Intramolecular Friedel-Crafts Acylation Reaction Promoted by 1,1,1,3,3,3-Hexafluoro-2-propanol

Article abstract of DOI:10.1021/acs.orglett.5b02851

Simple dissolution of an arylalkyl acid chloride in 1,1,1,3,3,3-hexafluoro-2-propanol promotes an intramolecular Friedel-Crafts acylation without additional catalysts or reagents. This reaction is operationally trivial in both execution and product isolation (only requiring concentration followed by purification) and accommodates a broad range of substrates. Preliminary studies that bear upon potential reaction mechanisms are reported.

Full text of DOI:10.1021/acs.orglett.5b02851

Letter
pubs.acs.org/OrgLett
Intramolecular Friedel−Crafts Acylation Reaction Promoted by
1,1,1,3,3,3-Hexafluoro-2-propanol
Hashim F. Motiwala, Rakesh H. Vekariya, and Jeffrey Aube*,†
́
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
S
* Supporting Information
ABSTRACT: Simple dissolution of an arylalkyl acid chloride in 1,1,1,3,3,3-
hexafluoro-2-propanol promotes an intramolecular Friedel−Crafts acylation
without additional catalysts or reagents. This reaction is operationally trivial in
both execution and product isolation (only requiring concentration followed by
purification) and accommodates a broad range of substrates. Preliminary studies
that bear upon potential reaction mechanisms are reported.
a
Table 1. Exploration of Reaction Conditions
he venerable Friedel−Crafts (FC) acylation reaction is
Tone of the most powerful tools for the synthesis of
aromatic ketones.1 The reaction is traditionally promoted by
excess amounts of Lewis or Brønsted acids such as AlCl3 and
H2SO4 and utilizes acyl halides, anhydrides, or sometimes
carboxylic acids as acylating reagents (Scheme 1).1e,2 The need
for superstoichiometric amounts of an acid catalyst has been
ascribed to product inhibition arising from complexation
between the ketone product and the acid catalyst and often
necessitates tedious product isolation involving aqueous
workup to hydrolyze the formed complex, leads to the loss of
the catalyst, and contributes to toxic and corrosive waste
streams.1c,d The importance of the FC acylation reaction for the
synthesis of aromatic ketones has spurred efforts to develop
more efficient and ecofriendly versions that overcome the
limitations of product inhibition and harsh reaction conditions,
often including >100 °C temperatures.1c,d,2c,3 Strategies to
accomplish this include the use of zeolites,4 solid superacid5 or
mixed acid systems,6 specialized ionic liquids,7 or highly
b
entry
solvent
HFIP (equiv) time (h) yield of 3a (%)
1
HFIP (0.20 M)
2
95
97
2
HFIP (0.40 M)
2
3
HFIP (1.2 M)
2
95
4
DCM/HFIP (4:1)
DCM/HFIP (8.4:1)
DCM/HFIP (22.8:1)
CH3CN/HFIP (4:1)
CH3NO2/HFIP (4:1)
C6H5CF3/HFIP (4:1)
THF/HFIP (4:1)
CF3CH2OH (TFE)
(CF3)3COH (PFTB)
CF3CH2SH (TFET)
9.5
5.0
2.0
9.5
9.5
9.5
9.5
2
96
5
2
95
6
3
93
7
6
93
8
6
91
9
4
94
10
11
12
13
6
34
4
31
0.75
4
> 98
7
Scheme 1. Comparison between Classical FC Reactions and
the HFIP-Promoted Version
a
The acid 1a (1.0 equiv) was converted to 2a using oxalyl chloride
(2.0 equiv) and catalytic DMF in DCM under N2 atmosphere for 30
min. The reaction mixture was concentrated under N2 and vacuum;
crude 2a was dissolved in the solvent(s) noted and stirred at rt for a
b
specified period. Isolated yield of purified 3a based on starting acid,
except for entries 11−13 (NMR yields). Products were ≥96% pure by
NMR except for entry 10, which was ca. 85% pure, and entry 13, which
contained numerous byproducts.
electrophilic acylating reagents as substrates.2c Here, we show
that the intramolecular version of this reaction may be simply
accomplished by dissolving readily available acid chlorides in
the strong hydrogen-bond-donating solvent 1,1,1,3,3,3-hexa-
fluoro-2-propanol (HFIP) at room temperature without any
additional reagents or catalysts, providing product unaccompa-
Received: October 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02851
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Letter
Figure 1. Yields and ratios of ketones prepared using standard conditions (see Table 1, entry 2). Compound 3ac was reacted for 16 h. See the
Supporting Information for details.
nied by byproducts through straightforward evaporation of the
solvent (bp 58 °C) and standard purification protocols.
