Transition-metal-free decarboxylative bromination of aromatic carboxylic acids

Article abstract of DOI:10.1039/c8sc01016a

Methods for the conversion of aliphatic acids to alkyl halides have progressed significantly over the past century, however, the analogous decarboxylative bromination of aromatic acids has remained a longstanding challenge. The development of efficient methods for the synthesis of aryl bromides is of great importance as they are versatile reagents in synthesis and are present in many functional molecules. Herein we report a transition metal-free decarboxylative bromination of aromatic acids. The reaction is applicable to many electron-rich aromatic and heteroaromatic acids which have previously proved poor substrates for Hunsdiecker-type reactions. In addition, our preliminary mechanistic study suggests that radical intermediates are not involved in this reaction, which is in contrast to classical Hunsdiecker-type reactivity. Overall, the process demonstrates a useful method for producing valuable reagents from inexpensive and abundant starting materials.

Full text of DOI:10.1039/c8sc01016a

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Transition-Metal-Free Decarboxylative Bromination of Aromatic
Carboxylic Acids
Jacob M. Quibell,a† Gregory J. P. Perrya,b†, D. M. Cannasa and Igor Larrosa*,a
Received 00th January 20xx,
Accepted 00th January 20xx
Methods for the conversion of aliphatic acids to alkyl halides have progressed significantly over the past century, however,
the analogous decarboxylative bromination of aromatic acids has remained a longstanding challenge. The development of
efficient methods for the synthesis of aryl bromides is of great importance as they are versatile reagents in synthesis and
are present in many functional molecules. Herein we report a transition metal-free decarboxylative bromination of
aromatic acids. The reaction is applicable to many electron-rich aromatic and heteroaromatic acids which have previously
proved poor substrates for Hunsdiecker-type reactions. In addition, our preliminary mechanistic study suggests that radical
intermediates are not involved in this reaction, which is in contrast to classical Hunsdiecker-type reactivity. Overall, the
process demonstrates a useful method for producing valuable reagents from inexpensive and abundant starting materials.
DOI: 10.1039/x0xx00000x
www.rsc.org/
corresponding alkyl bromides in the presence of either an
iridium or silver catalyst.
Introduction
Conversely, the decarboxylative bromination of aromatic
Aryl bromides are the substrate of choice when performing
transition metal-catalysed cross-coupling reactions1 or
preparing Grignard and organolithium reagents.2 They are also
used in a variety of other transformations, such as nucleophilic
substitution and HalEx reactions,3 and are the core structures
in many natural products and dyes.4 Consequently, developing
efficient methods for the synthesis of aryl bromides remains
an important objective.5 The ability to directly substitute a
carboxyl group with a bromo group has interested the
synthetic community for many years. This transformation was
first demonstrated by Borodine over a century ago, but came
to bear the name “The Hunsdiecker Reaction” during the
acids has suffered from a slower pace of development
(Scheme 1B). Early findings demonstrated that the
bromination of aromatic acids could indeed proceed, however,
the reaction with electron-rich substrates was unselective and
electron-deficient aromatics gave varying yields (Scheme 2).11
Many have looked to solve these issues, but current
procedures still suffer as they (a) require stoichiometric
transition metals, (b) are of poor generality, and/or (c) are
unselective.12 This is disappointing as decarboxylative
bromination holds potential as an economic route for aryl
halide formation;13 benzoic acids are inexpensive and
abundant, and the bromide group is a handle for selective
transformations. We were eager to reinvestigate the aromatic
Hunsdiecker reaction in order to establish a more efficient and
selective route for aryl bromide formation. Here we reveal the
1940’s and is now
a fundamental reaction in organic
synthesis.6,7 The reaction involves the mixing of an aliphatic
carboxylic acid with bromine in the presence of a silver salt to
produce the desired alkyl halide. Various developments in this
area were made during the latter half of the 20th century,8
however, the applicability of all these methods was limited
due to the requirement of stoichiometric transition metal salts
and/or poor generality. It is only recently that significant
progress has been made in the decarboxylative bromination of
aliphatic acids (Scheme 1A). Namely, the groups of Glorius9
and Li10 have demonstrated that primary, secondary and
tertiary carboxylic acids can be converted into the
development of
a transition metal-free decarboxylative
bromination that is applicable to a variety of electron-rich
aromatic acids. In addition, preliminary investigations begin to
shed light on the mechanism of this reaction.
