Xanthates derived from 1,3-dithiane and its monosulfoxide; one-carbon radical equivalents

Article abstract of DOI:10.1016/j.tet.2004.06.061

The behaviour and synthetic scope of the C-2 centred radicals derived from 1,3-dithiane and 1,3-dithiane 1-oxide have been studied. Both radicals are available from the corresponding xanthates and have proved suitable substrates for the xanthate transfer reaction. However, the synthetic scope of the former is severely limited by the fact that it does not add to unactivated olefins. The latter on the other hand is a more promising radical precursor and undergoes smooth radical addition to a wide range of alkenes. Furthermore, subsequent transformations of some of the radical adducts confirm its utility as a synthetic equivalent of both the methyl and the formyl radical.

Full text of DOI:10.1016/j.tet.2004.06.061

Tetrahedron 60 (2004) 7781–7791
Xanthates derived from 1,3-dithiane and its monosulfoxide;
one-carbon radical equivalents
*
Michiel de Greef and Samir Z. Zard
` ´
Laboratoire de Synthese Organique associe au C.N.R.S., Ecole Polytechnique, Route de Saclay, F-91128 Palaiseau, France
Received 7 April 2004; revised 28 May 2004; accepted 8 June 2004
Available online 2 July 2004
Dedicated with respect and admiration to Professor Dieter Seebach, recipient of last year’s Tetrahedron Prize
Abstract—The behaviour and synthetic scope of the C-2 centred radicals derived from 1,3-dithiane and 1,3-dithiane 1-oxide have been
studied. Both radicals are available from the corresponding xanthates and have proved suitable substrates for the xanthate transfer reaction.
However, the synthetic scope of the former is severely limited by the fact that it does not add to unactivated olefins. The latter on the other
hand is a more promising radical precursor and undergoes smooth radical addition to a wide range of alkenes. Furthermore, subsequent
transformations of some of the radical adducts confirm its utility as a synthetic equivalent of both the methyl and the formyl radical.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
past few years by our laboratory and is commonly referred
to as the xanthate transfer reaction.14–16 In contrast with
other common radical processes, this method is character-
ised by the fact that the major competing pathway is
degenerate. As a consequence, the intermediate radicals
acquire an extended effective lifetime and are able to
interact with a variety of relatively unreactive traps.
Accordingly, the radical derived from xanthate 1 is expected
to react with olefins 2 to give radical adducts 3. The latter
can then be further manipulated using established 1,3-
dithiane chemistry, such as hydrolysis (path A), reduction
(path B), or alkylation, followed by hydrolysis (path C) or
reduction (path D). In this paper, we provide a full account
of the progress that we have made while studying the
subject.
Over the past few decades, dithioacetals have become
common intermediates in organic synthesis. They are
widely used as protecting groups for carbonyl compounds
and provide a powerful method to make the normally
electrophilic carbonyl carbon behave as a nucleophile.1,2
The first reagent of this type that found general use was 1,3-
dithiane, which on lithiation provides a powerful nucleo-
philic acyl equivalent that reacts with a wide range of alkyl
halides, carbonyl compounds and other electrophilic
reagents.3 On the other hand, when halogenated, it provides
an electrophilic acyl equivalent that is reactive towards a
variety of carbon and heteroatom nucleophiles.4,5
Bearing these results in mind, it may be anticipated that the
C-2 centred radical derived from 1,3-dithiane represents an
interesting synthetic equivalent of the formyl radical and
other one-carbon radicals, such as methyl and carboxyl.
Despite its promising synthetic potential, however, the
radical chemistry of 1,3-dithiane and derivatives has
remained relatively unexplored and hence offers an
interesting opportunity to further extend the synthetic
scope of this heterocycle.6–13
2. Results and discussion
In order to access xanthate 1, we relied on a procedure that
was developed in the late 1970s by Kruse et al.4,5 This
procedure aims at transforming 1,3-dithiane into its
2-chlorinated derivative which is subsequently trapped by
a suitable nucleophile. Thus, treatment of commercially
available 1,3-dithiane 4 with sulfuryl chloride, followed
directly by slow addition of the resulting 2-chloro-1,3-
dithiane 5 to a solution of potassium O-ethyl xanthate in
acetone gave 1 in quantitative yield (Scheme 2). This two-
step-one-pot procedure turned out to be an effective and
reliable method to prepare large quantities of 1.
Our approach is summarised in Scheme 1 and relies on a
radical process that has been thoroughly developed over the
Keywords: Radicals; Xanthates; Dithioacetals; 1,3-Dithiane; 1,3-Dithiane
1-oxide.
*
Corresponding author. Tel.: þ33-1-69-33-43-52; fax: þ33-1-69-33-38-
51; e-mail address: zard@poly.polytechnique.fr
Subsequent attempts to use 1 in some intermolecular radical
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.061

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Scheme 1. Radical addition of xanthate 1 to olefins 2 and some of the conceivable transformations of the resulting radical adducts 3.
radical with N-methyl maleimide 9 (Table 1, entry d).
Thus, heating 1 with 2 equiv. of 9 in refluxing 1,2-
dichloroethane afforded the expected radical adduct 10 in
52% yield after addition of 0.25 equiv. of initiator.
Scheme 2. Reagents and conditions: (a) SO2Cl2 (1.05 equiv.), dry CHCl3,
240 8C!rt; (b) EtOC(S)S2, Kþ (1.1 equiv.), acetone, 210 8C!rt.
These results suggest that the radical derived from 1 is
relatively electron-rich and needs highly activated traps in
order to undergo efficient radical addition. It is interesting to
note that Byers et al. made similar observations when they
studied the photolytic addition of 2-phenylseleno-1,3-
dithiane.9 This reaction was successful only when elec-
tron-deficient alkenes were employed. In order to change
the electronic properties of 1 and to achieve reversed
reactivity, we decided to transform 1 into the corresponding
monosulfoxide 11 (Scheme 3). As opposed to the radical
derived from 1, the radical derived from 11 is susceptible to
take benefit from the captodative effect. Introduced in the
late 1970s by Viehe et al. this concept states that the
combined action of an electron-withdrawing and an
electron-releasing substituent on a radical centre leads to
enhanced stabilisation.17 Selective oxidation was achieved
by slow addition of 1 equiv. of mCPBA to a solution of 1 in
dichloromethane. Under these conditions 11 was obtained in
71% yield as a solid 10:11 mixture of separable dia-
stereomers. Although the isomers were isolated for
identification purposes, the mixture was used as such in
subsequent radical reactions, because of the fact that both
diastereomers give rise to the same radical.
additions under standard reaction conditions gave dis-
appointing results (Table 1, entries a–c). For example, when
heating 1 with 2 equiv. of either allyl acetate 6, or allyl-
trimethyl-silane 7 in refluxing 1,2-dichloroethane in the
presence of lauroyl peroxide (DLP), no reaction was
observed, despite the fact that 0.3 equiv. of initiator had
been added. Similar results were obtained when phenyl-
vinyl-sulfone 8 was used as olefin. Although in this case,
some reaction took place, no radical adduct could be
detected in the crude reaction product and a considerable
amount of 1 was still present, despite the fact that 0.8 equiv.
of DLP had been added. Slightly discouraged by these
results, we were relieved to confirm that 1 is nonetheless a
valid radical precursor, by trapping the corresponding
Table 1. Radical addition of xanthate 1
Entry
Olefin
Radical adduct (%)
—
a
6
b
c
7
8
—
—
Scheme 3. Reagents and conditions: (a) mCPBA (1.06 equiv.), CH2Cl2,
0 8C!rt.
To our delight, 11 turned out to be a much more promising
radical precursor than 1, as is reflected by the fact that it
underwent smooth radical addition to a wide range of
alkenes (Table 2, entries a–k). The corresponding radical
adducts 21–31 were normally obtained in reasonably good
yields (60–75%), although some exceptions were observed
d
9
10 (52)

M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
7783
Table 2. Radical addition of xanthate 11
Entry
Olefin
DLP (equiv.)
0.45
21–31 (%)
21 (70)
32–41 (%)
32 (63)
a
6
b
c
7
0.30
0.45
22 (75)
33 (88)
34 (67)
12
23 (56 (63a))
d
e
f
13
14
15
0.35
0.85
0.50
24 (69)
25 (32)
26 (69)
35 (69)
36 (89)
37 (77)
g
16
17
0.80
0.45
27 (34)
38 (66)
39 (67)
h
28 (66 (72a))
i
18
19
20
0.55
0.75
0.65
29 (75)
30 (39)
31 (61)
40 (77)
j
41 (60)
b
k
a
Yield based on recovered starting material.
