Iron-catalysed, general and operationally simple formal hydrogenation using Fe(OTf)3 and NaBH4

Article abstract of DOI:10.1039/c4ob00945b

An operationally simple and environmentally benign formal hydrogenation protocol has been developed using highly abundant iron(iii) salts and an inexpensive, bench stable, stoichiometric reductant, NaBH₄, in ethanol, under ambient conditions. This reaction has been applied to the reduction of terminal alkenes (22 examples, up to 95% yield) and nitro-groups (26 examples, up to 95% yield). Deuterium labelling studies indicate that this reaction proceeds via an ionic rather than radical mechanism.

Full text of DOI:10.1039/c4ob00945b

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Iron-catalysed, general and operationally simple
formal hydrogenation using Fe(OTf)3 and NaBH4†‡
Cite this: Org. Biomol. Chem., 2014,
12, 5082
Alistair J. MacNair,a Ming-Ming Tran,a Jennifer E. Nelson,a G. Usherwood Sloan,a
Received 7th May 2014,
Accepted 23rd May 2014
Alan Ironmongerb and Stephen P. Thomas*a
DOI: 10.1039/c4ob00945b
www.rsc.org/obc
An operationally simple and environmentally benign formal hydro- and highly active homogeneous iron complexes for catalytic
genation protocol has been developed using highly abundant iron hydrogenation have been developed,7 notably by Chirik,8 these
(III) salts and an inexpensive, bench stable, stoichiometric reduc- catalysts and pre-catalysts are highly air- and moisture-sensi-
tant, NaBH4, in ethanol, under ambient conditions. This reac- tive, so have not seen widespread adoption. On a small scale,
tion has been applied to the reduction of terminal alkenes the use of hydrogen gas has numerous drawbacks, particularly
(22 examples, up to 95% yield) and nitro-groups (26 examples, up with safe storage and handling. These can be circumvented by
to 95% yield). Deuterium labelling studies indicate that this the use of an inexpensive, bench-stable, solid hydrogen source.
reaction proceeds via an ionic rather than radical mechanism.
NaBH4 is air- and moisture stable and produced on kilotonne
scale annually.9
Ashby used LiAlH4 in conjunction with stoichiometric
amounts of transition metal halides, including FeCl3 and
FeCl2, to reduce 1-octene.10 Kano reported a biomimetic
reduction of styrene derivatives using an iron-porphinato
complex and NaBH4 however reductive homocoupling of
radical species was a major side-reaction.11 Recently, Boger
reported the hydrofunctionalisation of alkenes mediated by
superstoichiometric iron(III) salts and NaBH4.12 In the absence
of an electrophile, it was found that tertiary alkenes were
hydrogenated (Scheme 1).12a
Introduction
The hydrogenation of apolar and polar functionalities is routine
in both academia and industry for the production of fine and
bulk chemicals.1 Highly operationally simple hydrogenation
methods using heterogeneous (e.g. Pd/C–H2) or homogeneous
(e.g. Ru/NEt3–HCO2H) systems have allowed the broadest poss-
ible user base to exploit this reaction.2 To date, the most com-
monly used methods require precious or semi-precious
transition metal complexes or finely divided powders.1
Iron-based catalysts offer several advantages over more
traditional ‘noble’ metal systems due to the high abundance,
long-term availability,3 low cost and low toxicity of iron.4 On
an industrial scale, heterogeneous iron catalysts have been
widely exploited; however the use of soluble iron catalysts is
considerably less well developed.5
Iron-catalysed alkene reductions have been reported
however many systems suffer from the need for: elevated temp-
eratures; high hydrogen pressure; chemical activation or are
superstoichiometric in iron.6 Although several well defined
aSchool of Chemistry, University of Edinburgh, Joseph Black Building, West Mains
Road, Edinburgh EH9 3JJ, UK. E-mail: stephen.thomas@ed.ac.uk;
Fax: +44 (0)131 650 6453
bResearch and Development, GlaxoSmithKline, Gunnelswood Road, Stevenage SG1
2NY, UK
†We dedicated this paper to Dr Stuart Warren on the occasion of his 75th
birthday.
