Tandem ring-closing metathesis-radical cyclization based on 4-(phenylseleno)butanal and methyl 3-(phenylseleno)propanoate - A route to bicyclic compounds

Article abstract of DOI:10.1039/b100336b

α,ω-(Phenylseleno) carbonyl compounds, such as 4-(phenylseleno)butanal (1) and methyl 3-(phenylseleno)propanoate (2), are easily converted by anionic reactions into substances that undergo sequential ring-closing metathesis and radical cyclization, affording bicyclic products.

Full text of DOI:10.1039/b100336b

View Article Online / Journal Homepage / Table of Contents for this issue
Tandem ring-closing metathesis–radical cyclization based on
4-(phenylseleno)butanal and methyl 3-(phenylseleno)propanoate — a route to
bicyclic compounds
Derrick L. J. Clive* and Hua Cheng
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received (in Corvallis, OR, USA) 4th January 2001, Accepted 7th February 2001
First published as an Advance Article on the web 13th March 2001
a,w-(Phenylseleno) carbonyl compounds, such as 4-(phenyl-
seleno)butanal (1) and methyl 3-(phenylseleno)propanoate
(2), are easily converted by anionic reactions into substances
that undergo sequential ring-closing metathesis and radical
cyclization, affording bicyclic products.
to basic or nucleophilic reagents1 and, among the common
transformations, care need be exercised only in the choice of
oxidizing agent2,3 when selenium is present. We have found that
the PhSe group is compatible with the Grubbs catalyst
(Cy3P)2Cl2RuNCHPh,4–8 and we report that a,w-(phenylseleno)
carbonyl compounds, such as 4-(phenylseleno)butanal (19) and
methyl 3-(phenylseleno)propanoate (210) are useful for the
The usefulness of radical cyclization is often determined by the
ease with which the cyclization substrates can be made. In this
regard, the nature of the homolyzable group is, of course,
important, because this determines the stages at which it may be
introduced. In particular, early introduction can avoid the extra
steps involved in replacing a non-homolyzable group by one
that is homolyzable. For radical generation, phenyl selenides
have the distinct advantage that the PhSe group is usually inert
construction of substances that undergo sequential ring-closing
metathesis11 and radical cyclization. The PhSe group allows the
use of anionic chemistry that would not be suitable in the
Scheme 1 (a) Yield from 1. (b) Corrected for recovered 3b. (c) First yield
is for the oxidation of 6 to the corresponding ketone; second yield for
reaction of the ketone with allylmagnesium bromide.
Scheme 2 (a) Yield of more polar isomer [(3a,3ab,6ab)-stereochemistry]
60%; yield of less polar isomer [(3a,3aa,6aa)-stereochemistry] 25%.
DOI: 10.1039/b100336b
Chem. Commun., 2001, 605–606
This journal is © The Royal Society of Chemistry 2001
605

