Trifluoromethanesulfonic acid catalyzed Friedel-Crafts acylation of aromatics with β-lactams

Article abstract of DOI:10.1016/S0040-4020(02)01026-8

N-Protected and unprotected 2-azetidinones, protolytically activated by superacidic trifluoromethanesulfonic acid, react with aromatic compounds to give β-amino aromatic ketones in good to excellent yields (65-98%). Non-benzenoid aromatics (pyrrole and ferrocene) produced good yield (64-89%) of the corresponding ketones.

Full text of DOI:10.1016/S0040-4020(02)01026-8

Tetrahedron 58 (2002) 8475–8481
Trifluoromethanesulfonic acid catalyzed Friedel–Crafts acylation
of aromatics with b-lactams
*
Kevin W. Anderson and Jetze J. Tepe
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Received 9 August 2002; accepted 17 August 2002
Abstract—N-Protected and unprotected 2-azetidinones, protolytically activated by superacidic trifluoromethanesulfonic acid, react with
aromatic compounds to give b-amino aromatic ketones in good to excellent yields (65–98%). Non-benzenoid aromatics (pyrrole and
ferrocene) produced good yield (64–89%) of the corresponding ketones. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Friedel–Crafts reactions are among the most common and
important transformations in organic chemistry for electro-
philic aromatic alkylations and acylations.1 A significant
number of Lewis acid catalysts (AlCl3, FeCl3, SnCl4,
BF3·OEt2) have been shown to be very successful for the
acylation of aromatic substrates with acid chlorides or
anhydrides.2 Aromatic ketones can also be prepared by the
reaction of carboxylic acids with aromatic hydrocarbons
catalyzed by methanesulfonic acid,3 polyphosphoric acid,4
and Nafion-H.5 In addition, aromatic acylations have been
achieved with methyl benzoate and various aromatic
compounds (both electron-rich and electron-poor)
protolytically activated by the superacidic trifluoro-
methanesulfonic acid, to produce benzophenone derivatives
in good yields.6 Considering the proven generality and
usefulness of Friedel–Crafts acylations in organic syn-
thesis, as well as the easy access to a wide range of
substituted b-lactams, we envisioned that the b-lactam
would be a good substrate for acylating aromatics, due to its
high ring strain, to produce b-amino aromatic ketone
derivatives. We previously reported a very mild procedure
for the intermolecular acylation of aromatic substrates with
2-azetidinones and N-substituted 2-azetidinones with tri-
fluoromethanesulfonic acid to give the corresponding
b-amino aromatic ketones in good to excellent yields.7
Herein, we report these results and extensions to this
methodology to include heteroaromatic substrates.
The efficacy of 2-azetidinone 1 as a Friedel–Crafts substrate
for a variety of aromatic compounds, including bromo-
benzene, chlorobenzene, fluorobenzene, toluene, and
anisole, is illustrated in Table 1. Thus, 2-azetidinone 1
and the corresponding aromatic compound (10.0 equiv.)
were mixed with trifluoromethanesulfonic acid (1.1 equiv.)
in 1,2-dichloroethane at 08C and the mixture was allowed to
warm to room temperature and was stirred for 15–30 min.
With the exception of the highly deactivated nitrobenzene,
all trifluoromethanesulfonic acid (pKa (H2O)¼214; pKa
(DMSO)¼20.3)8 catalyzed reactions provided the b-amino
aromatic ketone derivatives 4a–f as their triflate salt in good
Table 1. Acylation of aromatics with 2-azetidinone using trifluoromethane-
sulfonic acid
Nucleophile
Acida
Product
R
Yield (%)b
Bromobenzene
Chlorobenzene
Fluorobenzene
Benzene
Anisole
Toluene
Toluene
Toluene
Nitrobenzene
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
MSA
TFA
4a
4b
4c
4d
4e
4f
4f
4f
4g
Br
Cl
F
92c
92
91
98
95
93
0d
H
OMe
Me
Me
Me
NO2
0d
TfOH
0d
a
TfOH¼trifluoromethanesulfonic acid; MSA¼methanesulfonic acid;
TFA¼trifluoroacetic acid.
b
c
d
Keywords: pyrrole; Friedel–Crafts acylation; aromatic hydrocarbons.
*
Isolated yields.