Scheme 1 Iron-catalysed reductions and reductive functionalisations.
TTP = tetraphenylporphyrinato. [Fe] = iron phenanthroline complex
pyrolysed onto a carbon support.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00945b
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Along with alkene hydrogenation, the reduction of nitro-
arenes to aniline derivatives represent another high-value indus-
trial process for the preparation of a wide range of synthetic pre-
cursors, including; dyes, pharmaceuticals, agrochemicals and
polymers.13 Iron-catalysed hydrogenation of nitroarenes is well
established using iron(0) carbonyl precursors acting via a cohort
of in situ generated iron species.14 Beller has developed a number
of homogeneous iron-catalysed nitroarene reductions15 and
Scheme 2 Formation of halogenated side products, X = Cl/Br.
recently carbon-supported heterogeneous systems using either FeBr3 were used, (3-chlorobutyl)benzene 4a and (3-bromo-
N2H4·6H2O or H2 as the stoichiometric reductant (Scheme 1).16
butyl)benzene 4b were obtained as side-products respectively.
NaBH4 is a poor reducing agent for nitro-groups under This was presumably as a result of radical formation, followed
ambient conditions, although it has been used in the presence by halide abstraction from the iron salt (Scheme 2).20
of palladium, nickel, copper catalysts for the reduction of
Use of Fe(OTf)3 prevented the halogenation reaction and in
nitro-groups to amines.17 Additionally, Sakaki and co-workers addition, it was found that Fe(OTf)3 gave the shortest reaction
have reported the use of NaBH4 and porphyrinatoiron com- times.21 At a 10 mol% iron loading, the quantity of NaBH4
plexes for the reduction of a limited number of nitroarenes.18
could be lowered to 1.5 equivalents and the reaction time
Herein we report an iron-catalysed, NaBH4-mediated reduced to 6 hours, without decreasing reaction yield (entry 8),
reduction procedure that is capable of reducing both alkene however in all cases, it was found the some isomerisation to
and nitroarene functionalities.
the internal alkene 3 was observed. An attempt to reduce the
catalyst loading to 1 mol% gave considerably diminished
yields, even after 48 h (entry 9).
The catalytic activity of iron was attested to by high purity
FeCl3 (>99.99%) showing equal catalytic activity (entry 6) to the
reagent grade salts.22 Additionally in the absence of iron, no
reduction of the alkene was observed: triflic acid and sodium
triflate (entries 11 and 12) were not catalytically active; only the
starting material 1a was recovered.
Presumably due to the high solubility of NaBH4 in these sol-
vents, successful reduction reactions were achieved in methanol,
1-butanol, 2-butanol and acetonitrile, however the highest yields
were obtained in ethanol.19 Along with the sustainability and
low toxicity of ethanol, makes it the favoured reaction solvent.
With the optimal conditions of Fe(OTf)3 (10 mol%), NaBH4
(150 mol%) in ethanol, the substrate scope of the formal
hydrogenation was investigated. The developed system was
found to be chemoselective for the reduction of terminal
alkenes (Table 2). Reductions in the presence of aryl halides
showed no protodehalogenation23 except in the case of aryl
bromide 1d where 18% of the protodehalogenated product
was observed (Table 2, entries 2–4).
