Clean-chemistry synthesis of 2-tetralones in a single-stage acylation - Cycloalkylation process

Article abstract of DOI:10.1021/jo0158074

The preparation of substituted-2-tetralones by direct reaction of a 1-alkene with a substituted phenylacetic acid in a reaction system of trifluoroacetic anhydride (TFAA) and phosphoric acid is described. This single-stage process involves in situ formation of a mixed anhydride of the phenylacetic acid and acylation of the alkene by this species followed by cycloalkylation of the aromatic ring. This is a cleaner approach to the synthesis of 2-tetralones compared to Friedel-Crafts aliphatic acylation-cycloalkylation in that use of thionyl chloride, aluminum trichloride, and a chlorinated hydrocarbon solvent is eliminated. In addition, the atom efficiency is augmented by recovery of the spent TFAA as trifluoroacetic acid (TFA) and conversion of this back to TFAA by dehydration.

Full text of DOI:10.1021/jo0158074

J . Org. Chem. 2001, 66, 7113-7117
7113
Clea n -Ch em istr y Syn th esis of 2-Tetr a lon es in a Sin gle-Sta ge
Acyla tion -Cycloa lk yla tion P r ocess
Anthony D. Gray and Timothy P. Smyth*
Department of Chemical and Environmental Sciences, University of Limerick,
National Technological Park, County Limerick, Ireland
timothy.smyth@ul.ie
Received May 31, 2001
The preparation of substituted-2-tetralones by direct reaction of a 1-alkene with a substituted
phenylacetic acid in a reaction system of trifluoroacetic anhydride (TFAA) and phosphoric acid is
described. This single-stage process involves in situ formation of a mixed anhydride of the
phenylacetic acid and acylation of the alkene by this species followed by cycloalkylation of the
aromatic ring. This is a cleaner approach to the synthesis of 2-tetralones compared to Friedel-
Crafts aliphatic acylation-cycloalkylation in that use of thionyl chloride, aluminum trichloride,
and a chlorinated hydrocarbon solvent is eliminated. In addition, the atom efficiency is augmented
by recovery of the spent TFAA as trifluoroacetic acid (TFA) and conversion of this back to TFAA
by dehydration.
Sch em e 1
In tr od u ction
We previously reported on the successful application
of TFAA/H3PO4-mediated acylation of aromatics as a
clean-chemistry alternative to the Friedel-Crafts pro-
cess, wherein the use of thionyl chloride, aluminum
chloride, and a chlorinated hydrocarbon solvent are all
eliminated.1 An acyl trifluoroacetate 2, formed in situ
from a carboxylic acid, is the acylation precursor which,
on reaction with phosphoric acid, leads to the formation
of an acyl bis(trifluoroacetyl)phosphate 4 (Scheme 1).
We obtained direct spectroscopic evidence (31P and 19F
NMR data) that substantiated the role of 4 as the most
active acylating agent in this reaction system. A value
of 0.71 was estimated for σm of OP(O)(OC(O)CF3)2, which
identifies the acyl carbonyl group in 4 as being more
polarized than in RC(O)OP(O)Cl2san established reac-
tive acylating agent.2 Phosphoric acid is thus seen to act
as a covalent catalyst rather than as a Brønsted acid in
the TFAA/H3PO4 acylation reaction.3 (Use of H2SO4
instead of H3PO4 led to sulfonation as well as acylation;
we will report elsewhere our studies on the use of TFAA/
H2SO4 as an aromatic sulfonation system.) The atom
efficiency of the acylation process is augmented by
recovery of the spent TFAA as trifluoroacetic acid (TFA)
and conversion of this back to TFAA by dehydration.4 We
successfully applied this acylation process to the forma-
tion of a precursor structure (96% yield) in an industrially
based synthesis of tamoxifen; in addition, reaction calo-
rimetry indicated the viability of the process for scale-
up.1b
Friedel-Crafts chemistry has also been used industri-
ally in the preparation of 9, a 2-tetralonesfor conversion
onward to a pharmaceutically active material (Mibe-
fradil)5sin a single-stage acylation-cycloalkylation pro-
cess (eq 1) using ethylene. It was of interest, therefore,
to ascertain if the TFAA/H3PO4 system could be applied,
in a similar single-stage manner, to a general synthesis
of 2-tetralones6 starting with the appropriate carboxylic
acid and alkene (eq 2). Herein, we report on the success-
ful application of this process to the synthesis of a variety
of 2-tetralones and detail some aspects of the scope of
the reaction.
