The formation of open-chain thioesters in the reaction of 2-lithio-2-methyl- and 2-lithio-2-phenyl-1,3-dithiane with chlorodiphenylphosphane followed by oxidation

Article abstract of DOI:10.1016/S0040-4039(03)01212-7

The unexpected formation of open-chain thioesters (3) and (6) from the reaction of 2-lithio-r-2-t-4-t-6-trimethyl (1-Li) and 2-lithio-r-2-phenyl-t-4-t-6-dimethyl-1,3-dithiane (4-Li), respectively, with chlorodiphenylphosphane followed by oxidation was observed instead of the anticipated gem-derivatives. The X-ray diffraction analysis of (6) and the trapped intermediate (10) confirmed the structure and the proposed mechanism of formation of the open-chain products.

Full text of DOI:10.1016/S0040-4039(03)01212-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5293–5297
The formation of open-chain thioesters in the reaction of
2-lithio-2-methyl- and 2-lithio-2-phenyl-1,3-dithiane with
chlorodiphenylphosphane followed by oxidationꢀ
Barbara Gordillo,* Zaira J. Dom´ınguez,† Noe´ Sa´nchez, Ricardo Gonza´lez, Magali Salas and
Efra´ın Barraga´n
Departamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apdo. Postal 14-740, 07000, Mexico D.F.
Received 1 April 2003; revised 5 May 2003; accepted 14 May 2003
Abstract—The unexpected formation of open-chain thioesters (3) and (6) from the reaction of 2-lithio-r-2-t-4-t-6-trimethyl (1-Li)
and 2-lithio-r-2-phenyl-t-4-t-6-dimethyl-1,3-dithiane (4-Li), respectively, with chlorodiphenylphosphane followed by oxidation was
observed instead of the anticipated gem-derivatives. The X-ray diffraction analysis of (6) and the trapped intermediate (10)
confirmed the structure and the proposed mechanism of formation of the open-chain products. © 2003 Elsevier Science Ltd. All
rights reserved.
In 1971 Hartmann and Eliel1 discovered that the 2-
dithiane10 shows the coordination of sulfur with lithio
in a dimeric structure (Fig. 1).
lithio
derivative
of
conformationally
fixed
(anancomeric2) cis-4,6-dimethyl-1,3-dithiane reacts with
electrophiles to afford, virtually as the exclusive
product, the equatorially substituted 1,3-dithianes (Eq.
Reported in the present work is evidence of the interac-
tion of the endocyclic sulfur of 1,3-dithianes with equa-
torial phosphorus-electrophiles attached to the C2
carbon. The 2-phosphoryl substituted 1,3-dithianes
have been used as Wittig–Horner precursors for the
synthesis of ketene-dithioketals,11–13 versatile intermedi-
ates in the homologation of umpolung carbonyl
compounds.14,15
(1)).
(1)
A systematic study of this reaction3,4 led to the conclu-
sion that the organolithium intermediate (contact or
solvent separated ion pair) exhibits a robust (>6 kcal/
mol,4 or 14.2 kcal/mol as suggested by ab initio
calculations5) preference for the equatorial orientation.
Among several explanations to rationalize the stabiliza-
tion of equatorial 2-lithio-1,3-dithiane,5–7 sulfur polariz-
ability was suggested by Bernasconi and Kittredge,8 as
to play a major role in the stabilization of sulfur
carbanions. Meanwhile spectroscopic9 studies discard
interpretation in terms of classical bidented coordina-
tion of the lithium gegenion by the sulfur atoms, a
The reaction of 1,3-dithianes with chlorodiphenylphos-
phane followed by oxidation has been widely used by
Juaristi et al.16 and Mikolajczyk et al.17 for the synthe-
sis of a variety of 2-diphenylphosphinoyl-1,3-dithianes
with noticeable conformational properties and reactiv-
ity. In a collaborative work with the group of Juaristi18a
dealing with the synthesis and conformational analysis
of 2,2-disubstituted 1,3-dithianes, we have found that
crystallographic
study
of
2-lithio-2-methyl-1,3-
Keywords: 1,3-dithianes; geminal substitution; phosphine oxidation;
open-chain thioesters.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)01212-7
* Corresponding author.
