The cyclization of 4-substituted 5-hexenyl iodides proceeds well, leading to cyclopentylz- inc iodides that can be trapped with various electrophiles such as 3-iodo-2-cyclohexenone, iodine, acid chlorides, allylic halides, and ethyl propiolate (carbocupration) (Scheme 7).[4]
Various substitution patterns allow a successful cyclization. Also, a range of functional groups like esters or nitriles are tolerated in the ring closure (Scheme 8).
The presence of an oxygen functionality (O-centered leaving group) is also compatible with the reaction conditions and the 2-pivaloyloxyalkyl iodide 9leads after allylation to the expected cyclopentane derivative 10(Scheme 9).[4]
Scheme 8 I
Ph
Ph
O
ZnI Ph
O
I I2
Br CO2Et
CO2Et
Ph O
I Ph
CO2Et Ph
Ph
CO2Et
73%
90%
>98% trans PdCl2(dppf)
1.5 mol %
1. CuCN • 2 LiCl 2.
1. CuCN • 2 LiCl 2.
64% >95% E
1. CuCN • 2 LiCl 2. PhCOCl
2.
76%
Et2Zn, THF
25 °C, 2h 1. CuCN • 2 LiCl
Scheme 7
I
FG
Bu I
PdCl2(dppf) 1.5 mol % 25 °C, 2 h
FG
ZnI
Bu ZnI
Br
Ph NO2
FG
NO2 Bu Ph
81%
2.
FG = CN 83%
FG = OCOt-Bu 62%
CO2Et Et2Zn (2 equiv)
PdCl2(dppf) 1.5 mol % 25 °C, 2 h Et2Zn (2 equiv)
1. CuCN • 2 LiCl
2.
1. CuCN • 2 LiCl CO2Et
R I
R I
Br COOEt
I
OAc
Cl OAc
OAc
AcO R
R R = (CH2)4OAc, Et, (CH2)3CN
75−87%
cis/trans ca. 78:22
R = (CH2)4OAc, (CH2)3CN 51−71%
cis/trans ca. 78:22
52%
cis/trans 77:23 PdCl2(dppf)
1.5 mol % 25 °C, 2 h Et2Zn (2 equiv)
PdCl2(dppf) 1.5 mol % 25 °C, 2 h Et2Zn (2 equiv)
PdCl2(dppf) 1.5 mol % 25 °C, 2 h Et2Zn (2 equiv)
2.
1. CuCN • 2 LiCl
2.
1. CuCN • 2 LiCl
2.
1. CuCN • 2 LiCl
CO2Et
CO2Et CO2Et
E I E
R I
Br
I
O E
E
R
O E = CO2Et
CO2Et 73%
E = CO2Et
R = Me, Et, c-Hex
62−81%
cis/trans ca. 70:30 PdCl2(dppf)
1.5 mol % 25 °C, 2 h Et2Zn (2 equiv)
PdCl2(dppf) 1.5 mol % 25 °C, 2 h Et2Zn (2 equiv)
2.
1. CuCN • 2 LiCl
2.
1. CuCN • 2 LiCl CO2Et
Scheme 8 (Continued)
I
OPiv PdCl2(dppf) 1.5 mol % 25 °C, 2 h
OPiv ZnI
Br CO2Et
OPiv EtO2C
10 87%
2.
80:20
9
Et2Zn 1. CuCN • 2 LiCl
Scheme 9
I
I I
CO2Et
CO2Et CO2Et
Br COOEt
Br CO2Et
EtO2C PdCl2(dppf) cat.
25 °C, 2 h 2. CuCN • 2 LiCl
90% endo/exo80:20
25 °C, 2 h 2. CuCN • 2 LiCl
70% endo/exo80:20
1. Et2Zn (2 equiv) Ni(acac)2 (2.5 mol %) 0 °C, 3h
2. CuCN • 2 LiCl
n = 1: 85 % endo/exo 1:2 n = 2: 63 %endo/ exo 1:2 11
12 n = 1 13 n = 2
n
1. Et2Zn
1. Et2Zn PdCl2(dppf) cat.
Scheme 10
Various domino cyclizations using substrates like 1 1–13have been used successfully (Scheme 10).[4],[11]
The intramolecular addition to unsaturated esters was also possible. Best results are obtained with a t-amyl ester, which leads to a product that is less prone to undergo Claisen condensation. The same reaction is observed with the corresponding acetylenic ester (Scheme 11).[4]
CO2R
I
CO2Me
I PdCl2(MeCN)2 ( 1.5 mol % ) 25°C, 4 h
CH2CO2R
CO2Me R = Et
R = t-Am
−78 °C to 25 °C, 4 h
R = Et 57%
R = t-Am 74%
73%
Et2Zn, THF PdCl2(MeCN)2 (1.5 mol %)
Et2Zn ( 2 equiv), THF
Scheme 11
The reactivity observed with acetylenic ketones is more complex and the two iodoalkynyl ketones 14and 15behave in a different way (Scheme 12). Thus, the phenyl ketone 14undergoes carbopalladation of the triple bond followed by a reductive elimina- tion, furnishing the exo-alkylidenecyclopentane derivative 16. On the other hand, the methyl ketone 15undergoes, after carbopalladation, a subsequent Michael addition, lead- ing to the ketone 17in 52% yield.
