Chemoselective reductions of nitroarenes: Bromoethanol-assisted phthalocyanatoiron/NaBH4 reductions

Article abstract of DOI:10.1016/S0040-4039(00)01920-1

Porphyrinatoiron/NaBH₄ and a novel phthalocyanatoiron/NaBH₄ catalyst systems were investigated for the reductions of nitroarenes. The phthalocyanatoiron/NaBH₄ system was superior to the porphyrinatoiron/NaBH₄ system. The reductions were performed in good yields and excellent chemoselectivities. The rate of reduction by the PcFe/NaBH₄ system increased upon the addition of 2-bromoethanol.

Full text of DOI:10.1016/S0040-4039(00)01920-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 167–170
Chemoselective reductions of nitroarenes: bromoethanol-assisted
phthalocyanatoiron/NaBH4 reductions
H. Scott Wilkinson, Gerald J. Tanoury,* Stephen A. Wald and Chris H. Senanayake*
Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, MA 01752, USA
Received 25 August 2000; revised 23 October 2000; accepted 26 October 2000
Abstract—Porphyrinatoiron/NaBH4 and a novel phthalocyanatoiron/NaBH4 catalyst systems were investigated for the reductions
of nitroarenes. The phthalocyanatoiron/NaBH4 system was superior to the porphyrinatoiron/NaBH4 system. The reductions were
performed in good yields and excellent chemoselectivities. The rate of reduction by the PcFe/NaBH4 system increased upon the
addition of 2-bromoethanol. © 2000 Elsevier Science Ltd. All rights reserved.
The use of transition metal complexes to effect the
reduction of a nitroarene to the corresponding aniline is
a well-known process.1 The most common methods
employ a heterogeneous Pd/C or Pt/C catalyst,2 or a
homogeneous ruthenium- or rhodium-based catalyst3
and a hydrogen source (hydrogen gas or transfer hy-
drogenation). Methods also exist for transition-metal-
catalyzed hydride reductions, and one of the most
promising methods employs NaBH4 as the hydride
source. The types of homogeneous catalysts used for
these NaBH4-mediated reductions vary widely from
simple metal chlorides and oxides4 to metallochelate
systems.5 Of the metallochelate systems studied to date,
metalloporphyrins have garnered considerable atten-
tion, mainly due to their applicability to biological
systems. However, metalloporphyrin complexes remain
expensive and are prone to reaction of the porphyrin
ligand. The closely analogous metallophthalocyanine
complexes, however, have not been studied in this
context, are less expensive, possess a more stable ligand,
and provide a novel method for the reduction of ni-
troarenes under metal-catalyzed hydride transfer condi-
tions. With a need to obviate the use of hydrogen gas in
performing the chemoselective reduction of 1 to 2 (Eq.
1), a key step in the total synthesis of (R,R)-formo-
terol, and with an opportunity to develop a new syn-
thethic method for the reduction of nitroarenes, studies
were commenced to develop and extent the application
of the metallochelate reduction methodology. Reported
herein is the discovery of a novel phthalocyana-
toiron(II)/NaBH4 catalytic system for the chemo-
selective reduction of nitroarenes and the use of 2-bro-
moethanol to increase the activity of the catalytic sys-
tem.
(1)
Initially, studies on the reduction of 1 focused on the
use of palladium- and platinum-based heterogeneous
catalysts under hydrogen transfer conditions.6 Using
2–5 mol% of 10% Pd/C or 5% Pt/C catalyst in the
presence of several hydrogen transfer reagents (formic
acid, ammonium formate, cyclohexene, limonene and
terpene) resulted in <13% formation of 2. Pt/C systems
afforded only starting material and Pd/C systems gave
<5% consumption of 1 with formic acid as the transfer
reagent and <13% of 2 with ammonium formate as the
transfer reagent. Due to the poor reactivity of these
systems, and a need to perform the transformation
under hydride transfer conditions, attention was fo-
cused on the application of metallochelate-catalyzed
nitro reductions.
Investigation of the literature indicated that the use of
NaBH4 as the hydride source in the presence of transi-
tion metal complexes were promising conditions for the
development of a new method for the conversion of 1
to 2.7 Initial studies using CoCl2 or Fe(acac)3 with
NaBH4 resulted in a combination of epoxide formation
(3), debromination (4), and/or nitroreduction (5). Com-
pound 2 was not observed. We then turned our atten-
tion to the use of metalloporphyrins to catalyze the
* Corresponding authors.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01920-1