† Current address: Unidad de Servicios de Apoyo en Resolucio´n
Anal´ıtica, Universidad Veracruzana, Xalapa Ver., Mexico.
Figure 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01212-7

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B. Gordillo et al. / Tetrahedron Letters 44 (2003) 5293–5297
the reaction of anancomeric 2-lithio-r-2-t-4-t-6-
trimethyl-1,3-dithiane (1-Li) and 2-lithio-r-2-phenyl-t-
4-t-6-dimethyl-1,3-dithiane (4-Li) with chlorodiphenyl-
phosphane followed by oxidation during work-up
(Scheme 1), afforded open-chain thioesters (3) and (6),
respectively, as main products, together with a minor
amount of the gem substituted (2) and (5), respec-
tively.18b,19
The structural identification of 3 and 6 was carried out
1
by H, 13C and 31P NMR spectroscopy.19 After recrys-
tallization, compound 6 was obtained as crystals suit-
able for X-ray diffraction analysis. The ORTEP
diagram confirms the open-chain nature of the struc-
ture of 6 (Fig. 2).
Scheme 2.
This assignment suggests that incorporation of the
diphenylphosphino group in the open-chain product
took place either via a nucleophilic attack of the endo-
cyclic sulfur on chlorodiphenylphosphane with the con-
comitant formation of the ylide intermediate (path 1),
or via the geminal precursor (path 2) as indicated in
Scheme 2.
In order to throw light on the mechanism of formation
of the open-chain products, reactions of carbanions
(1-Li) and (4-Li) with chlorodiphenylphosphane were
followed, separately, by 31P NMR. Formation of a
common specie at −14.4 ppm was observed within 10
min after the addition of chlorodiphenylphosphane to a
flask containing 1-Li or 4-Li in dry THF under a
nitrogen atmosphere at −20°C and transferred to NMR
tubes via syringe. This species was less important than
the one observed when the NMR tube was allowed to
spin for 30 min at room temperature (22.7 or 30.6 ppm,
for 1-Li or 4-Li, respectively). These two new species
were stable under nitrogen. Formation of no other
species was observed. After addition of 1–3 drops of
aqueous saturated ammonium chloride solution, open-
chain products 3 or 6 were formed predominantly,
although a minor amount of the gem products 2 or 5
was also observed.18b Under these conditions, the for-
mation of the products is slow (it can take 1 or 2 days
to complete); however, oxidation of the intermediates
and therefore formation of the open-chain products
(31P NMR: l 42.81 for 3 and 42.92 for 6)19 was
promoted by bubbling oxygen into the solutions.
Scheme 1.
The identification of the intermediate 7 (Scheme 2) was
performed by 1H and 13C NMR of mixtures with
different proportions of the specie at −14.4 and 22.7
ppm.20 The species at −14.4 ppm turned out to be the
butyldiphenylphosphane product of the reaction
between unreacted BuLi with chlorodiphenylphos-
phane.21 On the other hand, products at 22.7 and 30.6
ppm were characterized as the geminal phosphine pre-
cursors (Scheme 2).22 In addition we were able to trap
the intermediate by the addition of a solution of
borane–THF to a flask containing 2-lithio-2-phenyl-1,3-
dithiane and chlorodiphenylphosphane at −70°C
(Scheme 3). The product was purified by column chro-
matography and the characterization of the phosphine–
1
borane adduct 10 was performed by H, 13C, 11B and
31P NMR spectroscopy, elemental analysis and X-ray
crystallography of the sample.23 The ORTEP structure
of the adduct (Fig. 3) clearly shows that the interatomic
Figure 2. ORTEP structure of (1S,3R)-S-[3-(diphenylphos-
phinothioyl)-1-methylbutyl]thiobenzoate (6).

