Metal-Catalyzed Heterocyclization of Allenes

1
Metal-Catalyzed Heterocyclization of Allenes

• Chris M. Yates

2
What Makes an Allene an Interesting Substrate?

• Entrance into large number of highly
  functionalized heterocycles
• Cyclization products retain an olefin that can be
  further manipulated
• Cyclization products can be varied by changing
  metal and or reaction conditions
• Many intramolecular heterocyclizations can be
  done with high diastereoselectivity
• Reactions can be catalyzed by Silver, Palladium,
  Lanthanides, Cobalt, Ruthenium, Iron, and Gold

3
Discovery of Metal-Catalyzed Cyclization

• First discovered by Alf Claesson and co-workers
  when attempting to purify allenic amines by GLC
  at 210 C
• Noticed complete conversion of allenic amine 1
  into two new compounds, 2 and 3
• Lead to the discovery of a metal-catalyzed
  cyclization using Silver (I)

Claesson, A. Sahlberg, C. Luthman, K. Acta
Chem. Scand. 1979, B33, 309-310.
4
Extension to Oxygen Heterocycle Formation

• Synthesis of 2,5-Dihydrofurans
• Synthesis of 5,6-Dihydro-2H-pyrans

Olsson, L. I. Claesson, A. Synthesis 1979,
743-745.
5
Diastereoselective Tetrahydropyran Formation

• Synthesis of cis-2,6-disubstituted
  tetrahydropyrans

Yield Yield
1 2 3
R Me 71 4
R t-Bu 50 Trace
R cyclohexyl 90 7
R Ph 90 3
R CHCH2 50 Trace
Gallagher, T. J. Chem. Soc., Chem. Comm. 1984,
1554-1555.
6
Diastereoselective Pyrrolidine Formation

• Synthesis of cis-2,5-disubstituted pyrrolidines
• Synthesis of trans-2,3-disubstituded pyrrolidines

1 23 Yield
R tosyl gt501 100
R Bn gt501 93
R Boc gt501 70
R H 11 60
d
d
d
d
Kinsman, R. Lathbury, D. Vernon, P. Gallagher,
T. J. Chem. Soc., Chem. Comm. 1987,
243-244. Gallagher, T. Jones, S. W. Mahon, M.
F. Molloy, K. C. J. Chem. Soc., Perkin Trans. 1
1991, 2193-2198.
7
Formation of Nitrones

• Trans-2,6-disubstituted piperidines by trapping
  nitrone with styrene
• Trans-2,5-disubstituted pyrrolidines by trapping
  nitrone with styrene
• 7-Member nitrones can also be formed by this same
  method

Lathbury, D. C. Shaw, R. W. Bates, P. A.
Hursthouse, M. B. Gallagher, T. J. Chem. Soc.,
Perkin Trans. 1 1989, 2415-2424.
8
Cyclization of Allenyl Aldehydes and Ketones to
Furans

• Proposed mechanistic pathways

Marshall, J. A. Wang, X. J. J. Org. Chem. 1991,
56, 960-969.
9
Mechanism for Conversion of Allenones to Furans

• Possible pathways are determined by deuterium
  using labeled allenes and/or deuterated solvents
• No incorporation or loss of deuterium upon
  treatment of 1 or 2 to reaction conditions with
  no AgNO3 present

entry DH in 1 solvent yield DH in 2
1 919 Me2CO 92 5050
2 919 Me2CO-H20 91 2278
3 919 Me2CO-D20 88 955
4 0100 Me2CO-d6 91 595
5 0100 Me2CO-D20 92 7228
Marshall, J. A. Wang, X. J. J. Org. Chem. 1991,
56, 960-969.
10
Pd(II)-Catalyzed Cyclization

• All Ag(I) cyclizations are limited to
  cycloisomerization
• Pd(II) allows for further functional group
  incorporation
• Can achieve arylations, vinylations, and
  allylations of cyclization products
• Can achieve CO insertion to obtain ketones and
  acrylates

11
Palladium-Catalyzed Intramolecular Hydroamination
of Allenes

• Cyclization is achieved with catalytic Pd(II) and
  1 equivalent of acetic acid
• This method can also be applied to six member

(?3-C3H5)PdCl2 (5 mol ) dppf (10 mol ) acetic
acid (1 equiv) dppf 1,1-bis(diphenylphosphino
)ferrocene
(?3-C3H5)PdCl2 (5 mol ) dppf (10 mol ) acetic
acid (15 mol )
Meguro, M. Yamamoto, Y. Tetrahedron Lett. 1998,
39, 5421-5424.
12
Proposed Possible Catalytic Cycle
Meguro, M. Yamamoto, Y. Tetrahedron Lett. 1998,
39, 5421-5424.
13
Allylation, Vinylation, Arylation

