Metal-catalyzed [2+2+1] cycloadditions of 1,3-dienes, allenes, and CO

Article abstract of DOI:10.1002/anie.200600300

(Chemical Equation Presented) Closing the circle: Rh^I-catalyzed [2+2+1] cycloadditions are achieved under mild reaction conditions and in good to excellent yields with catalyst loading as low as 0.1 mol%. The diene-allenes react selectively wit

Full text of DOI:10.1002/anie.200600300

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200600300
Metal-Catalyzed [2+2+1] Cycloadditions of
1,3-Dienes, Allenes, and CO**
Paul A. Wender,* Mitchell P. Croatt, and
Nicole M. Deschamps
Step economy is a preeminent goal of synthesis.[1] It influences
the length, efficiency, cost, time, separation, and environ-
mental impact of a synthesis. Step economy is favored by the
use of single, serial, or multicomponent reactions that proceed
in one operation with a great increase in target revelant
complexity. The design or discovery of such reactions is thus
critical to extending the practical reach of organic synthesis.
Toward this end, we have directed effort at the identification
of new metal-catalyzed reactions, especially those which are
forbidden or difficult to achieve in the absence of a catalyst.
This program has thus far produced several new two-, three-,
and four-component reactions, including [4+4],[2] [4+2],[3]
[5+2],[4] [6+2],[5] [5+2+1],[6] [2+2+1],[7] [4+2+1],[7a] and
[5+1+2+1][8] cycloadditions. Herein, we report the first
examples of the [2+2+1] cycloaddition reaction of diene–
allenes and CO and preliminary examples of acceleration of
this process by Brønsted acids.
This investigation originated from our studies on the first
metal-catalyzed intramolecular [4+2] cycloadditions of
dienes and alkynes [Eq. (1)].[3,9] We recognized that the
metallacyclic intermediates in this process could be inter-
cepted by an additional component to produce three-compo-
nent cycloadducts. With CO as the trapping agent, this
approach indeed proved effective, thus resulting in the first
examples of an intramolecular dienyl Pauson–Khand reaction
[Eq. (2)] and a new [4+2+1] cycloaddition (not shown).[7a,10]
Significantly, the diene was found to facilitate the reaction
relative to an alkene [cf. Eqs. (2) and (3)].[7a,b] In the case of
[*] Prof. P. A. Wender, M. P. Croatt, N. M. Deschamps
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0259
E-mail: wenderp@stanford.edu
[**] This research was supported by the National Science Foundation
(CHE-040638). Fellowship support from Eli Lilly and Company
(M.P.C. and N.M.D.) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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A brief survey of different RhI complexes indicated that
[{RhCl(CO)2}2] is the best catalyst of those examined
(Table 1, entries 1–3). The nature of the solvent had a
substantial effect on the efficiency of the reaction. Poor-to-
moderate yields were obtained and long reaction times were
Table 1: Optimization of the [2+2+1] cycloaddition of 1.[a]
Entry
Catalyst
Solvent
t [h]
Yield of 2 [%][b]
1
2
3
4
5
6
7
8
9
[{RhCl(CO)2}2]
[Rh(naph)(cod)]SbF6
[{RhCl(dppb)}2]
[{RhCl(CO)2}2]
[{RhCl(CO)2}2]
[{RhCl(CO)2}2]
[{RhCl(CO)2}2]
[{RhCl(CO)2}2]
[{RhCl(CO)2}2]
DCE
DCE
DCE
7
1.5
32
24.5
21.5
45
12
0.25
8
99
32
80
38
64
77
96
92
97
toluene
dioxane
CH3CN
MeOH
TFE
the [2+2+1] cycloaddition reaction of diene-enes, the pres-
ence of the diene enabled the reaction to occur, as these
reactions do not proceed with simple bisalkenes.[7c] We
expected that dienes could be used as two-carbon-atom
components to enhance or enable other reactions because of
their special reactivity. For example, although many impres-
sive cases of the [2+2+1] cycloaddition reaction of alkyne–
allenes (the allenic Pauson–Khand reaction) have been
reported,[11] there have been no analogous reactions described
for simple alkene–allenes. In fact, Brummond[12] and Itoh[13,14]
found independently that simple alkene–allenes prefer to
undergo efficient RhI-catalyzed cycloisomerizations to seven-
membered rings rather than [2+2+1] cycloaddition reactions
(even in the presence of CO; Scheme 1).[13,14] We have now
TFE[c]
[a] Rhodium (10 mol%), 0.1m, RT, 1 atm CO. [b] Yield of isolated
product. [c] Catalyst (0.1 mol%), 0.5m. c od=1,5-cyclooctadiene, naph=
napthalene, and dppb=1,4-bis(diphenylphosphino)butane.
required when toluene, dioxane, and acetonitrile were used,
whereas excellent yields were obtained when the reaction was
carried out in either DCE, methanol, or 2,2,2-trifluoroethanol
(TFE; entries 1, 4–8). Significantly, a dramatic increase in the
reaction rate was observed with TFE.[16] Gratifyingly, when
the catalyst loading was lowered to 0.1 mol% and the
concentration in TFE was increased to 0.5m, an excellent
yield of 2 was obtained (entry 9).
