On the reduction of S-alkyl-thionocarbonates (xanthates) with phosphorus compounds

Article abstract of DOI:10.1021/ol0342610

(Matrix presented) Reductive cleavage of the carbon-sulfur bond present in S-alkyl-thionocarbonates (xanthates) was achieved by high-yielding, tin-free radical reactions based on phosphorus reagents. The combination hypophosphorous acid/triethylamine/AIBN

Full text of DOI:10.1021/ol0342610

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1645-1648
On the Reduction of
S-Alkyl-thionocarbonates (Xanthates)
with Phosphorus Compounds
Jean Boivin,* Rafik Jrad, Ste´phanie Juge, and Van Tai Nguyen
Institut de Chimie des Substances Naturelles, C.N.R.S., Gif-sur-YVette 91198, France
jean.boiVin@icsn.cnrs-gif.fr
Received February 14, 2003
ABSTRACT
Reductive cleavage of the carbon−sulfur bond present in S-alkyl-thionocarbonates (xanthates) was achieved by high-yielding, tin-free radical
reactions based on phosphorus reagents. The combination hypophosphorous acid/triethylamine/AIBN led to fast, efficient, and smooth formation
of the alkane. Reduction with diethyl phosphite was sufficiently slow to permit sequential intermolecular addition of a 2-oxoalkyl xanthate onto
an olefin followed by cleavage of the newly formed carbon−sulfur bond.
The last two decades have witnessed a tremendous develop-
ment of new radical reactions designed for organic synthesis.
In this field, Barton has been a pioneer, discovering or
sowing the seeds of countless original and useful reactions.1,2
In particular, xanthates have been found to be not only
convenient precursors for transforming an alcohol into the
corresponding alkane3 but also extremely efficient and versa-
tile sources of radicals. The concept of “degenerate reaction”
brought to light by Zard et al. has permitted radical processes
that would be otherwise difficult to realize by “conventional
methods” because of severe, unavoidable, and useless
competitive reactions.4,5 Special mention must be made of
intermolecular addition of 2-oxoalkyl radicals to olefins that
produces xanthate adducts in generally good yields and
tolerates many functional groups. On certain occasions, the
rich sulfur chemistry underlying the xanthate moiety in the
adduct has been exploited.6 However, in most cases, reduc-
tive cleavage of the newly formed carbon-sulfur bond is
needed. Essentially two methods are utilized. The first one
relies on the tin hydride chemistry with all its stringent draw-
backs in terms of toxicity, difficulties encountered in puri-
fication, and cost.7,8 The second one is much more conve-
nient. It requires 2-propanol (or similar compounds) as a
hydrogen atom donor and dilauroyl peroxide (DLP) as a
radical initiator9 but is also subject to limitations (vide infra).
We were also faced with the recurrent problem of
removing a xanthate located on a molecule sensitive to either
acidic or basic conditions. Thus, standard reduction of
compounds 1a and 1b10 with tributyltin hydride/AIBN in
refluxing toluene led to erratic results strongly depending
on the purity of the commercial reagent used. On the other
hand, removal of the xanthate group in compound 1a with
(1) Barton, D. H. R. In Half a Century of Free Radical Chemistry;
Cambridge University Press: Cambridge, 1993.
(2) Barton, D. H. R. In Reflections on Research in Organic Chemistry;
Barton, D. H. R., Ed.; ICP-Imperial College Press and World Scientific
Publishing Co.: Singapore, 1996.
(3) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585. (b) Barton, D. H. R.; Ferreira, J. A.; Jaszberenyi, J.
C. In PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997; pp 151-172.
(4) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 1997, 69, 645-650.
(5) (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 673-685. (b)
Zard, S. Z. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, pp 90-108.
(6) (a) Boivin, J.; Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1998, 39,
6877-6880. (b) Boivin, J.; Boutillier, P.; Zard, S. Z. Tetrahedron Lett.
1999, 40, 2529-2532.
(7) Baguley, P. A. Angew. Chem., Int. Ed. 1998, 37, 3072-3082.
(8) Studer, A.; Amrein, S. Synthesis 2002, 835-849.
(9) (a) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996,
37, 5877-5880. (b) Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1998,
39, 9435-9438.
10.1021/ol0342610 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003

