Gold-catalyzed stereocontrolled oxacyclization/[4+2]-cycloaddition cascade of ketone-allene substrates

Article abstract of DOI:10.1021/ja1043837

We report the first success on the Au-catalyzed tandem oxacyclization/[4+2] -cycloaddition cascade using ketone-allene substrates to give highly substituted oxacyclics with excellent stereocontrol. In contrast to oxo-alkyne substrates, the resulting cycloadducts are isolable and efficiently produced from a reasonable scope of enol ethers.

Full text of DOI:10.1021/ja1043837

Published on Web 06/22/2010
Gold-Catalyzed Stereocontrolled Oxacyclization/[4+2]-Cycloaddition Cascade
of Ketone-Allene Substrates
Tse-Min Teng and Rai-Shung Liu*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu, Taiwan, ROC
Received May 20, 2010; E-mail: rsliu@mx.nthu.edu.tw
Table 1. Screening of Catalytic Activity over Various Metal
Catalysts
Abstract: We report the first success on the Au-catalyzed tandem
oxacyclization/[4+2]-cycloaddition cascade using ketone-allene
substrates to give highly substituted oxacyclics with excellent
stereocontrol. In contrast to oxo-alkyne substrates, the resulting
cycloadducts are isolable and efficiently produced from a reason-
able scope of enol ethers.
catalyst
(mol %)
product
(yield)b
entry
1
substratea
1a
condition
Metal-catalyzed cycloaddition/annulation reactions are important
tools to access complex molecular frameworks.1 The Au- and Pt-
catalyzed activation of alkynes enables the generation of unusual
intermediates to react with dipolarophiles in a cycloaddition
fashion.2 Such reactions have attained considerable success only
on oxo-alkyne substrates.1a,b In the presence of Au or Pt catalysts,
2-oxo-1-alkynylbenzenes form metal-containing benzopyriliums (I)
or carbonyl ylides (I′) that react with dipolarophiles to give
hypothetic [4+2]- or [3+2]-cycloaddition intermediates.3,4 Genera-
tion of 1,n-dipole species remains unexplored for oxo-allene
substrates. This approach is mechanistically appealing because of
the uncertain workability of oxonium-vinylmetal (II) or benzopy-
rilium (III) as 1,n-dipoles (n ) 4, 5). Species II is kinetically
favored by the Pt or Au-π-allene bonding,5 but its participation is
absent in this work.
AuCl3 (5)
DCE
(80 °C, 24 h)
DCE
(50 °C, 20 h)
DCM
(30 °C, 8 h)
DCM
(30 °C, 2 h)
DCM
(30 °C, 2.5 h)
DCM
(30 °C, 1 h)
DCM
(30 °C, 2 h)
DCM
1a (85%)
1a (46%)c
3a (83%)
2
1a
PtCl2/CO (5)
3
1a
Ph3PAuCl (3)/
AgSbF6 (3)
AuCIL (3)/
AgSbF6 (3)
AuCIL (3)/
AgNTf2 (3)
AuCIL (3)/
AgNTf2 (3)
AuCIL (3)/
AgNTf2 (3)
AuCIL (5)
4
1a
4a (29%),
4a′ (56%)
4a (trace),
4a′ (79%)
3a (40%),
4a′ (46%)
4a (trace),
4a′ (86%)
1a (94%)
5
1a
6
1a
7
3a
8
1a
(30 °C, 20 h)
DCM
(30 °C, 20 h)
DCM
9
1a
AgNTf2 (5)
1a (62%),
3a (17%)
4a (48%),
4a′ (22%)
Scheme 1
10
1a
IPrAuCl (3)/
AgNTf2 (3)
(30 °C, 2 h)
a L
) P(t-Bu)2(o-biphenyl), [substrate] ) 0.1 M, DCM )
dichloromethane, DCE
)
1,2-dichloroethane. b Isolated yields were
reported after purification from a silica gel column. c Decomposition of
starting 1a was observed in entry 2.
conversion to 4a′ with the same gold catalyst (entry 7). Control
experiments indicate that ClAuP(t-Bu)2(o-biphenyl) and AgNTf2
alone were catalytically inactive (entries 8-9). An altered chemose-
lectivity was observed for IPrAuCl/AgNTf2 (IPr ) 1,3-bis(diiso-
propyl-phenyl)imidazol-2-ylidene) that preferably gave 4a as the
major product (entry 10). Characterization of the structure of product
4a′ relies on an X-ray diffraction study of its analogue 4b′ (Table
2, entry 1).