Our approach was inspired by our recent observation that
HFIP is able to suppress product inhibition in an intra-
molecular Schmidt reaction of alkyl azides and ketones8 and a
growing body of evidence that this solvent is highly effective in
promoting reactions that involve ionic intermediates. Relevant
here are FC alkylations in refluxing HFIP reported to occur on
cations generated from ionization of allylic alcohols9 or
epoxides.10 HFIP has also proven to be an effective medium
for FC reactions promoted by Cu11 or Li12 Lewis acids, as well
as H-bond activated Pictet−Spengler reactions.13 Contempo-
rary with our work, Paquin has described an FC benzylation
reaction in HFIP occasioned by H-bonding to a benzyl fluoride
substrate.14 while Porco and co-workers have cyclized a
preformed HFIP ester in the presence of K3PO4 at 60 °C.15
We felt that an HFIP-enabled FC acylation reaction of
commonly used acyl chlorides would have particular value for
preparing a range of useful heterocyclic systems.
We began by studying the intramolecular FC reaction of 4-
(3,4-dimethoxyphenyl)butanoic acid (1a) (Table 1). The acid
was converted into acid chloride using oxalyl chloride in
dichloromethane (DCM). Following concentration and drying
under vacuum, HFIP was added to the crude acid chloride 2a
and the reaction allowed to stir at room temperature for 2 h.
Concentration followed by chromatography afforded 6,7-
dimethoxy-1-tetralone (3a) in 95% yield (Table 1, entry 1).
Changing the molar concentration of the substrate had virtually
no effect on the yield (entries 1−3). Good results were also
obtained when HFIP was used as an additive to other solvents
(entries 4−9), particularly DCM, where the addition of 2.0, 5.0,
or 9.5 equiv of HFIP gave excellent results (entries 4−6),
although a qualitative decrease in rate was noted. In contrast,
THF had a deleterious effect, likely because it is a strong H-
bond acceptor (entry 10).16 Trifluoroethanol (TFE) was not an
effective medium for the reaction, but perfluoro-2-methylpro-
pan-2-ol (PFTB) gave excellent results (entries 11 and 12).17
B
DOI: 10.1021/acs.orglett.5b02851
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Letter
1a was converted to 3a in 83% yield in 3 h using 3.0 equiv of
HFIP without additional solvents.
Scheme 2. Experiments Pertaining to Mechanism
Scheme 2 summarizes experiments carried out to probe the
mechanism of this FC reaction. Treatment of HFIP ester 4a in
HFIP with 1.1 equiv of AcCl (HCl is generated in situ from the
action of HFIP on AcCl)8 showed that 4a is not an
intermediate en route to ketone 3a. Comparing the FC
promotion ability of 1 equiv of HCl with that of a similar
amount of HFIP in DCM, HFIP appears to be a considerably
better promoter. (It is conceivable that the miniscule amount of
dioxane present (75 μL in a 1.5 mL reaction) has a dampening
effect, but in our opinion this is unlikely.) The FC reaction was
diminished but not completely inhibited in the presence of
bases 2,6-di-tert-butyl-4-methylpyridine (DTBMP) or pyridine
(which is both a hydrogen bond acceptor (pKHB = 1.86) and a
proton scavenger18). In these cases, HFIP ester 4a was partly or
exclusively obtained. Finally, the reaction was exquisitely
sensitive to the stoichiometry between HFIP and the strong
H-bond acceptor Ph3PO, with even slight excesses of the latter
leading to very poor conversions.
These experiments support a mechanism in which the H-
bonding capabilities of HFIP are key as opposed to general acid
catalysis (the pKa of HFIP is 9.3 and HCl, likely a poorer
promoter, is −8.0). Being able to rule out a role for an in situ
formed HFIP ester by the inability of 4a to provide product,
one is left to consider some variation of the mechanism
generally accepted for conventional FC reactions or an
alternative suggested by Porco’s work.15 In the former case,
HFIP could promote the in situ ionization of acid chloride
(Scheme 3).1e,2a In this scenario, the strong hydrogen bond
donor strength of HFIP, complemented by its high ionizing
power and its ability to solvate chloride anions, could allow it to
function as solvent, hydrogen bond donor catalyst, and a Lewis
acid substitute.19 At the present time, the role, if any, of HCl
generated during the course of the reaction is unclear. Also, we
note that protonated acylium ions have also been proposed as
kinetically superior intermediates20 and might be in play here
due to the very strong H-bonding associated with HFIP. In the
latter case, the intermediate arising from attack of the aromatic
ring directly onto an acyl chloride hydrogen bonded at oxygen
would form the tetrahedral adduct shown near the bottom of
Scheme 3. Experiments to differentiate between these
possibilities are underway.
In conclusion, we have demonstrated an efficient, metal-free
variant of the intramolecular FC acylation reaction that simply
requires dissolution of a trivially available acyl chloride in HFIP.
