Facile construction of oxa-aza spirobicycles via a tandem carbon-hydrogen bond oxidation

Article abstract of DOI:10.1002/adsc.201100196

An efficient method to construct oxa-aza spirobicycles via an iodine(III)-mediated tandem carbon-hydrogen bond oxidation with the combination of iodobenzene diacetate and tetrabutylammonium iodide is reported. Copyright

Full text of DOI:10.1002/adsc.201100196

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DOI: 10.1002/adsc.201100196
Facile Construction of Oxa-Aza Spirobicycles via a Tandem
Carbon-Hydrogen Bond Oxidation
Yi Sun,a Jianhong Gan,b and Renhua Fana,*
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Peopleꢀs Republic of China
Fax : (+86)-216-510-2412; phone: (+86)-216-564-2019; e-mail: rhfan@fudan.edu.cn
College of Food Science and Technology, Shanghai Ocean University, Lingang New City Huchenghuan Road 999, 201306
b
Shanghai, Peopleꢀs Republic of China
Received: March 19, 2011; Published online: June 30, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100196.
Abstract: An efficient method to construct oxa-aza
spirobicycles via an iodine(III)-mediated tandem
carbon-hydrogen bond oxidation with the combina-
tion of iodobenzene diacetate and tetrabutylammo-
nium iodide is reported.
ketals[9] (path a, Scheme 1) and bicyclization of the
functionalized ketone derivatives[10] (path b,
Scheme 1) are the classical and commonly used ap-
proaches to oxa-aza spirobicyclic systems. Additional-
ly, the Suꢁrez group reported the preparation of oxa-
aza spirobicycles in carbohydrate systems via an N-
radical-mediated intramolecular hydrogen atom trans-
fer (path c, Scheme 1).[11] The Fishwick group found a
1,3-dipolar cycloaddition of azomethine ylides with al-
kenes to synthesize spiroaminals.[12] Imhof and co-
workers described a ruthenium-catalyzed [2+2+1]
cycloaddition of ketimines, carbon monoxide and eth-
AHCTUNGTRENNUNG
À
Keywords: C H activation; cyclization; hypervalent
compounds; oxidation; spiro compounds
As important heterocyclic compounds, oxa-aza spiro- ylene to access spiro[pyrrolidin-2-one] derivatives.[13]
bicycles (spiroaminals or spiroaminoketals) are widely The groups of Bermejo,[14a] Boger,[14b] and Yao[14c] de-
distributed in a number of biologically active com- veloped oxidative cyclizations of cyclic enamines to
pounds. For example, the natural products marineo- provide oxa-aza spirobicyclic compounds. In spite of
sins A and B,[1] azaspiracid,[2] tomatidine,[3] sanglifeh- the considerable amount of effort that has been ex-
rin A,[4] manzamine X,[5] stemotinine and isostemoti- pended in the preparation of spiroaminals, the direct
nine alkaloids[6] have an oxa-aza spirobicyclic unit as construction of oxa-aza spirobicyclic skeletons from
their core structure. These important skeletons have two carbon-hydrogen bonds is highly desirable (path
attracted the attention of a number of synthetic re- d, Scheme 1). Recently, we have directed our focus on
search groups, and many synthetic methods have been the hypervalent iodine[15] species-mediated oxidative
documented.[7] Cyclization of hemiaminals[8] or hemi- cyclizations to synthesize various cyclic compounds
Scheme 1. Approaches to oxa-aza spirobicyclic systems.
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Scheme 2. Proposed reaction pathway for the iodineACTHNUTRGNE(NUG III)-mediated construction of oxa-aza spirobicycles.
such as aziridines,[16a] cyclopropanes,[16b] oxetanes,[16c] (2-aminophenyl)-3-p-tolylprop-2-en-1-one under the
azetidines,[16d] and dihydrofurans.[16e] In order to fur- previously
optimized conditions [PhI(OAc)2
ACHTUNGTRENNUNG
ther extend the utility of this approach, we investigat- (2.0 equiv.), Bu4NI (2.0 equiv.), CH3CN, 258C]
ed the possibility of constructing oxa-aza spirobicycles [Scheme 3, Eq. (1)]. The reaction proceeded smoothly
via an iodineACHTUNGTRENNUNG(III)-mediated tandem carbon-hydrogen and afforded one major product after 10 min. How-
1
bond oxidation with the combination of iodobenzene
ACHTUNGTRENeNUNG ver, the H NMR spectrum of the isolated compound
diacetate
and
tetrabutylammonium
iodide indicated that it was not the expected oxa-aza spirobi-
(Scheme 2). The acyclic precursor 1 could be pre- cyclic compound 2a, but a cyclopropanation product
pared from the corresponding Michael addition of b- 3a.
dicarbonyl compounds with 1-(2-aminophenyl)-prop-
2-en-1-one derivatives.[17]
To inhibit the cyclopropanation, the malonate
group in 1a was replaced by a cyclohexane-1,3-dione
First, we examined the oxidative cyclization of com- group.[16e] To our delight, the desired oxa-aza spirobi-
pound 1a derived from diethyl malonate and N-Ts-1- cyclic product 2b was isolated in 54% yield from the
Scheme 3. Examination of the nitrogen protecting groups.
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Facile Construction of Oxa-Aza Spirobicycles via a Tandem Carbon-Hydrogen Bond Oxidation
Scheme 4. Construction of oxa-aza spirobicycles under the optimized conditions.
reaction of 1b (Scheme 3). Further investigation indi- experiments, when PhIACTHNUTRGNEUNG(OAc)2 was replaced by PhIO,
cated that N-Ts protection in substrate 1 was essential or when Bu4NI was replaced by Bu4NBr, no oxa-aza
