Tandem catalysis: Generating multiple contiguous carbon-carbon bonds through a ruthenium-catalyzed ring-closing metathesis/Kharasch addition

Article abstract of DOI:10.1021/ja055806j

Tandem catalysis can offer unique and powerful strategies for converting simple starting materials into more complex products in a single reaction vessel while generating less waste and minimizing handling. In this regard, Grubbs' ruthenium alkylidene (Cy

Full text of DOI:10.1021/ja055806j

Published on Web 10/28/2005
Tandem Catalysis: Generating Multiple Contiguous
Carbon-Carbon Bonds through a Ruthenium-Catalyzed
Ring-Closing Metathesis/Kharasch Addition
Benjamin A. Seigal, Cristina Fajardo,† and Marc L. Snapper*
Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
Received August 24, 2005; E-mail: marc.snapper@BC.edu
Abstract: Tandem catalysis can offer unique and powerful strategies for converting simple starting materials
into more complex products in a single reaction vessel while generating less waste and minimizing handling.
In this regard, Grubbs’ ruthenium alkylidene (Cy3P)2Cl2RudCHPh is shown to catalyze two mechanistically
distinct transformations to offer a unique protocol that effects multiple bond changes in a single operation.
A tandem ruthenium-catalyzed olefin ring-closing metathesis (RCM)/Kharasch addition allows for the facile
preparation of bicyclic [3.3.0], [4.3.0], and [5.3.0] ring systems in one step from the appropriately
functionalized acyclic precursors. For substrates where the intramolecular Kharasch addition fails, an
intermolecular Kharasch addition is possible. By combining the intra- and intermolecular Kharasch additions
with RCM, three new contiguous carbon-carbon bonds with multiple stereocenters can be generated by
the ruthenium catalyst in a controlled fashion in one operation through two mechanistically distinct pathways.
2, well-known for their olefin metathesis activities,4 have also
Introduction
Tandem, domino, and cascade processes1 can involve multiple
chemical transformations in a single reaction vessel, generating
less waste and minimizing the excessive handling in multistep
processes, while increasing significantly molecular complexity.2
A particularly valuable tandem or domino process occurs when
the different transformations are mediated by the same catalytic
precursor.3 In this regard, Grubbs’ ruthenium alkylidenes 1 and
been shown to function as procatalysts in olefin isomerizations,5
olefin hydrogenations,6 hydrogen atom and radical atom transfer
reactions,7 as well as other transformations.8
Examples where these other activities of alkylidenes 1 and 2
are combined with olefin metatheses offer particularly efficient
new entries into desired products. For example, as illustrated
in Scheme 1, Grubbs’ preparation of (-)-muscone through a
series of chemoselective ruthenium-catalyzed transformations,
† Current address: Universidad Auto´noma de Madrid.
(1) While efforts are being made to define differences between tandem, domino,
cascade, concurrent, and sequential catalytic processes, these terms are used
interchangeably in this article without bias for the mechanistic implications
of their emerging definitions. See ref 2b-d and Tietze, L. F.; Rackelmann,
N. Pure App. Chem. 2004, 76, 1967 for additional discussions.
(2) For reviews on tandem/domino catalysis, see: (a) De Meijere, A.; von
Zezschwitz, P.; Bra¨se, S. Acc. Chem. Res. 2005, 38, 413. (b) Wasilke, J.-
C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001.
(c) Ajamian, A.; Gleason, J. L. Angew, Chem. Int. Ed. 2004, 43, 3754. (d)
Fogg, D. E.; dos Santos, E. N. Coord. Chem. ReV. 2004, 248, 2365. (e)
Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. ReV. 2004, 33, 302. (f)
Neuschuetz, K.; Velker, J.; Neier, R. Synthesis 1998, 3, 227-255. (g)
Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
1237-1256. (h) Waldmann, H. Org. Synth. Highlights II 1995, 193-202.
(i) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137-165. (j)
Winkler, J. D. Chem. ReV. 1996, 96, 167-176. (k) Parsons, P. J.; Penkett,
C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195-206. (l) Tietze, L. F. Chem.
ReV. 1996, 96, 115. (m) Bunce, R. A. Tetrahedron 1995, 51, 13103-13159.
(n) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959.
