Gold-catalyzed domino reactions consisting of regio- and stereoselective 1,2-alkyl migration

Article abstract of DOI:10.1002/chem.201000667

[Chemical equation presented] Good as gold: A cationic gold(I)-catalyzed domino reaction involving highly regio- and stereoselective 1,2-alkyl migration and heterocyclization or oxygen transfer was developed, in which the counteranion of the gold catalyst could control the product selectivity (see scheme; DCE = 1,2dichloroethane, IPrAuCl= [1,3-bis(2,6diisopropylphenyl)-1H- imidazol2(3H)-ylidene]gold(I) chloride).

Full text of DOI:10.1002/chem.201000667

COMMUNICATION
DOI: 10.1002/chem.201000667
Gold-Catalyzed Domino Reactions Consisting of Regio- and Stereoselective
1,2-Alkyl Migration
Wenbo Li,[a] Yuying Li,[a] and Junliang Zhang*[a, b]
Domino or tandem reactions have shown their unrivalled
power in organic synthesis due to their high capability in
merging several reactions into one operation.[1] Recently, in-
corporation of a 1,2-alkyl migration step into the domino/
tandem reactions has been found to be a powerful strategy
for the rapid construction of architecturally complex mole-
cules.[2] Meanwhile, selective synthesis of different products
from the same starting material(s) by the subtle choice of
the catalyst is a challenging issue and has attracted much in-
terest by many chemists in recent years.[3–5]
Recently, Kirsch and co-workers reported an interesting
AuIII- and PtII-catalyzed tandem heterocyclization and pina-
col-type rearrangement for the efficient synthesis of substi-
tuted 3ACHTUNGTRENNUNG(2H)-furanones, in which the oxygen lone pair of the
hydroxy group may provide the critical driving force
(Scheme 1).[6] Very recently, we developed a tBuOK-cata-
lyzed tandem Michael addition of crotonate-derived malo-
nate 1 with 2-(1-alkynyl)-2-alken-1-ones 2 that led to the
formation of highly substituted, multifunctionalized cyclo-
pentanes 3 in good yields.[7] During this study, we envisioned
that compounds 3 would form an oxonium-containing vinyl–
gold intermediate in the presence of cationic gold complex,
which might in turn undergo a 1,2-alkyl migration through
pathway a or b (Scheme 1) and subsequent transformations
through pathway c or d. For this hypothesis, two challenging
selectivity issues need to be addressed: 1) the regioselective
Scheme 1. Previous work and proposed working hypothesis.
1,2-alkyl migration (pathway a or b), especially when R3 is
an alkyl group; 2) how to selectively get one product if sev-
eral products can be formed. We report herein a cationic
gold(I)-catalyzed domino reactions consisting of highly re-
gioselective and stereospecific 1,2-alkyl migration and heter-
ocyclization or oxygen transfer.[2k,8]
We tested this hypothesis by examining the tandem reac-
tion of ketone 3a under the catalysis of cationic gold(I)
complex. After several attempts, pleasingly, the reaction suc-
ceeded under conditions A (Scheme 2): IPrAuCl/AgOMs
(5 mol%), 1,2-dichloroethane (DCE), 808C gave the fused
5,6-bicyclic 6a containing a quaternary carbon stereocenter
in 94% isolated yield as a single diastereomer. The bicyclic
compound 6a was produced by a tandem regioselective 1,2-
[a] W. Li, Y. Li, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green
Chemistry and Chemical Processes
Department of Chemistry, East China Normal University
3663 N. Zhangshan Road, Shanghai 200062 (P.R. China)
Fax : (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Road
Shanghai 200032, (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000667.
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Scheme 2. Reaction conditions tested for the tandem reaction of 3a cata-
lyzed by a cationic gold(I) complex. DCE=dichloroethane, Ms=mesyl.
alkyl migration of the phenyl-substituted ketone and hetero-
cyclization. Interestingly, 84% yield of moncyclic compound
7a was achieved in a stereospecific fashion under condi-
tions B (Scheme 2). Compound 7a was formed by the
tandem selective 1,2-alkyl migration and oxygen-transfer
transformation. Under the catalysis of IPrAuCl/AgOMs
(5 mol%), compound 7a can be indeed afforded but in a
lower yield (77%) with some unidentified products after
longer reaction time (38 h).
With the optimal reaction conditions in hand, we next
turn to examine the scope of this product-selectivity con-
trolled tandem reaction (Scheme 3). Gratifyingly, under con-
ditions A and B, the 1,2-alkyl migration steps are highly re-
gioselective, that is, only the R3-substituted alkyl groups
would undergo the 1,2-migration. Under conditions A, the
reactions underwent a tandem heterocyclization and selec-
tive 1,2-alkyl migration leading to the fused 5,6-bicyclic
compounds in high to excellent yields. In contrast, monocy-
clic compounds 7 could be obtained in good to excellent
yields by a tandem 1,2-alkyl migration and oxygen-transfer
reaction in a stereospecific fashion under conditions B. Elec-
tron-donating and -withdrawing groups on the benzene ring
of R3 are compatible and the reactions give compounds 6 or
compounds 7 in good yields (Scheme 3, 6e, 7e, 6j, and 7j).
In some cases, 10 mol% of PTSA was added to accelerate
the reaction (Scheme 3, 7c, 7d, 7g, and 7j). The stereo-
chemistry and structures of representative compounds 6b
and 7a were further established by X-ray crystallography
analysis.[9]
Scheme 3. Selective transformations under two standard conditions.
[a] After consumption of the starting material, 10 mol% of 4-methylben-
zenesulfonic acid (PTSA) was added, E=CO2Me.
