Solvent-free friedel-crafts cyclization with trichloroacetic anhydride

Article abstract of DOI:10.1080/00397910802663394

Friedel-Crafts cyclization products were obtained using 1.1 equivalents of environmentally benign trichloroacetic anhydride as sole reagent and solvent. The resulting ketones included benzothiepins, benzothiopyrans, benzoxepins, dibenzothiepins, dibenzoxepins, and tetralones.

Full text of DOI:10.1080/00397910802663394

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Solvent-Free Friedel–Crafts
Cyclization with Trichloroacetic
Anhydride
Ben Andrews a , Kae Bullock b , Shannon Condon b
, John Corona b , Roman Davis b , John Grimes b
Andrew Hazelwood a & Elie Tabet b
,
a Chemical Development, GlaxoSmithKline, Research
Triangle Park, North Carolina, USA
b GlaxoSmithKline, Stevenage, Hertfordshire, UK
Available online: 26 Jun 2009
To cite this article: Ben Andrews, Kae Bullock, Shannon Condon, John Corona,
Roman Davis, John Grimes, Andrew Hazelwood & Elie Tabet (2009): Solvent-Free
Friedel–Crafts Cyclization with Trichloroacetic Anhydride, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
39:15, 2664-2673
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Synthetic Communications1, 39: 2664–2673, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663394
Solvent-Free Friedel–Crafts Cyclization with
Trichloroacetic Anhydride
Ben Andrews,1 Kae Bullock,2 Shannon Condon,2 John Corona,2
Roman Davis,2 John Grimes,2 Andrew Hazelwood,1 and Elie Tabet2
1Chemical Development, GlaxoSmithKline, Research Triangle Park,
North Carolina, USA
2GlaxoSmithKline, Stevenage, Hertfordshire, UK
Abstract: Friedel–Crafts cyclization products were obtained using 1.1 equivalents
of environmentally benign trichloroacetic anhydride as sole reagent and solvent.
The resulting ketones included benzothiepins, benzothiopyrans, benzoxepins,
dibenzothiepins, dibenzoxepins, and tetralones.
Keywords: Benzothiepins, benzothiopyrans, benzoxepins, dibenzothiepins,
dibenzoxepins, Friedel–Crafts cyclization, tetralones
INTRODUCTION
Friedel–Crafts acylation is one of the most powerful reactions used to
synthesize important structural units, including biologically important
heterocycles such as tetralones (precursors to naphthols), cytotoxic ben-
zothiepins, and antihypertensive benzoxepins.[1–3] In recent years,
increasing federal regulations have been the driver for modification of
the Friedel–Crafts acylation to a more regioselective and environmentally
friendly version, particularly when it is used for large-scale synthesis of
active drug substances. To support the clinical development of a drug
candidate, we required good regioselectivity in the cyclization of arylalk-
anoic acid to the corresponding ketone (Scheme 1). Although the
Received September 11, 2008.
Address correspondence to Roman Davis, Chemical Development, Glaxo-
SmithKline, Research Triangle Park, NC 27709. E-mail: roman.d.davis@gsk.com
2664

