Gold-catalyzed cyclization-cycloaddition cascade reactions of allenyl acetals with nitrones

Article abstract of DOI:10.1002/chem.201201777

Gold and silver: When allenyl acetals and nitrones are treated with a catalytic amount of a gold complex and a silver salt they react through a cyclization-cycloaddition cascade reaction to give a mixture of diastereomeric tricyclic products. The mixture converges to a single product upon acid hydrolysis (see scheme). The key intermediate is postulated to be a 1-methoxyfulvene species. Copyright

Full text of DOI:10.1002/chem.201201777

COMMUNICATION
DOI: 10.1002/chem.201201777
Gold-Catalyzed Cyclization–Cycloaddition Cascade Reactions of Allenyl
Acetals with Nitrones
Dhananjayan Vasu and Rai-Shung Liu*[a]
Gold-catalyzed cyclization–cycloaddition reactions[1] of
oxoalkynes,[2] oxoallenes,[3] oxoalkenes,[4] and allenyl ace-
tals[5] are powerful tools for accessing complicated carbo-
and oxacyclic frameworks. These reactions allow the simul-
taneous generation of two new rings and three chemical
bonds. In the presence of gold complexes, such difunctional
substrates undergo an initial cyclization to form reactive car-
bocation-like intermediates that can be trapped with suita-
ble nucleophiles to achieve stereocontrolled cycloaddi-
tions.[2–5] We recently reported[5b] a gold-catalyzed cascade
reaction between allenyl acetals and dinucleophilic phenols
and one between allylsilanes and cyclic 1,3-diones, reactions
that gave complex products stereoselectively. In those re-
ports, allenyl acetals function as dication equivalents
(Scheme 1). Herein, we report a different type of cycliza-
tion–cycloaddition cascade reaction of the same substrates
(1): they react as 1,2-dipole equivalents with suitable nitro-
nes in [3+2]-cycloadditions.[6,7]. Although the new reactions
afford two diastereomeric products 3, a subsequent HOAc-
Scheme 1. Different pathways for the cyclization–cycloaddition cascade
reaction of allenyl acetals.
catalyzed hydrolysis of this isomeric mixture gave tricyclic
ketones 6 as single diastereomers.
Table 1 shows our efforts to realize a cyclization–cycload-
dition cascade reaction between allenyl acetal 1a (1 equiva-
lent) and nitrone 2a (1.2 equivalents) in dichloroethane
Table 1. The activities of various gold complexes in catalyzing the cas-
cade reaction.
(DCE, 258C) by using various gold catalysts. Cationic gold
species were selected and screened for their activity in pro-
moting this cascade reaction because of their superior per-
formance in the cyclizations of allenyl acetals with dinucleo-
philic molecules.[5b] The use of [PPh3AuCl]/AgNTf2 resulted
in complete consumption of starting material 1a to give cy-
cloadducts 3a and 3a’ in 54% and 28% yields, respectively,
after their separation using silica-gel column chromatogra-
phy (Table 1, entry 1). We obtained product 3a exclusively
in 80% yield when using bulky complex [LAuNTf2] (L=(o-
Entry[a]
Catalyst
[PPh3AuCl]/AgNTf2
[LAuCl]/AgNTf2
[LAuCl]/AgSbF6
[IPrAuCl]/AgNTf2
[LAuCl]/AgNTf2
[LAuCl]/AgNTf2
AgNTf2
Solvent
3 Yield [%][b]
1
2
3
4
5
6
7
G
DCE
DCE
DCE
DCE
CH2Cl2
THF
3a (54), 3a’ (28)
3a (80)
3a (73)
3a (53), 3a’ (25)
3a (77)
3a (32), 3a’ (28)
3a (35), 3a’ (13)
AHCTUNGTRENNUNG
R
N
AHCTUNGTRENNUNG
biphenyl)PACHTUNGTRENNUNG(tBu)2; Table 1, entry 2). The use of [LAuSbF6]
G
led to a decrease in the yield of compound 3a (73%;
Table 1, entry 3). The use of [IPrAuCl]/AgNTf2 gave com-
pound 3a and 3a’ in 53% and 25% yields, respectively
DCE
[a] [1a]=0.2m. [b] Product yields were measured after purification. L=
(o-biphenyl)P(tBu)2, IPr=1,3-bis(diisopropylphenyl)imidazol-2-ylidene,
Tf=trifluoromethanesulfonyl.
