Intermolecular gold-catalyzed diastereo- and enantioselective [2+2+3] cycloadditions of 1,6-enynes with nitrones

Article abstract of DOI:10.1002/anie.201203507

Going for gold: The title reaction has been developed and demonstrates a wide substrate scope with respect to the 1,6-enynes and nitrones (see scheme; DCE=1,2-dichloroethane, Tf=trifluoromethanesulfonyl). The results for the enantioselective versions are

Full text of DOI:10.1002/anie.201203507

Angewandte
Chemie
DOI: 10.1002/anie.201203507
Synthetic Methods
Intermolecular Gold-Catalyzed Diastereo- and Enantioselective
[2+2+3] Cycloadditions of 1,6-Enynes with Nitrones**
Sagar Ashok Gawade, Sabyasachi Bhunia, and Rai-Shung Liu*
Metal-mediated cycloaddition reactions are a powerful tool
for accessing carbo- and heterocyclic frameworks.[1] Nitrones
serve as three-atom building units in various [3+2] and [3+3]
cycloadditions with suitable dipolarophiles to access five- and
six-membered nitrogen heterocycles.[2,3] The utility of such
reactions is manifested not only in the easy access to natural
products,[2a] but also in the development of many enantiose-
lective cycloadditions. We are aware of few reports of nitrone
cycloadditions for the synthesis of seven-membered hetero-
cycles.[4] The reported examples are exclusively focused on
[4+3] nitrone cycloadditions,[4–6] as shown by the work of
Hayashi and co-workers (Scheme 1).[4c] We report herein the
gold-catalyzed cyclization/[2+2+3] cycloaddition cascade[5,6]
between nitrones and the readily available 1,6-enynes 1 to
give the highly substituted 1,2-oxazepane derivatives 3 and 5
with satisfactory diastereo- and enantioselectivity. The impor-
tance of this reaction is reflected by the occurrence of 1,2-
oxazepane moieties in several bioactive molecules.[7]
fashion,[10a,c,11] but those reactions were inevitably accompa-
nied by a significant amount of side products.[10a] Helm-
chen[10b] studied the same cycloaddition using unsubstituted
1,6-enynes, but carbonyl compounds other than 2-nitrobenz-
aldehyde were used in large excess (20 equiv). The use of 1,6-
enynes as efficient 1,4-dipole equivalents is only feasible in
intramolecular system.[10c]
We sought to realize the reaction using the 1,6-enyne 1a
(Table 1). The primary task was to reduce the production of 3-
Table 1: Nitrone cycloaddition with various catalysts.
Entry
Catalyst[a]
Solvent
3a[b]
4[b]
Yield [%]
Yield [%]
1
2
3
4
5
6
7
8
AgSbF6
AgNTf2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
–
–
46
43
15
20
–
[PPh3AuCl]/AgSbF6
[PPh3AuCl]/AgNTf2
[LAuCl]/AgSbF6
[LAuCl]/AgNTf2
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgNTf2
[LAuCl]/AgSbF6
[LAuCl]/AgSbF6
[LAuCl]/AgSbF6
39
35
95
86
75
72
87
82
71
–
15
18
–
–
–
9
10
11
DCM
1,4-dioxane
toluene
[a] L=P(tBu)2(o-biphenyl), [substrate]=0.19m. [b] Product yields are
reported for compounds isolated after purification on silica gel.
DCE=1,2-dichloroethane, IPr=1,3-bis(diisopropylphenyl)imidazol-
2-ylidene, Tf=trifluoromethanesulfonyl.
Scheme 1. Cycloaddition reactions for nitrones.
isobutenyl-1H-indene (4), which results from a competitive
cycloisomerization.[12] In a standard operation, the nitrone 2a
(ca. 0.38m) was first stirred with the catalyst (5 mol%) in
DCE (258C) for five minutes, and then 1a in DCE (equal
volume) was slowly added to this solution, using a syringe
pump, over a 1 hour period.[13] The conversion was complete
at the end of the addition. As shown in entries 1 and 2, we
obtained only 4 in 46 and 43% yield using AgSbF6 and
AgNTf2, respectively. Cationic gold complexes, [PPh3AuCl]/
AgX (X = SbF6, NTf2), gave the nitrone cycloadduct 3a as
a single diastereomer in moderate yield (35–39%) together
with 4 in 15–20% yield (entries 3 and 4). Pleasingly, the use of
[P(o-biphenyl)(tBu)2AuCl]/AgX (X = SbF6, NTf2) gave the
desired 3a in 95 and 86% yield (entries 5 and 6). [IPrAuCl]/
AgX (X = SbF6, NTf2) gave 3a in 75–72% yield in addition to
a small amount of 4 (15–18%; entries 7 and 8). For
For 1,6-enynes, the interception of the 1,4-dipole equiv-
alent A is challenging because of its intrinsic reactivity toward
cycloisomerization.[8,9] Echavarren and co-workers attempted
to intercept A with carbonyl compounds in an intermolecular
[*] S. A. Gawade, Dr. S. Bhunia, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing Hua University
Hsinchu, 30013 (Taiwan)
E-mail: rsliu@mx.nthu.edu.tw
[**] We thank the National Science Council, Taiwan, for financial support
of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203507.