Results and discussion
We have recently reported
a
transition-metal-free
decarboxylative iodination of aromatic acids.14 The success of
this procedure lies in the ability to prepare a variety of aryl
iodides, simply by heating a benzoic acid in the presence of I2.
We therefore questioned whether a similarly efficient and low-
cost decarboxylative bromination could be developed. We
began our investigation by exposing the benzoic acid 1a to our
previous conditions, but switching the halogen source from I2
to Br2 (Table 1). Unfortunately, this resulted in the undesired
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Scheme 1: Timeline of the contrasting progress in A) aliphatic vs B) aromatic decarboxylative bromination.
suggesting the position of decarboxylation must be sufficiently
nucleophilic for the decarboxylative bromination to occur.
Other highly electron-rich substrates
undergo the desired transformation, including non-ortho-
substituted benzoic acids 1b 1h), which are generally
(1d-1h) could also
(
,
unreactive in transition metal-mediated decarboxylative
functionalisations. The procedure can also be applied on a
large scale, thus, 5.5 g of the brominated product 2e was
prepared using the standard conditions on the bench top at
room temperature, without requiring column
Scheme 2: Current status of the aromatic Hunsdiecker
reaction.
formation of the brominated acid 1a’ and dibrominated
product 2a’ and none of the desired product 2a (Table 1, Entry
1). This reactivity is comparable with the aromatic Hunsdiecker
reaction shown in Scheme 2 and demonstrates the challenges
Table 1. Optimisation of the Transition Metal Free
Decarboxylative Bromination.
for achieving
a selective bromination. By lowering the
equivalents of Br2 the selectivity could be improved, however,
a large amount of the brominated acid 2a’ was still produced
(Entry 2). We then investigated less electrophilic bromine
sources, such as NBS (N-bromosuccinimide) and DBH (1,3-
dibromo-5,5-dimethylhydantoin), however
a mixture of
products was still obtained and the desired product was
formed in low yield (Entries 3 and 4). We then turned to the
use of tribromide reagents as bromine sources for this
transformation. Although pyridinium tribromide performed
poorly in this reaction (entry 5), we found that tetraalkyl
ammonium tribromide salts, N(Me4)Br3 and N(nBu4)Br3,
displayed good reactivity and high selectivity for the desired
decarboxylative bromination (entries 6 and 7). N(nBu4)Br3 was
chosen as the brominating reagent of choice, allowing the
product to be isolated in 90% yield. Further control
experiments revealed that the reaction does not proceed in
the absence of a base (Entry 8), but that performing the
reaction in the dark or adding one equivalent of water had
little effect on the reaction (Entries 9 and 10).15
Entry
1b
[Br]
Br2
1a
2a
1a’
2a’
trace
0
23
72
2
3
Br2
NBSc
8
58
6
26
21
56
9
3
trace
7
4
DBHd
PyHBr3
40
32
54
5
e
5
39
6
6
0
6
N(Me4)Br3
N(nBu4)Br3
N(nBu4)Br3
N(nBu4)Br3
N(nBu4)Br3
85
2
7
5
91 (90)f
0
1
trace
0
8g
9h
10i
100
11
10
0
Having demonstrated an efficient transition metal-free
decarboxylative bromination, we then turned to exploring the
scope of this reaction (Scheme 3). Previously, the
decarboxylative bromination of 4-methoxybenzoic acid under
Hunsdiecker-type conditions resulted in a mixture of products
(Scheme 2), therefore we were impressed to observe the
formation of the aryl bromide 2b in high yield and high
selectivity. This clearly demonstrates the advantages of our
84
2
trace
3
85
trace
a
Reaction conditions: 1a (0.2 mmol), [Br] (0.2 mmol, 1.0 equiv),
K3PO4 (0.2 mmol, 1.0 equiv), MeCN (1.0 mL), 100 °C, 4 h. Br2 (0.6
mmol, 3.0 equiv).
