FeCl2-mediated Nucleophilic Chlorination of Iodoalkanes Accelerated by Phenanthroline Ligand

Full text of DOI:10.1002/bkcs.11453

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DOI: 10.1002/bkcs.11453
BULLETIN OF THE
J. Y. Hwang et al.
KOREAN CHEMICAL SOCIETY
FeCl2-mediated Nucleophilic Chlorination of Iodoalkanes Accelerated
by Phenanthroline Ligand
*
Joon Young Hwang, Jung Ha Shin, Eun Young Seong, and Eun Joo Kang
Department of Applied Chemistry, Kyung Hee University, Yongin 17104, South Korea.
*E-mail: ejkang24@khu.ac.kr
Received February 6, 2018, Accepted March 16, 2018
Keywords: Nucleophilic chlorination, Iron dichloride, 1,10-phenanthroline monohydrate, Alkyl iodides
Alkyl halides have been considered not only important
building blocks but also useful intermediates in synthetic
methods of nucleophilic substitution, metal-halogen
exchange, and cross-coupling reactions. As the practical
synthesis of various alkyl halides, the halogen exchange is
one of the fundamental and efficient reactions, which is
mainly used for preparing alkyl bromides or iodides.
Finkelstein-type reactions1 have been well studied for the
conversion of alkyl chlorides to the corresponding bro-
mides or iodides and alkyl bromides to iodides, which reac-
tion is an equilibrium shifted by taking advantage of the
different solubility of the resulting sodium salt in acetone.
However, the reverse processes, the replacement of iodide
by bromide or chloride, or of bromide by chloride, were
not simple.
As mentioned above, the conversion of iodides to the
corresponding chlorides mostly required more than an
equivalent of molecular chlorine, metal chloride, alkyl
ammonium chloride, strongly acidic hydrogen chloride or
oxidants under elevated temperature in long reaction time
(sometimes 10 or more days).9 Furthermore, much has been
devoted to the transformation of secondary or tertiary
iodides, but studies on primary iodide conversions are rare
or the corresponding reactions require even more harsh
conditions.
While we focused and investigated on the iron catalysis10
in terms of new reactivity and alternative substitutes to the
use of precious metals, under environmentally more accept-
able ‘green’ conditions, iron chlorides were thought to pro-
vide the chloride source in the halogen exchange reaction.
Moreover, to sufficiently activate the chloride and make the
iron center soft, it was considered that the introduction of a
bulky ligand was desperately needed. Herein, we report the
scope and limitations of the ligand-accelerated nucleophilic
chlorination of primary and secondary iodoalkanes with
stoichiometric amount of iron chlorides under mild
condition.
The early investigation on the chlorination of alkyl
iodides were involved with the reaction of molecular chlo-
rine or iodine monochloride,2 which afforded the alkyl
iodide-halogen intermediate (RIꢀClX, X = Cl or I). The
resulting trihalide ion could act as an electronegative leav-
ing group and promote the chloride substitution, showing
the preferred reactivity of tertiary and secondary iodides
3
over primary iodides. Metal chlorides such as MoCl5 and
To examine the prospect of using FeCln as potential
chloride nucleophile, the reaction system of FeCl2 and
1,10-phenanthroline monohydrate (phen-H2O) ligand were
subjected to a simple aliphatic iodoalkanes, toluene sulfon-
amide (1a). As described in Table 1, the reaction with
stoichiometric amounts of FeCl3 and 3 M equivalents of
phen-H2O smoothly promoted the formation of chloroalk-
4
BiCl3 were also discovered as the role of providing the
chloride source as well as activating the carbon-halogen
bond by Lewis acidic coordination to halogen leaving
group. This strategy showed the 1,2-migration phenomena
in the reaction with 1-iodooctane, supporting the intermedi-
acy of carbocations. Another approach was the oxidatively-
assisted substitution, where alkyl iodides were oxidized to
iodoso compounds (RI O) by mCPBA5 or hypervalent
iodine6 compounds for consecutive nucleophilic chlorina-
tion. In a similar way, oxidative ligand transfers between
alkyl iodides and aryliodine(III) reagents produced the req-
uisite hypervalent alkyliodine intermediates for substitution.
The methods described above make the iodide a good leav-
ing group and the modified iodine functional group cannot
act as a nucleophile again. On the other hand, a process of
separating the generated alkyl chlorides by boiling point
difference7 or separating the leaving iodide into fluorous
phase using fluorous phosphonium salt has been
developed.8
ꢁ
ane (2a) at 60 C within 30 min, and FeCl2 was determined
to serve as an effective complex in the nucleophilic chlori-
nation to afford 2a in 79% yield (entries 1–2). The use of
several types of ligands were tested: the reaction with 2,20-
bipyridine (bpy) resulted a comparable yield of 82% with
phen-H2O ligand. Other N or P-type ligands such as tetra-
methylethylenediamine (TMEDA), ethylenediamine (EDA),
triphenylphosphine, or 1,2-bis(diphenylphosphino)ethane
(dppe) did not exhibit noticeable reactivities (entries 4–7).
Furthermore, the efficiency of the reaction system and role
of each member in it was tested. In the absence of phen-
H2O ligand, the corresponding chloroalkane was not
obtained, implying that the choice of ligand seemed to be
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KOREAN CHEMICAL SOCIETY
Table 1. Optimization of conditions for nucleophilic
Table 2. Substrate scopes in nucleophilic chlorination.
chlorination.a
Yield (%)a
Entry
Time (h)
Yield(%)b
Entry
FeXn
Ligand
1a
2a
3a
1
2
3
4
5
6
7
8
9c
10d
11
12
a
FeCl3
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeF2
phen-H2O
phen-H2O
bpy
TMEDA
EDA
PPh3
dppe
—
—
—
—
—
—
99
99
99
8
61
79
82
—
—
—
—
—
—
—
—
—
—
7
Decomp.
