Stereochemical aspects and the synthetic scope of the SHi at the sulfur atom. Preparation of enantiopure 3-substituted 2,3-dihydro-1,2- benzoisothiazole 1-oxides and 1,1-dioxides

Article abstract of DOI:10.1039/c4cc01831a

Intramolecular homolytic substitution (S_Hi) on the sulfur atom at acyclic N-(o-bromobenzyl)sulfinamides takes place with a complete inversion of the configuration and provides an excellent tool to connect N-tert-butanesulfinylimines with enantiopure 3-substituted benzo-fused sulfinamides (1,2-benzoisothiazoline 1-oxides) and the related pharmacologically relevant sulfonamides. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01831a

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Stereochemical aspects and the synthetic scope
of the SHi at the sulfur atom. Preparation of
enantiopure 3-substituted 2,3-dihydro-1,2-
benzoisothiazole 1-oxides and 1,1-dioxides†
Cite this: Chem. Commun., 2014,
50, 6046
Received 11th March 2014,
Accepted 17th April 2014
Jose A. Fernandez-Salas, M. Mercedes Rodrıguez-Fernandez,* M. Carmen Maestro*
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DOI: 10.1039/c4cc01831a
and Jose L. Garcıa-Ruano
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www.rsc.org/chemcomm
Intramolecular homolytic substitution (SHi) on the sulfur atom at
acyclic N-(o-bromobenzyl)sulfinamides takes place with a complete
inversion of the configuration and provides an excellent tool to
connect N-tert-butanesulfinylimines with enantiopure 3-substituted
benzo-fused sulfinamides (1,2-benzoisothiazoline 1-oxides) and the
related pharmacologically relevant sulfonamides.
Intramolecular homolytic substitution (SHi) reactions have been
successfully used to prepare heterocyclic systems.1 Those involving
the sulfur atom have a special relevance because of the synthetic
and pharmacological usefulness of sulfinamides2 and sulfon-
amides.3 One of the most interesting reactions in this field is the
cyclization of o-bromoaryl sulfinamide 1 into the corresponding
cyclic sulfinamide 2 under radical conditions4 (Scheme 1a), mainly
due to its stereochemical course and the possibility of using 2 as a
precursor of chiral sulfonamides. Concerning the first aspect, the
inversion of the sulfur configuration at 1 was assumed on the basis
of the behavior of sulfoxides5 and sulfinates,6 but it was not
unambiguously proven (the absolute configuration of 2 was never
established). ROBH and HLYP/6-31++G(d,p) calculations suggest
this inversion to occur via hypervalent intermediates7,8 (A in
Scheme 1a), susceptible of giving pseudorotation processes prior
to its dissociation. It would explain the slight racemization
observed in the formation of 2 (94% ee) from optically pure 1.6
On the other hand, the synthetic interest of the SHi reaction to
prepare unsubstituted benzosulfinamides and benzosulfonamides
(Scheme 1a) is rather low, because it only provides products lacking
of substituents at the benzylic position. In contrast, C-3 substitution
is synthetically important since it is present at compounds exhibit-
ing pharmacological activity (often associated with the absolute
configuration at C-39) or valuable as chiral auxiliaries.10
Scheme 1 Antecedents of SHi reaction at the sulfur atom and the goal of
this work.
bearing substituents at C-3, would be that indicated in
Scheme 1b, starting from the N-tert-butanesulfinylimine 3. It can
be transformed with a complete control of the stereoselectivity
into 4,2b,11 which would evolve into 5 under radical reaction condi-
tions. As additional interest, the use of 4 as starting materials in SHi
reactions would provide unequivocal evidence of their stereo-
chemical course (inversion or retention), due to the diastereomeric
character of the obtained sulfinamides 5. Moreover, substituents at
C-3 could slow down the pseudorotation process in hypervalent
structures, thus avoiding the observed racemization. The synthetic
sequence shown in Scheme 1b represents an interesting alternative
to the methods used in the preparation of benzosultams 6 so far,
mainly based on the chemical manipulation of saccharin.12
In this paper, we report the synthesis of the enantiomerically
pure acyclic o-bromophenylsulfinamides 4 from the corre-
sponding N-tert-butanesulfinylimine 3 and the results obtained
in their radical cyclization to form 3-substituted benzo-fused
sulfinamides 5 and their further oxidation into the related
sulfonamides 6 (Scheme 1b).
