Rhodium-catalyzed synthesis of eight-membered rings

Article abstract of DOI:10.1021/jo0620462

(Chemical Equation Presented) Experiments to develop a rhodium catalyst for the [4 + 2 + 2] cycloisomerization of dienynes with a second alkyne are described. The generality of the reaction is probed in terms of dienyne structure and alkyne structure. A catalyst system that provides cyclooctatrienes in greater than 70% yield is reported. Several experiments to determine the nature of the catalyst are described.

Full text of DOI:10.1021/jo0620462

Rhodium-Catalyzed Synthesis of Eight-Membered Rings
Brenton DeBoef,† W. Richard Counts,‡ and Scott R. Gilbertson*
Department of Chemistry, Washington UniVersity, One Brookings DriVe, Saint Louis Missouri,
63130-4899, and Chemical Biology Program, Pharmacology and Toxicology, The UniVersity of Texas
Medical Branch, 301 UniVersity BouleVard, GalVeston Texas, 77555-0650
srgilber@utmb.edu
ReceiVed October 3, 2006
Experiments to develop a rhodium catalyst for the [4 + 2 + 2] cycloisomerization of dienynes with a
second alkyne are described. The generality of the reaction is probed in terms of dienyne structure and
alkyne structure. A catalyst system that provides cyclooctatrienes in greater than 70% yield is reported.
Several experiments to determine the nature of the catalyst are described.
Introduction
dienynes.10-12 While functionally analogous to the Diels-Alder
reaction, the rhodium-catalyzed cycloisomerization does not
require the HOMO-LUMO matching necessary in either the
thermal or Lewis acid catalyzed cycloaddition. Inspired by the
Livinghouse work, we reported a cationic rhodium catalyst
system that is highly effective and in many cases provides high
asymmetric selectivity in this reaction (Scheme 1).13,14 During
the work on the asymmetric system, using DuPHOS as the
phosphine ligand on the rhodium, the formation of a product
resulting from the dimerization of the dienyne was observed
(Scheme 1). This paper reports the details of the development
of a catalyst system optimized for dimer formation, the
development of a cross-reaction between a dienyne and another
alkyne, and work to examine the generality of the reaction.
Independent of our work, Evans and co-workers developed a
Over the last 30 years, several workers have achieved
moderate success performing intermolecular metal-catalyzed
[4 + 2] cyclodimerizations.1-9 In 1994, McKinstry and Liv-
inghouse reported the highly successful rhodium-catalyzed
intramolecular [4 + 2] cycloisomerization of trienes and
† University of Rhode Island.
‡ Arkansas State University.
(1) Dieck, H. T.; Diercks, R. Diels-Alder Reactions of Dienes with
Alkynes Catalyzed by Diazadieneiron. Angew. Chem., Int. Ed. Engl. 1983,
22, (10), 778.
(2) Carbonaro, A.; Greco, A.; Dall’Asta, G.; Oligomerization Catalysts.
III. Cyclodimerization of Conjugated Dienes with Acetylenic Hydrocarbons
Catalyzed by Iron(0) Complexes. Synthesis of 1,2-Diphenyl-1,4-cyclohexa-
diene. J. Org. Chem. 1968, 33, (10), 3948.
(3) Carmona, D.; Cativiela, C.; Garc´ıa-Correas, R.; Lahoz, F. J.; Pilar
Lamata, M.; Lo´pez, J. A.; Pilar Lo´pez-Ram de V´ıu, M.; Oro, L. A.; San
Jose´, E.; Viguri, F. Chiral rhodium complexes as catalysts in Diels-alder
reactions. Chem. Commun. 1996, 1247.
(4) Matsuda, I.; Shibata, M.; Sato, S.; Izumi, Y. Cyclo-codimerization
of 1,3-butadiene Derivatives with Non-Activated Terminal Acetylenes
Catalyzed by Cationic Rhodium(I) Complex. Tetrahedron Lett. 1987, 28,
(29), 3361.
(5) Siegal, H.; Hopf, H.; Germer, A.; Binger, P. Die Palladium(0)-
katalysierte Dimerisierung von 1,2,4-Pentatrien (Vinylallen). Chem. Ber.
1978, 111, 3112.
(6) Buchholz, H.; Heimbach, P.; Hey, H. J.; Selbeck, H.; Wiese, W.
Carbon-Carbon Bond Formation with the Aid of Nickel Catalysts. Coord.
Chem. ReV. 1972, 8, 129.