Friedel–Crafts with Trichloroacetic Anhydride
2665
Scheme 1. Intramolecular cyclization in TCAA.
traditional Friedel–Crafts acylation had been used successfully to synthe-
size drug substances in smaller quantities, there were a number of features
of the reaction that detracted from its viability for use in large-scale
synthesis. Metal halide–mediated acylation could not be optimized
beyond 90:10 for the desired isomer, and the undesired isomer was diffi-
cult to remove. In addition, multiple equivalents of metal halide were
needed and resulted in solvent- and metal-contaminated wastes, which
were expensive to treat.[4]
We had recently developed a metal-free intermolecular acylation by
treating the in situ generated acid chloride with methanesulfonic acid
(MSA) (unpublished data). We were gratified to find that treatment of
the arylalkanoic acid with 1.1 eq. of oxalyl chloride, followed by 2.0
equivalents of MSA, resulted in good yields of ketone product, with selec-
tivity of more than 95:5 for the desired isomer. Unfortunately, this
reaction was not without drawbacks, which impeded its usefulness in
large-scale chemistry. The cyclization reaction had to be monitored care-
fully and quenched within 60 min of completion because of the slow
decomposition of the product under the reaction conditions. Although
the reaction was adopted to generate quantities (50–100 g) of drug sub-
stance, we needed more robust reaction conditions to generate multiple
kilograms of the desired compound.
To that end, we were able to use trichloroacetic anhydride
(TCAA) successfully to effect the desired transformation. TCAA acti-
vated the acid via the mixed anhydride; the trichloroacetic acid formed
as a by-product was a strong enough acid to catalyze the desired cycli-
zation. Our production sites confirm that TCA waste is far more
environmentally acceptable than other wastes commonly generated
by the Friedel–Crafts reaction.[5] Meanwhile, typical halogenated sol-
vents were replaced. We found that in many cases the reaction could
be carried out with no solvent, as long as the mixture was mobile at
70ꢀC. Where the mixture was not mobile at 70ꢀC, small amounts of
sulfolane were added to affect mobility.

2666
B. Andrews et al.
DISCUSSION
Cyclizations proceeded smoothly for all oxy-substituted (electron-rich)
substrates but were significantly slower for unsubstituted substrates.
Reactions with poorly activated aromatics required several hours to go
to completion. Electron-poor substrates did not cyclize. The reactions
of electronically activated substrates were complete within 10 min; those
reactions should be suitable for continuous flow chemistry. We selected
70ꢀC for the reaction to keep the resulting low-melting trichloroacetic
acid liquid and therefore mobile. We found that 1.1 equivalents of TCAA
was sufficient to affect all cyclizations and that additional TCAA did not
speed up the slower reactions. The reactions were robust, and the result-
ing cyclized products were stable to the reaction conditions. Water-wet
substrates required an adjustment in TCAA. When water (2% volume)
was purposely added to a reaction and TCAA adjusted to 1.15 equiva-
lents, the reaction proceeded smoothly. We opted for a simple but
energetic workup of cold aqueous sodium hydroxide containing 10%
methanol. The methanol ensured rapid decomposition of excess TCAA
and any mixed anhydrides. In most cases, the desired product crystallized
from the quench mixture in high purity. Where required, the resulting
solid was purified by recrystallization from aqueous ethanol.
Reaction Monitoring by React-IR (One Substrate)
The Mettler Toledo iC-10, which couples a fiber-optic light path to a
9.5-mm pencil probe, was used for monitoring the tetralone preparation.
Figure 1. Spectra of carboxylic acid SM, TCAA, and ketone product.

Friedel–Crafts with Trichloroacetic Anhydride
2667
Figure 2. ConcIRT evaluation.
As can be observed from the spectrum (Fig. 1), the consumption of the
carboxylic acid was monitored by the disappearance of the carbonyl
stretching at 1714 cmꢁ1. The ketone product was observed to grow in
at 1777 cmꢁ1 over the course of the cyclization.
The ConcIRT evaluation (Fig. 2) shows a gradual growth of the
product as the starting material is consumed. Formation of the mixed
anhydride intermediate was observed upon addition of TCAA. Because a
slight excess of TCAA was used, the flat trend of unconsumed TCAA
remained at the end. The ketone product appeared immediately upon
TCAA addition, indicating very fast cyclization of the activated acid.
RESULTS
Tetralones
4-(3,4-Dimethoxyphenyl)butanoic acid cyclized in 6 min in essentially quan-
titative yield to 6,7-dimethoxy-1-tetralone. 4-(4-Methoxyphenyl)butanoic
acid was significantly slower but still provided 7-methoxy-1-tetralone in
78% yield. 4-Phenylbutanoic acid required >36 h to complete cyclization,
but a 64% yield could be obtained after 16 h. We deemed this long reaction
time unsuitable for preparative synthesis. However, pure unsubstituted
1-tetralone separated from the basic workup mixture and did not require dis-
tillation. The reaction is very forgiving: when 3-methyl-4-(3-methoxyphe-
nyl)butanoic acid of 85% purity (4-oxo was the major impurity) was

