Multicomponent reactions involving tricyclooxonium ylide intermediate: Diastereoselective synthesis of mono- and bisalkoxyoctahydro-1,4-benzodioxocin- 6(5H)-one frameworks

Article abstract of DOI:10.1039/b613008a

A highly diastereoselective tandem ring-enlargement and aldol condensation process involving multicomponent reactions of ethereal tricyclooxonium ylide intermediate with alcohols, mono- or dialdehydes in the presence of titanium(iv) isopropoxide is descri

Full text of DOI:10.1039/b613008a

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Multicomponent reactions involving tricyclooxonium ylide
intermediate: diastereoselective synthesis of mono- and
bisalkoxyoctahydro-1,4-benzodioxocin-6(5H)-one frameworks{
Sengodagounder Muthusamy,*a Janagiraman Krishnamurthia and Eringathodi Sureshb
Received (in Cambridge, UK) 8th September 2006, Accepted 3rd November 2006
First published as an Advance Article on the web 24th November 2006
DOI: 10.1039/b613008a
A highly diastereoselective tandem ring-enlargement and aldol
condensation process involving multicomponent reactions of
ethereal tricyclooxonium ylide intermediate with alcohols,
mono- or dialdehydes in the presence of titanium(IV) isoprop-
oxide is described to furnish alkoxyoctahydro-1,4-benzodiox-
ocin-6(5H)-one ring systems.
The rhodium(II)-catalyzed reaction of a-diazocarbonyl compounds
involves attractive transformations in organic synthesis.1 In
particular, transition metal catalyst derived carbenes or carbenoids
react with heteroatoms to form onium ylides. Sulfur, phosphorus
and nitrogen ylides have been utilized for synthesis because of the
relatively long lifetime of onium ylides.2 Carbenes or carbenoids
react with ethereal oxygen to form oxonium ylides,3 which have
been subsequently utilized in syntheses based on their rearrange-
ment3,4 or with the help of nucleophiles5 as well as Lewis acids.6
However, the use of oxonium ylides for synthesis has been limited,
probably due to their short lifetime,7 in comparison with the
widely acknowledged utility of carbonyl ylides.2,8 Further, the
Scheme 1 Reaction of diazocarbonyl-substituted dioxaspiro compound
1 in the presence of various alcohols or a carboxylic acid.
reactions of ethereal oxonium ylides are known to furnish a
mixture of isomers.4–6 The ambiphilic character of oxonium ylides
should be properly controlled by imparting a relatively long
lifetime. In continuation of our work9 on the chemistry of carbonyl
ylides, herein we report the multicomponent reactions involving
rhodium(II)-generated tricyclooxonium ylides with various
alcohols, mono- or dialdehydes in the presence of titanium
isopropoxide furnishing the mono- and bisalkoxyoctahydro-1,4-
benzodioxocin-6(5H)-one frameworks with high stereoselectivity.
To investigate the multicomponent reactions of the tricycloox-
onium ylide intermediate, initially, treatment of diazocarbonyl-
substituted dioxaspiro compound 1 with rhodium(II) acetate
catalyst afforded the cyclobutane fused tricyclic compound 4 via
Stevens rearrangement (Scheme 1, path a). Reaction of diazocar-
bonyl compound 1 was performed in the presence of rhodium(II)
acetate catalyst and methanol in dichloromethane to afford the
ring-enlarged dioxocinone compound 5a in 85% yield (Scheme 1,
path b). Product 5a was obtained as a single diastereoisomer and
the structure characterized by spectral data. We also observed the
similar ring-enlarged compound 5b when isopropanol was used as
a nucleophile. Similar reaction of diazocarbonyl compound 1 was
also carried out in the presence of other nucleophiles such as allyl
alcohol, butanol, m-cresol to afford the respective ring-enlarged
dioxocinone products 5c–e. Notably, reaction of 1 was also
performed with 4-methylbenzoic acid to furnish the carboxylate
substituted dioxocinone 5f. These experiments indicate that the
distinct formation of bicyclic dioxocinone compounds with trans-
fusion 5 occurs as a single diastereoisomer in the presence of
nucleophiles (alcohol/carboxylic acid), otherwise resulting only in
the rearrangement product 4. The tricyclooxonium ylide inter-
mediate 3a and its ring-opened bicyclic zwitterion 3b are stabilized
by charge delocalization between two oxygen atoms. Selective
nucleophilic attack on 3b furnished the trans-geometry in 5. The
possible product 6 via intramolecular H-migration5 of 3 was not
observed (path c).
Next, we were interested to study the ambiphilic character of
tricyclooxonium ylide 3 in the presence of a carbonyl compound
and a Lewis acid. Thus, Rh(II)-acetate catalysed reaction of
a-diazoketone 1, benzaldehyde and 1.1 equivalent of titanium(IV)
isopropoxide in dichloromethane furnished the product 7a in 79%
yield (Scheme 2). Significantly, the dioxocinone 7a was obtained as
a single diastereomer having four stereogenic centers. Similar
reaction in the presence of 0.5 equivalent of titanium(IV)
isopropoxide yielded major amounts of product 7a and a minor
quantity of 4 (Table 1, Entry b). The above reaction was extended
to various substituted aromatic aldehydes. Good yields were
aSchool of Chemistry, Bharathidasan University, Tiruchirappalli,
Tamilnadu, 620 024, India. E-mail: muthu@bdu.ac.in;
Fax: +91-431-2407043; Tel: +91-431-2407053
bCentral Salt & Marine Chemicals Research Institute, Bhavnagar,
Gujarat, 364 002, India
{ Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, representative NMR
spectra and X-ray structural data of compound 11d. See DOI: 10.1039/
b613008a
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 861–863 | 861

