A convenient conversion of terminal alkenes into homologous unsaturated and doubly unsaturated esters

Article abstract of DOI:10.1021/ol203387r

Unsaturated and doubly unsaturated esters have been synthesized in two steps by the application of a radical xanthate transfer process of a simple methylsulfoxide starting material to a range of terminal alkenes. syn-Elimination of the sulfoxide gives α,β

Full text of DOI:10.1021/ol203387r

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1020–1023
A Convenient Conversion of Terminal
Alkenes into Homologous Unsaturated
and Doubly Unsaturated Esters
€
Bill Hawkins, Victoria L. Paddock, Nina Tolle, and Samir Z. Zard*
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128
Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received December 19, 2011
ABSTRACT
Unsaturated and doubly unsaturated esters have been synthesized in two steps by the application of a radical xanthate transfer process of a
simple methylsulfoxide starting material to a range of terminal alkenes. syn-Elimination of the sulfoxide gives R,β-unsaturated esters, which
coupled with a xanthate elimination yields R,β,γ,δ-unsaturated esters.
The creation of CÀC bonds in an intermolecular fashion
starting with unactivated alkenes is a longstanding pro-
blem in organic synthesis that has in part been addressed
by the cross-metathesis reaction. This explains the large
impact of this remarkable process on the design of syn-
thetic strategies, especially with the emergence of later
generations of catalysts and the design of experimental
set-ups that circumvent the inherent problem of competing
self-metathesis.1 Thus, the conversion of an alkene 1 into
an unsaturated ester 2 can be accomplished directly
through cross-metathesis (Scheme 1), whereas a more
traditional approach would have required oxidative clea-
vage of the alkene to the aldehyde followed by a Wittig or a
HornerÀWadsworthÀEmmons condensation.
thus far be directly accomplished through a metathesis
process. In view of its potential synthetic utility, and in
connection with an ongoing total synthesis project, we
explored the possibility of effecting this transformation by
a radical based route. Our strategy relied on combining the
radical xanthate addition we have uncovered with the well-
known syn-elimination of sulfoxides.2
The seemingly straightforward approach displayed in
Scheme 2 could not, however, be readily implemented.
When we attempted the radical addition of sulfoxide 5 to ter-
minal alkenes under the usual conditions, the reactions were
disappointingly sluggish and low yielding. There was
no obvious reason to imagine that the radical addition was
the inefficient step or that the xanthate transfer process
was, which should also proceed normally. The untoward
generation of radical inhibitors in the medium is a more
plausible explanation. While sulfoxide elimination cannot
take place in the starting reagent 5, it could happen at the
In contrast, the conversion of the same alkene 1 into the
homologous unsaturated ester 3 or dienyl ester 4 cannot
(1) For a review on cross-metathesis, see: (a) Connon, S. J.; Blechert,
S. Angew. Chem., Int. Ed. 2003, 42, 1900. For recent, more general
reviews of the metathesis reaction, see: (b) Vougioukalakis, G. C.;
Grubbs, R. H. Chem. Rev. 2010, 110, 1746. (c) Samojlowicz, C.; Bieniek,
M.; Grela, K. Chem. Rev. 2009, 109, 3708. The hydroformylation and
hydrocyanation reactions, while less broadly used in academia, are
industrially important processes. See:(d) Maitlis, P.; Haynes, A. Metal-
catalysis in Industrial Organic Processes; Royal Society of Chemistry:
Cambridge, 2008.
(2) For reviews on xanthate radical addition-transfer reaction, see:
(a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b) Quiclet-
Sire, B.; Zard, S. Z. Chem.;Eur. J. 2006, 12, 6002. (c) Quiclet-Sire, B.;
Zard, S. Z. Top. Curr. Chem. 2006, 264, 201. (d) Zard, S. Z. Aust. J.
Chem. 2006, 59, 663. (e) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205.
(f) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2011, 83, 519.
r
10.1021/ol203387r
Published on Web 02/01/2012
2012 American Chemical Society