COMe I
COPh I
PdCl2(MeCN)2 (1.5 mol %) 25 °C, 4 h PdCl2(MeCN)2 (1.5 mol %)
25 °C, 4 h
COMe Et
COPh Et 16 60%
14
17 52%
15
Et2Zn, THF
Et2Zn, THF
Scheme 12
OBn
CO2Me
I Br Et
OBn
CO2Me
CO2Me Et
O
Et 2. CuCN • 2 LiCl
3.
−55 °C, 48 h
86%
95:5
18 epijasmonate 19
1. Et2Zn, Ni(acac)2 cat THF, 25 °C
Scheme 13
The scope of the reaction can be extended to unsaturated alkyl bromides as substrates by using Ni(acac)2as a catalyst[12],[13]instead of Pd(II) complexes. The use of Ni(acac)2as a catalyst even with several polyfunctional alkyl iodides gives better results. Thus, in the key step for the synthesis of methyl epijasmonate 18, the alkyl iodide 19 undergoes a smooth cyclization using Ni(acac)2and Et2Zn (Scheme 13).[12]
Polyfunctional alkyl bromides have been cyclized with Ni(acac)2/Et2Zn for the construction of various heterocycles[13] as well as for the antitumor antibiotic ()-methylenolactocin 20. In this case, the alkyl bromide 21is cyclized and selectively oxidized to the aldehyde 22, which is converted in a standard way to the natural product 20(Scheme 14).
D. SUMMARY
1. The treatment of an alkyl iodide with Et2Zn in the presence of catalytic amounts of palladium(II) salts leads to the corresponding organozinc iodide.
2. The reaction proceeds via a radical intermediate and can be used to perform radical cyclizations affording five-membered rings. However, the products of these reactions are organozinc reagents, which can be reacted with a wide range of electrophiles.
3. The cyclizations are stereoselective following the Beckwith rules and allow the elaboration of highly substituted cyclopentane derivatives.
4. Domino cyclizations can be performed.
5. Unsaturated alkyl bromides can be used as substrates if the Pd(II) catalyst is replaced by Ni(acac)2.
REFERENCES
[1] M. J. Rozema, S. AchyuthaRao, and P. Knochel, J. Org. Chem., 1992, 57, 1956.
[2] M. J. Rozema, C. Eisenberg, H. Lütjens, R. Ostwald, K. Belyk, and P. Knochel, Tetrahedron Lett., 1993, 34, 3115.
[3] H. Stadtmỹller, R. Lentz, W. Dửrner, T. Stỹdemann, C. E. Tucker, and P. Knochel, J. Am.
Chem. Soc., 1993, 115, 7027.
[4] H. Stadtmüller, A. Vaupel, C. E. Tucker, T. Stüdemann, and P. Knochel, Chem. Eur. J., 1996, 2, 1204.
[5] A. V. Kramer, J. A. Labinger, J. S. Bradley, and J. A. Osborn, J. Am. Chem. Soc., 1974, 96, 7145.
[6] A. V. Kramer and J. A. Osborn, J. Am. Chem. Soc., 1974, 96, 7832.
[7] C. Amatore, E. Carré, A. Jutand, H. Tanaka, Q. Ren, and S. Torii, Chem. Eur. J., 1996, 2, 957.
[8] M. Chanon, Bull. Soc. Chim. Fr., 1982, 2, 197.
[9] D. P. Curran, in Comprehensive Organic Chemistry, Vol. 4, B. M. Trost and I. Fleming, Eds., Pergamon Press, New York, 1991, 779.
O OBu
Pent C SiMe3 O O ZnX
O OBu
Pent OHC
O O
Pent HO2C
O O
Pent HO2C
Pent O OBu
Me3Si
Br
2. O2, TMSCl THF, −5 °C
90 % acetone,
0 °C, 15 min
20: (−)-methylenolactocin 22 55%
21
1. Et2Zn, LiI Ni(acac)2
THF, 40 °C
Jones reagent
Scheme 14