Fast and effective reduction of nitroarenes by sodium dithionite under PTC conditions: Application in solid-phase synthesis

Article abstract of DOI:10.1016/j.tetlet.2013.03.010

Herein, conditions for the fast and effective reduction of aromatic nitro groups bound to hydrophobic polystyrene-based Wang and Ring resins utilizing sodium dithionite in dichloromethane-water under PTC conditions are reported. Tetrabutylammonium hydrogen sulfate (TBAHS) was found to be an effective phase-transfer catalyst for this reaction. This method allows for the reduction of nitro groups to amino groups under mild conditions with complete conversion and is tolerant of other functional groups. This method is a superior alternative to tin(II) chloride-based reduction, which is known for its shortcomings.

Full text of DOI:10.1016/j.tetlet.2013.03.010

Tetrahedron Letters 54 (2013) 2600–2603
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fast and effective reduction of nitroarenes by sodium dithionite under PTC
conditions: application in solid-phase synthesis
a
a,b,
⇑
ˇ
Robert Kaplánek , Viktor Krchnák
a
´
Department of Organic Chemistry, Faculty of Science, Palacky University, 17. Listopadu 12, 771 46 Olomouc, Czech Republic
b Department of Chemistry and Biochemistry, 251 Nieuwland Science Center, University of Notre Dame, Notre Dame, IN 46556, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, conditions for the fast and effective reduction of aromatic nitro groups bound to hydrophobic
polystyrene-based Wang and Ring resins utilizing sodium dithionite in dichloromethane–water under
PTC conditions are reported. Tetrabutylammonium hydrogen sulfate (TBAHS) was found to be an effec-
tive phase-transfer catalyst for this reaction. This method allows for the reduction of nitro groups to
amino groups under mild conditions with complete conversion and is tolerant of other functional groups.
This method is a superior alternative to tin(II) chloride-based reduction, which is known for its
shortcomings.
Received 8 February 2013
Revised 1 March 2013
Accepted 4 March 2013
Available online 13 March 2013
Keywords:
Solid-phase synthesis
Sodium dithionite
Reduction
Ó 2013 Elsevier Ltd. All rights reserved.
Phase-transfer catalysis
Resin-bound nitroarene
Aromatic amines play a key role in the synthesis of heterocyclic
compounds, particularly in solid-phase synthesis. They are usually
prepared by the reduction of polymer-supported nitro derivatives.
In solution-phase chemistry, many reduction methods are
commonly used; unfortunately, many of these methods are not
applicable to solid-phase chemistry, including methods that in-
volve heterogeneous catalysts or acidic conditions (in the case of
typically used acid-labile linkers). The most common method for
the reduction of solid-phase-bound aromatic nitro groups involves
the use of tin(II) chloride in the presence of a base.1–6 The main dis-
advantages of this method are the formation of insoluble tin salts
that are practically impossible to wash from the resin matrix and
the possible coordination of tin salts to organic substances on the
resin. Tin salts are liberated during the final acidic cleavage step,
resulting in contamination of the product and complicating purifi-
cation. In addition, tin(II) chloride reductions are occasionally very
sluggish and require the use of a 2 M solution of tin(II) chloride in
DMF at an elevated temperature (80 °C) under argon.7
evaporated the solvent, and precipitated the product with ether.
The crude yield was greater than 400%, which indicated substantial
contamination. This material was dissolved in deuterated DMSO,
and the product quantity was estimated using 1H NMR spectros-
copy. The results indicated that the crude product contained less
than 25% of the target compound. Such crude preparations were
typically purified by reverse-phase HPLC. This purification re-
moved any inorganic components from the crude reaction mixture.
However, the tin salts precipitated at the head of the column,
which caused an increase in the column back-pressure and led to
an irreversible deterioration of the column performance. Therefore,
we included a pre-purification step that involved passing a solu-
tion of the crude material through a column that contained a plug
of octadecyl-functionalized silica gel to reduce the risk of damage
to the columns.6
For these reasons, the search for alternative reduction methods
that do not use metal salts is still required. One promising reducing
agent is sodium dithionite (sodium hydrosulfite; sodium hypodi-
sulfite; Na2S2O4).
We have synthesized and purified several hundred heterocyclic
compounds using solid-phase syntheses that involve the reduction
of nitro groups.8–10 In a model synthesis of a benzimidazolinopip-
erazinone,6 we reduced a resin-bound nitroarene with a 1 M solu-
tion of tin(II) chloride in DMF overnight. After we thoroughly
washed the resin beads with DMF, MeOH, and dichloromethane
(DCM), we released the products using 50% TFA in DCM for 1 h,
H
H
N
H
N
i, ii
H2N
N
S
L
S
O
O
NH2
O
O
O
O
NO2
Resin 1
(i) Na2S2O4, K2CO3, solvent, PTC, r.t., 20 h
(ii) 50% TFA/DCM, r.t., 1h
⇑
Corresponding author.
E-mail address: vkrchnak@nd.edu (V. Krchnák).
ˇ
Scheme 1. Optimization of the phase-transfer catalyst and solvent system.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.010