Radical adduct 31 was not reduced, but characterised after cyclisation and subsequent reduction.
b
(Table 2, entries e, g, and j). The radical reaction proceeds
under mild conditions and tolerates various functional
groups commonly encountered in organic synthesis. It is
worth noting that 11 displays a behaviour that is slightly
different from that observed for most other xanthates.14
Although it added correctly to most alkenes tested, its
radical additions needed significantly more than catalytic
quantities of peroxide to reach completion. In some cases
(entries i and k), trace amounts of cylised reaction product
were detected (TLC analysis), implying that some of the
initiator had been used for rearomatisation purposes. For the
other cases, the reason for this deviant behaviour is not fully
understood. Another difficulty stems from the fact that 11
contains two non-fixed stereocenters and that a third
stereocenter is created in a non-controlled way during the
radical process. As a consequence, all reaction products
21–31 were obtained as complicated mixtures of dia-
stereomers. Although several attempts have been made to
characterise each isomer separately, it was judged much
more convenient to subject the mixture to reductive
conditions, which would considerably facilitate the task of
characterisation since two stereocenters are removed in a
single reaction step. Among several available methods for
the transformation of sulfoxides into sulfides,18–21 the use
of trifluoroacetic anhydride and sodium iodide in dry
acetone proved particularly suitable for our purpose.18
This method allowed rapid reduction of sulfoxides 21–31
under mild conditions and gave the corresponding dithianes
32–41 in good yields (63–89%) after purification by flash
chromatography on silica gel (Table 2, entries a–j).
Dithiane 41 (Table 2, entry j) was obtained as an inseparable
mixture of diastereomers and had to be further reduced in

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M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
Scheme 4. Reagents and conditions: (a) (Me3Si)3SiH (2 equiv.), AIBN (cat.), heptane, reflux.
order to allow its full characterisation. Although other
methods are available,22 clean reduction was achieved by
exposing 41 to 2 equiv. of tris(trimethylsilyl)silane and a
small amount of AIBN in refluxing heptane, which afforded
42 in 56% yield (Scheme 4).
the 1,3-dithiane 1-oxide moiety. For example, clean and
efficient desulphurisation was achieved by treating 44 with
excess Raney nickel in refluxing ethanol (Scheme 7).
Inspection of the way 48 has been obtained reveals that the
overall sequence is equivalent to the addition of a methyl
radical 49 to 18. Methyl radicals are reactive intermediates
and it is worth noting that their generation and clean capture
by unactivated olefins is not generally feasible. As is the
case for 1,3-dithianes, 1,3-dithiane 1-oxides represent
masked carbonyl compounds and are expected to undergo
deprotection upon hydrolysis. Inspection of the literature
reveals that 1,3-dithiane 1-oxides are most commonly
hydrolysed by treatment with aqueous solutions of NBS.26
Indeed, hydrolysis was achieved by treating 45 with excess
NBS (8 equiv.) in aqueous acetone, but in modest yield and
not without brominating the aromatic ring (Scheme 7).
Attempts to achieve better selectivity by using less NBS and
performing the reaction at lower temperature were only
moderately successful. The best results were obtained by
using 4 equiv. of NBS and carrying out the reaction at
220 8C. In this case, 50 was obtained in 15% yield along
with an equimolar amount of its non-brominated derivative.
When other reagents such as aqueous solutions of methyl
iodide, Dess–Martin periodinane,27 trifluoroacetic
anhydride,28 or bis(trifluoroacetoxy)iodobenzene29 were
used, no hydrolysis at all was observed. Clean hydrolysis
was finally achieved by way of a two-step procedure. Thus,
reduction of 44 followed by alkylative hydrolysis of the
intermediate 1,3-dithiane 46, gave the expected reaction
product 51 in 47% overall yield (Scheme 7). These results
led us to conclude that 11 is a valid synthetic equivalent of
the formyl radical 52.
The difficulties related to moderate reactivity and stereo-
chemical complexity may be overcome by transforming 11
into a symmetric and more electrophilic derivative. The
most convenient way to do so seems to be the oxidation of
11 to the corresponding bis-sulfoxide 43 (Scheme 5). Initial
attempts to carry out this transformation have revealed that
the xanthate and the endocyclic sulfide show comparable
reactivity toward most common oxidising agents and
selective oxidation has become a challenge that we are
still addressing.
Scheme 5. Transformation of 11 into the corresponding bis-sulfoxide 43.
One of the major assets of the xanthate transfer reaction is
that its reaction products still contain the xanthate. At this
stage it may either serve to allow access to other functional
groups or be used in a second radical transformation.23–25 In
order to exemplify the latter, we exposed adducts 29 and 31
to stoichiometric amounts of DLP in refluxing 1,2-
dichloroethane (Scheme 6). In both cases, the reaction
proceeded as expected and cyclisation onto the aromatic
ring provided indolines 44 and 45 in 69 and 77% yield,
respectively. As was the case for radical adducts 21–31,
both reaction products were obtained as complicated
mixtures of diastereomers and had to be reduced as
discussed previously in order to be fully characterised
(Scheme 7).
In order to further extend the synthetic scope of 11, we
decided to attempt the alkylation of the 1,3-dithiane 1-oxide
moiety present in indoline 45. When followed by successful
hydrolysis to give the corresponding ketone (similar to
Scheme 1, path C), 11 provides a useful synthetic equivalent
of acyl radicals. Furthermore, when followed by successful
desulphurisation, 11 provides a synthetic equivalent of
primary alkyl radicals (similar to Scheme 1, path D).
Compared to the case of 1,3-dithianes, literature examples
of successful alkylation of 1,3-dithiane 1-oxides are
relatively scarce.30–35 According to Carey et al. metalation
of 2-substituted 1,3-dithiane 1-oxides is best carried out
with lithium diisopropylamide (LDA).32 However, when 45
was exposed to an equimolar amount of LDA, followed by
excess methyl iodide, no alkylation was observed and most
of the starting material was recovered unreacted. Inversion
of the order of events, involving alkylation of 11 instead of
45, seemed to be more promising. Thus, treatment of 11
with an equimolar amount of LDA and excess methyl iodide
afforded the expected reaction product 53 as a 1:5 mixture
Scheme 6. Reagents and conditions: (a) DLP (1.1–1.3 equiv.), 1,2-
dichloroethane, reflux; (b) trifluoroacetic anhydride (2.4–2.6 equiv.), NaI
(2.4 equiv.), dry acetone, 0 8C!rt.
In order to validate our approach (Scheme 1), we next
turned our attention to exploring some of the chemistry of

M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
7785
Scheme 7. Reagents and conditions: (a) NBS (8.3 equiv.), aqueous acetone, 0 8C; (b) trifluoroacetic anhydride (2.4–2.6 equiv.), NaI (2.4 equiv.), dry acetone,
0 8C!rt; (c) W2 Ra-Ni (excess), abs. EtOH, reflux; (d) MeI (50 equiv.), CH2Cl2, aqueous acetone, 45 8C.
of separable diastereomers in 50% yield (unoptimised)
(Scheme 8). Unfortunately, 53 did not behave as expected
when heated with 2 equiv. of 18 in refluxing 1,2-
dichloroethane in the presence of DLP. Although some
reaction took place, no radical adduct could be detected in
the crude reaction product and a small amount of 53 was still
present, despite the fact that 1.0 equiv. of DLP had been
added at the end of the reaction. The reason for this failure is
not clear, although it may be anticipated that the presence of
the electron-releasing methyl group partially cancels the
effect that the electron-withdrawing sulfoxide has on the
reactivity of the corresponding radical.
complements the well-established ionic chemistry of this
class of compounds.
4. Experimental
4.1. General
All reagents and solvents were purchased from commercial
sources and used as supplied or purified using standard
˚
methods. Silica gel 60 A C.C. 40-63 (SDS) was used for
flash chromatography. TLC analysis was done on silica gel
60 F254 TLC plates (Merck). Petroleum ether refers to the
fractions with bp 40–60 8C. 1H and 13C NMR spectra were
1
recorded on a Bruker AMX 400 instrument. H and 13C
chemical shifts are given with respect to the solvent as
internal standard. IR spectra were measured on a Perkin–
Elmer FT 1600 as solutions in CCl4. Low resolution mass
spectra were recorded at a HP 5989B mass spectrometer.
Microanalyses were carried out by the microanalytical
laboratory of the Institut de Chimie des Substances
Naturelles, Gif-sur-Yvette.
Scheme 8. Reagents and conditions: (a) LDA (1.1 equiv.), MeI (2.4 equiv.),
dry THF, 278 8C!rt.
3. Conclusion
In contrast with its anionic and cationic counterparts, the
C-2 centred radical derived from 1,3-dithiane has revealed
itself as being of rather limited synthetic scope. The
corresponding monosulfoxide on the other hand has proved
more useful. It is a suitable substrate for the xanthate
transfer reaction and as such adds to a wide range of
unactivated alkenes under mild, neutral conditions that are
compatible with most functional groups encountered in
modern organic synthesis. Furthermore, subsequent trans-
formations of some of the radical adducts confirmed its
utility as a synthetic equivalent of both the methyl and the
formyl radical. Finally, we believe that the results presented
in this paper justify the statement that our xanthate-based
methodology allows considerable broadening of the
synthetic scope of 1,3-dithiane chemistry and nicely
4.1.1. Dithiocarbonic acid S-[1,3]dithian-2-yl ester
O-ethyl ester (1). A solution of 1,3-dithiane 4 (12.1 g,
100 mmol) in dry CHCl3 (250 mL) was cooled to 240 8C
under a nitrogen atmosphere, before dropwise addition of a
solution of freshly distilled sulfuryl chloride (8.4 mL,
105 mmol) in dry CHCl3 (50 mL). The yellow suspension
thus obtained was allowed to warm to room temperature.