(1) (a) Smyth, T. P.; Corby, B. W. J . Org. Chem. 1998, 63, 8946-
8951. (b) Smyth, T. P.; Corby, B. W. Org. Process Res. Dev. 1997, 1,
264-267.
(2) Effenberger, F.; Ko¨nig, G.; Klenk, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 695-696.
(3) Acylation reactions using acyl trifluoroacetates were first re-
ported in detail by Tedder: Tedder, J . M. Chem. Rev. 1955, 787-827
and references therein. Catalysis by H3PO4 of aromatic acylation using
acyl trifluoroacetates was first reported by Galli: Galli, C. Synthesis
1979, 303.
Resu lts a n d Discu ssion
Initially, we examined the processes of alkene acylation
using a carboxylic acid and of aromatic alkylation using
(4) TFAA is produced commercially by dehydration of TFA. Some
processes use SO3 as the dehydrating agent giving H2SO4 as
a
coproduct. For small-scale use, P2O5 is more convenient to use: Swarts,
F. Bull. Cl. Sci. Acad. R. Belg. 1922, 343.
(5) For general information see: http://cponline.gsm.com/.
10.1021/jo0158074 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

7114 J . Org. Chem., Vol. 66, No. 21, 2001
Gray and Smyth
Ta ble 1. Gen er a l Resu lts for TF AA/H3P O4-Med ia ted
2-Tetr a lon e F or m a tion
Ra
R′
R′′
2-tetralone yield (%)
H
4-F
4-Me
4-MeOb
3,4-diMeOb
H
H
H
H
H
H
CH3
H
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
-(CH2)3Br
-(CH3)2
13a (55)
13b (37)
13c (74)
13d (62)
13ec (76)
13f (51)
13g (55)
13h (70)
H
4-Me
H
a
The numbers here refer to the substituted phenylacetic acid.
H3PO4 (0.2 equiv) used. c GC analysis showed only one major
b
peak. The 1H NMR data was consistent with the 6,7-dimethoxy
tetralone regioisomer rather than the 5,6-regioisomer.
acylation.8 Thus, in a reaction system of acetic acid
(1 equiv), cyclohexene (1 equiv), and toluene (2 equiv),
acetylation of cyclohexene was found to be the predomi-
nant reaction: neither the alkylated nor the acetylated
toluene products, 15 or 16, was formed to any appreciable
extent (eq 5).9
an alkene in the TFAA/H3PO4 system. 1-Acetyl-1-cyclo-
hexene (14) was obtained in 69% yield after 10 min at
room temperature in our reaction system (following
aqueous workup) (eq 3); a yield of 48% was obtained in
This is the reactivity sequence required for formation
of a 2-tetralone structure in a single-stage acylation-
cycloalkylation process (eq 2). It was satisfying, therefore,
to find that reaction of 1-hexene with phenylacetic acid
(1:1 equiv) in TFAA/H3PO4 (4:1 equiv) at ambient tem-
perature led to the rapid formation of 4-(1-butyl)-2-
tetralone (13a ) in 55% yield. The general results on
2-tetralone formation from reaction of a series of 1-alk-
enes with a set of phenylacetic acid structures are given
in Table 1.10 All products were characterized by 1H NMR,
HRMS, mass fragmentation pattern, and IR data (see the
Experimental Section and Supporting Information for
details). A typical set of data is given here for a sample
of 13a , which was found to be of 97% purity by GC
analysis following purification by flash chromatography.