B. Gordillo et al. / Tetrahedron Letters 44 (2003) 5293–5297
5295
distance of the non-bonded phosphorus-sulfur atoms
,
(2.97 A average) is smaller than the sum of the van der
,
,
,
Walls radii of them (3.65 A) [1.85 A (P) and 1.80 A
(S)].24
From these results it is evident that the formation of
the open-chain products (3) and (6) took place during
the oxidation step of the gem-phosphine precursors 7 or
8, and not via the ylide intermediates, as postulated
above (Scheme 2). The mechanism of oxidation of
phosphines with molecular oxygen has been already
reported,25 so that based on those grounds we proposed
the mechanism outlined in Scheme 4 to account for the
formation of the open-chain products from the gem-
precursors. Certainly we observed that the opening of
the dithiane ring is taking place only if the
diphenylphosphine group is constrained to occupy the
equatorial orientation in the gem-precursors. To say it
another way, the opening is not observed if the
diphenylphosphine group in the geminal intermediate is
axial, maybe due to the steric hindrance of the axial
attack by molecular oxygen, therefore the final product
in such a case, is the geminal 1,3-dithiane.18
Scheme 3.
Acknowledgements
We are grateful M. T. Cortez for the elemental analysis
of compound 10 and to Professor E. Juaristi for useful
comments. This work was financially supported by the
project 32221-E granted by CONACyT.
References
1. Hartmann, A. A.; Eliel, E. L. J. Am. Chem. Soc. 1971,
93, 2572.
2. (a) Anteunis, M.; Tavernier, D.; Borremans, F. Bull. Soc.
Chim. Belg. 1966, 75, 396; (b) Juaristi, E. Introduction to
Stereochemistry and Conformational Analysis; Wiley:
New York, 1991; p. 56; (c) Eliel, E. L.; Wilen, S. H.;
Mander, L. N. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; p. 1191.
Figure 3. ORTEP structure of 2-boron, trihydro(diphenyl-
phosphine)-2-phenyl-1,3-dithiane (10).
Scheme 4.

5296
B. Gordillo et al. / Tetrahedron Letters 44 (2003) 5293–5297
19. For the experimental procedure to synthezise 3 and 6, see
3. Eliel, E. L. Tetrahedron 1974, 30, 1503 and references
‡
§
cited therein.
footnotes and , respectively.
4. Abatjouglou, A. G.; Eliel, E. L.; Kuyper, L. F. J. Am.
Chem. Soc. 1977, 99, 8262.
5. Cuevas, G.; Juaristi, E. J. Am. Chem. Soc. 1997, 119,
7545.
6. (a) Lehn, J. M.; Wipff, G. J. Am. Chem. Soc. 1976, 98,
7498; (b) Epiotis, N. D.; Yates, R. L.; Bernardi, F.;
Wolfe, S. J. Am. Chem. Soc. 1976, 98, 5435; (c) Schleyer,
P.v. R.; Clark, T.; Kos, A. J.; Spitznagel, G. W.; Rohde,
C.; Arad, D.; Houk, K. N.; Rondan, N. G. J. Am. Chem.
Soc. 1984, 106, 6467; (d) Wiberg, K. B.; Castejon, H. J.
Am. Chem. Soc. 1994, 116, 10489.
7. Bordwell, F. G.; Zhang, X. M. J. Am. Chem. Soc. 1994,
116, 973.
8. Bernasconi, C. F.; Kittredge, K. W. J. Org. Chem. 1998,
63, 1944.
9. Eliel, E. L.; Hartman, A. A.; Abatjoglou, A. G. J. Am.
Chem. Soc. 1974, 96, 1807.
10. (a) Amstutz, R.; Seebach, D.; Seiter, P.; Schweiser, W. B.;
Dunitz, J. D. Angew. Chem., Int. Ed. Engl. 1980, 19, 53;
(b) Amstutz, R.; Dunitz, J. D.; Seebach, D. Angew.
Chem., Int. Ed. Engl. 1981, 20, 464.
