A Free-Radical Reduction and Cyclization of Alkyl Halides Mediated by FeCl2

Article abstract of DOI:10.1002/cctc.201900230

Iron mediated catalytic reactions are of great interest in the field of organic synthesis because they are economic and naturally abundant. However, the use of iron catalyst in the field of free radical cyclization or reduction of alkyl halides remains limited. Here we describe the use of an unprecedented combination of iron and zinc in the reduction and 5-exo-trig radical cyclization of alkyl halides under mild condition in the absence of added ligands or additives. The method is distinguished by its wide scope, functional group tolerance and the use of 1,4-cyclohexadiene as the source of hydrogen, which aids easy purification.

Full text of DOI:10.1002/cctc.201900230

Accepted Article
Title: A free radical reduction and cyclization of alkyl halides mediated
by FeCl2
Authors: Ramesh Rasappan, Feba Thomas Pulikottil, Ramadevi Pilli,
Vetrivelan Murugesan, and Chandu G Krishnan
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10.1002/cctc.201900230
ChemCatChem
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A free radical reduction and cyclization of alkyl halides mediated
by FeCl2
Feba Thomas Pulikottil,[a] Ramadevi Pilli,[a] Vetrivelan Murugesan,[a] Chandu G Krishnan[a] and Ramesh
Rasappan*[a]
Dedication ((optional))
Abstract: Iron mediated catalytic reactions are of great interest in the
field of organic synthesis because they are economic, naturally
abundant. However, the use of iron catalyst in the field of free radical
cyclization or reduction of alkyl halides remains limited. Here we
describe the use of an unprecedented combination of iron and zinc in
the reduction and 5-exo-trig radical cyclization of alkyl halides under
mild condition in the absence of added ligands or additives. The
method is distinguished by its wide scope, functional group tolerance
and the use of 1,4-cyclohexadiene as the source of hydrogen atom
that aids easy purification.
radical cyclization of unsaturated halogenoacetals (Scheme 1c),
we envisaged a complementary strategy in which zinc can be
used as a terminal reductant. We were also attracted towards the
use of 1,4-cyclohexadiene (CHD) as the source of hydrogen atom
since the resultant benzene could easily be removed, thus
simplifying the purification process. As part of our ongoing interest
in field of iron mediated catalytic reactions,[8] we present here an
iron mediated reduction and cyclization of alkyl halides.
Sustainable chemical reactions play a vital role in industries and
the search for economical, environmentally benign and naturally
abundant reagent is an important concern.[1] In this context, the
development of iron mediated catalysis is very attractive. Over the
past decade, iron catalysis has matured into a robust and
attractive alternative to precious transition metal catalysts.[2]
Despite the synthetic potential of iron catalysis, its application in
the field of radical generation from alkyl halides is still lacking.
Though the Bu3SnH (stoichiometric) mediated radical reactions
are very well established, the toxicity of tin reagents severely
limits their potential use.[3] Photoredox catalysis has been
proposed as an alternative to address these concerns raised by
tin reagents, however, it often requires the use of expensive
catalysts and is mostly limited to alkyl iodides.[4] Recently, there
are developments based on iron catalysis appeared in the
literature,[5] a close look into these studies reveals the requirement
of either Grignard (Scheme 1a) or NaBH4 reagents for the
activation of iron catalyst, otherwise stoichiometric Fe(0) was
used.[5a] Fensterbank et al. disclosed an elegant method to reduce
the halogenoacetals in presence of 10 mol% of FeCl2 and
NaBH4,[5b,5c,5h] Oshima et al. utilized PhMgBr for the activation of
FeCl2.[5g] Kang et al. used stoichiometric Fe(CO)5 for the reductive
radical cyclization.[5a] A methodology that can utilize iron and
avoid the use of harsh conditions or reagents is highly desirable.
