Iron-catalyzed protodehalogenation of alkyl and aryl halides using hydrosilanes

Article abstract of DOI:10.1039/c8ob02365d

A simple and efficient iron-catalyzed protodehalogenation of alkyl and aryl halides using phenylhydrosilane is disclosed. The reaction utilizes FeCl₃ without the requirement of ligands. Unactivated alkyl and aryl halides were successfully reduced in good yields; sterically hindered tertiary halides were also reduced including the less reactive chlorides. The scalability of this methodology was demonstrated by a gram-scale synthesis with a catalyst loading as low as 0.5 mol%. Notably, disproportionation of phenylsilane leads to diphenylsilane that further reduces the halides. Preliminary mechanistic studies revealed a non-radical pathway and the source of hydrogen is PhSiH₃via deuterium labeling studies. Our methodology represents simplicity and provides a good alternative to typical tin, aluminum and boron hydride reagents.

Full text of DOI:10.1039/c8ob02365d

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Iron-catalyzed protodehalogenation of alkyl and
aryl halides using hydrosilanes†
Cite this: DOI: 10.1039/c8ob02365d
Ramadevi Pilli, Venkadesh Balakrishnan, Revathi Chandrasekaran and
Received 23rd September 2018,
Accepted 1st November 2018
Ramesh Rasappan
*
DOI: 10.1039/c8ob02365d
rsc.li/obc
A simple and efficient iron-catalyzed protodehalogenation of alkyl generated from NaBH4/InCl3 efficiently reduces alkyl iodides
and aryl halides using phenylhydrosilane is disclosed. The reaction and bromides via a radical intermediate; however the chloride
utilizes FeCl3 without the requirement of ligands. Unactivated alkyl was ineffective.6 Recently, Fensterbank, Ollivier, Jutand et al.
and aryl halides were successfully reduced in good yields; sterically have reported the reductive cyclization of alkyl halides at elev-
hindered tertiary halides were also reduced including the less reac- ated temperature that proceeds via a radical intermediate
tive chlorides. The scalability of this methodology was demon- (10 mol% of FeCl2 and NaBH4) (Scheme 1b).7,10,11 The above-
strated by a gram-scale synthesis with a catalyst loading as low as mentioned methods are expected to undergo metal–halogen
0.5 mol%. Notably, disproportionation of phenylsilane leads to exchange followed by
a reductive protodehalogenation.
diphenylsilane that further reduces the halides. Preliminary Though the majority of these reactions are reported to proceed
mechanistic studies revealed a non-radical pathway and the source through a radical intermediate, Brookhart et al. reported a cat-
of hydrogen is PhSiH3 via deuterium labeling studies. Our method- ionic Ir(III)hydride–phosphine complex that does not follow a
ology represents simplicity and provides a good alternative to radical pathway and it can reduce a broad range of alkyl
typical tin, aluminum and boron hydride reagents.
halides including chlorides (Scheme 1a).8 Other transition
metal complexes including palladium,12,13 ruthenium,3,14
and iron/Grignard11 are reported to be effective for
protodehalogenation.
Introduction
In our ongoing studies, in the field of iron mediated cross-
coupling reactions, we found that 1-(3-bromobutyl)-4-methoxy-
Protodehalogenation is being utilized in various fields includ-
ing organic synthesis, biochemistry and environmental protec-
tion.1 In organic synthesis, bromo-cyclization followed by pro-
todehalogenation to cyclic molecules2 and the reduction of
carbonyl compounds to an alkane via alkyl halides are routi-
nely utilized.3 A most common method for protodehalogena-
tion is the tributyltin hydride mediated free radical transform-
ations. However, the toxic nature of tin reagents makes them
less attractive in the pharmaceutical industries due to the fact
that they are hard to be removed from the desired product.
There have been numerous efforts to circumvent the issue
including the immobilization of tin reagents,4 the use of
photocatalysis (limited to iodides and activated halides),5 and
metal hydrides.6–9
The robustness of metal hydrides attracted several research
groups. Baba et al. reported that indium hydride (10 mol%)
School of Chemistry, Indian Institute of Science Education and Research, Vithura,
Thiruvananthapuram, Kerala 695551, India. E-mail: rr@iisertvm.ac.in
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02365d
Scheme 1 Catalytic reduction of organic halides.
