Synthesis of α-Iodoketones from Allylic Alcohols through Aerobic Oxidative Iodination

Article abstract of DOI:10.1002/adsc.201800661

An efficient method for the synthesis of α-iodoketones from allylic alcohols and elemental iodine is reported. We show in this paper that the isomerization of allylic alcohols catalyzed by iridium(III) complexes can be combined with an aerobic oxidative iodination protocol, resulting in a straightforward method for the synthesis of a wide range of α-iodoketones as single constitutional isomers and in high yields under mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201800661

Title: Synthesis of α-Iodoketones from Allylic Alcohols through Aerobic
Oxidative Iodination
Authors: Amparo Sanz-Marco, Stefan Mozina, Samuel Martinez Erro,
Jernej Iskra, and Belén Martín Matute
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800661
Link to VoR: http://dx.doi.org/10.1002/adsc.201800661

10.1002/adsc.201800661
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of -Iodoketones from Allylic Alcohols through
Aerobic Oxidative Iodination
Amparo Sanz-Marco,[a] Štefan Možina,[b,c] Samuel Martinez-Erro,[a] Jernej Iskra,d,e* and
Belén Martín-Matute[a]*
a
Department of Organic Chemistry, Stockholm University, Stockholm 10691, Sweden
+468162438, E-mail: belen.martin.matute@su.se
Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova 39, Ljubljana, Slovenia
Jožef Stefan International Postgraduate School, Jamova 39, Ljubljana, Slovenia.
Department of Physical and Organic Chemistry, Jožef Stefan Institute, Jamova 39, Ljubljana, Slovenia.
b
c
d
e
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
E-mail: Jernej.Iskra@fkkt.uni-lj.si
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An efficient method for the synthesis of -
iodoketones from allylic alcohols and elemental iodine is
reported. We show in this paper that the isomerization of
allylic alcohols catalyzed by iridium(III) complexes can be
combined with an aerobic oxidative iodination protocol,
resulting in a straightforward method for the synthesis of a
wide range of -iodoketones as single constitutional isomers
and in high yields under mild reaction conditions.
Keywords: isomerization; aerobic oxidative iodination; -
iodoketones; -aminoketones; allylic alcohol
Iodine is often found in molecules with important
applications in industrial and medicinal chemistry.[1]
Iodinated organic compounds also play a pivotal role
in synthetic organic chemistry as versatile building
blocks, as reflected by the vast number of
derivatization procedures that exist in the literature.[2]
At present, numerous methods are known for the
synthesis of -iodinated carbonyl compounds starting
from esters,[3] ketones,[4] and even amides.[5] For
synthesizing -iodoketones, most of the reported
methods rely on the reaction of preformed enol or
enolate derivatives with electrophilic iodinating
agents. This approach works well when applied to
ketones with only one type of enolizable carbon or
when there is a strong electronic or steric bias
between the -carbons, ensuring a regioselective
outcome (Scheme 1a).[4c,d]
product in reasonable yield. Among these halogen
sources, I2 would be the most convenient option, as it
has a very low toxicity, is environmentally friendly
and a cheap and commercially available reagent.
From an atom-economy point of view, I2 is also the
best alternative.[7]
a) Ir-Catalyzed synthesis of a-iodoketones from allylic alcohols using 2,2-diododimedone
O
H
OH
[Cp*Ir]cat
H
R1
R1
R2
R2
I
I
I
O
O
- Single constitutional isomer
- Specifically designed [I+] source
b) This work: Ir-catalyzed synthesis of a-iodoketones using I2 under oxidative conditions
O
H
OH
[Cp*Ir]cat
R1
H
R2
R1
R2
I
I2 (0.5 equiv.)
I
Recently, we described an alternative procedure
for the preparation of -iodinated ketones as single
constitutional isomers, starting from allylic alcohols
(Scheme 1b).[6] The method relies on a 1,3-hydrogen
shift catalyzed by an Ir(III) complex, carried out in
the presence of an electrophilic iodinating agent. This
protocol gave access to -iodinated carbonyl
compounds formally derived from unsymmetrical
aliphatic ketones in excellent yields for the first time.
A key aspect was the use of a new mild iodinating
agent, 2,2-diiodo-5,5-dimethylcyclohexane-1,3-dione
(Scheme 1b). Commercially available and commonly
used electrophilic iodinating agents such as I2, ICl, or
NIS (N-iodosuccinimide) failed to give the desired
- Single constitutional isomer
- I2 as iodinating agent
- Total iodine economy
NO2 cat
NOcat
Electron Transfer Mediator
formed in-situ from NaNO2
O2
Stoichiometric final oxidant
Scheme 1. Different electrophilic iodination agents in the
iridium-catalyzed synthesis of -iodoketones from allylic
alcohols.