• Aryl, vinyl, and allyl palladium(II) complexes
  can be formed in situ and trigger cyclization
• These reactions seem to be tolerable to various
  substitution
• Cyclization can be completed by a variety of
  oxygen and nitrogen nucleophiles

14
Palladium-Catalyzed Allylamination

• Stereoselective cyclization of carbamates to form
  oxazolidinones
• All reactions proceeded to give trans-selectivity

entry R reaction time (h) yield
1 H 19 53
2 Me 17 65
3 Et 23 62
4 n-Pr 19 80
5 t-Bu 21 74
Kimura, M. Fugami, K. Tanaka, S. Tamaru, Y. J.
Org. Chem. 1992, 57, 6377-6379.
15
Mechanism and Stereochemical Model

• Reaction is proposed to proceed through either
  pathway A or B
• Stereochemistry can be rationalized according to
  pathway A

Kimura, M. Tanaka, S. Tamaru, Y. J. Org. Chem.
1995, 60, 3764-3772.
16
Scope of Aryl and Vinyl Pd(II) Cyclization

• Structurally and electronically diverse aryl and
  vinyl Pd(II) groups can trigger cyclization
• R-X, Pd(PPh3)4
• K2CO3, DMF
• 70 C, 1-3 h

entry aryl/vinyl Substrate yield
1 PhOTf 78
2 p-MePhI 78
3 m-MeOPhBr 72
4 1-bromonaphthalene 80
6 E-PhCHCHBr 84
7 PhC(Br)CH2 66
Davies, I. W. Scopes, D. I. C. Gallagher, T.
Synlett 1993, 85-87.
17
Formation of Arylated Pyrrolines and Pyrroles

• The number of carbons between the nucleophile and
  allene can affect the cyclization product
• Additives and reaction conditions can be used to
  control product formation

Dieter, R. K. Yu, H. Org. Lett. 2001, 3,
3855-3858.
18
Six-Membered Ring?

• Since a-amino allenes give lead to five-member
  endo-cyclization products, do ß-amino allenes
  give six-member endo-cyclization? No!
• Scope of reaction reaction also works in
  presence of allylating agents

Karstens, W. F. J. Rutjes, F. P. J. T.
Hiemstra, H. Tetrahedron Lett. 1997, 38,
6275-6278.
19
Mechanism For Intramolecular Attack of Central
Carbon of Allene
Karstens, W. F. J. Rutjes, F. P. J. T.
Hiemstra, H. Tetrahedron Lett. 1997, 38,
6275-6278.
20
Palladium-Catalyzed Oxirane Formation

• Intramolecular cyclization of 2,3-allenols yields
  attack at proximal carbon yielding
  2,3-disubstituted oxiranes
• This is a in contrast to the previously reported
  cyclization of a-aminoallenes that yield
  pyrrolines and pyrroles

Ma, S. Zhao, S. J. Am. Chem. Soc. 1999, 121,
7943-7944.
21
Palladium-Catalyzed Aziridination

• Switching solvents from DMF to 1,4-dioxane shifts
  attack on allene

entry allene R1 ArI time (h) product ratio yield
1 1 i-Pr PhI 2 3a3b 8416 83
2 1 i-Pr p-MePhI 6 3a3b 919 64
3 1 Ph PhI 4.5 3a3b 8515 79
4 2 i-Pr PhI 2.2 3a3b 290 79
5 2 i-Pr p-MePhI 3.5 3a3b 1285 44
6 2 Ph PhI 4 3a3b 1767 73
Ohno, H. Anzai, M. Toda, A. Ohishi, S. Fujii,
N. Tanaka, T. Takemoto, Y. Ibuka, T. J. Org.
Chem. 2001, 66, 4904-4914.
22
Stereochemical model

• Stereochemistry is controlled by irreversible
  olefin insertion to the less hindered face

Ohno, H. Anzai, M. Toda, A. Ohishi, S. Fujii,
N. Tanaka, T. Takemoto, Y. Ibuka, T. J. Org.
Chem. 2001, 66, 4904-4914.
23
Stereochemical model

• Stereochemistry is controlled by irreversible
  olefin insertion to the less hindered face

Ohno, H. Anzai, M. Toda, A. Ohishi, S. Fujii,
N. Tanaka, T. Takemoto, Y. Ibuka, T. J. Org.
Chem. 2001, 66, 4904-4914.
24
Palladium-Catalyzed Formation of Azetidines