At this point, we reasoned that a general method to obtain
enantiomerically pure sulfinamides 5 and sulfonamides 6,
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´
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Departamento de Quımica Organica, Universidad Autonoma de Madrid,
28049-Cantoblanco, Madrid, Spain. E-mail: mercedes.rodriguez@uam.es,
carmen.maestro@uam.es
Acyclic sulfinamides 4 with R and S configuration at the
benzylic carbon13 were prepared from (R)-N-tert-butanesulfinylimine
† Electronic supplementary information (ESI) available. CCDC 984456. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc01831a 3 using reactions with a different stereochemical course.
6046 | Chem. Commun., 2014, 50, 6046--6048
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Table 2 Homolytic cyclization of sulfinamides 4
Scheme 2 Stereochemical course of nucleophilic and radical additions
to N-tert-butanesulfinylimines.
Entry
R
Yielda (%)
deb (c)
1
2
3
4
5
6
7
8
9
Et (4a)
iPr (4b)
Cy (4c)
tBu (4d)
78 (5a)
96 (5b)
76 (5c)
74 (5d)
76 (5e)
86 (5f)
66 (5g)
73 (5h)
—
498 (R,SS)
498d (R,SS)
498 (R,SS)
498 (R,SS)
498 (S,SS)
498 (S,SS)
498 (R,SS)
498 (S,SS)
—
Nucleophilic additions of organometallic reagents, involving
intramolecular transfer of the organyl residues from intermediate
species with the metal associated to the sulfinyl oxygen,14 provide
different diastereoisomers to those resulting in the radical
additions,11,15 which are intermolecular processes with the
reagent approaching to the less hindered face of 3 adopting
its most stable conformation (Scheme 2).
Ph (4e)
3-TBSOCH2C6H4 (4f)
CH2SiPhMe2 (4g)
CH2CO2tBu (4h)
CN (4i)
10
CH2NHBOC (4j)
78 (5j)
498 (R,SS)
a
b
c
d
Isolated yield. Determined by 1H NMR. Configuration. 99% ee;
The results obtained in the synthesis of sulfinamides 4a–i
are reported in Table 1. Alkyl residues (Et, iPr, Cy, and t-Bu)
were introduced with very good yields and complete control of
the configuration (499% de) from alkyl iodides under radical
conditions11,16 (Et3B/O2 in the presence of Bu3SnH and Lewis
acid activation) to attain sulfinamides (R,RS)-4a–d (Table 1,
entries 1–4).
Sulfinamides (S,RS)-4 with the opposite configuration at the
benzylic carbon (4g and 4i have R,RS configuration because the
prelation order of the groups) were obtained with different
nucleophiles. Grignard reagents were used for introducing
Ph (4e), 3-TBSOCH2C6H4 (4f), and CH2SiPhMe2 (4g) groups in a
highly stereoselectivity manner (entries 5–7), whereas the Refor-
matsky reagent allowed us to insert the tert-butyl bromoacetate
residue present in 4h (entry 8). Finally, N-sulfinyl a-aminonitrile
4i was obtained under Strecker reaction conditions (entry 9).
Configurations assigned in Table 1 to 4a–i are based on the well
established stereochemical course of the different reactions
used in their preparation, confirmed by chemical correlation
(see ESI†).
Determined by HPLC analysis.
Homolytic cyclizations of compounds 4 were performed in
refluxing toluene in the presence of AIBN and Bu3SnH. The chiral
cyclic 3-substituted benzo-fused sulfinamides 5 were obtained in
good yields with complete stereocontrol (Table 2). The presence of
functional groups like OTBS (4f), SiR3 (4g) and even CO2tBu (4h)
has not any influence on the reaction course (entries 6–8),
whereas the reaction of 4i (entry 9) was unsuccessful because
the intramolecular addition of the ortho aryl radical to the CN
group (5-endo-dig)17 is faster. Reduction of the CN group at 4i with
BH3, and further protection of the resulting amino group, gives
the sulfinamide 4j (entry 10), which satisfactorily evolves into the
cyclic sulfinamide 5j under radical conditions.18
The absolute configuration of benzo-fused sulfinamide 5b
was established as (R,SS) by X-ray diffraction studies.19 Taking
into account the (R,RS) configuration of the precursor 4b, we can
unequivocally state that the SHi has taken place with a complete
inversion of the configuration at the sulfur atom. The exclusive
formation of only one diastereoisomer indicates that cyclization
occurs with complete inversion, regardless of the carbon
configuration of the starting sulfinamide (Table 2). This result
constitutes the first experimental evidence supporting this asser-
tion. On the other hand, the absence of epimerization in the
reactions reported in Table 2 contrasts with the slight racemiza-
tion observed in the conversion of the unsubstituted compound
1 into 2 shown in Scheme 1a, attributed to a pseudorotation
process at intermediate A. This fact suggests that the presence of
substituents at C-3 slowed down or hindered the pseudorotation,
probably due to steric factors.