20. Although attempts of purification of these intermediates
by column chromatography failed, the interchange of
THF by CDCl3 was successfully performed by careful
manipulation of the samples at room temperature, under
a nitrogen atmosphere (see NMR data of intermediates in
‡ Preparation of (1S,3R)-S-[3-(diphenylphosphinothioyl)-1-methyl-
butyl]thioacetate 3: to a solution of 2.0 g (0.0123 mol) of trans-1 in
dry THF under nitrogen at −20°C was added 5.4 mL (0.0135 mol)
of BuLi (2.5 M in hexanes). The solution was stirred at −20°C for
2 h and transferred dropwise with a double-ended needle under
nitrogen pressure to
a solution of 2.4 mL (0.0135 mol) of
chlorodiphenylphosphane in 10 mL of THF at −20°C. The mixture
was stirred at −20°C for 1.5 h and 3 h at room temperature. The
solution was poured into 120 mL of saturated ammonium chloride
solution and extracted with methylene chloride. The extract was
dried over sodium sulfate, filtered off and the solvent was removed
with a rotary evaporator. Crude material analyzed by 31P and 1H
NMR contained compounds 3, 2, CH3CH2CH2CH2P(O)Ph2 (
31P
NMR l 33.4 ppm, from the reaction of BuLi and ClPPh2 followed
by oxidation), and unreacted trans-1 in a ratio close to 3:1:1:2. The
residue was chromatographed on silica gel using a mixture of
solvents with a gradually polar increment, starting with 95% hex-
anes/ethyl acetate and ending with 60% hexanes/ethyl acetate. Com-
pound 3 (isolated yield 1.78 g, 38.7%): 31P NMR (CDCl3) l 42.81
ppm. 1H NMR (CDCl3) l 1.21 (d, JHH=6.9 Hz, 3H), 1.43 (d,
11. (a) Mikolajczyk, M.; Grzejszczak, S.; Zatorski, A.;
Mlotkowska, B. Tetrahedron Lett. 1976, 17, 2731; (b)
Mikolajczyk, M.; Grzejszczak, S.; Zatorski, A.;
Mlotkowska, B.; Gross, H.; Costisella, B. Tetrahedron
1978, 34, 3081.
J
HH=6.9 Hz, 3H), 1.77 (ꢀq, Jgem=14.2 Hz, 1H) 2.0 (ꢀq, Jgem
=
12. Juaristi, E.; Gordillo, B.; Valle, L. Tetrahedron 1986, 42,
1963 and references cited therein.
14.2 Hz, 1H), 2.30 (s, 3H), 3.36 (m, 3JPH=10.6 Hz, 3JHH=7.9 Hz,
3
3
1H), 3.70 (m, JHH=7.6 Hz, JHH=6.9 Hz, 1H), 7.57 (m, 6H), 7.97
(m, 4H). 13C NMR (CDCl3) l 21.17 (C5), 23.97 (d, 3JCP=2.2 Hz,
13. (a) Jones, P. F.; Lappert, M. F. J. Chem. Soc., Chem.
Commun. 1972, 526; (b) Jones, P. F.; Lappert, M. F.;
Szary, A. C. J. Chem. Soc., Perkin Trans. 1 1973, 2272.
14. (a) Seebach, D.; Gro¨bel, B. T.; Beck, A. K.; Braun, M.;
Geiss, K. H. Angew. Chem., Int. Ed. 1972, 11, 443; (b)
Seebach, D.; Kolb, M.; Gro¨bel, B. T. Chem. Ber. 1973,
106, 2277; (c) Gro¨bel, B. T.; Bu¨rstinghaus, R.; Seebach,
D. Synthesis 1976, 121.
15. (a) Schubert, U. Synthesis 1978, 365; (b) Carey, F. A.;
Neegaard, J. R. J. Org. Chem. 1971, 36, 2731; (c) Corey,
E. J.; Kozikowski, A. P. Tetrahedron Lett. 1975, 16, 925.
16. (a) Juaristi, E.; Valle, L.; Mora-Uzeta, C.; Valenzuela, B.
A.; Joseph-Nathan, P.; Fredrich, M. F. J. Org. Chem.
1982, 47, 5038; (b) Juaristi, E.; Valenzuela, B. A.; Valle,
L.; McPhail, A. T. J. Org. Chem. 1984, 49, 3026; (c)
Juaristi, E.; Valle, L.; Valenzuela, B. A.; Aguilar, M. A.