Inspired by the recent literature on the in-situ reduction of nickel[6]
and iron (Scheme 1b)[7] complexes by Mn/Zn and prompted by
our perception that an activated iron may effectively catalyze the
Scheme 1. Iron mediated reduction of alkyl halides.
We commenced our study with the 1-(3-bromobutyl)-4-
methoxybenzene 1a which was readily prepared from the
corresponding alcohol. After careful investigation, we pleasingly
found that
a combination of FeCl2, Zn and CHD (1,4-
cyclohexadiene) in CH3CN at 50 oC offered the best result,
affording 2a in 99% isolated yield (table 1, entry 1). As we
speculated, a simple filtration followed by the removal of volatiles
afforded the pure (by NMR) product 2a. We found that CHD was
more efficient to offer 2a as the sole product, whereas MeOH
(entry 2), catechol (entry 3) or Hantzsch ester (entry 4) offered the
expected product 2a in poor to moderate yield along with the
alkene byproducts that complicate the isolation of 2a. In the
absence of CHD (similar to the reported condition),[7a] we
observed only 44% of the protodehalogenated product (entry 5)
along with traces of alcohol byproduct.
[a]
F. T. Pulikottil, R. Pilli, V. Murugesan, C. G. Krishnan, Prof. Dr. R.
Rasappan
School of Chemistry
Indian Institute of Science Education and Research
Thiruvananthapuram
Vithura, Thiruvananthapuram
Kerala, India
E-mail: rr@iisertvm.ac.in
FeCl3 also offered the protodehalogenated product, albeit in low
yield (entry 7), while Fe(acac)3 did not exhibit noticeable reactivity
(entry 8). As shown in entries 9 and 10, no reactivity was found in
the absence of either FeCl2 or Zn, evidencing the role of FeCl2
and Zn in the catalytic cycle.[10] Interestingly, the use of Mn as
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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reductant resulted in
a
similar conversion (entry 11). In
and offered the products 2n and 2o in 73% and 96% yields. Even
the free carboxylic acid 1m and nitrile 1l were smoothly
protodehalogenated in 87% and 65% yields. The cholesterol
derivative 1i offered the protodehalogenated product in 55% yield.
Importantly, most of the products were obtained pure, just after
the filtration of insoluble salts and removal of the volatiles.[11] The
aryl halides and primary alkyl chlorides were intact under this
reaction condition.[12] In the case of substrates 1g, 1l, 1n, and 1o,
catechol was used instead of CHD.[13] In order to demonstrate the
synthetic applicability of this methodology, we carried out a large-
scale reaction in which 3.6 mmol of 1e was subjected to the
reaction condition with just 1 mol% of FeCl2 and 1 eq. of Zn and
CHD, to obtain the corresponding protodehalogenated product 2e
in 95% isolated yield.[14]
accordance with the literature on radical reactions, CH3CN stands
out to be the most suitable solvent for this transformation. DMF
and DMA also offered 2a in 95% and 94% yields respectively
(entries 12 and 13). As expected, Et2O was not suitable for this
transformation (entry 14) and 91% of the starting material was left
unreacted. Employing 5 mol% of FeCl2 was sufficient to obtain
96% of 2a (entry 15), albeit rather slowly (42h vs 21h). Carrying
out the reaction at room temperature reduced the rate of the
reaction (entry 17). Lowering the amount of CHD (entry 18) had
significant effect on the yield.
Table 1. Optimization of reaction condition.[a]
Table 2. Scope of substrates.[a]
entry
1
deviation from standard condition
none
1a (%)b
yield 2a (%)b
>99 (90)c
-
2
MeOH instead of CHD
Catechol instead of CHD
Hantzsch ester
9
70
58
18
44d
28
78
9
3
41
80
12
36
18
85
97
96
-
4
5
without CHD in DMA
without CHD
6
7
FeCl3 instead of FeCl2
Fe(acac)3 instead of FeCl2
Without Zn
8
9
0
10
11
12
13
14
15
16
17
18
without FeCl2
0
Mn instead of Zn
DMF instead of CH3CN
DMA instead of CH3CN
Et2O instead of CH3CN
5 mol% FeCl2
99
95
94
4
86 (96)e
96
42
80
-
-
91
12
-
1.0 eq. Zn
rt instead of 50 oC
45
13
1 eq. CHD
[a]
General reaction condition: 0.5 mmol of 1a, 1.5 mmol of CHD, 10 mol% of
FeCl2, 0.75 mmol of Zn, l.0 M CH3CN, 50 oC, 21 h. [b] GC yield. [c] isolated yield.