Table 1 Synthesis of sulfinamides 4
c
Entry Reagent
Compounda (yield %) drb
d
1
2
3
4
5
6
7
8
9
EtI-Et3B/O2
4a (80)
4b (91)
4c (90)
4d (75)
4e (90)
499 : 1 R,RS
d
iPrI-Et3B/O2
499 : 1 R,RS
499 : 1 R,RS
499 : 1 R,RS
92 : 8 S,RS
Once it was established that SHi of the acyclic sulfinamides
provides an excellent method to prepare enantiopure cyclic sulfina-
mides 5a–h,j, we studied their oxidation with mCPBA (it preserves
the configuration at C-3) in order to obtain benzosultams 6a–h,j,
with the results indicated in Table 3. Almost quantitative yields were
obtained in all cases and the optical purity and the configurational
assignment of these compounds were confirmed by comparison of
their [a]D values with those previously reported. Compound 6j can
d
CyI-Et3B/O2
tBuI-Et3B/O2
PhMgBr
d
3-TBSOCH2C6H4MgBr 4f (93)
95 : 5 S,RS
Me2PhSiCH2MgCl
tBuO2CCH2ZnBr
TMSCN/Y(OTf)3
4g (94)
4h (97)
4i (90)
499 : 1 R,RS
499 : 1 S,RS
96 : 4 R,RS
Isolated yield. Determined by 1H NMR. Absolute configuration.
a
d
b
c
In the presence of BF3ÁOEt2-Bu3SnH (see ESI).
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Table 3 Synthesis of benzo-fused sulfonamides 6
2 (a) C. H. Senanayake, Z. Han and D. Krishnamurthy, in Organosulfur
Chemistry in Asymmetric Synthesis, ed. T. Toru and C. Bolm, Wiley-
VCH, Weinheim, 2008, p. 233; (b) M. T. Robak, M. A. Herbage and
J. A. Ellman, Chem. Rev., 2010, 110, 3600.
3 (a) A. K. Kalgutkar, R. Jones and A. Sawant, in Metabolism,
Pharmacokinetics and Toxicity of Functional Groups, ed. D. A. Smith,
RSC Publishing, Cambridge, 2010, p. 210; (b) K. C. Majumdar and
S. Mondal, Chem. Rev., 2011, 111, 7749; (c) Z. Liu and Y. Takeuchi,
Heterocycles, 2002, 56, 693.
Entry
R
Yield (%)
ˆ
4 J. Coulomb, V. Certal, L. Fensterbank, E. Lacote and M. Malacria,
Angew. Chem., Int. Ed., 2006, 45, 633.
5 A. L. J. Beckwith and D. R. Boate, J. Chem. Soc., Chem. Commun.,
1986, 189.
1
2
3
4
5
6
7
8
9
Et (5a)
iPr (5b)
Cy (5c)
tBu (5d)
98, (R)-6a
96, (R)-6b
98, (R)-6c
97, (R)-6d
90, (S)-6e
91, (S)-6f
92, (R)-6g
90, (S)-6h
99, (R)-6j
6 J. Coulomb, V. Certal, M. H. Larraufie, C. Ollivier, J. P. Corbet,
ˆ
G. Mignani, L. Fensterbank, E. Lacote and M. Malacria, Chem. – Eur. J.,
Ph (5e)
2009, 15, 10225.
3-TBSOCH2C6H4 (5f)
CH2SiPhMe2 (5g)
CH2CO2tBu (5h)
CH2NHBOC (5j)
ˆ
7 S. H. Kyne, H. M. Aitken, C. H. Schiesser, E. Lacote, M. Malacria,
C. Ollivier and L. Fensterbank, Org. Biomol. Chem., 2011, 9,
3331.
8 H. M. Aiken, A. N. Hancock and C. H. Schiesser, Chem. Commun.,
2012, 48, 8326.
9 (a) L. N. Tumey, M. J. Robarge, E. Gleason, J. Song, S. M. Murphy,
G. Ekema, C. Doucette, D. Hanniford, M. Palmer, G. Pawlowski,
J. Danzig, M. Loftus, K. Hunady, B. Sherf, R. W. Mays, A. Stricker-
Krongrad, K. R. Brunden, Y. L. Bennani and J. J. Harrington, Bioorg.
