Three-component cycloadditions: The first transition metal-catalyzed [5+2+1] cycloaddition reactions

Article abstract of DOI:10.1021/ja0176301

Prompted by our studies of transition metal-catalyzed [4+4], [4+2], [5+2], and [6+2] cycloadditions and by the view that these two-component reactions could be intercepted by a third component of one or more atoms, a new three-component transition metal-c

Full text of DOI:10.1021/ja0176301

Published on Web 03/05/2002
Three-Component Cycloadditions: The First Transition Metal-Catalyzed
[5+2+1] Cycloaddition Reactions
Paul A. Wender,* Gabriel G. Gamber, Robert D. Hubbard, and Lei Zhang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received November 28, 2001
Scheme 2 a
Previous studies in our laboratory aimed at catalyzing forbidden
or difficult to achieve reactions1 have resulted in the first [4+4]
cycloadditions of bis-dienes,2 [4+2] cycloadditions of diene-ynes
(and allenes),3 [5+2] cycloadditions of vinylcyclopropanes (VCPs)
and π-systems (1f3),4 and [6+2] cycloadditions of vinylcyclobu-
tanones and π-systems (4f6).5 The present study was prompted
a Key: (a) CO (1 atm), [Rh(CO)2Cl]2 (5 mol %), 1,2-dichloroethane
by the view that these two-component [m+n] reactions could be
intercepted by a third component [o] of one or more atoms to
(0.1M, 7), 60 °C; H3O+.
produce new families of three-component [m+n+o] cycloadditions.
Scheme 3
Illustrative of this view, inspection of plausible mechanisms for
the [5+2] and [6+2] cycloadditions suggests a crossover point at
which the putative intermediate 2 of a [5+2] cycloaddition could
be intercepted by CO6 to produce intermediate 5 of a [6+2]
cycloaddition, from which cycloadduct 6 would be produced by
an overall [5+2+1] cycloaddition (1f6). Support for the feasibility
of this process is suggested by the observation of the reverse
crossover (5f2) as a minor [6+2-1] side reaction in some [6+2]
cycloadditions.5 Herein we report the first examples of [5+2+1]
cycloadditions of VCPs, alkynes, and CO, leading to eight-
membered rings, from which bicyclo[3.3.0]octenone derivatives are
obtained, often in excellent yields.
[3.3.0]octenone product 15 in >99% yield by GC and in 97%
isolated yield.
The effects of concentration, temperature, pressure, and catalyst
loading on the efficiency of the reaction are summarized in Table
1. These studies reveal that the preferred temperature for the reaction
is 60 °C, with higher temperatures leading to lower yields of the
[5+2+1] cycloadduct, and lower temperatures leading to long
reaction times and lower yields (cf. entries 3, 4, and 5). At 1 atm
CO pressure the optimal concentration of VCP 7 was 0.1 M (cf.
entries 1, 2, 4, and 7). However, raising the pressure of the reaction
provided higher yields and allowed for more concentrated reactions
(cf. entries 7, 8, and 9), culminating in a >99% GC yield and 98%
isolated yield of 15 at 0.5 M (entry 9). The reaction could be
performed at higher concentrations (1 M) with some loss in
efficiency (entry 10), although further optimization at this concen-
tration was not pursued. Interestingly, although lowering the catalyst
load resulted in longer reaction times, it also led to higher yields
(entries 11-14). For example, when the catalyst load was reduced
to 2.5 mol %, the reaction proceeded under reduced CO pressure
(2 atm) with a yield comparable to that of the reaction conducted
with 5 mol % catalyst and 4 atm CO (cf. entries 9 and 14).
With use of these preferred conditions, the propensity of other
alkynes to undergo the [5+2+1] reaction with VCP 7 was examined
(Table 2). Our studies indicate that carbonyl activated alkynes,9
including alkynyl ketones, esters, amides, and even aldehydes, work
well in this new process. The non-carbonyl subunit can be alkyl,
aryl, TMS, or ester. The X-ray structures of 17, 18, 21, and the
eight-membered ring product 23, along with 1D-nOe analysis of
15, serve to indicate that CO insertion occurs distal to the carbonyl
functionality of the alkyne. The regiochemistry of the other products
was assigned by analogy and supported by NMR analyses. In all
cases, with the exception of ethyl butynoate (Table 2, entry 8),
only one regioisomer was observed.
Scheme 1
Initial attempts to effect the [5+2+1] cycloaddition with VCP
74g and alkyne 8 in the presence of rhodium(I) catalyst were
marginally encouraging, providing only minor amounts of an eight-
membered-ring product 10 (18%) along with the [5+2] cycloadduct
9 (13%) and a third component 11 (32%), which was isomeric with
10 (Scheme 2). Extensive spectroscopic analysis7 of 11 led to the
realization that it was a bicyclo[3.3.0]octenone, arising from
transannular closure of intermediate 12 (Scheme 3). As such, the
major course of this original test reaction did indeed follow a
[5+2+1] path.