The initially formed precipitate went into solution and the
resulting orange solution was slowly transferred to a cooled
(210 8C) solution of dithiocarbonic acid O-ethyl ester
potassium salt (17.6 g, 110 mmol) in acetone (250 mL). The
yellow suspension thus obtained was stirred at 210 8C for
another 60 min before being warmed to room temperature.
The precipitate was removed by filtration and the resulting
yellow solution was concentrated under reduced pressure

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M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
before addition of Et2O (250 mL). The organic phase was
extracted with water (2£150 mL), washed with brine
(1£100 mL), and dried over anhydrous Na2SO4. Evapor-
ation of the solvent yielded 1 (23.9 g, 100%) as a yellow oil
which was sufficiently pure to be used directly in the next
step. Analytical samples and samples appropriate for radical
reactions were obtained by recrystallisation (petroleum
ether).
Analytical samples of both isomers were obtained by flash
chromatography on silica gel (Et2O–EtOAc, 60:40 v/v).
1
Less polar isomer (major). H NMR (400 MHz, CDCl3):
d¼1.44 (t, J¼7.2 Hz, 3H), 2.24–2.35 (m, 1H), 2.38–2.45
(m, 1H), 2.51 (dt, J¼3.6, 14.4 Hz, 1H), 2.74 (ddd, J¼2.8,
12.0, 14.4 Hz, 1H), 2.84 (dt, J¼3.2, 12.8 Hz, 1H), 3.08–
3.13 (m, 1H), 4.70 (dq, J¼1.2, 7.2 Hz, 2H), 6.13 (brs, 1H)
ppm. 13C NMR (100 MHz, CDCl3): d¼13.76 (CH3), 25.62
(CH2), 27.99 (CH2), 48.74 (CH2), 66.22 (CH), 71.60 (CH2),
208.78 (CvS) ppm. IR (CCl4): 2985, 2957, 2939, 2911,
2866, 2844, 1462, 1436, 1425, 1415, 1388, 1365, 1292,
1243, 1181, 1150, 1111, 1089, 1073, 1043 cm21. MS
(CI/NH3): 257 (MHþ), 274 (MNH4þ).
1H NMR (400 MHz, CDCl3): d¼1.44 (t, J¼7.2 Hz, 3H),
2.01–2.12 (m, 1H), 2.15–2.22 (m, 1H), 2.73–2.79 (m, 2H),
3.23 (ddd, J¼2.8, 11.8, 14.2 Hz, 2H), 4.67 (q, J¼7.2 Hz,
2H), 5.65 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3):
d¼13.66 (CH3), 25.01 (CH2), 26.72 (2£CH2), 49.84 (CH),
70.12 (CH2), 211.07 (CvS) ppm. IR (CCl4): 2985, 2955,
2939, 2904, 1442, 1432, 1424, 1414, 1388, 1363, 1292,
1280, 1229, 1148, 1111, 1045 cm21. MS (CI/NH3): 119
(M2C3H5OS2), 241 (MHþ), 258 (MNHþ4 ). Anal. calcd C,
34.97; H, 5.03; found C, 35.48; H, 5.16.
1
More polar isomer (minor). H NMR (400 MHz, CDCl3):
d¼1.44 (t, J¼7.2 Hz, 3H), 1.79–1.86 (m, 1H), 2.52–2.57
(m, 1H), 2.60–2.71 (m, 1H), 2.88 (ddd, J¼2.4, 11.6,
14.0 Hz, 1H), 2.90–2.95 (m, 1H), 3.04 (ddd, J¼2.8, 12.0,
14.8 Hz, 1H), 4.68 (q, J¼7.2 Hz, 2H), 5.54 (brs, 1H) ppm.
13C NMR (100 MHz, CDCl3): d¼13.75 (CH3), 15.65 (CH2),
25.98 (CH2), 43.35 (CH2), 63.04 (CH), 71.60, 207.62
(CvS) ppm. IR (CCl4): 2985, 2958, 2940, 2910, 2870,
1471, 1460, 1442, 1425, 1406, 1388, 1365, 1293, 1241,
1150, 1110, 1077, 1040 cm21. MS (CI/NH3): 257 (MHþ),
274 (MNHþ4 ).
4.1.2. Dithiocarbonic acid S-(4-[1,3]dithian-2-yl-1-
methyl-2,5-dioxo-pyrrolidin-3-yl) ester O-ethyl ester
(10). A solution of 1 (158 mg, 0.657 mmol) and 9
(148 mg, 1.33 mmol) in 1,2-dichloro-ethane (1.0 mL) was
refluxed for 30 min DLP (0.05 equiv.) was then added and
additional DLP (0.025 equiv.) was added every 90 min until
complete consumption of 1. After addition of 0.25 equiv. of
DLP the mixture was cooled to room temperature and the
solvent evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel (Et2O–
petroleum ether, 30:70 to 50:50 v/v) to afford 10 (104 mg,
52%) as a slightly yellow solid.
4.2. Radical addition of (11). General procedure
A solution of 11 (1.0 equiv.) and olefin (1.2–3.0 equiv.) in
1,2-dichloro–ethane (1.0 mL/mmol of 11) was refluxed for
15 min DLP (0.1 equiv.) was then added and additional
DLP (0.1 equiv.) was added every 90 min until complete
consumption of 11. The mixture was then cooled to room
temperature and the solvent evaporated under reduced
pressure. The residue was purified by flash chromatography
on silica gel to afford the reaction products as complicated
mixtures of diastereomers that were used as such in the next
reaction step.
1H NMR (400 MHz, CDCl3): d¼1.35 (t, J¼7.2 Hz, 3H),
1.77–1.88 (m, 1H), 2.10–2.17 (m, 1H), 2.87–2.91 (m, 2H),
2.99 (ddd, J¼2.4, 12.4, 14.4 Hz, 2H), 3.09 (s, 3H), 3.58 (dd,
J¼3.6, 5.6 Hz, 1H), 4.32 (d, J¼5.6 Hz, 1H), 4.57 (q,
J¼7.2 Hz, 2H), 4.84 (d, J¼3.2 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d¼13.48 (CH3), 24.66 (CH2), 25.57
(CH3), 30.01 (CH2), 30.95 (CH2), 46.64 (CH), 47.04 (CH),
51.77 (CH), 172.37 (CvO), 173.52 (CvO), 209.12 (CvS)
ppm. IR (CCl4): 2940, 2903, 1790, 1719, 1432, 1379, 1288,
1240, 1222, 1198, 1176, 1118, 1113, 1054 cm21. MS
(CI/NH3): 352 (MHþ), 369 (MNHþ4 ). Anal. calcd C, 41.00;
H, 4.87; found C, 41.49; H, 5.01.
4.2.1. Acetic acid 2-ethoxythiocarbonylsulfanyl-3-(1-
oxo-1l 4-[1,3]dithian-2-yl)-propyl ester (21). The reaction
was carried out with a solution of 11 (125 mg, 0.49 mmol)
and 6 (0.16 mL, 1.5 mmol) and needed 0.45 equiv. of DLP
to go to completion. Flash chromatography on silica gel
(Et2O, then MeOH–EtOAc, 5:95 v/v) afforded 21 (121 mg,
70%).
4.1.3. Dithiocarbonic acid O-ethyl ester S-(1-oxo-1l 4-
[1,3]dithian-2-yl) ester (11). A solution of 1 (23.9 g,
100 mmol) in CH2Cl2 (200 mL) was cooled to 0 8C under a
nitrogen atmosphere, before dropwise addition of a solution
of mCPBA (24.9 g, 106 mmol) in CH2Cl2 (225 mL). The
white suspension thus obtained was stirred at 0 8C for
another 60 min before being warmed to room temperature.
The mixture was then extracted with a saturated solution of
NaHCO3 (3£200 mL), washed with brine (1£150 mL), and
dried over anhydrous Na2SO4. Evaporation of the solvent
yielded crude 11 (24.8 g, 97%) as an orange oil. Purification
was carried out in two steps. Flash chromatography on silica
gel (Et2O–petroleum ether, 25:75 v/v to Et2O–EtOAc,
25:75 v/v) yielded nearly pure reaction product, which was
further purified by recrystallisation (EtOAc–petroleum
ether, 9:10 v/v) to afford 11 (18.4 g, 71%) as a solid 10:11
mixture (NMR analysis) of separable diastereomers.
4.2.2. Dithiocarbonic acid O-ethyl ester S-[2-(1-oxo-1l 4-
[1,3]dithian-2-yl)-1-trimethylsilanylmethyl-ethyl] ester
(22). The reaction was carried out with a solution of 11
(262 mg, 1.0 mmol) and 7 (0.48 mL, 3.0 mmol) and needed
0.30 equiv. of DLP to go to completion. Flash chromato-
graphy on silica gel (Et2O–petroleum ether, 50:50 v/v, then
Et2O–EtOAc, 80:20 to 40:60 v/v) afforded 22 (282 mg,
75%).
