Regio- and stereoselective transfer of p-toluenesulfonamido group from sulfur to carbon: Preparation of aminoalcohol derivatives from allylalcohols

Article abstract of DOI:10.1016/j.tetlet.2004.08.028

Stereospecific transformation of sulfilimines to sulfoxides and regio- and stereoselective transformation of alkenes to bromosulfonamides is disclosed. A novel methodology for the regio- and stereoselective synthesis of amino alcohol derivatives from allylalcohols/ethers via intramolecular nucleophilic participation by the sulfilimine moiety is disclosed. The sulfilimine moiety is stereospecifically transformed to a sulfinyl moiety with an inverted configuration. The reaction is general and affords highly functionalised products.

Full text of DOI:10.1016/j.tetlet.2004.08.028

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7231–7234
Regio- and stereoselective transfer of p-toluenesulfonamido
group from sulfur to carbon: preparation of aminoalcohol
derivatives from allylalcoholsq
Sadagopan Raghavan,a,* Ch. Naveen Kumar,a K. A. Tony,a S. Ramakrishna Reddya
and K. Ravi Kumarb
aOrganic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bX-ray Crystallography Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 21 July 2004; revised 4 August 2004; accepted 5 August 2004
Available online 21 August 2004
Abstract—A novel methodology for the regio- and stereoselective synthesis of amino alcohol derivatives from allylalcohols/ethers
via intramolecular nucleophilic participation by the sulfilimine moiety is disclosed. The sulfilimine moiety is stereospecifically trans-
formed to a sulfinyl moiety with an inverted configuration. The reaction is general and affords highly functionalised products.
Ó 2004 Elsevier Ltd. All rights reserved.
Vicinal1 and 1,3-amino alcohols2 are structuralmotifs
present in a variety of naturalproducts and pharmaceu-
ticalagents. Interest in these structuralunits has eld to
the development of a variety of methods for their syn-
thesis.3 The addition of nucleophiles to double bonds,
activated by complexation with electrophiles, affords
highly functionalized products regio- and stereoselec-
tively via asymmetric induction by allylic or homoallylic
substituents.4 We disclose herein an efficient, novel and
a generalmethod for the preparation of aminoaclohol
derivatives 2 from readily accessible b-hydroxy (silyloxy)
c,d-unsaturated sulfilimines 1 via intramolecular nucleo-
philic assistance,5 by the sulfilimine group (Eq. 1).
The sulfilimines 4 were prepared6 as a diastereomeric
mixture in nearly equimolar quantities from the sulfide
3 and separated by column chromatography (Scheme 1).
The reaction of diastereomerically homogeneous sulfil-
imines 4a–e with N-bromosuccinimide (NBS) was inves-
tigated with the aim of probing the influence of (a) the
relative configuration of sulfur and C2, (b) the protect-
ing group, (c) the geometry of the double bond and
(d) the substituent at C4, on the regio- and stereoselec-
tivity of product formation. The sulfilimines reacted at
ambient temperature in toluene in the presence of water
with NBS to yield the bromosulfonamides 5 (Table 1).
Inspection of Table 1 reveals the following: (1) The sul-
filimine moiety is stereospecifically transformed into a
sulfoxide with an inverted configuration. (2) The reac-
tion is generalfor a variety of substrates with different
olefinic substitution patterns. (3) The reaction is clean
and high yielding. (4) The reaction proceeds regioselec-
tively affording products arising from a 5-exo nucleophi-
lic attack by the sulfilimine group except for 4d, which
yields products resulting from 6-endo nucleophilic
attack. This can be rationalized by the ability of the
phenylgroup to stabiilze a partialpositive charge at C4
leading to the nucleophilic attack at C4 in accordance
with the MarkonokovÕs rule.7 (5) The reaction proceeds
to afford the products with good to high stereoselectiv-
ity. The reaction probably proceeds via p complexed
bromonium ion,8 which on nucleophilic attack by the
ð1Þ
Keywords: Sulfilimine; Bromosulfonamide; Intramolecular assistance;
Sulfoxide.
q IICT Communication No. 0408.
*
Corresponding author. Tel.: +91 04027160123; fax: +91
04027160512; e-mail: purush101@yahoo.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.028

