Catalytic Access to Alkyl Bromides, Chlorides and Iodides via Visible Light-Promoted Decarboxylative Halogenation

Article abstract of DOI:10.1002/chem.201602251

Herein is reported the catalytic, visible light-promoted, decarboxylative halogenation (bromination, chlorination, and iodination) of aliphatic carboxylic acids. This operationally-simple reaction tolerates a range of functional groups, proceeds at room temperature, and is redox neutral. By employing an iridium photocatalyst in concert with a halogen atom source, the use of stoichiometric metals such as silver, mercury, thallium, and lead can be circumvented. This reaction grants access to valuable synthetic building blocks from the large pool of cheap, readily available carboxylic acids.

Full text of DOI:10.1002/chem.201602251

DOI: 10.1002/chem.201602251
Communication
&
Photocatalysis
Catalytic Access to Alkyl Bromides, Chlorides and Iodides via
Visible Light-Promoted Decarboxylative Halogenation
Lisa Candish+, Eric A. Standley+, Adriꢀn Gꢁmez-Suꢀrez, Satobhisha Mukherjee, and
Frank Glorius*[a]
Abstract: Herein is reported the catalytic, visible light-pro-
moted, decarboxylative halogenation (bromination, chlori-
nation, and iodination) of aliphatic carboxylic acids. This
operationally-simple reaction tolerates a range of func-
tional groups, proceeds at room temperature, and is
redox neutral. By employing an iridium photocatalyst in
concert with a halogen atom source, the use of stoichio-
metric metals such as silver, mercury, thallium, and lead
can be circumvented. This reaction grants access to valua-
ble synthetic building blocks from the large pool of
cheap, readily available carboxylic acids.
Scheme 1. a) Classical Hunsdiecker reaction proceeding via a heavy metal
carboxylate. b) Visible light-promoted decarboxylative halogenation.
Alkyl halides are ubiquitous building blocks in synthetic
chemistry, acting as electrophiles in substitution[1] and cross
coupling reactions[2] and as pro-nucleophiles when reacted to
form organometallic species such as Grignard and organocup-
rates.[3] Generally, alkyl bromides display a good compromise
between reactivity and stability compared to the correspond-
ing chloro and iodo species and as such, several methods have
been developed for their synthesis. The classic decarboxylative
bromination of alkyl carboxylic acids, discovered by Borodine[4]
and Hunsdiecker,[5] yields the one-carbon-shorter alkyl bro-
mide. The reaction proceeds in two steps via the silver carbox-
ylate, which subsequently reacts with bromine.[6] Given the re-
action’s sensitivity to the purity of the silver carboxylate, modi-
fications utilizing mercury[5] or thallium[7] carboxylates are often
preferred (Scheme 1a). Alternatively, one-pot procedures using
(super)stoichiometric heavy metals including HgO[8] or
Pb(OAc)4,[9] or excess hypervalent iodine reagents[10] have been
reported, whereas the Barton modification allows decarboxyla-
tive bromination from the pre-formed thiohydroxamate
ester.[11] Given the synthetic importance of alkyl bromides, and
the availability of carboxylic acids as traceless activating
groups, it is highly desirable to develop a simple, catalytic
method for decarboxylative bromination.
In 2012, the group of Li reported the elegant silver-catalyzed
decarboxylative chlorination of alkyl carboxylic acids using tert-
butyl hypochlorite.[12] Additionally, the same group reported
the silver-catalyzed decarboxylative fluorination using Select-
fluor.[13] However, the corresponding silver-catalyzed decarbox-
ylative bromination using N-bromosuccinimide (NBS) was limit-
ed to aryl acetic acids which lack additional substituents at the
benzylic position.[14]
Building on ongoing studies into decarboxylative functionali-
zation within our group,[15] we were interested in developing
a mild and selective catalytic method for the decarboxylative
bromination of alkyl carboxylic acids. Recently, visible light-pro-
moted[16] decarboxylation has emerged as a mild method to
access alkyl radicals from carboxylic acids, and a number of
functionalizations have been developed from this mode of ac-
tivation,[17] including the decarboxylative fluorination of car-
boxylates using Selectfluor, reported by Sammis and Paquin
and co-workers[17j,k] as well as MacMillan et al..[17l] Herein we de-
scribe the first catalytic Hunsdiecker-type bromination of alkyl
carboxylic acids, and the extension of this method to chlorina-
tion and iodination (Scheme 1b).