Table 1. Reduction of Xanthates with Hypophosphorous
Acid/Triethylamine/AIBN under Reflux (Method A)16 and
Diethyl Phosphite/DLP [Method B, Dilauroyl Peroxide as
Initiator (Method B′, Dibenzoyl Peroxide as Initiator)]a
reaction
xanthate
(concn)
time
(h)
alkane
entry
method
solvent
dioxane
(% yield)
1
2
3
4
5
6
7
8
9
1a (0.1 M)
1a (0.4 M)
1a (0.4 M)
1b (0.1 M)
1e (0.1 M)
1c (0.2 M)
1d (0.04 M)
1c (0.2 M)
1d (0.2 M)
A
B
0.3
9
2a (69)
2a (66)
2a (70)
2b (69)
2e (89)
2c (79)
2d (75)
2c (60)
2d (49)
2b (54)
2f (75)
1,2-dichloroethane
B′
A
A
A
A
A
A
Ab
A
1,2-dichloroethane 12
dioxane
0.5
dioxane
0.3
0.5
0.5
0.75
1.5
10
0.3
dioxane
dioxane
n-propanolc
n-propanolc
ethanol
10 1b (0.1 M)
11 1f (0.1 M)
dioxane
Figure 1.
a Same reaction conditions as those described in ref 17. b Triethylamine
was replaced with NaHCO3. c One portion of 10% AIBN (mmol/mmol of
xanthate) was added every 0.75 h.
stoichiometric amounts of dilauroyl peroxide in 2-propanol
furnished 2a with only 33% yield together with a compound
resulting from cleavage of the acetal group because of the
acidity of the medium reaction in the process. Addition of a
base such as 2,6-lutidine to the reaction mixture only led to
the formation of a complex mixture due to â-elimination of
the sulfonyl moiety that produced a very reactive enone.
Some years ago, Barton and, more recently, other groups
have developed an efficient, low-cost, and environmentally
safe approach based on phosphorus derivatives.11-14 These
methods were originally designed for deoxygenation of
alcohols to alkanes through their O-alkylxanthate derivatives,
by cleavage of the carbon-oxygen bond, and were also
successfully applied to reduce other compounds such as
halides. However, there is no report that phosphorus com-
pounds have been used in radical reduction of an S-
alkylxanthate group. We wish to report herein the use of
hypophosphorous acid and diethyl phosphite to cleave the
carbon-sulfur bond in order to remove the xanthate function
in sensitive compounds such as 1a.
We were delighted to observe that when a solution of 1a
was heated at reflux under an inert atmosphere for 0.3 h in
dioxane in the presence of hypophosphorous acid (5 equiv),
triethylamine (5.5 equiv), and catalytic amounts of AIBN
(0.2 equiv), the corresponding alkane 2a was obtained in a
gratifying 69% isolated yield (Table 1, entry 1).15 When
compound 1a was refluxed for 9 h in 1,2-dichloroethane in
the presence of diethyl phosphite (15 equiv) and catalytic
amounts of DLP (0.3 equiv), the corresponding alkane 2a
was obtained in a slightly lower yield 66% (entry 2).
Dibenzoyl peroxide was also used as an initiator, but the
reaction remained very slow (12 h, entry 3). Ketals 1b, 1e,
and 1f, when treated with hypophosphorous acid (method
A), afforded the corresponding saturated compounds 2b, 2e,
and 2f in high yields (Table 1, entries 4, 5, and 11). Similarly,
adducts 1c and 1d, upon reduction with hypophosphorous
acid, furnished high yields of saturated compounds 2c and