We prepared alkynyl acetate 1a readily from 2′-bromoacetophe-
none. This substrate works as a precursor to generate ketone-allene
3a via a catalytic 1,3-acyloxy shift.6 As shown in Table 1, treatment
of compound 1a with n-butyl vinyl ether (2a, 3 equiv) with PtCl2/
CO or AuCl3 in hot dichloroethane (50-80 °C) gave an exclusive
recovery of unreacted 1a. The use of PPh3AuCl/AgSbF6 (3 mol
%) in dichloromethane (DCM) produced ketone-allene 3a in 83%
yield, but with no tractable amount of cycloadducts 4a/4a′. We
were pleased to discover that ClAuP(t-Bu)2(o-biphenyl)/AgSbF6 (3
mol %) enabled the desired cyclization/cycloaddition cascade to
give 4a (29%) and 4a′ (56%) as a diastereomeric mixture, separable
on a silica column. The stereoselectivity is greatly enhanced with
ClAuP(t-Bu)2(o-biphenyl)/AgNTf2, giving only 4a′ in 79% yield
(entry 5); within a brief time (1 h), we obtained ketone-allene 3a
in 40% yield in addition to the desired 4a′ (46%, entry 6). The
intermediacy of ketone-allene 3a was confirmed by a complete
We prepared ketone substrates 1b-1e bearing altered R1 and
R2 substituents to examine the scope of this catalysis, as depicted
in Table 2. Herein, the aldehyde substrates are not studied due to
the intrinsic instability of 2-allenyl benzaldehyde intermediates.7
This reaction works well with both ethyl- and n-butyl vinyl ether
(2a-2b), and it is also efficient with alterations of the R1 (Me,
n-Bu, i-Bu) and R2 alkyls (Me, n-Pr) of substrates 1a-1e. In entries
2, 4, and 5, due to the poor diastereoselectivity or chromatographic
inseparable property, the cycloadducts 4b/4b′ and 4c/4c′ were
subject to deacylation with NaOMe in MeOH to give ketone
derivatives 5b, 6b, and 6c with high dr values (8.5-10.0:1). For
9
9298 J. AM. CHEM. SOC. 2010, 132, 9298–9300
10.1021/ja1043837  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Au(I)-Catalyzed Oxacyclization/Cycloaddition Cascade
with Vinyl Ethers
Table 3. Au(I)-Catalyzed Oxacyclization/Cycloaddition Cascade
with Substituted Enol Ethers
t
(step i)
entry
1
substratesa
alkene
productsb
R1 ) n-Bu, R2 ) Me (1a) R3 ) Me, R4 ) Et
(2c, Z/E ) 1.8)
4 h
8a (76%,
dr > 20:1)
c
enol
ether
time
(step i)
products
(yield)b
R1 ) R2 ) Me (1b)
2c
4 h
4 h
4 h
8b (82%,
dr ) 7.3:1)
8c (81%,
entry
1
substratesa
R1 ) R2 ) Me (1b)
1b
2
c
R1 ) Me, R2 ) n-Pr (1c)
2c
R3 ) Et (2b)
1.5 h 4b (46%),
4b′ (42%)
1.5 h 5b (85%,
3
c
dr > 15:1)
4
R1 ) n-Bu, R2 ) Me (1a) 2c (Z/E ) 0.5)
8a (31%,
2
2b
c,d
dr > 20:1)
dr ) 9:1)c
5
R1 ) n-Bu, R2 ) Me (1a) R3, R4 ) -(CH2)3- (2d) 1 h
7a′ (82%,
3
R1 ) n-Bu, R2 ) Me (1a) R3 ) n-Bu (2a) 2 h
4a′ (79%,
dr > 20:1)
6b (83%,
dr > 20:1)
6
R1 ) R2 ) Me (1b)
2d
2d
2 h
1 h
2 h
3 h
5 h
9b (72%,
c
4
