Iodide as an activating agent for acid chlorides in acylation reactions

Article abstract of DOI:10.1021/ol400035f

Acid chlorides can be activated using a simple iodide source to undergo nucleophilic attack from a variety of relatively weak nucleophiles. These include Friedel-Crafts acylation of N-methylpyrroles, N-acylation of sulfonamides, and acylation reactions of hindered phenol derivatives. The reaction is believed to proceed through a transient acid iodide intermediate.

Full text of DOI:10.1021/ol400035f

ORGANIC
LETTERS
2013
Vol. 15, No. 3
702–705
Iodide as an Activating Agent for Acid
Chlorides in Acylation Reactions
Russell J. Wakeham,† James E. Taylor,† Steven D. Bull,*,† James A. Morris,‡ and
Jonathan M. J. Williams*,†
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY,
United Kingdom, and Syngenta Research and Development, Jealott’s Hill, Bracknell,
RG41 6EY, United Kingdom
j.m.j.williams@bath.ac.uk
Received January 6, 2013
ABSTRACT
Acid chlorides can be activated using a simple iodide source to undergo nucleophilic attack from a variety of relatively weak nucleophiles. These
include FriedelÀCrafts acylation of N-methylpyrroles, N-acylation of sulfonamides, and acylation reactions of hindered phenol derivatives. The
reaction is believed to proceed through a transient acid iodide intermediate.
The use of acid chlorides and activation of carboxylic
acids have long been established as successful ways to
acylate a wide variety of nucleophiles.1 Activation is
typically achieved using agents such as dicyclohexylcar-
bodiimide (DCC),2 1,1-carbonyldiimidazole (CDI),3 or
chlorotriazine.4 However, the process usually requires a
stoichiometric amount of these activating agents and the
substrate scope does have limitations. The need continues
for alternative approaches to the acylation of some prob-
lematic nucleophiles.
spectroscopic studies show the formation of the acid iodide
intermediate as well as evidence of its increased reactivity.
Although iodide has been widely used to enhance the
reactivity of alkyl chlorides in SN2 nucleophilic substitution
reactions,5 its application to acyl transfer reactions does
not appear to have been reported.
Scheme 1. Possible Mechanism for Activation of Acid Chlorides
To Allow Nucleophilic Attack from Poor Nucleophiles
Herein wedescribe how anacid chloride can beactivated
by nucleophilic attack from iodide leading to in situ for-
mation of the corresponding acid iodide which is more
electrophilic than the acid chloride (Scheme 1). 13C NMR
† University of Bath.
‡ Syngenta Research and Development.
(1) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
10827–10852.
N-Acylsulfonamides are typically synthesized by the
activation of carboxylic acids using CDI or DCC and
DMAP.6 Other notable methods are the use of rhodium
as a catalyst to access the nitrene intermediate7 and the use
(2) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 522–524.
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r
10.1021/ol400035f
Published on Web 01/23/2013
2013 American Chemical Society

of azides to activate sulfonamide.8 We proceeded on the
basis that lithium iodide could be used as an activating
agent for acid chlorides. Lithium iodide showed some
improvement over the background rate, but after a screen
of iodide sources, sodium and potassium iodide showed
the greatest enhancement of reactivity. Further optimiza-
tion led to the discovery that the rate enhancement was
completely suppressed inmostcommon solventsexceptfor
anhydrous acetonitrile and anhydrous ethyl acetate, with
the former proving to be the most effective. Finally, 60 mol %
potassium iodide and a slight excess of acid chloride were
required to drive the reaction to completion and a wide
range of N-acylsulfonamides could now be isolated in
excellent yields. It is interesting to note that increasing
the concentration of potassium iodide led to a reduction in
conversion into the N-acylsulfonamide product.
of the ester, with the steric hindrance seemingly influencing
the formation of the ketone (Table 3, entries 3 and 4).12
Table 1. Scope of Acylation of Sulfonamidesa
The reaction was extended to the synthesis of a range
of N-acylsulfonamide products (Table 1). Both aliphatic
and aromatic acid chlorides were found to be suitable
substrates, as were aliphatic and aromatic sulfonamides.
There was some partial racemization in the formation of
the chiral product in entry 12, Table 1. However, as the
product was not racemic, this suggests that the reaction did
not proceed wholly via a ketene intermediate.
Although large amounts of iodide were needed in order
to achieve a significantly beneficial rate enhancement, this
method offers clear advantages to a process where the
highly reactive acid iodide is isolated prior to use.
Next, we considered whether previous FriedelÀCrafts
acylations of pyrroles carried out within the group could
also be improved.9 We discovered that the additive lithium
iodide enhanced the reactivity of acid chlorides in these
reactions. Optimization of the process led to the discovery
that the use of lithium iodide in the presence of an acid
chloride in anhydrous ethyl acetate enhanced the FriedelÀ
Crafts acylation of N-methylpyrroles. The reaction with
benzoyl chloride could be completed within 1 h with the
reduced yield, relative to conversion, owing to difficulty in
purification.10 Table 2 summarizes the substrate scope of
this reaction.
We then continued to consider other nucleophiles that
potassium or lithium iodide might improve the acylation of,
and the formation of esters from hindered phenol derivatives
was investigated.11 2,6-Di-tert-butyl-4-methylphenol (BHT)
was chosen, and it was found that with 2.4 equiv of acid
chloride and 1.2 equiv of potassium iodide the ester product
could be produced in excellent yield (Table 3, entries 1 and 2).2
By contrast when 2,6-di-tert-butylphenol was reacted with
benzoyl chloride, the major product was the FriedelÀ
Crafts C-acylation of the para-position over the formation
a Reactions were performed on a 3 mmol scale using 3.6 mmol of acyl
chloride in 3 mL of MeCN. b Isolated yields after column chromato-
graphy. c Isolated after recrystallization (EtOH/H2O). d Isolated by
prep. HPLC.
In order to understand the possible mechanisms for the
activation of the acid chloride, several 13C NMR experi-
ments were carried out. From the literature, it is known
that the 13C carbonyl shift in benzoyl iodide occurs at
159.6 ppm, which is comparable with a shift of 168.6 ppm
for benzoyl chloride.3b We were able to run the experi-
ments within the NMR tube in CD3CN at 70 °C therefore
simulating the reaction conditions as closely as possible.
The first NMR experiment was to investigate whether the
acid iodide intermediate could be observed with the heat-
ingofbenzoylchloride and potassium iodideintheabsence
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Lett. 2010, 12, 5740–5743.
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Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA: 2000.
(11) Illi, V. O. Tetrahedron Lett. 1979, 20, 2431–2432.
(12) Teuber, H.-J.; Krause, H.; Berariu, V. Justus Liebigs Ann. Chem.
1978, 1978, 757–770.
Org. Lett., Vol. 15, No. 3, 2013
703

