Consecutive Rh(I)-catalyzed Alder-ene/Diels-Alder/Diels-Alder reaction sequence affording rapid entry to polycyclic compounds

Article abstract of DOI:10.1016/j.tet.2005.03.141

Conversion of acyclic allenynes to polycyclic compounds using consecutive transition metal catalyzed carbon-carbon bond forming reactions in a single chemical operation is described. Reaction of an allenyne with a Rh(I) catalyst affords a cross-conjugated

Full text of DOI:10.1016/j.tet.2005.03.141

Tetrahedron 61 (2005) 6180–6185
Consecutive Rh(I)-catalyzed Alder-ene/Diels–Alder/Diels–Alder
reaction sequence affording rapid entry to polycyclic compounds
*
Kay M. Brummond and Lingfeng You
Department of Chemistry, University of Pittsburgh, PA 15260, USA
Received 6 December 2004; revised 31 January 2005; accepted 4 March 2005
Available online 13 May 2005
Abstract—Conversion of acyclic allenynes to polycyclic compounds using consecutive transition metal catalyzed carbon–carbon bond
forming reactions in a single chemical operation is described. Reaction of an allenyne with a Rh(I) catalyst affords a cross-conjugated triene
via a formal Alder-ene reaction. The triene then participates in a Rh(I)-catalyzed intramolecular [4C2] cycloaddition reaction to generate a
new conjugated diene. An external dienophile is added to this diene which then undergoes a second [4C2] cycloaddition reaction to afford a
complex polycyclic ring system. This reaction sequence demonstrates the synthetic potential of allenynes and cross conjugated trienes and
highlights the rapid increases in molecular complexity that are possible by one-pot sequential transition metal catalyzed carbon–carbon bond
forming reactions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
While major advances in transition metals catalyzed
reactions have been made, it remains a continuing challenge
to organic chemists to efficiently produce structures of high
molecular complexity from readily available starting
materials. Clearly, one way this goal has been achieved is
(1)
Based upon the synthetic potential of tandem Diels–Alder
reactions alone, it would seem that the cross-conjugated
triene moiety would be ubiquitous in organic synthesis.
In fact, synthetic access and utilization of cross-conjugated
trienes has been described (vide infra), but in contrast to its
obvious synthetic potential, its exploitation has been
limited. This appears to be mostly due to the difficulty in
synthesizing this moiety. In a previous study, Tsuge
prepared an acyclic triene via a condensation of 2,4-
pentanedione and benzaldehyde to afford 3-benzylidene-
2,4-pentadione, which upon formation of the bis-silylenol
ether affords the cross-conjugated triene 1.3 Tsuge has
reacted this triene with a variety of cyclic-, acyclic-, and
heterodienophiles to give the corresponding cycloadducts
(Eq. 2).4 More recently, Fallis has effected the condensation
of pentadienyl anion with an aldehyde using indium
(Eq. 3).5 Elimination of the resulting alcohol gives the
cross-conjugated triene that can be trapped with a variety of
dienophiles to afford the tetracyclic compounds such as 2.
Schreiber has recognized the advantages of Fallis-type
trienes and has utilized them in the preparation of
structurally unique scaffolds.6
by combining two or more reactions in a single synthetic
operation.1 The inherent success of tandem or consecutive
reactions is dependent upon the substrate structure and the
potential for intermediates to participate in subsequent
reactions. Recently, it was discovered in our group that
allenynes undergo formal Rh(I)-catalyzed Alder-ene reac-
tions to provide cross-conjugated trienes.2 The scope of this
reaction is currently being examined and a variety of
substructures have been obtained in high yields with high
E/Z selectivity depending upon the catalyst and substrate.
Cross-conjugated trienes represent interesting building
blocks capable of undergoing a variety of reactions
subsequent to their formation. For instance, it has previously
been demonstrated that cross-conjugated trienes can
participate in tandem Diels–Alder reactions as shown in
Eq. 1. The triene reacts with a dienophile to give a
vinylcyclohexene that can react with another dienophile to
give a mono-unsaturated decalin ring system.