1
The H NMR (Figure 1a) showed chemical shift values
for the hydrogen atoms at C-1, C-3, and C-4 that are very
characteristic of 2-tetralone structures;6,11 the chemical
shift pattern of the (diastereotopic) C-3 hydrogens was
observed to be solvent dependent (Figure 1b). The HRMS
of 13a gave a value of 202.13675 which is within 4.86
ppm of the calculated value; the characteristic peaks
observed in the LRMS corresponded to the parent peak
M, M - side chain at C-4, and M - (side chain and CO);
a carbonyl stretching frequency was observed at 1717
the absence of phosphoric acid after 2.5 h at 37 °C.7 The
alkylation of toluene using cyclohexene gave a 70% yield
of monoalkylated toluene 15 (o/ p, 1:2) after 10 min at
room temperature (eq 4). In a simple competition reac-
tion, we established that alkene acylation was faster than
aromatic alkylation and was also faster than aromatic
cm-1
.
A successful outcome was obtained with isobutylene
(Table 1, 13h ) by running the reaction in a pressure
(6) For general references to 2-tetralone formation using Friedel-
Crafts acylation-cycloalkylation reactions, see: (a) Burckhalter, J . H.;
Campbell, J . R. J . Org. Chem. 1961, 26, 4232-4235. (b) Prasad, R. S.;
Roberts, R. M. Synth. Commun. 1991, 21, 385-393 and references
therein. (c) Pendergast, W.; J ohnson, J . V.; Dickerson, S. H.; Dev, I.
K.; Duch, D. S.; Ferone, R.; Hall, W. R.; Humphreys, J .; Kelly, J . M.;
Wilson, D. C. J . Med. Chem. 1993, 36, 2279-2291 and references
therein. (d) Lee, S.; Frescas, S. P.; Nichols, D. E. Synth. Commun. 1995,
25, 2775-2780. (e) Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond,
R.; Dolling, U.-H.; Frey, L.; Karady, S.; Shi, Y.-J .; Verhoeven, T. R. J .
Org. Chem. 1995, 60, 4324-4330. (f) Lin, C. H.; Ennis, M. D.; Hoffman,
R. L.; Phillips, G.; Haadsmasvennson, S. R.; Ghazal, N. B.; Chidester,
C. G. J . Heterocycl. Chem. 1994, 31, 129-139. (g) Yang, D. J .; Davisson,
J . N. J . Med. Chem. 1985, 28, 1361-1365. (h) For an alternative
method of 2-tetralone synthesis, see: Qandil, A. M.; Miller, D. W.;
Nichols, D. E. Synthesis, 1999, 2033-2035.
(8) Acylation of toluene requires more vigorous reaction conditions
(60 °C, 2.5 h).1a
(9) A small amount of cyclohexanol was also formed. Reaction of
cyclohexene and of 1-hexene on their own in the TFAA/H3PO4 system
generated the corresponding alcohols, following aqueous workup.
Alcohol sideproducts occurred to a very minor extent in reactions
leading to 2-tetralone formation: see GC traces included in the
Supporting Information.
(10) 2-Tetralone products were formedsas determined by GCMSs
with cyclohexene, and also with cis-3-hexene, as the alkene component.
Purification proved to be problematic, however, in these instances.
(11) (a) Covarrubias-Zu´n˜iga, A.; Cantu´, F.; Maldonado, L. A. J . Org.
Chem.1998, 63, 2918-2921. (b) Kolotuchin, S. V.: Meyers, A. I. J . Org.
Chem. 2000, 65, 3018-3026.
(7) Henne, A. L.; Tedder, J . M. J . Chem Soc. 1953, 3628-3630.