When the R3 group is aliphatic, the difference between
the two alkyl groups (the difference starts from the g
carbon) is very tiny. To our surprise, the 1,2-alkyl migrations
are still unbelievably highly selective; for example, the reac-
tion of compound 3i with R3 =n-C4H9 gave 6i (condi-
tions A) in 56% yield or 7i (conditions B) in 60% yield, re-
spectively (Scheme 4).
The reaction of compound 8 with a 6-membered ring
could give the 5,7-fused bicyclic compound 9 under both
conditions (82% yield under the catalysis of IPrAuCl/
AgPF6; Scheme 5a). Moreover, fused 5,6,5-tricyclic com-
pound 11 could be obtained from the reaction of bicyclic 10
in excellent yield, which provided a rapid and efficient route
to this kind of tricyclic compound (Scheme 5b).
Scheme 4.
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Gold-Catalyzed Domino Reactions
COMMUNICATION
Scheme 5.
Scheme 7.
Next, we examined substrate 12 with a cyclopentene ring.
Gratifyingly, 1,2-alkyl migration could also take place by a
3
3
À
chemoselective cleavage of the sp C sp C bond rather than
2
2
À
the sp C sp C bond. The reaction afforded a fused bicyclic
compound 13 under catalysis by IPrAuCl/AgSbF6 in DCE,
while 51% yield of substituted phenyl carboxylate was ob-
tained with Tf2NH (10 mol%; Tf=trifluoromethanesulfon-
yl) as an additive (Scheme 6).
Scheme 8. Plausible mechanism for product selectivity.
Scheme 6.
additional PTSA.[10] The final product 7 was formed by loss
of the acidic proton alpha to the ester group of intermediate
F.
Finally, to probe the stereoselectivity of the 1,2-alkyl mi-
gration step, optically active 3b (89% enantiomeric excess
(ee)) was prepared and subjected to conditions A and B. It
was found that the chiral information could be transferred
into the products to give 6b in 95% yield with 84% ee
under conditions A or 7b in 85% yield with 76% ee under
conditions B (Scheme 7). These results indicated that the
1,2-alkyl migration is a stereospecific step.
One plausible mechanism that accounts for the product
selectivity is depicted in Scheme 8. Spiro-bicyclic, oxonium-
containing vinyl–gold intermediate A, generated from the
intramolecular attack of the carbonyl group to the gold-acti-
vated alkyne,[2] would trigger a selective 1,2-alkyl migration
from the same face of the heterocyclic ring to give allylic
cation-containing vinyl–gold intermediate B. Deprotonation
would form the bicyclic vinyl–gold intermediate C. Upon
subsequent protonation, intermediate C would give the bicy-
clic product 6. Compound 6 would undergo further rear-
In summary, we have developed a cationic gold(I)-cata-
lyzed tandem reaction containing highly regioselective and
stereospecific 1,2-alkyl migration and heterocyclization or
oxygen transfer. The starting materials are easily prepared
from the tandem cyclization of 2-(1-alkynyl)-2-alken-1-ones
and crotonate-derived malonate, which would make these
reactions useful in target-oriented synthesis. Further studies
to expand the scope of the reaction, such as using substrates
with heterocyclic rings, and synthetic applications are ongo-
ing in our laboratory.
Experimental Section
Typical procedure for the synthesis of 6a under conditions A: IPrAuCl
(9.3 mg, 5 mol%), AgOMs (3.0 mg, 5 mol%) and dry DCE (2.5 mL)
were added to a dry Schlenk tube and the mixture was stirred at room
temperature for 0.5 h in the dark. Compound 3a (142.5 mg, 0.3 mmol)
was added and the resulting mixture was stirred at 808C for 3 h. After
the reaction was complete, which was determined by TLC analysis, the
À
rangement by the protonation and C O cleavage to give the
intermediates D, E, and F under catalysis by IPrAuPF6 or
Chem. Eur. J. 2010, 16, 6447 – 6450
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J. Zhang et al.
reaction mixture was concentrated under reduced pressure. The crude
product was purified by flash column chromatography on silica gel (hex-
anes/acetate=4: 1) to give 6a as a colorless oil (134.2 mg, 94%).
[3] For selected recent reports on product selectivity control by a cata-
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Typical procedure for the synthesis of 7a under conditions B: IPrAuCl
(9.3 mg, 5 mol%), AgPF6 (3.8 mg, 5 mol%) and dry DCE (2.5 mL) were
added to a dry Schlenk tube and the mixture was stirred at room temper-
ature for 0.5 h in the dark. Compound 3a (142.5 mg, 0.3 mmol) was
added and the resulting mixture was stirred at 808C for 22 h. After the
reaction was complete, which was determined by TLC analysis, the reac-
tion mixture was concentrated under reduced pressure. The crude prod-
uct was purified by flash column chromatography on silica gel (hexane/
acetate=4: 1) to give 7a as a white solid (119.9 mg, 84%).
Acknowledgements
We are grateful to the NSFC (20702015) and Science and Technology
Commission of Shanghai Municipality for financial support. This work
was also sponsored by the 973 program (2009CB825300).
[5] For examples from our research group, see: a) L. Liu, J. Zhang,
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Keywords: alkyl migration
chirality · domino reactions · regioselectivity
·
asymmetric synthesis
·
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[9] CCDC-755498 (6b) and 755499 (7a) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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3a (Scheme 2), indicating that the gold(I) catalyst may still play
some role for this transformation.
Received: March 16, 2010
Published online: April 30, 2010
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