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and Diene Cycloaddition Induced by Transition-Metal Carbonyls. Cy-
clodimerization of 5,6-Dimethylidene-7-oxabicyclo[2.2.1]hept-2-ene Cata-
lyzed by Dodecacarbonyltriosmium. HelV. Chim. Acta 1984, 67, 1638.
(8) Davis, R.; Green, M.; Hughes, R. P. Stepwise Diels-Alder Addition
of Hexafluorobut-2-yne to Co-ordinated 1,3-Dienes. Chem. Commun. 1975,
405.
(9) Genet, J. P.; Ficini, J. Cycloaddition Des Ynamines Avec Le
Butadiene Catalysee Par Le Fer(0): Synthese De Cyclohexadienamines-
1,4 Et De CycloHexenones â, δ Et R, â-insaturees. Tetrahedron Lett. 1979,
(17), 1499.
(10) McKinstry, L.; Livinghouse, T. On the Asymmetric Rh(I) catalyzed
[4+2] Cycloisomerization Reaction. Electronic and Torsionsl Ligand Control
of Absolute Stereoselection. Tetrahedron 1994, 50, (21), 6145.
(11) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. Novel
Cyclization Reactions on Transition-Metal Templates. The Catalysis of
Intramolecular [4 + 2] Cycloadditions by Low Valent Rhodium Complexes.
J. Am. Chem. Soc. 1990, 112, 4965.
(12) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. On the
Counterion Dependence of Rhodium(I)-Catalysed [4+2] Cycloaddition -
A Remarkable Accelerating Effect of the Hexafluoroantimonate Anion.
Synlett 1998, 443.
(13) Gilbertson, S. R.; Hoge, G. S.; Genov, D. Rhodium Catalyzed
Asymmetric [4+2] Cycloisomerization Reactions. J. Org. Chem. 1998, 63,
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10.1021/jo0620462 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/11/2007
J. Org. Chem. 2007, 72, 799-804
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DeBoef et al.
TABLE 1. Array of Catalysts Synthesized
SCHEME 1
catalyst
number
equivalents of
[Rh(NBD)Cl]2
equivalents of
Me-DuPHOS
equivalents of
AgSbF6
cat A
cat B
cat C
cat D
cat E
cat F
cat G
cat H
cat I
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
3
3
3
0
1
2
0
1
2
0
1
2
comparable approach to eight-membered rings using enynes and
butadiene.15-21
Dimer 3, the byproduct of the [4 + 2] cycloisomerization, is
rich in functionality, containing an eight-membered ring with
three double bonds. During the course of our [4 + 2]
cycloisomerization work, this product was observed sporadically.
Because of its interesting structure, an attempt was made to
develop a system that consistently provided this product.
Considerable work, examining different solvents, temperatures,
and reagent ratios, resulted in inconsistent results, however,
ultimately an approach to systematically screen rhodium species
resulted in the discovery of an effective catalyst system for this
transformation.
Results and Discussion
The formulation of the catalyst was arrived at through a
systematic screen of different reagent ratios for the formation
of the catalyst system. Utilizing a method previously employed
by researchers such as Morken and co-workers,22,23 Stambuli
et al.,24 and Reetz and co-workers,25-27 an array of catalysts,
each made with differing ratios of metal ligand and silver salt,
was tested. To avoid removal of minor species that may be
responsible for the desired product, the potential catalysts were
used without purification. Table 1 contains the ratios of the
reagents that were used for catalyst generation and qualitatively
illustrates the results of these catalysts’ reactions with dienyne,
1 (10 mol % catalyst, on the basis of Rh). As can be seen by
the thin-layer chromatography (TLC) in Table 1, we found that
reaction of [Rh(NBD)Cl]2 with one-half of an equivalent, or
less (on the basis of rhodium), of AgSbF6 in the presence of
Me-DuPHOS provided a catalyst system that upon heating to
60 °C with the substrate gave the desired product in good to
excellent yield (Table 1, E and I).
As shown in the TLC in Table 1, catalysts A and D failed to
produce either the [4 + 2] or the [4 + 2 + 2] dimer, while
catalysts B, C, and F exclusively produced the [4 + 2]
cycloadduct. Complexes E and I were the only catalysts that
produced the [4 + 2 + 2] product, 3, in 76% and 23% yield,
respectively. On the basis of this experiment, it was decided to
use [Rh(NBD)Cl]2 with one-half of an equivalent, or less (on
the basis of rhodium), of AgSbF6 in the presence of Me-
DuPHOS as the catalyst system.