Intrigued by the rate enhancement observed with TFE, we
wondered whether this effect could be due to the acidity of
the solvent, as the observed trend correlates poorly with the
corresponding dielectric constants or dipole moments of the
solvents used. To test this hypothesis, the effect of adding
acids to the [2+2+1] cycloaddition reaction of 1 was inves-
tigated (Table 2).[17] This study revealed that the addition of
Scheme 1. RhI-catalyzed cycloisomerization reaction of alkene–allenes.
Ts =tosyl.
found that if a diene–allene is used instead of an alkene–
allene, a new [2+2+1] cycloaddition reaction is achievable,
often in high yield.
Under the optimal conditions found for the analogous
[2+2+1] cycloaddition reaction of diene-enes,[7c] diene–allene
1 provides the [2+2+1] and the [4+2] cycloadducts 2 and 3
upon treatment with a catalytic amount of a Rhi complex in
1,2-dichloroethane (DCE) at 808C under one atmosphere of
CO (Scheme 2). It is noteworthy that diene–allenes give high
yields of the [4+2] product in the absence of CO.[15] Explora-
tion of the reaction conditions revealed that a decrease in
reaction temperature from 808C to room temperature led to
the exclusive formation of the [2+2+1] product 2, which was
structurally assigned by X-ray crystallographic analysis.
Table 2: Effect of acid on reaction time for diene–allene 1.[a]
Entry
Solvent
Acid (equiv)
t [h]
Yield [%]
1
2
3
4
5
6
7
8
DCE
TFE
none
none
7
99
92
81
93
96
93
94
95
0.25
1.3
4
2.5
2
DCE
DCE
DCE
AcOH
DCE
DCE
TsOH (0.05)
AcOH (6)
AcOH (100)
none
PhOH (14)
TFE (14)
0.25
2
[a] [{RhCl(CO)2}2] (5 mol%), 0.1m, RT, CO (1 atm).
acid provides a rate enhancement and, with the exception of
para-toluenesulfonic acid (TsOH; the most acidic of the acids
surveyed), has a negligible effect on the yield of the
[2+2+1] cycloaddition reaction. The fastest reactions were
obtained when the reaction was carried out in DCE in the
presence of 14 equivalents of phenol (entry 7) or in TFE
(entry 2). For practical reasons, including avoiding the need to
Scheme 2. Initial results and temperature effects for the competing
[2+2+1] and [4+2] cycloaddition reactions.
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separate phenol from the product at the end of the reaction,
TFE was chosen as the solvent in the initial studies on the
scope of this new [2+2+1] cycloaddition.
The [2+2+1] cycloaddition reaction of diene–allenes that
vary in diene and allene substitution and type of tether was
examined next (Table 3). In all cases, reaction at the proximal
double bond of the allene was observed. Me, H, and iPr
substitution at the 2-position of the diene is well tolerated;
however, approximately 10–25% of the olefin isomer was
observed for H substitution.[18] Entries 1–3 indicate that the
presence of heteroatoms in the tether has no deleterious
effect on the efficiency of the reaction. The [2+2+1] cyclo-
addition reaction of substrate 9, which has a terminally
methyl-substituted allene, gave both diastereomers 10 and 11.
When this reaction was carried out
in TFE, only a 39% overall yield
Table 3: Substrate scope for the diene–allene [2+2+1] cycloaddition reaction.
was obtained (entry 5); however, a
much cleaner and higher-yielding
process (81%) was obtained when
the reaction was carried out in
DCE at a concentration of 0.05m
(entry 6). The [2+2+1] cycloaddi-
tion reaction of 12, which is sub-
stituted with the larger tBu group,
can be carried out in TFE in an
excellent overall yield of 94%
(entry 7). Initial attempts to carry
out the [2+2+1] cycloaddition
reaction of diene–allene 15 in
either TFE or DCE were unsuc-
cessful. It was found that when the
temperature and CO pressure were
increased and the concentration in
DCE was decreased, a 43% yield
of the [2+2+1] product and a 19%
yield of the [4+2] product (entry 8)
were obtained.
