Ruthenium-catalyzed (2 + 2) intramolecular cycloaddition of allenenes

Article abstract of DOI:10.1021/ja200784n

We report a ruthenium-catalyzed (2 + 2) intramolecular cycloaddition of allenes and alkenes. We have found that the use of the ruthenium complex RuH₂Cl₂(PⁱPr₃)₂, which has previously gone unnoticed in catalytic applications, is crucial for the observed reactivity. The reaction proceeds under mild conditions and is fully diastereoselective, providing a practical entry to a variety of bicyclo[3.2.0]heptane skeletons featuring cyclobutane rings.

Full text of DOI:10.1021/ja200784n

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Ruthenium-Catalyzed (2 þ 2) Intramolecular Cycloaddition
of Allenenes
Moisꢀes Gulías,† Alba Collado,‡ Beatriz Trillo,† Fernando Lꢀopez,§ Enrique O~nate,‡ Miguel A. Esteruelas,*,‡ and
Josꢀe L. Mascare~nas*,†
†Departamento de Química Orgꢀanica y Centro Singular de Investigaciꢀon en Química Biolꢀogica y Materiales Moleculares, Unidad
Asociada al CSIC, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
‡Departamento de Química Inorgꢀanica - Instituto de Síntesis Química y Catꢀalisis Homogꢀenea (ISQCH), Universidad
de Zaragoza - CSIC, 50009 Zaragoza, Spain
§Instituto de Química Orgꢀanica General - CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
S Supporting Information
b
Scheme 1. Annulations of Allenedienes
ABSTRACT: We report a ruthenium-catalyzed (2 þ 2)
intramolecular cycloaddition of allenes and alkenes. We have
found that the use of the ruthenium complex RuH2Cl2(PiPr3)2,
which has previously gone unnoticed in catalytic applications, is
crucial for the observed reactivity. The reaction proceeds under
mild conditions and is fully diastereoselective, providing a
practical entry to a variety of bicyclo[3.2.0]heptane skeletons
featuring cyclobutane rings.
he extraordinary expansion of transition-metal catalysis
during the last decades has opened the door to the devel-
T
opment of a wide variety of cycloaddition reactions that otherwise
could not be accomplished.1,2 In some cases, it is even possible
to choose different cycloaddition channels for the same substrate
by just changing the metal complex that is used as the catalyst. This
is the case for allenedienes of type 1, which can participate
in different types of (4 þ 2), (4 þ 3), or (2 þ 2 þ 1) intramolecular
annulations depending on the choice of Rh,3,4 Ni,4 Au,5 or Pt6
catalysts (Scheme 1).
Scheme 2. Intramolecular (2 þ 2) Cycloaddition
Herein we report a new type of intramolecular cycloaddition
of allenedienes, namely, a ruthenium-catalyzed [2C þ 2C]
annulation process. The reaction proposes a new way of making
fused cyclobutanes and represents a significant addition to the
existing cycloaddition toolbox because of the scarcity of catalytic
(2 þ 2) intramolecular annulations of nonactivated systems.7,8
Indeed, the only reported examples of intramolecular (2 þ 2)
cycloadditions between allenes and alkenes have been restricted
to the use of arylalkenes and rely on gold catalysis.7c,g,h
optimization, we found that the use of (CH2)2Cl2 as the solvent
and a higher dilution increased the yield up to 52% (conditions b).
Importantly, other cycloadducts, such as the potentially competitive
(4 þ 2) product 3a, were not detected.
To check the importance of the nature of the Ru catalyst, we
browsed the performance of other Ru complexes previously used
in different types of cycloadditions, such as Cp*RuCl(COD),
[Cp*Ru(CH3CN)3]PF6, and RuCl2(PPh3)3.11 In each case,
however, we observed either no reactivity or very low conversion
to the desired (2 þ 2) adduct 2a. Thus, the scope of the
cycloaddition process was further investigated using RuH2Cl2-
(PiPr3)2 as the catalyst (Table 1).
