An efficient catalytic deprotection of thioacetals employing bismuth triflate: Synthesis of pyrrolo[2,1-c] [1,4] benzodiazepines

Article abstract of DOI:10.1016/S0040-4039(03)00437-4

A simple and efficient deprotection of thioacetals has been achieved by employing bismuth triflate. This method has been effectively employed in the preparation of DNA-binding pyrrolo[2,1-c] [1,4]benzodiazepine and its dimers.

Full text of DOI:10.1016/S0040-4039(03)00437-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2857–2860
An efficient catalytic deprotection of thioacetals employing
bismuth triflate: synthesis of pyrrolo[2,1-c] [1,4] benzodiazepines
Ahmed Kamal,* P. S. M. M. Reddy and D. Rajasekhar Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 3 January 2003; accepted 14 February 2003
Abstract—A simple and efficient deprotection of thioacetals has been achieved by employing bismuth triflate. This method has
been effectively employed in the preparation of DNA-binding pyrrolo[2,1-c] [1,4]benzodiazepine and its dimers. © 2003 Elsevier
Science Ltd. All rights reserved.
Thioacetals are frequently used to protect carbonyl
compounds in the course of total synthesis of organic
compounds and hence several reagents have been devel-
oped for their deprotection.1,2 Despite the availability
of many reagents and procedures for deprotection into
their parent carbonyl compounds most are usually not
straightforward. Therefore, considerable efforts have
been directed towards developing mild and selective
methods for thioacetal deprotection. Typically most of
these methods require the use of protic or Lewis acids
and a large number of these methods require drastic
conditions or toxic reagents such as mercuric,3 and
Fe(III) reagents or heavy metal salts.4 Thioacetals have
also been deprotected by the combined use of molecular
oxygen and catalytic amounts of Bi(NO3)3·5H2O.5
Recently, some non-metallic reagents such as trimethyl-
oxonium tetrafluoroborate,6 methylfluorosulphonate7
and oxides of nitrogen8 have also been used for depro-
tection. Usually these methods are expensive and
require multistep operations. More recently, we have
tives have attracted much attention, e.g. bismuth tri-
flate, which has been employed as an efficient catalyst
in organic synthesis that exhibits stronger activity than
other known metal triflates. Bismuth triflate is not
commercially available, but it can be easily synthesized
in large quantities at a relatively low cost.12 In the
present procedure bismuth triflate was freshly prepared
and employed for the dethioacetalization process.
The experimental procedure is simple and involves stir-
ring the substrate in a solution of CH2Cl2/H2O (8:2 v/v)
in the presence of bismuth triflate as catalyst (0.1
mol%).
Representative thioderivatives of aldehydes were readily
deprotected to give the parent carbonyl compounds in
good yields and the results are described in Table 1. In
addition to these results, it was observed that longer
reaction times were required for the deprotection of
thioacetals derived from propane and ethane dithiols.
reported
a facile method for dethioacetalization
employing FeCl3·6H2O.9 Herein we wish to report an
extremely mild method for the deprotection of thioac-
etals 1 to the corresponding carbonyl compounds 2
with a catalytic amount of bismuth triflate in a biphasic
system (Scheme 1).
We have an interest in the development of new syn-
thetic strategies for the DNA-binding pyrrolo[2,1-
c][1,4]benzodiazepine (PBD) ring system, that is known
to interact with DNA in a sequence selective manner
and as such has potential for the development of antitu-
Unlike the mercuric reagents that are usually employed
in the laboratory, bismuth(III) salts have very low
toxicity, are relatively stable to air and small amounts
of moisture, and have advantages as reagents in organic
synthesis.10,11 Over the last few years, bismuth deriva-
* Corresponding author. Tel.: +91-40-27193157; fax: 91-40-27193189;
e-mail: ahmedkamal@iict.ap.nic.in
Scheme 1. Reagents and conditions: (i) Bi(OTf)3×H2O, rt 10–
15 min.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00437-4