Keywords: Rh(I) allenic Alder ene; Diels–Alder reaction; Consecutive
transition metal catalyzed reactions; Allenynes; Polycycles; Cross-
conjugated trienes.
*
Corresponding author; e-mail: kbrummon@pitt.edu
There can be regioselectivity issues associated with
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.141

K. M. Brummond, L. You / Tetrahedron 61 (2005) 6180–6185
6181
unsymmetrical acyclic trienes and mixtures of products are
possible if one diene does not react selectively. Spino has
resolved this issue, albeit using a dienal, by fixing one diene
in a transoid configuration that cannot participate in the
Diels–Alder reaction (Eq. 4).7 The inverse demand
ytterbium-catalyzed intermolecular hetero-Diels–Alder
cycloaddition between 3 and ethyl vinyl ether affords the
intermolecular hetero-Diels–Alder adduct that then partici-
pates in an endo-selective intramolecular Diels–Alder
cycloaddition to give 4.
given that there are two dienes with which the cycloaddition
reaction can occur.
2. Results and discussion
In our preliminary communication on the rhodium(I)
catalyzed allenic Alder-ene reaction, we reported the
transformation of alkynyl allene 6 to triene 7 in high yield
(Scheme 1).2 Alkynyl allene 6 is easily prepared from
readily available starting materials in three steps involving:
(1) condensation of hexynoic acid and 3-butynol-2-ol
(DCC/DMAP) to afford ester 5; (2) treating ester 5 with
triisopropyl silyl triflate and triethylamine to afford an
allenic silyl ester via an Ireland-Claisen rearrangement;9
and (3) reduction of the silyl ester with LiAlH4 to afford the
alkynyl allene 6. Conversion of the alkynyl allene 6 to triene
7, catalyzed by rhodium biscarbonylchloride dimer
[Rh(CO)2Cl]2, occurred at room temperature in 80% yield.
(2)
(3)
The reactions in Scheme 1 also showcase the functional
group compatibility of the Rh(I) catalyst, which in this
example tolerates both the hydroxymethyl group and the
cross conjugated triene.10 The hydroxymethyl group also
serves as an ideal attachment point for a tethered-
dienophile. In addition to the ease of synthesis and mild
conditions, the triene generated in our laboratory has one of
the diene moieties locked in the s-trans configuration which
ensures that only one of the dienes participates in the initial
cycloaddition reaction. More importantly, we believed the
Rh(I) catalyst used to generate the triene could potentially
catalyze subsequent cycloaddition reactions in a one-pot
procedure.11
(4)
Initially, we opted to investigate [4C2] cycloaddition
reactions on isolated trienes. This strategy was adopted
due to the ease in which tethered dienophiles can be
introduced in the allenic Alder-ene precursor and the ample
precedent for effecting these formal cycloaddition reactions
using Rh(I) catalysts (vide infra). Thus, the next step in
our investigation involved determining the functional
group compatibility of various tethered-dienophiles to
the Alder-ene reaction conditions, since the dienophiles
Thus, the potential to rapidly increase molecular complexity
by using cross-conjugated trienes has not escaped attention
of synthetic chemists. Moreover, limited access to this
moiety is certainly not a result of lack of interest. Instead,
the limited access appears to be due to: (1) the requirement
of very specific substrates to effect the formation of
the triene;8 (2) the low stability of the trienes to the reaction
conditions used to generate them; and (3) in the case of
acyclic cross-conjugated trienes, the lack of regioselectivity
Scheme 1. Rh(I)-catalyzed Allenic Alder-ene reaction.
Scheme 2. Attaching dienophiles to the appending hydroxymethyl group (see text).

