Reactions of Bunte salts with carbocations of isobenzofuranone and isoindolone

Article abstract of DOI:10.1016/j.tetlet.2011.08.016

A convenient method for the preparation of functionalized derivatives of isobenzofuran-1(3H)-ones and isoindol-1(3H)-ones by reactions of their carbocations with Bunte salts is described. The reactions proceed by means of electrophilic attack on the S(II)

Full text of DOI:10.1016/j.tetlet.2011.08.016

Tetrahedron Letters 52 (2011) 5444–5447
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactions of Bunte salts with carbocations of isobenzofuranone and isoindolone
L.Yu. Ukhin a, A.R. Akopova a, A.V. Bicherov b, L.G. Kuzmina c, A.S. Morkovnik a, , G.S. Borodkin a
⇑
a Research Institute of Physical and Organic Chemistry, Southern Federal University, Rostov-on-Don 344090, Russia
b Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don 344006, Russia
c Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method for the preparation of functionalized derivatives of isobenzofuran-1(3H)-ones and
isoindol-1(3H)-ones by reactions of their carbocations with Bunte salts is described. The reactions pro-
ceed by means of electrophilic attack on the S(II)-atom of the Bunte salts.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 7 April 2011
Revised 27 July 2011
Accepted 2 August 2011
Available online 17 August 2011
Keywords:
Bunte salts
Isobenzofuranones
Isoindolones
Carbocations
Bunte salts (organic S-substituted thiosulfates)1 are interesting
as reagents for introducing sulfur-containing groups, particularly
by reactionswith different C-electrophiles. Theonly knownexample
of such reactions is the carbamoylmethylthiolation of a benzhydryl
carbocation using sodium carbamoylmethyl thiosulfate (1a)2 in
which atom S(II) plays the role of nucleophilic center. The reaction
is accompanied by hydrolytic cleavage of the S–S bond and S-desulf-
onation, giving an almost quantitative yield of 2-benzhydrylthioac-
etamide, the key intermediate in a new synthetic approach to the
nootropic drug ‘modafinil’ (2-benzhydrylsulfinylacetamide).3
Application of this approach to other carbocations and Bunte
salts is of considerable synthetic interest, in particular, for the syn-
thesis of new bioactive compounds. Due to the weak nucleophilic
character of Bunte salts, only highly active carbocations, for
example, 3-oxo-1,3-dihydroisobenzofuran-1-yliums (2) and their
isoindole analogs, 3-oxo-1,3-dihydroisoindol-1-ylium cations (3),
are the most promising for these reactions. Cation 2a (Scheme 1) is
generated by dissolving 3-hydroxyisobenzofuran-1(3H)-one (4a)
(the cyclic form of o-formylbenzoic acid) in concentrated H2SO4.
This cation, for example, readily reacts with arenes, such as benzene,
giving products of electrophilic aromatic substitution.4 It can be as-
(alkylsulfanyl)isoindol-1(3H)-ones 7 from the precursors of cations
2 and 3 by means of reactions with functionalized Bunte salts 1a–e
in acidic medium. Compounds of this type are useful for the prepara-
tion of quinones,5,6 including naturally occurring examples, via the
Hauser–Kraus reaction,7,8 and glucokinase inhibitors as potential
antidiabetic drugs.9 The common route to such compounds is via
nucleophilic alkylation of isobenzofuran-1(3H)-one and isoindol-
1(3H)-one 3-mercapto derivatives, or by heterocyclization of Schiff
bases derived from ethyl 2-formylbenzoate and alkyl 2-
mercaptoacetates.10,11 We found that compound 4a, the precursor
of cation 2a, reacts smoothly with thiosulfate 1a in concentrated
H2SO4 at room temperature to give 3-carbamoylmethylthio deriva-
tive 6a (yield 77%), the structure of which was established by X-ray
analysis (Fig. 1).12 The most important bond lengths are as follows:
S(1)–C(9) 1.812(1), S(1)–C(8) 1.800(1), C(1)@O(2) 1.207(1), C(1)–
O(1) 1.363, C(8)–O(1) 1.462(1), C(10)@O(3) 1.238(1), C(10)–N(1)
1.330(1) Å. These parameters do not differ from standard values.
The 6,7-dimethoxy derivative 4b, a cyclic form of opianic acid,
gave
6,7-dimethoxy-3-carbamoylmethylthio-isobenzofuran-
1(3H)-one (6b) following a similar reaction (Scheme 1).
2-Aryl-3-acetoxyisoindol-1(3H)-ones 5a,b and 2-cyanoacetyla-
mino-3-acetoxyisoindol-1(3H)-one 5c were also active as carbo-
cation precursors in reactions with Bunte salts. Generally, these
reactions were conveniently carried out in CF3COOH either at room
temperature or under moderate heating (Scheme 2, Table 1). Under
these conditions the Bunte salts were stable to CF3COOH.
Bunte acids containing an amino group as part of a pharmaco-
phoric dialkylaminoalkyl substituent, can also be used as effective
S-nucleophiles, because the amino group exists as the inactive
protonated form.
sumed that cations
roisobenzofuran-1-yl acetates
3
are generated from 3-oxo-1,3-dihyd-
in strong acidic medium
5
a
(CF3COOH) and are responsible for electrophilic reactions of these
compounds (Scheme 2).
In this work we present a new method for the synthesis of
functionalized 3-(alkylsulfanyl)isobenzofuran-1(3H)-ones 6 and 3-
⇑
Corresponding author. Tel.: +7 863 297 51 96; fax: +7 863 243 4028.
E-mail address: asmork2@ipoc.rsu.ru (A.S. Morkovnik).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.016