dimethylhydantoin. pyridinium tribromide Yield in parenthesis is
of isolated material. Isolated as a mixture with 2a’ (2a:2a’, >150:1).
g No K3PO4 added. h Performed in the dark. i 1.0 equiv H2O added.
b
c
d
N-bromosuccinimide.
1,3-dibromo-5,5-
e
f
procedure over previous techniques. The desired product, 2c
,
was not observed when using 3-methoxybenzoic acid,
2 | J. Name., 2012, 00, 1-3
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(
2o
substituents were unreactive under these conditions (2z
In light of this, we were surprised to observe good reactivity
with electron-poor polyfluorinated benzoic acids (2ad 2af).
-
2y). Benzoic acids that do not bear electron-donating
-2ac).
-
This goes against the general trend of reactivity in this reaction
and we are currently investigating the cause of this unique
behaviour.
The procedure could also be applied to
a range of
heteroaromatic acids (Scheme 4). The bromination of
heteroaromatic acids is highly limited as elevated
temperatures (>160
are generally necessary.16 Our conditions were applicable to
indoles (4a), benzothiophenes (4b 4c) and benzofurans (4d).
standard reaction conditions
°C) and stoichiometric transition metals
,
Unfortunately,
under
benzothiophene-(4e)
(4f) afforded undesirable levels of
and, to an extent, benzofuran-2-
carboxylic acid
dihalogenation. This side-reaction, namely the β-bromination
of benzo-fused five-membered heterocycles, is well-known to
proceed readily at room-temperature with
brominating agents; thus representing a limitation of our
methodology. A range of 5-membered heterocycles (4g 4j) as
well as pyridine (4k), chromone (4l) and cinnamic acid (4m
a variety of
-
)
derivatives all underwent the desired decarboxylative
bromination selectively.
Scheme 3: Scope of the decarboxylative bromination of aromatic
a
acids. Reactions carried out on a 0.5 mmol scale. Ratios in
brackets indicate mono:dibrominated material by NMR analysis
b
before separation. Asterisk indicates position of dibromination.
c
d
Isolated as mixture. Room temperature. Yields determined by
NMR analysis. e N(nBu4)Br3 (4.0 equiv).
Scheme 4: Scope of the decarboxylative bromination of
heteroaromatic acids. Reactions carried out on a 0.5 mmol scale
a Ratios in brackets indicate mono:dibrominated material by NMR
analysis before separation. Asterisk indicates position of
dibromination. b Isolated as mixture. c 50 °C.
chromatography. Polymethylated benzoic acids are poorly
reactive
decarboxylations, but they, and even simple toluic acid,
showed good reactivity under our conditions (2i 2l). The
procedure could also be applied to napthoic acids, despite a
slight loss in selectivity (2m 2n). The position of dibromination
substrates
in
transition
metal-mediated
-
Having established an efficient protocol for the
decarboxylative bromination of aromatic acids, we began a
preliminary mechanistic investigation. Our initial experiment
involved the use of the oxyallyl-substituted benzoic acid 1A as
a radical clock (Figure 1a). The formation of cyclised products,
via attack of an aryl radical on the pendent allyl chain of this
,
is indicated in both Schemes 3 and 4 by a red asterisk. A range
of halogenated and trifluoromethylated benzoic acids were
successfully decarboxylated, however, the presence of a
methoxy group was necessary to maintain efficient reactivity
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×
109 s–1),17
Figure 1. Mechanistic investigations.