J. Am. Chem. Soc. 1986, 108, 2000; (d) Juaristi, E.;
Lo´pez-Nun˜ez, N. A.; Valenzuela, A. A.; Valle, L. J. Org.
Chem. 1987, 52, 5185; (e) Juaristi, E.; Cuevas, G. Tetra-
hedron Lett. 1992, 33, 2271.
17. (a) Mikolajczyk, M.; Graczyk, P.; Balcewski, P. Tetra-
hedron Lett. 1987, 28, 573; (b) Graczyk, P.; Mikolajczyk,
M. Magn. Res. Chem. 1992, 30, 1261; (c) Mikolajczyk,
M.; Graczyk, P.; Kabachnik, M. I.; Baranov, A. P. J.
Org. Chem. 1989, 54, 2859.
18. (a) Gordillo, B.; Juaristi, E.; et. al. Conformational Anal-
ysis of 1,3-Dithianes. Lack of Conformational Additivi-
ties in 2-methyl-1-(diphenylphosphinoyl) and 2-methyl-
1-(diphenylthiophosphinoyl)1,3-dithianes, (manuscript in
preparation); (b) Compound 2 [l31P=33.7 ppm] and 5
[l31P=34.0 ppm]. Geminal products 2 and 5 were fully
characterized in Ref. 18a.
C4), 30.76 (C6
H3-CꢀO), 37.10 (C1), 39.16 (d, 3JCP=2.2 Hz, C2),
45.30 (d, 2JCP=4.6 Hz, C3), 128.67 (d, 2JCP=13.0 Hz, Cortho),
131.60 (d, 1JCP=21.3 Hz, Cipso), 131.61 (s, Cmeta), 132.27 (d,
4JCP=3.3 Hz, Cpara), 195.73 (CꢀO). Anal. calcd for C19H23S2PO2:
C, 60.30; H, 6.13. Found: C, 60.09; H, 6.38.
§
Preparation of (1S, 3R)-S-[3-(diphenylphosphinothioyl)-1-methyl-
butyl]thiobenzoate 6: to a solution of 3.6 g (0.0161 mol) of trans-4
in dry THF under nitrogen at −20°C was added 7.1 mL (0.0178
mol) of BuLi (2.5 M in hexanes). The solution was stirred at −20°C
for 2 h and transferred dropwise with a double-ended needle under
nitrogen pressure to
a solution of 3.2 mL (0.0178 mol) of
chlorodiphenylphosphane in 10 mL of THF at −20°C. The mixture
was stirred at −20°C for 1.5 h and 3 h at room temperature. The
solution was poured into 120 mL of saturated ammonium chloride
solution and extracted with methylene chloride. The extract was
dried over sodium sulfate, filtered off and the solvent was removed
with a rotary evaporator. Crude material analyzed by 31P and 1H
NMR contained compounds 6, 5, and CH3CH2CH2CH2P(O)Ph2
(
31P NMR l 33.4 ppm, from the reaction of BuLi and ClPPh2
followed by oxidation) in a ratio close to 8:2:1. The residue was a
solid chromatographed on silica gel using a mixture of solvents with
a gradually polar increment, starting with 95% hexanes/ethyl ace-
tate and ending with 60% hexanes/ethyl acetate. Compound 6
(isolated yield 3.8 g, 54%): 31P NMR (CDCl3) l 42.92 ppm. 1H
NMR (CDCl3) l 1.24 (d, JHH=6.7 Hz, 3H), 1.40 (d, JHH=6.7 Hz,
3H), 1.83 (ꢀq, Jgem=14.1 Hz, 1H), 2.12 (ꢀq, Jgem=14.3 Hz, 1H)
3.33 (m, 3JPH=10.1 Hz, 3JHH=3.2 Hz, 3JHH=6.9 Hz, 1H), 3.85 (m,
3JHH=7.4 Hz, 3JHH=7.2 Hz, 1H), 7.46 (m, 9H), 7.88 (m, 6H). 13C
NMR (CDCl3) l 21.22 (C5), 24.08 (C4), 37.18 (C1), 39.33 (C2),
45.58 (d, 2JCP=5.2 Hz, C3), 127.28 (Cortho%), 128.58 (Cmeta), 128.79
(d, 2JCP=3.0 Hz, Cortho), 131.61 (d, 1JCP=20.8 Hz, Cipso), 131.62
(Cmeta%), 132.27 (Cpara), 133.36 (Cpara%), 137.15 (Cipso%), 191.59 (CꢀO).