ˇ
R. Kaplánek, V. Krchnák / Tetrahedron Letters 54 (2013) 2600–2603
2601
Fmoc
Only a few examples of the use of sodium dithionite as a reduc-
ing agent for nitro derivatives on a solid support have been re-
ported. In 1996, Hughes11 reported using sodium dithionite in
refluxing ethanol for the reduction of a nitrobenzyl group bound
NH OMe
OH
O
O
OMe
Wang resin
Rink resin
H
to
a phosphinium-type polystyrene resin. Unfortunately, the
OH
author did not provide any experimental details, such as the ratio
of nitro group:Na2S2O4, the conversion, or the yield. In 2000,
Scheuerman and Tumelty12 published an account of the reduction
of nitroarene acids immobilized on hydrophilic polyethylene gly-
col-based resins with an aqueous solution of Na2S2O4/K2CO3.
Hydrophobic polystyrene resins do not swell in water, and the
use of various organic co-solvents was also not successful. Thus,
Rink resin-bound 4-nitrobenzoic acid was reduced using
Na2S2O4/K2CO3 in a 9:1 mixture of DCM and water with an alkyl
viologen (N,N0-dialkyl-4,40-bipyridinium dihalogenide) as a sin-
gle-electron phase-transfer catalyst (SET catalyst, etc.). In 2007,
Zimmermann et al13 reported the reduction of nitroarenes linked
via a triazine spacer to a resin using Na2S2O4/K2CO3 in a DMF–
water (9:1) or THF–MeOH–water (5:1:1) mixture at 40 °C for 2–
5 days without any catalyst, which showed 29–87% conversion.
As previously mentioned, viologens were used as single-
electron phase-transfer catalysts in this work.12,14 We hypothesize
that their catalytic effect is due to their phase-transfer ability.
Thus, we focused on the examination of sodium dithionite as a
mild and selective reducing agent for nitroarenes bound to hydro-
phobic polystyrene resins (Wang and Rink resins) under PTC
conditions.
N
L
L
L
L
Fmoc
v, vi
i
H
N
NH
Fmoc
O
N
N
H
O
O
ii) or iii)
or iv)
ii) or iii)
or iv)
H
N
NO
R
2
NO
R
X
2
X
N
L
N
H
N
O
O
L
O
O
vii
vii
L
H
N
NH
R
2
X
NH
R
2
N
X
L
N
H
N
O
O
viii
viii
To find a suitable phase-transfer catalyst and solvent system,
we first prepared a model nitroarene compound on Rink resin (Re-
sin 1 in Scheme 1). In the initial screening, three commonly utilized
phase-transfer catalysts were tested: tetrabutylammonium hydro-
gen sulfate (TBAHS), hexadecylpyridinium chloride (CPC), and hex-
adecyltrimethylammonium chloride (HTAC) in two solvent
systems: DCM–water (1:1, v/v) and DMF–water (1:1, v/v)
(Scheme 1). These solvent systems were chosen because hydro-
phobic polystyrene resins swell well in both DCM and DMF and be-
cause water is the best solvent for inorganic salts. Common phase-
transfer catalysts are soluble in both water and organic solvents.
The concentration of the phase-transfer catalyst was 10 mol % in
all of the experiments. Our results demonstrated that only TBAHS
NH
R
NH
R
2
2
X
H N
2
X
N
N
H
HN
O
X = none;CO, COCH2,SO2
(i) 1. CDI, Py, r.t., 3 h; 2. Piperazine,DCM, r.t., on; (ii) Ar-F, DIEA, DMSO,
50°C, on; (iii) ArRCOOH,HOBt, DIC, DCM-DMF,r.t., on; (iv) ArSO2Cl,
Lutidine,DCM, r.t., 4 h; (v) Piperidine,DMF, r.t., 30 min; (vi) Fmoc-Ala-OH,
HOBt,DIC, DCM-DMF, r.t., on; (vii) Na2S2O4, K2CO3, TBAHS, H2O-DCM,
r.t., 2 h; (viii) TFA-DCM (1:1), r.t., 1 h
Scheme 2. Synthesis of nitro derivatives bound to Wang resin (left) and Rink resin
(right).
Table 1
Structures of amino derivativesa and yieldsb of reduction by Na2S2O4 under PTC conditions
Entry
Amino derivative
Yield (%)
Entry
Amino derivative
Yield (%)
84
Entry
19
Amino derivative
Yield (%)
70
O
NH2
NH2
O
O
S
S
N
N
N
1
87
10
N
HN
HN
N
HN
HN
HN
HN
NH2
NH2
CF3
O
O
O
NH2
N
2
86
11
79
20
92
N
NH2
Cl
CF3
NH2
NH2
O
O
O
O
S
S
Cl
NH2
O
N
N
N
3
4
75
93
12
13
79
94
21
22
68
64
HN
HN
HN
HN
N
N
HN
HN
NH2
O
O
NH2
O
F
O
NH2
Cl
N
NH2
(continued on next page)

