Literature Seminar(D2 part)

Xu Jay (D1)2011/3/9

Gold-Catalyzed Nucleophilic Cyclization of Allenes

Norbert Krause graduated from Technical University of

1. Introduction

Braunschweig in 1984 and received his Ph.D. in 1986. After
postdoctoral stays at ETH Zürich and Yale University, he joinedTechnical University of Darmstadt and obtained his Habilitationin 1993. In 1994, he moved to the University of Bonn as
Associate Professor, before being appointed to his present
position at Dortmund University of Technology as Full Professor
in 1998. He was a Fellow of the Japan Society for the Promotionof Science (2003 and 2009), and Guest Professor at theUniversit e Catholique de Louvain, Belgium (2007), at theUniversity of California, Santa Barbara, CA, USA (2009), andat the Ecole Supérieure de Physique et de Chimie Industrielles dela Ville de Paris (ESPCI), France (2009). Since 2006, he is amember of the Editorial Board of the European Journal ofOrganic Chemistry. His review on "Recent Advances in Catalytic
Enantioselective Michael Additions" was the World's Most Cited
Chemistry Paper in Nov. 2002. His research focuses on thestereoselective synthesis and transformation of functionalizedallenes, taking advantage of coinage metal (copper, silver, andgold) catalysis. In his free time, he enjoys snorkeling and riding
his motorbike.
Review: Chem. Rev. 2011, ASAP

F. Dean Toste

Ross A. Widenhoefer

Review: Chem. Rev. 2008, 108, 3351

Review: Eur. J. Org. Chem. 2006, 4555.

Gold-Catalyzed Nucleophilic Cyclization
Reactions of Functionalized Allenes
Au --- [Xe] 4f 145d106s1
AuI --- [Xe] 4f 145d106s0
AuIII--- [Xe] 4f 145d86s0

1. Introduction
2. Nucleophilic Attack of Heteroatom Nucleophiles
2.1. Oxygen Nucleophiles
2.2. Nitrogen Nucleophiles
2.3. Sulfur Nucleophiles
3. Conclusion

12. Nucleophilic Attack of Heteroatom Nucleophiles
2.1. Oxygen Nucleophiles
2.1.1. Isomerization of Allenyl Ketones : synthesis of multisubstituted furans
The f irst gold-catalyzed addition of a heteroatom nucleophile
Hashmi, A. S. K. et al. Angew. Chem., Int. Ed. 2000, 39, 2285.

123

In contrast to other transition metals :>1 week (silver)
shorter reaction times
1 h (palladium)
milder conditions
1 min (gold)(lower catalyst loadings)
The formation of the undesired dimerization product 3 (which isalso generated in the corresponding silver-catalyzed cyclization)
is a serious drawback.

4a5a7aGold(III) porphyrin-catalyzed cycloisomerization
Che, C.-M. et al. Org. Lett. 2006, 8, 325.

0.5 h

7a7a45Gold -allene complex
Widenhoefer, R. A. et al.Organometallics 2010, 29, 4207.

DAC

B

The Au(III) catalyst 6 is highly reactive and can be recovered andreused in up to nine consecutive runs with no appreciable loss ofreactivity or decrease of yield.
The employment of CF3CO2H and a temperature of 60°C for thecycloisomerization reaction is essential.

=a rapid irreversible demetalation step resulting from unfavorable
steric interactions between the porphyrin ring and the newly formed
furyl moiety.
The active gold species is coordinated to the "distal" double bondof the allene2Cyclization of haloallenyl ketone
Gevorgyan, V. et al. J. Am. Chem. Soc. 2005, 127, 10500.
J. Am. Chem. Soc. 2008, 130, 6940.
BrBr
H

C8H17

cat.
rtHH

O

C8H172aO

C8H17

solventtime

GC yield, %(2a:3a)12345toluene
tolueneTHF
toluenetoluene

1 day
5 min
5 min
9h9h29 (2a only)
86 (95:5)
78 (5:95)
ND (16:85)
ND (<1:99)

path A

4a5atoluene, rt

R11O

R3

23aentry cat.(mol %)CuCl (10)
AuCl3 (1)
AuCl3 (1)Au(PPh3)Cl (1)Au(PEt3)Cl (1)

R3O

BrR2X
AuCl3 (1-3 mol %)

R1+O
1aR2X

path B

1a6a8a[1,2]-H-shift

7a2a3apath A :more oxophilic Au(III) chloride: coordinates to oxygen.
intramolecular Michael addition of Br to the enone
moiety lead to bromoirenium ion 5a.
path B :more philic Au(I) species: coordinates to the distal double bond of allene.