6182
K. M. Brummond, L. You / Tetrahedron 61 (2005) 6180–6185
themselves could potentially react under the Alder-ene
reaction conditions.
silyl ether 13. Finally, addition of the sodium anion of
dimethylpropargyl malonate to the iodide prepared from 6
gave 43% yield of 14. We were poised to examine the
allenic Alder-ene reaction of substrates 8–14.
A series of Alder-ene precursors were prepared as follows
(Scheme 2). Propargyl tosylamide 8 was prepared in 91%
yield by reaction of the hydroxymethyl group of 6 with
propargyl tosylamide, diisopropylazodicarboxylate and
triphenylphosphine (Scheme 2). Transformation of 6 to
the silicon-tethered allenediyne 9 involved a four-step
protocol, where the hydroxyl group was converted to an
iodide in 87% yield via initial formation of the mesylate
(MsCl, NEt3) followed by the addition of NaI. Metal–
halogen exchange using n-BuLi affords the corresponding
alkyl lithium species that was trapped by the addition of
chlorodiphenylethynylsilane to give compound 9 in 68%
yield. Acryloyl chloride and triethylamine were added to
compound 6 affording a 76% yield of the acyclic ester 10.
Deprotonation of 6 with sodium hydride and the addition of
allyl bromide and propargyl bromide afforded ethers 11 and
12, respectively, each in 96% yield. Exposure of 6 to
triethylamine and diphenylchlorosilane gave a 68% yield of
Each of the alkynyl allenes was subjected to the standard
allenic Alder-ene conditions, rhodium biscarbonyl chloride
dimer in dichloroethane at rt.2 The results from these studies
are shown in Table 1. Conversion of the propargyl
tosylamide 8 and alkynyl silanes 9 and 13 to the
corresponding trienes was extremely rapid taking place in
less than 20 min (entries 1, 2, and 6 Table 2). Triene
formation in the presence of the acrylate ester 10 (entry 3),
allyl ether 11 (entry 4), propargyl ether 12 (entry 5) and
propargyl malonate 14 (entry 7) tethers was slower, but the
yields remained high. Alternative rhodium(I) catalysts for
effecting triene formation were briefly examined. For
example, alkynyl allene 12 was reacted with 5 mol% of
Wilkinson’s catalyst [chlorotris(triphenylphosphine) rho-
dium(I)] in trifluoroethanol at 80 8C for 12 h to afford triene
19 in 48% yield. Moreover, alkynyl allene 12 was subjected
to rhodium cyclooctadiene chloride dimer and silver
hexafluoroantimonate to give 68% of compound 19 in
15 min. The results obtained when using these two
alternative catalysts were inferior to rhodium biscarbonyl
chloride dimer. Unfortunately, a spontaneous intra-
molecular [4C2] cycloaddition was not observed under
any of these reaction conditions.
Table 1. Allenic Alder ene reaction
Entry
Allenyne
Triene
Time
Yield
93%
1
8
10 min
15
16
We next turned our attention to effecting the intramolecular
Diels–Alder reaction of isolated trienes 15–21. Initial
investigations involved the [4C2] cycloaddition reaction
of the acrylic ester 17. Treatment of compound 17 with
dichloromethylalane resulted in the formation of the diene
23a in 80% yield (entry 1, Table 2), which presumably
results from the isomerization of the initial cycloadduct 22
(Eq. 5). Unfortunately, all attempts to convert compound 17
to the cycloadduct 22 using other Lewis acids were
unsuccessful [BF3$OEt2, AlCl3, EtAlCl2, Sc(OTf)3,
Yb(OTf)3, SnCl4 all gave either decomposition or recovery
of the starting material]. Heating ester 17 in DCE to 140 8C
in a sealed tube for 24 h gave the endoadduct 22 in 47%
yield. Heating 17 at 160 8C in DMSO gave a mixture of 23a
and 23b in a combined yield of 42%.