ˇ
R. Kaplánek, V. Krchnák / Tetrahedron Letters 54 (2013) 2600–2603
2602
Table 1 (continued)
Entry
5
Amino derivative
Yield (%)
81
Entry
14
Amino derivative
Yield (%)
Entry
23
Amino derivative
Yield (%)
91
O
NH2
O
Cl
Cl
Cl
Br
NH2
N
N
0
HN
HN
H2N
N
HN
H
O
NH2
NH2
O
NH2
O
O
NH2
H2N
N
N
N
6
7
82
98
15
16
84
66
24
25
84
92
H
O
HN
NH2
O
O
NH2
NH2
NH2
O
O
O
N
N
H2N
N
N
N
HN
HN
HN
HN
NH2
H
O
NH2
O
O
H2N
S
N
H
8
9
87
75
17
18
89
26
92
O
NH2
O
O
NH2
NH2
O
N
0
N
HN
HN
NH2
a
Structure of the amino derivative after acidic cleavage from the resin.
Determined by 1H NMR of the crude product after cleavage from the resin.
b
Figure 1. Optimization of reaction time (NMR of the aromatic moiety after reduction).
was able to catalyze reductions in both solvent systems (reduction
with complete conversion of the nitro group to an amino group as
determined by LC–MS analysis of the reaction mixture after cleav-
age with 50% TFA in DCM). The reduction reaction failed if either
CPC or HTAC was used.
In the next phase of screening, the tolerance for several differ-
ent functional groups and types of spacers between the resin and
nitroarene in the developed reduction conditions, which involved
Na2S2O4/K2CO3/TBAHS in DCM–water, was investigated. Thus, we
prepared a set of nitroarenes linked via piperazine spacers to Wang