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[(o-biphenyl)P(tBu)2AuSbF6], the yields of 3a depended on
solvents: CH2Cl2 (87%), 1,4-dioxane (82%), and toluene
(71%). Structural characterization of 3a relied on an X-ray
diffraction study[14] (see the Supporting Information).
We examined the reactions of 2a with various 1,6-enynes
(1b–m) to assess the substrate scope, including benzenoid and
nonbenzenoid bridges (Scheme 2). The cycloaddition reac-
Scheme 3. Cycloadditions of enyne 1a with various nitrones. [a] [sub-
strate]=0.19m. [b] All product yields are reported for compounds
isolated after purification on silica gel. L=P(tBu)2(o-biphenyl).
greater than 91%. For the nitrones 2j and 2k bearing a 2- and
3-thienyl group, respectively, the corresponding cycloadducts
5j and 5k were obtained in 76–78% yield.
Scheme 2. [2+2+3] Nitrone cycloadditions on various 1,6-enynes.
[a] [substrate]=0.19m. [b] All product yields are reported for com-
pounds isolated after purification on silica gel. L=P(tBu)2(o-biphenyl),
DCE=1,2-dichloroethane.
Scheme 4 shows a plausible mechanism to rationalize the
stereochemistry of the resulting cycloadducts 3a and 3l using
the 1,6-enynes 1a and 1l, respectively, and nitrone 2a. The
substrates 1a and 1l are less flexible in conformation and
facilitate the initial cyclization. In the presence of a gold
catalyst, we postulate that an initially formed cyclopropylgold
carbenoid[4–5] has a strong alkenylgold carbocation character
(B’),[15] which is attacked by nitrone 2a in a concerted
pathway, thus giving either the cycloadduct 3a or 3l with
excellent diastereoselectivity.
tions were performed in DCE (258C) using [P(o-biphenyl)-
(tBu)2AuCl]/AgSbF6 (5 mol%). This cycloaddition is appli-
cable to substrates bearing various alkenes, such as 3-
pentylidene, cyclopentylidene, and cyclohexylidene, thus
giving the desired cycloadducts 3b–d in 62–84% yield. For
the benzenoid substrates 1e–g bearing a C4 substituent (X =
OMe, F, Cl), the reactions proceeded smoothly to give the
desired compounds 3e–g with yields exceeding 91%. Excel-
lent yields (85–92%) were obtained also for products 3h–j
bearing various C5 substituents (X = OMe, Me, Cl). The
scope of this cycloaddition is substantially expanded with its
applicability to nonbenzenoid substrates containing a cyclo-
pentenyl, cyclohexenyl, and cycloheptenyl bridge, thus giving
the corresponding products 3k–m in 78–90% yield.
Scheme 3 shows the applicability of the cycloaddition of
the 1,6-enyne 1a with various nitrones (2b–k). We obtained
only the desired cycloadducts 5b–k as single diastereomers
with yields exceeding 76%. We tested the cycloadditions on
nitrones 2b–e, bearing both electron-deficient and electron-
rich aniline moieties (Ar1 = 4-XC6H4; X = OMe, Me, Cl,
CO2Et), and the corresponding cycloadducts 5b–e were
obtained in excellent yields (92–97%). These cycloadditions
can also be extended to the nitrones 2 f–i bearing electron-
deficient imines (Ar2 = 4-XC6H4; X = Cl, Br, CF3, NO2), thus
giving the corresponding cycloadducts 5 f–i with yields of
Scheme 4. A proposed mechanism for the diastereoselective [2+2+3]
cycloaddition.