4.2.3. Dithiocarbonic acid S-[1-cyclopentyl-2-(1-oxo-
1l 4-[1,3]dithian-2-yl)-ethyl] ester O-ethyl ester (23).
The reaction was carried out with a solution of 11
(257 mg, 1.0 mmol) and 12 (288, 3.0 mmol) and needed
0.45 equiv. of DLP to go to completion. Flash chromato-
graphy on silica gel (Et2O–petroleum ether, 50:50 v/v, then

M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
7787
Et2O–EtOAc, 60:40 to 0:100 v/v, then MeOH–EtOAc,
5:95 v/v) afforded 23 (150 mg, 56%).
4.2.11. Dithiocarbonic acid S-[1-{[(2,2-dimethyl-propio-
nyl)-phenyl-amino]-methyl}-2-(1-oxo-1l 4-[1,3]dithian-
2-yl)-ethyl] ester O-ethyl ester (31). The reaction was
carried out with a solution of 11 (256 mg, 1.0 mmol) and 20
(439, 2.0 mmol) and needed 0.65 equiv. of DLP to go to
completion. Flash chromatography on silica gel (Et2O–
petroleum ether, 50:50 v/v, then MeOH–EtOAc, 0:100 to
5:95 v/v) afforded 31 (288 mg, 61%).
4.2.4. Dithiocarbonic acid O-ethyl ester S-[1-(1-oxo-1l 4-
[1,3]dithian-2-ylmethyl)-heptyl] ester (24). The reaction
was carried out with a solution of 11 (254 mg, 0.99 mmol)
and 13 (0.47 mL, 3.0 mmol) and needed 0.35 equiv. of DLP
to go to completion. Flash chromatography on silica gel
(Et2O–petroleum ether, 50:50 v/v, then Et2O–EtOAc,
80:20 to 40:60 v/v) afforded 24 (252 mg, 69%).
4.3. Reduction of radical adducts (21)–(31). General
procedure
4.2.5. Dithiocarbonic acid S-[2-cyano-1-(1-oxo-1l 4-
[1,3]dithian-2-ylmethyl)-ethyl] ester O-ethyl ester (25).
The reaction was carried out with a solution of 11 (255 mg,
1.0 mmol) and 14 (0.24 mL, 3.0 mmol) and needed
0.85 equiv. of DLP to go to completion. Flash chromato-
graphy on silica gel (Et2O, then MeOH–EtOAc, 0:100 to
10:90 v/v) afforded 25 (105 mg, 32%).
A solution of sulfoxide (1.0 equiv.) and NaI (2.4 equiv.) in
dry acetone (5.2 mL/mmol of sulfoxide) was cooled to 0 8C
before dropwise addition of a solution of TFAA (2.4–
2.6 equiv.) in dry acetone (2.0 mL/mmol TFAA). The red
brown solution thus obtained was allowed to warm to room
temperature and diluted with Et2O. The mixture was
extracted twice with a saturated solution of Na2S2O3,
washed once with water, and dried over anhydrous Na2SO4.
The solvent was then removed under reduced pressure and
the residue purified as specified below.
4.2.6. Dithiocarbonic acid S-[1-(4-chloro-phenoxy-
methyl)-2-(1-oxo-1l 4-[1,3]dithian-2-yl)-ethyl] ester
O-ethyl ester (26). The reaction was carried out with a
solution of 11 (254 mg, 0.99 mmol) and 15 (338 mg,
2.0 mmol) and needed 0.50 equiv. of DLP to go to
completion. Flash chromatography on silica gel (Et2O–
petroleum ether, 50:50 v/v, then Et2O–EtOAc, 85:15 to
20:80 v/v) afforded 26 (291 mg, 69%).
4.3.1. Acetic acid 3-[1,3]dithian-2-yl-2-ethoxythiocar-
bonylsulfanyl-propyl ester (32). The reaction was carried
out with 21 (99 mg, 0.28 mmol), TFAA (0.10 mL,
0.73 mmol), and NaI (102 mg, 0.67 mmol). Flash chroma-
tography on silica gel (EtOAc–petroleum ether, 15:185 to
10:90 v/v) afforded 32 (60 mg, 63%).
4.2.7. Dithiocarbonic acid O-ethyl ester S-[4-oxo-1-(1-
oxo-1l 4-[1,3]dithian-2-ylmethyl)-pentyl] ester (27). The
reaction was carried out with a solution of 11 (256 mg,
1.0 mmol) and 16 (0.35 mL, 3.0 mmol) and needed
0.80 equiv. of DLP to go to completion. Flash chromato-
graphy on silica gel (Et2O–petroleum ether, 50:50 v/v, then
MeOH–EtOAc, 3:97 to 10:90 v/v) afforded 27 (119 mg,
34%).
1H NMR (400 MHz, CDCl3): d¼1.45 (t, J¼7.2 Hz, 3H),
1.85–1.95 (m, 1H), 2.05–2.25 (m, 3H), 2.09 (s, 3H), 2.85–
2.90 (m, 4H), 4.17 (dd, J¼6.0, 9.2 Hz, 1H), 4.22–4.28 (m,
2H), 4.34–4.39 (m, 1H), 4.66 (q, J¼7.2 Hz, 2H) ppm. 13C
NMR (100 MHz, CDCl3): d¼13.67 (CH3), 20.74 (CH3),
25.66 (CH2), 29.67 (CH2), 29.91 (CH2), 35.77 (CH2), 43.92
(CH), 46.00 (CH), 65.07 (CH2), 70.25 (CH2), 170.56
(CvO), 211.98 (CvS) ppm. IR (CCl4): 2984, 2939,
2902, 1749, 1462, 1441, 1423, 1380, 1362, 1227, 1112,
1051 cm21. MS (CI/NH3): 341 (MHþ), 358 (MNHþ4 ).
4.2.8. Dithiocarbonic acid O-ethyl ester S-[1-(6-methoxy-
2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-2-
(1-oxo-1l 4-[1,3]dithian-2-yl)-ethyl] ester (28). The
reaction was carried out with a solution of 11 (259 mg,
1.0 mmol) and 17 (398, 2.0 mmol) and needed 0.45 equiv.
of DLP to go to completion. Flash chromatography on silica
gel (Et2O–petroleum ether, 50:50 v/v, then MeOH–EtOAc,
0:100 to 5:95 v/v) afforded 28 (300 mg, 66%).
4.3.2. Dithiocarbonic acid S-(2-[1,3]dithian-2-yl-1-tri-
methylsilanylmethyl-ethyl) ester O-ethyl ester (33). The
reaction was carried out with 22 (111 mg, 0.30 mmol),
TFAA (0.11 mL, 0.78 mmol), and NaI (109 mg,
0.72 mmol). Flash chromatography on silica gel (EtOAc–
petroleum ether, 2:98 v/v) afforded 33 (93 mg, 88%).
4.2.9. Dithiocarbonic acid S-[1-[(acetyl-phenyl-amino)-
methyl]-2-(1-oxo-1l 4-[1,3]dithian-2-yl)-ethyl] ester
O-ethyl ester (29). The reaction was carried out with a
solution of 11 (437 mg, 1.71 mmol) and 18 (600 mg,
3.43 mmol) and needed 0.55 equiv. of DLP to go to
completion. Flash chromatography on silica gel (MeOH–
EtOAc, 0:100 to 10:90 v/v) afforded 29 (557 mg, 75%).
1H NMR (400 MHz, CDCl3): d¼0.10 (s, 9H), 1.07 (dd,
J¼8.4, 14.8 Hz, 1H), 1.18 (dd, J¼6.8, 14.8 Hz, 1H), 1.44 (t,
J¼7.2 Hz, 3H), 1.84–1.94 (m, 1H), 2.03 (ddd, J¼5.6, 8.4,
14.4 Hz, 1H), 2.09–2.16 (m, 2H), 2.81–2.92 (m, 4H),
4.04–4.11 (m, 1H), 4.15 (dd, J¼5.6, 8.4 Hz, 1H), 4.61–4.69
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): d¼20.69
(3£CH3), 13.77 (CH3), 23.29 (CH2), 25.76 (CH2), 29.94
(CH2), 30.08 (CH2), 41.99 (CH2), 44.63 (CH), 45.42 (CH),
69.62 (CH2), 213.51 (CvS) ppm. IR (CCl4): 2956, 2900,
1423, 1276, 1250, 1216, 1111, 1051 cm21. MS (CI/NH3):
233 (MHþ2C3H6OS2), 355 (MHþ). Anal. calcd C, 44.02;
H, 7.39; found C, 44.13; H, 7.35.