compound, is an extremely fast process (k = 8
therefore, if cyclised products were to be observed in this
reaction a radical mechanism could be suggested. Upon
exposing oxyallyl-substituted benzoic acid 1A to our standard
reaction conditions we only observed the formation of the aryl
bromide 2A and none of the cyclised product. In light of this,
we can suggest that either the reaction does not proceed
through a radical mechanism or, if radicals are involved, then
the rate at which the product is formed from the radical
intermediate is an exceptionally fast process. This is an
interesting observation as similar experiments that have
a) Radical clock experiment
O
O
CO2H
Br
K3PO4
MeCN, 50 °C
N(nBu4)Br3
+
(1.0 equiv)
MeO
MeO
1A
cyclised products not observed
2A 60%
b) DFT study of the proposed path
previously
decarboxylations of aliphatic carboxylic acids have strongly
supported
radical mechanism.18 Likewise, previous
been
conducted
on
Hunsdiecker-type
O
O
O
OMe
OMe
OMe
OMe
Br
a
Br
O
OH
OMe
O
Hunsdiecker-type decarboxylations of aromatic acids have also
been proposed to proceed through radical intermediates.12k-l,
Overall, although the above result does not definitively
Br
OMe
OMe
(0.0)
OMe
15b,18
(19.2)
(-49.9)
2e + CO2
1e
I
TS-II
rule out a radical mechanism, it calls for a more thorough
evaluation of Hunsdiecker-type reactivity.
c) Experimental and calculated 13C-KIEs
Our previous work on decarboxylative iodinations
established a concerted decarboxylation-iodination process,
via a 4-membered transition state, as a possible non-radical
pathway for decarboxylative halogenations.14 Following a
similar protocol (Figure 1b), our DFT study found a pathway for
decarboxylative bromination proceeding through an analogous
OMe
O
C1
C2
C3
C4
C5
2
1
1.014(4) 1.028(4) 0.996(2) 1.000*
1.009(6) 1.025(5) 0.992(2) 1.000*
1.001(5)
0.997(4)
1.001
OH
5
1.013
1.023
0.997
1.000
3
4
OMe
a) Standard reaction conditions with benzoic acid 1A at 50 °C for 30
min. b) Energies calculated in acetonitrile (B3LYP-D3BJ/6-
31+G(d)).24 Gibbs free energies (G) in kcal mol-1. c) Experimental
KIEs (in black), the uncertainty on the last figure is reported in
brackets. For C4 a KIE of 1.000 was assumed. 25 Calculated KIEs (in
red) for the proposed path. 26
concerted decarboxylation-bromination transition state, TS-II
.
Thus, our current mechanistic hypothesis is as follows: the
benzoic acid is initially transformed into the hypobromite
species
hypobromite then undergoes decarboxylation via
I
upon exposure to K3PO4 and N(nBu4)Br3.19 The
a
4-
membered transition state (TS-II), to provide the product 2e
with concomitant loss of CO2. The barrier for this
transformation was calculated to be 19.2 kcal mol-1, which is
and 1.025 ± 0.005 were measured for C2. This values are
consistent with the proposed pathway where a concerted
decarboxylation-bromination transition state is involved in the
product determing step (Figure 1b). The lower KIE for C1 in
comparison to C2 suggests either an early transition state,27 or
that another kinetically relevant step is occuring prior to the
product determing step.Error! Bookmark not defined.e
Examination of the reaction path by DFT (TS-II to 2e) revealed
an early formation of C1–Br bond, resulting in an “hidden”
Wheeland intermediate.28 Extrusion of CO2 from this transient
species took place late along the reaction coordinates, thus in
agreement with the experimental observations.29 To further
probe our mechanistic hypothesis, the KIE values for the
proposed path were calculated (Figure 1c). Computed and
experimental values were found to be in excellent agreement,
lending strong support to the proposed concerted
decarboxylation-bromination pathway.
