Wacker-type oxidative functionalization of β-substituted unsaturated sulfoxides

Article abstract of DOI:10.1016/j.tetlet.2008.06.059

The Wacker-type oxidation is an important procedure catalyzed by palladium complexes. A mild and general method for the preparation of β-substituted-δ-oxosulfoxides from the corresponding β-substituted-γ,δ-unsaturated sulfoxides is described. The products are versatile synthetic intermediates for the preparation of syn- and anti-1,3-diol and 1,3-aminoalcohol derivatives.

Full text of DOI:10.1016/j.tetlet.2008.06.059

Tetrahedron Letters 49 (2008) 4999–5002
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Wacker-type oxidative functionalization of b-substituted
unsaturated sulfoxides
*
Sadagopan Raghavan , V. Krishnaiah, Kailash Rathore
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The Wacker-type oxidation is an important procedure catalyzed by palladium complexes. A mild and
Received 7 May 2008
Revised 10 June 2008
Accepted 14 June 2008
Available online 18 June 2008
general method for the preparation of b-substituted-d-oxosulfoxides from the corresponding b-substi-
tuted-c,d-unsaturated sulfoxides is described. The products are versatile synthetic intermediates for
the preparation of syn- and anti-1,3-diol and 1,3-aminoalcohol derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Unsaturated sulfoxide
1,3-Diol
1,3-Aminoalcohol
Wacker-type oxidative functionalization
Palladium catalyst
Stoichiometric copper
A large number of dense vicinally functionalized compounds
are present in Nature. The method of choice to introduce vicinal
functionality is through nucleophilic attack, either inter- or intra-
molecular, initiated by the addition of an electrophile to an
alkene.1 The palladium catalyzed oxidative functionalization
of unsaturated alcohols to 2-vinyltetrahydrofurans was first
described by Hosokowa and co-workers2 using catalytic Pd(OAc)2
in the presence of stoichiometric Cu(OAc)2 under an oxygen atmo-
sphere, Eq. 1.
center was expected to be introduced with good diastereoselectiv-
ity. In addition, the alkene diol was envisioned to be further
transformed by reaction with NBS into a bromotriol via intramo-
lecular sulfinyl group participation.
We describe herein the results of our investigation on the Wac-
ker-type reaction of b-substituted-c,d-unsaturated sulfoxides.
Reaction of allyl alcohol5
1 with stoichiometric amounts of
Pd(OAc)2(CH3CN)2 in anhydrous THF6 in the presence of potassium
carbonate and water (2 equiv) yielded the keto alcohol 2 in 75%
PdOAc
O
O
OH
Ph
Ph
Cat. Pd(OAc)2
Cu(OAc)2, O2
ð1Þ
+
HPdOAc
Ph
Sole isomer
In continuation of our interest in utilizing the sulfinyl group as an
intramolecular nucleophile for the hetero-functionalization of al-
kenes3 activated by electrophiles,4 we were attracted to the possi-
bility of using catalytic amounts of a Pd2+ salt in a Wacker-type
reaction to prepare an alkene diol from an allyl alcohol, Scheme
1. By way of 1,2-asymmetric induction, the new carbinol stereo-
yield and none of the expected diol7 3. Interestingly, 2 was
obtained in a better yield using only catalytic amounts of PdCl2
in the presence of stoichiometric amounts of CuCl in aq DMF8
under an oxygen atmosphere.9 It is noteworthy that the sulfoxide
configuration is retained in the product.10 The reaction probably
proceeds via intermediate I formed by chelation of PdCl2 to sulfur
and the alkene,11 followed by intermolecular attack of water12 to
afford intermediate II, which then undergoes dehydropalladation
to yield HPdCl and enol 4 which tautomerizes to keto alcohol 2,
Scheme 2.
* Corresponding author. Tel.: +91 040 27191643; fax: +91 040 27160512.