AHCTUNGTRENNUNG
[a] Dr. D. Vasu, Prof. Dr. R.-S. Liu
Department of Chemistry
National Tsing Hua University
Hsinchu 30013, Taiwan (ROC)
Fax : (+886)3-5711082
(Table 1, entry 4). The solvent was varied for the reaction
catalyzed by [LAuCl]/AgNTf2 and it was found that di-
chloromethane (CH2Cl2) was as effective as DCE, giving cy-
cloadduct 3a as the sole product; however, the use of THF
gave compounds 3a and 3a’ in 32 and 28% yields, respec-
E-mail: rsliu@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201777.
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Table 3. The reaction with various allenyl acetals.
tively, (Table 1, entry 6). In a control experiment, we found
that AgNTf2 in DCE in the absence of a gold complex also
afforded compounds 3a and 3a’, albeit in low yields
Entry[a]
Allenyl acetal
Products (Yield)[b]
1
(Table 1, entry 7). In its H NMR spectrum, the signals asso-
ciated with the hydrogen atoms on the isoxazolidine ring in
compound 3a showed a coupling constant indicative of a
trans relationship (JH,H =1.6 Hz) whereas those in 3a’
showed a coupling constant indicative of a cis relationship
(JH,H =8.8 Hz). The molecular structure of compound 3a
was confirmed by X-ray diffraction analysis of derivative
4c.[8]
Table 2 shows the results of cyclization–cycloaddition re-
actions of allenyl acetal 1a with various nitrones 2b–2l; for
several of these reactions, we obtained the corresponding di-
astereomeric cycloadducts, which were separable using
1
2
3
Table 2. The reaction with various nitrones.
4
5
Entry[a]
Nitrone
t [min]
3 Yield [%][b]
R1, R2 (2)
1
2
3
4
5
6
7
8
Me, Ph (2b)
25
15
20
10
25
5
20
10
5
3b (65), 3b’ (17)
3c (82)
3d (61), 3d’ (17)
3e (87)
3 f (56), 3 f’ (19)
3g (58), 3g’ (28)
3h (67)
3i (56), 3i’ (23)
3j (43), 3j’ (41)
3k (43), 3k’ (41)
3l (38), 3l’ (15)
4-ClC6H4, Ph (2c)
4-BrC6H4, Ph (2d)
4-MeOC6H4, Ph (2e)
2-furanyl, Ph (2 f)
3-furanyl, Ph (2g)
2-thienyl, Ph (2h)
3-thienyl, Ph (2i)
Ph, 4-BrC6H4 (2j)
Ph, 4-MeC6H4 (2k)
Ph, 4-MeOC6H4 (2l)
6
9
10
11
10
5
[a] [1a]=0.2m. [b] Product yields were measured after purification.
7[c]
complicated mixture
silica-gel column chromatography. Using nitrone 2b, which
bears a methyl group at the nitrone carbon atom, desired
products 3b and 3b’ were obtained in 65% and 17% yields,
respectively (Table 2, entry 1). For nitrones 2c–2e, which
contain electron-deficient and electron-rich imine moieties
(R1 =4-XC6H4; X=Cl, Br, and OMe), the corresponding cy-
cloadducts 3c, 3d/3d’, and 3e were obtained in good yields
(total yield of diastereomeric products; Table 2, entries 2–4).