Clean-Chemistry Synthesis of 2-Tetralones
J . Org. Chem., Vol. 66, No. 21, 2001 7115
Sch em e 2
Use of reactive alkenes such as styrene and vinyl
acetate was not successful as these components reacted
with the acidic medium. Thus, styrene readily dimerized
in TFAA/H3PO4, nonetheless, some (15%) 4-phenyl-2-
tetralone was formed (as determined from the GCMS
data). Vinyl acetate formed an acetyl trifluoroacetyl
geminal diester resulting from the addition of TFA (to
vinyl acetate)sno tetralone product was observed. It has
been shown that vinyl ethers are efficiently trifluoro-
acylated by perfluoroacyl anhydrides12 and therefore are
not suited to acylation by an acyltrifluoroacetate.
F igu r e 1. 1H NMR of 13a in (a) acetone-d6 (*residual
hydrogens) and (b) in CDCl3.
Ta ble 2. Yield (%) of 13c a s a F u n ction of Tim e a n d of
H3P O4 Con cen tr a tion u n d er Sta n d a r d Rea ction
Con d ition s
H3PO4 (equiv)
3 h
6 h
9 h
1.0
0.1
0.01
0.00
74
34
12
4
45
58
Con clu sion s
vessel (see the Experimental Section) wherein this alkene
was, largely, liquified. The process of bubbling isobuty-
lene through a solution of p-methylphenylacetic acid in
TFAA/H3PO4 was not successful (the 2-tetralone product
was formed in 11% yield); the removal, by entrainment,
of volatile components such as TFAA and TFA was
problematic in this instance. Likewise, passing a stream
of ethylene through a reaction mixture of 3,4-dimeth-
oxyphenylacetic acid (in TFAA/H3PO4) yielded only a
trace of the 2-tetralone product (2.6%); in both cases, the
bulk of the phenylacetic acid material was recovered.
The effect of varying the concentration of H3PO4 (with
4 equiv of TFAA throughout) was studied in the reaction
of p-methylphenylacetic and 1-hexene; the findings are
given in Table 2. The key dependence on H3PO4 concen-
tration observed here mirrors that found in the case of
the aromatic acylation reaction that we had studied
earlier.1a In both cases, the concentration of the acyl bis-
(trifluoroacetyl)phosphate type structure (11 in eq 2) is
dependent on the concentration of H3PO4. In the multi-
step reaction leading to 2-tetralone formation, however,
the concentration of the cycloalkylation precursor
(In ter m ed ia te-A in eq 2) should be critical and should
also be influenced by the concentration of H3PO4. The
effect of varying the aromatic-ring substituent on the
yield of 2-tetralone (Table 1) supports the view that
cycloalkylation is a critical step in the overall process.
Thus, it is unlikely that the ring substituent should have
much influence on the rate of the aliphatic acylation step
whereas it should have a significant influence on the rate
of cycloalkylation. It is noteworthy that 0.2 equiv of H3-
PO4 was sufficient for effective catalysis of 2-tetralone
formation with the activated phenylacetic acids bearing
methoxy and dimethoxy substituents on the aromatic
ring; this is similar to our earlier results on aromatic
acylation.1a
Our results show that the TFAA/H3PO4 system can be
usefully extended beyond aromatic acylation to a multi-
step reaction involving acylation of 1-alkenes coupled
with cycloalkylation, in a single-stage process, leading
to 4-substituted-2-tetralone formation. For both aromatic
acylation and 2-tetralone formation the atom efficiency
of the overall reaction is highest when using an activated
aromatic ring in that relatively high yields are obtained
with a catalytic quantity of H3PO4 (0.1-0.2 equiv).
Common to both systems is the opportunity to recover
the spent TFAA as TFA and convert this back to TFAA
by dehydration (Scheme 2).
Exp er im en ta l Section
1H NMR spectra were recorded in acetone-d6 (with tetra-
methylsilane as internal standard) unless otherwise stated.