With an effective catalyst system, the scope of the reaction
was probed with several substrates. As illustrated in Table 2,
both 3- and 4-atom tethers can be effective, giving either the
[6.3.0] or [6.4.0] ring systems. Tethers containing either oxygen
or nitrogen, as the sulfonamide, were effective. When substrates
where the diene does not have a terminal alkyl group are used,
two regioisomers, resulting from the incorporation of the alkyne
in two orientations, can be obtained (Table 2 entry 2). However,
in the case of entry 4, only one regioisomer was observed.
(15) Evans, P. A.; Lai, K. W.; Sawyer, J. R. Regio- and Enantioselective
Intermolecular Rhodium-Catalyzed [2+2+2] Carbocyclization Reactions
of 1,6-Enynes with Methyl Arylpropiolates. J. Am. Chem. Soc. 2005, 127,
(36), 12466-12467.
(16) Evans, P. A.; Sawyer, J. R.; Lai, K. W.; Huffman, J. C. Intermo-
lecular rhodium-catalyzed [2 + 2 + 2] carbocyclization reactions of 1,6-
enynes with symmetrical and unsymmetrical alkynes. Chem. Commun. 2005,
(31), 3971-3973.
(17) Baik, M.-H.; Baum, E. W.; Burland, M. C.; Evans, P. A. Diaste-
reoselective Intermolecular Rhodium-Catalyzed [4 + 2 + 2] Carbocycliza-
tion Reactions: Computational and Experimental Evidence for the Inter-
mediacy of an Alternative Metallacycle Intermediate. J. Am. Chem. Soc.
2005, 127,(6), 1602-1603.
(18) Evans, P. A.; Baum, E. W.; Fazal, A. N.; Pink, M. Diastereoselective
metal-catalyzed [4 + 2 + 2]-carbocyclization reactions utilizing a rhodium
N-heterocyclic carbene (NHC) complex: the first example of a rhodium
NHC-catalyzed [m + n + o]-carbocyclization. Chem. Commun. 2005, (1),
63-65.
(19) Evans, P. A.; Baum, E. W. Diastereoselective Intramolecular
Temporary Silicon-Tethered Rhodium-Catalyzed [4+2+2] Cycloisomer-
ization Reactions: Regiospecific Incorporation of Substituted 1,3-Buta-
dienes. J. Am. Chem. Soc. 2004, 126, (36), 11150-11151.
(20) Evans, P. A.; Robinson, J. E.; Baum, E. W.; Fazal, A. N.
Intermolecular Transition Metal-Catalyzed [4 + 2 + 2] Cycloaddition
Reactions: A New Approach to the Construction of Eight-Membered Rings.
J. Am. Chem. Soc. 2003, 125, (47), 14648.
(21) Evans, P. A.; Robinson, J. E.; Baum, E. W.; Fazal, A. N.
Intermolecular Transition Metal-Catalyzed [4 + 2 + 2] Cycloaddition
Reactions: A New Approach to the Construction of Eight-Membered Rings.
J. Am. Chem. Soc. 2002, 124, (30), 8782-8783.
(22) Lavastre, O.; Morken, J. P. Discovery of novel catalysts for allylic
alkylation with a visual colorimetric assay. Angew. Chem., Int. Ed. 1999,
38, (21), 3163-3165.
(24) Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F.
Screening of Homogeneous Catalysts by Fluorescence Resonance Energy
Transfer. Identification of Catalysts for Room-Temperature Heck Reactions.
J. Am. Chem. Soc. 2001, 123, (11), 2677-2678.
(25) Reetz, M. T. Directed evolution of selective enzymes and hybrid
catalysts. Tetrahedron 2002, 58, (32), 6595-6602.
(26) Zha, D.; Wilensek, S.; Hermes, M.; Jaeger, K.-E.; Reetz, M. T.
Complete reversal of enantioselectivity of an enzyme-catalyzed reaction
by directed evolution. Chem. Commun. 2001, (24), 2664-2665.
(27) Reetz, M. T.; Wilensek, S.; Zha, D.; Jaeger, K.-E. Directed evolution
of an enantioselective enzyme through combinatorial multiple-cassette
mutagenesis. Angew. Chem., Int. Ed. 2001, 40, (19), 3589-3591.