for the formation of oxa-aza spirobicyclic product. spirobicyclic product was formed.
When a Ms group was used instead of the Ts group,
With the optimized reaction conditions established,
only one oxygen-cyclization product 5c was generat- various substrates were examined, and representative
ed. When the protecting group was changed to the results are shown in Scheme 4. The reaction was
benzoyl group, a nitrogen-cyclization product 4d was found to tolerate a range of different groups with dif-
obtained. When N-acetyl protected substrate 1e was ferent electronic demands on the aromatic rings. Sub-
employed, no reaction was observed under the same strates containing a cyclohexane-1,3-dione group were
conditions.
successfully converted to the oxa-aza spirobicyclic
The screening of solvents revealed that the reaction products in yields ranging from 72% to 90%. When
could be conducted in various organic solvents, and the cyclohexane-1,3-dione group was replaced by the
DMF was the best choice, in which product 2b was 5,5-dimethylcyclohexane-1,3-dione group, the corre-
formed in 81% yield. Increasing or decreasing the sponding products 2n and 2o were also formed in
amounts of PhIACHTUNGTRENNUNG(OAc)2 and Bu4NI did not improve good yields. When substrate 1p derived from cyclo-
the yield. A sluggish reaction was observed when the pentane-1,3-dione was employed, a complicated reac-
reaction was conducted at 08C. While optimizing the tion was observed, and no desired oxa-aza spirobicy-
reaction conditions, we found that the reaction was clic product was isolated. The oxa-aza spirobicyclic
not sensitive to moisture and air. Even when the reac- structure of the obtained products was further con-
tion was carried out in an air-open system with water firmed by the single-crystal diffraction analysis of
as the solvent, the reaction gave rise to the oxa-aza product 2o (Figure 1).[18]
spirobicyclic product 2b in 51% yield. As the control
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the same product 8 in similar yields. However, the fur-
ther treatment of 8 with PhIACTHNUTRGNEU(NG OAc)2 and Bu4NI in
DMF and in CH3CN provided compound 6 and com-
pound 7 as the major product, respectively. According
to the above results, products 6 and 7 are presumed
to be formed from oxa-aza spirobicyclic product 2q
via a selective cleavage of a carbon-nitrogen or a
carbon-oxygen bond, and this bond cleavage is sol-
vent dependent (Scheme 6).
In conclusion, we have developed an efficient
method to construct oxa-aza spirobicycles via an
iodineACHTNUTRGNE(UNG III)-mediated tandem carbon-hydrogen bond
oxidation with the combination of iodobenzene diace-
tate and tetrabutylammonium iodide. Currently work
is in progress to extend its scope, to explore its reac-
tion mechanism and possible synthetic applications.
Figure 1. X-ray diffraction structure of 2o.
Experimental Section
Interestingly, the reaction of substrate 1q, which
was prepared from the Michael addition of N-Ts 1-(2-
aminophenyl)-3-phenylprop-2-en-1-one with 4-hy-
droxy-2H-chromen-2-one, did not afford oxa-aza spi-
Typical Experimental Procedure
PhI
ACHTUNGRTENUN(NG OAc)2 (161 mg, 0.5 mmol) was added into the mixture
of substrate 1b (126 mg, 0.25 mmol) and Bu4NI (185 mg,
robicyclic product 2q, but gave rise to a furan deriva- 0.5 mmol) in DMF (2 mL) at 258C. Upon completion by
TLC after 15 min, the reaction mixture was quenched with
saturated Na2S2O3 (25 mL), and extracted by ethyl acetate
(25 mLꢃ3). The organic layer was dried over Na2SO4, and
concentrated under vacuum. The residue was purified by
column chromatography on silica gel (30% ethyl acetate in
hexanes) to give product 2b as a colorless solid; yield:
tive 6 and a 2-methyleneindolin-3-one derivative 7 in
71% and 14% yields, respectively. Moreover, further
studies revealed that the ratio of product 6 to product
7 was solvent dependent. When the reaction was con-
ducted in acetonitrile, 2-methyleneindolin-3-one de-
rivative 7 was generated as the major product in 67%
yield (Scheme 5). When the amounts of PhIACTHUNRGTNEUNG(OAc)2
and Bu4NI were decreased to 1 equivalent each, both
of the reactions in DMF and in CH3CN gave rise to
1
101 mg (81%); mp 188–1908C. H NMR (400 MHz, CDCl3):
d=7.73 (d, J=7.3 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.48 (t,
J=7.8 Hz, 1H), 7.24–7.27 (m, 1H), 7.17 (d, J=7.8 Hz, 2H),
7.13 (t, J=7.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 6.83 (d, J=
Scheme 5.
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Adv. Synth. Catal. 2011, 353, 1735 – 1740

Facile Construction of Oxa-Aza Spirobicycles via a Tandem Carbon-Hydrogen Bond Oxidation
Scheme 6.
7.8 Hz, 2H), 4.83 (s, 1H), 2.71–2.88 (m, 2H), 2.45–2.66 (m,
2H), 2.33 (s, 3H), 2.27 (s, 3H), 2.10–2.35 (m, 2H); 13C NMR
(100 MHz, CDCl3): d=194.9, 194.1, 176.6, 152.0, 144.6,
138.7, 137.4, 136.0, 130.2, 129.7, 129.1, 128.6, 127.8, 125.3,
124.4, 120.7, 115.0, 114.8, 102.4, 55.0, 37.3, 24.2, 21.7, 21.6,
21.3; HR-MS: m/z=522.1320, calcd. for C29H25NNaO5S
[M+Na]+: 522.1351.
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Financial support from National Natural Science Foundation
of China (21072033) and Fudan University is gratefully ac-
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