2668

Friedel–Crafts with Trichloroacetic Anhydride
2669
subjected to the reaction conditions, 6-methoxy-3-methyl-1-tetralone could
be obtained in 90% yield after adjustment for 85% input purity.
Benzothiepins, Benzoxepins, Dibenzothiepins, and Dibenzoxepins
8-Methoxy-3,4-dihydro-1-benzothiepin-5(2H)-one was obtained from
3-(3-methoxyphenylthio)propanoic acid in 71% yield after 30 min.
3-(3-Methoxyphenoxy)propanoic acid cyclized cleanly, but 8-methoxy-3,
4-dihydro-1-benzoxepin-5(2H)-one could not be isolated from the waxy
mixture, even after chromatographic purification. 3-(Methoxy)dibenzo
[b,e]oxepin-11(6H)-one was obtained from 2-(3-methoxyphenoxy)-
methylbenzoic acid (10 min, 86% yield) and 8-(methoxy)dibenzo[b,e]
oxepin-11(6H)-one was obtained from 2-(3-methoxyphenyl)methoxyben-
zoic acid (10 min, 90% yield). Surprisingly, 3-(methoxy)dibenzo[b,e]thie-
pin-11(6H)-one, obtained from 2-(3- methoxyphenylthio)methylbenzoic
acid (3 h, 77% yield), and 8-(methoxy)dibenzo[b,e]thiepin-11(6H)-one,
obtained from 2-(3-methoxyphenyl)methlthiobenzoic acid (6 h, 70%
yield), were significantly slower.
Other Substrates
5-(3-Methoxyphenoxy)-pentanoic acid gave only a dark mixture under the
reaction conditions, in which the desired 9-methoxy-2,3,4,5-tetrahydro-6H-
1-benzoxocin-6-one could not be detected. Phenoxypropanoic acid and
phenylthiopropanoic acid did not cyclize under the reaction conditions,
and the starting materials were recovered. However, 7-methoxy-1H-2-
benzothiopyran-4(3H)-one was obtained from 2-([3-methoxyphenyl]-
methylthio)acetic acid in 74% yield after charcoal treatment and
recrystallization.
Table 2. Reactions that failed to cyclize
Entry
Substrate acid
Ketone product
1
2
3
4
2-Benzyloxybenzoic acid
Benzyloxyacetic acid
Benzylthioacetic acid
5-(3-Methoxyphenoxy)-
pentanoic acid
Dibenzo[b,e]oxepin-11(6H)-one
1H-2-Benzopyran-4(3H)-one
1H-2-Benzothiopyran-4(3H)-one
9-Methoxy-2,3,4,5-tetrahydro-6H-1-
benzoxocin-6-one

2670
B. Andrews et al.
CONCLUSIONS
Friedel–Crafts-type intramolecular cyclizations for arylalkanoic acids,
aryloxyalkanoic acids, and arylthioalkanoic acids were accomplished
under environmentally benign conditions. The resulting cyclic ketones
separated from the quench solution, leaving behind any remaining
carboxylic acids and acid-containing impurities. Cyclization times were
significantly slower for arylthio- and alkylthio-substituted acids than
for the aryloxy-counterparts.
EXPERIMENTAL
All temperatures are uncorrected. High-performance liquid chromatography
(HPLC) reaction monitoring and analysis were conducted on an Agilent
Zorbax SB-C18, 50ꢂ 3.0 mm, 1.8-um column at 60ꢀC, flow rate of
1.5 mL=min, and UV visualization at 220 nm with mobile phase A: H2O
(0.05% TFA), mobile phase B: CH3CN (0.05% TFA), and gradient: 0–95%
B over 2.5 min. All but one of the products are known in the literature and
were identified by melting point and NMR only. 1H NMR spectra were mea-
sured at 500 MHz, whereas 13C NMR spectra were measured at 125 MHz.
General Procedure
The substrate carboxylic acid was stirred in a reactor heated to 70ꢀC. If
required, sulfolane (1mL for each g of substrate) was added. Trichloroace-
tic anhydride (1.1 eq.) was added, and the reaction mixture was stirred at
70ꢀC until the reaction was complete. Then, the warm reaction mixture
was added to briskly stirring cold 3 M NaOH (4–5 eq) containing 10%
by volume of methanol at such a rate that the temperature of the hydroxide
solution did not exceed 15ꢀC. The resultant slurry was cooled to 5–10ꢀC
and stirred for at least 2 h. The solid was collected by filtration and washed
with water. If required, the solid was recrystallized from aqueous ethanol.
Solids were dried at 50–60ꢀC under house vacuum (20–25 inches Hg).
NMR Data
6,7-Dimethoxy-1-tetralone [13575-75-2]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 2.01 (p, J ¼ 6.1 Hz, 2H), 2.51 (t,
J ¼ 6.7 Hz, 2H), 2.86 (t, J ¼ 6.0 Hz, 2H), 3.77 (s, 3H), 3.84 (s, 3H), 6.89
13
(s, 1H), 7.33 (s, 1H). C NMR (DMSO-d6, 125 MHz, 25ꢀC) 23.2, 28.6,
38.0, 55.3, 55.7, 107.8, 110.8, 125.0, 139.3, 147.4, 153.2, 196.0.