E-mail addresses: sraghavan@iict.res.in, purush101@yahoo.com (S. Raghavan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.059

5000
S. Raghavan et al. / Tetrahedron Letters 49 (2008) 4999–5002
O
S
OH
O
S
OH PdX
OH
PdX2, Co-catalyst
Solvent, H2O
- HPdX
R
R
p
-Tol
p-Tol
O
S
OH
O
S
OH OH
OH Br
NBS, H2O
Toluene
R
R
p
-Tol
p-Tol
OH
Oxypalladation product
Scheme 1.
HO
O
S
O
O
S
OH
PdCl2, CuCl
H2O
-HPdCl
HO
-Tol
HO
-Tol
S
PdCl2
PdCl
O2, DMF, H2O
p-Tol
p
p
1
I
II
O
S
OH O
O
S
OH
O
S
OH OH
p
-Tol
p
-Tol
p
-Tol
OH
4
2
3
Scheme 2.
The generality of the reaction was explored, and the results are
tabulated in Table 1. A perusal of the Table reveals that the reaction
outcome is not affected by (a) the relative configurations at sulfur
and carbon (compare entries 1, 2 and 4, 5), (b) protecting the
hydroxy group (entry 3), and (c) double bond geometry13 (compare
entries 1 and 4). Terminal alkenes14 cleanly afforded the corres-
Table 1
a
Oxidative functionalization of alkenes with catalytic PdCl2
Entry
1
Alkene
Aldehyde/ketone
Yield (%) Time (h)
95 (12)
O
S
OH
O
S
OH
O
O
p
p
-Tol
-Tol
p
p
-Tol
-Tol
1
2
O
S
OH
O
S
OH
2
95 (12)
65 (12)
78 (6)
5
6
OTBS
O
S
OTBS
O
S
O
3b
p-Tol
p
-Tol
7
8
O
OH O
O
OH
4
4
4
S
S
4
4
Ph
Ph
Ph
10
OH
9
O
S
O
O
S
OH
5
80 (6)
Ph
11
OH
12
OH
O
S
O
S
O
Ph
6
89 (12)
p
-Tol
p
-Tol
Ph
14
13

S. Raghavan et al. / Tetrahedron Letters 49 (2008) 4999–5002
5001
Table 1 (continued)
Entry
Alkene
Aldehyde/ketone
Yield (%) Time (h)
76 (8)
OH
OH
O
O
7
S
S
p-Tol
p-Tol
p-Tol
p
p
p
-Tol
-Tol
-Tol
15
OH
16
OH
O
S
O
S
8
9
83 (8)
85 (5)
O
O
17
OTBS
19
OH
21
18
O
S
O
S
OTBS
O
20
O
S
OPMB
10
11
—
—
p
-Tol
-Tol
O
S
OH
OTBDPS
p
22
O
S
NHTs
O
S
NHTs
24
NHTs
12
84 (5)
p
p
-Tol
-Tol
p-Tol
O
23
O
S
NHTs
25
O
O
13
85 (12)
81 (12)
73 (12)
S
Ph
p
-Tol
Ph
26
Me
O
Me
O
S
O
OTBDPS
14c
S
OTBDPS
Ph
Ph
Ph
Ph
27
28
OTBDPS
O
S
OTBDPS
O
S
15d,e
OTBDPS
OTBDPS
30
29
O
a
All reactions were carried out on 0.5 mmol scale using 10 mol % of PdCl2 and 1 equiv of CuCl in aq DMF under an oxygen atmosphere at 65 °C for 5–12 h.
25% of 2 was also isolated.
Racemic substrate was used.