consistent with
temperature.20
a
process that proceeds at room
We further probed the mechanism of this reaction by
conducting 13C/12C KIE experiments. Heavy atom isotope
effects have been widely used as
a means to study
decarboxylation events in chemical and enzymatic processes.21
The KIE at the C1 position for decarboxylation processes can
be accurately determined at natural abundance by measuring
the isotopic composition of the evolved CO2 through mass-
spectroscopy technique.22 Unfortunately, with this method no
information is gained on the other carbon atoms. Exploiting
quantitative 13C-NMR, Singleton and co-workers have devised
a useful procedure for determining intermolecular competitive
13C/12C KIEs at all positions at natural abundance.23 Over the
course of the reaction, the starting material is progressively
enriched in the slowest reacting isotopologues. By evaluating
the isotopic composition in the starting material before and
after the reaction the KIEs can be determined. This has proved
a powerful tool in elucidating reaction mechanisms and we
were eager to test its value on our system. Two independent
experiments were performed on 2,6-dimethoxybenzoic acid
We have conducted a preliminary mechanistic study of the
developed decarboxylative bromination of aromatic acids. At
present, we have strong evidence that excludes the
intermediacy of aryl radicals (Figure 1a). By measuring the
13C/12C KIEs and performing DFT calculations we identified a
concerted decarboxylation-bromination as possible pathway
for this transformation (Figure 1b-c). This represents an
alternative mechanism for hunsdiecker-type reactivity, as
radicals are usually considered key intermediates in similar
processes. While further investigations are necessary to better
(
1e) under standard reaction conditions at 30 °C for 70
minutes (Figure 1c). Remarkably, a primary KIE was observed
at both C1 and C2 positions: KIEs of 1.014 ± 0.004 and 1.009 ±
0.006 were obtained for C1, while larger KIEs of 1.028 ± 0.004
4 | J. Name., 2012, 00, 1-3
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establish the mechanism of this reaction, we believe that these
initial studies highlight previously unrealised features of our
system. We hope that these results inspire future studies that
may greatly impact this and related procedures, and lead to
the development of more efficient decarboxylative
technologies.
1996. (d) N. Sotomayor and E. Lete, Curr. Org. Chem. 2003, 7, 275–
300.
3
For nucleophilic substitution see (a) J. F. Burnett and R. E. Zahler,
Chem. Rev. 1951, 49, 273–412. (b) J. F. Hartwig, Synlett 2006, 1283–
1294. Halogen Exchange see: (c) A. Klapars and S. L. Buchwald, J.
Am. Chem. Soc. 2002, 124, 14844–14845. d) M. Chen, S. Ichikawa
and S. L. Buchwald, Angew. Chem. Int. Ed. 2015, 54, 263–266. e) T.
D. Sheppard, Org. Biomol. Chem. 2009, 7, 1043–1052. aryl radical
formation see (f) W. P. Neumann, Synthesis 1987, 665–683. (g) H.
Kim and C. Lee, Angew. Chem. Int. Ed. 2012, 51, 12303–12306. (h) I.
Ghosh, T. Ghosh, J. I. Bardagi and B. Konig, Science 2014, 346, 725–
728. aryne generation see (i) H. Pellissier and M. Santelli,
Tetrahedron 2003, 59, 701–730. (j) R. A. Moss, M. S. Platz and M.
Jones, Jr., In Reactive Intermediate Chemistry; Winkler, M.; Wenk,
H. H.; Sander, W., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, USA,
2005; pp 741–794.