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benzene 1a was efficiently reduced (protodehalogenated) to and 6). The inorganic bases and sodium methoxide offered a
alkane. In this context, we became interested in exploring the quantitative yield (99%, entry 1) in 5 h whereas phosphate, car-
iron mediated protodehalogenation since it is economical, bonate (see the ESI†), fluorides (entry 11) and an organic base
environmentally benign, and naturally abundant,15 and the (entry 13) were poor yielding. While NaOMe as a base offered a
use of iron catalysis in the reduction of alkyl halides is very quantitative yield, KOMe gave traces of the product (entry 12).
limited. Moreover, hydrosilanes are not much explored in iron Hydrosilanes other than PhSiH3 were ineffective (entries 3 and
catalysis. Hydrosilanes, being less toxic, can be an attractive 4). Having an excess of PhSiH3 and NaOMe (3 eq.) was useful
alternative to tin-hydrides; however the activation towards the in driving the reaction to completion in a shorter time,
reduction of halides is challenging, In(OAc)3/PhSiH3 in combi- although stoichiometric reagents proved to be sufficient to
nation with Et3B and oxygen is reported to reduce the alkyl obtain a similar yield provided that the reaction was allowed to
halides that proceed through a radical intermediate.18 AlCl3,16 run for a longer time (10 h, Scheme 2, 1d). While THF offered
PdCl2,17 and Ir(III)phosphine complexes8 have also been used a quantitative yield, the reaction was sluggish in Et2O (see the
in the formation of metal-hydrides that subsequently reduce ESI†) and CH3CN gave only 31% of 2a along with the elimi-
alkyl halides.
nated product 2b in 15 h (entry 17).
Herein, we report a simple FeCl3/PhSiH3 system that does
With the optimized reaction conditions in hand, we
not require additional ligands but is highly efficient to reduce explored the scope of the substrates. As expected, the second-
alkyl as well as aryl halides at room temperature in a shorter ary alkyl iodide 1c took only 30 minutes for the complete con-
time with moderate to excellent yields; even the unreactive
chlorides, sterically crowded tertiary halides, were also
reduced seamlessly (Scheme 1c). Studies began with the focus
of improving the yield of the reduced product that we observed
in iron mediated coupling reactions (see the ESI† for more
details). The major challenge was to avoid the formation of 2b
that is inseparable from the product and also to find a suitable
hydrogen donor to improve the yield of 2a.
We found that PhSiH3 was very effective and observed no
detectable amount of the eliminated product. FeCl3 proved to
be a better catalyst over FeCl2 and Fe(acac)3 (Table 1, entries 5
Table 1 Optimization of the reaction conditions
Deviation from the standard
conditions
Time
(h)
Yield 2aa
(%)
Entry
1
None
5
99 (92)
ND
ND
5
59
62
82
53
83 (78)
12
<5
<5
ND
7
ND
ND
31
2
tBuOH instead of PhSiH3
Me2PhSiH or Et3SiH
Ph3SiH
32
15
15
15
15
32
32
15
5
32
15
12
4
3b
4
5
6
10 mol% FeCl2
10 mol% Fe(acac)3
1.8 eq. NaOtBu
1.8 eq. KOtBu
2 eq. PhSiH3
0.3 eq. NaOMe
1.8 eq. CsF
1.8 eq. KOMe
Lutidine
Without FeCl3
Without NaOMe
Without PhSiH3
CH3CN
7c,d
8b,c,d
9
10e
11d
12d,e
13
14
15
16
17b
12
12
15
Scheme 2 Substrate scope. Reaction conditions: 0.36 mmol of halide,
2 mL of THF, 5 mol% FeCl3, 1.08 mmol of PhSiH3 and NaOMe, the yields
are isolated; a2.04 mmol of 1a, 1 mol% FeCl3, 15 h; b75 °C; c1.9 mmol of
1e; dGC yield; e1.9 mmol of 1f, 1 mol% FeCl3, 1.5 eq. PhSiH3 and 1.7 eq.
NaOMe, 19 h; f6.04 mmol of 1 h, 0.5 mol% of FeCl3; g100 °C; h0 °C;
General reaction conditions: 0.36 mmol of 1a, 2 mL of THF, 5 mol%
FeCl3, 1.08 mmol of PhSiH3 and NaOMe. a Determined by GC analysis
using dodecane as an internal standard, values in parentheses are the
isolated yields. b Elimination to 2b was observed. c 1.5 eq. of PhSiH3.
d Instead of NaOMe (3 eq.). e 10 mol% of FeCl3. ND: not detectable.
j
i60 °C; carbonyl group also got reduced to alcohol; k10 mol% FeCl3, 6
eq. of PhSiH3 and NaOMe.
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version with 92% isolated yield (Scheme 2); the corresponding this can be attributed to the formation of a silyl-coupled side
bromide 1a offered a similar yield in 5 h, and chloride 1b took product. When 5-bromo-N,N-dimethylpyridin-2-amine 6 was
overnight for the complete conversion with 63% isolated yield. subjected to the optimized reaction conditions, we observed
While the primary alkyl bromides 1d, 1h and 1j were also the formation of silane coupled product 7 in 24% isolated
reduced efficiently at room temperature in 90%, 94% and 80% yield along with the expected reduced product 8 in 20% yield
isolated yield (Scheme 2), the corresponding chlorides exhibi- (Scheme 3). A similar coupled product was also observed with
ted reduced reactivity and required elevated temperature. 1-bromonaphthalene 4a. Our efforts to suppress the formation
Chloride 1e took 19 h to offer the reduced product in 40% of the silylated product were not successful.