needed to cause the elimination of the analogous methyl-
sulfoxides.6 The phenyl group weakens the carbonÀsulfur
bond and stabilizes the partial negative charge that appar-
ently builds up on the sulfur atom in the transition state.
Thus, replacing the phenyl with a methyl group should
hopefully sufficiently raise the temperature needed for the
onset of the syn-elimination to allow the normal radical
chain to proceed under practical conditions. A methyl
group would also obviate any complications from a
Smiles-type rearrangement of the intermediate adduct
radical.
The desired methylsulfoxide was synthesized from
the commercially available ethylmethylthio-acetate, which
was monochlorinated following literature precedent.7 The
chlorinated product was then transformed into the xan-
thate upon treatment with potassium O-ethyl xanthate and
finally oxidation of the thioether with m-CPBA gave the
sulfoxide in good yield, without affecting the xanthate
group.
Scheme 1. Conversion of Alkenes to Unsaturated Esters
level of the addition product 6. The decomposition need
not be extensive: even a small amount of phenylsulfenic
acid in the medium would be sufficient to inhibit the chain
process. Another, less obvious side reaction leading to
potential inhibitors arises from a radical Smiles rearrange-
ment leading to an aryl shift and the formation of sulfur-
centered and chain-terminating sulfenyl radical 10.3
With methylsulfoxide 11 in hand it was pleasing to find
that when the xanthate transfer reaction was conducted
strictly between 70 and 75 °C with dilauryl peroxide (DLP,
0.8À1.8 equiv)8 in ethyl acetate, the desired addition
product, xanthate 12, could be isolated in a high yield
without any trace of the syn-eliminated product being
observed. With optimal reaction conditions developed
the radical addition of methylsulfoxide 11 to a range of
terminal alkenes was successfully carried out (Table 1). In
all cases, either microwave irradiation or refluxing a
toluene solution of the isolated or crude addition products,
xanthates 12aÀq, induced the syn-elimination of the sulf-
oxide to yield the desired R,β-unsaturated esters 8aÀq in
good to excellent yields (Table 1). Aryl allylic alkenes
bearing both electron-withdrawing and -donating groups
were successfully transformed (entry 1), as well as allyl and
homoallyl amine derivatives with various substituents on
the nitrogen (entries 2, 3, and 6). Alkyl alkenes containing
common functionalities such as acetates, esters, ethers
(entries 4, 5, and 7À11), or cyclic ketones (entries 12À14)
were useful substrates. Finally, the complex, highly sub-
stituted tetrahydrofuran derivative 12q was isolated in a
good yield over the two steps (entry 15).
Scheme 2. Attempted Radical Addition of Sulfoxide 5 to an
Alkene
One possible way of circumventing these difficulties
would consist of operating at a much lower temperature
than that of the usual refluxing ethyl acetate, for example
by initiating the system photochemically or by using a
combination of triethylborane and oxygen.4 Both of these
experimental variations were not appealing, because of
problems of scale up with the former and because of the
capriciousness of the latter.5
A better solution was found in an early work by Trost
and co-workers, who noted that phenylsulfoxides under-
went elimination at about 70 °C below the temperature
It is known that xanthates can undergo intramolecular
cyclization onto aromatic rings in the presence of stoichio-
metric amounts of DLP, which acts as both the radical
initiator and the oxidant for the final rearomatization.9
Therefore, it was not surprising to find that adducts
derived from allyl and homoallyl amines with an aromatic
group on the nitrogen, such as xanthates 12d and 12e,
could undergo further addition onto the aromatic ring to
(3) For a review on radical aryl migrations, see: (a) Studer, A.;
Bossart, M. Tetrahedron 2001, 57, 9649. (b) Studer, A.; Bossart, M. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; Vol. 2, p 62.
(4) (a) Briggs, M. E.; Zard, S. Z. Synlett 2005, 334. (b) Jean-Baptiste,
L.; Yemets, S.; Legay, R.; Lequeux, T. J. Org. Chem. 2006, 71, 2352.
(c) Charrier, N.; Gravestock, D.; Zard, S. Z. Angew. Chem., Int. Ed.
ꢁ
ꢁ
Engl. 2006, 45, 6520. (d) Garcıa-Merinos, J. P.; Hernandez-Perez, J. P.;
ꢁ
Martınez-Garcıa, L.; Rojas-Lima, S.; Lopez-Ruiz, H. J. Mex. Chem.
Soc. 2007, 51, 209. (e) Boivin, J.; Nguyen, V. T. Beilstein J. Org. Chem.
2007, 3, 45–47. For the capricious nature of the process, see footnote 6 in
ref 4c and Legrand, N. PhD Thesis, Ecole Polytechnique, France, 2001.
(5) Another potential solution would be to start with the sulfide of 5
and oxidize to the corresponding sulfoxide after the radical addition.
The problem is that the derived radical PhSC•HCO2Et is a captodative
radical and therefore stabilized and rather unreactive towards unacti-
vated alkenes.
(7) Bass, J. Y.; Deaton, D. N.; McFadyen, R. B.; Mills, W. Y.; Navas,
F., III; Smalley, T. L., Jr; Spearing, P. K.; Cavavella, J. A.; Madauss,
K. P.; Miller, A. B.; Williams, S. P.; Chen, L.; Creech, K. L.; Marr, H. B.;
Parks, D. J.; Wisley, G. B.; Todd, D. Bioorg. Med. Chem. Lett. 2011, 21,
1206.
(8) Because the half-life of the peroxide is much longer at this lower
temperature, a greater amount is required to keep a useful flux of
initiating radicals. Most of the peroxide in fact remains unconsumed
at the end of the reaction.
(6) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976,
98, 4887.
(9) de Greef, M; Zard, S. Z. Tetrahedron 2004, 60, 7781.
Org. Lett., Vol. 14, No. 4, 2012
1021