Chlorinated and iodinated allenes show a similar behavior and can be converted to the corresponding halogenated furans.
Moreover,silyl-, thio-, or selenofurans can be obtained from the corresponding allenes by a 1,2-Si, 1,2-S, or 1,2-Se shift.

Potential energy surf aces f or AuCl 3- and Au(PR' 3)Cl-catalyzed cycloisomerizations
Li, Y. et al. J. Am. Chem. Soc. 2008, 130, 6940.
computational studies confirmed possible formation of the originally proposed Au(III)-coordination
complex 4a; however, neither cyclization transition state nor halirenium intermediate 5a were located.
AuCl3 -catalyzed cycloisomerization

1,2-H shift : 2 TS2 4
14.3 kcal/mol
1,2-Br migration : 2 TS1 3

1,2-H shift : 6 TS5 8

Au(PH3)Cl-catalyzed cycloisomerization

15.5 kcal/mol
1,2-Br migration : 6 TS4 7
chloride-assisted H-migration: 9 8(only 8.7 kcal/mol)entry1234(R = CH3, R' = H).

1,2-H shift in Au(PR3)+-catalyzed reactions canbe assisted by the counterions
OTf --assisted 1,2-H shift :9.6 kcal/mol
BF4-: 20.2 kcal/mol
SbF6-: 29 kcal/mol

3

Au(III)-catalyzed 1,2-Si migration in allenes
Gevorgyan, V. et al. J. Am. Chem. Soc. 2010, 132, 7645.

regiodivergent

R3

52R1O

R3

1,2-H~
4R2R'Si

1,2-Si~

R2

1

3R'Si

Potential energy surfaces for the AuCl3-catalyzed cycloisomerizationof allenes 4 (R = H)

R1O

42

kinetically more favorable 1,2-Si migration over the 1,2-H shift
led to the product complex 2-AuCl3.

a Isolated yield of product for reactions performed on 0.5 mmol scale.
b

Isolated yield of 2e for reaction performed in MeNO2.
2e for reaction performed with 1 mol % of catalyst.

c Isolated yield of

2.1.2. Isomerization of hydroxyallenes : formation of chiral heterocycles
alkyl-substituted -hydroxyallenes

Krause, N. et al. Org. Lett. 2001, 3, 2537.
Synthesis 2002, 1759.

(7~10 mol %)811679105-endo-cyclization

the cyclization is accelerated in the presence of external proton donors(water, methanol)
this suggests that the protodeauration of 10 is the rate-limiting step.

hydroxyallenes substrates with phenyl or electron-rich aromatic substituents
Krause, N. et al. Synlett 2007, 1790.

Proposed mechanism

12aentry
12345cat.(mol %)13aadditive (%)

AuCl3 (2)
AuCl (2)
AuCl3 (2.5) 2,2-bipyridine (5)AuCl (2.5) 2,2-bipyridine (3.8)
AuCl3 (1)temp.

time (h) % yield(cis:trans)

rt
rtrt
rt-30°C

11110281 (75:25)
85 (60:40)
70 (>97:3)
96 (95:5)
92 (97:3)

1214

15

cis-1316trans-13

epimerization during the gold-catalyzed cyclization of phenyl-substituted -hydroxyallene 12 to dihydrofuran 13.

AuCl3 /CH2Cl2 epimerizes both the allene and the dihydrofuran.
AuCl/CH2Cl2 epimerizes only the allene , but not the dihydrofuran.

zwitterionic intermediates(a planar benzyl cationsubstructure)

epimerization prevented if
the Lewis acidity of the gold catalyst is reduced so that the formation of zwitterionic intermediates 14/16 is disfavored;
weakly coordinating solvents decreased the reactivity of the gold catalyst only slightly and led to an improved diastereoselectivity;
original AuCl3/CH2Cl2 system at -30°C instead of room temperature.

4

cycloisomerization of-dihydroxyallenes
Kocienski, P. J. et al. Angew. Chem., Int. Ed. 2009, 48, 5022.

Krause, N. et al. Org. Biomol. Chem. 2007, 5, 1519.
Tetrahedron 2009, 65, 1902.

30 min

125

67
43

The gold-catalyzed cycloisomerization of-dihydroxyallenes is not only stereoselective but also highly chemoselective.
(because no product resulting from nucleophilic attack of the -hydroxy group was observed.)
Cycloisomerization of -hydroxyallenes are often very slow, resulting in reaction times of several days.

cycloisomerization of -hydroxyallenes (6-endo cyclization)
Krause, N. et al. Org. Lett. 2006, 8, 4485.

8aNo trace of the 5-exo isomer could be detected
Addition of pyridine or 2,2-bipyridine induced a remarkable increase of thereactivity.
The yield was hardly affected by the solvent and the presence of silver salts.
(leads to the formation of cationic gold species.)

