Synthetic Utility and Mechanistic Implications of the Fries Rearrangement of Hydroquinone Diesters in Boron Trifluoride Complexes

Article abstract of DOI:10.1021/jo000412q

Reactions of boron trifluoride methyl and ethyl etherate complexes with hydroquinone diesters yield monomethyl and monoethyl derivatives of acetylhydroquinones. The use of sterically hindered boron trifluoride etherate complexes results in acetylhydroquinone derivatives. This procedure represents a one-step synthesis of acetylhydroquinone derivatives, important building blocks for a variety of synthetic applications.

Full text of DOI:10.1021/jo000412q

4712
J . Org. Chem. 2000, 65, 4712-4714
Syn th etic Utility a n d Mech a n istic Im p lica tion s of th e F r ies
Rea r r a n gem en t of Hyd r oqu in on e Diester s in Bor on Tr iflu or id e
Com p lexes
J essica L. Boyer, J odie E. Krum, Michael C. Myers, Aleem N. Fazal, and Carl T. Wigal*
Department of Chemistry, Lebanon Valley College, Annville, Pennsylvania 17003
wigal@lvc.edu
Received March 21, 2000
Reactions of boron trifluoride methyl and ethyl etherate complexes with hydroquinone diesters
yield monomethyl and monoethyl derivatives of acetylhydroquinones. The use of sterically hindered
boron trifluoride etherate complexes results in acetylhydroquinone derivatives. This procedure
represents a one-step synthesis of acetylhydroquinone derivatives, important building blocks for a
variety of synthetic applications.
Sch em e 1
Constant interest in the synthesis of quinone-related
compounds stems from their diverse biological activity,
including antimicrobial and cytotoxic properties.1 Acetyl
quinone derivatives are of particular interest due to the
proximity of the carbonyl to the quinone ring.2 Several
acetyl quinones are natural products3 whereas others
have served as versatile synthetic intermediates4 and
biosynthetic precursors.3 In our continued investigations
into quinone alkylations,5-8 we required a convenient,
versatile preparation of acetylquinone derivatives. Previ-
ous work has demonstrated that acetylquinones can be
prepared from the oxidation of corresponding hydro-
quinones, the latter obtained from the Fries rearrange-
ment of aromatic esters followed by hydrolysis.9 While
useful, these reactions are of limited synthetic scope and
mechanistically lacking in detail. Herein, we report here
the synthetic utility and mechanistic details of our
findings.
Resu lts a n d Discu ssion
Earlier studies have shown that the Fries rearrange-
ments of 1,4-diacetoxynaphthalene 1a in BF3-acetic acid
complex results in 4-acetoxy-2-acetyl-1-naphthol 2a in
good yield.2 These results were born out in our laboratory
as well as the analogous reaction of 1,4-diacetoxybenzene
3a which resulted in 5-acetoxy-2-hydroxyacetophenone
4a in 94% yield as shown in Scheme 1. In each instance,
no evidence of a second Fries rearrangement was ob-
served. This observation is consistent with previous
reports stating that Fries reactivity is reduced by the
presence of electron-withdrawing groups, in this case the
acyl group at carbon 2 resulting from the initial Fries
rearrangement.10 To assess the scope and limitations of
this reaction, the dipropionate ester of hydroquinone 3b
was subjected to identical reaction conditions to that of
3a which resulted in a mixture of 4a (82%) and 5-acetoxy-
2-hydroxypropiophenone 4b (9%) as determined by GCMS
and NMR. On the basis of these results, we can conclude
that the BF3-acetic acid complex acts as a acyl donor
for both the carbon acylation and subsequent oxygen
acylation at position 5.
(1) Patai, S. The Chemistry of Quinoid Compounds; Wiley: New
York, 1974.
(2) Kurosawa, E. Bull. Chem. Soc. J pn. 1961, 34, 300.
(3) Thomson, R. H. Naturally Occurring Quinones III; Chapman and
Hall: New York, 1987.