Friedel–Crafts with Trichloroacetic Anhydride
2671
7-Methoxy-1-tetralone [6836-19-7]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 2.01 (p, J ¼ 6.2 Hz, 2H), 2.57 (t,
J ¼ 6.7 Hz, 2H), 2.86 (t, J ¼ 6.1 Hz, 2H), 3.78 (s, 3H), 7.14 (dd,
J1 ¼ 8.4 Hz, J2 ¼ 2.8 Hz, 1H), 7.27 (d, J ¼ 8.4 Hz, 1H), 7.35 (d, J ¼ 2.8 Hz,
13
Hz, 1H). C NMR (DMSO-d6, 125 MHz, 25ꢀC) 23.0, 28.0, 38.4, 55.2,
108.9, 120.8, 130.2, 132.9, 137.0, 157.8, 192.3.
6-Methoxy-3-methyl-1-tetralone [5563-21-3]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 1.04 (d, J ¼ 6.3 Hz, 3H), 2.15–2.23
(m, 1H), 2.21–2.27 (m, 1H), 2.53 (br dt, J1 ¼ 14.9 Hz, J2 ¼ 2.8 Hz, 1H),
2.61 (dd, J1 ¼ 16.2 Hz, J2 ¼ 10.3 Hz, 1H), 2.89 (br dd, J1 ¼ 16.2 Hz,
J2 ¼ 2.8 Hz, 1H), 3.83 (s, 3H), 6.83 (d, J ¼ 2.1 Hz, 1H), 6.87 (dd,
J1 ¼ 8.7 Hz, J2 ¼ 2.4 Hz, 1H), 7.83 (d, J ¼ 8.7 Hz, 1H). 13C NMR
(DMSO- d6, 125 MHz, 25ꢀC) 20.9, 30.0, 37.4, 46.2, 55.3, 112.7, 113.0,
125.3, 128.5, 146.3, 163.2, 195.9.
3-Methoxy-6H-dibenzo[b,e]oxepin-11-one [23949-36-2]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 3.84 (s, 3H), 5.29 (s, 2H), 6.62 (d,
J ¼ 2.1 Hz, 1H), 6.79 (dd, J1 ¼ 9.0 Hz, J2 ¼ 2.2 Hz, 1H), 7.54 (t,
J ¼ 7.5 Hz, 1H), 7.56 (d, J ¼ 7.9 Hz, 1H), 7.65 (t, J ¼ 7.3 Hz, 1H), 7.84
(d, J ¼ 7.6 Hz, 1H), 8.11 (d, J ¼ 9.0 Hz, 1H). 13C NMR (DMSO-d6,
125 MHz, 25ꢀC) 55.7, 73.0, 103.3, 110.4, 118.6, 128.1, 128.8, 129.0,
132.6, 133.2, 135.7, 139.9, 162.8, 165.1, 188.3.
8-Methoxy-6H-dibenzo[b,e]oxepin-11-one
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 3.89 (s, 3H), 5.28 (s, 2H), 7.08 (dd,
J1 ¼ 8.7 Hz, J2 ¼ 2.3 Hz, 1H), 7.11–7.16 (m, 2H), 7.20 (t, J ¼ 7.4 Hz, 1H),
7.58 (br t, J ¼ 7.6 Hz, 1H), 7.89 (t, J ¼ 8.7 Hz, 1H), 8.19 (dd, J1 ¼ 8.1 Hz,
13
J2 ¼ 1.3 Hz, 1H). C NMR (DMSO-d6, 125 MHz, 25ꢀC) 55.6, 73.2,
113.1, 114.5, 120.6, 122.2, 125.5, 131.5, 131.8, 132.1, 135.2, 138.8,
160.7, 163.0, 187.7.
3-Methoxy-6H-dibenzo[b,e]thiepin-11-one [49679-26-7]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 3.84 (s, 3H), 4.21 (s, 2H), 6.94 (dd,
J1 ¼ 8.6 Hz, J2 ¼ 2.6 Hz, 1H), 6.98 (d, J ¼ 2.5 Hz, 1H), 7.33–7.37 (m, 1H),

