Wittig olefination-claisen rearrangement protocol for cyclohexene annulation

Article abstract of DOI:10.1080/00397910902985473

A two-step iterative sequence of Wittig olefination followed by Claisen rearrangement resulted in 1,7-octadienes, which afforded the corresponding cyclohexene carbaldehydes upon ring-closing metathesis with Grubbs catalyst.

Full text of DOI:10.1080/00397910902985473

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Wittig Olefination–Claisen
Rearrangement Protocol for Cyclohexene
Annulation
Mukund G. Kulkarni a , Dnyaneshwar D. Gaikwad a , Ajit S. Borhade
a , Yunus B. Shaikh a , Vijay B. Ningdale a , Sanjay W. Chavhan a ,
Attrimuni P. Dhondge a , Mayur P. Desai a & Deekshaputra R. Birhade
a
a Department of Chemistry, University of Pune, Ganeshkhind, Pune,
India
Version of record first published: 06 Jan 2010.
To cite this article: Mukund G. Kulkarni, Dnyaneshwar D. Gaikwad, Ajit S. Borhade, Yunus B. Shaikh,
Vijay B. Ningdale, Sanjay W. Chavhan, Attrimuni P. Dhondge, Mayur P. Desai & Deekshaputra R.
Birhade (2010): Wittig Olefination–Claisen Rearrangement Protocol for Cyclohexene Annulation,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:3, 423-433
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Synthetic Communications1, 40: 423–433, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902985473
WITTIG OLEFINATION–CLAISEN REARRANGEMENT
PROTOCOL FOR CYCLOHEXENE ANNULATION
Mukund G. Kulkarni, Dnyaneshwar D. Gaikwad,
Ajit S. Borhade, Yunus B. Shaikh, Vijay B. Ningdale,
Sanjay W. Chavhan, Attrimuni P. Dhondge,
Mayur P. Desai, and Deekshaputra R. Birhade
Department of Chemistry, University of Pune, Ganeshkhind, Pune, India
A two-step iterative sequence of Wittig olefination followed by Claisen rearrangement
resulted in 1,7-octadienes, which afforded the corresponding cyclohexene carbaldehydes
upon ring-closing metathesis with Grubbs catalyst.
Keywords: Claisen rearrangement; cyclohexene annulation; ring-closing metathesis; Wittig olefination
Among the different types of ring systems, the six-membered ring system is by far the
best studied and the most well-understood ring system. Apart from other reasons,
this could be because the six-membered ring is one of the most ubiquitous ring sys-
tems present in nature. The cyclohexane-based pool of natural products is vast and
includes important classes of natural products such as terpenoids, steroids, and anti-
biotics. Several methods[1–16] have been reported in the literature for the construction
of the cyclohexane ring and its highly functionalized derivatives, including the
famous Robinson annulation, Diels–Alder reaction, and ring-closing metathesis.
Many of these and other methods are capable of furnishing cyclohexane and its
unsaturated derivatives in a highly regio- and=or stereoselective manner. However,
in several situations, the required structural specificity may be lacking in highly
unsymmetrically substituted cyclohexenes formed using these methods.
A cyclopentannulation protocol based on Wacker oxidation–Aldol conden-
sation of 4-pentenals to obtain substituted 2-cyclopentenones has been reported
from this laboratory.[17] The 4-pentenals in turn were obtained using a standardized
Wittig olefination–Claisen rearrangement sequence.[18] The usefulness of 4-pentenals
could be further expanded if these could be converted to cyclohexene derivatives.
Efforts in this direction are described in this communication.
The 4-pentenals (2a–g), obtained from aldehydes (1a–g) under optimized
reaction conditions, were treated with allyloxymethylenetriphenylphosphorane gave
the allyl vinyl ethers (3a–g) in good yields (Scheme 1).
Received January 19, 2009.
Address correspondence to Dnyaneshwar D. Gaikwad, Department of Chemistry, University of
Pune, Ganeshkhind, Pune-411 007, India. E-mail: dshwar@gmail.com
423