For recent examples of tandem processes, see: (o) Braddock, D. C.;
Matsuno, A. Tetrahedron Lett. 2002, 43, 3305-3308. (p) Molander, G.
A.; Brown, G. A.; Storch de Gracia, I. J Org. Chem. 2002, 67, 3459-
3463. (q) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Eur. J. 2002,
8, 1719-1729. (r) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J.
Am. Chem. Soc. 2002, 124, 4552-4553. (s) Murakami, M.; Ubukata, M.;
Ito, Y. Chem. Lett. 2002, 294-295. (t) Lebel, H.; Paquet, V. J. Am. Chem.
Soc. 2004, 126, 11152. (u) Breit, B.; Zahn, S. K. Angew. Chem. Int. Ed.
2001, 40, 1910. (v) Breit, B.; Zahn, S. K. Angew. Chem. Int. Ed. 1999, 38,
969.
(4) For recent reviews on olefin metatheses, see: (a) Fu¨rstner, A. Angew. Chem.
Int. Ed. 2000, 39, 3012-3043. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29.
(5) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am.
Chem. Soc. 2002, 124, 13390-13391. (b) Schmidt, B. Eur. J. Org. Chem.
2003, 816-819. (c) Schmidt, B. Chem. Commun. 2004, 742-743. (d)
Schmidt, B. J. Org. Chem. 2004, 69, 7672-7687.
(6) (a) Drouin, S.; Zamanian, F. Fogg, D. Organometallics 2001, 20, 5495.
(b) Schmidt, B.; Pohler, M. Org. Biomol. Chem. 2003, 1, 2512.
(7) (a) Tallarico, J. A.; Malnick, L. M.; Snapper, M. L. J. Org. Chem. 1999,
64, 344-345. (b) Simal, F.; Demonceau, A.; Noels, A. F. Tetrahedron
Lett. 1999, 40, 5689-5693. (c) Bielawski, C. W.; Louie, J.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 12872. (d) Quayle, P.; Fengas, D.; Richards,
S. Synlet 2003, 1797. (e) Schmidt, B.; Pohler, M.; Costisella, B. J. Org.
Chem. 2004, 69, 1421. (f) Lee, B. T.; Schrader, T. O.; Mart´ın-Matute, B.;
Kauffman, C. R.; Zhang, P.; Snapper, M. L. Tetrahedron 2004, 60, 7391-
7396-345.
(8) (a) Maifeld S. V.; Miller R.; Lee D. Tetrahedron Lett. 2002, 36, 6363-
6365. In addition, see: (b) Watson, M. D.; Wagener, K. B. Macromolecules
2000, 33, 3196-3201. For a recent review of nonmetathetic reactions of
Grubbs’ catalyst, see: (c) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003,
9, 1258. For an overview of ruthenium-catalyzed reactions, see: (d) Naota,
T.; Takaya, H.; Murahashi, S.-I. Chem. ReV. 1998, 98, 2599-2660. (e)
Trost, B. M.; Toste, D. F.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067-
2096. (f) De Clercq, B.; Verpoort, F. Tetrahedron Lett. 2001, 42, 8959.
(3) For recent examples, see: (a) Guo, R.; Morris, R. H.; Song, D. J. Am.
Chem. Soc. 2005, 127, 516. (b) Ackermann, L. Org. Lett. 2005, 7, 439. (c)
Ashfeld, B. L.; Miller, K. A.; Smith, A. J.; Tran, K.; Martin, S. F. Org.
Lett. 2005, 7, 1661.
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A R T I C L E S
Seigal et al.
Scheme 2. Ruthenium-Catalyzed Olefin Metathesis/Double
Kharasch Addition; Generation of Five New σ-Bonds in a Single
Reaction Flask
Scheme 1. Preparation of (-)-Muscone
Results and Discussion
The trihaloacetimides employed in this study were prepared
through either a direct acylation of the amine or through the
known a [3,3]-rearrangement of the corresponding allylic
imidates;11g,13 the rearrangement sequence is illustrated in eq 1
(Scheme 3). Since the stereogenic center generated in the
rearrangement controls the stereochemistry of the subsequent
tandem transformations, an asymmetric introduction of the
allylic amidate provides an opportunity to access the bicyclic
tandem products prepared in this study in an enantioenriched
fashion.14 Alternatively, the trichloroalkyl substrate 15 was
prepared through an alkylation of the corresponding alkyl iodide
with trichloromethyllithium as described by Weinreb and co-
workers (eq 2).15
including an olefin metathesis, hydrogen atom transfer, and
olefin hydrogenation, illustrates the efficiency that can be
achieved in converting an acyclic precursor into the desired
natural product in a single reaction vessel.9 Given the value of
the tandem strategies and the range of ruthenium-catalyzed
reactions,10 opportunities for new ruthenium-catalyzed tandem
transformations are abundant.