[a] Dr. L. Candish,+ Dr. E. A. Standley,+ Dr. A. Gꢀmez-Suꢁrez, S. Mukherjee,
Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfꢂlische Wilhelms-Universitꢂt Mꢃnster
Corrensstrasse 40, 48149 Mꢃnster (Germany)
E-mail: glorius@uni-muenster.de
Initial experiments on 18 carboxylic acids using the common
brominating reagent NBS, Cs2CO3, and photocatalyst
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (PC, dF(CF3)ppy=2-(2,4-difluoro-
phenyl)-5-(trifluoromethyl)pyridine, dtbbpy=4,4’-di-tert-butyl-
2,2’-bipyridine) in chlorobenzene under irradiation with blue
LEDs (lmax =455 nm) gave the desired product in low yield (ca.
[+] Authors contributed equally.
Supporting information for this article and ORCID for the corresponding
author are available on the WWW under
http://dx.doi.org/10.1002/chem.201602251.
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10%), which demonstrates the viability of the proposed cata-
lytic bromination. Screening of standard reaction parameters
including solvent, base and photocatalyst did not improve re-
action yield and hence, a series of control and doping experi-
ments were undertaken which suggested that the primary
alkyl bromide products were being consumed under the reac-
tion conditions (see Supporting Information for details of opti-
mization and doping experiments). Thus, alternative bromina-
tion reagents were explored, with diethyl bromomalonate
1 proving to be the best reagent evaluated.
malonate, this is presumably due to the CÀCl bond strength,
while ethyl iodoacetate proved to be too electrophilic, and
predominantly an SN2 reaction with the carboxylate was ob-
served. Fortuitously, in both cases, N-chlorosuccinimide (NCS)
3a and N-iodosuccinimide (NIS) 3b function as effective re-
agents for the desired transformations, furnishing the products
4 and 5 in good yields across a range of substrates (Table 2).
Table 2. Scope of the decarboxylative chlorination and iodination.
Using the optimized conditions, the scope of the bromina-
tion reaction was evaluated. 18, 28, and 38 carboxylic acids are
all competent substrates, though the yields of the 18 bromides
were generally lower than those obtained for the 28 and 38
products (Table 1). A wide variety of functional groups, includ-
Table 1. Scope of the decarboxylative bromination.
[a] Conditions for chlorination: carboxylic acid (1 equiv), 3a (2 equiv). PC
(2 mol%), Cs2CO3 (1 equiv), C6H5Cl (0.05m), blue LED (455 nm), 14 h. Con-
ditions for iodination: carboxylic acid (1 equiv), 3b (1.5 equiv). PC
(2 mol%), Cs2CO3 (1.5 equiv), C6H5Cl (0.05m), blue LED (455 nm), 14 h.
Interestingly, in the case of chlorination, primary carboxylic
acids give significantly higher yields than the corresponding
bromination and iodination. This could potentially reflect their
lower electrophilicity, and thus greater stability under the reac-
tion conditions.
[a] Conditions: carboxylic acid (1 equiv),
1 (2.5 equiv). PC (2 mol%),
Cs2CO3 (1 equiv), C6H5Cl (0.05m), blue LED (455 nm), 4 h. [b] EtOAc used
as solvent. [c] Reaction performed on 5 mmol scale. [d] Isolated after
chromatography as a mixture of the corresponding trisubstituted alkenes.
To further demonstrate the utility and value of this transfor-
mation, several one-pot transformations of the bromide prod-
uct were evaluated (Scheme 2). Specifically, bromide 2a was
treated with potassium phthalimide, sodium azide, sodium ni-
trite, and sodium thiocyanate to form the corresponding SN2
products. In all cases, the crude reaction mixture was diluted
with a small quantity of DMF or DMSO, the necessary reagent
was added, and the mixture was stirred at room temperature
or 808C. The desired products were isolated in good yield and
purity from this two-step, one-pot operation.
ing esters 2c, protected amines 2b and 2k, and aryl 2d and
silyl 2j ethers were well-tolerated. If chlorinated solvents are to
be avoided, the reaction can be carried out in ethyl acetate
while still providing good yields of products. Gratifyingly, this
reaction can be carried out on gram scale (5 mmol) for 2l with-
out decreasing the yield, although a longer reaction time is
necessary.
An additional application of this chemistry was demonstrat-
ed in the context of functionalization of long-chain fatty acids
(LCFA). Long aliphatic chains are essential components of de-
tergents, as well as micelles, biological membranes, and nu-
merous natural products and pheromones. Even-numbered
LCFA are cheap and readily available, while the odd-numbered
Having successfully developed the target reaction, we
turned our attention to the synthesis of other alkyl halides,
specifically chlorides[12] and iodides.[18] Preliminary efforts, using
diethyl chloromalonate and ethyl iodoacetate, did not yield
the desired alkyl chlorides or iodides. In the case of the chloro-
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carboxyl radical would afford the corresponding alkyl radical,
and atom transfer from 1 should provide the desired product
and the malonyl radical. Electron transfer to the malonyl radi-
cal from the IrII would then regenerate the photocatalyst and
furnish the malonate anion.