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Scheme 3
Scheme 2
Table 2 Synthesis of alkooxyoctahydro-1,4-benzodioxocin-
6(5H)-one systems 11a–e
Table 1 Synthesis of isopropoxyoctahydro-1,4-benzodioxocin-
6(5H)-one systems 7a–g
Entry
R1
R2
Yield (%)a of 11
Entry
R
Product
Yield (%)a
a
b
c
d
e
a
CH3
C6H5
C6H5
C6H5
4-CHOC6H4
3-CHOC6H4
81
CH3CH2
CH3CH2CH2CH2
CH3
77
50b
78c
64c
a
b
c
d
e
f
C6H5
C6H5
7a
7a
7b
7c
7d
7e
7f
79
42b
87
4-HOC6H4
4-CH3OC6H4
4-CHOC6H4
3-CHOC6H4
4-BrC6H4
CH3
90
Yields are unoptimized and refer to isolated pure compounds 11.
All the above reactions were carried out at 10 uC with the slow
addition of 1 for 3 h into the reaction mixture containing 1.0 equiv.
78c
72c
82
g
a
b
Ti(OiPr)4 and the appropriate aldehyde. Additionally product 7a
(15%) was also isolated. No observation of product 12d or 12e
based on crude NMR data.
c
Yields are unoptimized and refer to isolated pure compounds 7.
All the above reactions were carried out at rt with the slow addition
of 1 for 2 h into the reaction mixture containing 1.1 equiv. Ti(OiPr)4
b
and the appropriate aldehyde. The compound 4 (20%) was isolated
in addition to 7a when 0.5 equiv. Ti(OiPr)4 were used. No
observation of product 12a or 12b based on crude NMR data.
c
This methodology reveals that the methoxy group exclusively acts
as nucleophile and the isopropoxy group from the titanium
reagent did not participate as described in Scheme 2. This reaction
forms an example of a three-component reaction. A similar
reaction was performed in the presence of ethanol or n-butanol to
furnish the respective alkoxydioxocinones 11b, c. Reaction with
dialdehydes bearing electron-withdrawing substituents in the
presence of methanol also furnished the products 11d, e in good
yield. The structure and stereochemistry of 11 were established by
solving the single crystal X-ray crystallographic analysis10 of the
representative methoxydioxocinone 11d (Fig. 2). Notably, the
above three-component reactions yielded alkoxydioxocinones 11
having four stereogenic centers with complete diastereoselectivity.
As a preliminary illustration of the utility of the above reactions,
it is planned to perform the reaction with symmetrical bis-carbonyl
compounds. Thus, the reaction of terephthalaldehyde, two
equivalents of a-diazoketone 1 and titanium(IV) isopropoxide in
the presence of Rh2(OAc)4 catalyst in dichloromethane afforded
the bis-isopropoxydioxocinone 12a in 82% yield (Scheme 4 and
Table 3) as a single isomer. Similar reaction in the presence of
isophthalaldehyde yielded bis-dioxocinone 12b. But the reaction
with p-benzoquinone resulted a mixture of diastereomers 12c in the
ratio of 2 : 1. The observation of a mixture of diastereomers 12c is
due to the presence of asymmetry on the quinone carbonyl group
of 10 after the first ring enlargement–aldol condensation process.
observed from aromatic aldehydes bearing electron-donating (OH,
OMe) or electron-withdrawing (CHO, Br) groups affording
products 7b–f in a diastereoselective manner via ring-enlargement
and aldol condensation process of oxonium ylide intermediate 3.
Subsequently, we studied the reactions involving ethereal tricy-
clooxonium ylide intermediate 3 with keto-group in the presence of
titanium(IV) isopropoxide. Thus, the reaction of 1 with cyclohex-
anone was carried out to afford the isopropoxide induced ring-
enlargement followed by aldol condensation product 8in 82% yield
(Fig. 1). The structure of the product 8 was confirmed by spectral
analysis as a single diastereomer having three stereogenic centers.
Similar reaction with 1,4-cyclohexanedione or benzoquinone was
alsofurnished the respective products9, 10. Interestingly, the above
reactions with aromatic aldehydes as well as symmetrical ketones
provided the products 7–10 with complete diastereoselectivity.
Further, we extended the study to include the three-component
reactions involving a diazoketone, an alcohol and an aldehyde.
Towards this, reaction of diazoketone 1, an excess amount of
methanol and equimolar quantities of titanium(IV) isopropoxide
and benzaldehyde in dichloromethane at 10 uC furnished the
methoxydioxocinone 11a in 81% yield (Scheme 3 and Table 2).
Interestingly, 1H NMR analysis of the crude reaction mixture
indicated that the product was obtained as a single diastereomer.
Fig. 2 ORTEP view of the compound 11d, using 50% probability for the