Due to the complexity of the reaction with 8, further optimization
studies were conducted with hexynone 14 (Table 1). Significantly,
under optimized conditions, VCP 7 and hexynone 14 (1.2 equiv)
in the presence of CO (2 atm) and with [Rh(CO)2Cl]2 catalyst (2.5
mol %) in 1,4-dioxane8 gave, after hydrolytic workup, the bicyclo-
In conclusion, a new transition metal-catalyzed three-component
[5+2+1] cycloaddition is described. It proceeds in good to excellent
yield and with high or complete regioselectivity with a variety of
9
2876 VOL. 124, NO. 12, 2002 J. AM. CHEM. SOC.
10.1021/ja0176301 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. [5+2+1] Optimization Studies
Supporting Information Available: Representative procedure and
tabulated spectral data for compounds 10, 11, and 15-23 (PDF) and a
CIF file containing X-ray information on compounds 17, 18, 21, and
23. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Wender, P. A.; Love, J. A. In AdVances in Cycloaddition; JAI Press:
Greenwich, 1999; Vol. 5, pp 1-45. (b) Frau¨hauf, H.-W. Chem. ReV. 1997,
97, 523-596. (c) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96,
49-92. (d) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem.
ReV. 1996, 96, 635-662. (e) Rigby, J. H. Acc. Chem. Res. 1993, 26, 579-
585. (f) Schore, N. E. Chem. ReV. 1988, 88, 1081-1119.
conc
[M]
T
[°C]
CO
[atm]
loading
[mol %]
t
[h]
yielda
[%]
entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0.01
0.05
0.10
0.10
0.10
0.10
0.50
0.50
0.50
1.00
0.10
0.10
0.50
0.50
60
60
40
60
80
60
60
60
60
60
60
60
60
60
1
1
1
1
1
2
1
2
4
4
1
1
1
2
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
1.0
2.5
2.5
72
36
72
15
5
26
7
10
14
7
87
88
77b
(2) (a) Wender, P. A.; Nuss, J. M.; Smith, D. B.; Sua´rez-Sobrino, A.; Vagberg,
J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908-4909. (b)
Wender, P. A.; Tebbe, M. J. Synthesis 1991, 1089-1094. (c) Wender, P.
A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678-4679.
92 (90)
59
>99 (97)
62
79
>99 (98)
82
(92)
(99)
(86)
(97)
(3) For the first examples, see: (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem.
Soc. 1989, 111, 6432-6434. (b) Wender, P. A.; Jenkins, T. E.; Suzuki,
S. J. Am. Chem. Soc. 1995, 117, 1843-1844. For representative subsequent
work from our and other laboratories, see: (c) Wender, P. A.; Smith, T.
E. Tetrahedron 1998, 54, 1255-1275. (d) Wang, B.; Cao, P.; Zhang, X.
M. Tetrahedron Lett. 2000, 41, 8041-8044. (e) Paik, S.-J.; Son, S. U.;
Chung, Y. K. Org. Lett. 1999, 1, 2045-2047. (f) Gilbertson, S. R.; Hoge,
G. S.; Genov, D. G. J. Org. Chem. 1998, 63, 10077-10080. (g) Kumar,
K.; Jolly, R. S. Tetrahedron Lett. 1998, 39, 3047-3048. (h) Murakami,
M.; Ubukata, M.; Itami, K.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1998,
37, 2248-2250. (i) O’Mahoney, D. J. R.; Belanger, D. B.; Livinghouse,
T. Synlett 1998, 443-445.
25
65
15
20
a GC yield (isolated yield). b At 90% conversion.
(4) For the first examples, see: (a) Wender, P. A.; Takahashi, H.; Witulski,
B. J. Am. Chem. Soc. 1995, 117, 4720-4721. (b) Wender, P. A.; Rieck,
H.; Fuji, M. J. Am. Chem. Soc. 1998, 120, 10976-10977. For representa-
tive subsequent work from our and other laboratories, see ref 3d and: (c)
Wender, P. A.; Gamber, G. G.; Scanio, M. J. C. Angew. Chem., Int. Ed.
2001, 40, 3895-3897. (d) Wender, P. A.; Bi, F. C.; Brodney, M. A.;
Gosselin, F. Org. Lett. 2001, 3, 2105-2108. (e) Wender, P. A.; Barzilay,
C. M.; Dyckman, A. J. J. Am. Chem. Soc. 2001, 123, 179-180. (f)
Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323-2326. (g) Wender, P.