R1 ) Me, R2 ) Me (1b)
R1 ) Me, R2 ) n-Pr (1c)
2a
2a
2 h
2 h
2 h
3 h
dr ) 10:1)
9c (64%,
dr ) 10:1)c
6c (76%,
7
R1 ) Me, R2 ) n-Pr (1c)
c
dr ) 7.5:1)
5
R1 ) n-Bu, R2 ) n-Pr (1d) 2d
7d′ (75%,
dr ) 8.5:1)c
4d′ (69%,
dr > 20:1)
4e′ (61%,
dr > 20:1)d
8
dr > 20:1)
6
R1 ) n-Bu, R2 ) n-Pr (1d) 2a
R1 ) i-Bu, R2 ) Me (1e)
9
R1 ) i-Bu, R2 ) Me (1e)
R1 ) Ph, R2 ) Me (1f)
R1 ) R2 ) Me (1b)
2d
2d
7e′ (63%,
e
dr > 20:1)
7
2a
10
11
7f′ (58%,
dr > 20:1)
10b (53%,
dr ) 6.5:1)
e
R3, R4 ) -(CH2)2- (2e) 2 h
c,e
a ClAuP(t-Bu)2(o-biphenyl)/AgNTf2 (3 mol %), [substrate] ) 0.1 M,
DCM, enol ethers (3 equiv). b Isolated yields were reported after
purification from a silica gel column. c The configuration at the *C
carbon is responsible for the occurrence of two diastereomers. d Messy
mixture was obtained for portion of 1e.
a ClAuP(t-Bu)2(o-biphenyl)/AgNTf2 (3 mol %), [substrate] ) 0.1 M,
DCM, enol ethers (3 equiv). b Isolated yields were given after
purification from a silica gel column. c The configuration at the *C
carbon is responsible for the occurrence of two diastereomers.
d Ketone-allene 3a was obtained in 61%. e Messy mixture was obtained
for portion of 1b, 1e, or 1f.
substrates 1a and 1d-1e bearing a bulky R1 (R1 ) n-Bu or i-Bu),
the same reactions gave compounds 4a′ and 4d′-4e′ with excellent
dr values (>20:1), due to a large steric interaction of the other
isomers 4. The structure of representative compound 4b′ is
determined by an X-ray diffraction study.8
Table 4. Au(I)-Catalyzed Oxacyclization/Cycloaddition Cascade of
Substituted Aromatic Substrates
The scope of this new synthetic method is substantially expanded
with its compatibility with substituted enol ethers including
1-ethoxypro-1-ene (2c, Z/E ) 1.8, 3 equiv) and cyclic enol ethers
2d-2e, as illustrated in Table 3. These enol ethers proceeded with
excellent diastereoselectivity that we did not obtain any epimers
bearing mutual trans-R3 and OR4 substituents. For starting ketones
1a-1c and 1-ethoxypro-1-ene (entries 1-3), their cycloadducts
8a-8c were obtained as one single diastereomer with its structure
carefully determined by 1H-NOE, suggesting that cis-enol ether 2c
is more active than its trans isomer. Indeed, the reaction of 2c (Z/E
) 0.5, 3 equiv) with ketone 1a gave cycloadduct 8a in diminished
yield (31%) together with ketone-allene 3a (61%). This new tandem
cascade also works with 3,4-dihydro-2H-pyran (2d) that reacts with
ketones 1a-1f smoothly (entries 5-10), giving satisfactory yields
(58-82%) of the expected cycloadducts 7a′, 7d′-7f′ or the
deacylation products 9b-9c. 2,3-Dihydrofuran is also applicable
to this catalysis, and it reacts with ketone 1b to deliver compound
10b in 53% yield (dr ) 6.5:1).