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R. Kaplánek, V. Krchnák / Tetrahedron Letters 54 (2013) 2600–2603
2603
resin or via alanine spacers to Rink resin (Scheme 2). We used stan-
dard synthetic procedures, including the nucleophilic substitution
of fluorine in fluoro-nitroarenes, acylation by substituted benzoic
and phenylacetic acids, and reaction with arylsulfonyl chlorides,
to prepare these substrates (Scheme 2). The nitroarenes used as
substrates contained both electron-donating and electron-with-
drawing substituents (Table 1).
renes bound to hydrophobic polystyrene resins. This method al-
lows for the fast reduction of nitro groups to amino groups with
a complete conversion under mild conditions and tolerates other
functional groups and spacers.
Acknowledgements
Reduction with sodium dithionite under phase-transfer cataly-
sis conditions in DCM–water occurred with a complete conversion
of the nitro group to an amino group (Scheme 2). The structures of
the amino products and their yields are summarized in Table 1.
Calculated yields and structures consistent with the LC-MS and
1H NMR data obtained for the final amino derivatives in the unpu-
rified product were determined via 1H NMR15 after acidic cleavage
and were typically 64–98%. In the case of dinitro derivatives (en-
tries 14 and 18 in Table 1), no product was isolated after TFA cleav-
age, probably due to premature cyclative cleavage during
reduction.5 A typical procedure for the reduction is described in
the Notes section.16
This research was supported by the Department of Chemistry
and Biochemistry, University of Notre Dame, by projects P207/
12/0473 from GACR and CZ.1.07/2.3.00/20.0009 from the European
Social Fund.
References and notes
1. Dörwald, F. Z. In Organic Synthesis on Solid Phase: Supports, Linkers, Reactions;
Wiley-VCH Verlag GmbH: Weinheim, 2002; pp 283–284.
ˇ
2. Krchnák, V.; Holladay, M. W. Chem. Rev. 2002, 102, 61.
3. Nefzy, A.; Arutyunyan, S. Tetrahedron Lett. 2010, 51, 4797.
4. Liu, Z.; Ou, L.; Giulianotti, M. A.; Houghten, R. A. Tetrahedron Lett. 2011, 52,
2627.
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5. Neagoie, C.; Krchnák, V. ACS Comb. Sci. 2012, 14, 399.
In the last phase of screening, the reaction time was optimized.
The reduction was stopped after 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and
20 h. The results indicated that the reduction of nitroarenes is fast
for nitroarenes that possess both electron-donating and electron-
withdrawing groups. In Figure 1, the 1H NMR spectra of the aro-
matic region of three differently substituted substrates after reduc-
tion for different times are shown (i.e., after subsequent cleavage
with 50% TFA in DCM for 1 h; the spectra and structure of the cor-
responding nitro compounds are shown at the bottom). These
spectra clearly demonstrate that the reduction is complete within
30 min and that a prolonged reaction time did not result in deteri-
oration of the products.
ˇ
ˇ
6. Cankarová, N.; Krchnák, V. J. Org. Chem. 2012, 77, 5687.
7. Morales, G. A.; Corbett, J. W.; DeGrado, W. F. J. Org. Chem. 1998, 63, 1172.
8. Smith, J.; Krchnák, V. Tetrahedron Lett. 1999, 40, 7633.
9. Krchnák, V.; Smith, J.; Vagner, J. Collect. Czech. Chem. Commun. 2001, 66, 1078.
10. Soural, M.; Bouillon, I.; Krchnák, V. J. Comb. Chem. 2008, 10, 923.
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11. Hughes, I. Tetrahedron Lett. 1996, 37, 7595.
12. Scheuerman, R. A.; Tumelty, D. Tetrahedron Lett. 2000, 41, 6531.
13. Zimmermann, V.; Avemaria, F.; Bräse, S. J. Comb. Chem. 2007, 9, 200.
14. Park, K. K.; Oh, C. H.; Joung, W. K. Tetrahedron Lett. 1993, 34, 7445.
15. Cironi, P.; Alvarez, P.; Albericio, P. Mol. Divers. 2003, 6, 165.
16. Typical procedure for reduction: resin-bound nitroarene (500 mg; loading
ꢀ0.5 mmol/g) was swollen in DCM. Then, a solution of sodium dithionite
(1050 mg, 5 mmol), potassium carbonate (968 mg, 7 mmol), and TBAHS
(170 mg, 0.5 mmol) in water (5 mL) and DCM (5 mL) was added, and the
reaction slurry was shaken at room temperature for 2 h. Then, the resin was
washed three times with each solvent: DCM–water (1:1, v/v), DMF, MeOH and
DCM.
In summary, we have demonstrated that Na2S2O4/K2CO3/TBAHS
in DCM–water is an efficient system for the reduction of nitroa-