L. Yu. Ukhin et al. / Tetrahedron Letters 52 (2011) 5444–5447
5445
O
C
R
R
7
O
R
O
1
R
R
R
H2SO4
6
NaO3SSCH2CONH2
(1a)
O
2
O
O
C+
5
20 o
C
H
3
NH2
4
OH
S
H
H
2a,b
4a,b
6a,b
55-77%
O
R=H (a), OCH3(b)
Scheme 1. Reactions of the Bunte salt 1a with isobenzofuranone carbocations.
O
O
H+
R1
N
R1
N
C+
OAc
H
H
3a-c
5a: R1 = Ph
5b: R1 = β-Py
5c: R1 = NHCOCH2CN
O
7
4
1
H2SO4 or
CF3COOH
R2
6
2
O
N
R1
R2
3a-c
+
S
S
5
O
20 oC
S
O
3
H
X
7a: R1 = Ph,
R2 = CH2CONH2
R2 = CH2CO2H
1a: R2 = CH2CONH2, X=Na
7b: R1 = Ph,
1b: R2 = CH2CO2H, X=Na
1
: R = β-Py
R2 = CH2CONH2
7c
2
1c
: R = CH2CH2NEt2 X=H
1
2
7d
: R = NHCOCH2CN, R = CH2CONH2
1d: R2 = CH2CH2-
N
7e: R1 = Ph,
R2 = CH2CH2NEt2
R2 = CH CH -
, X=H
, X=H
7f: R1 = Ph,
7g: R1 = Ph,
N
N
1e: R2 = CH2CH2-
N
O
2
2
R2 = CH CH -
O
2
2
Scheme 2. Reactions of the Bunte salts 1a–e with isoindolone carbocations.
Figure 1. A SHELXTL-Plus drawing of the molecular structure of 6a. Thermal ellipsoids are shown at the 50% probability level.