(23) Taylor, S. J.; Morken, J. P. Catalytic Diastereoselective Reductive
Aldol Reaction: Optimization of Interdependent Reaction Variables by
Arrayed Catalyst Evaluation. J. Am. Chem. Soc. 1999, 121, (51), 12202-
12203.
800 J. Org. Chem., Vol. 72, No. 3, 2007

Rhodium-Catalyzed Synthesis of Eight-Membered Rings
TABLE 2. Dimer Formationa
TABLE 3. [4 + 2 + 2] Cyclization with Incorporation of a Second
Alkyne
a The catalyst was generated from a ratio of 1:2:1 of [Rh(NBD)Cl]2:
DuPHOS:AgSbF6 and was run in CH2Cl2:EtOAc (6:1). Reaction was run
at room temperature approximately 12 h. b Reaction was run at 60 °C,
approximately 12 h. c The products were isolated as single diastereomers.
d Stereochemistry assigned by analogy to earlier examples.
In the case where the diene section of the dienyne is
substituted with a methyl group, the yields vary from 0 to 60%
(entries 5-8). When either end of the diene is disubstituted
(entries 5 and 8), only starting material is recovered from the
reaction. Neither the [4 + 2 + 2] nor the [4 + 2] reactions take
place. In the case where the diene is substituted in the 3 position,
a 10% yield of the [4 + 2 + 2] product is obtained with 23%
of the [4 + 2] product also isolated. The highest yield (61%)
was obtained when the methyl group is in the 2-position of the
diene (entry 7). While on the basis of steric arguments it is easy
to rationalize why the substrates that are disubstituted on the
ends (11 and 17) do not react, it is not so clear why 13 with the
internal methyl does not participate well in the [4 + 2 + 2]
reaction. One reason for the low yield with substrate 13 may
be the steric interaction between the methyl group and the
methylene next to the oxygen tether. Steric crowding between
the methyl and the CH2 may prevent the planar geometry
necessary for closure.
a The catalyst was generated from a ratio of 1:2:1 of [Rh(NBD)Cl]2:
DuPHOS:AgSbF6 and was run in CH2Cl2:EtOAc (6:1). Reaction was run
at room temperature approximately 12 h. b The products were isolated as
single diastereomers. c Reactions where run following bubbling acetylene
gas through the solvent while cooling to 0 °C. d The products where isolated
as single diastereomers and the stereochemistry was assigned by analogy
to earlier examples.
a second alkyne, the desired cross-coupled-cyclized product is
obtained (Table 3).
In addition to ether and sulfonamide tethers, carbon tethers,
in the form of an aromatic ring (entry 9), were also found to be
useful. When the nitrogen in the tether is protected as its
acetamide, no product was observed. Many different alkynes
are accepted. While simple terminal alkyl acetylenes will provide
the desired product (Table 3 entry 4), there appears to be a
While dimer formation was used as a model to optimize the
reaction conditions, it was desirable to insert a different alkyne
during the reaction. Table 3 illustrates that such a cycloisomer-
ization cross-coupling reaction is indeed possible. When the
cycloisomerization reaction is run in the presence of 5 equiv of
J. Org. Chem, Vol. 72, No. 3, 2007 801

DeBoef et al.
(NBD)Cl]2 with 1 equiv of AgSbF6, on the basis of rhodium,
in acetone, which is then added to the appropriate phosphine.
This procedure provides a yellow homogeneous solution that
is then treated with H2 or is used as is to catalyze the desired
reaction. As stated above, in the system reported here, the
catalyst is generated by treatment of a solution of [Rh(NBD)-
Cl]2 and Me-DuPHOS with one-half of an equivalent or less of
AgSbF6 in tetrahydrofuran (THF). Following exchange of the
solvent, the catalyst is used after treatment with H2 gas.
Approximately 1 h into the reaction, a dark brown precipitate
forms on the walls of the reaction vessel.
FIGURE 1. [4 + 2 + 2] Cocyclizations with various amounts of the
auxiliary alkyne.
Several experiments were performed to identify the active
catalyst precursor that was responsible for producing the dimer
(3). Attempts were made to purify catalysts E and I (Table 1)
by flash chromatography. Four fractions were isolated, but upon
treatment of each of these with dienyne 1 none of them produced
the desired product, although one fraction did produce the
[4 + 2] product.