Entry
1
Diene–allene
Conditions[a]
t [h]
Product
Yield
A
8
97
2
3
B
C
1.5
0.3
97 (2.9:1)
92
4
D
1.5
81
In conclusion, the first exam-
ples
of
the
diene–allene
reaction
[2+2+1] cycloaddition
are reported, thus providing an
efficient, selective, and operation-
ally facile route (room tempera-
ture, 1 atm CO) to highly substi-
tuted alkylidenyl cyclopentanones.
The reaction is chemoselective
with respect to the allene as the
proximal olefin is targeted. The use
of the diene leads exclusively to the
[2+2+1] cycloadduct instead of the
product from the carbocyclization
reaction, which has been reported
with alkene–allenes (Scheme 1),
thus resulting in a process of mech-
anistic and synthetic utility. An
additional point of significance is
that the reaction is accelerated in
several cases when performed in
TFE or in the presence of certain
Brønsted acids, thus suggesting co-
catalysis possibly involving CO
protonation in the migratory-inser-
tion step. Further investigations on
this and other [m + n + o] cycload-
dition reactions of dienes are ongo-
ing.[19]
5
6
7
8
E
F
16
39 (4.6:1)
81 (1.2:1)
94 (7.5:1)
62 (2.3:1)
24
24
B
G
1.5
[a] Conditions: A: [{RhCl(CO)2}2] (0.1 mol%), TFE (0.5m), RT, CO (1 atm); B: [{RhCl(CO)2}2]
(2.5 mol%), TFE (0.1m), RT, CO (1 atm); C: [{RhCl(CO)2}2] (1 mol%), TFE (0.1m), RT, CO (1 atm);
D: [{RhCl(CO)2}2] (5 mol%), DCE (0.1m), RT, CO (1 atm); E: [{RhCl(CO)2}2] (2.5 mol%), TFE (0.5m),
RT, CO (1 atm); F: [{RhCl(CO)2}2] (1 mol%), DCE (0.05m), RT, CO (1 atm); G: [{RhCl(CO)2}2]
(5 mol%), DCE (0.01m), 608C, CO (4 atm).
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Communications
de Meijere, P. A. Wender, J. Am. Chem. Soc. 2005, 127, 6530 –
6531.
Experimental Section
Typical procedure: Preparation of the catalyst solution:
[7] a) For the first report of a diene-yne [4+2+1] and dienyl
Pauson–Khand reaction, see: P. A. Wender, N. M. Deschamps,
G. G. Gamber, Angew. Chem. 2003, 115, 1897 – 1901; Angew.
Chem. Int. Ed. 2003, 42, 1853 – 1857; b) for the first intermolec-
ular dienyl Pauson–Khand reaction, see: P. A. Wender, N. M.
Deschamps, T. J. Williams, Angew. Chem. 2004, 116, 3138 – 3141;
Angew. Chem. Int. Ed. 2004, 43, 3076 – 3079; c) for the first
[2+2+1] cycloaddition reaction of diene-enes and CO, see: P. A.
Wender, M. P. Croatt, N. M. Deschamps, J. Am. Chem. Soc. 2004,
126, 5948 – 5949; d) Y. K. Chung, S. I. Lee, J. H. Park, S.-G. Lee,
J. Am. Chem. Soc. 2004, 126, 10190 (Y. K. Chung, S. I. Lee, J. H.
Park, S.-G. Lee, J. Am. Chem. Soc. 2004, 126, 2714 – 2715).
[8] P. A. Wender, G. G. Gamber, R. D. Hubbard, S. M. Pham, L.
Zhang, J. Am. Chem. Soc. 2005, 127, 2836 – 2837.
[{RhCl(CO)2}2] was weighed into an oven-dried test tube equipped
with a magnetic stir bar, and TFE was added by syringe to make a
0.005m solution. The test tube was capped with a septum, and the
solution was stirred under a balloon of CO vented to a bubbler for
45 min.
Diene–allene 1 (21 mg, 0.063 mmol) was weighed into an oven-
dried test tube equipped with a magnetic stir bar, TFE (0.114 mL) was
added by syringe, and the test tube was capped with a rubber septum.
The solution was stirred under a balloon of CO vented to a bubbler
for 30 min. The catalyst solution ([{RhCl(CO)2}2]; 0.0127 mL,
0.000063 mmol) was added by syringe, and the reaction mixture was
stirred under a balloon of CO for 8 h. The solution was concentrated
by rotary evaporation, and the residue was purified by column
chromatography on silica gel (EtOAc/CH2Cl2 2:98). The product-
containing fractions were combined and concentrated to give 2
(20.6 mg, 97%) as a white solid; the compounds were chromato-
graphically homogeneous.