The sulfoxide 30 was characterized as the corresponding sulfone.
b
c
d
e
The reaction did not proceed to completion even after 12 h and some unreacted starting material was recovered; yield is based on recovered starting material.
ponding aldehydes as the sole products15 without any trace of the
dard reaction conditions to furnish an x-keto alcohol which was
methyl ketone (entries 9 and 12). The reaction did not proceed
when attempted on tri-substituted alkenes16 employing the stan-
dard reaction conditions. Over extended periods of time, at higher
temperatures and/or using stoichiometric amounts of PdCl2,
decomposition was observed. Steric factors are probably responsi-
ble for the lack of reactivity of tri-substituted alkenes. A sulfide and
a sulfone are suitable substrates and afford keto alcohols in good
yields (entries 7 and 8). Interestingly there was no poisoning of
the catalyst by the sulfide and the sulfone which are also capable
of complexing palladium chloride. The b-protected amino sulfox-
ide17 yielded the expected amino ketone derivative without inci-
dent (entry 13). That a heteroatom at the b-position to the
sulfoxide is not required was shown from the result of the reaction
of a b-methyl substituted alkene18 (entry 14). Finally a mixture of
characterized after oxidation to the sulfone (entry 15). The reaction
conditions are mild, and protecting groups are tolerated.
The b-hydroxy d-ketosulfoxide can be reduced to the corres-
ponding syn- or anti-1,3-diols following literature procedures to
furnish important intermediates in the synthesis of polyhydroxy-
lated natural products.20 The b-amino protected-d-ketosulfoxide
can likewise be reduced selectively to furnish syn- or anti-1,3-
aminoalcohol derivatives. 1,3-Aminoalcohols are structural sub-
units present in many synthetic21 and natural products22 possess-
ing potent biological activity. Their potential as chiral auxiliaries
and ligands in asymmetric synthesis is well recognized.23 In this
context, it is noteworthy that b-hydroxy-d-ketosulfoxides are
obtained readily using the present methodology in comparison to
the methodology reported by Solladie and co-workers using a
b-dioxolane protected b-keto ester as starting material.24
b-siloxy-d,x
-unsaturated sulfoxide19 was subjected to the stan-

5002
S. Raghavan et al. / Tetrahedron Letters 49 (2008) 4999–5002
Pedregal, C.; Rodrigues, J. H.; Rubio, A.; Sanchez, J.; Solladie, G. J. Org. Chem.
In summary, we have described a novel, general and mild meth-
1990, 55, 2120. Also the sign of optical rotation remained unchanged in the
product indicating retention of sulfur configuration.
11. The same product 2 is expected when the PdCl2 chelates to the other face of the
alkene to yield an intermediate diastereomeric to I.
12. anti Oxypalladation assumed though syn oxypalladation cannot be ruled out.
For a leading reference on the mechanism of Pd2+ catalyzed oxypalladation see:
(a) Uenishi, J.; Vikhe, Y. S.; Kawai, N. Chem. Asian J. 2008, 3, 473; (b) Hayashi, T.;
Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
13. The cis di-substituted alkenes were prepared by the following sequence of
reactions: (i) reaction of the lithio anion of (S)-methyl phenylsulfoxide with a
1-formyl alkyne to furnish an approximately equimolar mixture of propargylic
alcohols, followed by (ii) stereoselective cis reduction using nickel boride to
furnish readily separable allyl alcohols.
od for the preparation of b-substituted-d-oxosulfoxide derivatives
from mono- and di-substituted alkenes. These are useful synthons
for the preparation of polyhydroxylated and aminoalcohol subunit-
containing natural products.
Acknowledgments
S.R. is thankful to Dr. J. M. Rao Head, Org. Div. I and Dr. J. S.
Yadav, Director, IICT for constant support and encouragement.
V.K. and K.R. are thankful to the CSIR, New Delhi for fellowships.
O
O
S
OH
LDA, THF
S
+
OHC
4
Ph
Me
Ph
Ph
81%
O
S
OH
O
S
OH
Ni(OAc)2, NaBH4
EtOH, H2
4
4
+
Ph
11
9
H2N NH2
75%
14. For the preparation of the alkene in entry 9 see: (a) Raghavan, S.; Mustafa, S.
Tetrahedron Lett. 2008, 49, 3216; (b) The details of the preparation of the alkene
in entry 12 will be disclosed elsewhere.