Med. Chem. Lett., 2010, 20, 3287; (b) J. Mao and D. C. Baker,
US Pat., 6,458,962 B1, 2003; (c) A. Jirgensons, G. Leitis, I. Kalvinsh,
D. Robinson, P. Finn and N. Khan, Patent Appl., WO 2008142376 A1,
2008.
be easily deprotected into the 3-aminomethyl derivative 6k, poten-
tially useful as a coordinating ligand (see ESI†).
At this point, the comparison of our method to obtain enantio-
pure benzosulfonamides (three steps from N-tert-butanesulfinyl-
imine 3, Scheme 1b) with the mostly used procedure so far,
consisting of the addition of organometallic reagents to saccharin,
followed by catalytic asymmetric reduction, with hydrogen (usually
requiring autoclave) or hydrogen transfer reagents (affording rather
moderated ee with 3-aryl derivatives) is interesting. Fixing the
attention on the pharmacologically important20 and enantio-
merically pure compounds 6e, 6f and 6h, they were, respec-
tively, prepared from 3 in 62%, 73% and 64% overall yields,
whereas 63% (6e),9b,21 47% (6f),9b,21a and 25% (6h)12c yields
were obtained starting from saccharin. These data suggest that
our procedure constitutes a valuable alternative to prepare
3-substituted benzosultams 6.
In summary, we describe a very efficient method to obtain
enantiopure 3-substituted benzosulfinamides 5 and sulfon-
amides 6 from N-tert-butanesulfinylimines 3. Moreover, we have
unequivocally established that the SHi reactions occur with
complete inversion of the sulfur configuration and that the
presence of a-substituents in ortho-bromobenzyl sulfinamides
4 precludes the racemization at the sulfur atom, thus providing
enantiopure 3-substituted cyclic benzosulfinamides 5.
10 (a) W. Oppolzer, M. Wills, C. Starkemann and G. Bernardinelli,
Tetrahedron Lett., 1990, 31, 4117; (b) K. H. Ahn, C. Ham, S. K. Kim
and C. W. Cho, J. Org. Chem., 1997, 62, 7047.
´
´
´
11 J. A. Fernandez-Salas, M. C. Maestro, M. M. Rodrıguez-Fernandez,
´
J. L. Garcıa-Ruano and I. Alonso, Org. Lett., 2013, 15, 1658.
12 For the asymmetric synthesis of 3-substituted benzosultams see:
(a) K. H. Ahn, H.-H. Baek, S. J. Lee and C.-W. Cho, J. Org. Chem., 2000,
65, 7690 and references cited therein; (b) M. Seppelt and D. Enders,
Synlett, 2011, 402 and references cited therein; (c) C. B. Yu, K. Gao,
D. S. Wang, L. Shi and Y. G. Zhou, Chem. Commun., 2011, 47, 5052;
(d) M. Ichinose, H. Suematsu, Y. Yasutomi, Y. Nishioka, T. Uchida
and T. Katsuki, Angew. Chem., Int. Ed., 2011, 50, 9884.
13 The possible existence of matched and mismatched pairs of reagents
in SHi reactions, determined the need of exploring the behavior of
both diastereoisomers.
14 (a) N. Plobeck and D. Powell, Tetrahedron: Asymmetry, 2002,
13, 303; (b) K. Brinner, B. Doughan and D. J. Poon, Synlett, 2009,
991.
15 (a) T. Akindele, K.-I. Yamada, T. Sejima, M. Maekawa, Y. Yamamoto,
M. Nakano and K. Tomioka, Chem. Pharm. Bull., 2010, 58, 265; For a
intramolecular process see: (b) E. M. Rochette, W. Lewis, A. G.
Dossetter and R. A. Stockman, Chem. Commun., 2013, 49, 9395.
16 A detailed discussion about the preparation of these and other
o-substituted sulfinamides from N-sulfinylimines under radical
conditions will be reported in due course.
The Spanish Government (grant CTQ2012-35957) and Comu-
nidad de Madrid (CCG08-UAM/PPQ-4151; S2009/PPQ1634) are
gratefully acknowledged. J. A. F.-S. thanks Comunidad de
Madrid for a predoctoral contract.
17 (a) The 1H NMR spectrum of the obtained compound is compatible
with the N-(1H-indol-3-yl)-2-methylpropane-2-sulfinamide; (b) A. Beaume,
C. Courillon, E. Derat and M. Malacria, Chem. – Eur. J., 2008, 14,
1238.
18 All the attempts to carry out the synthesis of benzosulfinamide 5b
from sulfinimine 3 as a one-pot procedure, failed.
19 CCDC 984456 contains the supplementary crystallographic data for
compound 5b.
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6048 | Chem. Commun., 2014, 50, 6046--6048
This journal is ©The Royal Society of Chemistry 2014