1
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10.1002/adsc.201800661
Advanced Synthesis & Catalysis
In electrophilic monoiodination reactions that use
ecofriendly alternative to THF.[12] Upon dilution of
the reaction mixture (0.04 M vs 0.2 M), the yield of
2a increased further to 90% (entry 7). Control
experiments were also carried out (entries 8-11). Both
catalysts, iridium complex II and NaNO2, were found
to be essential for the formation of the desired
product (entries 8 and 9, respectively). Replacement
of I2 by NIS or KI under otherwise identical reaction
conditions did not give the product either (entries 10-
11). The reaction conditions of entry 7 were chosen
I2 as the halogen source, only one of the two halogen
atoms can be used as electrophile (I+); one equivalent
of iodide (I–) is formed as a by-product. The halogen
atom economy can be improved through the addition
of an oxidant to the reaction mixture to oxidize the
iodide formed. Several oxidants have been used in
oxidative iodinations in stoichiometric amounts; i.e.
MnO2,[8a] CuO,[8b] graphene oxide,[8c] hypervalent
iodine
compounds,[8d-f] oxone,[8g] di-tert-butyl
peroxide,[8h] and H2O2.[8i,j]
Table 1. Optimization of the reaction conditions.
We envisioned that under milder oxidative
conditions, I2 may be used as the halogen source.
Iskra and collaborators have described the aerobic
oxidative iodination of organic molecules in excellent
yields, using elemental iodine together with oxygen
or air as the stoichiometric oxidant.[9] The process
requires the use of NaNO2 as an electron-transfer
mediator catalyst uunde acidic conditions, and
involves nitrogen oxide intermediates. Oxidative
iodination protocol has been used for the -iodination
of ketones, but no regiocontrol was achieved for
unbiased unsymmetrical ketones.[8d,i],[9b,c]
Entry[a] [Cp*Ir]
atm. Solvent / H2O
2a/3
(%)[b]
1
2
3
4
Air
Air
Air
O2
O2
O2
O2
O2
O2
O2
O2
THF / H2O
THF / H2O
THF / H2O
THF / H2O
2-MeTHF / H2O
Acetone / H2O
2-MeTHF / H2O
2-MeTHF / H2O
2-MeTHF / H2O
2-MeTHF / H2O
2-MeTHF / H2O
47/8
60/8
60/8
70/-
72/-
13/7
90/-
-
I
II
III
II
II
II
II
-
II
II
II
In this paper, we report the synthesis of -
iodoketones as single constitutional isomers from
readily available allylic alcohols using 0.5
equivalents of iodine as the halogen source under
aerobic oxidative conditions (Scheme 1b). The
method combines a 1,3-hydrogen shift mediated by
iridium(III) catalysts with a CI bond formation
5
6
7[c]
8[c]
9[c],[d]
10[c],[e]
11[c],[f]
32/-
-
-
[a] Unless otherwise noted, 1a (0.2 mmol), solvent / H2O
As a starting point to study this transformation, we
chose to test the reaction conditions reported by one
of us[9d] for oxidative iodination, i.e., I2 (0.5 equiv.)
and NaNO2 (5 mol%) and applied them to allylic
alcohol 1a (Table 1). First, we tested several iridium
catalysts of the general structure [Cp*Ir(III)], that we
used successfully in the halogenation of allylic
alcohols, and in the isomerization of allylic alcohols
into carbonyl compounds in a mixture of THF and
H2O (3:1).[10,11] Catalysts II and III showed similar
activities, higher to that of Ir(III) chloride complex I.
-Iodoketone 2a was formed in all cases, in yields
ranging from 47 to 60%. An important challenge of
this chemistry is to minimize the formation of enone
by-products, formed by direct oxidation of the allylic
alcohols. For the three catalysts screened, only up to
8% of enone 3 was produced (Table 1, entries 1-3).
Complex II ([Cp*Ir(H2O)3]SO4) was chosen to
continue the optimization studies. Higher yields of 2a
were obtained when the reaction was run under an
atmosphere of O2 (70 vs 60%, entry 4 vs entry 2).