This research arose in the context of recent findings on the
stoichiometric reactivity of the complex RuH2Cl2(PiPr3)2 with
allenes.9 We reasoned that tethering the allene to another unsatu-
rated unit (e.g., a conjugated diene) could offer opportunities for
annealing both partners in a catalytically productive manner.10
A
preliminary experiment was carried out using allendiene 1a, a type of
precursor that was recently used by us in Pt- and Au-catalyzed
cycloaddition reactions.5a,c,6 Gratifyingly, treatment of this substrate
with 10 mol % RuH2Cl2(PiPr3)2 in toluene at 45 °C afforded the
(2 þ 2) cycloadduct 2a as a single diasteroisomer, although in a
modest 30% yield (Scheme 2, conditions a). After a brief
Received: February 4, 2011
Published: April 28, 2011
r
2011 American Chemical Society
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Table 1. Scope of the Ru-Catalyzed (2 þ 2) Cycloadditiona
gave the expected adducts in good yields and complete selectivity
with regard to the exo geometry of the double bond (Table 1,
entries 1ꢀ3). Allenedienes 1e and 1f equipped with aromatic
substituents at the allene terminus also participated in the
cycloaddition, providing the corresponding (2 þ 2) adducts as
single isomers in 64 and 60% yield, respectively (entries 4 and 5).
The reaction also worked with substituted dienes 1g and 1h,
providing the corresponding adducts 2g and 2h in good yields of
82 and 80%, respectively (entries 6 and 7). Substrate 1i bearing a
methyl group at the most internal position of the diene did not
react, but precursor 1j with a methyl group at the internal
position of the allene underwent the cycloaddition. Although
the yield was moderate, this reaction provides an entry to
important bicyclo[3.2.0]heptane systems with one quaternary
stereocenter at the ring fusion (entry 9).
Mechanistically meaningful allenene 1k bearing two methyl
substituents at the distal position of the allene afforded only traces
of the desired product, even after several hours at 45 °C. Indeed,
most of the starting material was recovered unreacted from the
resulting reaction mixture. On the other hand, substrate (Z)-1c
featuring an internal cis alkene afforded 2c0 (entry 11), a cycload-
duct that is epimeric to 2c at the stereocenter incorporating the
vinyl group. This result confirmed that the cycloaddition is
stereospecific with regard to the diene stereochemistry.
Having browsed the scope with conjugated dienes, we next
investigated whether the presence of the conjugated alkene is a
strict requirement for the cycloaddition. Remarkably, allenene 1l
did also participate in the process, providing the expected
cycloadduct in 52% yield (entry 12). Meanwhile, allenene 1m
containing an unsubstituted alkene underwent an efficient (2 þ 2)
cycloaddition (78% yield; entry 13). Interestingly, while substrate
1n containing a dimethylalkene did not react even at higher
temperatures, the alkylidenecyclopropane analogue 1o gave the
expected cycloadduct in good yield (entry 15).13
In order to gain mechanistic insights, we studied the transfor-
mation using density functional theory (DFT) calculations
(B3PW91/LANL2DZ/6-31G**) with 1p as a model substrate
(Scheme 3 and Figure 1). These DFT calculations suggested that
the catalytic cycle is initiated by the unsaturated species RuCl2-
(PiPr3) (A),14 which arises from the dissociation of molecular
hydrogen and one triisopropylphosphine ligand from the ruthe-
nium precursor (Scheme 3). Coordination of the conjugated
diolefin unit and the internal allenic double bond of the substrate
to the metal center of A generates complex B, which evolves into
the ruthenabicycle C by oxidative cyclometalation. Intermediate C
might be represented as two main rotameric species C1 and C2,
depending on the spatial disposition of the isopropylphosphine
(seethe Supporting Information). Aσ- toπ-allyl transformation of
C affords D, which also exhibits two low-energy phosphine
rotamers (D1 and D2). Intermediate D eliminates the (2 þ 2)
product by migration of the metalated carbon atom of the alkenyl
unit to the internal site of the allyl moiety. The calculations suggest
that formation of C rather than the final reductive elimination is
the rate-determining step.15 Indeed, reductive elimination from
intermediate D (CꢀRuꢀC angle 61.6°) is rather easy and much
more favored than an alternative direct transformation of C into
the product (CꢀRuꢀC angle 104.0°). The proximity of the
carbon atoms in D seems to facilitate this reductive step.
a Conditions: RuH2Cl2(PiPr3)2 (10 mol %), DCE (20 mM), 45 °C,
2ꢀ6 h. The relative stereochemistries of the products were determined
by nuclear Overhauser effect (NOE) NMR experiments. Some structures
were also solved by X-ray crystallographic analysis. See the Supporting
Information for details. b Yield was not optimized because of volatility of
the product. c RuH2Cl2(PiPr3)2 (20 mol %) was used. d Some of the side
products that could be detected in the reaction mixture most probably
e
arose from competitive β-hydride elimination processes. The substrate
was contaminated by a small proportion of the cis isomer.