Like olefin metathesis, atom transfer radical additions (e.g.
Kharasch additions) have been shown to be powerful methods
for forming carbon-carbon bonds.11 We, and others, have
observed that Grubbs’ ruthenium alkylidene 112 catalyzes atom
transfer radical reactions of haloalkanes across olefins under
relatively mild conditions.7 Given the dual reactivity of this
catalyst, it is easy to envision a tandem process involving an
olefin metathesis and a radical atom transfer reaction. Indeed,
using a specially designed ruthenium alkylidene, Grubbs was
able to prepare unique block polymers in a single reaction vessel
through a ruthenium-catalyzed ring-opening metathesis polym-
erization of cyclooctadiene run concurrently with a ruthenium-
catalyzed atom transfer radical polymerization methyl meth-
acrylate.7c In contrast to this achievement, we demonstrate herein
a tandem ruthenium-catalyzed olefin ring-closing metathesis
(RCM)/Kharasch addition that allows for the facile preparation
of polycyclic compounds in one step from appropriately
functionalized acyclic precursors. In this process, a single metal
precursor, 1, catalyzes the formation of up to three new carbon-
carbon and two carbon-halogen bonds in one operation
through two mechanistically unique pathways (Scheme 2).
Scheme 3. Preparation of Starting Dienes
Table 1 illustrates a series of bicyclic ring systems prepared
from acyclic dienes through a tandem RCM/intramolecular
Kharasch addition reaction sequence. Entries 1-3 indicate that
bicyclic [3.3.0], [4.3.0], and [5.3.0] ring systems can be prepared
in one step from the corresponding acyclic diene precursors. In
these examples, the metathesis reaction forms the 5, 6, or
7-membered rings, at room temperature, followed by a Kharasch
addition that generates the 5-membered lactam under more
forcing conditions. Interestingly, the tandem protocol employing
alkylidene 1 as the catalyst generates compound 6 in higher
yields than the known (Ph3P)3RuCl2-catalyzed Kharasch addition
on the corresponding cyclohexenyl substrate.16 The stereochem-
ical outcome of the reaction supports an atom transfer radical
mechanism compared to a ruthenium-mediated oxidative addi-
tion/reductive elimination pathway. The high temperature
required for this intramolecular Kharasch addition is attributed
to the unfavorable amide bond rotomer required for ring closure
(9) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123,
11312-11313.
(10) For an overview of ruthenium-catalyzed reactions, see: (a) Naota, T.;
Takaya, H.; Murahashi, S.-I. Chem. ReV. 1998, 98, 2599-2660. (b) Trost,
B. M.; Toste, D. F.; Pinkerton, A. B. Chem. ReV., 2001, 101, 2067-2096.
(11) (a) Kharasch, M. S.; Jensen, E. V.; Urry, U. H. Science 1945, 102, 128.
(b) DeMalde`, M.; Minisci, F. Pallini, U.; Volterra, E.; Quilico, A. Chim.
Ind. (Milan) 1956, 38, 371. (c) Asscher, M.; Vofsi, D. J. Chem. Soc. 1963,
1887-1896. (d) De Clercq, B.; Verpoort, F. Tetrahedron Lett. 2002, 43,
4687-4690 and references therein. (e) Matsumoto, H.; Nakano, T.; Nagai,
Y. Tetrahedron Lett. 1973, 14, 5065-5150. (f) Mori, Y.; Tsuji, J.
Tetrahedron 1972, 28, 29-35. (g) Lee, G. M.; Weinreb, S. M. J. Org.