[d] 5 eq. of Zn, FeBr2, DMA instead of CH3CN. [e] 46 h instead of 21 h.
With the optimized condition in hand, we sought to investigate the
scope of substrates. The results are summarized in table 2. As
expected, the alkyl iodides 1c and 1f, benzyl bromides 1g and 1h
were protodehalogenated efficiently (Table 2). The unreactive
chloride 1b, activated chlorides 1e and 1o were also suitable for
[a]
Reaction condition: 0.5 mmol of 1, 1.5 mmol of CHD, 10 mol% of FeCl2, 0.75
mmol of Zn, 1.0 M of CH3CN, 50 oC, isolated yield.
GC yield.
3 eq. of
[b]
[c]
[d]
catechol was added instead of CHD.
CH3CN.
0.1 M of CH3CN instead of 1.0 M of
this
transformation
and
offered
the
corresponding
protodehalogenated products in 57%, 99% and 96% yields
respectively. Apart from the primary and secondary alkyl halides,
sterically hindered tertiary halides 1d and 1e also underwent
successful reduction to the corresponding protodehalogenated
products in 98% and 99% yields respectively. 1-
Bromoadamantane gave only 25% isolated yield (see SI).
To further demonstrate the synthetic utility of this method, we
subjected unsaturated halogenoacetals to the optimized condition
and observed the formation of synthetically versatile cyclized
products (Table 3).[3a-b, 5a-c, 5g-h, 15] The bromoacetal derivative 3a
offered the cis-fused syn-substituted 5-exo-trig cyclized product
4a in 60% yield with 84:16 diastereoselectivity, reminiscent of
recent literature that demonstrates the intermediacy of alkyl
radical in these reactions. The corresponding iodide 3b also
offered the cyclized product 4a in 56% yield (88:12 dr). Traces of
We next examined the functional group tolerance; ketones 1j and
1k were compatible under the reaction condition and the
corresponding products 2j and 2k were isolated in 83% and 57%
yields respectively. The esters 1n and 1o were also compatible
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Table 3. Radical cyclization of alkyl halides[a]
unsaturated product was seen along with the expected product
4a which might account to the moderate yield of substrates 3a
and 3b.
fused syn-substituted bicyclic product 4c with excellent internal
alkene also successfully offered the cyclized product albeit in
lower yield (entry 3).16 Further, the halogenoacetals 3f-3i also
resulted in the bicyclic products 4f and 4h with moderate to
excellent yields. The acyclic halogenoacetal 3j offered the
corresponding cyclized product 4j in 77% isolated yield. The O-
homoallyl derivatives 3k and 3l gave the cyclized (6-exo-trig)
product 4k (entry 7) in relatively low yield along with the
uncyclized protodehalogenated product 4k’ in 27% and 46%
yields respectively.5h In accordance to the literature,[3a-b,5a-c,5g-h,15]
the observed selectivity towards cis-fused syn substitution can be
explained by a transition state shown in scheme 2b, where the
endo cyclization of the alkene occurs predominantly.
