A facile access to polyfunctional oxygen-containing heterocycles via intramolecularly formed protic oxonium ylide trapping processes

Article abstract of DOI:10.1002/asia.201301115

Based on the assumption that intramolecularly formed protic oxonium ylides could be trapped by electrophiles, transition-metal-catalyzed reactions of diazoesters bearing a primary hydroxy group with electron-deficient aldehydes and isatins were examined.

Full text of DOI:10.1002/asia.201301115

COMMUNICATION
DOI: 10.1002/asia.201301115
A Facile Access to Polyfunctional Oxygen-containing Heterocycles via
Intramolecularly Formed Protic Oxonium Ylide Trapping Processes
Xin Guo, Wei Liu, and Wenhao Hu*[a]
À
Abstract: Based on the assumption that intramolecularly
formed protic oxonium ylides could be trapped by electro-
philes, transition-metal-catalyzed reactions of diazoesters
bearing a primary hydroxy group with electron-deficient al-
dehydes and isatins were examined. Good to high chemo-
and diastereoselectivities were achieved with reactions cata-
Meanwhile, intramolecular O H insertions have also
been extensively studied and offer a convenient way to con-
struct cyclic ethers.[5] The reaction may occur via a two-step
process: 1) Formation of a protic oxonium ylide intermedi-
ate and 2) Inter- or intramolecular proton transfer. Howev-
er, no direct evidence to prove such a stepwise process has
been reported.[6] Based on our previous experience in the
trapping process of protic oxonium ylides, we assumed that
the intramolecularly formed protic oxonium ylide may be
trapped by a proper electrophile if the proton transfer is
a rate-determining step in the aforementioned two-step
process.[4a] Herein, we report the first example of the
tandem intramolecular formation of a protic oxonium ylide
and subsequent trapping of such a ylide through an aldol-
type addition with carbonyl compounds (Scheme 1). The
lyzed by CuACHTUNGTRENNUNG(hfacac)2. The reactions were assumed to occur
via tandem intramolecular protic oxonium ylide formation
and subsequent aldol-type addition. They not only provided
an efficient entry to 3-substituted 1,4-dioxan-2-one heterocy-
cles with at least one quaternary carbon center but also pro-
vided experimental evidence for a stepwise pathway for the
À
transition-metal-catalyzed intramolecular O H insertion of
diazo compounds.
Due to the advantages of atom efficiency and ease of im-
plementation, tandem reactions have received considerable
attention for the rapid generation of complex and diverse
molecules.[1] Tandem processes involving metallo carbenoids
and onium ylide intermediates have been applied in organic
synthesis. For example, tandem carbonyl ylide formation
and 1,3-dipolar cycloaddition sequences have an inherent
advantage in assembling polycyclic structures.[2] A similar
tandem process involving intramolecular ethereal or thioe-
thereal ylide formation and subsequent intermolecular
carbon–carbon bond formation was also reported to afford
medium-sized oxygen/sulfur-containing rings with a b-hy-
droxy alkyl ether moiety.[3] Recently, we have uncovered
a series of novel three-component reactions, in which protic
oxonium ylides, generated in situ from carbenoids and alco-
hols or water, underwent nucleophilic addition to carbonyl
compounds, thereby providing a convergent synthesis of
a,b-dihydroxy acid derivatives.[4] Successful trapping of the
protic oxonium ylides also provided evidence for a stepwise
ylide-mediated pathway rather than a concerted one for in-
Scheme 1. Proposed reaction pathway for trapping of cyclic protic oxoni-
um ylide.
successful trapping reaction provides an efficient entry for
polyfunctional 1,4-dioxan-2-one heterocycles. The 1,4-
dioxan-2-one moiety is present in many biologically active
compounds such as lactonized oligosialic and polysialic acid
derivatives,[7] and it also serves as a building block for the a-
hydroxy acid motif.[8]
To study a model reaction, we designed and prepared di-
azoesters 1 bearing a primary hydroxy group and examined
the transition-metal-catalyzed diazo decomposition of 1 in
the presence of an electron-deficient aromatic aldehyde
(Scheme 1).