424
M. G. KULKARNI ET AL.
Scheme 1. Reagents and conditions: (a) CH2CHCH2OCH2Ph3PþClꢀ, tetrahydrofuran (THF), t-
BuOꢀNaþ, 0ꢁC; (b) xylene, "#, 4–5 h; and (c) Grubbs catalyst (first generation), dicholormethane
(DCM), rt, 12 h.
Upon thin-layer chromatography (TLC), these allyl vinyl ethers appeared to be
homogeneous, but from the NMR spectra it was clear that these allyl vinyl ethers are
mixtures of E and Z isomers. All attempts to separate the E and Z isomers did not
materialize. However, the NMR signals of E and Z isomers in the olefinic region
were well separated, which allowed us to estimate the ratio of these isomers (Table 1).
The allyl vinyl ethers (3a–g), on refluxing in xylene, smoothly underwent the
Claisen rearrangement to give the corresponding 1,7-octadienes (4a–g), which are
required for the synthesis of substituted cyclohexenes, in good yield. In this case,
these octadienes appear to be homogeneous on TLC, but NMR spectra of these
compounds showed them to be a mixture of diastereomers. From the NMR signals,
Table 1. Expedient protocol for the synthesis of 4,5-disubstituted cyclohexene carbaldehydes
Yield (%)
Entry
R
2
3 (Z:E)
4 (dr)
5 (dr)
a
b
c
3,4-(OMe)2C6H3
C4H3O
95
92
87
66 (1:1)
78 (1:4)
69 (1:1.4)
90 (1:2)
87 (1:1.2)
82 (1:1)
95 (1:2)
91 (1:1.2)
87 (1:1)
d
e
90
82
85 (1:2.1)
74 (1.2:3)
91 (1:1.5)
78 (1:0.9)
90 (1:1.5)
77 (1:0.9)
f
78
83
58 (1:1.7)
62 (1:2.1)
75 (2:3)
87a (2:3)
g
77 (1.7:2)
81a (1.7:2)
aYield is calculated on the basis of recovered starting material; Z=E geometrical and diastereomeric
ratios were obtained from the NMR.

CYCLOHEXENE ANNULATION PROTOCOL
425
it was possible to estimate the diastereomeric ratio of these compounds. Ring-closing
olefin metathesis of these 1,7-octadienes was effected using Grubbs first-generation
=
catalyst [PhCH RuCl2(PCy3)2] to get the desired functionalized cyclohexene carbal-
dehydes (5a–g) in good yield. The beauty of this protocol is that the whole sequence
(total of four steps) to prepare the 1,7-octadienes could be conducted without purify-
ing the intermediates. This significantly cuts down the efforts and time required to
obtain the 1,7-octadienes. As a result, this short sequence for the preparation of
cyclohexenes could be completed in a span of only a day and half.
CONCLUSION
Thus, a new methodology for cyclohexene annulations, with 25–32% overall yield,
has been developed through an iterative sequence of Wittig–Claisen rearrangement.
EXPERIMENTAL
All solvents were distilled and dried before use. Silica gel (100–200 mesh)
was used for column chromatography and eluted using hexane=ethyl acetate solvent
system. The Fourier transform–infrared (FT-IR) spectra were recorded on a
Perkin-Elmer 1600 series instrument. 1H and 13C NMR spectra were recorded
on Jeol FX 90Q=Varian Mercury 300- and 75-MHz instruments respectively.
Low-resolution mass spectra (LRMS; Shimadzu GCMS-Q 5050A) connected to
GC-17A were recorded at an ionization potential of 70 eV, and the fragmentation
pattern is given after the corresponding m=z value.
General Procedure
Wittig olefination. A solution of t-BuOꢀNaþ (1.2 eq) in dry THF was added
to a suspension of the aldehyde and allyloxymethylenetriphenylphosphonium chlor-
ide (1.2 eq) in dry THF at 0ꢁC in a dropwise manner. After 40–45 min (TLC check),
THF was removed under vacuum. On normal aqueous extractive workup, the crude
product was obtained after removal of the solvent under reduced pressure. The crude
allyl vinyl ether was purified by using a silica-gel column (mobile phase 1–4% ethyl
acetate in hexane) and gave the product in good yield.
Claisen rearrangement. The allyl vinyl ethers were subsequently dissolved in
xylene, and the solution was refluxed for 4–5 h. After evaporation of xylene at room
temperature, 4-pentenals were obtained in 75–90% yield.
Ring-closing olefin metathesis. The Grubbs first-generation catalyst
=
([PhCH RuCl2(PCy3)2], 0.2 mol%) was added to a solution of 1,7-octadiene obtained
from 4a–g in dry DCM, and the reaction mixture was stirred for 10–12 h at ambient
temperature (TLC check). The crude products were purified using a silica-gel column
(ethyl acetate in hexane), which gave pure cyclohexene carbaldehydes in 80–95% yield.
Data
Selected data are shown in Table 2.

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CYCLOHEXENE ANNULATION PROTOCOL
431
ACKNOWLEDGMENTS
D. D. G., A. S. B., Y. B. S., V. B. N., S. W. C., A. P. D., M. P. D., and D. R. B.
thank the Council of Scientific and Industrial Research, New Delhi, India, for the
fellowships.
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