Nitrones 2 f–2i, which contain heteroaryl imine moieties
(R1 =2- and 3-furanyl, and 2- and 3-thienyl), were also used
as substrates in this cyclization–cycloaddition reaction and
the corresponding cycloadducts 3 f/3 f’, 3g/3g’, 3h, and 3i/3i’
with yields of greater than 67% (Table 2, entries 5–8). For
nitrones 2j–2l, which contain alterable aniline moieties
(R2 =4-XC6H4; X=Br, Me, and OMe), cycloadducts 3j/3j’,
3k/3k’, and 3l/3l’ were obtained in moderate to good yields
(53–84%; Table 2, entries 9–11).
[a] [1]=0.2m; reaction time of 15 min [b] Product yields were measured
after purification. [c] Reaction time of 60 min.
ene moieties, gave the desired cycloadducts 4b/4b’ and 4c
in 76–79% yields. The structure of compound 4c was con-
firmed by X-ray diffraction analysis.[8] The fact that species
4c was obtained with excellent diastereoselectivity is not
surprising because it has a similar structure to that of allenyl
acetal 1a. For substrate 1d, which contains a cycloheptenyl
moiety, the gold-catalyzed reaction gave cycloadduct 4d and
dienyl ester 5d in 41% and 35% yields, respectively
(Table 3, entry 3). For allenyl acetal 1e, which was used as
an isomeric mixture (Z/E=3.2:1), we obtained the desired
[3+2]-cycloadducts 4e/4e’ as two inseparable diastereomers
in equal proportions; the yield (73%) was estimated based
on the Z isomer of starting material 1e. We also prepared
acyclic Z-configured allenyl acetals 1 f and 1g and when
they were used as substrates in the cyclization–cycloaddition
reaction, the corresponding products 4 f/4 f’ and 4g/4g’ were
obtained in 75–83% overall yields (Table 3, entries 5 and 6).
We examined the reactions of nitrone 2a with various al-
lenyl acetals 1b–1g including both cyclic and acyclic com-
pounds (Table 3). The cyclization–cycloaddition of sub-
strates 1b and 1c, which both contain substituted cyclohex-
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Gold-Catalyzed Cyclization–Cycloaddition
COMMUNICATION
In contrast, the use of E-configured acyclic substrate 1g’
gave a complicated mixture of unknown species.
To our delight, the isomeric products of this reaction un-
dergo Brønsted-acid-catalyzed hydrolysis to give the same
product, an a-isopropylidene cyclopentanone. As shown in
Table 4, treatment of major diastereomer 3a with neat
Table 4. HOAc-catalyzed hydrolysis of cycloadducts.
Scheme 2. A plausible reaction mechanism.
Entry[a]
Cycloadduct
T [h]
Product (Yield)[b]
cloaddition reaction. In the presence of a cationic gold spe-
cies, the acetal moiety of species 1 is converted into an oxo-
nium ion moiety, thus giving intermediate A, which then un-
dergoes an intramolecular cyclization to give allylic cation
B. We envisage that the released Au–OMe species then as-
sists in the deprotonation of species B to give highly nucleo-
philic 1-methoxyfulvene C,[9–12] which reacts with nitrone
through an exo cycloaddition reaction to afford diastereo-
meric cycloadducts 3 and 4 as the major products. The ster-
eochemical outcome is consistent with a report on a [3+2]-
cycloaddition reaction of fulvene and nitrone.[12] This reac-
tion together with previous reports show that these allenyl
acetal substrates can undergo two different cascade reac-
tions catalyzed by similar gold catalysts.
1
8
2
3
4
8
12
12
The cyclization–cycloaddition cascade reaction described
herein involves an attack of 1-methoxyfulvene C on nitrone
whereas in the previously reported cascade reaction
(Scheme 1) a nucleophilic attack of either 1,3-diketones or
phenols at allylic cation B is involved.
We then attempted to obtain enantioenriched 3a to un-
derstand the nature of its hydrolysis with HOAc. The treat-
ment of substrate 1a with a range of chiral bisphosphine–
gold complexes, [LAu2Cl2]/2AgX, gave diastereomer 3a ex-
clusively in greater than 63% yield, albeit with low ee values
(5–18%).[13] With [LAu2Cl2]/2AgX (L=(R)-DM-Segphos
and X=NTf2), we obtained (+)-3a in 18% ee (Scheme 3).