168
H. S. Wilkinson et al. / Tetrahedron Letters 42 (2001) 167–170
Table 1. Comparison of reduction of 1 with (TPP)FeCl and PcFe(II)/(III) catalyst systemsa
Entry
Catalyst (mol%)
NaBH4 (equiv.)
Time (h)
1 (%)
2 (%)
5 (%)
1
2
3
4
5
(TPP)FeCl (0.4)
(TPP)FeCl (0.4)
(TPP)FeCl (1.5)
PcFe(II) (2.0)
1.0
2.0
1.5
2.0
2.0
4
4
1
2
2
54
3
0
1
1
29
37
36
57
58
13
13
20
29
31
PcFe(III)Cl (2.0)
a Reactions were conducted in diglyme as solvent at room temperature. Ratios were determined by HPLC analysis.
reduction of nitroarenes to anilines.8 The reports indi-
cated that tetraphenylporphyrinatoiron(III) chloride
((TPP)FeCl) reduced nitroaromatics to the correspond-
ing anilines in high yield in the presence of NaBH4
using diglyme as solvent. This system was extended to
the reduction of 1, as shown in Table 1.9 With diglyme
as solvent, the product ratios (1:2:5) were found to be a
function of the number of equivalents of NaBH4 and
the catalyst loading. At 0.4 mol% (TPP)FeCl, the extent
of reaction after 4 h at room temperature rose from
46% conversion with 1.0 equiv. of NaBH4 to 97%
conversion with 2.0 equiv. of NaBH4 (entries 1 and 2).
In both cases, the product mixture contained no de-
brominated by-products, but 13% of 5 and only 29–
37% of 2 were observed. Raising the catalyst loading to
1.5 mol% resulted in complete consumption of 1 after 1
h at room temperature with 1.5 equiv. of NaBH4
present (entry 3). Although the amount of 2 in the
product mixture was 36%, and no debromination was
observed, 5 was present at a level of 20%. The related
phthalocyanatoiron complexes were evaluated as poten-
tial catalysts to effect the conversion of 1 to 2. To our
knowledge, these complexes have never been used to
catalyze the reduction of nitroarenes. Also, the phthalo-
cyanine systems are more practical than the porphyrin
complexes due to their lower cost and greater availabil-
ity. In the presence of 2 mol% of PcFe(II) or
PcFe(III)Cl, 1 was converted to 2 and 5 in 57 and 28%
yields, respectively. Even though mixtures of 2 and 5
were obtained, the reaction was cleaner than the TPP
systems, and both Fe(II) and Fe(III) performed the
reduction with identical results, indicating the active
catalyst was a Fe(II) species.10 The reactions were suc-
cessful with 1.8 equiv. of NaBH4 in diglyme at room
temperature in 2 h. Due to the consistently superior
reactivity and selectivity of the PcFe(II)/(III) system,
our attention focused on the development of this
catalyst.
99% consumed after 2 h at room temperature with 2
mol% catalyst (Table 2, entries 4 and 5). The slow rate
of reduction of rac-4 compared to 1, and the concomi-
tant formation of epoxide 5 during the rapid reduction
of 1 indicated that the generation of HBr during the
formation of 5 could account for the faster rate of
reduction of 1.
(2)
To determine the effect of HBr on the nitroarene
reduction with PcFe(II), rac-4 was reduced in the pres-
ence of various amounts of HBr, or HBr equivalents,
and the data are shown in Table 2. In the presence of
2.5 mol% PcFe(II), and no HBr, 77% of rac-4 remained
after 2 h at room temperature (entry 1). With the
addition of 5 and 10 mol% HBr, 46 and 62% of rac-4
remained after 1 h of reaction (entries 2 and 3). At a
level of 40 mol% HBr, the rate of reaction increased
dramatically, and only 2% of rac-4 remained after 1 h
(entry 4). This corresponded to a 16:1 ratio of
HBr:PcFe(II). Nearly identical results were obtained
with 100 mol% HBr (entry 5). Due to the safety issues
associated with handling large quantities of HBr, a
Table 2. Reduction of rac-4 with PcFe(II) as catalyst with
various amounts of HBra
Entry
Acid additive
(mol%)
Time (h)
Rac-4 (%)
6 (%)
1
2
3
4
5
6
HBr (0)
HBr (5)
2
1
1
1
1
2
77
62
46
2
3
0
23
35
46
85
86
87
HBr (10)
HBr (40)
HBr (100)
2-Bromoethanol
(100)
The new catalytic system was investigated in greater
detail by studying the conversion of rac-4 to 6 (Eq. (2)).
Unexpectedly, the rate of reduction of rac-4 was less
than one-tenth the rate of reduction of 1: after 2 h at
room temperature only 10% of rac-4 was consumed
and converted to 6, while 1 was converted to 2 and was
a Reactions were conducted in diglyme at 2.5 mol% PcFe(II) and 1.8
equiv. of NaBH4 at room temperature. Ratios were determined by
HPLC analysis.