entry
substratesa
t [h]
products (yield)b
1
2
3
4
5
6
X ) H, Y ) F (1g)
X ) F, Y ) H (1h)
X ) H, Y ) Cl (1i)
X ) Cl, Y ) H (1j)
X ) H, Y ) OMe (1k)
X ) OMe, Y ) H (1l)
6
8
6
6
2
2
7g′ (78%, dr >20:1)
7h′ (72%, dr >20:1)
7i′ (42%, dr >20:1)
7j′ (47%, dr >20:1)
7k′ (87%, dr >20:1)
7l′ (85%, dr >20:1)
a ClAuP(t-Bu)2(o-biphenyl)/AgNTf2 (3 mol %), [substrate] ) 0.1 M,
DCM, enol ethers (3 equiv.). b Isolated yields were given after
purification from a silica gel column.
Scheme 2
We also prepared new substrates 1g-1l to examine the effects
of their phenyl substituents; their reactions with 3,4-dihydro-2H-
pyran are described in Table 4. Good yields (72-87%) were
obtained for cycloadducts 7g′-7h′ and 7k′-7l′ bearing fluoro and
methoxy substituents because these π-donor groups stabilize
proposed benzopyriliums III (Vide infra). Hypothetic [4+2]-
cycloadditions of free benzopyriliums3f-h and their metal-containing
analogues3 are restricted to unsubstituted benzenes and methoxy
derivatives. The workability with substrates 1i and 1j bearing
electron-deficient benzenes highlights the high reactivity of our new
benzopyrilium (III).
Structural analysis of resulting cycloadducts asserts the inter-
mediacy of benzopyrilium (III), although gold-π-allene species 3
has cationic character located mainly at the C(1)- and C(3)-carbons.5
We hypothesize a fast equilibrium between ketone-allene (3) and
intermediate (II), but the cycloadducts expected from species (II)
fail to proceed. Here, we propose a concerted mechanism (i) for
9
J. AM. CHEM. SOC. VOL. 132, NO. 27, 2010 9299

C O M M U N I C A T I O N S
Md.; Liu, R.-S. Chem. Soc. ReV. 2009, 38, 2269. (c) Shapiro, N. D.; Toste,
F. D. Synlett 2010, 675.
the [4+2]-cycloadditions of the new benzopyrilium (III). As shown
in Scheme 2, cis-substituted enol ether approaches the pyrilium
core of species III with its R3 and OR4 lying away from the bulky
gold-containing substituent. We envisage that the allylic gold
fragment of benzopyrilium III raises the HOMO energy level at
the C(4)-carbon, facilitating this concerted process.2b,9 The stepwise
pathway (ii) involving cationic intermediates V and V′ is opposed
by our observation that no epimers resulted from the conformer V′
which is actually favored by steric interactions of the cis-R3 and
OR4 substituents of species V. Species (III) is more useful than
reported benzopyriliums3 in synthetic utility, because of its isolable
and stereocontrolled [4+2]-cycloadducts.
(2) Selected examples: (a) Shapiro, N. D.; Shi, Y.; Toste, F. D. J. Am. Chem.
Soc. 2009, 131, 11654. (b) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc.
2008, 130, 9244. (c) Li, G.; Huang, X.; Zhang, L. J. Am. Chem. Soc. 2008,
130, 6944. (d) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc.
2008, 130, 1814. (e) Liu, F.; Yu, Y.; Zhang, J. Angew. Chem., Int. Ed. 2009,
48, 5505.
(3) [4+2]-Cycloadducts from benzopyrilium (I) are kinetically unstable and
easily rearranged to naphthalene derivatives; only allylic alcohols3e allow
the interception. See selected examples: (a) Asao, N. Synlett 2006, 1645.
(b) Asao, N.; Kasahara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003,
42, 3504. (c) Asao, N.; Akiwa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 7458. (d) Dyker, G.; Hildebrandt, D.; Liu, J.; Merz, K. Angew. Chem.,
Int. Ed. 2003, 42, 4399. (e) Hsu, Y.-C.; Ting, C.-M.; Liu, R.-S. J. Am. Chem.