Chem. 1990, 55, 1281. For recent ruthenium-catalyzed examples, see: (h)
Quebatte, L.; Solari, E.; Scopelliti, R.; Severin, K. Organometallics 2005,
24, 1404. (i) Delaude, L.; Demonceau, A.; Noels, A. F. Top. Organomet.
Chem. 2004, 11, 155. (j) Tutusaus, O.; Delfosse, S.; Demonceau, A.; Noels,
A. F.; Vinas, C.; Teixidor, F. Tetrahedron Lett. 2003, 44, 8421. (k) Tutusaus,
O.; Vinas, C.; Nunez, R.; Teixidor, F.; Demonceau, A.; Delfosse, S.; Noels,
A. F.; Mata, I.; Molins, E. J. Am. Chem. Soc. 2003, 125, 11830. (l) De
Clercq, B.; Verpoort, F. J. Organomet. Chem. 2003, 672, 11.
(13) (a) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901 (b) Donohoe, T. J.;
Mitchell, L.; Waring, M. J.; Helliwell, M.; Bell, A.; Newcombe, N. J. Org.
Biomol. Chem. 2003, 1, 2173.
(14) For example, see: Anderson, C. E.; Donde, Y.; Douglas, C. J.; Overman,
L. E. J. Org. Chem. 2005, 70, 648 and references therein.
(15) Lee, G. M.; Weinreb, S. M. J. Org. Chem. 1990, 55, 1281.
(16) Nagashima, H.; Wakamatsu, H.; Ozaki, N.; Ishii, T.; Watanabe, M.; Tajima,
T.; Itoh, K. J. Org. Chem. 1992, 57, 1682.
(12) Preliminary screening efforts indicated that Grubbs’ alkylidene 1 was more
effective in catalyzing the Kharasch addition than the second-generation
catalyst 2.
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Tandem Catalysis
A R T I C L E S
Table 1. Tandem RCM/Kharasch Addition
ring closure when the tandem process was performed at slightly
higher dilutions than the previous examples.
Attempts to generate a 7-membered ring through the radical
Kharasch addition of a trichoroethylcarbamate (Troc)-containing
substrate were unsuccessful. As illustrated in eq 3, treatment
of Troc-protected cyclohexenylamine 19 with Grubbs’ ruthe-
nium catalyst 1 led to only reduced product 20. For substrates
where the intramolecular Kharasch addition fails, however, an
intermolecular Kharasch addition is possible (eqs 4 and 5). For
example, heating diene 21 with alkylidene 1 effects the RCM,
followed by addition of styrene, and continued heating allows
for an intermolecular Kharasch addition to produce compound
22 as a mixture of diastereomers. In a similar fashion, diene
23, also participates in a tandem RCM/intermolecular Kharasch
addition with styrene to provide compound 24.
Scheme 4. Tandem RCM/Intramolecular Kharasch/Intermolecular
Kharasch
in the radical cyclization. As discussed below, this supposition
is supported through studies with the more substituted amides.
Entries 4 and 5 demonstrate that adding a benzyl or tosyl
group to the amide functionality facilitates the Kharasch
addition; the reactions proceed at lower temperatures, although
requiring longer reaction times. The Kharasch reactivity can
be enhanced further by switching the trichloroacetamide to the
corresponding tribromoacetamide. As shown in entry 6, the
tandem RCM/Kharasch occurs with substrate 13 even at reduced
temperatures. It is likely that the higher Kharasch reactivity
observed with this substrate contributes to the reduced yield of
desired cycloadduct; the radical atom transfer reactivity com-
petes with olefin metathesis, leading not only to the desired
adduct 14 but also to a variety of other side products.
Scheme 4 illustrates two examples of tandem processes
extended to include both intra- and intermolecular Kharasch
additions. When diene 5 is heated in the presence styrene,
compound 25 is generated selectively in 78% yield as a 1:1
mixture of benzyl chlorides (eq 6). In this reaction, Grubbs’
catalyst 1 first effects the RCM and then upon heating promotes
an intramolecular Kharasch addition, before carrying out an
intermolecular Kharasch on 6 with the addition of styrene. The
net result is the ruthenium-catalyzed formation of three new
contiguous carbon-carbon bonds, two carbon-halogen bonds,
and four new stereogenic centers in a single reaction flask. A
similar transformation is observed with diene 3 (eq 7). In both
cases, these benzyl chloride products (25 and 26) are trans-
Interestingly, the aliphatic substrate 15 provides the highest
yield of a tandem cycloadduct 16 (entry 7). Evidently, the
conformational freedom offered by removing the amide linkage
more than compensates for the reduced Kharasch activity of
the trichloroalkyl functionality. An alternative route to the 5,6-
ring system is illustrated in entry 8. In this case, a RCM is used
to prepare the furanyl ring, followed by a Kharasch addition
that installs the 6-membered lactam. Improved yields were
observed for the 6-membered ring-forming radical atom transfer
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A R T I C L E S
Seigal et al.