Analysis of Table 1 reveals that the most active catalyst (E)
contains one bidentate ligand for each atom of rhodium but only
one-half of an equivalent of AgSbF6 is present. To see if this
exact ratio was necessary, the amount of AgSbF6 was decreased
to 25% and 10% of the molar rhodium content. The [4 + 2 +
2] reaction proceeded smoothly with the 25% silver, but only
starting material was isolated in the example with 10% AgSbF6.
Since insoluble material is formed during the reaction sequence,
two experiments were attempted in which [Rh(NBD)Cl]2, in
the absence of phosphine, was mixed with 1 and 2 equiv (one-
half and 1 equiv on the basis of rhodium) of AgSbF6,
respectively. Each of these mixtures was subjected to the
reaction conditions and in both cases, only the [4 + 2]
cycloadduct (2) was observed.
preference for propargyl ethers, with propargylbenzyl ether
generally giving the highest yields. Toluene sulfonamide
protected propargyl amine also provided the desired product
(Table 3 entry 7). Reaction with propargyl alcohol did not
proceed and attempted reaction with 3-hexyne or phenyl
acetylene gave only product from dimerization of the dienyne.
The substrates that possess methyl substituents on the diene
provided the same reactivity profile in the cross-coupling
cyclization as with dimer formation with only the dienyne
possessing a methyl group in the 2-position of the diene
providing the desired product in acceptable yield (64%,
entry 12).
In addition to proceeding with terminal alkynes, the reaction
runs well with acetylene. The reaction of dienynes 1, 13, and
15 proceeds to provide the expected product in greater than 60%
yield. The reaction is run by simply bubbling acetylene into
the reaction solution prior to sealing the Schlenk tube and
heating.
The stereochemical control in the reaction system is interest-
ing. In all the cases where the diene has a terminal methyl group,
only one diastereomer of the product has been observed. In our
work with asymmetric [4 + 2] cycloisomerizations, we have
found that Me-DuPHOS is effective in transferring its chirality
to the products of simple dieneynes.13,14 This is not the case
with the catalyst system developed here. The highest selectivity
observed in these reactions was in Table 3 entry 3 (41% ee).
A study was performed in which the amount of the auxiliary
alkyne was varied to determine the dependence of the quantity
of the alkyne on the ratio of dimer to cross-coupling products.
As can be seen in Figure 1, the ratio of 20 to 3 consistently
increases as the ratio of benzyl propargyl ether to dienyne
increases. Five equivalents of this terminal alkyne produced a
5.4:1 mixture of the two products. For practical reasons, the
reaction was not examined with more than 5 equiv of the alkyne.
We have discussed earlier that propargyl ethers appear to be
optimal substrates for the incorporation of an alkyne into the
reaction. In the study shown in Figure 1, the dienyne 1 and the
auxiliary alkyne 19 are both propargyl ethers, and it may be
difficult for the catalyst to discriminate between them. Using
less similar molecules, that is, a tether that is not a propargyl
ether, should diminish the competition between the two
substrates and could enhance the reaction’s preference for the
cocyclized product. Despite the similarity between the dienyne
and alkyne, reasonable yields of the [4 + 2 + 2] type product
are obtained using only 5 equiv of alkyne. In cases where the
alkyne is valuable, its quantity can be reduced to 3 equiv while
maintaining a ratio of products of 3:1.
When forming the [4 + 2 + 2] catalyst having the Rh/
DuPHOS/SbF6 ratio of 2:2:1 (E), several interesting observations
can be made. The initial solution of [Rh(NBD)Cl]2 in THF is
orange. Once this solution is mixed with a solution of Me-
DuPHOS in THF, an immediate color change from orange to
red is observed. After stirring for 15 min, this red solution is
mixed with a solution of AgSbF6 (one-half equiv) in THF. After
a few minutes, a dark-colored precipitate begins to form. This
is in contrast to the white precipitate of AgCl that forms in the
[4 + 2] catalyst preparations (1:1:1 stoichiometry). This
precipitate is filtered after 15 min using a syringe filter, and
the mother liquor is evaporated to dryness. The resulting orange
solid is used without further purification. While the reaction
mixture starts out homogeneous, during the course of the [4 +
2 + 2] cyclizations, it becomes heterogeneous. It is possible
that the [4 + 2 + 2] reaction is catalyzed by a heterogeneous
rhodium species and not by the initially formed solution.