Soc. 2009, 131, 2090. (f) Barluenga, J.; Va´zquez-Villa, H.; Ballesteros, A.;
Gonza´lez, J. M. AdV. Synth. Catal. 2005, 347, 526. (g) Barluenga, J.;
Va´zquez-Villa, H.; Ballesteros, A.; Gonza´lez, J. M. Org. Lett. 2003, 5, 4121.
(h) Hu, Z.-L.; Qian, W.-J.; Wang, S.; Wang, S.; Yao, Z.-J. Org. Lett. 2009,
11, 4676.
(4) For [3+2]-cycloadducts, see selected examples: (a) Kusama, H.; Funami,
H.; Shido, M.; Hara, Y.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2005,
127, 2709. (b) Kusama, H.; Funami, H.; Takaya, J.; Iwasawa, N. Org. Lett.
2004, 6, 605. (c) Oh, C. H.; Lee, J. H.; Lee, S. J.; Kim, J. I.; Hong, C. S.
Angew. Chem., Int. Ed. 2008, 47, 7505. (d) Oh, C. H.; Lee, S. M.; Hong,
C. S. Org. Lett. 2010, 12, 1308.
(5) For metal-allene bonding having the following dipolar character, see selected
examples:(a) Kusama, H.; Ebisawa, M.; Funami, H.; Iwasawa, N. J. Am.
Chem. Soc. 2009, 131, 16352. (b) Lee, J. H.; Toste, F. D. Angew. Chem.,
Int. Ed. 2007, 46, 912. (c) Lemiere, G.; Gandon, V.; Cariou, K.; Hours, A.;
Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem.
Soc. 2009, 131, 2993.
Equation 1 shows the use of this catalysis for a stereoselective
synthesis of a highly oxygenated molecule. A sequential treatment
of compound 6c with m-CPBA (1.5 equiv), followed by the
DIBAL-H cleavage of resulting acetal, gave triol derivative 11
(65%) as a single diastereomer.
In summary, we report the first success on the Au-catalyzed
tandem oxacyclization/[4+2]-cycloaddition cascade using ketone-
allene substrates to give highly substituted oxacyclics with excellent
stereocontrol. Control experiments reveal the involvement of
benzopyrilium intermediates (III) that is active for [4+2]-cycload-
dition reactions.9 In contrast to oxo-alkyne substrates,3 the resulting
cycloadducts are isolable and efficiently produced from a reasonable
scope of enol ethers. Efforts to realize the asymmetric version of
this catalysis is under current investigation.
(6) (a) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (b)
Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804. (c) Shi, F.-Q.; Li, X.; Xia,
Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 15503. (d) Schwier,
T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am.
Chem. Soc. 2007, 129, 9868. (e) Cordonnier, M.-C.; Blanc, A.; Pale, P. Org.
Lett. 2008, 10, 1569.
(7) Previously, we attempted to synthesize allenyl aldehydes in pure form, but
its rapid decomposition in solution hampers its purification and isolation.
See: Teng, T.-M.; Lin, M.-S.; Vasu, D.; Bhunia, S.; Liu, T.-A.; Liu, R.-S.
Chem.sEur. J. 2010, 16, 4744.
Acknowledgment. The authors wish to thank the National
Science Council, Taiwan for supporting this work.
Supporting Information Available: Experimental procedures,
characterization data of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(8) The X-ray crystallographic data of compound 4b′ are provided in the
Supporting Information.
(9) (a) Bhunia, S.; Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16488. (b) Jime´nez-
Nu´n˜ez, E.; Raducan, M.; Lauterbach, T.; Molawi, T.; Solorio, C. R.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2009, 48, 6152.
References
(1) Reviews for gold-catalyzed annulation and cycloaddition reactions, see:(a)
Patil, N. T.; Yamamoto, Y. Chem. ReV. 2008, 108, 3395. (b) Abu Sohel, S.
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9300 J. AM. CHEM. SOC. VOL. 132, NO. 27, 2010