Results and discussion
Alkene reduction was first investigated and successful ‘hydro-
genation’ of 4-phenyl-1-butene 1a, to the alkane 2a, was found
using stoichiometric (Table 1, entries 1–4) and substoichio-
metric (entries 5–10) amounts of simple, commercially avail-
able, iron salts in the presence of NaBH4.19
Iron(III) chloride, bromide and triflate supported the
reduction (entries 1–4); however when stoichiometric FeCl3 or
Table 1 Initial screen of activity of iron salts for the reduction of
4-phenyl-1-butenea
Yieldb (%)
Despite previous reports of the reduction of esters and
amides with NaBH4 in MeOH,24 chemoselective alkene
reduction was observed for substrates being both ester and
amide functionalities (entries 6–8). Although a carboxylic acid
functionalised substrate was poorly tolerated (entry 5),
reduction of 4-phenyl-1-butene 1a in the presence of acetic
acid, using excess NaBH4, was successful. Despite the lability
of benzyl protecting groups under conventional hydrogenation
conditions, both benzyl and silyl ethers were conserved during
alkene reduction (entries 9 and 10).
Although the reduction was carried out in ethanol,
inclusion of an alcohol or ketone in the alkene substrate
diminished reduction yields (entries 12 and 13). Styrene
derivatives were successfully reduced; however longer reaction
times and higher quantities of NaBH4 were required and yields
were generally lower than the alkyl analogues (entries 14–17).
FeX2/3
(mol%)
Equiv.
NaBH4
Entry
FeX2/3
2a
3
1
2
3
4
5
6
7
8
FeCl3
FeBr3
100
100
100
100
10
10
10
10
1
10
10
2
2
1
2
2
2
2
1.5
2
15
42
19
91
91
89
90
90
47
11
6
2
1
3
9
5
6
10
10
7
Fe(OTf)3
Fe(OTf)3
FeCl3 c
FeCl3
Fe(OTf)3 d
Fe(OTf)3 e
Fe(OTf)3
Fe(OTf)2
HOTf
9
10
11
12
2
2
2
0
0f
NaOTf
10
4
0g
a Conditions: 0.50 mmol 4-phenyl-1-butene, n mol% iron(III) salt,
n equiv. NaBH4, EtOH (2 ml), r.t., 16 h. b Yield measured by 1H NMR of
the crude reaction product using 1,3,5-trimethoxybenzene as internal
standard. c >99.99% purity. d 6 h. e 48 h. f 75% starting material
recovered. g 80% starting material recovered.
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Table 2 Scope and limitation of the iron-catalysed, hydride-mediated reductiona
Entry
1
Substrate
Product
Yieldb (%)
90 (83)
2
3
4
R = F (1b)
R = Cl (1c)
R = Br (1d)
2b
2c
2d
92 (79)
93 (77)
78 (71)c
5
6
7
R = OH (1e)
2e
2f
2g
25
95 (94)
73
R = OMe (1f)
R = NHtBu (1g)
8
2h
92 (87)
50 (50)
9
10
56
11
12
>95 (69)
22
13
10
14
15
16
17
R = 4-Cl (1n)
R = 4-tBu (1o)
R = 4-OMe (1p)
R = 3-CF3 (1q)
2n
2o
2p
2q
58d
55 (45)d
56 (46)d
50d
18
>95 (73)
19
75
20
21
3
0
22
7, 34e
a Conditions: 1 mmol alkene, 10 mol% Fe(OTf)3, EtOH (4 ml), 1.5 equiv. NaBH4, r.t., 6 h. b Determined by 1H NMR using 1,3,5-trimethoxybenzene as
internal standard. Isolated yield in parentheses. c 18% phenylbutane 2a also recovered. d Conditions: 1 mmol alkene, 10 mol% Fe(OTf)3, EtOH (4 ml),
2 equiv. NaBH4, r.t., 18 h. e 20 equiv. NaBH4.