A.; Dyckman, A. J.; Husfeld, C. O.; Scanio, M. J. C. Org. Lett. 2000, 2,
1609-1611. (h) Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit,
D.; Love, J. A.; Rieck, H. J. Am. Chem. Soc. 1999, 121, 10442-10443.
(i) Wender, P. A.; Glorious, F.; Husfeld, C. O.; Langkopf, E.; Love, J. A.
J. Am. Chem. Soc. 1999, 121, 5348-5349. (j) Wender, P. A.; Fuji, M.;
Husfeld, C. O.; Love, J. A. Org. Lett. 1999, 1, 137-139. (k) Wender, P.
A.; Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am. Chem. Soc. 1998,
120, 1940-1941. (l) Trost, B. M.; Shen. H. Angew. Chem., Int. Ed. 2001,
40, 2313-2316. (m) Trost, B. M.; Toste, F. D.; Shen. H. J. Am. Chem.
Soc. 2000, 122, 2379-2380.
Table 2. Alkyne Substrates in the [5+2+1] Cycloaddition
Reaction
entry
R
1
R
2
CO [atm]
t [h]
product
yielda [%]
1
2
3
4
5
6
7
8
9
-COCH3
-COCH3
-COCH3
-CONH2
-CHO
-CO2Et
-CO2Et
-CO2Et
-CO2Me
-Et
2
1
1
1
2
1
1
1
1
20
42
26
40
26
24
26
20
30
15
16
17
18
19
20
21
22
11
97
54
88
-TMS
-Ph
-Ph
96
-Ph
69b
79
-Ph
(5) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000,
122, 7815-7816.
-TMS
-Me
67c
85d
48e
(6) Some of the most studied examples of metal-catalyzed [m+n+o]
cycloadditions include [2+2+2] cyclotrimerization reactions, which are
reviewed in ref 1, and the Pauson-Khand [2+2+1] cycloaddition. For
lead references on CO insertions see: [2+2+1]: (a) Brummond, K. M.;
Kent, J. L. Tetrahedron 2000, 56, 3263. (b) Chung, Y. K. Coord. Chem.
ReV. 1999, 188, 297-341. (c) Geis, O.; Schmalz, H.-G. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 911. [4+1]: (d) Murakami, M.; Itami, K.; Ito, Y.
J. Am. Chem. Soc. 1999, 121, 4130-4135. [4+4+1]: (e) Morimoto, T.;
Chatani, N.; Murai S. J. Am. Chem. Soc. 1999, 121, 1758-1759. (f)
Murakami, M.; Itami, K.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1998, 37,
3418. [5+1]: (g) Kamitani, A.; Chatani, N.; Morimoto, T.; Murai, S. J.
Org. Chem. 2000, 65, 9230-9233. (h) Murakami, M.; Itami, K.; Ubukata,
M.; Tsuji, I.; Ito, Y. J. Org. Chem. 1998, 63, 4-5.
-CO2Me
a Isolated yield. b Also 14% yield of [5+2] product. c Also 11% yield
of eight-membered-ring product 23. d 6:1 ratio of regioisomers by 1H NMR.
e Also 30% yield of [5+2] product and 8% yield of eight-membered-ring
product.
carbonyl-substituted alkynes to give bicyclo[3.3.0]octenone adducts
resulting from transannular closure of the intermediate eight-
membered rings. The process provides access to complex building
blocks for synthesis based on simple, commercially available
components.10 Further studies on the scope and limitations of this
new process and related [m+n+o] processes, including substrate
and catalyst variations, are in progress.
(7) The assignment was made on the basis of 1H NMR, 13C NMR, and MS
analysis, as well as IR and deuterium exchange experiments (1H NMR)
indicating the presence of hydroxyl functionality, 13C NMR (gated mode)
showing the presence of a methine carbon, and 1H-COSY showing the
presence of methylene-methine and methylene-methylene spin systems.
Details can be found in the Supporting Information.
(8) Other solvents screened include: toluene, 1,2-dichloroethane, tetrahydro-
pyran, acetone, ethanol, 1,2-dimethoxyethane, ethyl acetate, tetrahydro-
furan, and 2,2,2-trifluoroethanol.
(9) Simple terminal and non-carbonyl-substituted alkynes react inefficiently
under the above conditions. Further studies on these simple alkynes are
in progress.
Acknowledgment. Support for this work was provided by the
National Science Foundation (CHE-9800445). Fellowship support
from the Stanford Graduate Fellowship (G.G.G.) and Eli Lilly and
Co. (L.Z.) is gratefully acknowledged.
(10) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765-769.
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