Hexafluoro-2-propanol-Promoted Intermolecular Friedel-Crafts Acylation Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01460

The intermolecular Friedel-Crafts acylation was carried out in hexafluoro-2-propanol to yield aryl and heteroaryl ketones at room temperature without any additional reagents.

Full text of DOI:10.1021/acs.orglett.6b01460

Letter
pubs.acs.org/OrgLett
Hexafluoro-2-propanol-Promoted Intermolecular Friedel−Crafts
Acylation Reaction
Rakesh H. Vekariya‡ and Jeffrey Aube*,†
́
†Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, 125 Mason Farm Road, CB 7363,
University of North Carolina, Chapel Hill, North Carolina 27599-7363, United States
‡Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: The intermolecular Friedel−Crafts acylation was
carried out in hexafluoro-2-propanol to yield aryl and heteroaryl
ketones at room temperature without any additional reagents.
Scheme 1. Examples of HFIP-Promoted FC Chemistry
he Friedel−Crafts (FC) acylation is a fundamental way of
1
Tgenerating aromatic ketones. In its traditional form, the
reaction is promoted by Lewis acids (most commonly AlCl3) or
protic acids, generally requiring a full equivalent of catalyst or
more due to product inhibition. In recent years, numerous
researchers have sought to improve the FC reaction through
the development of effective catalysts.2 In related approaches,
researchers have also employed novel media such as ionic
liquids3 and heterogeneous supports and catalysts (e.g., zeolites,
clays, metal oxides, acids, nafion, and graphene).4 The FC
acylation can utilize a number of activated carboxylic acid
equivalents in place of the classical acyl chlorides,5 a recent
example being the use of twisted amides reported by Szostak
and co-workers.6
Hexafluoro-2-propanol (HFIP) is a useful solvent, cosolvent,
and additive in organic synthesis with a nearly unique set of
properties that include high ionizing power, strong hydrogen
bond donating ability, mild acidity, and low nucleophilicity.7 All
of these properties are favorable for electrophilic aromatic
substitution reactions, and accordingly, a number of inves-
tigators have studied FC alkylation chemistry in HFIP (Scheme
1). In 1994, Cativiela et al. studied the Diels−Alder reactions of
furan and acrolein in HFIP and observed an FC alkylation
product 3-(2-furyl)-propanal as a byproduct.8 Subsequent FC
alkylations have been reported from allylic alcohols,9
epoxides,10 and benzyl halides11 in HFIP. In addition, HFIP
has been a critical additive in asymmetric FC alkylations
catalyzed by chiral Lewis acids.12 Recently, we reported an
intramolecular FC acylation reaction in HFIP toward numerous
heterocyclic ring systems.13 Given the importance of the
standard FC acylation for synthesizing aromatic ketones, we
sought to extend the intramolecular reaction to the more
demanding intermolecular case and report our initial results
here.
dimethoxybenzene in HFIP solvent and the reaction mixture
was stirred for 5 h at rt. Solvent evaporation followed by
chromatographic purification afforded 3a/3a′ in 66% yield
(Table 1, entry 1). When added to DCM, it was necessary to
utilize 80:20 HFIP/DCM (corresponding to 10 equiv of HFIP)
to achieve results comparable to those obtained in HFIP alone
(Table 1, entries 2−4; cf. 2 equiv needed in the intramolecular
reactions13). As previously observed,13 H-bond accepting
solvents THF and acetonitrile had strongly inhibiting effects;
in the former case, 4-chlorobutyl benzoate resulting from THF
cleavage was also obtained (entries 5 and 6).14
A comparison of HFIP with the fluorinated alcohols
trifluoroethanol (TFE) and perfluoro-tert-butyl alcohol
(PFTB) was interesting insofar as neither afforded the FC
product at all (Table 1, entries 7−8). In TFE, only solvolysis of
benzoyl chloride occurred. In contrast, when PFTB was
The intermolecular FC acylation between 1,3-dimethox-
ybenzene (1a) and benzoyl chloride (2a) was used in our initial
studies (Table 1). Thus, benzoyl chloride was added to 1,3-
Received: May 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01460
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Organic Letters
Letter
a
employed, only starting materials were observed (this
phenomenon has been observed in another context15). These
results point to the privileged position of HFIP for the
promotion of these reactions and specifically downplay the role
of solvent acidity in promoting these reactions (pKa values:
TFE, 12.8; HFIP, 9.3; PFTB, 5.416). Curiously, PFTB was
found to be equally efficient in promoting the intramolecular
version of this reaction as HFIP,13 raising the possibility that in
the intermolecular reaction PFTB could tightly hydrogen bond
with the acyl chloride, thus activating it toward attack, but the
relative bulk of the solvent could prevent attack by an external
nucleophile (which would not be a problem in the intra-
molecular cases).
Best results were obtained when the nucleophilic arene was
used in excess, with the optimal ratio being about 3:1 (Table
S1, Supporting Information). In addition, no dependence of
yield on bolus vs slow addition of benzoyl chloride was noted.
Our currently optimized conditions employ 3:1 arene/acyl
chloride stoichiometry and a 0.75 M concentration of the acyl
chloride.
Table 1. Effect of Solvent on Yield
b
entry
solvent
yield,%
1
2
3
4
5
6
7
8
HFIP
8:92 HFIP/DCM
66
0
c