A further treatment of this sample with neat HOAc (258C,
8 h) gave desired 6a (2% ee) with a large loss in optical
purity. This observation suggests that Brønsted acid not only
enables the hydrolysis of the enol ether of 3a to ketone 6a,
but also leads to the racemization of 3a, a process that pre-
sumably involves the two key steps, 6a!D and F!ent-6a;
this process causes the configurations of all three stereogen-
ic centers to invert in a reversible manner.
In summary, we have developed a gold-catalyzed cycliza-
tion–cycloaddition cascade reaction between allenyl ace-
tals[14] and nitrones. A key intermediate in the cascade reac-
tion is postulated to be a 1-methoxyfulvene species.[12] These
reactions reveal that the allenyl acetal substrates act as 1,2-
dipole equivalents, a behavior that is in contrast with the
“dication behavior” described in our previous investiga-
tion.[5b] Although we often obtained two diastereomeric
products in this cascade reaction, HOAc-catalyzed hydroly-
5
10
[a] [Cycloadduct]=0.2m. [b] Product yields were measured after purifica-
tion.
HOAc at 258C (8 hours) afforded tricyclic ketone 6a in
76% yield (Table 4, entry 1); 1H NOE spectra and X-ray
diffraction analysis[8] confirmed its structure, which contains
trans-related geminal hydrogen atoms on the isoxazolidine
ring. Interestingly, a similar hydrolysis of its isomer, 3a’, af-
forded the same ketone 6a in 73% yield (Table 4, entry 2).
We also subjected other diastereomeric mixtures to this
acid-catalyzed hydrolysis: 4b/4b’ (d.r.=3.9:1) and 4e/4e’
(d.r.=1:1) were converted into bicyclic ketones 6b (60%)
and 6d (76%), respectively, as the only products (Table 4,
entries 3 and 5). Compound 4c was converted into desired
ketone 6c in 71% yield (Table 4, entry 4).
This new nitrone-based cyclization—cycloaddition reac-
tion is mechanistically interesting because the allenyl acetals
function as 1,2-dipole equivalents. Scheme 2 shows a plausi-
ble mechanism for the nitrone-based cyclization–[3+2]-cy-
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R.-S. Liu and D. Vasu
R.-S. Liu, J. Am. Chem. Soc. 2009, 131, 2090; i) A. S. K. Hashmi, A.
Littmann, Chem. Asian J. 2012, 7, 1435.
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[6] For [3+2]-cycloaddition reactions of nitrones, see selected reviews:
a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; A. Padwa, W. H. Pear-
son, Eds.; John Wiley & Sons Inc.: New York, 2002; b) L. M. Stan-
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Jørgensen, Chem. Rev. 1998, 98, 863; d) F. Cardona, A. Goti,
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[7] For gold-catalyzed [3+n]-cycloaddition reactions of nitrones, see
Refs. [2c] and [2d] and: a) Y. Bai, J. Fang, J. Ren, Z. Wang, Chem.
Eur. J. 2009, 15, 8975; b) Y. Zhang, F. Liu, J. Zhang, Chem. Eur. J.
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[8] CCDC-879022 (4c) and 879023 (6a) contains 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.
Scheme 3. Loss of optical purity in HOAc-catalyzed hydrolysis.
[9] Fulvenes are known to be nucleophilic; for a review, see: M. Neu-
enschwander, Chem. Double-Bonded Funct. Groups 1989, 2, 1131.
[10] Selected examples of various cycloaddition reactions of fulvenes
with dipolarophiles: a) B.-C. Hong, Y.-J. Shr, J.-L. Wu, A. K. Gupta,
K.-J. Lin, Org. Lett. 2002, 4, 2249; b) N. Cos¸kun, J. Ma, S. Azimi, C.