(4) (a) Konieczny, M. T.; Horowska, B.; Kunikowski, A.; Konopa, J .;
Wierzba, K.; Yamada, Y.; Asao, T. J . Org. Chem. 1999, 64, 359. (b)
Naruta, Y.; Uno, H.; Maruyama. K. J . Chem. Soc. Chem. Comm. 1981,
1277.
(5) Wigal, C. T.; Grunwell, J . R.; Hershberger, J . J . Org. Chem. 1991,
56, 3759.
(6) Anderson, S. J .; Hopkins, W. T.; Wigal, C. T. J . Org. Chem. 1992,
57, 4304.
(7) McKinley, J .; Aponick, A.; Raber, J . C.; Fritz, C.; Montgomery,
D.; Wigal, C. T. J . Org. Chem. 1997, 62, 4874.
(8) McKinley, J .; Aponick, A.; Raber, J . C.; Wigal, C. T. J . Org. Chem.
1998, 63, 2676.
(9) Rao, P. S.; Gakhar, K. L. Proc. Indian Acad. Sci. 1949, 30A, 327.
(10) Effenberger, G. Chem. Ber. 1982, 115, 1089.
10.1021/jo000412q CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

Fries Rearrangement of Hydroquinone Diesters
J . Org. Chem., Vol. 65, No. 15, 2000 4713
Sch em e 2
In an effort to eliminate the participation of the BF3
complex as an acyl donor, we investigated the use of
BF3-etherate complexes. Reaction of 1a with BF3-
dimethyl etherate resulted in formation of 2-acetyl-4-
methoxy-1-naphthol 2b (89%) as the only observed
product. Similar results were observed for the reaction
of 3a resulting in 2-hydroxy-5-methoxyacetophenone 4c
in 90% yield. The use of BF3-diethyl etherate complex
with 1a and 3a gave similar results giving 2-acetyl-4-
ethoxy-1-naphthol 2c and 4-ethoxy-2-hydroxyacetophe-
none 4d , respectively. These results indicate that the acyl
groups of compounds 2b,c and 4c,d are derived from the
corresponding diacetoxyaromatic and that the BF3-
etherate complexes act as an alkylating agent toward the
oxygen meta to the acyl group. To our knowledge, this is
the first reported case of boron trifluoride-etherate
complexes acting as an alkylating agent.
Previous reports have indicated that the transfer of the
acyl group may involve intermolecular and/or intramo-
lecular transfer of the acyl group depending on the
substrate.11,12 To determine the nature of acyl transfer
for the aforementioned systems, a crossover experiment
was performed employing 1a and 3b. Reaction of equimo-
lar concentrations of 1a and 3b in BF3-diethyl etherate
complex resulted in a mixture of products. Compounds
derived from 3b were identified as 4-ethoxy-2-hydroxy-
acetophenone 4d (43%) and 4-ethoxy-2-hydroxypropiophe-
none (52%). Also present in the reaction mixture were
products derived from 1a , which were identified as
2-acetyl-4-ethoxy-1-naphthol 2c (59%) and 4-ethoxy-2-
propionyl-1-naphthol (40%) as determined by GCMS. On
the basis of the presence of 4-ethoxy-2-hydroxyacetophe-
none and 4-ethoxy-2-propionyl-1-naphthol in the reaction
mixture, one can conclude that a significant portion of
the observed products result from intermolecular acyl
transfer, presumably through an acylium ion intermedi-
ate.11,13
The use of alkoxy-substituted acetophenone and pro-
piophenone derivatives has been reported in the synthe-
ses of chalcone derivatives, which are inhibitors of
cyclooxygenase and 5-lipoxygenase.14 In an attempt to
expand the synthetic utility of these compounds, we
investigated the use of other BF3-etherate complexes,
attempting to synthesize ether analogues of 2 and 4.