Interestingly, substitution at the terminal position of the allene
by a methyl group led a cleaner reaction and a significant increase
in the reaction efficiency.12 Therefore, precursors 1bꢀd featur-
ing different connecting tethers between the allene and the diene
We also carried out calculations on substrate 1d, which was
experimentally tested, and the results suggest a similar energy
profile (see the Supporting Information for details). On the
other hand, calculations with allenenes instead of allenedienes
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Scheme 3. Mechanistic Proposal
Also in agreement with this mechanism, we found that treat-
ment of an enantioenriched sample of allenediene 1e (42% ee)16
under the reaction conditions produced the expected cycloadduct
2e with the same degree of enantiopurity (Scheme 4). In view of
the ample number of possibilities for preparing optically active
allenes, the methodology presents an interesting alternative to
ensemble fused cyclobutanes in an enantioselective manner.17
In conclusion, we have developed a new type of metal-catalyzed
(2 þ 2) intramolecular cycloaddition of allenes and alkenes that
represents the first catalytic application of RuH2Cl2(PiPr3)2. The
reaction proceeds under mild conditions and is fully diastereose-
lective, providing a new practical entry to bicyclic structures
featuring cyclobutanes.18
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, spec-
b
troscopic data, crystallographic information files, additional calcula-
tions, and energies and Cartesian coordinates of optimized
geometries. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
maester@unizar.es; joseluis.mascarenas@usc.es
’ ACKNOWLEDGMENT
This work was supported by the Spanish MICINN (Projects
SAF2007-61015, SAF2010-20822-C02, CTQ2008-00810, and
Consolider-Ingenio 2010 CSD2007-00006), CSIC, Xunta de
Galicia (GRC2010/12, INCITE09 209 122 PR), Comunidad de
Madrid (CCG08-CSIC/PPQ3548), Diputaciꢀon General de Ara-
gꢀon (E35), the Marie Curie Foundation (PERG06-GA-2009-
256568), and the European Social Fund. M.G. thanks the Xunta
de Galicia for a Parga Pondal Contract. A.C. thanks the CSIC for
her JAE Grant.
’ REFERENCES
(1) Kobayashi, S.; Jorgensen, K. A. Cycloaddition Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2002.
Figure 1. Energy profile (kcal molꢀ1; ΔG values at 1 atm and 298.15 K
are given in parentheses).
(2) For a comprehensive review of metal-catalyzed cycloadditions, see:
Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49–92.
(3) (a) Wender, P. A.; Croatt, M. P.; Deschamps, N. M. Angew.
Chem., Int. Ed. 2006, 45, 2459–2462. (b) For a discussion of the “diene
effect”, see: Croatt, M. P.; Wender, P. A. Eur. J. Org. Chem. 2010, 19–32.
(4) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995,
117, 1843–1844.
Scheme 4. Cycloaddition of Enantioenriched 1e
(5) (a) Trillo, B.; Lꢀopez, F.; Montserrat, S.; Ujaque, G.; Castedo, L.;
Lledꢀos, A.; Mascare~nas, J. L. Chem.—Eur. J. 2009, 15, 3336–3339.
(b) Mauleꢀon, P.; Zeldin, R. M.; Gonzꢀalez, A. Z.; Toste, F. D. J. Am. Chem.
Soc. 2009, 131, 6348–6349. (c) Alonso, I.; Trillo, B.; Lꢀopez, F.;
Montserrat, S.; Ujaque, G.; Castedo, L.; Lledꢀos, A.; Mascare~nas, J. L.
J. Am. Chem. Soc. 2009, 131, 13020–13030.
indicated a similar pathway, although the reductive elimination
from an intermediate related to C but lacking the pendant vinyl
group is more difficult, causing that step to become rate-
determining.
This mechanism is fully consistent with the stereospecificity
and diastereoselectivity observed experimentally. It is also con-
cordant with the high sensitivity of the transformation to
disubstitution of the distal carbon of the allene (such as in 1k),
as this introduces a serious steric congestion between one of the
allene’s groups and the isopropyl groups of the phosphine ligand.