À
termolecular O H insertions triggered by catalytic reactions
of diazo compounds.
[a] Dr. X. Guo, W. Liu, Prof. Dr. W. Hu
Shanghai Engineering Research Center of Molecular Therapeutics
and New Drug Development
East China Normal University
Shanghai 200062 (China)
E-mail: whu@chem.ecnu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301115.
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Wenhao Hu et al.
copper complexes have shown
different properties in three-
component aldol or Michael-
type coupling reactions.[5e,11a,b]
Several copper complexes have
been investigated in the current
reaction, and the results are
summarized in Table 1. Gener-
ally, a slightly higher d.r. ratio
of 6a/7a was achieved as com-
pared with that from the use of
À
Scheme 2. Rh(II)-catalyzed reaction of 1a and 2a.
Rh
G
Initially, Rh
2A
tion product 5a and expoxidation product 8a were not ob-
formed in refluxing CH2Cl2 in the presence of 4-nitrobenzal-
dehyde (2a). We were pleased to find that the expected
trapping products 6a and 7a were obtained in 55% yield
with 67:33 d.r. favoring 6a (Scheme 2). Under such condi-
tions, the epoxidation side product 8a was isolated in 15%
served. The diastereoselectivity of the reaction varied when
copper catalysts were used. CuACHTNUTRGENNG(U hfacac)2 (hfacac=1,1,1,5,5,5-
hexafluoroacetyl acetonate) resulted in the highest d.r.
(71:29 d.r.) among the catalysts used (Table 1, entry 6).
The trapping process was found to be sensitive to the
electronic feature of aromatic aldehydes and the diazo com-
pounds. Electron-deficient aromatic aldehydes gave the de-
sired products in moderate to good yield with high diaste-
reoselectivity (Table 2, entries 1–3). No desired three-com-
À
yield (Table 1, entry 1). In addition, no intramolecular O H
Table 1. Screening of catalysts.
Table 2. CuACTHNUGRTENUNG(hfacac)2-catalyzed reaction of 1 and 2.
Entry[a]
Catalyst
Rh2A(OAc)4
CuOTf
Yield [%][b]
d.r. (6a/7a)[c]
1
2
3
4
5
6
7
G
40
59
60
60
58
54
56
67:33
51:49
64:36
62:38
50:50
71:29
52:48
Entry[a]
1
2
Yield (6+7)[b]
d.r. (6:7)[c]
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
1
2
3
4
5
6
1a
1a
1a
1a
1b
1c
p-CF3C6H4
p-CNC6H4
2,4-(NO2)2C6H3
p-MeOC6H4
p-NO2C6H4
p-NO2C6H4
61 (6b+7b)
60 (6c+7c)
80 (6d+7d)
–
70 (6e+7e)
–
93:7
91:9
90:10
–
92:8
–
ACHTUNGTRENNUNG
[d]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] All reactions were carried out in refluxing CH2Cl2 in the presence of
Rh2A(OAc)4 (1 mol%) or copper catalysts (10 mol%) with 1a/2a=1.2:1.0.
[b] Isolated yields of (6a+7a) after chromatography based on 2a. [c] De-
termined by 1H NMR spectroscopy of crude reaction mixtures.
[d] tfacac=1,1,1-trifluoroacetyl acetonate.
CHTUNGTRENNUNG
[a] All reactions were carried out in refluxing CH2Cl2 in the presence of
Cu(hfacac)2 (10 mol%) with 1a/2a=1.2:1.0. [b] Isolated yields of (6a+
7a) after chromatography based on 2a. [c] Determined by H NMR spec-
AHCTUNGTRENNUNG
1
troscopy of crude reaction mixtures.
insertion product was observed, thus indicating that the rate
of the ylide-trapping process was much faster than the 1,2-
proton transfer process. The stereochemistry of 6 was estab-
lished through single-crystal X-ray analysis of 6a
(Figure 1).[9]
ponent trapping product was obtained with electron-rich ar-
omatic aldehydes and aliphatic aldehydes. The reaction of
the bromo-substituted 1b gave 6g/7g in 70% isolated yield
with 92:8 d.r. (Table 2, entry 5). However, electron-rich
diazo compound 1c gave no desired trapping product
(Table 2, entry 6).