Optimal yields obtained when heated to 808C for 2 h.
Reaction was heated to reflux with no desired product isolated.
Corresponding author. Tel.: þ1-517-355-9715x147; fax: þ1-517-353-
1793; e-mail: tepe@cem.msu.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01026-8

8476
K. W. Anderson, J. J. Tepe / Tetrahedron 58 (2002) 8475–8481
to excellent yields (Eq. (1)), see also Table 1). The protic
acids, methanesulfonic acid (pKa (H2O)¼20.6; pKa
(H2O)¼20.25; pKa (DMSO)¼3.45)8 proved to be too
weak to catalyze the Friedel–Crafts acylation with
2-azetidinone even under more vigorous conditions
(5.0 equiv., 808C).
Table 2. Actylation of aromatics with N-protected 2-azetidinones with
trifluoromethanesulfonic acid
(DMSO)¼1.6)
and
trifluoroacetic
acid
(pKa
Substrate 7
R1
R2
Acida
TfOH
TfOH
TfOH
TfOH
TfOH
Product Yield (%)b
7a
7b
7c
7c
7c
7c
7c
7c
7c
7c
7c
7c
7c
7c
COPh
CO2Me
CO2CH2CCl3 Br
CO2CH2CCl3 Cl
CO2CH2CCl3
CO2CH2CCl3 CMe TfOH
Me
H
8a
8b
8c
8d
8e
8f
8g
8h
8h
8h
8h
70
65
84
87
85
86
85
91
0c
F
ð1Þ
ð2Þ
CO2CH2CCl3 Me
TfOH
TfOH
MSA
TFA
AlCl3
BF3·OEt2 8h
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
H
H
H
H
H
H
0c
0c
0c
SnCl4
TfOH
8h
8i
0c
CO2CH2CCl3 NO2
0c
a
TfOH¼trifluoromethanesulfonic acid; MSA¼methanesulfonic acid;
TFA¼trifluoroacetic acid.
Also, the less strained b-butyrolactam 5 failed to undergo
the Friedel–Crafts reaction with benzene under forcing
conditions.
b
c
Isolated yields.
No reaction at room temperature; reaction was heated to reflux with no
desired product isolated.
A possible mechanism of acylation consistent with previous
reported studies is an acid catalyzed, N-protonated,
unimolecular (AN1) mechanism where the rate-limiting
step involves formation of the acylium ion V as shown in
Scheme 1.9 The AN1 mechanism is favored due to the
enhanced rate of C–N bond fission that occurs in
2-azetidinones, resulting from the relief in ring strain
(,119.4 kJ/mol).10 The formation of dicationic inter-
mediates such as VI are known and have been well explored
in superacidic media, however, a possible second protona-
tion is anticipated to occur on the more basic nitrogen atom
providing intermediate VII.11 The highly reactive acyl
carbonium ion V or VII then react with the aromatic
substrate, providing the acylated product (Scheme 1).
The Friedel–Crafts acylation of various N-acylated
2-azetidinones 7 with a variety of aromatics was sub-
sequently investigated. The results are shown in Table 2.
Treatment of 2-azetidinones 7a–c and the aromatic
substrate (10.0 equiv.) with trifluoromethanesulfonic acid
(2.0 equiv.) in 1,2-dichloroethane at 08C to room tempera-
ture over 30 min provided the corresponding products 8a–h
in excellent yields. Treatment of the 2-azetidinone 7c with
traditional Lewis acids (AlCl3, SnCl4, BF3·OEt2) and protic
acids (MSA, TFA) did not result in any Friedel–Crafts
acylation of benzene, not even under more forcing
conditions (refluxing conditions for several hours). Treat-
ment of N-Troc (2,2,2-trichloroethoxycarbonyl)-2-azetidi-
none 7c, under the reaction conditions, in the presence of
naphthalene (10.0 equiv.) provided a mixture of the 1- and
2-substituted naphthalene isomers in overall 84% yield
(Eq. (3)). Using ferrocene as the aromatic substrate,
acylation was accomplished to give ferrocene-ketone 10 in
89% yield (Table 3).