Conclusions
Due to slow progress and issues with selectivity, the utility of
the aromatic Hunsdiecker reaction has previously failed to be
fully realised. In this report we have detailed the successful
development of a high yielding aromatic Hunsdiecker-type
reaction. This has led to the development of a decarboxylative
bromination of electron-rich aromatic acids using low-cost and
abundant starting materials. The avoidance of transition
metals and the ability to scale-up the reaction make the
process attractive for its simplicity and low cost. The
Hunsdiecker reaction is commonly proposed to proceed via a
radical pathway, however, our combined experimental and
theoretical mechanistic study has suggested an alternative
mechanism that does not involve radical intermediates. These
results directly challenge a long-held view of Hunsdiecker-type
reactivity. Further studies are necessary, but we hope that
4
(a) A. Butler and J. V. Walker, Chem. Rev. 1993, 93, 1937–1944. (b)
J. L. Wolk and A. A. Frimer, Molecules 2010, 15, 5473–5580. (c) J. L.
Wolk and A. A. Frimer, Molecules 2010, 15, 5561–5580. (d) G. W.
Gribble, J. Chem. Educ. 2004, 81, 1441–1449.
5
For selected approaches for the preparation of aryl bromides see
Ref 3e and (a) R. Taylor, Electrophilic Aromatic Substitution; John
Wiley: New York, 1990. (b) V. Snieckus, Chem. Rev. 1990, 90, 879–
933. (c) A. Roglans, A. Pla-Quintana and M. Moreno-Mañas, Chem.
Rev. 2006, 106, 4622–4643. (d) D. Kalyani, A. R. Dick, W. Q. Anani
future investigations will better elucidate this mechanism. and M. A. Sanford, Org. Lett. 2006, 8, 2523–2526. (e) C. J. Teskey, A.
Y. W. Lui and M. F. Greaney, Angew. Chem. Int. Ed. 2015, 54,
Overall, we believe that this report demonstrates the potential
of decarboxylative halogenation as an efficient route to value-
added chemical commodities.
11677–11680.
6
(a) A. Borodine, Justus Liebigs Ann. Chem. 1861, 119, 121–123. (b)
H. Hunsdiecker and C. Hunsdiecker, Ber. Dtsch. Chem. Ges. 1942,
75B, 291–297. (c) C. Wilson, in Org. React., John Wiley & Sons, Inc.,
Hoboken, NJ, USA, 2011, pp. 332–387.
Conflicts of interest
7 (a) D. Crich, In Comprehensive Organic Synthesis; B. M. Trost, I.
Fleming, Eds.; Pergamon Press, 1991; Vol. 7, pp 717–734. (b) D.
Crich and K. Sasaki, in Comprehensive Organic Synthesis II. P.
Knochel, G. A. Molander, Eds.; Elsevier, 2014, pp. 818–836. (c) J.
J. Li, In Name Reactions. A Collection of Detailed Reaction
Mechanisms, 3rd Edition.; Springer-Verlag Berlin Heidelberg,
2006, pp. 310–311. d) L. Kürti and B. Czakó, In Strategic
Applications of Named Reactions in Organic Synthesis; Elsevier,
California, SD, USA, 2005, pp. 218–219.
“There are no conflicts to declare”.
Acknowledgements
We gratefully acknowledge the Engineering and Physical
Sciences Research Council for funding (EP/L014017/2 and
EP/K039547/1). We thank Dr. Ralph Adams (UoM) for the
quantitative NMR experiments.
8
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For reports that require stoichiometric transition metals see
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ARTICLE
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24 For information on the solvent correction model (SMD) see: (a) V.
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25
The signal of C4 and C6 was used as “internal standard” in the
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26
Kinetic isotope effects were calculated using ISOEFF98 according
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14
G. J. P. Perry, J. M. Quibell, A. Panigrahi and I. Larrosa, J. Am.
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15
Previous decarboxylative halogenation procedures have required
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Attempts to establish benzoyl hypobromite I as a definite
29 See SI for further details.
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DOI: 10.1039/C8SC01016A
Transition-Metal-Free Decarboxylative Bromination of Aromatic Carboxylic
Acids
Jacob M. Quibell, Gregory J. P. Perry, D. M. Cannas and Igor Larrosa*
Aromatic acids are converted into aryl bromides simply and efficiently via decarboxylation
providing new depth and insight into Hunsdiecker-type reactivity