The 31P-NMR spectrum of a solution of the “catalyst” shows
that the [4 + 2 + 2] catalyst (E) contains at least three rhodium-
phosphorus species (31P-NMR 120 MHz, CDCl3 δ ) 100, 79.2,
78.5). Generally, the ratios of the three species differ from batch
to batch of the catalyst. Despite this variation in the ratio of
complexes, each batch is a competent catalyst for the desired
[4 + 2 + 2] cycloaddition reaction. Consequently, it is not clear
which, if any, of the species observed by 31P NMR is responsible
for the [4 + 2 + 2] product.
An experiment was designed to determine whether the
precipitate was essential for the reaction to proceed. A [4 + 2
+ 2] reaction was set up using the ether-linked substrate, 1
(Scheme 2). The reaction proceeded to completion with the
At the present time, we do not know the exact nature of the
catalyst system. In our work on the rhodium-catalyzed [4 + 2]
reaction, we have generated the catalyst by treatment of [Rh-
802 J. Org. Chem., Vol. 72, No. 3, 2007

Rhodium-Catalyzed Synthesis of Eight-Membered Rings
SCHEME 2. Heterogeneous vs Homogeneous Catalysis
dark and cloudy, after which 0.5 mL of EtOAc was added followed
by sparging with N2 for 3 min. The dienyne (0.38 mmol) was then
added along with 1 mL of CH2Cl2. The reaction was freeze-pump-
thawed three times, was back-filled with N2, and was stirred
overnight at room temp (60 °C for the tosyl amide dienynes). Flash
chromatography with 5% EtOAc in hexanes (10% for the tosyl
amides) yields the pure product.
reaction mixture appearing dark and heterogeneous. The reaction
mixture was then split in two. Half of the reaction mixture was
filtered through a syringe filter into a second reaction containing
the tosylamide-linked substrate, 7. The other half of the
heterogeneous reaction was mixed with 7 without filtration. The
filtered reaction mixture appeared orange and homogeneous,
while the unfiltered reaction mixture was heterogeneous and
gray/brown colored. Both the filtered and unfiltered versions
of the catalyst provided the [4 + 2 + 2] product. A 40% yield
of the tosylamide [4 + 2 + 2] dimer (8) was obtained from the
filtered reaction while a 35% yield was obtained from the control
reaction (Scheme 2). This experiment does not conclusively rule
out the involvement of small-suspended colloidal particles, but
it appears that the precipitate is not likely to be involved in
catalyzing the [4 + 2 + 2] reaction.
The [4 + 2 + 2] Dimerization To Form 8-{[(2E,4E)-Hexa-
2,4-dienyloxy]methyl}-6-methyl-1,3,3a,6-tetrahydrocycloocta[c]-
furan (3). To a clean, dry 15-mL Schlenk tube, 30 mg of catalyst
was added as a solution in 2 mL of CH2Cl2. H2 was gently bubbled
through the orange/red solution for 3 min causing it to become
dark and cloudy. One-half of a milliliter of EtOAc was added, and
N2 was gently bubbled through the solution for 3 more minutes. 1
(52 mg, 0.38 mmol) was then added along with 1 mL of CH2Cl2.
The reaction was freeze-pump-thawed three times, was back-
filled with N2, and was stirred overnight at room temp (60 °C for
the tosyl amide dienynes). Flash chromatography with 5% EtOAc
in hexanes yielded 40 mg (78%) of 3. 1H-NMR (300 MHz, CDCl3)
δ 6.19-5.98 (m, 2H), 5.73-5.51 (m, 4H), 5.40 (d, J ) 6.6 Hz,
1H), 5.03 (dd, J ) 10.0, 5.9 Hz, 1H), 4.42 (d, J ) 13.7 Hz, 1H),
4.30 (d, J ) 13.7 Hz, 1H), 4.20-4.07 (m, 2H), 3.90 (d, J ) 6.1
Hz, 2H), 3.85-3.73 (m, 3H), 1.07 (d, J ) 6.7 Hz, 3H); 13C-NMR
(75 MHz, CDCl3) δ 149.1, 136.9, 136.8, 133.3, 130.9, 130.8, 129.9,
126.7, 120.8, 117.1, 76.5, 75.2, 74.0, 70.0, 42.4, 32.4, 20.2, 18.1;
IR (thin film) 2852.6, 2868.0, 2914.3,2929.7, 2959.6, 2998.2,
3015.5, 2338.6, 2361.7, 1362.6, 1374.2, 1435.9, 1457.1, 1652.9,
1662.5, 1669.3, 1675.1, 1684.7, 1690.5, 1695.3, 1700.2, 1717.5,
1733.9, 668.3, 937.3, 990.3, 990.4, 1054.0, 1073.3, 110.9, 1139.9
cm-1; MS-EI m/z (% relative intensity) 272 (M+, 4), 174.1 (30),
159.1 (8), 145.1 (21), 133.1 (29), 105.1 (55), 91.7 (57), 81.1 (100),
65.1 (17), 53.1 (28), MS-HREI calculated for C18H24O2 (M+) m/e
272.1776, measured m/e 272.1775.