Reaction of 3a with BF3-dipropyl etherate resulted in
formation of a mixture of 2,5-dihydroxyacetophenone 4e
(89%) and 2-hydroxy-5-propoxyacetophenone 4f (9%).
Identification of 4f was based on GCMS and NMR data
of the crude reaction mixture as compared to an authentic
sample synthesized by a previously reported method.15
Reaction of 3a with BF3-dibutyl etherate resulted in
formation of 4e as the only observed product. Likewise,
the reaction of 3b with BF3-dibutyl etherate resulted
in 2,5-dihydroxypropiophenone 4g in 42% yield. No
oxygen alkylation was observed. Similar results were
observed for the reaction of 1a resulting in 2-acetyl-1,4-
dihydroxynaphthalene 2d in 83% yield. The use of BF3-
THF complex with 1a and 3a also resulted in formation
of 2d and 4e, respectively, in similar yield. Once again,
oxygen alkylation was not observed. While unexpected,
the aforementioned boron trifluoride complexes can be
used to carry out a one-pot synthesis of acetyl hydro-
quinone derivatives. Subsequent oxidation of these hy-
droquinone derivatives using resin-bound periodate can
convert the hydroquinones to acetylquinones in near
quantative yields.16
On the basis of these observations, a plausible mech-
anism is shown in Scheme 2. Reaction of hydroquinone
diesters with boron trifluoride gives the Lewis adduct 5.
Dissociation of 5 results in formation of an acylium ion-
aromatic anion pair. The acylium ion can diffuse from
the solvent cage, accounting for the intermolecular nature
of the reaction as observed in the cross-over experiment.
Electrophilic aromatic substitution of the acylium ion
with 6 results in 7. Reaction of 7 with boron trifluoride
gives the second Lewis adduct 8 which also dissociates
to an ion pair. The electron-withdrawing effects of the
acetyl group on 9 deactivates the ring, disfavoring acyl
alkylation. Oxygen alkylation of 9, resulting from nu-
cleophilic addition to the boron trifluoride etherate
complex, results in formation of 10. Increasing the steric
effects of the ether complexes disfavors alkylation allow-
ing for formation of acetylhydroquinone via protonation.
In conclusion, the use of boron trifluoride etherate
complexes represents a convenient one-step synthesis of
acetylhydroquinones, acetylnaphthohydroquinones, and
their respective monomethyl and monoethyl ethers, all
of which can serve as important building blocks for a
variety of synthetic applications. Currently we are in-
(11) Warshawsky, A.; Kalir, R.; Patchornik, A. J . Am. Chem. Soc.
1978, 100, 4544.
(12) Martin, R. Bull. Soc. Chim. Fr. 1974, 983.
(13) Baltzyl, R.; Phillips, A. P. J . Am. Chem. Soc. 1948, 70, 4191.
(14) Sogawa, S.; Nihro, Y.; Ueda, H.; Izumi, A.; Miki, T.; Matsumoto,
H.; Satoh, T. J . Med. Chem. 1993, 36, 3904.
(15) Vyas, G. N.; Shah, N. M. Organic Syntheses; Wiley: New York,
1963; Collect. Vol. IV, p 836.
(16) Harrison, C.; Hodge, P. J . Chem. Soc. 1981, 509.

4714 J . Org. Chem., Vol. 65, No. 15, 2000
Boyer et al.
in boron trifluoride dimethyl ether complex (4.0 mL) afforded
2b (788 mg, 89%). Recrystallization from ethanol afforded a
yellow solid; mp 161-164 °C. 1H NMR (CDCl3) δ 13.75 (s, 1H),
8.55 (dd, J ) 8.5, 2.0 Hz, 1H), 8.17 (dd, J ) 8.5, 2.0 Hz, 1H),
7.82 (dt, J ) 8.5, 2.0 Hz, 1H), 7.65 (dt, J ) 8.5, 2.0 Hz, 1H),
6.56 (s, 1H), 3.98 (s, 3H), 2.83 (s, 3H); 13C NMR δ 203.68,
157.35, 147.32, 129.69, 126.59, 125.89, 124.32, 121.85, 111.93,
106.59, 100.64, 55.62, 26.99. Anal. Calcd for C13H12O3: C,
72.21; H, 5.59. Found: C, 72.19; H, 5.54.
vestigating the scope of this reaction in regard to other
nonquinoid substrates.