Anal. Calcd for C24H25S2PO2: C, 65.44; H, 5.72. Found: C: 65.51;
H, 5.92.

B. Gordillo et al. / Tetrahedron Letters 44 (2003) 5293–5297
5297
Refs. 21 and 22 below). The identity of CH3CH2CH2-
CH2PPh2 was also confirmed by reacting 1 equiv. of
chlorodiphenylphosphane with 1 equiv. of BuLi in THF.
21. CH3CH2CH2CH2PPh2: 31P NMR (CDCl3) l −14.91 ppm.
1H NMR (CDCl3) l 0.88 (t, JHH=7.0 Hz, 3H), 1.42 (m,
135.43 (d, 2JCP=20.0 Hz, Cortho), 134.49 (d, 1JCP=17.7
Hz, Cipso).
23. Phosphine–borane adduct 10: 31P NMR (CDCl3) l 45.41
ppm. 11B NMR (CDCl3) l −39.0 ppm. 1H NMR (CDCl3)
l 0.90–1.36 (br.s, BH3, 3H), 1.95 (m, 2H), 2.68 (m, 4H),
7.36 (m, 9H), 7.69–7.89 (m, 6H). 13C NMR (CDCl3) l
2
4H), 2.01 (m, JHP=7.3 Hz, 2H), 7.31 (m, 6H), 7.41 (m,
3
1
3
4H). 13C NMR (CDCl3) l 13.80 (CH3), 24.31 (d, JCP
=
24.14 (C5), 27.68 (d, JCP=3.8 Hz, C4,6), 37.34 (d, JCP
=
1
13.3 Hz, C3), 27.95 (d, 1JCP=41.3 Hz, C1), 28.01 (d,
2JCP=14.39 Hz, C2), 128.34 (d, 2JCP=9.4 Hz, Cortho),
128.38 (s, Cmeta), 132.66 (d, 3JCP=18.31 Hz, Cpara),
33.8 Hz, C2), 126.87 (d, JCP=89.2 Hz, Cipso), 127.62 (d,
4JCP=3.1 Hz, Cpara%), 127.91 (Cmeta%), 127.94 (d, JCP
=
3
3
10.0 Hz, Cmeta), 131.59 (d, JCP=3.0, Cortho%), 131.89 (d,
4JCP=3.8 Hz, Cpara), 133.35 (d, 2JCP=8.5 Hz, Cipso%),
135.09 (d, 2JCP=8.5 Hz, Cortho). Anal. calcd for
C22H24S2PB: C, 67.01; H, 6.13. Found: C, 66.60; H, 6.19.
24. Huheey, J. E.; Keiter, E. A.; Keiter, R. L. Inorganic
Chemistry, 4th ed.; Harper Collins: New York, NY, 1993;
p. 292.
1
139.01 (d, JCP=13.0 Hz, Cipso).
22. Intermediate 7: 31P NMR (CDCl3) l 21.27 ppm. 1H
NMR (CDCl3) l 1.21 (d, 3JHH=6.6 Hz, 6H), 1.87 (d,
3JHP=12.1 Hz, 3H), 2.04 (m, 1H), 2.07 (m, 1H), 3.14 (m,
2H), 7.37 (m, 6H), 7.78 (m, 4H). 13C NMR (CDCl3) l
3
21.29 (s, C
6
H3CH), 29.22 (d, JCP=12.3 Hz, C
6
H3C), 35.84
3
1
25. Lindner, E.; Ebert, H. D. Angew. Chem., Int. Ed. 1971,
10, 565.
(d, JCP=7.7 Hz, C4,6), 43.54 (s, C5), 50.18 (d, JCP=32.3
Hz, C2), 127.92 (d, 4JCP=7.7 Hz, Cpara), 129.22 (s, Cmeta),