ð3Þ
All attempts to di-acylate ferrocene by using an excess of
2-azetidinone 7c failed, giving only single acylation of
ferrocene. The 2-azetidinones also proved to be substrates
for the acylation of aromatic heterocycles. The N-protected
pyrroles, N-trityl-pyrrole and N-phenylsulfonyl-pyrrole
(Table 3), were also examined, under the same reaction
conditions, giving the corresponding 3-substituted 11 and
2-substituted 12 pyrroles in moderate yields (Table 3).
Scheme 1. Proposed mechanism for Friedel–Crafts acylation with
b-lactams.

K. W. Anderson, J. J. Tepe / Tetrahedron 58 (2002) 8475–8481
8477
Table 3. Acylation of ferrocene and N-substituted pyrroles with N-(Troc)-
2-azetidinone using trifluoromethanesulfonic acid
Crafts reaction by running the reaction using benzene as the
solvent.
Nucleophile
Product
Yield (%)a
ð4Þ
As anticipated, the intramolecular Fries-type rearrangement
giving quinolones 14a (87%) and 14b (93%) was favored
over the intermolecular Friedel–Crafts reaction to give 15a
(10%) and 15b (5%) in excellent combined overall yield.
10
89
11
12
65
64
3. Conclusions
In summary, we have shown that 2-azetidinones can be
activated by trifluoromethanesulfonic acid to undergo
Friedel–Crafts acylation of aromatic and heteroaromatics
to give their respective b-amino aromatic ketones in
preparatively good yields.
a
Isolated yields.
4. Experimental
In addition, we examined the N-aryl 2-azetidinones (p-Cl, p-F,
p-H, p-OMe, p-NO2) 13a–e under the same mild reaction
conditions due to their high propensity to suffer CO–N bond
cleavage under both acidic and basic conditions.12 The N-aryl
2-azetidinones were prepared by standard protocols.13 N-Aryl
2-azetidinones 13 have previously been shown to undergo a
Fries-type rearrangement (intramolecular Friedel–Crafts),
resulting in the corresponding 2,3-dihydro-4(1H)-quinolones
14 under forcing conditions (reflux in trifluoroacetic acid
for 2 h).14 We report here a significantly milder method for
the preparation of quinolones 14a–e using trifluoro-
methanesulfonic acid (1.0–2.0 equiv.) in 1,2-dichloroethane
(08C to room temperature over 15 min) in excellent yields
(Table 4).
Reactions were carried out in oven-dried glassware under
nitrogen atmosphere, unless otherwise noted. All com-
mercial reagents were used without further purification. All
solvents were reagent grade. THF was freshly distilled from
sodium/benzophenone under nitrogen. All reactions were
magnetically stirred and monitored by thin layer chroma-
tography with Analtech 0.25-mm pre-coated silica gel
plates. Column chromatography was carried out on silica
gel 60 (230–400 mesh) supplied by EM Science. Yields
refer to chromatographically and spectroscopically pure
compounds unless otherwise stated. Melting points were
determined on a Mel-Temp (Laboratory devices) apparatus
with a microscope attachment. Infrared spectra were
recorded on a Nicolet IR/42 spectrometer. Proton, carbon,
and fluorine NMR spectra were recorded on a Varian
Gemini-300 spectrometer or a Varian VXR-500 spec-
trometer. Chemical shifts are reported relative to the residue
We also examined the competition between the intramole-
cular Fries-type rearrangement and intermolecular Friedel–
1
peaks of solvent chloroform (d 7.24 for H and d 77.0 for
13C) and dimethyl sulfoxide (d 2.49 for 1H and d 39.5
for 13C). High-resolution mass spectra were obtained at the
Mass Spectrometry Laboratory of the University of South
Carolina, Department of Chemistry & Biochemistry with a
Micromass VG-70S mass spectrometer. Gas chromato-
graphy/low-resolution mass spectra were recorded on a
Hewlet–Packard 5890 Series II gas chromatograph con-
nected to a TRIO-1 EI mass spectrometer. Microanalyses
were recorded on a Perkin–Elmer Series II CHNS/O 2400
Analyzer. All chemicals were obtained from Aldrich
Chemical Co. and used as received. 1-trityl-pyrrole,15
1-phenylsulfonyl-pyrrole,16 and N-(benzoyl)-2-azetidi-
none17 were prepared by literature protocols. Caution:
Table 4. Fries-type rearrangement of aryl 2-azetidinones with trifluoro-
methanesulfonic acid
Substrate 13
R
Yield 14 (%)a
13a
13b
13c
13d
13e
Cl
F
H
OMe
NO2
97
98
96b
97b
0
trifluoromethanesulfonic acid is
a
corrosive and
a
hygroscopic liquid that should be handled with care under
a dry atmosphere.