View Article Online
presence of halogen or carboxy groups as the eventual source of
radicals.12 Several publications have reported that the catalyst is
usually not compatible with sulfide substrates.4,5
Notes and references
1 A. Y. Mohammed and D. L. J. Clive, J. Chem. Soc., Chem. Commun.,
1986, 588.
The starting materials 3b–8b (Scheme 1) for the metathesis–
radical closure sequence were made as follows. Aldehyde 1 was
converted into alcohols 3 (80%), 5 (87%), and 6 (60%)
(Scheme 1) by reaction with vinyllithium, allylmagnesium
bromide, and but-3-enylmagnesium bromide, respectively.
Reaction of 1 with phenyllithium (50%), oxidation, using
pyridine·SO3 in DMSO2 (87%), and treatment of the resulting
ketone with vinyllithium afforded alcohol 7 (85%).
2 Cf. J. R. Parikh and W. von E. Doering, J. Am. Chem. Soc., 1967, 89,
5505.
3 Other oxidation methods: (a) R. Baudat and M. Petrzilka, Helv. Chim.
Acta, 1979, 62, 1406; (b) D. H. R. Barton, D. J. Lester, W. B.
Motherwell and M. T. B. Papoula, J. Chem. Soc., Chem. Commun.,
1980, 246; (c) G. H. Posner and M. J. Chapdelaine, Tetrahedron Lett.,
1977, 3227; (d) M. Shimizu, H. Urabe and I. Kuwajima, Tetrahedron
Lett., 1981, 22, 2183; (e) J. Lucchetti and A. Krief, C. R. Acad. Sci., Ser.
C, 1979, 288, 537.
The alcohols 3, 5, 6 and 7 were easily converted into
substrates for ring-closing metathesis by simple ionic reactions.
Acylation of 3 and 5 with acryloyl chloride (Et3N, DMAP,
CH2Cl2) gave 3b (64%) and 5b (71%), respectively (Scheme 1),
and the ethers 4b (65%) and 7b (73%) were made by alkylation
(NaH, THF) of 3 with 2-chloromethyl-3-[(phenylmethyl)-
oxy]prop-1-ene13,14 and of 7 with allyl bromide, respectively.
The metathesis substrate 6b was prepared by oxidation of 6
(87%), again using the pyridine·SO3–DMSO system—which is
an excellent reagent for selective oxidation of phenylseleno
alcohols—and treatment with allylmagnesium bromide
(78%).
4 Sulfides and disulfides have been subjected to ring-closing metathesis,
using a molybdenum catalyst; in some experiments a ruthenium catalyst
[(Cy3P)2Cl2RuNCHCHNCPh2] was unsatisfactory (Ref. 5), as was
(Cy3P)2Cl2RuNCHPh (Ref. 6).
5 E.g. (a) S.-Y. Shon and T. R. Lee, Tetrahedron Lett., 1997, 38, 1283; (b)
S. K. Armstrong and B. A. Christie, Tetrahedron Lett., 1996, 37,
9373.
6 A. G. M. Barrett, M. Ahmed, S. P. Baker, S. P. D. Baugh, D. C.
Braddock, P. A. Procopiou, A. J. P. White and D. J. Williams, J. Org.
Chem., 2000, 65, 3716.
7 For a rare example of ring-closing metathesis of a sulfide, using
(Cy3P)2Cl2RuNCHPh, see: A. G. M. Barrett, S. P. D. Baugh, D. C.
Braddock, K. Flack, V. C. Gibson, M. R. Giles, E. L. Marshall, P. A.
Procopiou, A. J. P. White and D. J. Williams, J. Org. Chem., 2000, 63,
7893.
The bis-allyl selenide 8b was obtained directly from ester 2
by the action of allylmagnesium bromide (78%).
Each of the bis-olefins shown in Scheme 1 underwent ring-
closing metathesis in the presence of (Cy3P)2Cl2RuNCHPh
(8–12 mol%; 22% for 3b), and the products were isolated by
flash chromatography. The reactions were usually run in PhH at
50 °C for 12 h [4b, 6b (65 °C), 7b, 8b (refluxing PhH,15 8 h)],
or in refluxing CH2Cl2 in the presence of Ti(OPr-i)4,16 (42 h,17
3b, 8 h, 5b). In the case of the acrylates (3b, 5b), Ti(OPr-i)4
must be added to complex the ester carbonyl and prevent
unproductive complexation of carbenoid intermediates.18
The radical cyclization step (see Scheme 2), leading to 3d,
4d,e, 5d–8d, was carried out under standard conditions by
syringe pump addition (over ca. 10 h) of a PhH solution of
Bu3SnH (1.4–2.2 equiv., 0.01–0.08 M) and AIBN (0.2–0.4
equiv., 0.006–0.03 M) to a refluxing solution (0.01–0.02 M) of
the substrate (1 equiv.) in the same solvent. In the case of 6c we
isolated only the product of 6-exo cyclization, and not the
isomeric alcohol resulting from 7-exo closure.19
8 For an extensive table of functional group-catalyst compatibility, see:
S. K. Armstrong, J. Chem. Soc., Perkin Trans. 1, 1998, 371.
9 (a) D. L. J. Clive and R. J. Bergstra, J. Org. Chem., 1990, 55, 1786; (b)
C. Bigogno, B. Danieli, G. Lesma and D. Passarella, Heterocycles,
1995, 41, 973.
10 K. Hiroi, J. Abe, K. Suya, S. Sato and T. Koyama, J. Org. Chem., 1994,
59, 203.
11 For one of several recent reviews, see: R. H. Grubbs and S. Chang,
Tetrahedron, 1998, 54, 4413.
12 For synthesis of bridgehead bicyclic sultams by tandem ring-closing
metathesis–radical cyclization (in which the radical is derived from a
halomethylsulfonyl group), see: L. A. Paquette and S. M. Leit, J. Am.
Chem. Soc., 1999, 121, 8126.
13 T. Konosu, Y. Furukawa, T. Hata and S. Oida, Chem. Pharm. Bull.,
1991, 39, 2813.
14 In the alkylation with this reagent, NaI was added to generate the iodide
in situ.
15 Reaction was very slow in refluxing CH2Cl2. Cf. A. Fürstner, O. R.
Thiel, L. Ackermann, H.-J. Schanz and S. P. Nolan, J. Org. Chem.,
2000, 65, 2204.
The above experiments establish that the PhSe group, which
serves as a very convenient radical source, can be introduced at
an early stage in synthetic routes that involve ionic reactions and
that end with sequential application of two powerful bond-
forming processes, ring-closing metathesis and radical cycli-
zation.
16 A solution of the substrate was refluxed in the presence of Ti(OPr-i)4
before adding the Grubbs catalyst.
17 A fresh portion of catalyst was added after 30 h.
18 (a) A. Fürstner and K. Langemann, J. Am. Chem. Soc., 1997, 119, 9130;
(b) A. K. Gosh, J. Cappiello and D. Shin, Tetrahedron Lett., 1998, 39,
4651.
All new compounds were characterized spectroscopically,
including high resolution mass measurements.
19 Cf. A. L. J. Beckwith, Tetrahedron, 1981, 37, 3073.
Acknowledgment is made to the Natural Sciences and
Engineering Research Council of Canada and to Merck Frosst
for financial support.
606
Chem. Commun., 2001, 605–606