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In contrast to the work of de Vries using iron nanoparticles,25
Using these conditions, substrate scope was investigated.
acrylate and acrylamide derivatives were chemoselectively o-, m-, p-Methyl nitrobenzene, and even the sterically hindered
reduced at the alkene (entries 18 and 19). The reaction was 2,6-dimethyl nitrobenzene were all successfully reduced
highly selective for the reduction of unsubstituted terminal (Table 4, entries 2–5). Nitroarenes bearing electron-withdraw-
alkenes; only trace reduction of β-methyl styrene 1t was ing (–CF3) and electron-donating (–OMe) substituents were
observed and neither the internal nor 1,1-disubstituted both tolerated (entries 6–10). Nitro-groups were successfully
alkenes of (+)-limonene 1u underwent reduction (entries 20 reduced in the presence of aryl-chloride and fluoride sub-
and 21).26 Attempts to extend the reaction scope to the term- stituents without protodehalogenation (entries 11–14),
inal alkyne; 5-phenyl-butyne 1v, resulted in a poor yield of however, 4-bromo-nitrobenzene 5o was reduced to both 4-bro-
alkane, even with excess NaBH4 (entry 22). The reduction of 4- moaniline and to the proto-dehalogenated product aniline
phenyl-1-butene in the presence of 10 mol% diphenylacetylene (entry 15).
resulted in a reduced yield of phenylbutane (15%) and no evi-
dence of reduction of the diphenylacetylene.
Chemoselective nitro-group reduction was observed in the
presence of ester and amide functionalities (entries 17–19).
During the development of the alkene ‘hydrogenation’, the The synthesis of the analgesic benzocaine 6r from the corres-
reduction of the nitro-group of 3-nitrostyrene was observed to ponding nitroarene showcases the utility of this methodology.
occur competitively with the reduction of the alkene. Using Perhaps unsurprisingly, a substrate bearing a ketone 5p
nitrobenzene as a model substrate, simple iron salts were showed poor chemoselectivity with the carbonyl being reduced
investigated for catalytic activity in the reduction of the nitro- in addition to the nitro-group (entry 16).
group to primary amines. FeCl3 offers an inexpensive and
p-(Methylthio)-aniline 5t was successfully produced from
readily available iron(III) source and good reactivity was found the corresponding nitroarene in good yield (entry 20). The
with increased NaBH4 loading (Table 3, entries 1–3). The use corresponding methylsulfonyl substituted nitroarene 5u was
of high-purity FeCl3 (≥99.99%) again did not change the also successfully reduced, albeit with lower isolated yield
observed reactivity, (entry 4). However, returning to Fe(OTf)3 (entry 21). 8-Nitroquinoline 5w was successfully reduced to
gave higher conversions to aniline (entry 6), and allowed reac- 8-aminoquinoline (entry 23). Interestingly, treatment of nitro-
tion times to be reduced to 4 h.
substituted benzoxazole 5x and benzothiazole 5y derivatives
Even using the apparently more active salt, Fe(OTf)3, it was with NaBH4 in the absence of an iron salt exclusively gave the
found that the quantity of NaBH4 could not be reduced reductively ring-opened product. However, in the presence of
without diminishing conversion to the product. In the absence Fe(OTf)3, only the chemoselective reduction of the nitro-group
of an iron salt, no reduction of nitrobenzene to aniline was was observed (entries 24 and 25). Aliphatic nitro-groups were
observed, irrespective of the amount of NaBH4 used. Lewis also reduced by the Fe(OTf)3/NaBH4 system (entry 26), however
acids; BF3 and AlCl3, were ineffective as catalysts (entries 10 increased loadings of both the catalyst and stoichiometric
and 11) and the use of triflic acid (entry 12) also resulted in reductant were required.
only starting material being recovered.
Two contrasting mechanisms have been proposed for pre-
viously reported iron-catalysed, NaBH4-mediated, alkene
reductions. We sought to gain insight into which of the follow-
ing mechanisms is operating in our developed reaction con-
ditions. Kano proposed the addition of an iron-hydride to the
alkene, followed by proton abstraction from ethanol.11a In con-
trast, Boger proposed that both hydrogen atoms originated
from sodium borohydride.12a Additionally, NaBH4 has been
shown to reduce iron(II/III) salts to a range of nanoparticulate
or low oxidation-state iron and iron/boron species.25,27
While the formation of nanoparticles cannot be ruled out, the
lack of stabilisers or an induction period would appear to
suggest against these being the active catalytic species. In
order to investigate the origin of the added hydrogen, and gain
insight into the mode of operation of the low-valent catalyst, a
series of deuterium incorporation experiments were carried
out.