5446
L. Yu. Ukhin et al. / Tetrahedron Letters 52 (2011) 5444–5447
Table 1
Yields of compounds 7a–g obtained by reaction of isoindolones 5a–c and Bunte salts 1a,b or Bunte acids 1c–e13
Entry
Acid
Bunte salt (acid)
3-Acetoxyisoindolone
Product
Yield (%)
O
O
N
N
NH2COCH2SSO3Na
1a
1
H2SO4
80
OAc
H
5a
SCH2CONH2
H
H
7a
O
N
HO2CCH2SSO3Na
1b
2
3
4
H2SO4
5a
67
86
77
SCH2CO2H
7b
O
N
TFA
1b
1a
5a
H
SCH2CO2H
7b
O
O
N
N
N
N
TFA
H
SCH2CONH2
H
OAc
7c
5b
O
O
N
NHCOCH2CN
N
NHCOCH2CN
5
6
TFA
TFA
1a
49
40
SCH2CONH2
OAc
H
H
7d
5c
O
N
HSO3SCH2CH2NEt2
1c
5a
5a
H
7e
SCH2CH2NEt2
O
N
S
N
O
S
7
TFA
48
O
S
O
H
N
H
7f
1d
O
N
O
S
N
O
S
O
8
TFA
5a
53
S
O
H
N
O
H
7g
1e
The structures of compounds 7 were established by mass spec-
trometry and 1D, 2D 1H, 13C and 15N NMR spectroscopy.
General procedure for the synthesis of isobenzofuranones 6. The
appropriate o-formylbenzoic acid (3.3 mmol) was titrated with
concentrated H2SO4 (2 mL) until dissolution and then with thiosul-
fate 1a (0.7 g, 3.6 mmol). The mixture was left for 12 h at rt and
then treated with cold H2O (25 mL). The solid product was filtered,
washed with H2O, and dried.
In summary, we have developed a new approach to the synthesis
of isobenzofuran-1(3H)-ones and isoindol-1(3H)-ones bearing
3-alkylthio groups. The synthetic strategy used is based on the
nucleophilic properties of Bunte salts which enable their efficient
interaction with reactive carbocationic electrophiles. It is important
to note that Bunte salts, according to our preliminary data, are also
Compound 6a: yield 0.57 g (77%), colorless crystals, mp 182–
183 °C (MeCN).
active toward strongly electrophilic organic halides such as
a-halok-
1H NMR (300 MHz, DMSO-d6), d: 3.25 (d, 1H, CH2, J = 14.4 Hz),
3.37 (d, 1H, CH2, J = 14.4 Hz), 6.97 (s, 1H, CH), 7.01 (s, 1H, NH2),
etones, for which the SN2 mechanism is characteristic Table 1.