4.2.10. Acetic acid 3,5-diacetoxy-2-acetoxymethyl-6-[2-
ethoxythiocarbonylsulfanyl-3-(1-oxo-1l 4-[1,3]dithian-
2-yl)-propyl]-tetrahydro-pyran-4-yl ester (30). The
reaction was carried out with a solution of 11 (59 mg,
0.23 mmol) and 19 (104, 0.28 mmol) and needed
0.75 equiv. of DLP to go to completion. Flash chromato-
graphy on silica gel (Et2O–petroleum ether, 50:50 v/v,
then MeOH–EtOAc, 4:96 v/v) afforded 30 (55 mg,
39%).
4.3.3. Dithiocarbonic acid S-(1-cyclopentyl-2-
[1,3]dithian-2-yl-ethyl) ester O-ethyl ester (34). The

7788
M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
reaction was carried out with 23 (72 mg, 0.20 mmol), TFAA
(74 mL, 0.52 mmol), and NaI (72 mg, 0.48 mmol). Flash
chromatography on silica gel (EtOAc–petroleum ether,
0:100 to 2:98 v/v) afforded 34 (45 mg, 67%).
(EtOAc–petroleum ether, 0:100 to 2:98 v/v) afforded 37
(95 mg, 77%).
1H NMR (400 MHz, CDCl3): d¼1.43 (t, J¼7.2 Hz, 3H),
1.87–1.96 (m, 1H), 2.10–2.15 (m, 1H), 2.20 (ddd, J¼6.0,
9.2, 14.8 Hz, 1H), 2.44 (ddd, J¼5.6, 9.2, 14.8 Hz, 1H),
2.81–2.89 (m, 4H), 4.09 (dd, J¼6.4, 10.0 Hz, 1H), 4.18 (dd,
J¼5.6, 8.8 Hz, 1H), 4.27 (dd, J¼3.6, 9.6 Hz, 1H), 4.36–
4.43 (m, 1H), 4.66 (q, J¼7.2 Hz), 6.86 (d, J¼9.2 Hz, 2H),
7.24 (d, J¼9.2 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d¼13.73 (CH3), 25.69 (CH2), 29.52 (CH2), 29.79 (CH2),
35.68 (CH2), 43.98 (CH), 46.70 (CH), 69.31 (CH2), 70.27
(CH2), 115.91 (CH), 126.02 (C), 129.26 (CH), 156.84 (C),
212.62 (CvS) ppm. IR (CCl4): 2978, 2935, 2901, 2867,
1597, 1583, 1492, 1464, 1424, 1381, 1276, 1240, 1170,
1148, 1112, 1094, 1052 cm21. MS (CI/NH3): 406 (Mþ2H2,
1H NMR (400 MHz, CDCl3): d¼1.22–1.39 (m, 2H), 1.43 (t,
J¼7.2 Hz, 3H), 1.47–1.68 (m, 4H), 1.75–1.92 (m, 3H),
2.01–2.15 (m, 3H), 2.19–2.29 (m, 1H), 2.82–2.92 (m, 4H),
4.09–4.14 (m, 1H), 4.17 (dd, J¼5.6, 8.8 Hz, 1H), 4.64 (q,
J¼7.2 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d¼13.73 (CH3), 25.23 (CH2), 25.48 (CH2), 25.78 (CH2),
29.57 (CH2), 29.78 (CH2), 30.05 (CH2), 30.29 (CH2), 39.18
(CH2), 43.78 (CH), 44.43 (CH), 52.55(CH), 69.90 (CH2),
213.99 (CvS) ppm. IR (CCl4): 2955, 2903, 2869, 1433,
1424, 1387, 1362, 1292, 1276, 1216, 1145, 1112,
1051 cm21. MS (CI/NH3): 337 (MHþ). Anal. calcd C,
49.96; H, 7.19; found C, 49.64; H, 7.16.
35
37
C16H ClO3S4), 408 (Mþ2H2, C16H ClO3S4), 409 (MHþ,
21
35
21
C16H ClO3S4), 411 (MHþ, C16H ClO3S4), 426 (MNH4þ,
37
21
35
21
21
37
21
4.3.4. Dithiocarbonic acid S-(1-[1,3]dithian-2-ylmethyl-
heptyl) ester O-ethyl ester (35). The reaction was carried
out with 24 (89 mg, 0.24 mmol), TFAA (90 mL,
0.63 mmol), and NaI (87 mg, 0.58 mmol). Flash chroma-
tography on silica gel (EtOAc–petroleum ether, 0:100 to
3:197 v/v) afforded 35 (58 mg, 69%).
C16H ClO3S4), 428 (MNHþ4 , C16H ClO3S4). Anal. calcd
C, 46.98; H, 5.17; found C, 46.61; H, 5.21.
4.3.7. Dithiocarbonic acid S-(1-[1,3]dithian-2-ylmethyl-
4-oxo-pentyl) ester O-ethyl ester (38). The reaction was
carried out with 27 (119 mg, 0.34 mmol), TFAA (0.12 mL,
0.87 mmol), and NaI (121 mg, 0.81 mmol). Flash chroma-
tography on silica gel (EtOAc–petroleum ether, 0:100 to
15:85 v/v) afforded 38 (76 mg, 66%).
1H NMR (400 MHz, CDCl3): d¼0.88 (t, J¼6.4 Hz, 3H),
1.22–1.51 (m, 8H), 1.44 (t, J¼7.2 Hz, 3H), 1.65–1.76 (m,
2H), 1.85–1.95 (m, 1H), 2.04–2.16 (m, 3H), 2.82–2.92 (m,
4H), 3.95–4.02 (m, 1H), 4.16 (t, J¼7.6 Hz, 1H), 4.66 (dq,
J¼2.0, 7.2 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d¼13.74 (CH3), 14.00 (CH3), 22.48 (CH2), 25.77
(CH2), 26.50 (CH2), 28.93 (CH2), 29.86 (CH2), 29.99
(CH2), 31.56 (CH2), 34.07 (CH2), 39.29 (CH2), 44.42 (CH),
47.82 (CH), 69.76 (CH2), 213.59 (CvS) ppm. IR (CCl4):
2957, 2929, 2857, 2359, 1458, 1424, 1379, 1276, 1218,
1145, 1112, 1052 cm21. MS (CI/NH3): 353 (MHþ), 370
(MNHþ4 ). Anal. calcd C, 51.09; H, 8.00; found C, 50.92; H,
8.05.
1H NMR (400 MHz, CDCl3): d¼1.44 (t, J¼7.2 Hz, 3H),
1.82–1.93 (m, 2H), 2.00–2.19 (m, 4H), 2.17 (s, 3H), 2.64 (t,
J¼8.0 Hz, 2H), 2.84–2.92 (m, 4H), 3.95–4.02 (m, 1H),
4.16 (t, J¼7.6 Hz, 1H), 4.65 (q, J¼7.2 Hz, 2H) ppm. 13C
NMR (100 MHz, CDCl3): d¼13.70 (CH3), 25.68 (CH2),
27.57 (CH2), 29.81 (CH2), 29.89 (CH2), 30.00 (CH3),
39.77 (CH2), 40.57 (CH2), 44.18 (CH), 47.36 (CH), 70.08
(CH2), 208.34 (CvO), 212.96 (CvS) ppm. IR (CCl4):
2984, 2937, 2902, 1721, 1442, 1423, 1367, 1276, 1217,
1162, 1112, 1050 cm21. MS (CI/NH3): 339 (MHþ), 356
(MNHþ4 ). Anal. calcd C, 46.12; H, 6.55; found C, 46.36; H,
6.55.
4.3.5. Dithiocarbonic acid S-(2-cyano-1-[1,3]dithian-2-
ylmethyl-ethyl) ester O-ethyl ester (36). The reaction was
carried out with 25 (100 mg, 0.31 mmol), TFAA (0.11 mL,
0.81 mmol), and NaI (112 mg, 0.74 mmol). Flash chroma-
tography on silica gel (EtOAc–petroleum ether, 10:90 to
20:80 v/v) afforded 36 (85 mg, 89%).
4.3.8. Dithiocarbonic acid S-[2-[1,3]dithian-2-yl-1-(6-
methoxy-2,2-dimethyl-tetrahydro-furo[2,3-d]-
[1,3]dioxol-5-yl)-ethyl] ester O-ethyl ester (39). The
reaction was carried out with 28 (135 mg, 0.30 mmol),
TFAA (0.11 mL, 0.77 mmol), and NaI (113 mg,
0.75 mmol). Flash chromatography on silica gel (EtOAc–
petroleum ether, 13:87 to 20:80 v/v) afforded 39 (88 mg,
67%) as a 8:5 mixture (NMR analysis) of separable
diastereoisomers.