GC analyses were carried out on an RTX-1 column, 0.25 µm,
0.25 mm × 30 m; carrier gas: N2, flow rate 5 mL min-1; split
ratio: 20/1; temperature program: 75 °C (2 min); 10 °C to 250
°C (10 min). This system was used to assay the yield of
materials formed or isolated. GCMS analyses were carried out
on a DB-5 column, 0.25 µm, 0.25 mm × 30 m; carrier gas: N2,
flow rate 1 mL min-1; split ratio: 100/1; temperature pro-
gram: 75 °C (2 min); 10 °C to 250 °C (10 min); mass selective
detector operated at 70 eV electron impact. High-resolution
mass spectra were recorded at the Mass Spectroscopy Service,
University College, Cork.
All solvents except trifluoroacetic anhydride were rigorously
dried and purified by distillation before use. 2-Tetralone
products were purified by dry flash chromatography13 and were
generally obtained as yellow or yellow-brown oils after removal
of solvent; their purity was assayed by GC.
(12) (a) Gorlov, D. V.; Kurykin, M. A.; Petrova, O. E.; Russ. Chem.
Bull. 1999, 48, 1791-1792. (b) Hojo, M.; Masuda, R.; Kokuryo, Y.;
Shioda, H.; Matsuo, S. Chem. Lett. 1976, 499-502.
(13) Casey, M.; Leonard, J .; Lygo B.; Procter, G. Advanced Practical
Organic Chemistry; Blackie: Glasgow, 1990; Chapter 9.

7116 J . Org. Chem., Vol. 66, No. 21, 2001
Gray and Smyth
Gen er a l TF AA/H3P O4 Meth od . Trifluoroacetic anhydride
(4.15 mL, 29.40 mmol) was added directly to the required
carboxylic acid (7.35 mmol) to generate the mixed anhydride.
This solution was stirred for 10 min. The mixed anhydride was
cooled (ice water), and 85% phosphoric acid (0.85 g, 7.35 mmol)
was added with stirring. After complete dissolution of the
phosphoric acid, the alkene substrate (7.35 mmol) was added
at such a rate that the temperature did not exceed 30 °C. The
reaction mixture was cooled briefly and was then stirred at
room temperature for 3 h (unless otherwise stated). (The
removal of TFA by distillation as the initial isolation step is
appropriate for large scale preparations.1b For the scale of the
typical reaction carried here the following extraction procedure
was used.) The reaction mixture was cooled (ice water) and
water (25 mL) added. The solution was extracted with dichlo-
romethane (25 mL), separated, washed with 30% NaOH (50
mL) and water (25 mL). The combined aqueous layers were
extracted with a second portion of dichloromethane (25 mL).
The combined organic layers were dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure.
This general procedure was used for aliphatic acylation
(formation of 14), aromatic alkylation (formation of 15) and
2-tetralone formationsthe substrate was varied as required.
The workup procedure above ensured removal of TFA, TFAA,
H3PO4, any unreacted carboxylic acid and/or unreacted alkene.
The weight of material recovered is given below as the mass
balance and is listed as a percent of the starting weight of
carboxylic acid and alkene minus the weight of one molecule
of water for acylation and tetralone forming reactions. GC
assay of material obtained at this stage gave the percent yield
of the identified product(s). For spectroscopic analysis small
samples of the 2-tetralones were purified by dry flash chro-
matography13 using silica gel S 0.032-0.063 mm and n-hexane/
diethyl ether as eluant. The ratio of n-hexane/diethyl ether of
the solvent fraction (20 mL volume), in which the purified
2-tetralone product eluted, is stated. The purity of the samples
was assayed using GC.
eluted in the (82.5/17.5) fraction (purity assay 95%); δ 0.70-
1.05 (br m, 3H, CH3), 1.05-1.72 (br m, 6H, -(CH2)3-), 2.39
(dd, J ) 4.1, 15.55 Hz, 1H, H-3 (diastereotopic)), 2.68, (dd, J
) 5.4, 15.55 Hz, 1H, H-3 (diastereotopic)), 2.95-3.28 (br m,
1H, H-4), 3.50 (s, 2H, H-1), 3.83 (s, 3H, CH3O), 6.84 (s, 1H,
aromatic), 6.76-7.3 (m, 2H, aromatic); MS(EI) m/z 232 (M),
175 (M - C4H9), 147 (1M - C4H9/- CO); HRMS calcd for
C
15H20O2 232.14633, found 232.14683 (dev 2.17 ppm); IR (neat)
1716 cm-1
.
