Highly efficient, facile, room temperature intermolecular [5 + 2] cycloadthtions catalyzed by cationic rhodium(I): One step to cycloheptenes and their libraries

Article abstract of DOI:10.1021/ol100337m

(Figure Presented) A cationic rhodium(I) complex-[(C₁₀H ₈)Rh(cod)]⁺ SbF₆^--catalyzes the remarkably efficient intermolecular [5 + 2] cycloaddition vinylcyclopropanes (VCPs) and various alkynes, providing cycloheptene cycloadducts in excellent yields in minutes at room temperature. T efficacy and selectivity of this catalyst are also shown in a novel diversification strategy, affording a cycloadduct library In one step from ni commercially available components.

Full text of DOI:10.1021/ol100337m

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1604-1607
Highly Efficient, Facile, Room
Temperature Intermolecular [5 + 2]
Cycloadditions Catalyzed by Cationic
Rhodium(I): One Step to Cycloheptenes
and Their Libraries
Paul A. Wender,* Lauren E. Sirois, Rene´ T. Stemmler, and Travis J. Williams†
Departments of Chemistry and of Chemical and Systems Biology, Stanford UniVersity,
Stanford, California 94305-5080
wenderp@stanford.edu
Received February 9, 2010
ABSTRACT
A cationic rhodium(I) complex;[(C10H8)Rh(cod)]+ SbF6-;catalyzes the remarkably efficient intermolecular [5 + 2] cycloaddition of
vinylcyclopropanes (VCPs) and various alkynes, providing cycloheptene cycloadducts in excellent yields in minutes at room temperature. The
efficacy and selectivity of this catalyst are also shown in a novel diversification strategy, affording a cycloadduct library in one step from nine
commercially available components.
New reactions play a uniquely important role in the evolution
of synthesis as they enable new ways to think about bond
construction, often leading to practical, step economical, and
green options for high value target preparation.1 Guided by
this view, we reported in 1995 the first examples3a of a metal-
catalyzed [5 + 2] cycloaddition involving vinylcyclopropanes
(VCPs) and π-systems, a formal homologue of the Diels-
Alder reaction that provides a facile route to seven-membered
rings.2 While we3 and others4 have since reported new
catalysts for the intramolecular process and applications in
synthesis,5 the intermolecular [5 + 2] process,6 which draws
benefit from the abundance of alkyne feedstocks and from
its convergent nature, has thus far been reported only with
[RhCl(CO)2]2. Other catalysts (vide infra) either do not work
or give low yields. This severely limits what can be done in
optimizing efficiency and selectivity with problematic sub-
strates. Moreover, the use of [RhCl(CO)2]2 in [5 + 2]
reactions often requires heating, which in turn promotes
competing cyclotrimerization of alkyne starting materials,
decomposition of the VCP, or formation of undesired
secondary isomerization products. Such transition metal-
catalyzed intermolecular cycloadditions pose particular chemo-
and regioselectivity challenges as well as entropic penalties
not encountered in intramolecular processes, as the latter
benefit from tether-derived alignment and proximity of
reactive functionalities not possible in the former. As evident
from the multitude of catalysts reported for the Diels-Alder
cycloaddition, for example, the introduction of alternative
† Present address: Loker Hydrocarbon Research Institute, University of
Southern California, Los Angeles, CA 90089-1661.
(1) (a) Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard,
R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.; Zhang, L. Pure Appl.
Chem. 2002, 74, 25. (b) Wender, P. A.; Gamber, G. G.; Williams, T. J. In
Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; WILEY-
VCH: Weinheim, Germany, 2005; p 263. (c) Wender, P. A.; Croatt, M. P.;
Witulski, B. Tetrahedron 2006, 62, 7505, and references cited therein. (d)
Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res.
2008, 41, 40. (e) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197.