• Surprisingly the best solvent for this reaction
  is DMF giving all cis product

entry R1 R2 RX time (h) yield
1 i-Bu Mts PhI 3.5 84
2 i-Bu Ts PhI 3.0 89
3 Bn Ts PhI 1.0 89
4 TBSOCH2 Mts PhI 1.5 53
5 MeO2C(CH2)2 Mts PhI 1.5 73
6 i-Bu Ts PhCHCHBr 0.75 81
7 MeO2C(CH2)2 Mts PhCHCHBr 0.5 75
8 Bn Ts p-MePhI 1.5 81
Ohno, H. Anzai, M. Toda, A. Ohishi, S. Fujii,
N. Tanaka, T. Takemoto, Y. Ibuka, T. J. Org.
Chem. 2001, 66, 4904-4914.
25
Stereochemical Model
Ohno, H. Anzai, M. Toda, A. Ohishi, S. Fujii,
N. Tanaka, T. Takemoto, Y. Ibuka, T. J. Org.
Chem. 2001, 66, 4904-4914.
26
Carbonylation and Alkoxide Coupling

• Attempted previous cyclization reactions in the
  presence of CO and methanol to form acrylate
  esters

entry R R1 yield cistrans (2a2b)
1 H H 51 N/A
2 Me H 72 5050
3 Me SiMe2tBu 60 5050
4 Me H 92 5050
5 CH2COC(CH3)3 SiMe2tBu 90 5050
6 CH2COCH3 H 44 5050
7 CH2COCH3 SiMe2tBu 68 5050
8 CH2CH(OH)CH3 SiMe2tBu 44 5050
Walkup, R. D. Park, G. Tetrahedron Lett. 1987,
28, 1023-1026.
27
Alternative Method With High Selectivity

• Obtain same product, but by addition of Hg(II)
  first, then palladium catalyzed
  carbonylation/coupling reaction, high cis
  selectivity is realized

entry R R1 yield cistrans (2a2b)
1 Me SiMe2tBu 53 946
2 CH2COC(CH3)3 SiMe2tBu 80 928
3 CH2COCH3 SiMe2tBu 70 5050
4 CH2CH(OH)CH3 SiMe2tBu 67 928
Walkup, R. D. Park, G. Tetrahedron Lett. 1987,
28, 1023-1026.
28
Source of Selectivity in Hg(II) Cyclization

• Selectivity is controlled by the bulky protecting
  group

d
d
d
d
d
d
d
d
Walkup, R. D. Park, G. J. Am. Chem. Soc. 1990,
112, 5388.
29
Pd(II)-Catalyzed Cyclization-Carbonylation-Couplin
g Reaction

• When ?-hydroxy allenes are reacted with aryl
  halides in the presence of Pd(II) and CO one can
  obtain cyclization-carbonylation-coupling products