2
3
9
10 min
79%a
10
2 h
78%
17
18
19
4
5
11
12
2 h
1.5
83%
86%
(5)
6
7
13
14
20 min
85%
79%
Table 2. Results for Diels–Alder reaction (Eq. 5)
20
21
Entry
Conditions
Yield
1
2
3
MeAlCl2, toluene, K78 8C
DCE, 140 8C 24 h
DMSO, 160 8C
23a (80%)
22 (47%)
23a (32%)
23b (10%)
4.5 h
Conditions: 5 mol% [Rh(CO)2Cl]2, DCE, N2, room temperature.
a Compound 9 and 16 both possess sillyl-containing contaminants.
The stereochemistry of 23a was assigned by 2D-NOESY
experiments, with the main NOE enhancements in 23a

K. M. Brummond, L. You / Tetrahedron 61 (2005) 6180–6185
6183
gave the cycloadducts 25b and 26 in a 10:1 ratio in a
combined 77% yield (entry 1, Table 3). The best results
were obtained when [Rh(C10H8)(COD)]CSbF6K was used in
DCE, which after 20 min gave 25a as the only product in
92% yield (entry 2, Table 3).
Figure 1. NOE enhancements for tricyclic compounds 23a.
being Ha–Hc, Hb–Hc, Ha–Hb (Fig. 1). The structure of 23b
was assigned based upon similarities of the spectral data to
that of 23a.
(8)
Next, we examined the Diels–Alder reactions between
electronically similar dienes and dienophiles using tran-
sition metal catalysis. For the conversion of 15 to cyclo-
adduct 24, conditions reported by Zhang12 ([Rh(dppe)Cl]2,
AgSbF6) and Wender13 ([Rh(C10H8)(COD)]SbF6) appeared
to be equally effective, providing the cycloadduct 24 in 91
and 92% yields, respectively, (Eq. 6).14 Similar results were
obtained when trienyne 21 was exposed to 5 mol%
[Rh(C10H8)(COD)]SbF6, affording a 94% yield of cyclo-
adduct 27 in 15 min at rt (Eq 7).
Attempts to effect the intramolecular Diels–Alder reaction
on substrates 16, 18 and 20 with either [Rh(dppe)Cl]2/
AgSbF6 or [Rh(C10H8)(COD)]CSbF6K afforded none of the
corresponding cycloaddition products. The recalcitrant
nature of alkynyl silanes 16 and 20 toward cycloaddition
is thought to be steric in nature. For substrate 18, it is
recognized that alkenes do not readily participate in
transition metal catalyzed formal [4C2] cycloaddition
reaction to form decalin ring systems.15
To examine whether the second Diels–Alder reaction could
be effected, isolated diene 24 was exposed to an external
dienophile. The very reactive dienophile tetracyanoethyl-
ene, underwent rapid intermolecular Diels–Alder reactions
affording a 69% yield of the tetracyclic product 28 (Eq. 9).
(6)
(9)
An ultimate goal of this investigation is the rapid synthesis
of complex molecules via tandem reaction sequences. Thus,
formation of complex polycyclic compounds via consecu-
tive Alder-ene/Diels–Alder/Diels–Alder reactions in one
pot was investigated (Scheme 3). Dialkynylallene 12 was
first converted to cross-conjugated triene 19 using
[Rh(CO)2Cl]2. The reaction was complete in 1 h at room
temperature (as monitored by TLC). Next, 5 mol%
[Rh(dppe)Cl]2 and 10 mol% AgSbF6 was added to the
reaction flask. In 30 min, 19 had been completely converted
to 25a (as monitored by TLC).16 A variety of external
dienophiles (see Table 4) were then added at rt to give the
intermolecular Diels–Alder products 29a and 29b. It is
likely the Rh(I) catalyst functions as a Lewis acid to activate
(7)
Propargyl ether 19 was subjected to the same reaction
conditions as described above (Eq. 8). However, for this
substrate the results were much more dependent upon the
catalyst. For example, [Rh(dppe)Cl]2 activated with AgSbF6
Table 3. Intramolecular Rh(I)-catalyzed Diels–Alder reaction
Entry
1
Conditions
Ratios, yield
5 mol% [Rh(dppe)Cl]2,
10 mol% AgSbF6, DCE, 1 h
5 mol% [Rh(C10H8)(COD)]CSF6K
DCE, 20 min
25b:26, 10:1, 77%
2
,
25a, 92%
Scheme 3.