10.1021/ol100337m  2010 American Chemical Society
Published on Web 03/02/2010

or improved catalysts for a given process allows for its
broader utilization in synthesis.
proved to be vastly superior, providing, after brief hydrolytic
workup, the cycloheptenone 4b in 94% isolated yield
(Scheme 1). The reaction was complete in less than 15 min
Recently, we described a general synthetic method for
accessing bicyclo[5.3.0]decanes in which [RhCl(CO)2]2 (or
[RhCl(cod)]2) and AgSbF6 are used to catalyze in one
synthetic operation both a [5 + 2] cycloaddition and Nazarov
cyclization.7 While in preliminary earlier work we found that
cationic rhodium complexes gave low yields in intermolecu-
lar [5 + 2] cycloadditions of VCPs and alkynes, their
encouraging performance in these serial reactions involving
enynones prompted a more in-depth examination of their
utility as catalysts for intermolecular [5 + 2] reactions. We
report herein a catalyst (1)8 and optimized conditions for
intermolecular [5 + 2] cycloadditions of VCPs with a
structurally and electronically diverse set of alkynes that
provide cycloadducts in excellent yields (>90%) and often
in only minutes at room temperature.
Scheme 1. [5 + 2] Cycloaddition of VCP 2 and Propargyl Ether
-
3b at Room Temperature, Using [(C10H8)Rh(cod)]+ SbF6 (1)
at 23 °C and required only 1 equiv of 2 and 1.1 equiv of 3b.
More thorough investigation of reaction conditions estab-
lished that halogenated solvents (e.g., 1,2-dichloroethane,
dichloromethane, or 2,2,2-trifluoroethanol9) gave the fastest
rates and highest yields, though the cycloaddition is also
reasonably efficient at room temperature in nonhalogenated
ethereal solvents.10
Table 1 summarizes the exceptional efficacy of this catalyst
in cycloadditions with a wide range of alkynes. With just 0.5
mol % of 1 at a substrate concentration of 0.5 M, VCP 2
The reaction of VCP 2 and propargyl ether 3b served as
a starting point for screening the activities of a range
of neutral and cationic rhodium(I) catalysts, including
-
[(C10H8)Rh(cod)]+ SbF6 (1), [RhCl(CO)2]2, [RhCl(cod)]2,
RhCl(CO)(PPh3)2, and RhCl(PPh3)3 (vide infra). Of these, 1
(2) For reviews on metal-mediated synthesis of seven-membered and
other medium-sized rings, see: (a) Yet, L. Chem. ReV. 2000, 100, 2963. (b)
Wender, P. A.; Croatt, M. P.; Deschamps, N. M. In ComprehensiVe
Organometallic Chemistry III; Crabtree, R. H., Mingos, D. M. P., Eds.;
Elsevier: Oxford, UK, 2007; Vol. 10, p 603. (c) Butenscho¨n, H. Angew.
Chem., Int. Ed. 2008, 47, 5287.
(3) (a) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc.
1995, 117, 4720. (b) Wender, P. A.; Sperandio, D. J. Org. Chem. 1998,
63, 4164. (c) Wender, P. A.; Williams, T. J. Angew. Chem., Int. Ed. 2002,
41, 4550. (d) Wender, P. A.; Love, J. A.; Williams, T. J. Synlett 2003,
1295. (e) Wender, P. A.; Haustedt, L. O.; Lim, J.; Love, J. A.; Williams,
T. J.; Yoon, J.-Y. J. Am. Chem. Soc. 2006, 128, 6302. (f) Go´mez, F. J.;
Kamber, N. E.; Deschamps, N. M.; Cole, A. P.; Wender, P. A.; Waymouth,
R. M. Organometallics 2007, 26, 4541.
Table 1. Intermolecular [5 + 2] Cycloadditions Catalyzed by
Complex 1
(4) (a) Gilbertson, S. R.; Hoge, G. S. Tetrahedron Lett. 1998, 39, 2075.
(b) Trost, B. M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379.
(c) Wang, B.; Cao, P.; Zhang, X. Tetrahedron Lett. 2000, 41, 8041. (d)
Trost, B. M.; Shen, H. C.; Horne, D. B.; Toste, F. D.; Steinmetz, B. G.;
Koradin, C. Chem.sEur. J. 2005, 11, 2577. (e) Zuo, G.; Louie, J. J. Am.