L. Yu. Ukhin et al. / Tetrahedron Letters 52 (2011) 5444–5447
5447
7.44 (s, 1H, NH2), 7.62 (t, 1H, H(6), J = 7.3 Hz), 7.66 (d, 1H, H(4),
J = 7.9 Hz), 7.79 (td, 1H, H(5), J = 7.5 Hz), 7.84 (d, 1H, H(7),
authors also thank Drs. V. Spiglasov and E. Shepelenko for the valu-
able advice.
J = 7.6 Hz) ppm; IR (neat):
mmax = 3400, 3340, 3304, 3250,
3201(NH), 1754, 1665 (CO), 1599 (aromatic C@C), 1060,
933 cmÀ1 (C–O–C). Anal. Calcd for C10H9NO3S: C, 53.80; H, 4.66;
N, 6.27; S, 14.36. Found: C, 53.86; H, 4.85; N, 6.64; S, 14.02; MS
(EI, 70 eV): m/z = 165 (M-CH2CONH2), 133 (MÀSCH2CONH2); the
product did not produce a stable molecular ion.
Supplementary data
Supplementary data (procedures and characterization data for
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.08.016.
General procedure for the synthesis of isoindolones 7. To a solution
of appropriate 3-acetoxyisoindolone 5 (1 mmol) in concentrated
H2SO4 (2 ml) or TFA (1 mL), thiosulfate 1 (1.0–1.1 mmol) was
added and the mixture triturated until dissolution of the starting
compounds. The reaction times and temperatures were as follows:
7a—1 h (20–25 °C); 7b—0.5 h (20–25 °C); 7c,d—1 min (at reflux),
7e–g—3 h (20–25 °C). The isoindolones were precipitated by addi-
tion of Et2O or a mixture of Et2O–iPrOH. The products were sepa-
rated, triturated with concentrated NH4OH (5 mL) and cooled
with ice until they solidified. The solid was filtered, washed with
H2O and dried.
References and notes
1. For a review, see: Distler, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 544–553.
2. Bicherov, A. V.; Akopova, A. R.; Spiglazov, V. I.; Morkovnik, A. S. Russ. Chem. Bull.
Int. Ed. 2010, 59, 91–101.
3. Rambert, F.; Hermant, J.; Schweizer, D. In Comprehensive Medical Chemistry II;
Taylor, J. B., Trigge, D. J., Eds.; Elsevier, 2006; Vol. 8, p 149.
4. Al-Hamdany, R.; Al-Rawi, J. M.; Ibrahim, S. J. Prakt. Chem. 1987, 329, 126–130.
5. Wheeler, D. P.; Young, D. C.; Erley, D. S. J. Org. Chem 1957, 22, 547–556.
6. Sakulsombat, M.; Angelin, M.; Ramstrom, O. Tetrahedron Lett. 2010, 51, 75–78.
7. Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892–1918.
8. Rathwell, K.; Brimble, M. A. Synthesis 2007, 643–662.
9. Bian, H.; Dudash, J.; Patel, M.; Rybczynski, P.; Zhang, Y. U.S. Patent 2007/
0099936 A1 2007; Chem. Abstr., 2007, 146, 484368.
10. Liebl, R.; Handtl, R. Liebigs Ann. Chem. 1985, 1092–1093.
11. Ukhin, L. Yu.; Suponitskii, K. Yu.; Belousova, L. V.; Orlova, Zh. I. Russ. Chem. Bull.
Int. Ed. 2009, 58, 2478–2487.
12. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data Centre:
CCDC 816680. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336-033; e-
mail: deposit@ccdc.cam.ac.uk).
13. The syntheses of the Bunte salts and acids 1a–c,e are described in Ref. 2 and
elsewhere: Haugland, R.; Kang, H., U.S. Patent, Publ. No: 20050250957; Chem.
Abstr., 2005, 143, 9187; Bretschneider, H. Monatsh. Chem. 1950, 81, 372–384;
Klayman, D. L.; Kenny, D.; Silverman, R. B.; Tomaszewski, J. E. J. Org. Chem.
1971, 36, 3681–3686; Foye, W. O.; Lanzillo, J. J.; Lowe, Y. H.; Kauffman, J. M. J.
Pharm. Sci. 1975, 64, 211–216. Compound 1d was prepared analogously to 1c,e
starting from b-piperidinoethyl chloride and sodium thiosulfate (see
Supplementary data for details).
Compound 7a: colorless crystals, mp 183–185 °C (MeCN). 1H
NMR (300 MHz, DMSO-d6): 2.53 (d, 1H, CH2, J = 14.2 Hz), 2.66 (d,
1H, CH2, J = 14.2 Hz), 6.74 (s, 1H, C(3)H), 6.88 (s, 1H, NH2), 7.22
(s, 1H, NH2), 7.27 (t, 1H, p-H of Ph, J = 7.4 Hz), 7.46 (t, 2H, m-H of
Ph, J = 7.8 Hz), 7.60–7.80 (m, 4H, C(4)H–C(7)H), 7.81 (d, 2H, o-H
of Ph, J = 7.5 Hz) ppm; IR (neat): mmax = 3408, 3288, 3238, 3187
(NH), 1686, 1630 (CO), 1620, 1600, 1494 cmÀ1 (arom.). Anal. Calcd
for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.40; S, 10.74. Found: C,
64.23; H, 5.00; N, 9.63; S, 10.68; MS (EI, 70 eV): m/z = 298 (M+),
240 (MÀCH2CONH2), 208 (M-SCH2CONH2).
Acknowledgments
This work was supported by the Program of Scientific Develop-
ment of Southern Federal University (Grant No. 3-K-11-1). The