Isolated yields.
2 equiv. trifluoromethanesulfonic acid were required for optimal yield.
b

8478
K. W. Anderson, J. J. Tepe / Tetrahedron 58 (2002) 8475–8481
4.1. Preparation of 3-amino-1-phenyl-propan-1-one
trifluoromethylsulfonate (4d) from 2-azetidinone and
benzene under trifluoromethanesulfonic acid catalysis
(typical procedure for 4a–4f)
(q, CF3, J¼318 Hz), 36.4, 34.8; 19F NMR: (282.35 MHz)
(d6-DMSO) d 222078.29; IR: (NaCl) 3221 (NH), 1682
(CO), 1288 (SO2); LRMS (%) 149 (M, 10), 132 (20), 105
(100), 77 (78), 51 (43), 44 (85). Anal. calcd for
C10H12F3NO4S: C, 40.13; H, 4.04; N, 4.68. Found: C,
40.56; H, 3.81; N, 4.13.
Trifluoromethanesulfonic acid (1.5 mmol, 232 mg) was
added slowly to a solution of 2-azetidinone (1.4 mmol,
100 mg) in benzene (14.0 mmol, 1.25 mL) and 1,2-
dichloroethane (0.5 mL) at 08C under a dry nitrogen
atmosphere. The solution was stirred at room temperature
for 15–30 min. The reaction mixture was then carefully
neutralized with ice-water (10 mL) containing saturated
NaHCO3 solution and extracted with ethyl acetate. The
organic layer was separated, washed with water, brine
solution, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure to give product 4d as
a white flaky solid, which was re-crystallized in ethyl
acetate (412 mg, 98%).
4.1.5. 3-Amino-1-(4-methoxy-phenyl)-propan-1-one tri-
1
fluoromethylsulfonate (4e). 95%; mp 1558C; H NMR:
(300 MHz) (d6-DMSO) d TMS: 3.13 (t, 2H, J¼6 Hz), 3.30
(t, 2H, J¼6 Hz), 3.85 (s, 3H), 6.2 (br-s, 3H), 7.07 (d, 2H,
J¼9 Hz), 7.96 (d, 2H, J¼9 Hz); 13C NMR: (74.47 MHz)
(d6-DMSO) d 196.3 (CO), 164.2, 130.9, 129.6, 114.7, 123.5
(q, CF3, J¼318 Hz), 56.3, 35.9, 34.9; 19F NMR:
(282.35 MHz) (d6-DMSO) d; IR: (NaCl) 3250–3171
(NH), 1670 (CO), 1249 (SO2); LRMS 179 (M). Anal.
calcd for C11H14 F3NO5S: C, 40.12; H, 4.29; N, 4.25.
Found: C, 40.40; H, 4.53; N, 4.14.
4.1.1. 3-Amino-1-(4-bromo-phenyl)-propan-1-one tri-
1
4.1.6. 3-Amino-1-(4-methyl-phenyl)-propan-1-one tri-
fluoromethylsulfonate (4f). 93%; mp 1608C; 1H NMR:
(300 MHz) (d6-DMSO) d TMS: 2.38 (s, 3H), 3.16 (t, 2H,
J¼6 Hz), 3.35 (t, 2H, J¼6 Hz), 7.36 (d, 2H, J¼8 Hz), 7.40
(br-s, 3H), 7.88 (d, 2H, J¼8 Hz); 13C NMR: (74.47 MHz)
(d6-DMSO) d 197.5 (CO), 144.9, 134.2, 130.1, 128.8, 123.5
(q, CF3, J¼318 Hz), 36.3, 34.9, 21.8 (Me); 19F NMR:
(282.35 MHz) (d6-DMSO) d 222075.24; IR: (NaCl) 3288–
3220 (NH), 1680 (CO), 1263 (SO2); LRMS (%) 163 (M,
12), 146 (18), 134 (22), 119 (100), 91 (83), 65 (39), 44 (51).