Chem. Soc. 2005, 127, 5798. (f) Lee, S. I.; Park, S. Y.; Park, J. H.; Jung,
I. G.; Choi, S. Y.; Chung, Y. K.; Lee, B. Y. J. Org. Chem. 2006, 71, 91.
(g) Saito, A.; Ono, T.; Hanzawa, Y. J. Org. Chem. 2006, 71, 6437. (h)
Fu¨rstner, A.; Majima, K.; Mart´ın, R.; Krause, H.; Kattnig, E.; Goddard,
R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 1992. (i) Shintani, R.;
Nakatsu, H.; Takatsu, K.; Hayashi, T. Chem.sEur. J. 2009, 15, 8692.
(5) (a) Wender, P. A.; Fuji, M.; Husfeld, C. O.; Love, J. A. Org. Lett.
1999, 1, 137. (b) Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323. (c)
Wender, P. A.; Bi, F. C.; Brodney, M. A.; Gosselin, F. Org. Lett. 2001, 3,
2105. (d) Ashfeld, B. L.; Martin, S. F. Tetrahedron 2006, 62, 10497. (e)
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781.
(f) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2008, 130, 16424.
(6) Reactions with alkynes: (a) Wender, P. A.; Rieck, H.; Fuji, M. J. Am.
Chem. Soc. 1998, 120, 10976. (b) Wender, P. A.; Dyckman, A. J.; Husfeld,
C. O.; Scanio, M. J. C. Org. Lett. 2000, 2, 1609. (c) Wender, P. A.; Barzilay,
C. M.; Dyckman, A. J. J. Am. Chem. Soc. 2001, 123, 179. (d) Wender,
P. A.; Gamber, G. G.; Scanio, M. J. C. Angew. Chem., Int. Ed. 2001, 40,
3895. Reactions with allenes: (e) Wegner, H. A.; de Meijere, A.; Wender,
P. A. J. Am. Chem. Soc. 2005, 127, 6530.
(7) Wender, P. A.; Stemmler, R. T.; Sirois, L. E. J. Am. Chem. Soc.
2010, 132, 2532.
(8) For the X-ray structure and use of 1 in intramolecular [5 + 2]
cycloadditions, see ref 3c. For pioneering cycloaddition work with a related
catalyst, see: (a) Paik, S.-J.; Son, S. U.; Chung, Y. K. Org. Lett. 1999, 1,
2045. For representative other uses of 1, see: (b) Evans, P. A.; Baum, E. W.
J. Am. Chem. Soc. 2004, 126, 11150. (c) Barluenga, J.; Vicente, R.; Lo´pez,
´
L. A.; Rubio, E.; Toma´s, M.; Alvarez-Ru´a, C. J. Am. Chem. Soc. 2004,
126, 470. (d) Brummond, K. M.; You, L. Tetrahedron 2005, 61, 6180. (e)
Trost, B. M.; Fandrick, D. R.; Dinh, D. C. J. Am. Chem. Soc. 2005, 127,
14186. (f) Wender, P. A.; Croatt, M. P.; Ku¨hn, B. Organometallics 2009,
28, 5841.
a 1,2-Dichloroethane:2,2,2-trifluoroethanol (90:10, v:v). b Isolated yield.
c 0.2 mol % of catalyst 1. d 60 °C, 0.4 M, DCE:TFE (80:20).
Org. Lett., Vol. 12, No. 7, 2010
1605

engages in fast, room temperature [5 + 2] cycloadditions with
sterically and electronically diverse internal and terminal
alkynes. The majority of these reactions were complete in 15
min or less, with isolated yields of cycloheptenones 4 greater
than 90% in all cases. Only 1 equiv of 2 and 1.1 equiv of alkyne
were used. The ability to conduct these reactions at room
temperature allows one to avoid heating procedures and the loss
of starting materials or products to thermal decomposition
pathways. In these experiments, neither significant alkyne
cyclotrimerization, VCP decomposition, nor cycloadduct isomer-
izations were observed. Ether, silane, sulfonamide, ester, ketone,
and aryl functionalities were all well-tolerated, as was an
unfunctionalized internal alkyne (entry 10). Only 2-butynamide
(3g) required a higher temperature and longer time to reach
full conversion but still gave the [5 + 2] product in excellent
(92%) isolated yield (entry 8). The slower rate for this reaction
is presumably a consequence of lower effective catalyst
concentration due to reversible coordination of rhodium to the
amide functionality.
only a modest decrease in isolated yield (86%, entry 6). A gram-
scale [5 + 2] reaction of VCP 2 and 3h also proceeded smoothly
(entry 7).