Gꢃrtner, I. Erden, Org. Lett. 2011, 13, 5952; c) Y. Hayashi, H.
Gotoh, M. Honma, K. Sankar, I. Kumar, H. Ishikawa, K. Konno, H.
Yui, S. Tsuzuki, T. Uchimaru, J. Am. Chem. Soc. 2011, 133, 20175;
d) T.-C. Wu, K. N. Houk, J. Am. Chem. Soc. 1985, 107, 5308; e) L.-
C. Dunn, Y.-M. Chang, K. N. Houk, J. Am. Chem. Soc. 1976, 98,
7095; f) B.-C. Hong, S.-C. Sun, Y.-C. Tsai, J. Org. Chem. 1997, 62,
7717.
sis of these isomeric mixtures afforded isopropylidene cyclo-
pentanones as single products.
Acknowledgements
We thank National Science Council, Taiwan and National Tsing Hua
University for financial support of this work.
[11] Generation of fulvene compounds by using gold catalysis; see a) L.
Ye, Y. Wang, D. H. Aue, L. Zhang, J. Am. Chem. Soc. 2012, 134, 31;
b) A. S. K. Hashmi, I. Braun, M. Rudolph, F. Rominger, Organome-
tallics 2012, 31, 644; c) A. S. K. Hashmi, M. Wieteck, I. Braun, P.
Nçsel, L. Jongbloed, M. Rudolph, F. Rominger, Adv. Synth. Catal.
2012, 354, 555; d) A. S. K. Hashmi, I. Braun, P. Nçsel, J. Schꢃdlich,
M. Wieteck, M. Rudolph, F. Rominger, Angew. Chem. 2012, 124,
4532; Angew. Chem. Int. Ed. 2012, 51, 4456.
Keywords: allenes
homogeneous catalysis · nitrones
·
G
·
gold
·
[1] For reviews on gold-catalyzed cycloaddition reactions, see:
a) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180; b) A. Fꢁrstner,
Chem. Soc. Rev. 2009, 38, 3208; c) N. T. Patil, Y. Yamamoto, Chem.
Rev. 2008, 108, 3395; d) S. M. Abu Sohel, R.-S. Liu, Chem. Soc. Rev.
[12] For [3+2]-cycloaddition reactions of fulvenes and nitrones of a spe-
cial type, see F. Djapa, K. Clamala, J.-M. Melot, J. Vebrel, G.
Herlem, J. Chem. Soc. Perkin Trans. 1 2002, 687.
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[13] The ee values and yields of compound 3a observed when using
other chiral bisphosphine–gold complexes [LAu2Cl2]/2AgX in cold
DCE (08C) are as follows: L=(R)-DTBM-Segphos (X=NTf2, 71%
yield, 11% ee; X=OTf, 67% yield, 5% ee) and L=(R)-MeO-
DTBM-Biphep (X=NTf2, 63% yield, 11% ee).
[14] For other metal-mediated reactions of allenyl acetals, see reported
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Y. Lim, Tetrahedron Lett. 2002, 43, 9105; b) F. Villar, P. Renaud, Tet-
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Received: May 21, 2012
Revised: August 20, 2012
Published online: && &&, 0000
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Gold-Catalyzed Cyclization–Cycloaddition
COMMUNICATION
Gold Catalysis
D. Vasu, R.-S. Liu* .......... &&&& — &&&&
Gold-Catalyzed Cyclization–Cycload-
dition Cascade Reactions of Allenyl
Acetals with Nitrones
Gold and silver: When allenyl acetals
and nitrones are treated with a cata-
lytic amount of a gold complex and a
silver salt they react through a cycliza-
tion—cycloaddition cascade reaction
to give a mixture of diastereomeric tri-
cyclic products. The mixture converges
to a single product upon acid hydroly-
sis (see scheme). The key intermediate
is postulated to be a 1-methoxyfulvene
species.
Chem. Eur. J. 2012, 00, 0 – 0
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