1H NMR (400 MHz, CDCl3): d¼1.45 (t, J¼7.2 Hz, 3H),
1.88–1.98 (m, 1H), 2.09–2.16 (m, 1H), 2.28 (ddd, J¼2.8,
6.8, 8.8 Hz, 2H), 2.81–3.04 (m, 6H), 4.14 (dd, J¼6.4,
8.4 Hz, 1H), 4.16–4.23 (m, 1H), 4.67 (q, J¼7.2 Hz, 2H)
ppm. 13C NMR (100 MHz, CDCl3): d¼13.69 (CH3), 23.63
(CH2), 25.52 (CH2), 29.28 (CH2), 29.56 (CH2), 37.18
(CH2), 43.33 (CH), 43.44 (CH), 70.58 (CH2), 116.76 (CN),
211.29 (CvS) ppm. IR (CCl4): 2984, 2938, 2903, 2250,
1423, 1363, 1292, 1276, 1231, 1148, 1112, 1052 cm21. MS
(CI/NH3): 308 (MHþ), 325 (MNHþ4 ). Anal. calcd C, 42.96;
H, 5.57; found C, 42.82; H, 5.57.
1
Less polar isomer (major). H NMR (400 MHz, CDCl3):
d¼1.32 (s, 3H), 1.44 (t, J¼7.2 Hz, 3H), 1.48 (s, 3H), 1.86–
1.96 (m, 1H), 2.04–2.12 (m, 1H), 2.25 (ddd, J¼4.8, 9.6,
14.8 Hz, 1H), 2.53 (ddd, J¼4.0, 10.0, 14.4 Hz), 2.72–2.92
(m, 4H), 3.38 (s, 3H), 3.79 (d, J¼3.2 Hz, 1H), 4.15–4.21
9M, 2H), 4.44 (dd, J¼3.2, 8.8 Hz, 1H), 4.54 (d, J¼3.6 Hz,
1H), 4.62–4.70 (m, 2H), 5.91 (d, J¼3.6 Hz, 1H) ppm. 13C
NMR (100 MHz, CDCl3): d¼13.74 (CH3), 25.76 (CH2),
26.15 (CH3), 26.74 (CH3), 28.78 (CH2), 29.20 (CH2), 36.98
(CH2), 43.80 (CH), 45.96 (CH), 57.75 (CH3), 70.05 (CH2),
81.02 (2£CH), 84.26 (CH), 105.15 (CH), 111.59 (C),
212.43 (CvS) ppm. IR (CCl4): 2989, 2934, 2901, 2830,
4.3.6. Dithiocarbonic acid S-[1-(4-chloro-phenoxy-
methyl)-2-[1,3]dithian-2-yl-ethyl] ester O-ethyl ester
(37). The reaction was carried out with 26 (128 mg,
0.30 mmol), TFAA (0.11 mL, 0.78 mmol), and NaI
(110 mg, 0.73 mmol). Flash chromatography on silica gel

M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
7789
1454, 1443, 1423, 1382, 1373, 1293, 1275, 1220, 1164,
1113, 1082, 1052, 1021 cm21. MS (CI/NH3): 441 (MHþ).
1H NMR (400 MHz, CDCl3): d¼1.45–1.54 (m, 2H), 1.66–
1.91 (m, 5H), 2.03 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.10–
2.17 (m, 1H), 2.11 (s, 3H), 2.80–2.93 (m, 4H), 3.82 (ddd,
J¼2.4, 5.2, 9.2 Hz, 1H), 4.04–4.11 (m, 2H), 4.16 (ddd,
J¼3.6, 5.6, 11.2 Hz, 1H), 4.23 (d, J¼5.2, 12.0 Hz, 1H), 4.97
(t, J¼9.2 Hz, 1H), 5.07 (d, J¼5.6, 9.2 Hz, 1H), 5.31 (t,
J¼9.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): 20.76
(CH3), 20.81 (CH3), 20.84 (CH3), 20.90 (CH3), 22.19
(CH2), 25.02 (CH2), 26.00 (CH2), 30.48 (2£CH2), 35.00
(CH2), 47.27 (CH), 62.37 (CH2), 68.76 (CH), 68.86 (CH),
70.43 (CH), 70.48 (CH), 72.47 (CH), 169.65 (CvO),
169.76 (CvO), 170.30 (CvO), 170.86 (CvO) ppm. IR
(CCl4): 2952, 2902, 2831, 1757, 1455, 1424, 1367, 1226,
1099, 1065, 1031 cm21. MS (CI/NH3): 494 (MHþ), 511
(MNHþ4 ).
1
More polar isomer (minor). H NMR (400 MHz, CDCl3):
d¼1.32 (s, 3H), 1.43 (t, J¼7.2 Hz, 3H), 1.48 (s, 3H), 1.84–
1.93 (m, 1H), 2.05–2.13 (m, 2H), 2.30–2.37 (m, 1H), 2.75–
2.92 (m, 4H), 3.41 (s, 3H), 3.79 (d, J¼3.2 Hz), 4.18 (dd,
J¼4.0, 10.0 Hz, 1H), 4.40–4.51 (m, 2H), 4.57 (d, J¼3.6 Hz,
1H), 4.66 (q, J¼7.2 Hz, 2H), 5.92 (d, J¼3.6 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3): d¼13.72 (CH3), 25.77 (CH2),
26.23 (CH3), 26.80 (CH3), 29.30 (CH2), 29.89 (CH2), 34.90
(CH2), 44.24 (CH), 46.39 (CH), 57.56 (CH3), 70.02 (CH2),
79.81 (CH), 81.06 (CH), 84.69 (CH), 104.97 (CH), 111.61
(C), 212.77 (CvS) ppm. IR (CCl4): 2990, 2933, 2830, 2359,
1454, 1423, 1382, 1373, 1294, 1276, 1220, 1165, 1110,
1081, 1053 cm21. MS (CI/NH3): 441 (MHþ).
4.4. Radical cyclisation of adducts (29) and (31). General
procedure
4.3.9. Dithiocarbonic acid S-{1-[(acetyl-phenyl-amino)-
methyl]-2-[1,3]dithian-2-yl-ethyl} ester O-ethyl ester
(40). The reaction was carried out with 29 (272 mg,
0.63 mmol), TFAA (0.21 mL, 1.5 mmol), and NaI
(227 mg, 1.5 mmol). Flash chromatography on silica gel
(EtOAc–petroleum ether, 25:75 v/v) afforded 40 (203 mg,
77%).
A solution of cyclisation precursor in 1,2-dichloro-ethane
(10 mL/mmol of cyclisation precursor) was refluxed for
15 min DLP (0.1 equiv.) was then added and additional
DLP (0.1 equiv.) was added every 90 min until complete
consumption of starting material. The mixture was then
cooled to room temperature and the solvent evaporated
under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the reaction products
as complicated mixtures of diastereomers that were used as
such in the next reaction step.
1H NMR (400 MHz, CDCl3): d¼1.21 (t, J¼7.2 Hz, 3H),
1.81–1.90 (m, 4H), 1.99–2.13 (m, 2H), 2.23 (ddd, J¼4.0,
10.8, 14.8 Hz, 1H), 2.78–2.91 (m, 4H), 3.61 (dd, J¼5.6,
13.6 Hz, 1H), 3.92–4.00 (m, 1H), 4.19 (dd, J¼4.0, 10.8 Hz,
1H), 4.40–4.49 (m, 3H), 7.23–7.25 (m, 2H), 7.35–7.38 (m,
1H), 7.42–7.45 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d¼13.41 (CH3), 22.64 (CH3), 25.75 (CH2), 29.92 (CH2),
30.28 (CH2), 35.94 (CH2), 44.50 (CH), 45.47 (CH), 51.02
(CH2), 69.84 (CH2), 128. 17 (CH), 128.30 (CH), 129.69
(CH), 142.01 (C), 170.89 (CvO), 212.12 (CvS) ppm. IR
(CCl4): 3066, 3038, 2984, 2937, 2902, 1668, 1596, 1496,
1472, 1452, 1433, 1424, 1414, 1389, 1364, 1288, 1276,
1219, 1112, 1052 cm21. MS (CI/NH3): 416 (MHþ), 433
(MNHþ4 ).
4.4.1. 1-[3-(1-Oxo-1l 4-[1,3]dithian-2-ylmethyl)-2,3-
dihydro-indol-1-yl]-ethanone (44). The reaction was
carried out with a solution of 29 (638 mg, 1.48 mmol) and
needed 1.1 equiv. of DLP to go to completion. Flash
chromatography on silica gel (MeOH–EtOAc, 0:100 to
25:75 v/v) afforded 44 (310 mg, 69%).
4.4.2. 2,2-Dimethyl-1-[3-(1-oxo-1l 4-[1,3]dithian-2-
ylmethyl)-2,3-dihydro-indol-1-yl]-propan-1-one
(45).
The reaction was carried out with a solution of 31 (3.1 g,
6.4 mmol) and needed 1.3 equiv. of DLP to go to
completion. Flash chromatography on silica gel (Et2O–
petroleum ether, 50:50 v/v, then MeOH–EtOAc, 5:95 to
10:90 v/v) afforded 45 (1.7 g, 77%).
4.3.10. Acetic acid 3,5-diacetoxy-2-acetoxymethyl-6-(3-
[1,3]dithian-2-yl-2-ethoxythiocarbonylsulfanyl-propyl)-
tetrahydro-pyran-4-yl ester (41). The reaction was carried
out with 30 (55 mg, 0.088 mmol), TFAA (33 mL,
0.23 mmol), and NaI (33 mg, 0.22 mmol). Flash chroma-
tography on silica gel (EtOAc–petroleum ether, 30:70 v/v)
afforded 41 (32 mg, 60%) as a liquid 10:13 mixture (NMR
analysis) of inseparable diastereoisomers.