[9] For the first example of a RhI-catalyzed [4+2] cycloaddition
reaction of diene-ynes and diene-enes, see: R. S. Jolly, G.
Luedtke, D. Sheehan, T. Livinghouse, J. Am. Chem. Soc. 1990,
112, 4965 – 4966.
[10] For a [4+2+2] cycloaddition reaction of diene-ynes and alkynes,
see: S. R. Gilbertson, B. DeBoef, J. Am. Chem. Soc. 2002, 124,
8784 – 8788.
Received: January 24, 2006
Published online: March 9, 2006
[11] For a recent review featuring work by Brummond, Narasaka,
Cazes, Livinghouse, Alcaide, Mukai, Cook, and Shibata, see: B.
Alcaide, P. Almendros, Eur. J. Org. Chem. 2004, 3377 – 3383.
[12] K. M. Brummond, H. Chen, B. Mitasev, A. D. Casarez, Org. Lett.
2004, 6, 2161 – 2163.
[13] T. Makino, K. Itoh, J. Org. Chem. 2004, 69, 395 – 405.
[14] Only the vinylsilane substrate below reacted in a [2+2+1]
fashion:
Keywords: allenes · cycloaddition · dienes ·
Pauson–Khand reaction · rhodium
.
[1] a) P. A. Wender, F. C. Bi, G. G. Gamber, F. Gosselin, R. D.
Hubbard, M. J. C. Scanio, R. Sun, T. J. Williams, L. Zhang, Pure
Appl. Chem. 2002, 74, 25 – 31; b) P. A. Wender, S. T. Handy, D. L.
Wright, Chem. Ind. (London) 1997, 765; c) P. A.
Wender, B. L. Miller, Organic Synthesis: Theory and
Applications, Vol. 2 (Ed.: T. Hudlicky, JAI, Greenwich,
1993, p. 27.
[2] a) P. A. Wender, N. C. Ihle, J. Am. Chem. Soc. 1986,
108, 4678 – 4679; b) P. A. Wender, N. C. Ihle, C. R. D.
Correia, J . Am. Chem. Soc. 1988, 110, 5904 – 5906.
[3] For the first examples, see: a) P. A. Wender, T. E.
Jenkins, J. Am. Chem. Soc. 1989, 111, 6432 – 6434;
b) P. A. Wender, T. E. Jenkins, S. Suzuki, J. Am. Chem.
Soc. 1995, 117, 1843 – 1844.
[4] For the first examples, see: a) P. A. Wender, H. Takahashi, B.
Witulski, J. Am. Chem. Soc. 1995, 117, 4720 – 4721; b) P. A.
Wender, H. Rieck, M. Fuji, J. Am. Chem. Soc. 1998, 120, 10976 –
10977; for the most recent, see: c) P. A. Wender, T. J. Williams,
Angew. Chem. 2002, 114, 4732 – 4735; Angew. Chem. Int. Ed.
2002, 41, 4550 – 4553; d) P. A. Wender, J. A. Love, T. J. Williams,
Synlett 2003, 1295 – 1298.
[15] For the first example of a metal-catalyzed intramolecular diene–
allene [4+2] cycloaddition reaction, see: P. A. Wender, T. E.
Jenkins, S. J. Suzuki, J. Am. Chem. Soc. 1995, 117, 1843 – 1844.
[16] A similar rate enhancement was observed for the intermolecular
[5+2] cycloaddition reaction of vinyl cyclopropanes and alkynes,
see: P. A. Wender, C. M. Barzilay, A. J. Dyckman, J. Am. Chem.
Soc. 2001, 123, 179 – 180.
[17] Although protic acids accelerate the [2+2+1] cycloaddition
reaction, the Lewis acid MgBr2(OEt2) does not have the same
effect in this case.
[5] P. A. Wender, A. G. Correa, Y. Sato, R. Sun, J. Am. Chem. Soc.
2000, 122, 7815 – 7816.
[18] Similar isomerizations are observed in the [2+2+1] cycloaddi-
tion reaction of diene-enes and CO; ref. [7c].
[19] Full procedural details and characterization data are given in the
Supporting Information.
[6] a) For the first report with alkynes, vinylcyclopropanes, and CO;
see: P. A. Wender, G. G. Gamber, R. D. Hubbard, L. Zhang, J.
Am. Chem. Soc. 2002, 124, 2876 – 2877; b) for the first report
with allenes, vinylcyclopropanes, and CO; see: H. A. Wegner, A.
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