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A. Kamal et al. / Tetrahedron Letters 44 (2003) 2857–2860
Table 1. Deprotection of thioacetals by Bi(OTf)3×H2O
mour agents and gene targeting drugs.13,14 A number of
methods are known for the synthesis of this ring system
via a dithioacetal deprotection that have met with
varying degrees of success but which have different
limitations.15 The results obtained with bismuth triflate
outlined above prompted us to extend such an environ-
mentally friendly methodology to the benzodiazepines.
This process would avoid the use of mercuric reagents
for the well-known ethanethiol deprotective cyclization,
thus enabling the introduction of a mild cyclization
process where the product would be free from toxic
mercuric salts.
bismuth triflate afforded the PBD dimeric imines 8 in
good yields 65–80% in the final step (Scheme 2).
Typical procedure: To a stirred solution of (2S)-N-(4-
hydroxy-5-methoxy-2-aminobenzoyl)pyrrolidine-2-carb-
oxaldehyde diethyl thioacetal 4 (185 mg, 0.5 mmol) in
CH2Cl2/H2O (8:2) was added Bi(OTf)3×H2O (6.5 mg, 2
mol%) at room temperature. After completion of the
reaction (40 min) as indicated by TLC, the reaction
mixture was diluted with CH2Cl2 and washed with
saturated NaHCO3 (10 ml) and brine. The organic layer
was dried over anhydrous Na2SO4 and the solvent
removed under reduced pressure. The residue was
purified by flash chromatography on silica gel using
ethyl acetate: hexane (9:1) to afford the pure PBD
imine 5 in 80% yield.18
The precursor, (2S)-N-(4-hydroxy-5-methoxy-2-amino-
benzoyl)pyrrolidine-2-carboxaldehyde diethyl thioacetal
4 was prepared as described in the literature.16 This
upon deprotective cyclization with bismuth triflate
afforded the desired PBD imine 5. Unlike the general
procedure for deprotection of thioacetals this deprotec-
tive cyclization required 2 mol% of bismuth triflate.
This approach was also applied to the synthesis of PBD
dimers. The precursor (2S)-N-(4-hydroxy-5-methoxy-2-
nitrobenzoyl)pyrrolidine-2-carboxaldehyde diethyl thio-
acetal 3 was alkylated using a series of dibromoalkanes
to obtain the 4,4%-(alkane-a,v-diyldioxy)bis[(2S)-N-(5-
methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxaldehyde
diethyl thioacetals 6.17 These upon reduction with
SnCl2·2H2O gave the corresponding aminodiethyl-
thioacetals 7, which on deprotective cyclization with
In summary, this work demonstrates a new method for
the deprotection of thioacetals to their carbonyl com-
pounds using bismuth triflate. We have further demon-
strated its application towards the synthesis of the PBD
ring system and its dimers resulting in significant
improvements in yields and, most importantly, the
products were devoid of contamination from mercuric
salts. Therefore, this work will find use in organic
synthesis involving thioacetal deprotection and also in
the preparation of biologically significant PBD based
DNA-interactive compounds.

A. Kamal et al. / Tetrahedron Letters 44 (2003) 2857–2860
2859
Scheme 2. Reagents and conditions: (i) dibromoalkanes, K2CO3, acetone, reflux, 36–48 h, 93–95%; (ii) SnCl2·H2O, CH3OH, reflux,
2 h, 80–85%; (iii) Bi(OTf)3×H2O, CH2Cl2:H2O, rt, 40 min, 65–80%.
Acknowledgements
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One of the authors (P.S.M.M.R) is thankful to CSIR
(New Delhi) for the award of a Research Fellowship.
6. Oishi, T.; Kamemoto, K.; Ban, Y. Tetrahedron Lett.
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17. Preparation of compound 6: To a stirred solution of
1,3-dibromopropane (101 mg, 1.0 mmol) in dry acetone
(30 ml) was added anhydrous potassium carbonate (410
mg, 3 equiv.) and the monomer 3 (400 mg, 1 mmol). The
reaction mixture was refluxed for 36–48 h. After comple-
tion of the reaction as indicated by TLC, potassium
carbonate was removed by filtration and the filtrate was
evaporated under reduced pressure. The residue was
purified by column chromatography using ethyl acetate–
hexane (7:3) as eluent to afford pure PBD dimer (n=3) in
93% yield.
18. Selected spectroscopic data for compound 5: 1H NMR
(CDCl3): l 2.01–2.09 (m, 2H), 2.29–2.35 (m, 2H), 3.54–
3.61 (m, 1H), 3.70–3.74 (m, 1H), 3.79–3.85 (m, 1H), 3.96
(s, 3H) 6.40 (br s, 1H), 6.86 (s, 1H), 7.5 (s, 1H), 7.67 (d,
1H J=4.2 Hz); EI MS: m/z 246 (M+); 8 (n=3). 1H NMR
(CDCl3): l 2.01–2.17 (m, 2H), 2.27–2.44 (m, 8H), 3.50–
3.86 (m, 6H), 3.92 (s, 6H), 4.24–4.34 (m, 4H), 6.86 (s,
2H), 7.51 (s, 2H), 7.65 (d, 2H, J=4.4 Hz); FAB MS: m/z
533 (M+H).