1-Siloxy- or 1-alkoxy-VCPs (such as commercially avail-
able compound 2)11 are known to be more reactive than
unsubstituted or 1-alkyl-VCPs in rhodium(I)-catalyzed in-
termolecular [5 + 2] cycloadditions;12 the latter typically
require higher temperature, catalyst loading, or dilution and
often provide lower yields. In contrast, with only 0.5 mol %
of 1, 1-alkyl-VCP 5 reacted with 1,4-dimethoxy-2-butyne
(3j) at room temperature to provide cycloadduct 6 in nearly
quantitative yield (Scheme 2). Full conversion of starting
Scheme 2. Room Temperature Cycloadditions of VCP 5
Reducing the catalyst loading to 0.2 mol % had no impact
on the high isolated yields and led to only moderate increases
in reaction time in some cases (Table 1, entry 2; Table 2, entries
materials could be achieved in 14 h by increasing the catalyst
loading to 2 mol %, providing an excellent (92%) isolated
yield of cycloheptadiene 6.
Table 2. Temperature, Catalyst Loading, and Concentration
Effects on the [5 + 2] Cycloaddition of Vinylcyclopropane 2
Complex 1 is easily prepared from [RhCl(cod)]2 by treatment
with silver salt, filtration, and subsequent introduction of the
naphthalene ligand.3c Complex 1 is also air- and moisture-stable
and retains its significant activity even after long-term storage
(>6 months), adding to its attractiveness as a robust precatalyst
for intermolecular [5 + 2] cycloadditions. Importantly, however,
an active catalytic species can also be formed in situ by
treatment of [RhCl(cod)]2 with AgSbF6 prior to addition of VCP
and alkyne, thereby providing an equally efficient and opera-
tionally convenient [5 + 2] reaction procedure. Reaction of 2
with 3b using this alternative protocol afforded a 93% isolated
yield of 4b in less than 15 min at room temperature (2 mol %
of [Rh], Table 3, entry 2). The active catalyst formed from either
cat. loading concn
t
yieldb
(%) TONc
entry alkyne
(mol %)
(M) (°C)
time
1d
2d
3
3e
3e
3e
3e
3h
3h
3h
0.5
0.5
0.2
0.1
0.2
0.2
0.2
0.5
0.5
0.5
1.0
0.5
1.0
0.5
0
60 min
97
96
97
54
97
86
85
194
192
485
540
485
430
425
-23 7 h
23 15 min
60 48 h
23 75 min
23 75 min
23 120 min
4e
5f
6f
7g
a Solvent for 3e: DCE:TFE (90:10); solvent for 3h: DCE. b Isolated
yield. c Turnover number. d Catalyst solution was cooled to the indicated
temperature prior to addition of VCP 2 and alkyne 3e. e Unreacted VCP 2
was recovered. f 1.0 mmol scale. g 10.0 mmol scale (1.42 g of 2).
Table 3. Comparison of Rhodium(I) Catalysts for the
Intermolecular [5 + 2] Cycloaddition of VCPs and Alkynes
3 and 5). Catalyst loadings of 0.1 mol % or less on small
laboratory scales resulted in incomplete conversion of starting
material; however, at higher concentration and temperature (1.0
M, 60 °C), cycloadduct 4e could be isolated in 54% yield (TON
) 540 at 0.1 mol % catalyst loading, Table 2, entry 4).
While a room temperature process would generally be
preferred, lower temperature cycloadditions can also be effected
with 1. For example, the cycloaddition of VCP 2 and 3-butyn-
2-one (3e) catalyzed by 1 was found to proceed at 0 °C and
even at -23 °C to give 4e in nearly quantitative yields (Table
2, entries 1 and 2). Moreover, in another example of reduced
catalyst loading (0.2 mol %), the cycloaddition of 2 with methyl
2-butynoate (3h) can be performed at 1.0 M concentration with
entry
Rh(I) catalyst
additivea
time
24 hc
yieldb (%)
1
2
3
4
5
6
7
8
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(CO)2]2
[RhCl(CO)2]2
RhCl(CO)(PPh3)2
RhCl(PPh3)3
none
29
93
85
79
45
61
39
5
AgSbF6
AgBF4
AgOTf
none
AgSbF6
AgSbF6
AgSbF6
<15 min
<15 min
<15 min
24 hc
24 hc
24 hc
24 hc
a 1:1 ratio of Ag+ to Cl-. b Isolated yield. c VCP 2 was recovered.