Financial assistance from DST (New Delhi) is gratefully acknowl-
edged. We thank Dr. A. C. Kunwar for the NMR spectra.
15. Methyl ketones are expected from terminal alkenes. Reversal of the
regioselectivity has been observed in alkenes containing heteroatoms which
probably coordinate with palladium intermediates, for example, see: (a) Bose,
A. K.; Krishnan, L.; Wagle, D. R.; Manhas, M. S. Tetrahedron Lett. 1986, 27, 5955;
(b) Lai, J.-Y.; Shi, X.-x.; Dai, L.-x. J. Org. Chem. 1992, 57, 3485; (c) Hosokawa, T.;
Ohta, T.; Kanayama, S.; Murahashi, S.-I. J. Org. Chem. 1987, 52, 1758; Also see
(d) Ho, T.-L.; Chang, M. H.; Chen, C. Tetrahedron Lett. 2004, 44, 6955 for the
abnormal Wacker oxidation of 1,5-dienes.
16. For the preparation of tri-substituted alkenes in entries 10 and 11 see:
Raghavan, S.; Sreekanth, T. Tetrahedron Lett. 2008, 49, 1169.
17. For the preparation of the alkene in entry 13 see: Raghavan, S.; Rajender, A.
Tetrahedron Lett. 2004, 45, 1919.
References and notes
1. (a) Harding, K. E.; Tiner, T. H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 363 and references
cited therein; (b) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321 and
references cited therein.
2. Hosokawa, T.; Hirata, M.; Murahashi, S.-I.; Sonoda, A. Tetrahedron Lett. 1976, 17,
1821–1824.
3. Mono-, cis-, trans di-substituted and tri-substituted alkenes have been shown
to be suitable substrates for heterofunctionalization.
4. For the use of NBS as an electrophile, see: (a) Raghavan, S.; Rasheed, M. A.;
Joseph, S. C.; Rajender, A. Chem. Commun. 1999, 1845; (b) Raghavan, S.;
Ramakrishna Reddy, S.; Tony, K. A.; Naveen Kumar, Ch.; Varma, A. K.; Nangia, A.
J. Org. Chem. 2002, 67, 5838; (c) Raghavan, S.; Rajender, A.; Joseph, S. C.;
Rasheed, M. A.; Ravi Kumar, K. Tetrahedron: Asymmetry 2004, 15, 365.; For the
use of Hg(OC(O)CF3)2 as an electrophile, see: (d) Raghavan, S.; Ramakrishna
Reddy, S. Tetrahedron Lett. 2004, 45, 5593.
5. Raghavan, S.; Krishnaiah, V. Tetrahedron Lett. 2006, 47, 7611.
6. Korte, D. E.; Hegedus, L. S.; Wirth, R. K. J. Org. Chem. 1977, 42, 1329.
7. Diol 3 was expected based on Pd2+ attacking the same face of the alkene as Br+
attacks 1.
18. For the preparation of the alkene in entry 14 see: Ref. 4b.
19. For the preparation of alkene in entry 15 see: Raghavan, S.; Ramakrishna
Reddy, S. J. Org. Chem. 2003, 68, 5754.
20. (a) Solladie and co-workers have utilized b-hydroxy-d-ketosulfoxides as
intermediates in
a number of synthesis; see: Hanquet, G.; Colobert, F.;
Lanners, S.; Solladie, G. ARKIVOC 2003, vii, 328.; (b) Solladie, G.; Colobert, F.;
Denni, D. Tetrahedron: Asymmetry 1998, 9, 3081; (c) Solladie, G.; Bauder, C.;
Rossi, L. J. Org. Chem. 1995, 60, 7774; (d) Solladie, G.; Huser, N. Tetrahedron:
Asymmetry 1995, 6, 2679; (e) Solladie, G.; Dominguez, C. J. Org. Chem. 1994, 59,
3898.