give indoline 13a and, more remarkably, tetrahydroquino-
line 13b in good yields (Scheme 3). The syn-elimination of
the sulfoxide could then also be carried out to give the
unsaturated esters 14a and 14b (Scheme 3).
Table 1. Xanthate Transfer with Methylsulfoxide 11 and
Terminal Alkenes Followed by syn-Elimination
Scheme 3. Intramolecular Radical Cyclizations
In addition to the syn-elimination of the sulfoxide, the
versatility of adducts 12 was demonstrated by reduction of
the xanthate in the presence of the sulfoxide. Treatment of
xanthate 12 with triethylammonium hypophosphite and a
small amount of AIBN10 at 70À75 °C allowed the isolation
of sulfoxide 15 in good to excellent yields (Table 2).
Substrates containing aromatic groups (entry 1), amines
(entry 2), and cyclic ketones (entry 3) could be successfully
converted into sulfoxides 15aÀc. syn-Elimination of these
products would then give access to R,β-unsaturated esters
free of the xanthate group.
It has previously been shown that xanthates can be
eliminated by thermolysis to yield unsaturated com-
pounds, when the carbon bearing the xanthate is substi-
tuted with a nitrogen or a sulfur, weakening the carbon
sulfur bond.11 We envisaged that syn-elimination of the
sulfoxide with a simultaneous elimination of the xanthate
would give us access to the extremely useful and versatile
R,β,γ,δ-unsaturated esters. Although our addition pro-
ducts, xanthates 12aÀq, do not possess any substituents
that weaken the carbon sulfur bond, we were reasonably
confident that thermolysis would be successful. The reac-
tion was therefore attempted and a solution of xanthate
12a in diphenyl ether was heated to 190 °C for 2 h. We were
pleased find that after this time complete conversion of
the starting material had occurred and we could isolate
the desired doubly unsaturated ester 16a in 54%. How-
ever, when we attempted the reaction with xanthate 12b
the reaction was sluggish and a reaction time of over 3 h
was required for complete conversion. In order to allow
for the reaction to be run at higher temperatures the
elimination was attempted using microwave irradiation.
a Radical adducts 12aÀ12q were not fully characterised due to the high
number of possible diastereoisomers and instead full characterisation of syn-
eliminated products 8aÀ8q was carried out. Xa = SCSOEt. b Reflux in
toluene. c Addition product not isolated. d Microwave irradiation.
(10) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron
Lett. 1992, 33, 5709. (b) Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V. T. Org.
Lett. 2003, 5, 1645.
(11) Gagosz, F.; Zard, S. Z. Org. Lett. 2003, 5, 2655. (b) Braun, M.-G.;
Zard, S. Z. Org. Lett. 2011, 13, 776.
1022
Org. Lett., Vol. 14, No. 4, 2012

Table 2. Xanthate Reduction in the Presence of the Sulfoxidea
Table 3. Simultaneous Elimination of the Sulfoxide and the
Xanthatea
a Xa = SCSOEt.
a Xa = SCSOEt.
Unfortunately, after much experimentation, no improve-
ment on the yield was achieved. Finally, we found that by
intensely heating a solution of xanthate 12a in Ph2O to
reflux (∼ 260 °C) for 4À10 min our desired product could
be isolated in a slightly improved yield of 57% (Table 3,
entry 1). Additionally the reaction of 12b could now be
carried out on the same time scale to yield ester 16b in 53%
yield (Table 3, entry 2). Using our optimized reaction
conditions, alkyl xanthates 12m and 12o, containing a
quaternary center at the β-position to the xanthate, were
used and yielded the desired esters 16c and 16d in moderate
to good yields (Table 3, entries 3 and 4).
Although the reaction was successful, to a certain extent,
with other alkyl substrates, such as xanthates 12j and 12k,
without a quaternary center at the β-position, the reaction
times were longer (10À15 min) and the products were only
isolated in low yields (<20%, not reported). Furthermore,
the products were hard to isolate from other alkene side
products, presumably formed due to the prolonged reac-
tion times required, which ultimately caused decomposi-
tion of the highly reactive diene products. It was also noted
that with xanthates such as 12l and 12n, where the resulting
dienes are in conjugation with the ester or ketone function-
ality, a complex mixture of products was formed under the
reaction conditions, with none of the desired products
being isolated. Even though this reaction may be limited
to substrates with bulky substituents, it provides products
that may not be easily accessible via more conventional
methods due to this steric hindrance.
In conclusion, we have developed the synthesis of un-
saturated and doubly unsaturated esters in only two steps
from easily accessible and commercially available starting
materials, methylsulfoxide 11 and terminal alkenes. The R-
β-unsaturated esters can be synthesized simply by affecting
the syn-elimination by subjecting the xanthate addition
products to refluxing toluene or microwave irradiation.
Additionally we have shown that the xanthate can be
removed before syn-elimination widening the scope of this
reaction. A double elimination of both the sulfoxide and
the xanthate demonstrates the synthesis of the nontrivial
R,β,γ,δ-unsaturated esters. The rapid assembly of diene
16d is remarkable in this respect, as such a compound
would be tedious to make by classical routes.
Acknowledgment. We dedicate this paper to the memory
of Professor Hans Wijnberg (University of Groningen).
Some of us (B.H., V.L.P., and N.T.) thank Ecole Polytech-
nique for scholarships.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data and copies of 1H and 13
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
C
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1023