entry R ArI (2) yield cistrans
1 Me PhI 63 2377
2 Me p-MeOPhI 52 3961
3 Me 1-iodonaphthalene 24 2575
4 Et PhI 84 2179
5 Et 1-iodonaphthalene 76 2179
6 Et p-MeOPhI 87 2773
7 Et p-NO2PhI 66 2872
8 i-Pr PhI 72 1684
9 i-Pr 1-iodonaphthalene 69 1981
Walkup, r. D. Guan, L. Kim, Y. S. Kim, S. W.
Tetrahedron Lett. 1995, 36, 3805-3808.
30
Expansion to Nitrogen Nucleophiles
entry substrate ArI (2) product yield
1 PhI 83
2 p-MeOPh 91
3 PhI 61
4 p-MeOPh 65
Kang, S.-K. Kim, K.-J. Org. Lett. 2001, 3,
511-514.
31
Proposed Catalytic Cycle for Pd (II)-Catalyzed
Cyclization-Carbonylation-Coupling Reaction
Kang, S.-K. Kim, K.-J. Org. Lett. 2001, 3,
511-514.
32
Organolanthanide-Catalyzed Intramolecular
Hydroamination-Cyclization
entry substrate Precatalyst Product Conversion ( Yield) Z/E
1 Cp2YCH(TMS)2 gt95 (93) 8614
2 Cp2LuCH(TMS)2 gt95 5545
3 Cp2SmCH(TMS)2 gt95 6733
4 Cp2SmCH(TMS)2 gt95 (91) 955
5 Cp2LaCH(TMS)2 gt95 (85) 7228
Arredondo, V. M. McDonald, F. E. Marks, T. J.
J. Am. Chem. Soc. 1998, 120, 4871-4872.
Arredondo, V. M. McDonald, F. E. Marks, T. J.
Organometallics 1999, 18, 1949-1960.
33
Kinetic and Mechanistic Studies of
Organolanthanide-Catalyzed Reaction
catalyst ionic radius Nt, h-1 (23 C)
Cp2La 1.106 4
Cp2Sm 1.079 13
Cp2Y 1.019 31
Cp2Lu 0.977 7
Arredondo, V. M. McDonald, F. E. Marks, T. J.
Organometallics 1999, 18, 1949-1960.
34
Stereochemical Model for trans-Pyrrolidines
Arredondo, V. M. McDonald, F. E. Marks, T. J.
Organometallics 1999, 18, 1949-1960.
35
Stereochemical Model for cis-Piperidines
Arredondo, V. M. McDonald, F. E. Marks, T. J.
Organometallics 1999, 18, 1949-1960.
36
Cobalt-Mediated Acylation-Cyclization of Allenes
entry RX Nucleophile base yield
1 MeI OH NaH 30
2 BnOCH2Cl OH i-Pr2NEt 25
3 MeI NHTs NaH 69
4 BnOCH2Cl NHTs NaH 80
5 EtO2CCH2Br NHTs i-Pr2NEt 23
6 PhCH2Br NHTs i-Pr2NEt 41
7 PhthCH2Br NHTs i-Pr2NEt 76
8 H2CCHCH2Br NHTs i-Pr2NEt 27
Bates, R. W. Devi, T. R. Tetrahedron Lett. 1995,
36, 509-512.
37
Mechanism of Cobalt-Mediated Reaction

• When using 1,3-disubstituted allenes, only E
  olefin products are observed

Bates, R. W. Devi, T. R. Tetrahedron Lett. 1995,
36, 509-512.
38
Ru-Catalyzed Cyclocarbonylation

• Good yields are also obtained from ß-sulfonamides
  to obtain d-unsaturated lactams
• Reaction also works to yield seven and eight
  member rings

entry substrate Time (h) product yield
1 9 91
2 16 70
3 16 80
4 12 95
Kang, S.-K. Kim, K.-J. Yu, C.-M. Hwang, J.-W.
Do, Y.-K. Org. Lett. 2001, 3, 2851-2853. Yoneda,
E. Kaneko, T. Zhang, S.-W. Onitsuka, K.
Takahashi, S. Org. Lett. 2000, 2,
441-443. Yoneda, E. Zhang, S. W. Onitsuka, K.
Takahashi, S. Tetrahedron Lett. 2001, 42,
5459-5461.
39
Ru-Catalyzed Cyclocarbonylation Catalytic Cycle
Kang, S.-K. Kim, K.-J. Yu, C.-M. Hwang, J.-W.
Do, Y.-K. Org. Lett. 2001, 3, 2851-2853.
40
Natural Product Synthesis Using Metal-Catalyzed
Heterocyclization of Allenes
()-Rhopaloic
Acid A Clavepictine A R Ac

()-Xenovernine Clavepictine B R H
()-Furanomycin
()-Kallolide A
41
Synthesis of ()-Rhopaloic Acid A
()-Rhopaloic Acid A
Snider, B. B. He, F. Tetrahedron Lett. 1997, 38,
5453-5454.
42
Synthesis of Clavepictine A and B
Ha, J. D. Cha, J. K. J. Am. Chem. Soc. 1999,
121, 10012-10020.
43
Synthesis of ()-Xenovernine
Arredondo, V. M. Tian, S. McDonald, F. E.
Marks, T. J. J. Am. Chem. Soc. 1999, 121,
3633-3639.
44
Synthesis of ()-Furanomycin
VanBrunt, M. P. Standaert, R. F. Org. Lett.
2000, 2, 705-708.
45
Synthesis of Kallolide A
Marshall, J. A. Liao, J. J. Org. Chem. 1998, 63,
5962-5970.
46
Summary

• Hydroxy-allenes and Amino-allenes are versatile
  substrates that can be utilized to form a variety
  of heterocycles
• Metal-catalyzed heterocyclization of allenes is
  tolerant to substitution
• Many cyclizations of allenes are highly
  diastereoselective
• A variety of metals can be utilized depending on
  the desired structure
• Metal-catalyzed heterocyclization of allenes can
  be useful for natural product synthesis

47
Acknowledgements

• Dr. Jeff Johnson
• Johnson Group
• UNC Chapel Hill