Fig. 1
ellipsoids.
862 | Chem. Commun., 2007, 861–863
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Scheme 4
Scheme 5 Mechanistic pathway for the formation of dioxocinones.
Table 3 Synthesis of bis-alkoxyoctahydro-1,4-benzodioxocin-
6(5H)-one systems 12a–e
three-component reaction in which ethereal tricyclooxonium ylide
participates as an intermediate. The potential application and
mechanism of this stereoselective methodology involving oxonium
ylides are in progress.
Yield (%)a
Entry
R
-X-
-Y-
12
Other products
a
b
c
d
e
a
CH(CH3)2 -1,4-C6H4-
CH(CH3)2 -1,3-C6H4-
CH(CH3)2 -1,4-Benzoquinone-
H
H
82
70
—
5b (5)
This research was supported by DST, New Delhi. JK thanks
CSIR, New Delhi for a Research Fellowship.
65b 10 (15)
CH3
CH3
-1,4-C6H4-
-1,3-C6H4-
H
H
63
54
5a (trace)
5a (6), 5b (4)
Notes and references
Yields are unoptimized and refer to isolated pure compounds 12
1 M. P. Doyle, M. A. Mckervey and T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds, Wiley, New York, 1998.
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and all the above reactions were carried out at 5 uC with the slow
for 5.0 h.
diastereomeric mixture in the ratio of 2 : 1.
b
addition of
1
12c derived as an inseparable
The three-component reaction is extended further as described
in Scheme 3 in the presence of dialdehydes. To this end, reactions
of 11d, e were repeated in the presence of two equivalents of
diazoketone 1 as well as titanium(IV) isopropoxide to yield the bis-
methoxydioxocinone 12d, e, respectively as a single isomer. The
formation of 12d, e can be considered as a double three-
component reaction (equivalent to a five-component reaction).
Furthermore bis-alkoxydioxocinones 12a, b, d, e were isolated as
single isomers, which may exist as a mixture of meso and dl-
mixtures, based on the reaction of dicarbonyl compounds with the
opposite or same enantiomers of enolate 13 (Scheme 5),
respectively. In turn, this tandem ring enlargement and C–C bond
formation process, from simple starting materials, provides up to
six new bonds with eight stereocentres and with stereoselectivity in
a single synthetic operation.
Mechanistically, the tricyclooxonium ylide 3 as an intermediate
is proposed to contribute to the stereoselectivity. The selectivity
behavior could tentatively be attributed to the presence of fused
tricyclooxonium ylide 3 system with a relatively longer lifetime
than previously reported oxonium ylides.7,8 The diastereoselective
products 7–12 were obtained via ring-enlargement followed by an
aldol condensation process. The alkoxide either from the titanium
reagent or the alcohol participates in nucleophilic addition on ylide
3 followed by the formation of titanium enolate 13, and the
titanium reagent also activates the aldehyde towards C–C bond
formation11 (Scheme 5). The diastereoselectivity (Schemes 3, 4)
indicates that the multicomponent reaction selectively occurs
between bottom face of the titanium enolate 13 and the top face of
the titanium activated carbonyl compound.
10 Crystal data for compound 11d: Colourless block crystal. C19H24O6,
M 5 348.39, 0.32 6 0.26 6 0.22 mm3, monoclinic, space group P21/c,
˚
˚
˚
a 5 9.6678(14) A, b 5 11.1324(17) A, c 5 16.858(3) A, b 5 101.138(3)u,
3
V 5 1780.2(5) A , T 5 273(2) K, R1 5 0.0649, wR2 5 0.1588 on
˚
observed data, Z 5 4, Dcalcd 5 1.300 g cm23, F(000) 5 744, absorption
coefficient 5 0.096 mm21, l 5 0.71073 A, 8627 reflections were
˚
collected on a smart apex CCD single crystal X-ray diffractometer,
3111 unique measured reflections, 2016 observed reflections (I ¢ 2s (I)).
In conclusion, the Rh(II)-catalyzed multicomponent reactions
involving diazocarbonyl-substituted dioxaspiro compound, alco-
hol and carbonyl compound are described. The mono- as well as
bisalkoxyoctahydro-1,4-benzodioxocin-6(5H)-one ring systems
have been successfully synthesized with complete diastereo-
selectivity. This method constitutes a distinct example for a
23
,
˚
The largest difference peak and hole 5 0.279 and 20.252 e A
respectively. The structure was solved by direct methods and refined by
full-matrix least squares on F3 using SHELXL-97 software. CCDC
619131. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b613008a.
11 Y. Sawada, T. Mori and A. Oku, Chem. Commun., 2001, 1086.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 861–863 | 863