Our results for the enantioselective cycloaddition of the
1,6-enyne 1a with nitrone 2e are shown in Table 2. Among
the commonly used C2-bisphosphine ligands, (R)-DTBM-
MeO-Biphep gave the best performance for enantioselectiv-
ity (see the Supporting Information). The use of [LAu2Cl2]/
2AgSbF6 (L = (R)-DTBM-MeO-Biphep, 5 mol%) gave the
desired compound (À)-5e in 71% yield with 70% ee
2
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Table 2: Enantioselective cycloaddition with nitrone.
Entry
Catalyst (mol%)[a,b]
T [8C]
9e
ee [%][c]
Yield [%]
1
2
3
4
5
[LAu2Cl2] (5)/AgSbF6 (10)
[LAu2Cl2](5)/AgOTf (10)
[LAu2Cl2] (5)/AgOTf (10)
[LAu2Cl2] (5)/AgOTf (5)
[LAu2Cl2] (3.8)/AgOTf (3.8)
25
25
0
0
0
71
73
71
76
74
(À)-70
(À)-75
(À)-76
(À)-84
(À)-92
[a] [substrate]=0.19m. [b] All product yields are reported for compounds
isolated after purification on silica gel. [c] The ee values were determined
by HPLC using a Chiralpak OD-H column.
(entry 1). [LAu2Cl2]/2AgOTf at a 5 mol% loading improved
the enantioselectivity of compound (À)-5e to 75% ee
(entry 2). The reaction in a cold DCE solution (08C) had
little influence on its ee value (entry 3). However, a change of
the Ag/Au ratio to 1:1 for [LAu2Cl2]/AgOTf increased the
À
ee value to 84% at 08C; here, one Au Cl bond in gold catalyst
remains intact (entry 4). We managed eventually to obtain
(À)-5e with 92% ee and 74% yield at a low loading catalyst
loading (Au/Ag = 1:1, 3.8 mol%, entry 5). We assigned the
absolute configuration of (À)-5e according to an X-ray
diffraction study on its analogue (À)-5m (see the Supporting
Information).
Scheme 5. Gold-catalyzed enantioselective cycloadditions. [a] [substra-
te]=0.19m. [b] All product yields are reported for compounds isolated
after purification on silica gel. [c] The ee values were determined by
HPLC using a Chiralpak OD-H or AD-H column. L=(R)-DTBM-OMe-
Biphep.
With [LAu2Cl2]/AgOTf (3.8 mol%, L = (R)-DTBM-
MeO-Biphep), we conducted enantioselective cycloadditions
on additional 1,6-enynes and nitrones (Scheme 5). The initial
results show the enantioselectivity of the prototype product
(À)-3a for which the ee value was up to 95%. We tested this
chiral gold catalyst on the benzenoid substrates 1e, 1g, 1h,
and 1j, and their corresponding products (À)-3e, (À)-3g, (À)-
3h, and (À)-3j were obtained with high ee values (89–94%).
We studied the reaction of nitrones bearing an electron-rich
aniline moiety and the resulting product (À)-5b was obtained
in 73% yield and 89% ee. The same reactions on several
nitrones bearing an electron-deficient imine produced the
cycloadducts (À)-5i, (À)-5l, and (À)-5m with satisfactory
ee values (87–93%). For the nonbenzenoid substrate 1l, the
resulting cycloadduct (À)-3l was obtained in 84% ee. X-xay
diffraction of compound (À)-5m was performed to clarify its
absolute configuration.
but also 1,6-enynes of benzenoid and nonbenzenoid systems.
We also report the success on the enantioselective synthesis of
cycloadducts using [LAu2Cl2]/AgOTf (L = (R)-DTBM-MeO-
Biphep). Most nitrone cycloadducts were obtained with high
enantiopurity.
Received: May 7, 2012
Published online: && &&, &&&&
Keywords: cycloaddition · fused-ring systems · gold ·
.
heterocycles · synthetic methods
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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4
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Chemie
Communications
Synthetic Methods
S. A. Gawade, S. Bhunia,
R.-S. Liu*
&&&& — &&&&
Intermolecular Gold-Catalyzed Diastereo-
and Enantioselective [2+2+3]
Cycloadditions of 1,6-Enynes with
Nitrones
Going for gold: The title reaction has
been developed and demonstrates a wide
substrate scope with respect to the 1,6-
enynes and nitrones (see scheme; DCE=
1,2-dichloroethane, Tf=trifluorometha-
nesulfonyl). The results for the enantio-
selective versions are also presented.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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These are not the final page numbers!