7232
S. Raghavan et al. / Tetrahedron Letters 45 (2004) 7231–7234
OP R1
OP R1
OP R1
NTs
S
NTs
S
NaNTsCl
CH3CN
80-95%
+
S
Ph
R2
Ph
R2
Ph
R2
4
2
4
2
1
3
3
4a
4s
1
2
a, P = R = R = H
1
2
b, P = TBDPS, R = R = H
c, P = TBDPS, R = n-Bu, R = H
1
2
1
2
d, P = TBDPS, R = H, R = Ph
1
2
e, P = R = H, R = CH OBn
2
Scheme 1. Preparation of the diastereomeric mixture of sulfilimines.
Table 1. Preparation of bromosulfonamides from unsaturated sulfiliminesa
S. No.
Sulfilimine
Bromosulfonamide
Yield % C2–C3 (syn:anti)
O
OTBDPS
NTs
S
OTBDPS
S
80
>95:<5
1
Ph
Ph
Br
Ph
Ph
4ba
5bs
NHTs
OTBDPS
O
S
NTs
S
OTBDPS
2
82
>95:<5
Br
4bs
5ba
NHTs
O
S
OTBDPS
Br
OTBDPS
NTs
S
3
4
90
<5:>95
Ph
Ph
Ph
4ca
5cs
NHTs
O
S
OTBDPS
Br
NTs
S
OTBDPS
85
1:2b,c,d
Ph
Ph
4cs
5ca
NHTs
OTBDPS
O
S
NTs
S
OTBDPS
NHTs
5
6
86
1:3b,c,d
Ph
Ph
Ph
Ph
4da
5ds
Br
OTBDPS
NHTs
O
S
NTs
S
OTBDPS
4ds
82
<5:>95
Ph
Ph
Ph
Ph
5da
Br
O
S
NTs
S
OH
OH
7
8
86
>95:<5
Ph
Ph
Br
Br
4aa
OH
4as
5as
NHTs
O
S
OH
NTs
S
85
>95:<5
Ph
Ph
5aa
NHTs
O
S
OH
NTs
S
OH
Br
OBn
9
OBn
OBn
90
>95:<5
Ph
4ea
5es
NHTs
O
S
OH
NTs
S
OH
Br
OBn
10
86
3:1b,c,d
Ph
Ph
4es
5ea
NHTs
a All reactions were done on 0.5mmol scale in toluene as the solvent in the presence of 1.3equiv of NBS and 1.2equiv of H2O.
b The yield refers to the combined yield of both the products.
c The major product is depicted.
d The isomers are inseparable.
sulfilimine (pathway a or b) would afford the interm-
ediates I, II/III, from the anti and the syn sulfilimines,
respectively. Further hydrolysis of the salts by the attack
of water at the sulfur atom would yield the inverted sulf-
oxide/the 1,2- (pathway a) or the 1,3-aminoalcohol
derivatives (pathway b, Scheme 2).
When R = H and P = H/TBDPS, the reaction proceeds
with excellent regio- and stereoselectivity to afford the
1,2-aminoalcohols. The intermediate II from 4es would
experience steric interactions between the substituent
R (CH2OBn) and the N-Ts group thus explaining for
the erosion of stereoselectivity in the reaction; inter-

S. Raghavan et al. / Tetrahedron Letters 45 (2004) 7231–7234
7233
O
OP
Br
S
H O
2
Ph
Ph
R
Ts
S
a
NHTs
NTs
S
Ph
OP
N
5bs/5es
NBS
a
b
R
Ph
O
S
R
OP
Br
b
PO
NHTs
R
I
4ba/4da/ 4ea
Br
5ds
O
OP
Br
S
Ph
R
OP
NTs
S
Br
OP
NHTs
a
NBS
5ea/5ea
R
Ts
H
b
a
Ph
R
S
H O
2
O
S
N
OP
NHTs
4bs/4ds/ 4es
b
Ph
Ph
R
R
II
Br
5da
OP
O
S
NTs
S
OP
OP
R
Br
H
NBS
Br
Ts
S
H O
Ph
2
Ph
N
(
)
Ph
NHTs
4cs
R
5ca
III
Scheme 2. Proposed probable pathway for the regio- and stereoselective formation of bromosulfonamides.
NTs
S
O
S
OTBDPS
mediate I from 4ea does not suffer from such steric
repulsions. Likewise the intermediate I from 4da has a
boat-like structure, while the intermediate II from 4ds
has a chair-like structure explaining for the excellent
stereoselectivity observed with the latter. The poor
stereoselectivity observed in the reaction of 4cs can be
rationalized by invoking the intermediacy of III, which
suffers from steric repulsions between the butyl chain
and N-Ts. (6) The outcome of the reaction is the same
for the substrates wherein the hydroxy group is pro-
tected or is free (compare entries 1, 2 with 7, 8). The silyl
ether protected sulfilimines were chosen for study mostly
due to the ease of their preparation and for the ease of
isolation and purification of the products resulting from
them. It is thereby apparent that the regio- and stereo-
selectivity of the reaction is influenced by the nature of
the substituent R at C4, the olefin geometry and the rel-
ative configurations of sulfur and C2. The isomeric nat-
ure of the products 5as and 5aa was proven by oxidation
individually, to yield an identical sulfone. A similar exer-
cise proved the isomeric character of sulfoxides 5bs/5ba,
5cs/5ca, 5ds/5da and 5es/5ea. The structure of 4da with
an anti orientation of the sulfilimine moiety and the
silyloxy group was confirmed by single crystal X-ray dif-
fraction.9 The structure of sulfilimines 4aa, 4ba, 4ca and
4ea were assigned by comparison, which revealed simi-
larities in the chemical shifts of C1, C2 protons to those
in 4da. The sulfilimines 4as–4es also revealed similarities
OTBDPS
a
Ph
Ph
Ph
Ph
6s
4ba
NTs
S
O
S
OTBDPS
OTBDPS
a
6a
4bs
Scheme 3. Stereoselective preparation of sulfilimines from sulfoxides.
Reagents and conditions: (a) TsNCO, t-BuSMe, CH3CN, rt, 48–72h,
70–75%.
C3 and C4. The structure of the product from 4ca was
deduced by X-ray crystallography on the derived
sulfone.9 The syn disposition of the hydroxy and sulfon-
amido groups in 5aa was confirmed by NOE studies on
the derived acetonide. The structures assigned to 5bs
and 5ba were confirmed by deprotection to yield 5as
and 5aa, respectively. The structure assigned to 5es
was confirmed by transformation to the corresponding
acetonide, which revealed a value of 2.9Hz10 for the
coupling between C2H and C3H indicating the trans
orientation of these protons in the acetonide.
Finally for exploiting the full potential of the methodol-
ogy, it is clear from the results disclosed herein that the
b-hydroxy sulfilimines be available as single diastereo-
mers. Cram and co-workers11 have shown that N-Ts-
methyl-p-tolyl sulfilimine can be obtained with inversion
of configuration from methyl-p-tolyl sulfoxide. Thus dia-
stereomerically pure sulfoxides 6s and 6a12 were readily
transformed using the Cram protocolto yiedl 4ba and
4bs,13 respectively (Scheme 3). Similarly the other sul-
filimines used in the study should be accessible from
the corresponding b-hydroxy sulfoxides, which can be
1
in their H NMR spectra. The difference in chemical
shifts (Dd) between the methylene protons is lesser and
the methine proton resonates downfield in 4aa–4ea com-
pared to 4as–4es. The structure of the bromosulfon-
amide 5ds was secured by X-ray crystallography.9 The
X-ray structure established beyond doubt the inversion
of sulfur configuration in going from the starting mate-
rial to the product and also relative configuration at C2,