4-(1-Bu tyl)-6,7-d im eth oxy-2-tetr a lon e (13e): H3PO4 (0.2
equiv) used; obtained as a dark brown oil after workup (1.83
g, mass balance 95%, yield 76%); GC retention time 19.80 min;
obtained as a brown-yellow oil after flash chromatography,
eluted in the (45/55) fraction (purity assay 95%); δ 0.70-1.05
(br m, 3H, CH3), 1.05-1.72 (br m, 6H, -(CH2)3-), 2.45-2.85
(2dd (poorly resolved), 2H, H-3 (diastereotopic)), 2.90-3.20 (br
m, 1H, H-4), 3.55 (s, 2H, H-1), 3.90 (s, 3H, CH3O), 3.94 (s, 3H,
CH3O), 6.64 (s, 1H, aromatic), 6.75 (s, 1H, aromatic); MS(EI)
m/z 262 (M), 205 (M - C4H9), 177 (1M - C4H9/- CO); HRMS
calcd for C16H22O3 262.15689, found 262.15747 (dev 2.19 ppm);
IR (neat) 1715 cm-1
.
1-Meth yl-4-(1-bu tyl)-2-tetr a lon e (13f): obtained as a dark
brown oil after workup (1.25 g, mass balance 87%, yield 51%);
GC retention time 15.70 and 15.76 min (two diastereomeric
pairs of stereoisomers: 1:1.6); obtained as a clear oil after flash
chromatography, eluted in the (86.25/13.75) fraction (purity
assay 93%); δ(CDCl3) 0.70-1.05 (br m, 3H, CH3), 1.05-1.72
(br m, 6H, -(CH2)3- overlapping with 1.45 (d, J ) 6.67 Hz)
and 1.49 (d, J ) 6.67 Hz, 1-CH3), 2.10-2.95 (4dd (partially
overlapping), 2H, H-3 (diastereomeric and diastereotopic)),
2.95-3.25 (br m, 1H, H-4), 3.36-3.72 (2q (partially overlap-
ping), J ) 6.67 Hz, 1H, H-1 (diastereomeric)), 7.25 (s, 4H,
aromatic); MS(EI) m/z 216 (M), 159 (M - C4H9), 131 (1M -
C4H9/- CO); HRMS calcd for C15H20O 216.15142, found
216.15107 (dev -1.60 ppm); IR (neat) 1717 cm-1
.
4-(1-(3-Br om op r op yl))-2-tetr a lon e (13g): obtained as a
dark brown oil after work up (1.81 g, mass balance 92%, yield
55%); GC retention time 18.45 min; a dark yellow oil after flash
chromatography, eluted in the (73.75/26.25) fraction (purity
assay 92%); δ (CDCl3) 1.49-2.09 (br m, 4H, -(CH2)2-), 2.52
(dd, J ) 4.2, 16.35 Hz, 1H, H-3 (diastereotopic)), 2.78 (dd, J )
4.75, 16.35 Hz, 1H, H-3 (diastereotopic)), 2.98-3.25 (br m, 1H,
H-4), 3.39 (t, J ) 6.23 Hz, 2H, -CH2Br), 3.60 (s, 2H, H-1),
6.98-7.49 (m, 4H, aromatic); MS(EI) m/z 266 (M: 79Br), 268
(M: 81Br), 145 (M - C3H6Br), 117 (M - C3H6Br/-CO); HRMS
calcd for C13H15BrO 266.03063, found 266.03119 (dev 2.13
4-(1-Bu tyl)-2-tetr a lon e (13a ): obtained as a dark brown
oil after workup (1.38 g, mass balance 93%, yield 55%); GC
retention time 15.4 min; obtained as a yellow-brown oil after
flash chromatography, eluted in the (85/15) fraction (purity
assay 97%): δ 0.70-1.05 (br m, 3H, CH3), 1.05-1.72 (br m,
6H, -(CH2)3-), 2.40 (dd, J ) 4.6, 15.95 Hz, 1H, H-3 (diaste-
reotopic)), 2.70 (dd, J ) 5.35, 15.95 Hz, 1H, H-3 (diaste-
reotopic)), 3.00-3.25 (br m, 1H, H-4), 3.57 (s, 2H, H-1), 7.13-
7.35 (m, 4H, aromatic); MS(EI) m/z 202 (M), 145 (M - C4H9),
117 (M - C4H9/- CO); HRMS calcd for C14H18O 202.13577,
ppm); IR (neat) 1715 cm-1
.