21. (a) Friedrichs, E.; Christoph, T.; Buschmann, H. In Ullmann’s Encyclopedia of
Industrial Chemistry; McGuire, J. L., Ed.; Wiley-VCH: Weinheim, 2000; (b) Gais,
H.-J.; Griebel, C.; Buschmann, H. Tetrahedron: Asymmetry 2000, 11, 917; (c)
Carlier, P. R.; Lo, K. M.; Lo, M. M.-C.; Williams, I. D. J. Org. Chem. 1995, 60, 7511.
22. (a) Benedetti, F.; Norbedo, S. J. Chem. Soc. 2001, 203; (b) Carlier, P. R.; Lo, M.
M.-C. ; Lo, P. C.-K.; Richelson, E.; Tatsumi, M.; Reynold, J.; Sharma, T. A. Bioorg.
Med. Chem. Lett. 1997, 7, 1511; (c) Musso, D. L.; Mehta, N. B.; Soroko, F. E.
Bioorg. Med. Chem. Lett. 1997, 7, 1; (d) Sakai, R.; Kamiya, H.; Murata, M.;
Shimamoto, K. J. Am. Chem. Soc. 1997, 119, 4112; (e) Barrett, A. G. M.; Lebold, S.
A. J. Org. Chem. 1991, 56, 4875; (f) Hashiguchi, S.; Kawada, A.; Natsugari, H. J.
Chem. Soc., Perkin Trans. 1 1991, 2435.
23. (a) Vilaplana, M. J.; Molina, P.; Arques, A.; Andres, C.; Pedrosa, R. Tetrahedron:
Asymmetry 2002, 13, 5; (b) Li, X.; Yeung, C.; Chan, A. S. C.; Yang, T.-K.
Tetrahedron: Asymmetry 1999, 10, 759; (c) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A.
Tetrahedron: Asymmetry 1997, 8, 293; (d) Cho, B. T.; Kim, N. Tetrahedron Lett.
1994, 35, 4115.
8. (a) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62, 9; (b) Typical
experimental procedure:
A flask containing a suspension of palladium(II)
chloride (9 mg, 0.05 mmol) and copper(I) chloride (50 mg, 0.5 mmol) in N,N-
dimethylformamide (1 mL) and water (1 mL) was stirred under an oxygen
atmosphere for 1 h. Alkene 1 (67 mg, 0.5 mmol) in N,N-dimethylformamide
(0.5 mL) and water (0.5 mL) was added, and the reaction mixture was stirred at
65 °C for 12 h. The reaction mixture was diluted with ether and the organic
layer washed with water, brine; dried over Na2SO4, and evaporated.
Purification by column chromatography on silica gel yielded hydroxy ketone
2 (67 mg) in 95% yield.
9. Reactions attempted in the absence of copper catalyst as reported in the
literature failed to afford the desired product, see: (a) Trend, R. M.; Ramtohul, Y.
K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892; (b) Trend,
R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778; (c)
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126,
3036; (d) Ronn, M.; Backvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36,
7749; (e) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298.
10. The coupling constants for the protons directly bonded to the carbon in the b-
hydroxy sulfoxide moiety are diagnostic for assigning the relative
configuration, see: Carreno, M. C.; Garcia Ruano, T. L.; Martin, A. M.;
24. (a) Hanquet, G.; Salom-Roig, X. J.; Gressot-Kempf, L.; Lanners, S.; Solladie, G.
Tetrahedron: Asymmetry 2003, 14, 1291; (b) Hanquet, G.; Solladie, G.; Salom-
Roig, X. J. Tetrahedron Lett. 2000, 41, 2737; (c) Hanquet, G.; Solladie, G.; Salom-
Roig, X. J. Tetrahedron Lett. 2000, 41, 551.