4.5. Reduction of cyclisation products (44)–(45). General
procedure
A solution of sulfoxide (1.0 equiv.) and NaI (2.4 equiv.) in
dry acetone (5.2 mL/mmol of sulfoxide) was cooled to
0 8C before dropwise addition of a solution of TFAA
(2.4–2.6 equiv.) in dry acetone (2.0 mL/mmol TFAA).
The red brown solution thus obtained was allowed to
warm to room temperature and diluted with Et2O. The
mixture was extracted twice with a saturated solution of
Na2S2O3, washed once with water, and dried over
anhydrous Na2SO4. The solvent was then removed
under reduced pressure and the residue purified as specified
below.
IR (CCl4): 2953, 2902, 1756, 1432, 1367, 1276, 1220, 1146,
1112, 1051 cm21. MS (CI/NH3): 613 (MHþ), 630 (MNHþ4 ).
4.3.11. Acetic acid 3,5-diacetoxy-2-acetoxymethyl-6-(3-
[1,3]dithian-2-yl-propyl)-tetrahydro-pyran-4-yl ester
(42). A solution of 41 (31 mg, 0.051 mmol) and tris(tri-
methylsilyl) silane (31 mL, 0.10 mmol) in heptane (1 mL)
was refluxed for 15 min before addition of a few crystals of
AIBN. The solution was kept at reflux temperature and
stirred for another 2 h before it was cooled to room
temperature. The solvent was then removed under reduced
pressure and the residue purified by flash chromatography
on silica gel (EtOAc–petroleum ether, 27:73 v/v) to afford
42 (14 mg, 56%) as a slightly yellow solid.
4.5.1. 1-(3-[1,3]Dithian-2-ylmethyl-2,3-dihydro-indol-1-
yl)-ethanone (46). The reaction was carried out with 44
(464 mg, 1.5 mmol), TFAA (0.51 mL, 3.6 mmol), and NaI

7790
M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
(540 mg, 3.6 mmol). Recrystallisation of the crude reaction
product from acetone afforded 46 (404 mg, 92%).
water (10 mL) was cooled to 0 8C before dropwise addition
of a solution of 45 (86 mg, 0.24 mmol) in a 97:3 mixture of
acetone and water (0.5 mL). After another 10 min of stirring
at 0 8C the reaction was quenched by addition of a saturated
solution of Na2SO3 (20 mL). The aqueous mixture thus
obtained was extracted with CH2Cl2 (3£20 mL) and the
collected organic layers were extracted with water
(1£30 mL), washed with brine (1£30 mL) and dried over
anhydrous Na2SO4. The solvent was then removed under
reduced pressure and the residue purified by flash
chromatography on silica gel (EtOAc–petroleum ether,
20:80 v/v) to afford 50 (27 mg, 35%) as a slightly yellow
solid.
1
Major conformer. H NMR (400 MHz, CDCl3): d¼1.82–
2.04 (m, 2H), 2.14–2.26 (m, 2H), 2.24 (s, 3H), 2.84–2.98
(m, 4H), 3.70–3.78 (m, 2H), 4.14 (t, J¼6.8 Hz, 1H), 4.23 (t,
J¼8.8 Hz, 1H), 7.04 (t, J¼7.2 Hz, 1H), 7.19–7.24 (m, 2H),
8.20 (d, J¼8.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
d¼24.17 (CH3), 25.66 (CH2), 30.29 (2£CH2), 37.36 (CH),
41.02 (CH2), 45.16 (CH), 55.15 (CH2), 116.96 (CH), 123.61
(CH), 123.75 (CH), 128.13 (CH), 133.69 (C), 142.50 (C),
168.53 (CvO) ppm. IR (CCl4): 2939, 2904, 2252, 1653,
1598, 1482, 1461, 1406, 1358, 1338, 1290, 1277, 1244,
1177, 1132, 1032 cm21. MS (CI/NH3): 294 (MHþ), 311
(MNHþ4 ). Anal. calcd C, 61.39; H, 6.53; found C, 59.91; H,
6.43.
1H NMR (400 MHz, CDCl3): d¼1.35 (s, 9H), 2.75 (dd,
J¼9.2, 19.2 Hz, 1H), 3.02 (dd, J¼4.0, 18.4 Hz, 1H), 3.75–
3.86 (m, 2H), 4.50 (dd, J¼8.4, 10.4 Hz, 1H), 7.25 (dd,
J¼0.8, 2.0 Hz, 1H), 7.33 (ddd, J¼0.4, 6.0, 8.4 Hz, 1H), 8.11
(d, J¼8.8 Hz, 1H), 9.87 (s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): d¼27.48 (3£CH3), 34.91 (CH), 40.12 (C(CH3)3),
48.52 (CH2), 55.45 (CH2), 100.54 (C), 116.06 (C), 119.86
(CH), 126.30 (CH), 130.94 (CH), 135.05 (C), 176.93
(CvO), 199.70 (C(O)H) ppm. IR (CCl4): 2972, 2931,
2820, 2720, 1727, 1656, 1592, 1474, 1400, 1371, 1350,
1329, 1242, 1204, 1177, 1108, 1065 cm21. MS (CI/NH3):
4.5.2. 1-(3-[1,3]Dithian-2-ylmethyl-2,3-dihydro-indol-1-
yl)-2,2-dimethyl-propan-1-one (47). The reaction was
carried out with 45 (177 mg, 0.50 mmol), TFAA
(0.18 mL, 1.3 mmol), and NaI (184 mg, 1.2 mmol). Flash
chromatography on silica gel (EtOAc–petroleum ether,
10:90 v/v) afforded 47 (120 mg, 71%).
1H NMR (400 MHz, CDCl3): d¼1.39 (s, 9H), 1.85–2.01
(m, 2H), 2.13–2.21 (m, 2H), 2.83–2.99 (m, 4H), 3.59–3.66
(m, 1H), 4.00 (dd, J¼5.2, 10.4 Hz, 1H), 4.13 (t, J¼7.6 Hz,
1H), 4.37 (dd, J¼8.4, 10.4 Hz, 1H), 7.05 (t, J¼7.2 Hz, 1H),
7.21–7.25 (m, 2H), 8.22 (d, J¼7.6 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d¼25.76 (CH2), 27.76 (3£CH3), 30.32
(CH2), 30.47 (CH2), 38.51 (CH), 40.12 (CH2), 40.17
(C(CH3)3), 45.42 (CH), 55.91 (CH2), 118.53 (CH), 123.68
(CH), 123.76 (CH), 128.07 (CH), 133.52 (C), 144.30 (C),
176.50 (CvO) ppm. IR (CCl4): 2933, 2903, 1652, 1598,
1477, 1460, 1432, 1423, 1414, 1400, 1372, 1360, 1334,
1288, 1276, 1242, 1186, 1107, 1090, 1026 cm21. MS
(CI/NH3): 336 (MHþ), 353 (MNH4þ).
323 (MHþ, C15H BrNO2), 325 (MHþ, C15H BrNO2), 340
79
81
18
18
81
(MNHþ4 , C15H BrNO2), 342 (MNH4þ, C15H BrNO2).
79
18
18
4.5.5. (1-Acetyl-2,3-dihydro-1H-indol-3-yl)-acetaldehyde
(51). To a solution of 46 (143 mg, 0.49 mmol) in CH2Cl2
(2 mL) were added methyl iodide (1.6 mL, 25 mmol),
acetone (4 mL), and water (0.15 mL) and the mixture was
stirred at 45 8C for 26 h. The resulting orange solution was
concentrated under reduced pressure before addition of
EtOAc (20 mL). The organic phase was extracted with
water (1£20 mL), then with a saturated solution of NaS2O3
(1£20 mL), washed with brine (1£20 mL), and dried over
anhydrous Na2SO4. The solvent was then removed under
reduced pressure and the residue purified by flash
chromatography on silica gel (EtOAc–petroleum ether,
10:90 v/v) to afford 51 (51 mg, 51%) as a slightly yellow
solid.
4.5.3. 1-(3-Ethyl-2,3-dihydro-indol-1-yl)-ethanone (48).
To a suspension of freshly prepared W2 Raney Nickel
(400 mg of residual material/0.1 mmol of 44) in absolute
EtOH (5 mL) was added 44 (178 mg, 0.57 mmol). The
resulting mixture was refluxed for 4 h, then cooled to room
temperature and filtered over Celite. Evaporation of the
solvent gave analytically pure 48 (104 mg, 95%) as a white
solid.