9a898a8b8c8d8e8f8b

Addition of N-iodosuccinimide (NIS) to the reaction mixture induces a tremendous
acceleration, leading to the formation of the corresponding iodinated dihydropyran.
This effect is probably caused by a very rapid iododeauration of a -goldintermediate(10, page 4) by NIS, which is activated by the gold catalyst.
Krause, N. et al. Eur. J. Org. Chem. 2010, 311.
108a1010(NIS 1.1-1.5 equiv.)

exo-hydroalkoxylation of hydroxyallenes
Widenhoefer, R. A. et al. J. Am. Chem. Soc. 2006, 128, 9066.

1112(5-exo)

13(6-exo)
12a13a141414 : Au[P(t-Bu)2(o-biphenyl)]Cl

the regioselectivity of Au-catalyzed hydroalkoxylation
depended strongly on the nature of the counterion. ?

5Mechanism.
Au[P(t-Bu)2(o-biphenyl)]Cl(5 mol%)

5.3
22

1

3:
1

1
3

enantioselective exo-hydroalkoxylation of hydroxyallenes
Widenhoefer, R. A. et al. Angew. Chem., Int. Ed. 2007, 46, 283.

Mechanism.
OH[Au2{(S)-4}Cl2] (2.5 mol%)
AgOTs (5 mol %)XRnOOHOtolune, -20 Cn-PrRAB

rac-9(S)-4HO

cat.

+tolune, -20 Cn-Pr(R,E)-10(28% ee):Hn-Pr(R,Z)-10 = 1.5:1(39%ee)45910910

In the major pathway, complexation of Au to the Si faceof the C4=C5 bond of rac-9 would form Au-allene complexes(Si,S)-I and (Si,R)-I.
The minor enantiomers (S,Z)-10 and (S,E)-10 would beformed through outer-sphere cyclization of the Au-allene
complexes (Re,S)-I and (Re,R)-I.

[a] Ratio of isomers refers to trans/cis or E/Z. [b] Combined yield of all diastereomers with>95% purity. [c] For reactions that form two diastereomers, ee values are reported astrans/cis or E/Z. [d] Determination of the enantiomeric purity was complicated by the coelutionof one enantiomer of (E)-6 with one enantiomer of (Z)-6 in HPLC. [e] Yield determined by 1H
NMR analysis with reaction carried out in [D8]toluene.

Toste, F. D. et al. Science 2007, 317, 496.

13aentry
123414bligand (L)(R)-3,5-xylyl-BINAP(R)-3,5-xylyl-BINAP(R)-DTBMSegphos
dppm

yield (%)
X
BF468
OPNB 89
BF479
1576

1314ee (%)
08265(S,S)-DIPAMP
15The use of chiral counterions, rather than chiral neutral ligands, could
provide high enantioselectivity in additions of oxygen nucleophiles to allenes.
Neither noncoordinating (BF4) nor more coordinating (OPNB) counterions
associated with dicationic chiral bisphosphine(digold) species induced
significant enantioselectivity in the cyclization.
Chiral Binol-derived phosphoric acid 15 in conjunction with thedppm ([bis(diphenyl)phosphino]methane) ligand proved optimal.

more-polar solvents, such as nitromethane or acetone,gave significantly lower enantiomeric excess values.
the less-polar benzene proved to be the optimal medium,providing the desired product in an exceptional 97% ee.
These findings are consistent with an ion-pair model, in which
the degree of enantioinduction depends on the proximity of thecounteranion to the cationic gold center

The chiral counterion can be combined additively with chiral ligands to enable
an asymmetric transformation that cannot be achieved by either method alone.
For the terminal allene(Entry 8), the enantiomeric excess could be improved from 80 to 92%
by using a chiral gold catalyst [(S,S)-DIPAMP](AuCl)2 together with the chiral silver salt.

62.1.3. Isomerization of allenic esters : formation of lactones
cyclization of allenic esters
Hammond, G. B. et al. J. Am. Chem. Soc. 2008, 130, 17642.
3a73a8In the presence of triflic acid or iodine, vinylgold compounds 3a undergo
protodeauration or iododeauration to the corresponding butenolides.

Thus, the mechanism of the gold-catalyzed cyclization ofallenic esters is similar to that proposed for -hydroxyallenes

1AThe structure of 3 was determined by
H, 13C, and 31P NMR spectroscopic data
and X-ray crystallography of complex 3d.

13B

dual-catalytic C-C bond formation as analternative to protodemetalation

10Blum, S. A. et al. J. Am. Chem. Soc. 2009, 131, 18022.

69116556b5a5b5h5i6h

The observed crossover is consistent with the intermediacy of 10 and 11
followed by intermolecular transmetalation and reductive elimination.

cyclization-oxidative alkynylation of allenic esters

14Gouverneur, V. et al. Org. Lett. 2010, 12, 4904.