yield at 75 °C and chloride 1k took 17 h at 100 °C for the com-
plete conversion with 62% yield (Scheme 2). A double protode- find the source of the hydrogen atom. When PhSiD3 (>99% D,
halogenation of substrate 1i was also effected with 61% yield. synthesized from PhSiCl3 and LiAlD4) was used, we observed
Deuterium labeled experiments were conducted in order to
Sterically crowded and challenging tertiary alkyl bromides 72% of deuterium incorporation in the product; however when
1f and 1l were successfully reduced with 78% and 54% yields the reaction was conducted in THF-d8, we observed no incor-
respectively; even 1-chloroadamantane 1g was reduced with poration of deuterium in the product (Scheme 4). These
89% yield. Cholesteryl iodide 1m offered the protodeiodinated results clearly indicate that the source of the hydrogen atom is
cholest-5-ene in 86% yield. Competitive experiments were con- PhSiH3. Based on the earlier studies,7 our initial expectation
ducted to determine the order of reactivity, chlorodecane 1j, was the formation of a radical intermediate and the sub-
bromide 1k and iodide were subjected to the standard reaction sequent reduction to the product; however, our mechanistic
conditions in a single pot, the complete consumption of studies revealed a non-radical pathway. When we introduced
iodide was observed within 20 minutes, bromide 1k took 24 h either a TEMPO or galvinoxyl radical inhibitor in the reaction
to get completely consumed; however, the chloride 1j was medium, the reaction was not inhibited and we obtained the
intact even after 48 h (see the ESI† for more details). We reduced product (1a to 2a) in 72% and 92% yields respectively.
carried out a gram-scale synthesis to demonstrate the practic- Moreover, the alkene substrate 9a is expected to undergo cycli-
ability of this iron mediated protodehalogenation; it is worth zation if the reaction proceeds through a radical intermediate;
noting that 0.5 mol% of FeCl3 offered 2a in 89% isolated yield. however we observed the formation of uncyclized reduced
The moderate yield of certain substrates can be attributed to product 10b (Scheme 5).
the low volatile nature of the product, for example, the sub-
When the reaction was carried out in CH3CN (a favorable
strates 1a, 1e, and 1f were obtained in 91%, 95%, and 95% solvent for the radical reaction) instead of THF (no reaction in
yields (Scheme 2) when the synthesis was carried out on a
large scale (∼2 mmol). Even 1.5 eq. of PhSiH3 and NaOMe
were sufficient to obtain an excellent yield (substrate 1f,
Scheme 2). These examples clearly illustrate the simplicity of
the methodology and the results obtained are comparable
to that of tin, aluminum and boron hydride reagents.
Interestingly, the above optimized reaction conditions for alkyl
halides are also applicable for the reduction of aryl halides.
Notably, the reported metal hydrides (FeCl3/NaBH4, In(OAc)/
PhSiH3 and InCl3/Et3SiH) for the reduction of alkyl halides are
known to follow a radical pathway that does not reduce aryl
halides and it was usually carried out with PdCl2,12
[RuCl2X]2,14 (PNN)RuHCl(CO),3,7 and Fe(acac)3/RMgX.11
1-Bromonaphthalene 4a was reduced with 40% yield in
30 minutes and 1-chloronaphthalene 4b took 12 h to complete
the reaction with 71% isolated yield (Scheme 2). While
1-bromo-4-(tert-butyl)benzene 4c offered 74% yield in 1 h,
1-chloro-4-methylbenzene 4e and 5-bromoindole 4d required
elevated temperature and gave 74% and 40% yields respect-
ively (Scheme 2). 5-Bromo-1,2,3-trimethoxybenzene 4f and
4-chloro, bromo and iodo anisole 4g–i offered 61%, 78%, 66%
and 46% yields respectively; 1-chloro-4-iodobenzene 4k was
also reduced in 50% yield. The functional groups that are sus-
ceptible to reductions (ketone 4j and ester 1p) were also
reduced (Scheme 2). Both the alkyl and aryl fluorides were
intact under the reaction conditions.
Scheme 3 Formation of a silyl-coupled side product.
Scheme 4 Deuterium labeling studies.
Despite the successful reduction of aryl halides, certain
substrates offered poor yields (Scheme 2; see the ESI†) and Scheme 5 Cyclization of iodoalkene.
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Acknowledgements
We thank the Science and Engineering Research Board, DST
No: EMR/2015/001103/OC and the Ramanujan Fellowship SB/
S2/RJN-059/2015 for financial support. RP and VB acknowledge
the IISER-Trivandrum for fellowship. RC acknowledges the
CSIR for fellowship.
Scheme 6 Disproportionation of phenylsilane.
Notes and references
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Conflicts of interest
There are no conflicts to declare.
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