These results are of both theoretical and practical importance
given the stature of the FC acylation reaction in laboratory and
industrial scale chemistry. In comparing the results of the
present method with those previously published (see the
Supporting Information, Table S1), these conditions are mild
and avoid excesses of harsh acids. The lack of need for an
aqueous workup provides a significant practical advantage over
classic methods. Although further work to elucidate the
mechanism of this reaction is necessary (and underway), the
utility of the method for heterocyclic synthesis has been
demonstrated and should lead to numerous applications in
organic and applied organic chemistry.
Scheme 3. Potential Reaction Intermediates
Trifluoroethanethiol (TFET) gave lower conversion compared
to TFE (cf. entries 11 and 13).
The scope of this HFIP-promoted FC acylation reaction was
probed applying the conditions in Table 1, entry 2, to a range
of structurally diverse carboxylic acids (Figure 1). In an
intramolecular FC acylation, the formation of six-membered
rings is generally favored over seven- and five-membered
rings.2c Thus, high yields of carbo- and heterocyclic compounds
bearing six-membered ketones were obtained (3a−u). Con-
sistent with known FC behavior, electron-rich aromatics and
heteroaromatics were preferred substrates. We also examined
seven- and five-membered ring-forming reactions (3v−al); the
latter, in particular, can be challenging to make via standard FC
chemistry.2c Here, cyclization to seven-membered rings
proceeded in good yields (3v−ab), and although the formation
of thiophene fused cyclopentanone (3ac) proved difficult, the
indole-fused cyclopentanones (3ad−af) were readily obtained.
Electron-rich biarylcarboxylic acids were favorable substrates
affording corresponding fluorenones and related cyclic ketones
in excellent yields (3ag−am). Finally, one example was scaled
up to gram scale without incident. Thus, 1.14 g (5.0 mmol) of
C
DOI: 10.1021/acs.orglett.5b02851
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Organic Letters
Letter
(9) Trillo, P.; Baeza, A.; Naj
7354.
́
era, C. J. Org. Chem. 2012, 77, 7344−
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02851.
■
S
(10) Li, G.-X.; Qu, J. Chem. Commun. 2010, 46, 2653−2655.
(11) (a) Arai, T.; Yokoyama, N. Angew. Chem., Int. Ed. 2008, 47,
4989−4992. (b) Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.;
Wang, Z. Org. Lett. 2014, 16, 3192−3195.
(12) Willot, M.; Chen, J. C.; Zhu, J. Synlett 2009, 2009, 577−580.
(13) Wang, L.-N.; Shen, S.-L.; Qu, J. RSC Adv. 2014, 4, 30733−
30741.
Experimental procedures, characterization data, and
NMR spectra of new compounds; comparison of results
with previously reported examples (PDF)
(14) Champagne, P. A.; Benhassine, Y.; Desroches, J.; Paquin, J.-F.
Angew. Chem., Int. Ed. 2014, 53, 13835−13839.
(15) Winter, D. K.; Endoma-Arias, M. A.; Hudlicky, T.; Beutler, J. A.;
Porco, J. A. J. Org. Chem. 2013, 78, 7617−7626.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jaube@unc.edu.
Present Address
(16) (a) Middleton, W. J.; Lindsey, R. V. J. Am. Chem. Soc. 1964, 86,
4948−4952. (b) Berkessel, A.; Adrio, J. A.; Huttenhain, D.; Neudorfl,
J. M. J. Am. Chem. Soc. 2006, 128, 8421−8426.
̈
̈
(17) PFTB is considerably more expensive than HFIP (1 g/$5.8 for
PFTB vs 1 g/$0.16 for HFIP; Oakwood Products).
(18) Laurence, C.; Berthelot, M. Perspect. Drug Discovery Des. 2000,
18, 39−60.
†Division of Chemical Biology and Medicinal Chemistry, UNC
Eshelman School of Pharmacy, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599.
Notes
(19) (a) Ratnikov, M. O.; Tumanov, V. V.; Smit, W. A. Angew. Chem.,
́ ́
Int. Ed. 2008, 47, 9739−9742. (b) Begue, J.-P.; Bonnet-Delpon, D.;
The authors declare no competing financial interest.
Crousse, B. Synlett 2004, 18−29.
(20) (a) Olah, G. A.; Prakash, G. K. S.; Donald, P.; Loker, K.;
Lammertsma, K. Res. Chem. Intermed. 1989, 12, 141−159. (b) Sato, Y.;
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Mathew, T.; Olah, G. A. J. Org. Chem. 2010, 75, 2219−2226.
ACKNOWLEDGMENTS
■
We are grateful to the University of Kansas for financial
support. Support for the NMR instrumentation was provided
by NIH Shared Instrumentation Grants (S10RR024664 and
S10RR014767) and an NSF Major Research Instrumentation
Grant 0320648.
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