Reduction of 4-phenyl-1-butene 1a using NaBD4 and
d1-ethanol gave exclusively the dideuterated alkane d2-2a
(Scheme 3a). In line with previous reports of deuterium
exchange between NaBD4 and alcoholic solvents,28 performing
the reduction with NaBD4 and ethanol gave a mixture of deut-
erated and non-deuterated alkanes (Scheme 3b). In both cases
deuterium was incorporated in both C3 and C4 positions of
Table 3 Optimisation of nitroarene reductiona
Entry
FeX2/3
NaBH4 equiv.
t (h)
Conversionb (%)
1
2
FeCl3
FeCl3
2
4
18
18
18
18
18
18
18
18
4
15
51
88
90
62
60
99
32
99
0d
0e
3
4
5
6
7
8
9
10
11
12
FeCl3 c
20
20
20
20
20
10
20
20
20
20
FeCl3
FeCl2
Fe(OTf)2
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
BF3·Et2O
AlCl3
4
4
4
HOTf
1 f
a Conditions: 0.5 mmol 4-phenyl-1-butene, 10 mol% iron salt, NaBH4,
ethanol (4 ml), r.t. b Conversion measured by 1H NMR. c >99.99%
purity. d 57% starting material recovered. e 31% starting material
recovered. f 78% starting material recovered.
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Table 4 Scope and limitation of the iron-catalysed, hydride-mediated reductiona
Entry
1
Substrate
Product
Yieldb (%)
90 (80)c
Entry
14
Substrate
Product
Yieldb (%)
80 (47)
2
3
80d (80)
61d (49)
15
16
51 (51)e
68 (15)
4
5
6
73 (66)
79 (59)c
76d (75)
17
18
19
87 (80)
93 (28)
80 (32)
7
81 (68)c
68 (24)
82d (55)
83 (76)c
20
21
22
23
>95 (76)
(53)
8
9
82 (77)c
54 (51)
10
11
73d
24
33 (24)
12
13
87d
25
26
60 (56)
20f
70d (17)
a Conditions: 0.5 mmol nitroarene, 10 mol% FeOTf3, EtOH (4 ml), 20 equiv. NaBH4, r.t., 4 h. b Yield determined by 1H NMR using
1,3,5-trimethoxybenzene as internal standard. Isolated yield in parentheses. c Isolated as the HCl salt. d 1,2-Dichloroethane used as internal
standard. e 9% aniline also recovered. f Conditions: 50 mol% FeOTf3, 30 equiv. NaBH4.
the alkane. In order to probe the existence of a radial inter-
mediate, d5-EtOH was used as the reaction solvent to probe
Conclusions
radical abstraction from the CD2OH position, however, no deu- In conclusion, a single, general, operationally simple and
terium incorporation was observed (Scheme 3c). This suggests highly applicable protocol for the formal hydrogenation of
an ionic, rather than radical mechanism.
apolar (alkene) and polar (nitro-) functionalities has been deve-
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Scheme 3 Deuterium labelling studies for the investigation of the
mechanism of iron-catalysed, NaBH4 mediated, alkene reduction.
loped using a simple iron salt as catalyst. Using Fe(OTf)3
(10 mol%) and NaBH4 as the stoichiometric reductant, a wide
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Acknowledgements
AJM thanks GlaxoSmithKline and the University of Edinburgh
for the provision of a studentship. JEN thanks the Wellcome
Trust, Nuffield Foundation and RSC for summer scholarships.
SPT thanks the University of Edinburgh and GlaxoSmithKline
for continued support. Additionally, we would like to thank
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