Copper catalysts are highly attractive for chemical synthe-
sis from environmental and economic points of view,[10] and
Isatins have been reported to be highly reactive electro-
philes to trap protic oxonium ylides with excellent chemo-
and diastereoselectivity.[4c] Trapping of the intramolecularly
formed cyclic protic ylide with isatins would produce frame-
works containing both the 3-substituted 1,4-dioxan-2-one
and 3-substituted 3-hydroxyindolin-2-one moieties with ad-
jacent quaternary carbon centers, the latter of which was
found in a number of biologically active alkaloids.[12] Initial-
ly, the reaction of 1a with N-methyl isatin (9a) was sur-
veyed. Copper catalysts led to a higher diastereoselective
Figure 1. ORTEP illustration of 6a.
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Wenhao Hu et al.
Table 3. CuACHTUNGTRENNUNG(hfacac)2-catalyzed reaction of 1 and 9.
(Table 3, entry 10), while no desired trapping product was
obtained with the electron-donating diazo compound 1c
(Table 3, entry 11).
In conclusion, CuACTHNUTRGNEUNG(hfacac)2-catalyzed trapping of intramo-
lecularly formed protic oxonium ylides with electron-defi-
cient aldehydes and isatins was successfully achieved. The
reaction afforded oxygen-containing heterocyclic frame-
works bearing the 3-substituted 1,4-dioxan-2-one moiety in
moderate to good yield with high diastereoselectivity. This is
the first example of an intramolecularly formed protic oxo-
nium ylide trapping process. The success of the trapping re-
action also provides experimental evidence for the existence
of the protic oxonium ylide intermediate for rhodium- and
Entry[a]
1[d]
2
3
4
5
6
7
8
1
R1
R2
Yield [%][b]
d.r.[c]
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
Me
Me
Ph
Ac
H
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Br
Cl
60 (10a+11a)
74 (10a+11a)
76 (10b+11b)
87 (10c+11c)
–
91 (10d+11d)
89 (10e+11e)
85 (10 f+11 f)
92 (10g+11g)
92 (10h+11h)
–
75:25
95:5
95:5
59:41
–
98:2
96:4
98:2
95:5
93:7
–
À
copper-catalyzed intramolecular O H insertion of diazo
F
compounds.
9
10
11
NO2
NO2
NO2
[a] All reactions were carried out in refluxing CH2Cl2 in the presence of
Cu(hfacac)2 (10 mol%) with 1/9=1.2:1.0. [b] Isolated yields of (10+11)
after chromatography based on 9. [c] Determined by 1H NMR spectros-
Acknowledgements
ACHTUNGTRENNUNG
This work was supported by NSFC (21125209), the MOST of China
(2011CB808600), and by STCSM (12JC1403800).
copy of crude reaction mixtures. [d] In the presence of Rh
(1 mol%).
2ACHTUNGERTN(NUNG OAc)4
Keywords: aldol-type reaction · heterocycles · quaternary
carbon · tandem reactions · ylides
control of the ylide-trapping process than Rh
2ACHTUNGERTN(NUNG OAc)4
(Table 3, entry 1). Again, Cu(hfacac)2 gave the highest yield
AHCTUNGTRENNUNG
(74%) and diastereoselectivity (95:5 d.r.) (Table 3, entry 2).
A number of substituted isatins were then used in the reac-
tion with 1a. N-phenyl isatin gave a similar yield and diaste-
reoselectivity, while N-acetyl isatin gave a higher yield but
lower diastereoselectivity (Table 3, entries 3 and 4). No ad-
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Received: August 24, 2013
Published online: November 6, 2013
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