Interestingly, this change also inhibited the formation
of enone 3 (entry 4). When the reaction was carried
out in a mixture of 2-methyltetrahydrofuran (2-
MeTHF) and H2O in a 3:1 ratio, 2a was obtained in
72% yield (entry 5). When a mixture of acetone and
H2O (3:1) was used, 2a was formed in only 13%
yield (entry 6). 2-MeTHF/H2O was chosen as the
optimal solvent mixture being 2-MeTHF an
(0.2 M, (3:1)), [Ir] (2 mol%), NaNO2 (5 mol%), I2 (0.5
1
equiv.) were used. [b] Yield determined by H NMR
spectroscopy against an internal standard. [c] 0.04 M. [d]
Without NaNO2. [e] NIS instead of I2; a mixture of
unknown byproducts was observed. [f] KI instead of I2;
after 48 h, only starting material was observed.
as the optimal conditions for studying the substrate
scope, i.e., 0.5 equiv. of I2, 5 mol% of NaNO2, and 2
mol% of iridium complex II. Remarkably, oxidation
by-products, such as enone 3, were not observed
under these reaction conditions. The reaction time
was kept to 48 h in all instances, which is the time
needed to obtain the reported yields (see the
Supporting Information, Figure S1).
Having established these optimal conditions, the
substrate scope was investigated (Scheme 2).
Aliphatic allylic alcohols bearing terminal alkenes
(2a-2c) gave the desired -iodoketones in yields of
ca. 65%. Aromatic allylic alcohols (2d-2e) were also
well tolerated. Additional functional groups in the
allylic alcohols, such as benzyl-protected alcohols,
additional double bonds, and silyl ethers, were well
tolerated, and the corresponding -iodinated products
were formed (2g-2i). Allylic alcohols bearing internal
alkenes (1j-1n) and even primary allylic alcohols (1o-
1q) also underwent the isomerization / halogenation
2
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10.1002/adsc.201800661
Advanced Synthesis & Catalysis
reaction under the optimized reaction conditions. For
the latter, aldol byproducts were not detected. A
competition experiment between alcohol 1a and 1j,
having a terminal and an internal double bond,
respectively, was performed. It was observed that the
former reacted slightly faster (See Scheme S2).
Importantly, in all instances, the products (2) were
obtained as single constitutional isomers.
previous studies on the isomerization of allylic
alcohols with [Cp*Ir(III)] complexes,[11] the iridium
catalyst promotes a 1,3-hydrogen shift. This was
supported by performing the reaction of allylic
alcohol 1m[D1] (97% D), which afforded 2m[D1]
with a 96% D at C (Scheme 4). Remarkably, the
reactions were carried out using only 5 mol% of
NaNO2 and 0.5 equiv. of I2, and, in contrast to our
previous reports,[9] in the absence of an acid additive.
A proposed mechanism is shown in Scheme 5. The
[IrCp*(H2O)3]SO4 (2 mol%)
O
OH
NaNO2 (5 mol %), I2 (0.5 equiv.)
R1
R2
R1
R2
2-MeTHF / H2O (3:1), rt, O2 atm., 48 h
R1 = Alkyl, aryl or H; R2 = Alkyl, aryl or H
I
2
1
O
O
O
O
Ph
Ph
Ph
I
I
I
I
2c
2b
2d
2a
64%
65%
64%
79%
O
O
O
O
BnO
I
I
I
I
iBu
2e
71%
2f
2g
47% (d.r. = 1:1)
2h
66%
67% (d.r. = 1:1.2)
TBSO
O
O
O
O
O
Ph
Ph
Ph
Ph
I
I
I
I
I
2m
2i[a]
2j
2k
2l
40%
62% (d.r. = 1:2)
42%
35%
49%
O
O
O
O
Scheme 3. Synthesis of-aminoketones. Yield
OBn
Ph
1
determined by H NMR spectroscopy against an internal
I
I
I
I
2n
2o
57%
2p
2q
standard. Isolated yields in parentheses.
60% (d.r. = 1:1)
60%
47%
reaction of the allylic alcohol with the iridium
catalyst[11,13] promotes the 1,3-hydrogen shift,
resulting in formation of a enolate intermediate. Upon
Scheme 2. Substrate scope. [a] TBS
butyldimethylsilyl. Only isolated yields.
=
tert-
[IrCp*(H2O)3]SO4 (2 mol%)
O
D
It was observed that the isolated yields differed
OH
NaNO2 (5 mol %), I2 (0.5 equiv.)
D
1
substantially from the yields determined by H NMR
Ph
Ph
1m[D1] (97% D)
2-MeTHF / H2O (3:1), rt, O2 atm., 48 h
I
spectroscopy using an internal standard (See Scheme
S1) in the Supporting Information). For example, a
90% yield of 2a was measured against an internal
standard (Table 1, entry 7), but only 64% yield could
be isolated. We anticipated that this was due to the
instability of -iodoketones, which decomposed
during purification procedures. To prove this
hypothesis, the crude reaction mixtures were treated
with a variety of amines, and the corresponding -
aminoketones 3a-3g were isolated in yields that in
general corresponded well with those determined by
internal standard (Scheme 3). Since -aminoketones
3a-3g are formally derived from unsymmetrical
aliphatic ketones (i.e., with unbiased enolizable
methylene groups), their direct preparation from
these precursors would result in the formation of
mixtures of - and ’-aminoketones. In contrast, the
synthetic route shown in Scheme 4 affords these
compounds as single constitutional isomers and in
excellent yields.