40:60 HFIP/DCM
80:20 HFIP/DCM
80:20 HFIP/THF
39
63
d
16
80:20 HFIP/CH3CN
23
0
e
CF3CH2OH (TFE)
c
(CF3)3COH (PFTB)
0
a
To 1,3-dimethoxybenzene (0.75 mmol, 1.0 equiv) in solvent (1 mL)
was added benzoyl chloride (0.75 mmol, 1.0 equiv). The reaction
b
mixture was stirred at rt for 5 h. Isolated yields (3a/3a′ ratios ca. 92:8
c
d
in each case). No FC reaction observed. In addition to 3a and 3a′, 4-
e
chlorobutyl benzoate was obtained in 28% yield. TFE ester of benzoyl
The scope of the reaction was then studied (Figure 1). As
observed in the intramolecular examples, electron-rich arenes
worked best, affording aryl ketones in moderate to good yields
chloride was observed by GCMS.
Figure 1. Reaction scope.
B
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(3a−3i). The singly activated anisole reacted with benzoyl
chloride to give 3j in 34% yield, but benzene did not give FC
product 3k under these conditions. Electron-rich heteroarenes,
including pyrrole, indoles, and benzothiophenes, reacted with
acyl chlorides to give corresponding heteroaryl ketones (3l−
3s). Ferrocene reacted with benzoyl chloride to give
benzoylferrocene 3t in 62% yield.
Various substituents at the para-position of benzoyl chloride
were explored. Both electron-donating and electron-with-
drawing substituents worked well under FC acylation
conditions with 1,3,5-trimethoxybenzene (3u−3y). Interest-
ingly, the strongly deactivated p-NO2-benzoyl chloride did not
react with 1,3,5-trimethoxybenzene to give an FC product (3z);
in this case, only starting materials were observed. Since this
compound also does not undergo esterification in HFIP (data
not shown), we presume that the lack of reactivity here is due
to poor activation of the acid chloride by HFIP.
A common complaint is that HFIP is too expensive to use in
fine organic synthesis. Although not cheap, HFIP can be had at
relatively low prices from specialty vendors ($0.16/g for 1 kg,
Oakwood Products, Inc.), and the lack of need for any other
reagents along with the trivial workup goes a long way toward
making up for this perceived deficiency. Moreover, the reaction
can be readily scaled up and the solvent recycled with ease.
Thus, 1,3,5-trimethoxybenzene 4 (22.71 g, 135 mmol) was
reacted with benzoyl chloride 2a (6.33 g, 45 mmol) in HFIP
(12 equiv, 57 mL) at rt to give 10.51 g of 3f (86%) (Figure 2).
°C.17 However, as previously reported13 a preformed HFIP
ester of an intramolecular acyl chloride substrate does not
undergo FC reaction when HCl is added. This observation was
also found to be true in the intermolecular version reported
here, and together these experiments strongly suggest that
HFIP acylation is not on the reaction pathway leading to
ketone. We also previously suggested that the in situ formation
of an acyl cation might be a possible reaction pathway in accord
with the mechanism usually ascribed to a classic FC reaction
(e.g., promoted by AlCl3).1e However, preliminary in situ IR
examination of the current reaction reveals direct trans-
formation into product without any sign of an acyl cation
(reported to appear at about 2308 cm−1 for the metal
complexed version18).19 Due to the absence of evidence to
the contrary, we contemplate a mechanism whereby H-bond
activation of the acyl chloride activates it for nucleophilic attack
by the arene, followed by the usual final steps of a traditional
FC reaction (Scheme 2).
Scheme 2. Plausible Reaction Mechanism
In conclusion, we have shown that our previously reported
HFIP-assisted FC acylation reaction can be carried out
intermolecularly. Both electron-rich arenes and heteroarenes
worked efficiently with a variety of acyl halides to give FC
acylation products. The workup of reaction avoids water-waste
generation which is a common drawback of traditional Lewis
acid catalyzed FC acylation reactions. In addition, we have
successfully demonstrated that HFIP can be recovered and
reused without loss of efficiency on the decagram scale.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01460.
Figure 2. Gram scale reaction.
Experimental procedures, characterization data, and
NMR spectra of new and previously reported com-
pounds (PDF)
Distillation of HFIP directly from the reaction pot afforded 46
mL of solvent, 19 mL of which were reused in a subsequent
reaction between 4 and 2a to give 3.80 g of 3f (93% yield) and
permitting the recovery of 18 mL of HFIP. Repeating this
procedure in a third cycle using this HFIP (9.5 mL) added 1.85
g of 3f (91% yield). Overall, a total of 16.16 g of 3f was
obtained from the original batch of 57 mL of HFIP, which cost
ca. $14.80 in total, leaving 45 mL of recovered solvent to use on
other occasions (in other words, we lost about $3.17 of
solvent). Most importantly, the recovered solvent was equally
as good at promoting the FC reaction as the store-bought
material (maybe even better, considering the possibility that
these recovered samples could contain traces of HCl).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jaube@unc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Hashim Motiwala (University of Michigan) for
helpful discussions and some early experiments. Financial
support by the UNC Eshelman School of Pharmacy and the
Porco and co-workers previously showed that a preformed
HFIP ester led to FC cyclization in the presence of K3PO4 at 60
C
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