2d, respectively (entries 6 and 7). It is worthy of note that
dioxane can be replaced by cheaper and less toxic 1-propanol
(Table 1, entries 8 and 9). Sodium hydrogen carbonate has
also been used in conjunction with hypophosphorous acid
in refluxing ethanol to reduce ketal 1b with 54% yield (entry
10). Thus, it appears that cleavage of the carbon-sulfur bond
with the aid of hypophosphorous acid/triethylamine or diethyl
phosphite can be achieved under very mild conditions with
good to excellent yields.
As reported in Table 1, diethyl phosphite seems to be as
efficient as hypophosphorous acid but requires much longer
reaction times. What appears as a drawback can in fact be
turned into a benefit. Thus, when xanthate 3 was refluxed
in 1,2-dichloroethane for 9 h in the presence of 1-decene (2
equiv), diethyl phosphite (15 equiv), and catalytic amounts
of DLP (0.4 equiv), the corresponding reduced adduct 1c
was isolated in an encouraging 70% yield (Table 2, entry
1). This means that the reduction process is sufficiently slow
to permit the intermolecular addition of the transient
2-oxoalkyl radical onto the olefin to occur. This gives rise
to an intermediate xanthate adduct that is progressively
reduced, as shown by a careful TLC monitoring. It is
noteworthy that addition of diethyl phosphite to olefin, which
could be feared on the basis of literature data,16 does not
interfere, at least to a large extent, with the reduction of the
xanthate group. Moreover, we showed by a competition
(10) Full experimental details concerning the preparation of the starting
materials mentioned in this Letter will be given in due course.
(11) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron
Lett. 1992, 33, 5709-5712. (b) Barton, D. H. R.; Jang, D. O.; Jaszberenyi,
J. Cs. J. Org. Chem. 1993, 58, 6838-6842. (c) Barton, D. H. R.; Jang, D.
O.; Jaszberenyi, J. Cs. Tetrahedron Lett. 1992, 33, 2311-2314. (d) Barton,
D. H. R.; Parekh S. I.; Tse, C.-L. Tetrahedron Lett. 1993, 34, 2733-2736.
(12) Jang, D. O.; Cho, D. H.; Barton, D. H. R. Synlett. 1998, 9, 39-40.
(13) (a) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Bull. Chem. Soc. Jpn.
2001, 74, 225-235. (b) Takamatsu, S.; Katayama, S.; Hirose, N.; Naito,
M.; Izawa, K. Tetrahedron Lett. 2001, 42, 7605-7608.
(15) Typical Procedure for Reduction with Hypophosphorous Acid
and NEt3. A solution of xanthate (1.25 mmol), hypophosphorous acid (50%
solution in water, 0.64 mL, 6.2 mmol), and triethylamine (0.69 mL, 6.82
mmol) in dioxane (15 mL) was degassed by refluxing under an argon
atmosphere for 0.25 h. The reaction mixture was cooled to room temperature.
A 0.4 M solution of AIBN in dioxane (0.44 mL) was then added, and the
reaction mixture was refluxed under argon for 0.3-0.5 h. The reaction
mixture was cooled and poured into water. Extraction with ether and
subsequent flash chromatography afforded the reduced compound.
(14) (a) Jang, D. O.; Cho, D. H.; Chung, C.-M. Synlett 2001, 12, 1923-
1924. (b) Jang, D. O.; Cho, D. H. Synlett 2002, 13, 1523-1525.
1646
Org. Lett., Vol. 5, No. 10, 2003