2672
B. Andrews et al.
7.41–7.48 (m, 2H), 7.60 (d, J ¼ 8.6 Hz, 1H), 8.17 (dd, J1 ¼ 8.1 Hz,
13
J2 ¼ 1.4 Hz, 1H). C NMR (DMSO-d6, 125 MHz, 25ꢀC) 35.1, 55.5,
111.6, 113.1, 125.7, 129.3, 131.9, 132.3, 132.4, 132.5, 135.5, 140.4,
141.0, 162.2, 192.8.
8-Methoxy-6H-dibenzo[b,e]thiepin-11-one [36266-84-9]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 2.15 (p, J ¼ 6.8 Hz, 2H), 2.90 (t,
J ¼ 6.7 Hz, 2H), 3.00 (t, J ¼ 6.8 Hz, 2H), 3.83 (s, 3H), 6.87 (dd,
J1 ¼ 8.8 Hz, J2 ¼ 2.5 Hz, 1H), 7.02 (d, J ¼ 2.5 Hz, 1H), 7.73 (d, J ¼ 8.7 Hz,
13
Hz, 1H). C NMR (DMSO-d6, 125 MHz, 25ꢀC) 28.7, 34.6, 40.0, 55.5,
112.7, 114.0, 130.8, 131.8, 144.2, 160.8, 200.0.
8-Methoxy-3,4-dihydro-1-benzoxepin-5(2H)-one [98232-51-0]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 2.15 (p, J ¼ 6.8 Hz, 2H), 2.90 (t,
J ¼ 6.7 Hz, 2H), 3.00 (t, J ¼ 6.8 Hz, 2H), 3.83 (s, 3H), 6.87 (dd,
J1 ¼ 8.8 Hz, J2 ¼ 2.5 Hz, 1H), 7.02 (d, J ¼ 2.5 Hz, 1H), 7.73 (d, J ¼ 8.7 Hz,
13
Hz, 1H). C NMR (DMSO-d6, 125 MHz, 25ꢀC) 28.7, 34.6, 40.0, 55.5,
112.7, 114.0, 130.8, 131.8, 144.2, 160.8, 200.0.
7-Methoxy-1H-2-benzothiopyran-4(3H)-one [16994-31-3]
1H NMR (DMSO-d6, 500 MHz, 25ꢀC) 3.57 (s, 2H), 3.83 (s, 3H), 3.97 (s,
2H), 6.87 (s, 1H), 6.91 (d, J ¼ 8.1 Hz, 1H), 7.91 (d, J ¼ 8.5 Hz, 1H). 13C
NMR (DMSO-d6, 125 MHz, 25ꢀC) 29.5, 35.8, 55.4, 112.2, 113.2, 124.7,
130.2, 144.7, 162.4, 189.8.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Dennis Heyer for frequent and
varied discussions and Pascal Toma for the use of the automated
DSC=MP apparatus.
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