6184
K. M. Brummond, L. You / Tetrahedron 61 (2005) 6180–6185
Table 4. Consecutive reaction results from Scheme 4
Acknowledgements
Entry
1
Dienophile
Time (h)
Yield (%)
74
dr (29a:29b)
We thank the National Science Foundation, the National
Institutes of Health (P50GM067982), and the Johnson and
Johnson Focused Giving Award for supporting this research
and Dr. Steven Geib, University of Pittsburgh for X-ray
crystallographic analysis.
7
1:1
2
3
24
12
87
75
2:1
1:1
Supplementary data
Supporting information available: Spectra and experi-
mentals for all new compounds are provided as supporting
information.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.03.
141
4
5
6
RZPh
RZMe
RZH
24
24
20
66
82
68
2:1
5:1
1:2
the dienophiles since the intermolecular Diels–Alder
reactions also occur at rt.17
References and notes
1. Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
2. (a) Brummond, K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem.
Soc. 2002, 124, 15186. (b) Brummond, K. M.; Mitasev, B.
Org. Lett. 2004, 5, 2245. (c) Shibata, T.; Takesue, Y.;
Kadowaki, S.; Takagi, K. Synlett 2003, 268.
The one-pot, three step reaction was used to generate a
library of polycyclic compounds using different dienophiles
(Table 4). Maleic anhydride (entry 1) and benzoquinone
(entry 2) were added as dienophiles to give very high yields
of the cycloadducts but with low diastereoselectivity. The
unsymmetrical and less active dienophile methyl vinyl
ketone reacted with complete regioselectivity to give the
cycloadducts as a 1:1 mixture of diastereomers with the
methyl ketone group at the C1 position (entry 3). In
addition, we investigated the intermolecular Diels–Alder
reaction with functionalized maleimides. The group on the
nitrogen of the maleimide moiety played no apparent role in
the rate of the cycloaddition, but did appear to effect the
diastereoselectivity (entries 4–6). The stereochemical
assignments shown Table 4 are based on X-ray analysis of
29a (entry 2, Table 4) and 29b (entry 3, Table 4).18 Thus far
attempts to effect the consecutive Alder-ene/Diels–Alder
reaction with a single Rh(I) catalyst have not been
successful.19
3. Tsuge, O.; Wada, E.; Kanemasa, S. Chem. Lett. 1983, 239.
4. Tsuge, O.; Wada, E.; Kanemasa, S. Chem. Lett. 1983, 1525.
5. (a) Woo, S.; Squires, N.; Fallis, A. G. Org. Lett. 1999, 1, 573.
(b) Woo, S.; Legoupy, S.; Parra, S.; Fallis, A. G. Org. Lett.
1999, 1, 1013.
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(b) Spino, C.; Liu, G.; Tu, N.; Girard, S. J. Org. Chem. 1994,
59, 5596.
8. Cross-conjugated trienes have been accessed previously using
transition metal mediation. Malacria has subjected an allenyne
to a cobalt(I) complex and obtained a mixture of two cross-
conjugated trienes by using a tert-butyl group on the proximal
double bond of the allene to direct the regiochemistry of the
cyclization reaction to the distal double bond of the allene.
(a) Lierena, D.; Aubert, C.; Malacria, M. Tetrahedron Lett.
1996, 37, 7027. Sato has effected an Alder-ene reaction from
an allenynol by using a two-carbon tether that favors reaction
with the distal double bond of the allene. (b) Yamazaki, T.;
Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39, 7333.
Livinghouse has observed a cross conjugated triene as a
minor byproduct (21% yield) when using cobalt to catalyze a
Pauson–Khand reaction. Pagenkopf, B. L.; Belanger, D. B.;
O’Mahony, D. J. R.; Livinghouse, T. Synthesis 2000, 1009.