found 202.13675 (dev 4.86 ppm); IR (neat) 1717 cm-1
.
4,4-Dim eth yl-6-m eth yl-2-tetr a lon e (13h ): isobuylene gas
(3.2 mL, 33.5 mmol) was condensed, under nitrogen, into a
cooled (-25 °C) graduated cylinder and rapidly transferred to
a Parr hydrogenator vessel under nitrogen and held at -25
°C. A pre-prepared solution (see General TFAA/H3PO4 Method)
of the mixed anhydride of p-methylphenylacetic acid (33.33
mmol) and H3PO4 was added slowly. The reaction mixture was
then shaken at room temperature for 3 h using a Parr
apparatus. 13h was obtained as a dark brown oil after workup
(5.64 g, mass balance 90%, yield 70%); GC retention time 13.32
min; obtained as a yellow oil after flash chromatography,
eluted in the (92.5/7.5) fraction (purity assay 98%); δ (CDCl3)
1.33 (s, 6H, (4,4-dimethyl), 2.36 (s, 3H, 6-CH3), 2.51 (s, 2H,
H-3), 3.64 (s, 2H, H-1), 7.05 (s, 2H, aromatic), 7.26 (s, 1H,
aromatic); MS(EI) m/z 188 (M), 173 (M - CH3), 145 (M -
4-(1-Bu tyl)-6-flu or o-2-tetr a lon e (13b): obtained as a dark
brown oil after workup (1.56 g, mass balance 96%, yield 37%);
GC retention time 15.08 min; obtained as a yellow-brown oil
after flash chromatography, eluted in the (82.5/17.5) fraction
(purity assay 93%), δ 0.70-1.05 (br m, 3H, CH3), 1.05-1.70
(br m, 6H, -(CH2)3-), 2.42 (dd, J ) 5.2, 18.8 Hz, 1H, H-3
(diastereotopic)), 2.75 (dd, J ) 6.2, 18.8 Hz, 1H, H-3 (diaste-
reotopic)), 3.00-3.25 (br m, 1H, H-4), 3.57 (s, 2H, H-1), 7.15-
7.37 (m, 3H, aromatic); MS(EI) m/z 220 (M), 163 (M - C4H9),
135 (1M-C4H9/-CO); HRMS calcd for C14H17FO 220.12634,
found 220.12771 (dev 3.50 ppm); IR (neat) 1719 cm-1
.
4-(1-Bu tyl)-6-m eth yl-2-tetr a lon e (13c): obtained as a
dark brown oil after workup (1.42 g, mass balance 95%, yield
74%); GC retention time 16.29 min; obtained as a yellow oil
after flash chromatography, eluted in the (83.75/16.25) fraction
(purity assay 95%); δ 0.70-1.05 (br m, 3H, CH3), 1.05-1.72
(br m, 6H, -(CH2)3-), 2.30 (s, 3H, 6-CH3 and 0.5H, H-3), 2.37
(dd (partially masked at 2.30), J ) 4.35, 15.7 Hz, 0.5H H-3
(diastereotopic)), 2.68 (dd, J ) 4.98, 15.7 Hz, 1H, H-3 (dias-
tereotopic)), 2.90-3.25 (br m, 1H, H-4), 3.50 (s, 2H, H-1), 6.96-
7.16 (m, 3H, aromatic); MS(EI) m/z 216 (M), 159 (M - C4H9),
131 (M - C4H9/- CO); HRMS Calcd. for C15H20O 216.15142,
CH3/- CO), 130 (M - (CH3)2/- CO); HRMS calcd for C13H16
188.12012, found 188.12037 (dev 1.36 ppm); IR (neat) 1719
cm-1
O
.
