishihara, Y.; Yoda, C.; Osakada, K. Organometallics 2001,
20, 2124–2126. (d) Nu¨ske, H.; Bra¨se, S.; Kozhushkov, S. I.; Noltemeyer,
M.; Es-Sayed, M.; de Meijere, A. Chem. Eur. J. 2002, 8, 2350–2369. (e)
Nishihara, Y.; Yoda, C.; Itazaki, M.; Osakada, K. Bull. Chem. Soc. Jpn.
2005, 78, 1469–1480. (f) Shi, M.; Wang, B.-Y.; Huang, J.-W. J. Org. Chem.
(16) CCDC-678126 (13a), -688765 (13b), and -678125 (14) contain the
supplementary crystallographic data for these compounds. The data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or deposit@ccdc.cam.
ac.uk).
2005, 70, 5606–5610
.
Org. Lett., Vol. 10, No. 16, 2008
3411

The rate of the final reductive elimination in the catalytic
cycle is at least of the order as the one observed for the well-
known, very fast (cyclopropylmethyl)metal-to-homoallyl-
metal rearrangement.8c,21 The latter reorganization, along
with a subsequent ꢀ-hydride elimination, results in the
formation of buta-1,3-dienes as byproduct (see Supporting
Information).21c–f When using 1a-[D5] as substrate, the
generated [Ru-D] intermediate is, therefore, converted into
the corresponding [Ru-H] complex, which likely accounts
for the observed deuterium-proton exchange reactions.
In conclusion, we have developed the first protocol for
intermolecular hydroarylations of highly strained methyl-
enecyclopropanes via C-H bond functionalizations. Al-
though these transformations involved (cyclopropylcarbi-
nyl)metal intermediates, the high selectivity of our new
catalytic system resulted in complete retention of the
cyclopropane moieties in the products. This unique reactivity
pattern is a strong testament for the mild reaction conditions
of ruthenium-catalyzed C-H bond functionalizations.
Scheme 5
.
Proposed Catalytic Cycle for Hydroarylations of
Methylenecyclopropanes
Acknowledgment. Support by the DFG, the Fonds der
Chemischen Industrie, EPSRC (UK), and Saltigo GmbH
(Leverkusen) is gratefully acknowledged.
Supporting Information Available: Crystallographic data
(CIF) for 13a, 13b, and 14; experimental procedures and
characterization data (1H and 13C NMR) for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
tiates a rapid and reVersible C-H bond activation, providing
ruthenacycle 17. Subsequently, cyclometalated complex 17
adds to alkene 2. Reductive elimination from complex 18
yields the desired product 3a, thereby regenerating the
catalytically active species 15.
OL8011875
3412
Org. Lett., Vol. 10, No. 16, 2008