9. To the best of our knowledge, this type of Ireland–Claisen
rearrangement is an unprecedented protocol for the formation
of allenes.
3. Conclusion
A consecutive one-pot Alder-ene/Diels–Alder/Diels–Alder
reaction has been developed to demonstrate the potential of
the cross-conjugated triene for accessing polycyclic com-
pounds. The reaction sequence is highly chemoselective
with the Alder-ene and the first Diels–Alder reaction only
providing a single isomer 25a and the intramolecular Diels–
Alder reaction giving two endoaddition products resulting
from addition to either face of 25a. The transformation is
highly atom-efficient with all the atoms of the starting
dialkynyl allenes and dienophiles appearing in the products.
Investigations are currently directed towards the application
of this new method to the preparation of novel steroidal-like
compounds.
10. More recently our group has found that performing Alder-ene
reactions at lower concentrations (0.05-0.01 M) gives higher
yields of trienes in faster reaction times suggesting product
inhibition.

K. M. Brummond, L. You / Tetrahedron 61 (2005) 6180–6185
6185
11. For references regarding rhodium(I) transition metal catalyzed
[4C2] cycloaddition reactions between electronically similar
dienes and dienophiles, see: Gilbertson, S. R.; Hoge, G. S.;
Genov, D. G. J. Org. Chem. 1998, 63, 10077. Jolly, R. S.;
Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc.
1990, 112, 4965. Wang, B.; Cao, P.; Zhang, X. Tetrahedron
Lett. 2000, 41, 8041. Paik, S.-J.; Son, S. U.; Chung, Y. K. Org.
Lett. 1999, 1, 2045. Matsuda, I.; Shibata, M.; Sato, S.; Izumi,
Y. Tetrahedron Lett. 1987, 28, 3361. McKinstry, L.; Living-
house, T. Tetrahedron 1994, 50, 6145. For a diene-allene
cycloaddition, see: Wender, P. A.; Jenkins, T. E.; Suzuki, S.
J. Am. Chem. Soc. 1995, 117, 1843.
15. A few groups have reported rhodium catalyzed formal [4C2]
reactions using alkenes as the dienophile to form fused [6K5]
ring systems. (a) Gilbertson, S. R.; Hoge, G. S. Tetrahedron
Lett. 1998, 39, 2075. (b) Jolly, R. S.; Luedtke, G.; Sheehan, D.;
Livinghouse, T. J. Am. Chem. Soc. 1990, 112, 4965. (c) Sato,
Y.; Oonishi, Y.; Mori, M. Organometallics 2003, 22, 30.
16. Surprsingly, 5 mol% [Rh(dppe)Cl]2/10 mol% AgSbF6 gave
better results than [Rh(C10H8)(COD)]CSbF6K for the one pot
process. Compare the results of Table 3 and Scheme 3.
17. Wender, P. A.; Gamber, G. G.; Scanio, M. J. C. Angew. Chem.,
Int. Ed. 2001, 40, 3895.
18. The X-ray crystallographic data have been included in the
supporting information as a CIF file and have been deposited at
the Cambridge Crystallographic Data Centre and allocated the
deposition numbers CCDC 256297 and 256298.
12. Wang, B.; Cao, P.; Zhang, X. Tetrahedron Lett. 2000, 41,
8041.
13. Wender, P. A.; Williams, T. J. Angew. Chem., Int. Ed. 2002,
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19. For a recent review on using a single catalyst to mediate two or
more reactions, see: Ajamian, A.; Gleason, J. L. Angew.
Chem., Int. Ed. 2004, 43, 3754.
14. Other catalysts were examined, but without success.
Wilkinson’s catalyst in trifluoroethanol, and activation of
Wilkinson’s catalyst with silver hexafluoroantimonate both
led to decomposition while [Rh(nbd)(dppe)]CSbF6K gave no
reaction.