1606
Org. Lett., Vol. 12, No. 7, 2010

protocol significantly outperformed at room temperature all
other common neutral or cationic rhodium(I) catalysts inves-
tigated (Table 3). When forming the active catalyst by using
silver salts with somewhat more coordinating counterions, no
difference in reaction rates and only subtle differences in product
yields were observed (Table 3, entries 3 and 4).13
In summary, the cationic rhodium(I) complex
-
[(C10H8)Rh(cod)]+ SbF6 (1) is a convenient and highly
effective catalyst for the intermolecular [5 + 2] cycloaddition
of 1-alkoxy- or 1-alkyl-VCPs and a wide range of terminal
and internal alkynes, many of which are commercially
available feedstocks. At low catalyst loadings (0.2-0.5 mol
% of [Rh]) and practical reaction concentrations (0.5-1.0
M), highly efficient (>90% isolated yields) [5 + 2] reactions
were achieved, in most cases within minutes at room
temperature. Successful application of 1 to low-temperature
and gram-scale cycloadditions and to small molecule library
generation was also demonstrated. If desired, the active
catalyst for these transformations can be generated in situ
from a commercially available rhodium(I) precatalyst. In-
vestigations of the remarkable reactivity of complex 1 in
[5 + 2] and related cycloadditions are ongoing.
The remarkable activity and mode selectivity of
-
[(C10H8)Rh(cod)]+ SbF6 (1) can also be harnessed for the
rapid generation of [5 + 2] cycloadduct libraries.14 In an
initial demonstration of this diversification concept, VCP 2
was treated with a mixture of eight commercially available
alkynes at room temperature in the presence of 1 mol % of
1 (Figure 1). Within 15 min, all VCP 2 had been consumed.
GC analysis of the unpurified reaction mixture after brief
hydrolytic workup confirmed the corresponding eight cy-
cloheptenones to be the overwhelmingly major products
formed in ca. 70% to >95% yield each (Figure 1, see the SI
for details).
Acknowledgment. This work was funded by the National
Science Foundation (CHE-0450638), the NSF Graduate
Research Fellowship (L.E.S.), and the German Academic
Exchange Service (DAAD, R.T.S.). We thank Sigma-Aldrich
for a generous gift of 1-(2-methoxyethoxy)-1-vinylcyclo-
propane (2).
Supporting Information Available: Complete experi-
mental details and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100337M
(9) For a review on the beneficial effects of fluorinated alcohols as
solvents or co-solvents in metal-catalyzed reactions, see: Shuklov, I. A.;
Dubrovina, N. V.; Bo¨rner, A. Synthesis 2007, 2925.
(10) These include dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran.
For a more comprehensive solvent screen, see the SI.
(11) Available from Sigma-Aldrich (product no. 666246).
(12) Liu, P.; Cheong, P. H.-Y.; Yu, Z.-X.; Wender, P. A.; Houk, K. N.
Angew. Chem., Int. Ed. 2008, 47, 3939, and references cited therein.
(13) The effects of different counterions on reaction rate or product yield
for complexes similar to 1 were also found to be minimal in the case of
intramolecular [5 + 2] reactions, though complex stabilities differ. See ref
3c.
(14) For library synthesis using an intramolecular [5 + 2] cyclization,
see: Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int. Ed.
2006, 45, 3635.
Figure 1. Synthesis and GC analysis of a cycloheptenone library
generated with catalyst 1 (portion of chromatogram of unpurified
cycloadducts). Conditions: [(C10H8)Rh(cod)]+ SbF6- (1 mol % with
respect to VCP 2), DCE:TFE (90:10, 0.2 M), rt, then 1% HCl/
EtOH.
Org. Lett., Vol. 12, No. 7, 2010
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