Major conformer. 1H NMR (400 MHz, CDCl3): d¼2.22 (s,
3H), 2.80 (dd, J¼9.6, 18.8 Hz, 1H), 3.10 (dd, J¼4.4,
18.8 Hz, 1H), 3.61 (dd, J¼6.0, 18.8 Hz, 1H), 3.86–3.93 (m,
1H), 4.38 (dd, J¼9.2, 10.8 Hz, 1H), 7.05 (dt, J¼0.8, 7.4 Hz,
1H), 7.15 (d, J¼7.2 Hz, 1H), 7.24–7.26 (m, 1H), 8.22 (d,
J¼8.0 Hz, 1H), 9.89 (s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): d¼24.07 (CH3), 33.93 (CH), 49.69 (CH2), 55.00
(CH2), 116.85 (CH), 123.34 (CH), 123.61 (CH), 128.17
(CH), 132.87 (C), 142.40 (C), 168.54 (CvO), 200.14
(C(O)H) ppm. IR (CCl4): 2889, 2819, 2720, 1727, 1672,
1600, 1483, 1462, 1399, 1354, 1331, 1282, 1133,
1029 cm21. MS (CI/NH3): 204 (MHþ), 221 (MNHþ4 ).
Major conformer. 1H NMR (400 MHz, CDCl3): d¼0.99 (t,
J¼7.2 Hz, 3H), 1.54–1.65 (m, 1H), 1.81–1.91 (m, 1H),
2.24 (s, 3H), 3.31–3.39 (m, 1H), 3.69 (dd, J¼6.0, 10.4 Hz,
1H), 4.16 (t, J¼10.0 Hz, 1H), 7.04 (t, J¼7.6 Hz, 1H), 7.17–
7.23 (m, 2H), 8.21 (d, J¼8.0 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d¼11.07 (CH3), 24.16 (CH3), 28.02
(CH2), 41.38 (CH), 54.60 (CH2), 116.79 (CH), 123.44 (CH),
123.70 (CH), 127.67 (CH), 134.84 (C), 142.62 (C), 168.55
(CvO) ppm. IR (CCl4): 2963, 2931, 2876, 1670, 1599,
1482, 1461, 1400, 1353, 1332, 1286, 1274, 1173, 1131,
1096, 1030 cm21. MS (CI/NH3): 190 (MHþ), 207 (MNHþ4 ).
Anal. calcd C, 76.16; H, 7.99; found C, 76.16; H, 8.09.
4.5.6. Dithiocarbonic acid O-ethyl ester S-(2-methyl-1-
oxo-1l 4-[1,3]dithian-2-yl) ester (53). A solution of freshly
distilled diisopropyl amine (0.21 mL, 1.5 mmol) in dry THF
(7mL) was cooled to 278 8C under a nitrogen atmosphere,
before dropwise addition of a 1.5 M solution of nBuLi in
hexanes (0.73 mL, 1.1 mmol). To the colourless solution
thus obtained was added a solution of 11 (256 mg,
4.5.4. [5-Bromo-1-(2,2-dimethyl-propionyl)-2,3-dihydro-
1H-indol-3-yl]-acetaldehyde (50). A solution of NBS
(362 mg, 2.0 mmol) in a 97:3 mixture of acetone and

M. de Greef, S. Z. Zard / Tetrahedron 60 (2004) 7781–7791
7791
´ ´
8. Juaristi, E.; Jimenez-Vazquez, H. A. J. Org. Chem. 1991, 56,
1623.
1.0 mmol) in dry THF (5 mL). After 30 min of stirring at
278 8C methyl iodide (0.15 mL, 2.4 mmol) was added and
the yellow solution thus obtained was allowed to warm to
room temperature. After 90 min of additional stirring at
room temperature, ice-cold water (20 mL) was added and
the aqueous mixture extracted with CH2Cl2 (3£15 mL). The
collected organic layers were washed with brine (1£40 mL)
and dried over anhydrous Na2SO4. The solvent was then
removed under reduced pressure and the residue purified by
flash chromatography on silica gel (Et2O–EtOAc, 60:40
v/v) to afford 53 (135 mg, 50%) as a liquid 1:5 mixture
(NMR analysis) of separable diastereomers.
9. Nishida, A.; Kawahara, N.; Nishida, M.; Yonemitsu, O.
Tetrahedron 1996, 52, 9713.
10. Byers, J. H.; Whitehead, C. C.; Duff, M. E. Tetrahedron Lett.
1996, 37, 2743.
11. Foulard, G.; Brigaud, T.; Portella, C. J. Org. Chem. 1997, 62,
9107.
12. McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63,
9924.
13. Vath, P.; Falvey, D. E. J. Org. Chem. 2001, 66, 2887.
14. Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672.
15. Quiclet-Sire, B.; Zard, S. Z. Phosphorus Sulfur Silicon Relat.
Elem. 1999, 137.
1
Less polar isomer (minor). H NMR (400 MHz, CDCl3):
d¼1.48 (t, J¼7.2 Hz, 3H), 2.27 (s, 3H), 2.29–2.47 (m, 3H),
3.04–3.15 (m, 2H), 3.32 (dt, J¼3.2, 13.2 Hz, 1H), 4.66–
4.74 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): d¼13.51
(CH3), 25.46 (CH3), 27.03 (CH2), 29.44 (CH2), 48.23
(CH2), 70.61 (CH2), 73.82 (C), 208.20 (CvS) ppm. IR
(CCl4): 2983, 2923, 1436, 1424, 1410, 1365, 1292, 1258,
1242, 1113, 1077, 1067, 1033 cm21. MS (CI/NH3): 271
(MHþ).
16. Quiclet-Sire, B.; Zard, S. Z. Phosphorus Sulfur Silicon Relat.
Elem. 1999, 153.
´
17. Viehe, H. G.; Janousek, Z.; Merenyl, R.; Stella, L. Acc. Chem.
Res. 1985, 18, 148.
18. Drabowicz, J.; Oae, S. Synthesis 1977, 404.
19. Olah, G. A.; Gupta, B. G. B.; Narang, S. C. Synthesis 1978,
137.
20. Olah, G. A.; Gupta, B. G. B.; Narang, S. C.; Malhotra, R.
Synthesis 1979, 61.
1
More polar isomer (major). H NMR (400 MHz, CDCl3):
21. Denis, J. N.; Krief, A. Tetrahedron Lett. 1979, 20, 3995.
22. For example, Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetra-
hedron Lett. 1996, 37, 5877.
d¼1.47 (t, J¼7.2 Hz, 3H), 1.71–1.78 (m, 1H), 2.03 (s, 3H),
2.38–2.45 (m, 1H), 2.47–2.55 (m, 1H), 2.97–3.02 (m, 1H),
3.18 (ddd, J¼2.0, 12.4, 14.0 Hz, 1H), 3.34 (ddd, J¼2.8,
13.2, 14.8 Hz, 1H), 4.59–4.72 (m, 2H) ppm. 13C NMR
(100 MHz, CDCl3): d¼12.43 (CH2), 13.61 (CH3), 24.17
(CH3), 25.68 (CH2), 42.58 (CH2), 69.36 (C), 70.76 (CH2),
208.41 (CvS) ppm. IR (CCl4): 2984, 2980, 2918, 1442,
1424, 1404, 1364, 1292, 1242, 1113, 1068, 1034 cm21. MS
(CI/NH3): 271 (MHþ).
23. Barbier, F.; Pautrat, F.; Zard, S. Z. Synlett 2002, 811.
24. Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717.
25. Gagosz, F.; Zard, S. Z. Synlett 2003, 387.
26. For example, Page, P. C. B.; McKenzie, M. J.; Allin, S. M.;
Klair, S. S. Tetrahedron 1997, 53, 13149.
27. Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5,
575.
28. Ottow, E.; Recker, H. G.; Winterfeldt, E. Tetrahedron 1983,
39, 3669.
References and notes
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31. Carey, F. A.; Dailey, O. D.; Hernandez, O.; Tucker, J. R.
J. Org. Chem. 1976, 41, 3975.
1. Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis; 3rd ed. Wiley: New York, 1999; pp 297–348.
¨
2. Grobel, B. T.; Seebach, D. Synthesis 1977, 357.
32. Carey, F. A.; Dailey, O. D.; Hernandez, O. J. Org. Chem.
1976, 41, 3979.
3. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
4. Kruse, C. G.; Broekhof, N. L. J. M.; Wijsman, A.; Van der
Gen, A. Tetrahedron Lett. 1977, 18, 885.
33. Page, P. C. B.; Shuttleworth, S. J.; Schilling, M. B.; Tapolczay,
D. J. Tetrahedron Lett. 1993, 34, 6947.
5. Kruse, C. G.; Wijsman, A.; Van der Gen, A. J. Org. Chem.
1979, 44, 1847.
34. Page, P. C. B.; Shuttleworth, S. J.; McKenzie, M. J.; Schilling,
M. B.; Tapolczay, D. J. Synthesis 1995, 73.
35. Auret, B. J.; Boyd, D. R.; Cassidy, E. S.; Hamilton, R.; Turley,
F. J. Chem. Soc., Perkin Trans. 1 1985, 1547.
6. Gaze, C.; Gilbert, B. C. J. Chem. Soc., Perkin Trans. 2 1979,
763.
7. Chung, S. K.; Dunn, L. B. J. Org. Chem. 1984, 49, 935.