Conclusions
The cocyclization reaction, using 3-5 equiv of an auxiliary
terminal alkyne, proved to be quite general in that a variety of
both dienynes and terminal alkynes were readily cocyclized.
The system does not tolerate disubstitution at the ends of the
diene or internal alkynes, but a variety of linking groups appear
to be tolerated, so long as they are sufficiently unreactive. While
work to determine the nature of the catalyst was not successful
in determining the structure of the catalyst or the precatalyst,
the system has been sufficiently developed so that it can
consistently be generated and used. Work is presently being
done to utilize this reaction in the total synthesis of several
natural products.
General Procedure for the [4 + 2 + 2] Cocyclization of a
Dienyne and Terminal Alkyne. To a clean, dry 15-mL Schlenk
tube, 30 mg of catalyst was added as a solution in 2 mL of CH2-
Cl2. H2 was gently bubbled through the orange/red solution for 3
min causing it to become dark and cloudy. One-half of a milliliter
of EtOAc was added, followed by sparging with N2 for 3 min. The
terminal alkyne (1.9 mmol) was added along with 0.5 mL of CH2-
Cl2, and the reaction was stirred to ensure homogeneity. Finally,
the dienyne (0.38 mmol) was added along with 0.5 mL of CH2Cl2.
The reaction was freeze-pump-thawed three times, was back-
filled with N2, and was stirred overnight in a 60 °C oil bath. Flash
chromatography with 5% or 10% EtOAc in hexanes provided the
pure product.
8-[(Benzyloxy)methyl]-6-methyl-1,3,3a,6-tetrahydrocycloocta-
[c]furan (20). To a clean, dry 15-mL Schlenk tube, 30 mg of
catalyst was added as a solution in 1 mL of CH2Cl2. H2 was gently
bubbled through the orange/red solution for 3 min causing it to
become dark and cloudy. One-half of a milliliter of EtOAc was
added, and N2 was gently bubbled through the solution for 3 more
minutes. Benzyl propargyl ether (278 mg, 1.9 mmol) was added
Experimental Section
Representative Procedure for the Preparation of Catalyst.
To a vial containing [Rh(NBD)Cl]2 (75 mg, 0.16 mmol), 2 mL of
THF is added. After stirring for 15 min, this orange solution is
quickly transferred via cannula to a vial containing a solution of
(S,S)-Me-DuPHOS (98 mg, 0.32 mmol) in 2 mL of THF. After
stirring for 15 min, this red solution is transferred via cannula to a
vial containing a solution of AgSbF6 (56 mg, 0.16 mmol) in 2 mL
of THF. After 15 min, this dark suspension is transferred to a tared
vial using a syringe fitted with a filter. The cherry red filtrate is
concentrated in vacuo and is kept under vacuum (<1 mmHg)
overnight to remove all solvent. Two hundred eleven milligrams
of orange/red solid was collected. This catalyst can be stored under
nitrogen at 0 °C for a short period of time.
General Procedure for the [4 + 2 + 2] Dimerization of a
Dienyne. To a clean, dry 15-mL Schlenk tube, 30 mg of catalyst
was added as a solution in 2 mL of CH2Cl2. H2 was gently bubbled
through the orange/red solution for 3 min causing it to become
J. Org. Chem, Vol. 72, No. 3, 2007 803

DeBoef et al.
with 1 mL of CH2Cl2. 1 (47 mg, 0.38 mmol) was then added along
with 1 mL of CH2Cl2. The reaction was freeze-pump-thawed three
times, was back-filled with N2, and was stirred overnight 60 °C.