RCM/Kharasch Addition. In a glovebox, a solution of the
halogenated dienyl substrate (1 equiv) in toluene or xylene (0.2 M)
was added to Grubbs’ catalyst 1 (5 mol %) in a thick-walled pressure
tube and sealed with a Teflon screw cap. The tube was removed from
the glovebox and was allowed to stir at ambient temperature. After 2
h the reaction was placed in a heated oil bath and allowed to stir for
approximately 2 h. After allowing the tube to cool, the RCM/Kharash
product was obtained upon removal of solvent and purification through
silica gel chromatography.
formed to the corresponding benzyl nitrates upon chromato-
graphic separation with Ag-impregnated silica gel.
Conclusions
In summary, we have shown that Grubbs’ ruthenium alky-
lidene 1 can catalyze two distinct transformations in the same
reaction vessel to offer a unique ring-forming protocol, effecting
multiple bond changes in a single operation. The outcome is a
new tandem RCM/Kharasch addition that converts acyclic
halogenated diene precursors into highly functionalized poly-
cyclic systems, versatile intermediates that can be functionalized
further through a variety of strategies, including selective
reduction of the halogens,7e hydrolytic conversion of halogens
to R,â-unsaturated carbonyls compounds,17 generation of olefins
through eliminations, or new carbon-carbon bonds through
secondary radical atom transfer16 or alkylation reactions.18
Indeed, two examples are provided where the tandem RCM/
Kharasch addition products are further functionalized in the
same reaction flask through a second ruthenium-catalyzed
Kharasch addition to provide bicyclic products containing three
new adjacent carbon-carbon bonds.
RCM/Double Kharasch Addition. In a glovebox, a solution of the
halogenated dienyl substrate (1 equiv) in xylenes (0.05 M) was added
to Grubbs’ catalyst 1 (5 mol %) in a flask and fitted with a reflux
condenser. The flask was removed from the glovebox and was allowed
to reflux for approximately 2 h, at which time styrene (5 equiv) was
added and the reaction was allowed to reflux for an additional 4 h.
After allowing the tube to cool, the benzyl chloride products were
obtained as an inseparable mixture upon removal of solvent and
purification through silica gel chromatography. If the reaction was
purified by chromatography on 10% AgNO3/SiO2 (wt/wt) column (1:
4; ethyl acetate:hexane), the nitrated Kharasch diastereomers are isolated
individually.
Acknowledgment. We thank the National Science Foundation
and Boston College for financial support. We are grateful to
Schering-Plough for X-ray facility support and Materia for the
gift of metathesis catalyst. We also thankfully acknowledge
Wayne Lo for assistance with X-ray crystallography studies.
Experimental Section
General Methods. All reactions were carried out under N2 atmo-
sphere in oven-dried glassware (135 °C, 12 h) using standard air-free
manipulation techniques. Starting materials and reagents were purchased
from commercial suppliers and used without further purification, except
the following: tetrahydrofuran, benzene, diethyl ether, and dichlo-
romethane were dried on alumina columns using a solvent dispensing
system;19 pentane, hexanes, and diethyl ether used in chromatography
were distilled prior to use.
Supporting Information Available: Experimental procedures
and data on new compounds are provided (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA055806J
(17) Lee, B. T.; Schrader, T. O.; Mart´ın-Matute, B.; Kauffman, C. R.; Zhang,
P.; Snapper, M. L. Tetrahedron 2004, 60, 7391-7396-345.
(18) Kleschick, W. A.; Reed, M. W.; Bordner, J. J. Org. Chem. 1987, 3168.
(19) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers,
F. J Organometallics 1996, 15, 1518.
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