To further probe the photophysical properties of the reac-
tion, quantum yield analysis, following the procedure of Yoon
and Cismesia,[21] was carried out. The reaction with a primary
carboxylic acid displayed a quantum yield of 2.7, which, based
on the experimental determination of the reaction’s quenching
fraction suggests a chain length of 3.6. This outcome demon-
strates that a chain mechanism is operative in addition to the
direct, iridium-mediated reaction. Thus, two possibilities could
explain the quantum yield being greater than 1: a) the reaction
could simply be proceeding via the acyl hypobromite, as in
the classical Hunsdiecker reaction, or b) a chain-carrying spe-
cies capable of oxidizing the carboxylate must be present in
the reaction.
To examine these possibilities, an acyl hypobromite was pre-
pared from silver carboxylate 9[22] and irradiated with visible
light in the absence of photocatalyst, which yielded the corre-
sponding bromide product in quantitative yield ([Eq. (1)]). To
ascertain whether the same process can occur under the de-
veloped reaction conditions with the cesium carboxylate, 10
was prepared, treated with Br2, and irradiated with visible light,
again in the absence of photocatalyst ([Eq. (2a)]). The product
was observed in 6% yield, which suggests that a background
Hunsdiecker reaction via the hypobromite can in fact occur,[5]
but it does not account for the observed quantum yield.
Scheme 2. Derivatization of alkyl bromide and synthesis of long-chain hal-
oalkanes. See Supporting Information for details.
LCFA are generally not naturally abundant and hence much
more expensive, as are products derived from them. Therefore,
on a mole-for-mole basis, 1-bromoheptadecane costs roughly
100 times more than 1-bromooctadecane.[19] Utilizing the de-
veloped bromination reaction, stearic acid (C18) was readily
converted into 1-bromoheptadecane in a single step in 47%
yield on 5 mmol scale using 1 mol% PC. Furthermore, the anal-
ogous reactions to produce 1-chloroheptadecane and 1-iodo-
heptadecane were also demonstrated.
To examine the reaction mechanism, a series of experiments
were undertaken. Control experiments demonstrated that in
the absence of either light or photocatalyst, no reaction takes
place. Stern–Volmer luminescence quenching studies (see Sup-
porting Information) indicated the cesium carboxylate to be
the only competent quencher present in the reaction mixture.
Based on these experiments, a mechanism for the bromination
is proposed in Figure 1. Photoexcitation of the IrIII photocata-
lyst produces a strong oxidant (E1re=d2([IrIII*/IrII])= +1.21 V vs. SCE
in CH3CN) that should promote a thermodynamically favorable
single-electron oxidation of the alkyl carboxylate (hexanoate
red
1=2
ion E = +1.16 V vs. SCE in CH3CN).[20] Decarboxylation of the
Cesium carboxylate 10 was also reacted with Br2 in the pres-
ence of the PC and the product was observed in 51% yield
([Eq. (2b)]). This result and the measured quantum yield sug-
gest that a chain-carrying species derived from bromine is op-
erative.[23] As reported in the literature, species such as Br or
C
CÀ
Br2 possess sufficient potentials to oxidize the carboxylate,[24]
and thus could be functioning as the chain-carrier.
In summary, we have developed a visible light-mediated
process for the catalytic decarboxylative bromination, chlorina-
tion, and iodination of aliphatic carboxylic acids. The reaction
is redox neutral, operationally simple, and provides rapid
access to a variety of synthetic building blocks. The demon-
strated one-pot derivatization of the alkyl bromide products
generates diversely functionalized species. Additionally, the re-
action was carried out on gram scale. To the best of our knowl-
edge, this constitutes the first catalytic decarboxylative bromi-
Figure 1. Proposed mechanism for the visible light-promoted bromination.
Counterions are omitted for clarity.
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Acknowledgements
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Keywords: decarboxylation
reaction · photocatalysis · visible light
· halogenation · Hunsdiecker
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Received: May 12, 2016
Published online on && &&, 0000
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COMMUNICATION
&
Photocatalysis
L. Candish, E. A. Standley,
A. Gꢀmez-Suꢁrez, S. Mukherjee, F. Glorius*
&& – &&
Catalytic Access to Alkyl Bromides,
Chlorides and Iodides via Visible
Light-Promoted Decarboxylative
Halogenation
Br-ight approach: The catalytic, visible
light-mediated, decarboxylative bromi-
nation, chlorination, and iodination of
aliphatic carboxylic acids is reported.
This transformation requires no stoichio-
metric heavy metals and provides
access to valuable synthetic building
blocks starting from the large pool of
readily available aliphatic carboxylic
acids.
Chem. Eur. J. 2016, 22, 1 – 5
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