Scheme 1. Postulated Mechanism for the Reaction of
2-Oxoalkyl Xanthates with Olefins in the Presence of
(EtO)2PHO
Table 2. Concomitant Addition/Reduction of Xanthates to
Olefins in the Presence of Diethyl Phosphite17 a
reaction
initiator
time
(h)
product
entry xanthate olefin (equiv vs xanthate)
(% yield)
1
2
3
4
5
6
3
3
3
3
4
1d
5
6
11
9
6
10
DLP (0.4)
DLP (0.4)
BPO (0.6)
DLP (0.3)
DLP (0.4)
AIBN (0.1)
12
12
18
9
12
2
2c (71)
2a (58)
12 (44)
14 (76)
13 (49)
15 (15)
a Solvent: 1,2-dichloroethane. DLP ) dilauroyl peroxide; BPO )
dibenzoyl peroxide; AIBN ) azo-bis-isobutyronitrile.
reaction that the xanthate adduct was reduced faster than the
starting 2-oxoalkyl xanthate.
When the same methodology was applied to addition of
xanthate 3 to the more sensitive vinylic ketal 6, a satisfactory
yield of compound 2a was obtained (58%, Table 2, entry
2). Addition/reduction of derivative 3 to allyl acetate 11,
initiated with benzoyl peroxide, also proceeded smoothly and
gave compound 12 in 44% yield (Table 2, entry 3). In a
similar manner, xanthate 4 afforded derivative 13 in 49%
yield (entry 7). Addition of xanthate 3 to (-)-â-pinene
furnished compound 14 in a fair 76% isolated yield, through
an addition/fragmentation/reduction cascade (entry 6).17
Some limitations were observed when the addition/
reduction sequence was attempted between xanthate 3 and
olefins 7 and 8. Compounds 7 and acrolein diethyl acetal 8
did not produce the desired reduced adducts. For example,
in the case of the reaction between xanthate 3 and olefin 7
in the presence of DLP (0.3 equiv), only 30% starting
material 3 and 13% 4-p-toluenesulfonyl-2-butanone could
be isolated even after prolonged heating (9 h). The removal
of the stabilizer present in the commercial reagent 8 did not
change this situation. It is worthy of note that reduction of
adduct 1b with (EtO)2PHO also failed, whereas reduction
with H3PO2 proceeded smoothly (Table 1, entry 4). Obvi-
ously, further investigations are needed to clarify these points.
From a mechanistic viewpoint, one can follow Barton’s
proposal11 in which the radical initiator first abstracts an
hydrogen from (EtO)2PHO to produce a phosphorus centered
radical. The latter in turn reacts with the thiocarbonyl group
(Scheme, route a). In our case, this results in the breaking
of the carbon-sulfur bond to give rise to radical A′. The
same radical A′ can also be generated by reaction between
RCH2‚ and A (route b). The transient radical A′, besides the
degenerate reactions with thiocarbonyl compounds A, B, or
C, can either be reduced very slowly to A′′ (route c) or add
to an olefin (route d) to furnish radical B′. The latter either
reacts with A, B, or C to give B or abstracts a hydrogen
atom from (EtO)2PHO to produce the reduced product B′′
and the chain carrier (EtO)2P‚O. That we can observe the
(16) See ref 11a.
(17) Typical Procedure for Addition/Reduction. A stirred solution of
xanthate (0.5 mmol), olefin (2 equiv), and diethyl phosphite (15 equiv) in
degassed 1,2-dichloroethane (2 mL) was refluxed under an argon atmosphere
for 15 min. Initiator (0.1 equiv) was added every 3 h until the TLC showed
completion of the reaction. The solvent was evaporated under reduced
pressure, and saturated aqueous potassium carbonate (20 mL) was added
to the resulting residue. The latter was extracted with diethyl ether. The
ethereal extract was washed with brine and dried (Na2SO4) and the solvent
removed by evaporation. Purification by flash chromatography over silica
gel afforded the reduced adduct.
Figure 2.
Org. Lett., Vol. 5, No. 10, 2003
1647

formation of the xanthate adduct as an intermediate in the
reaction means that transfer of a xanthate moiety onto a
carbon radical such as B′ is probably faster than hydrogen
abstraction from (EtO)2PHO. This could indicate that initia-
tion of the process through route b cannot be neglected.
Finally, we showed that even the relatively unfavorable
addition/reduction of xanthate 1b onto phenyl vinyl sulfone
occurred, albeit in low yield (15%, entry 6). However, Jang’s
findings on iodo-derivatives suggest that this process could
be improved.14b
the reactions involved should lead to further improvements.
We are currently working along these lines.
Acknowledgment. This research was supported by grants
from the “Institut de Chimie des Substances Naturelles” and
from the “Ministe`re de l’Education Nationale, de la Recher-
che et de la Technologie”.
Supporting Information Available: Detailed procedures
for preparation of new compounds and their spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
The preliminary results reported herein demonstrate that
the impediment often encountered in the removal of an
S-alkyl thionocarbonate can by circumvented. A more
accurate understanding of the mechanisms and kinetics of
OL0342610
1648
Org. Lett., Vol. 5, No. 10, 2003