7234
S. Raghavan et al. / Tetrahedron Letters 45 (2004) 7231–7234
M.; Chow, J.; DuBois, J. J. Am. Chem. Soc. 2001, 123,
6935; (c) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu,
W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465.
4. For a review refer: Cardillo, G.; Orena, M. Tetrahedron
1990, 46, 3321.
5. For intermolecular nucleophilic assistance refer: Ragha-
van, S.; Ramakrishna Reddy, S.; Tony, K. A.; Naveen
Kumar, Ch.; Nanda, S. Synlett 2001, 851.
6. Marzinzik, A. L.; Sharpless, K. B. J. Org. Chem. 2001, 66,
594.
7. (a) Midland, M. M.; Holterman, R. L. J. Org. Chem. 1981,
46, 1227, and references cited therein; (b) Parker, K. A.;
OÕFee, R. J. Am. Chem. Soc. 1983, 105, 654.
readily elaborated as single diastereomers by diaste-
reoselective reduction of the corresponding b-keto
sulfoxides.14
In conclusion, we have disclosed herein a novel protocol
for the elaboration of aminoalcohol derivatives from
allyl ethers via intramolecular nucleophilic sulfilimine
group participation. The reaction has been shown to
proceed highly regio- and stereoselectively. The sulfinyl
group in the product can be utilized for C–C bond for-
mation and the bromine atom for introducing other
heteroatoms. The potentialof the methodool gy for the
synthesis of bioactive molecules is presently under pro-
gress and shall be reported in due course.
8. In the case of halogen additions, onium intermediates are
generally freely reversible. See: Guindon, Y.; Slassi, A.;
Ghiro, E.; Bantle, G.; Jung, G. Tetrahedron Lett. 1992, 33,
4257, and references cited therein.
9. Crystallographic data (excluding structure factors) for
4da, 5ds and sulfone from 5cs have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers 233344-233346. Copy of the
data can be obtained free of charge, on application to
CCDC, 12, Union Road, Cambridge CB2 11EZ, UK [fax:
+44(0)-1223-336033] or deposit@ccdc.cam.ac.uk.
10. Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.;
Zlatoidsky, P. J. Org. Chem. 1997, 62, 9348.
11. Garwood, D. C.; Jones, M. R.; Cram, D. J. J. Am. Chem.
Soc. 1973, 95, 1925.
12. The sulfoxides 6a and 6s were readily obtained by NaIO4
oxidation of 3a to yield an inseparable mixture of hydroxy
sulfoxides followed by treatment with tert-butyldiphenyl-
chlorosilane and separation.
References and notes
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4bs from 6s, while 4bs was obtained from 6a as a single
compound.
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