Product 4
entry
1
3
time
4
drb
(%)c
3a = Br
3b = I
16 h
12 h
84:16
88:12
60d
56
4a
2
It has been proposed in the previous studies[7] that the Fe(I) is
generated upon mixing either FeCl2 and Zn or FeCl2 and
NaBH4,[5b,5c,5h] though Fe(0) cannot be ruled out. It is also noticed
that the alkyl halide is intact in the absence of either FeCl2 or Zn
(entries 9 and 10, table 1). The presence of a radical intermediate
is evident from the formation of a cis-fused bicyclic product. Based
on these results, we propose a catalytic cycle as shown in scheme
2a. A single electron transfer (SET) from Fe(I) to an alkyl halide A
leads to the formation of a radical intermediate B, subsequent
intramolecular endocylic radical cyclization (5-exo-trig) followed
by the abstraction of hydrogen atom from CHD led to the desired
product C. The observed diastereoselectivity for substrates 3a-d
can be understood using the transition state model presented in
Scheme 2b.[17,18]
3c = Br
3c = Br
3d = I
16 h
16 h
12 h
95:5
90:10
97:3
74d
93d,e
66
4c
3
4
32 h
50:50
27
3f = Br
3g = I
16 h
12 h
33:67
33:67
52d
94
4f
5
3h = Br
3i = I
16 h
12 h
50:50
50:50
56d
29
4h
6
7
32 h
-
77f
Scheme 2. Mechanistic proposal and a transition state model.
In summary, we have developed an iron mediated free radical
trans:cis
(65:35)
trans:cis
(68:32)
o
protodehalogenation of alkyl halides (1o, 2
and 3 o) and
3k= Br
3l= I
16 h
12 h
4k:4k’(36:64)
4k:4k’(23:77)
27d
46
cyclization of unsaturated halogenoacetals using Zn as a terminal
reductant and CHD as the hydrogen donor. The developed
catalytic system is compatible with various functional groups and
sterically hindered halides. Initial studies revealed a radical
intermediate during the reaction which serves as a useful
alternative to the tin and photochemical mediated reactions.
[a] Reaction conditions: 0.5 mmol of 3, 1.5 mmol of CHD, 10 mol% of FeCl2, 0.75
mmol of Zn, l.0 M of CH3CN, 50 oC. [b] based on crude 1H NMR. [c] isolated yield.
[d] 80 oC instead of 50 oC. [e] catechol used instead of CHD. [f] DMA instead of
CH3CN.
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Experimental Section
Under an inert atmosphere, the oven dried Schlenk tube was charged with
iron (II) chloride (10 mol%, 0.05 mmol, 6.4 mg) and zinc (1.5 eq., 0.75
mmol, 49 mg) followed by the addition of acetonitrile (0.5 mL) and 1, 4-
cyclohexadiene (3.0 eq., 1.5 mmol, 142 µL). After stirring for a minute at
room temperature, the alkyl halide (1.0 eq., 0.5 mmol) was added and
continued stirring at 50 oC. The completion of reaction was monitored
using TLC. After the reaction was complete, the mixture was filtered
through plug of Celite or silica, eluting with Et2O/CH2Cl2/EtOAc (based on
the volatility and polarity of the material) to remove metal salts and the
filtrate was concentrated under vacuum to obtain protodehalogenated
product. If needed the crude was subjected for further purification by flash
column chromatography (petroleum ether/ethyl acetate) to give the
corresponding product.
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Acknowledgements
We thank the Science and Engineering Research Board, DST No:
EMR/2015/001103/OC
and
Ramanujan
Fellowship
SB/S2/RJN059/2015 for financial support. FTP, RP and VM
acknowledge IISER, Trivandrum for fellowship.
Keywords: iron; catalysis; protodehalogenation; reductive
cyclization; radicals; zinc
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[12] see SI for more details
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10.1002/cctc.201900230
ChemCatChem
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Feba Thomas Pulikottil, Ramadevi Pilli,
Vetrivelan Murugesan, Chandu G
Krishnan and Ramesh Rasappan*
Page No. – Page No.
A free radical reduction and
cyclization of alkyl halides mediated
by FeCl2
Iron catalysis: Protodehalogenation and cyclization of alkyl halides using
inexpensive iron catalyst was developed, the use of 1,4-cyclohexadiene was crucial
to obtain excellent yields.
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