(6) Trillo, B.; Lꢀopez, F.; Gulías, M.; Castedo, L.; Mascare~nas, J. L.
Angew. Chem., Int. Ed. 2008, 47, 951–954.
(7) For transition-metal-catalyzed intramolecular (2 þ 2) cyclo-
additions, see: (a) Oh, C. H.; Gupta, A. K.; Park, D. I.; Kim, N. Chem.
Commun. 2005, 45, 5670–5672. (b) Jiang, X.; Cheng, X.; Ma, S. Angew.
Chem., Int. Ed. 2006, 45, 8009–8013. (c) Luzung, M. R.; Mauleꢀon, P.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402–12403. (d) Kim, S. M.;
Park, J. H.; Kang, Y. K.; Chung, Y. K. Angew. Chem., Int. Ed. 2009,
48, 4532–4535. (e) Saito, N.; Tanaka, Y.; Sato, Y. Organometallics 2009,
7662
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28, 669–671. (f) Saito, N.; Tanaka, Y.; Sato, Y. Org. Lett. 2009,
11, 4124–4126. (g) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.;
F€urstner, A. Angew. Chem., Int. Ed. 2010, 49, 2542–2546. Also see:(h)
Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804–16805.
(8) For recent reviews of (2 þ 2) cycloadditions, see: (a) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783–816.
(b) Ma, S. Chem. Rev. 2005, 105, 2829–2872.
(9) Collado, A.; Esteruelas, M. A.; Lꢀopez, F.; Mascare~nas, J. L.;
O~nate, E.; Trillo, B. Organometallics 2010, 29, 4966–4974.
(10) For a preliminary use of this complex in a dehalogenation
reaction, see: Esteruelas, M. A.; Herrero, J.; Olivꢀan, M. Organometallics
2004, 23, 3891–3897.
(11) For selected recent examples of Ru-catalyzed cycloadditions of
nonactivated unsaturated systems, see: (a) Garcia-Rubin, S.; Varela,
J. A.; Castedo, L.; Saꢀa, C. Chem.—Eur. J. 2008, 14, 9772–9778 and
references therein. (b) Grecian, S.; Fokin, V. V. Angew. Chem., Int. Ed.
2008, 47, 8285–8287. (c) Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem.
Soc. 2007, 129, 11781–11790. (d) Villeneuve, K.; Tam, W. Organome-
tallics 2006, 25, 843–848. (e) Lꢀopez, F.; Delgado, A.; Rodríguez, J. R.;
Castedo, L.; Mascare~nas, J. L. J. Am. Chem. Soc. 2004, 126, 10262–10263.
(12) Probably the presence of a substituent at the allene terminus
avoids competitive side reactions of the allene moiety, and therefore, the
cycloaddition pathway becomes preferential.
(13) Substrate 1o undergoes an intramolecular (3 þ 2) cycloaddi-
tion when treated with appropriate Pd catalysts. See: Trillo, B.; Gulías,
M.; Lꢀopez, F.; Castedo, L.; Mascare~nas, J. L. Adv. Synth. Catal. 2006,
348, 2381–2384. On the other hand, it has also been shown that related
alkylidenecyclopropanes can participate in Ru-catalyzed intramolecular
(3 þ 2) cycloadditions to alkynes (see ref 11e).
(14) Barriers higher than 30 kcal molꢀ1 were found using RuCl2-
(PiPr3)2 as the active species for the first step of the process.
(15) Preliminary calculations suggested that the (4 þ 2) pathway is
more costly than the (2 þ 2) route. See the Supporting Information for
more details.
(16) The synthesis of this enantioenriched allenediene 1d (42% ee)
was carried out following a procedure similar to that described in the
following reference: Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T.
J. Am. Chem. Soc. 2001, 123, 2089–2090.
(17) For a review of the synthesis and use of chiral cyclobutanes, see:
Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1484.
(18) For some examples of naturally occurring cyclobutanes and
their applications, see: (a) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev.
2003, 103, 1485–1538. (b) Sergeiko, A.; Poroikov, V. V.; Hanus, L. O.;
Dembitsky, V. M. Open Med. Chem. J. 2008, 2, 26–37.
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