2m[D1]
(96% D only at Cb)
Scheme 4. Deuterium labelling studies.
+ H3O
[*CpIrX]
O
H
1/2 O2
I2
NO
R1
R2
x 2
NO2
2HI
[Cp*IrX]
OH
H
R1
R2
NO + NO2 + H2O
2NaNO2
1
O
H
R1
R2
2HNO2
precatalyst phase
2
I
Scheme 5. Proposed mechanism.
reaction with molecular iodine, -iodoketone 2 is
formed.[6,10] HI is formed as a byproduct, which in
turn protonates NaNO2 to give nitrous acid.[14] The in
The mechanism was investigated. Under the
reaction conditions, and in agreement with our
3
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10.1002/adsc.201800661
Advanced Synthesis & Catalysis
Reference
situ formation of HI justifies that no acid additive is
needed for ensuring protonation of NaNO2. [9d,15] Once
HNO2 is formed, it rapidly decomposed into NO2,[15]
a good oxidant that acts as an electron-transfer
mediator in the oxidation of iodide by oxygen, the
stoichiometric oxidant.
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In conclusion, we have described the synthesis of
-iodoketones from the corresponding allylic
alcohols and molecular iodine. The method relies on
an Ir(III)-catalyzed 1,3-hydrogen shift followed by an
aerobic oxidative iodination. The reaction uses just
0.5 equivalents of molecular iodine, in combination
with NaNO2 as oxidation catalyst and oxygen as the
final terminal oxidant. A wide range of -
iodocarbonyl compounds have been synthesized, all
as single constitutional isomers. A one-pot procedure
for the transformation of allylic alcohols into -
aminoketones has also been developed.
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Experimental Section
General procedure for the synthesis of -iodoketones
from allylic alcohols: In a pressure tube, NaNO2 (0.7 mg,
0.01 mmol, 5 mol%), [Cp*Ir(H2O)3]SO4 (2 mg, 0.004
mmol, 2 mol%) and I2 (25.3 mg, 0.1 mmol, 0.5 equiv.)
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(3.75 mL) and H2O (1.25 mL) was added to the mixture.
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stirred at room temperature for 48 h, and subsequently
quenched with an aqueous solution of Na2S2O3 (1.5 mL)
and extracted with Et2O (3 x 2 mL). The combined organic
phases were dried over MgSO4 and the solvent was
reduced under pressure. The final product was purified by
column chromatography using petroleum ether / EtOAc
(99:1) mixture as eluent.
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General procedure for the synthesis of -aminoketones
from allylic alcohols: In a pressure tube, NaNO2 (0.7 mg,
0.01 mmol, 5 mol%), [Cp*Ir(H2O)3]SO4 (2 mg, 0.004
mmol, 2 mol%) and I2 (25.3 mg, 0.1 mmol, 0.5 equiv.)
were added. The tube was sealed with a Teflon lined cap
and the allylic alcohol 1c (26 mg, 0.2 mmol) dissolved in
2-MeTHF (3.75 mL) and H2O (1.25 mL) was added to the
mixture. The pressure tube was purged with oxygen (1
atm) and kept under oxygen (1 atm) by using a balloon.
The reaction was stirred at room temperature for 24 h, and
the corresponding amine (0.3 mmol) was added. The
mixture was stirred 16 h under air, and subsequently
quenched with an aqueous solution of Na2S2O3 (1.5 mL)
and extracted with Et2O (3 x 2 mL). The combined organic
phases were dried over MgSO4 and the solvent was
reduced under pressure. The final product was purified by
column chromatography using petroleum ether / EtOAc
(9:1) mixture as eluent.
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Acknowledgements
This project was supported by the Swedish Research Council
through Formas, and also by the Knut and Alice Wallenberg
Foundation, and the Slovenian Research Agency (P1- 0134 and
MR 36492, ARRS-SP-2990/17). A. S.-M. was supported by the
Generalitat Valenciana, the European Social Fund and
Universitat de València (Spain) through a postdoctoral grant. Š.
M. was supported by COST Action CM1205 CARISMA (Catalytic
Routines for Small Molecule Activation) and an Ad-Futura grant.
We also thank Dr A. Bermejo Gómez for helpful discussions.
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Mohannazadeh,
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under otherwise identical conditions, a substantial
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10.1002/adsc.201800661
Advanced Synthesis & Catalysis
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