12a13a1314a15C12D

121448 h13entryRyield (%)

entryRyield (%)

12345Ph
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H494427298
88678910

4-FC6H4
4-CF3C6H4
4-NO2C6H4Hn-Pr

78
6345
16287

2.2. Nitrogen Nucleophiles
2.1.1. endo-selective hydroamination
first intramolecular endo-selective hydroamination of allenes

the diminished reactivity of unprotected aminoallene is probably due
to deactivation of the gold catalyst by the Lewis-basic amino group.

Krause, N. et al. Org. Lett. 2004, 6, 4121.

12An oxygen atom of the protecting group could stabilize thezwitterionic complex C by coordination, and the cyclization
would proceed with partial isomerization (via single bond rotation)
to complex D, leading to a diminished diastereoselectivity.

cycloisomerization of allenic hydroxylamine or hydroxylamine ether
Krause, N. et al. Angew. Chem., Int. Ed. 2009, 48, 6339.
Different reaction rates in the endo cycloisomerization

all cycloisomerizations proceeded with exclusive 5-endo regioselectivity.

7a6apossible consequences for the cyclization of N-hydroxy-a-aminoallenes

53467
allenic substrates in which the heteroatom
positions were exchanged.
cyclization proceeded by the nucleophilic attack of the nitrogen atom
afforded a mixture of the 3,6-dihydro-1,2-oxazine and the 4,5-dihydroisoxazole

8a6-endo 9a9a85-endo

10a10a9a/10a10highly regioselective cyclization of the allenic hydroxylamine ether 8a to
4,5-dihydroisoxazole 10a could be achieved in the presence of cationic gold(I)complexes

8Proposed mechanism for the formation of cis-substituted dihydroisoxazoles
coordination of the gold catalyst to the allenic double bondadjacent to the hydroxylamine moiety affords complex Acomplex A undergoes a 5-endo cyclization to the zwitterionicspecies B.
the bulky gold moiety is preferentially situated trans to the group R35-endo cyclization

10 (cis)8

2.1.2. exo-selective hydroamination
exo-selective hydroamination of N-allenyl carbamates
Widenhoefer, R. A. et al. J. Am. Chem. Soc. 2006, 128, 9066.
Au[P(t-Bu)2(o-biphenyl)]Cl(5 mol%)Au[P(t-Bu)2(o-biphenyl)]Cl(5 mol%)81

92

formation of the E-alkene moiety of (R)-9 requires
selective cyclization of gold-allene intermediate cis-I
Au-catalyzed conversion of (S)-8 to (R)-9 presumably
involves rapid and reversible formation of trans-I followedby irreversible cyclization of cis-I to form II.
the transition state for C-N bond formation is destabilized
to a greater extent by a cis arrangement of the carbamate
moiety and n-propyl group (trans-III) than by a cis
arrangement of the Au[P(t-Bu)2-(o-biphenyl)] moiety andthe n-propyl group (cis-I II).

dynamic kinetic enantioselective hydroamination(DKEH) of allenes
Widenhoefer, R. A. et al. J. Am. Chem. Soc. 2007, 129, 14148.

9highly enantioselective hydroamination of allenes
Toste, F. D. et al. J. Am. Chem. Soc. 2007, 129, 2452.

the remaining coordinated counterion was crucial for stereoinduction.
replacing chloride with a larger coordinated counterion could further increase the transmission of chiral information.

enantioselective hydroaminations and hydroalkoxylations of allenes with hydroxylamines and hydrazines
Toste, F. D. et al. Angew. Chem., Int. Ed. 2010, 49, 598.

10

2.3. Sulfur Nucleophiles
cycloisomerization of -thioallenes
Krause, N. et al. Angew. Chem., Int. Ed. 2006, 45, 1897.

11

3. Conclusion(1) For carbophilic activation with Au(I), the reactivity and selectivityof cationic Au(I) complexes may be tuned by switching the ligand.
Biphenyl-substituted phosphines ligands have repeatedly been
observed to induce greater reactivity and modulate selectivity
among competing reaction pathways.
(b) The stability of Au(III) catalysts may be greatly improved with
N-donor ligands. In some cases, the reactivity of the Au(III) center may
be attenuated. Such ligands have also been successfully employedwith Au(I) precatalysts in oxidation and group transfer reactions.

Corma, A. et al. Angew. Chem., Int. Ed. 2007, 46, 1536.

[AuI][AuIII](54%)

The homogeneous catalysis studies show us that AuI,
which has the same d10 electronic configuration as Pd
metal and CuI, is active and very selective for performing
the Sonogashira reaction.
AuIII does not catalyze the cross-coupling reaction but
does catalyze the homocoupling condensation.

12