Flash chromatography with 5% EtOAc in hexanes yielded 76.3 mg
SbF6 (60 mg) was added as a solution in CH2Cl2 (4 mL). The
solution was stirred at room temperature while ethyl acetate (1 mL)
was added via syringe. (2E,4E)-1-(Prop-2-ynyloxy)-hexa-2,4-diene
(1) (51.7 mg, 0.38 mmol) was added as a solution in CH2Cl2
(2 mL), and the tube was sealed. The tube was then put through a
freeze-pump-thaw cycle three times and was placed in an ice
bath. Acetylene was bubbled through the solution for 5 min and
the tube was once again sealed and stirred overnight in a 60 °C oil
bath. Upon completion, the reaction mixture was concentrated and
flash chromatography (10% ethyl acetate in hexanes) afforded 70.5
mg (62% yield) of 6-methyl-1,3,3a,6-tetrahydrocycloocta[c]furan
1
(73%) of 20. H-NMR (300 MHz, CDCl3) δ 7.38-7.26 (m, 5H),
5.79 (dd, J ) 2.5 Hz, 1H), 5.60 (ddd, J ) 9.5, 9.5, 2.2, 1H), 5.44
(d, J ) 6.6 Hz, 1H), 5.07 (ddd, J ) 9.9, 5.5, 1.1 Hz, 1H), 4.47 (m,
3H), 4.31 (d, J ) 13.5 Hz, 1H), 4.21 (t, J ) 7.7 Hz, 1H), 4.17-
4.11 (m, 1H), 3.86 (s, 2H), 3.82-3.80 (m, 1H), 3.66 (t, J ) 7.7
Hz, 1H), 1.11 (d, J ) 6.9 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ
149.2, 138.2, 137.1, 136.9, 130.7, 128.3, 127.8, 127.5, 120.7, 117.1,
76.6, 75.2, 74.0, 71.4, 42.4, 32.4, 20.2; IR (thin film) 3305.8, 3065.7,
3030.7, 2939.6, 2856.1, 2247.2, 1952.3, 1731.7, 1640.1, 1496.3,
1454.0, 1357.7, 1357.7, 1311.7, 1249.4, 1206.2, 1161.2, 1069.0,
1
as a yellow liquid. H NMR (300 MHz, CDCl3) δ 5.67 (dd, J )
7.7, 2.2 Hz, 1H), δ 5.50 (d, J ) 13.4 Hz, 1H), δ 5.47 (d, J ) 10.1
Hz, 1H), δ 5.32 (dd, J ) 11.8 Hz, 5.7 Hz, 1H), δ 5.05 (dd, J )
9.9, 6.3 Hz, 1H), δ 4.39 (d, J ) 13.4 Hz, 1H), δ 4.26 (d, J ) 14.0
Hz, 1H), δ 4.23-4.16 (m, 2H), δ 3.83-3.76 (m, 1H), δ 3.69-
3.61 (m, 1H), δ 1.10 (d, J ) 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 149.5, 139.1, 135.3, 122.4, 120.7, 115.5, 75.2, 73.8, 41.9,
32.3, 20.4. MS-HRES calculated for C11H14O (M+Na) m/e 185.0942,
measured m/e 185.0945.
1028.0, 924.6, 909.1, 845.7, 733.1, 698.2, 605.6, 542.2, 464.2 cm-1
;
MS-HREI calcd for C18H20O2Li (MLi+) m/e 275.1623, measured
m/e 275.1620.
General Procedure for the [4 + 2 + 2] Cocyclization of a
Dienyne and Acetylene. To a clean, dry 15-mL Schlenk tube
equipped with a stir bar, Rh/DuPHOS/SbF6 (30 mg) was added as
a solution in CH2Cl2 (2 mL). The solution was stirred at room
temperature while ethyl acetate (0.5 mL) was added via syringe.
The dienyne (0.38 mmol) was added as a solution in CH2Cl2
(1 mL), and the tube was sealed. The tube was then put through a
freeze-pump-thaw cycle three times and was placed in an ice
bath. Acetylene was then bubbled through the solution for 5 min
and the tube was once again sealed and stirred overnight in a 60
°C oil bath. The reaction mixture was then concentrated and flash
chromatography (10% ethyl acetate in hexanes) afforded the pure
product.
Acknowledgment. This work was supported by NSF CHE-
0412927. We also acknowledge the support of the Robert A.
Welch Foundation.
Supporting Information Available: Complete experimental
details including procedures for the preparation of the dienyne
substrates, compound characterization, and NMR spectra are
available. This material is available free of charge via the Internet
at http://pubs.acs.org.
6-Methyl-1,3,3a,6-tetrahydrocycloocta[c]furan (43). To a clean,
dry 15-mL Schlenk tube equipped with a stir bar, Rh/DuPHOS/
JO0620462
804 J. Org. Chem., Vol. 72, No. 3, 2007