Table 2. Scope of Acylation of N-Methylpyrrolea
Table 3. Scope of Acylation of BHTa
a Reactions were performed on a 1 mmol scale using 1.3 mmol of
N-methylpyrrole in 1 mL of EtOAc. b Isolated yields after column
chromatography; figures in parentheses are conversions determined by
analysis of the 1H NMR spectra. c 4 h reaction time. d 20 h reaction time.
a Reactions were performed on a 3 mmol scale using 7.2 mmol of acyl
chloride in 3 mL of MeCN. b Isolated yields after column chromatography.
The formation of the N-acylsulfonamide product could be
readily followed, but no acid iodide was observed during
this time. After 24 h, all of the p-toluenesulfonamide had
been consumed and the presence of acid iodide was then
observed to reach its equilibrium position after an addi-
tional 3 h.
It seems reasonable to conclude that the rate-determining
step is the slow formation of acid iodide by reaction of
acid chloride with the iodide source. Although iodide is an
excellent nucleophile in SN2 reactions, this is not the case
for addition to the carbonyl group. The difference has been
attributed to the hard nature of an sp2 carbonyl carbon
compared with the relatively soft nature of the sp3 carbon;
therefore soft nucleophiles such as iodide are more effec-
tive at soft carbon sites.4,13
of any additional nucleophile. We were pleased to see a
peak at 159.6 ppm appear within 2 h, and this peak
remained stable at a relative (to the peak at 168.6 ppm)
integration of ∼20% implying that this is the approximate
equilibrium amount of acid iodide present. In order to
determine if the acid iodide formation caused the increase
in reactivity or whether the Lewis acidity of the potassium
was enhancing the reactivity, another experiment was car-
ried out. When tetrabutylammonium iodide was used as
the iodide source, analysis of the 13C NMR spectra re-
vealed that no acid iodide was formed in situ, with only
benzoyl chloride being detected. We therefore assume that
the potassium is necessary for the formation of the acid
iodide. However, the use of other potassium salts (KCl
or KBr) in the formation of N-acylsulfonamides produced
much reduced conversions indicating that the reaction was
not occurring via a purely Lewis acid mechanism.
In order to test the relative reactivity of the acid halides,
20 mol % benzylamine was added to the NMR tube after
the PhCOCl/PhCOI equilibrium had been reached. We
were pleased to observe that the acid iodide immediately
disappeared and that the acid chloride peak remained
present, implying that the acid iodide reacted preferentially
with the nucleophilic benzylamine.
Given the greater electronegativity of chlorine over
iodine, it is not necessarily obvious why the acid iodide is
inherently more reactive.14 We suggest that the acid iodide
is more reactive due to its greater polarizability and to the
fact that the lone pairs on the iodine are less able to overlap
with π*CdO
.
In conclusion, we have developed a synthetically useful
approach to activating acid chlorides via a proposed in situ
acid iodide intermediate, using readily available potassium
A subsequent NMR experiment involved the addition
of p-toluenesulfonamide and 1.2 equiv of benzoyl chloride
to 60 mol % KI in CD3CN; the reaction was followed by
13C NMR, and spectra were taken every 20 min for 24 h.
(13) (a) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84,
16–24. (b) Jencks, W. P.; Gilchrist, M. J. Am. Chem. Soc. 1968, 90, 2622–
2637. (c) Bender, M. L. Chem. Rev. 1960, 60, 53–113.
(14) Shagun, V. A.; Voronkov, M. G. Russ. J. Org. Chem. 2003, 39,
331–335.
704
Org. Lett., Vol. 15, No. 3, 2013

or lithium iodide. Thus, poor nucleophiles can be acylated
in good to excellent yields, sometimes using a substoichio-
metric amount of group I iodide.
Supporting Information Available. Experimental details,
optimization reactions, characterizations, 13C NMR experi-
ments, and spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the EPSRC and Syngenta
for funding and the University of Bath for further support.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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