Exp er im en ta l Section
1
Gen er a l Meth od s. H (300 MHz) and 13C (75 MHz) NMR
spectra were determined in CDCl3 unless otherwise specified.
Chemical shifts are reported in ppm downfield from internal
TMS (δ). Melting points were obtained with open capillary
tubes and are uncorrected. Compounds 1a , 3a , and 3b were
prepared using previously reported procedures.17,18 All other
materials were obtained from commercial suppliers.
Gen er a l P r oced u r e for F r ies Rea r r a n gem en t. In a 10-
mL round-bottom flask equipped with a condenser and a stir
bar were placed 4.0 mL of boron trifluoride complex and 1.0 g
of the aromatic diester. Heat was then applied, and the
mixture was refluxed for 1 h. The resulting solution was
allowed to cool to room temperature and then poured into
water and extracted with dichloromethane. The organic phase
was washed with water and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure. The crude
products were purified by flash chromatography (silica gel,
30% acetone/hexane) or recrystallization. All reported com-
pounds are known except for those listed below.19-25
2-Acetyl-4-eth oxy-1-n a p h th ol (2c). Following the general
procedure, a solution of 1,4-diacetoxynaphthalene (1.0 g) in
boron trifluoride diethyl ether complex (4.0 mL) afforded 2c
(867 mg, 92%). Recrystallization from ethanol afforded a yellow
solid; mp 113-115°. 1H NMR (CDCl3) δ 13.74 (s, 1H), 8.60 (dd,
J ) 8.3, 1.4 Hz, 1H), 8.23 (dd, J ) 8.3, 1.4 Hz, 1H), 7.83 (dt,
J ) 8.3, 1.4 Hz, 1H), 7.66 (dt, J ) 8.3, 1.4 Hz, 1H), 6.51 (s,
1H), 4.16 (q, J ) 6.9 Hz, 2H), 2.80 (s, 3H), 1.57 (t, J ) 6.9 Hz.
1H); 13C NMR δ 196.52,163.42, 148.20, 134.48, 133.79, 127.95,
126.61, 125.72, 122.75, 110.79, 96.86, 64.05, 23.26, 14.59. Anal.
Calcd for C14H14O3: C, 73.02; H, 6.13. Found: C, 72.89; H,
6.08.
Ack n ow led gm en t. The authors are grateful to the
National Science Foundation (CHE-9806311) and the
donors of the Petroleum Research Fund (33313-B1),
administered by the American Chemical Society, for
grants in support of this work.
2-Acetyl-4-m eth oxy-1-n a p h th ol (2b). Following the gen-
eral procedure, a solution of 1,4-diacetoxynaphthalene (1.0 g)
(17) Prichard, W. W. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. III, p 452.
(18) Fieser, L. F. J . Am. Chem. Soc. 1948, 70, 3165.
(19) Spruit, C. J . P. Rec. Trav. Chim. 1947, 66, 655.
(20) Baker, W. J . Chem. Soc. 1934, 1953.
(21) Nicolosi, G.; Piatelli, M.; Sanfilippo, C. Tetrahedron 1993, 49,
3143.
(22) Wiley, P. F. J . Am. Chem. Soc. 1951, 73, 4205.
(23) Nencki, S.; Schmid, H. J . Prakt. Chem. 1881, 23, 546.
(24) Cram, D. J . J . Am. Chem. Soc. 1949, 71, 3953.
(25) Goldzweig, W.; Kaiser, R. J . Prakt. Chem. 1891, 43, 93.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and compilation of NMR data for all
compounds and MS spectra of new compounds 2b and 2c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000412Q