Decomp.
—
—
—
75
8
phen-H2O
phen-H2O
phen-H2O
phen-H2O
92
92
8
—
FeBr3
—
43
Reaction condition: 1a (0.12 mmol), FeXn (0.12 mmol, 1.0 equiv),
ligand (0.36 mmol, 3.0 equiv), CH3CN (0.1 M), 60 C for 0.5 h.
Isolated yield.
Reaction with 2.0 equiv of ligand.
Reaction with 1.0 equiv of ligand.
ꢁ
b
c
d
critical. When an amount of phen-H2O was decreased, an
equimolar amount of ligand sharply dropped the yield of
product formation (entries 9–10). Additional possibility of
other halogen nucleophile was investigated with the com-
mercial source of iron salts, FeF2 and FeBr3. Instead of
expected transfer-halogenation products, aziridine 3a were
obtained, which suggests that the intramolecular cyclization
reaction was proceeded due to the Lewis acidic character of
the iron complexes.
a
Isolated yield.
Accompanied with 1-tosylpyrrolidine (16%).
b
c
Reaction condition: iodide (0.12ꢁmmol), Fe(phen)3Cl2 (0.12 mmol,
1.0 equiv), CH3CN (0.1 M), 60 C.
With the optimal reaction conditions in hand,11 the sub-
strate scope of chlorination of primary and secondary
iodoalkanes was evaluated, and the results were summa-
rized in Table 2. Various types of iodoalkanes were effi-
ciently converted into corresponding chloroalkanes in
moderate to high yields (entries 1–3). It is of interest to
note that the pre-complexed Fe(phen)3Cl2 reagent were suf-
ficiently comparable, which was thought to be the critical
species generating a chloride nucleophile. However, Boc-
protected tosylamide (1d) could not successfully afford the
chlorinated product (2d, entry 4), suggesting that the neigh-
boring group seems to have some effect on the chlorination
reaction. Iodoalkanes having allyl and styrenyl group were
also generally effective, but benzyl iodide (1h) and hydrox-
ylated substrate (1i) significantly retarded the efficiency of
reaction (entries 5–9). Ester and carbamate functional
groups were well tolerated under the reaction conditions,
delivering the corresponding chloroalkanes in up to 85%
yield. Interestingly, α-chloromethyl carbonyl unit in 2j
could be an essential core in biologically active small mole-
cules.12 Remarkably, secondary chlorides were obtained by
reacting iodides in acyclic substrates also converted into
chlorides in high yield (entries 12–13).
To investigate the nucleophilic chlorination processes
mediated by the FeCl2/phen system, we performed mecha-
nistic experiments employing the enantio-rich secondary
alcohol compound (Scheme 1, Eq. (1)). (R)-(−)-1-Amino-2-
propanol (98% ee) was converted to the corresponding sec-
ondary iodide by Cbz protection and iodination reaction,
and the expected (S)-1m substrate was treated with the iso-
lated Fe(phen)3Cl2 compound. The chlorination reaction
was smoothly proceeded and predominantly afforded the
(R)-2m enantiomer as a major product in the ratio of
approximately 85:15, which verifies that Fe(phen)3Cl2-
mediated chlorination is mainly proceeded by SN2 reaction
pathway.13 Additional evidence of the phenomenon of
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1.0 equiv) in CH3CN (1.2 mL) was added FeCl2 (0.12 mmol,
1.0 equiv) and 1,10-phenanthroline monohydrate (0.36 mmol,
ꢁ
3.0 equiv). After being stirred at 60 C for 0.5 h, solvent
evaporation and silica gel column chromatography afforded
N-(2-chloroethyl)-4-methylbenze-nesulfonamide (2a).16 Yield
22 mg (79%); white solid; Rf = 0.49 (Hex:EtOAc = 2:1); 1H
NMR (300 MHz, CDCl3) δ 7.77 (d, 2H, J = 8.3 Hz), 7.33 (d,
2H, J = 8.2 Hz), 5.01 (t, 1H, J = 6.1 Hz), 3.55 (t, 2H,
J = 5.9 Hz), 3.30 (q, 2H, J = 5.9 Hz), 2.44 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 143.9, 136.9, 129.9, 127.1, 44.6,
43.5, 21.4 ppm; HRMS (EI): calcd for C9H12ClNO2S (M+)
233.0277, found 233.0276.
Acknowledgments. This study was supported by the
Ministry of Education, Science and Technology, National
Research Foundation (Grant No. 2015R1D1A1A01060349
and 2017M1A2A2043147 “Next Generation Carbon Upcy-
cling Project”).
Scheme 1. Experiments for mechanistic investigations.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
generating applicable chloride anions from Fe(phen)3Cl2
was also found in the following cyclic carbonate synthesis
(Eq. (2)). A catalytic amount of Fe(phen)3Cl2 could be used
for the conversion of styrene oxide (4) into cyclic carbonate
(5), while an ammonium halide (R4N+X−) is generally
employed in the oxide ring opening pathway during the
carbonate synthesis.14 The feasibility of an iron catalysis
accompanied with external chloride sources was examined
under the reaction condition with 10 mol % of FeCl2, how-
ever, experiments conducted with TMSCl or NaCl failed to
generate the measurable amount of the chlorinated product
2b.15 Interestingly, the deiodinative acetoxylation was suc-
cessfully achieved by Fe(phen)3(OAc)2 complex to afford
the acetate 4b even under the elongated reaction time
(21 h). These results indicated that it was advantageous for
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Bull. Korean Chem. Soc. 2018
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