1-Acetyl-1-cycloh exen e (14): acetic acid (2 g, 33.33 mmol)
was used in the standard procedure (see General TFAA/H3-
PO4 Method) with a reaction time of 10 min. Compound 14
was obtained as a dark yellow oil after workup (3.97 g, mass
balance 96%, yield 69%); GC retention time 6.95 min; obtained
as a light yellow oil after distillation (2.98 g, 23.98 mmol, 96%
purity), bp 41-42 °C/0.6 mm (lit.7 bp 86-88 °C /28 mm);
δ(CDCl3) 1.50-1.74 (br m, 4H, -(CH2)2-), 2.11-2.35 (br m,
4H, -(CH2)2-), 2.27 (s, 3H, CH3), 6.82-6.97 (br m, 1H,
-HCdC-); MS(EI) m/z 124 (M), 109 (M - CH3), 81 (M - CH3/
found 216.15072 (dev -3.24 ppm); IR (neat) 1717 cm-1
.
4-(1-Bu tyl)-6-m eth oxy-2-tetr alon e (13d): H3PO4 (0.2 equiv)
used; obtained as a dark brown oil after workup (1.56 g, mass
balance 91%, yield 62%); GC retention time 17.88 min;
obtained as a dark yellow oil after flash chromatography,

Clean-Chemistry Synthesis of 2-Tetralones
J . Org. Chem., Vol. 66, No. 21, 2001 7117
CO) 43 (M - C6H9); IR (neat) 1666 cm-1. This material was
found to be identical (1H NMR, GCMS) with an authentic
sample (Aldrich).
1-Cycloh exyl-3-m et h ylb en zen e a n d 4-Cycloh exyl-1-
m eth ylben zen e (15). cyclohexene (0.89 g, 10.87 mmol) and
toluene (1 g, 10.87 mmol) were used in the standard procedure
(see General TFAA/H3PO4 Method) with a reaction time of 10
min. Obtained as a light yellow liquid after workup (1.61 g,
mass balance 85%, yield 70%: o/ p, 1:2); GCMS: at 10.89 min,
MS(EI) m/z 174 (M), 83 (M - (C6H4 - CH3)); at 11.00 min,
MS(EI) m/z 174 (M), 83 (M - (C6H4 - CH3)).
at 6.53 min, 124 (M) 1-acetyl-1-cyclohexene; at 7.90 min 132
(M) unknown.
Ack n ow led gm en t. A.D.G. thanks Roche Ireland
Ltd, Clarecastle, County Clare, and Enterprise Ireland
for financial support through the Irish American Part-
nership Program. We thank Drs. Dennis Smith and
J ohn O’Reilly of Roche Ireland and Dr. Tony Daly,
formerly of Roche Ireland, for their support throughout
this work.
Com p etition Rea ction . Acetic acid (1 g, 16.66 mmol),
cyclohexene (1.4 g, 16.66 mmol), and toluene (3.03 g, 33.33
mmol) were used in the standard procedure (see General
TFAA/H3PO4 Method) with a reaction time of 10 min. A yellow-
brown oil was obtained after workup (2.25 g, yield of 1-acetyl-
1-cyclohexene ∼52%); GCMS: at 1.75 min 92 (M) toluene; at
2.75 min, 100 (M) cyclohexanol; at 5.33 min, 123 (M) unknown;
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
13b,c,f-h ; GC traces for 13a after aqueous workup and after
chromatography and for the competition reaction involving
acetic acid, cyclohexene, and toluene. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0158074