H. S. Wilkinson et al. / Tetrahedron Letters 42 (2001) 167–170
169
Table 3. Reduction of nitroarenes with PcFe(II)/NaBH4/2-bromoethanol systema
more easily manipulated and readily available HBr
equivalent was investigated: 2-bromoethanol. As shown
in entry 6, 100 mol% of 2-bromoethanol afforded a
rapid reduction of 6 in high yield: 87% after 2 h at
room temperature.11 Extending these new reaction con-
ditions to the TPPFeCl system resulted in consumption
of rac-4 but with <50% of 6 present. Also, no rate
acceleration was observed for the (TPP)FeCl system
upon addition of 2-bromoethanol or HBr. Again, the
PcFe(II)/NaBH4/2-bromoethanol catalyst system was
superior to the corresponding (TPP)FeCl system.
and practical catalytic system for the reduction of ni-
troarenes. The presence of HBr, generated in a con-
trolled manner from 2-bromoethanol, has been shown
to be crucial for a rapid and chemoselective reduction.
The reductions can be conducted in the presence of
other labile functionality, and the PcFe(II) complex (or
PcFe(III)Cl) is a readily available and inexpensive cata-
lyst. The ability of the PcFe(II) complex to catalyze the
reduction, while the corresponding (TPP)FeCl system
was troublesome, remains unclear. This new catalyst/
reagent combination will prove to be valuable in the
arsenal of the synthetic chemist. Further studies are
underway to better understand the differences between
the porphyrin and phthalocyanine systems, and the
cause of the rate increase upon addition of HBr or an
HBr equivalent.
To determine the generality of the 2-bromoethanol-me-
diated reduction of rac-4 with PcFe(II) and NaBH4, the
scope and utility of the reaction was studied on numer-
ous substrates.12 From the data shown in Table 3, an
electron-withdrawing ester group attached to the aryl
ring underwent reduction ten times slower than the
parent nitrobenzene (entries 1 and 2). For iodobenzene,
the carbonꢀiodine bond, highly reactive under Pd/C
and Pt/C hydrogenation conditions, was stable to the
reaction conditions (entry 3),13 as were nitriles and
benzyl-protected anilines (entries 4 and 5). The result
shown in entry 6 demonstrated that CBZ protecting
group, removed under standard Pd/C-catalyzed hydro-
genation conditions, remained intact during reduction
of the nitro group using the PcFe(II)/NaBH4/2-bro-
moethanol conditions. The stability of a CBZ-protected
amine to the reaction conditions should allow for these
reduction conditions to be applied to solid phase syn-
thesis. Enantiopure 1 was subjected to the optimized
reaction conditions (entry 7) and was found to convert
rapidly to 2 in 67% isolated yield without loss of
enantiomeric purity.
Acknowledgements
We thank Professor Peter Wipf for helpful discussions.
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170
H. S. Wilkinson et al. / Tetrahedron Letters 42 (2001) 167–170
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1
desired product (130 mg, 98% yield) as a yellow oil. H
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NMR (300 MHz, CDCl3): l 3.75 (s, 2H), 4.83 (s, 2H),
6.73 (d, 2H), 7.07 (d, 2H). 13C NMR (75 MHz, CDCl3):
l 22.81, 116.80, 120.46, 120.80, 129.90, 148.71.
9. Ru(TPP) and Ni(TPP) catalysts were also used. With
both catalysts, under an atmosphere of Ar or air, and
13. No products corresponding to dehalogenation of the
haloarenes were observed by HPLC and NMR analysis.
.