Anal. calcd for C11H14F3NO4S: C, 42.17; H, 4.50; N, 4.47.
Found: C, 42.46; H, 4.71; N, 4.32.
fluoromethylsulfonate (4a). 92%; mp 1638C; H NMR:
(300 MHz) (d6-DMSO) d TMS: 3.17 (t, 2H, J¼6 Hz), 3.37
(t, 2H, J¼6 Hz), 7.5–7.8 (br-s, 3H), 7.75 (d, 2H, J¼9 Hz),
7.90 (d, 2H, J¼9 Hz); 13C NMR: (74.47 MHz) (d6-DMSO)
d 197.2 (CO), 135.6, 132.6, 130.6, 128.5, 123.5 (q, CF3,
J¼318 Hz), 36.3, 34.7; 19F NMR: (282.35 MHz) (d6-
DMSO) d 222075.24; IR: (NaCl) 3300–3215 (NH), 1684
(CO), 1261 (SO2); LRMS (%) 229 (M, 20), 210 (24), 198
(20), 183 (100), 155 (60). Anal. calcd for C10H11Br
F3NO4S: C, 31.76; H, 2.93; N, 3.70. Found: C, 32.09; H,
3.05; N, 3.47.
4.1.2. 3-Amino-1-(4-chloro-phenyl)-propan-1-one tri-
1
4.1.7. 2-Oxo-azetidine-1-carboxylic acid methyl ester
(7b). In a 100 mL round bottom flask under dry N2,
2-azetidinone (7.03 mmol, 513 mg) was dissolved in
anhydrous tetrahydrofuran (23 mL). The solution was
then cooled to 2788C (acetone/dry ice bath) causing
precipitation of the insoluble lactams, and then n-butyl
lithium (7.86 mmol, 0.785 mL) was carefully and slowly
added dropwise with stirring. After 30 min of stirring, a
solution of methyl chloroformate (7.86 mmol, 0.61 mL) in
anhydrous tetrahydrofuran (7 mL) was added dropwise. The
reaction mixture was stirred at 2788C for 1 h and allowed to
warm to room temperature for 1 h after which it was
quenched with 20 mL aqueous saturated ammonium
chloride. The solution was then washed with diethyl-ether
(3£20 mL), separated, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The
crude material was further purified by column chromato-
graphy on silica gel (dichloromethane/ethanol, 99:1) to
fluoromethylsulfonate (4b). 92%; mp 1488C; H NMR:
(300 MHz) (d6-DMSO) d TMS: 3.17 (t, 2H, J¼6 Hz), 3.37
(t, 2H, J¼6 Hz), 7.34 (br-s, 3H), 7.58 (d, 2H, J¼9 Hz), 7.97
(d, 2H, J¼9 Hz); 13C NMR: (74.47 MHz) (d6-DMSO) d
196.9 (CO), 139.3, 135.2, 130.5, 129.6, 123.5 (q, CF3,
J¼317 Hz), 36.4, 34.8; 19F NMR: (282.35 MHz) (d6-
DMSO) d 222084.40; IR: (NaCl) 3291–3209 (NH), 1684
(CO), 1281 (SO2); LRMS (%) 184 (12), 163 (19) 139 (100),
75 (42), 44 (69). Anal. calcd for C10H11ClF3NO4S: C,
35.99; H, 3.32; N, 4.20. Found: C, 36.28; H, 3.48; N, 4.10.
4.1.3. 3-Amino-1-(4-fluoro-phenyl)-propan-1-one tri-
1
fluoromethylsulfonate (4c). 91%; mp 1328C; H NMR:
(300 MHz) (d6-DMSO) d TMS: 3.16 (t, 2H, J¼6 Hz), 3.37
(t, 2H, J¼6 Hz), 7.0–7.7 (br-s, 3H), 7.37 (t, 2H, J¼9 Hz),
8.06 (t, 2H, J¼9 Hz); 13C NMR: (74.47 MHz) (d6-DMSO) d
196.0 (CO), 167.0, 163.7, 132.7, 131.1, 131.0, 122.9 (q,
CF3, J¼318 Hz), 116.1, 115.8, 35.8, 34.2; 19F NMR:
(282.35 MHz) (d6-DMSO) d 222087.45, 229845.49; IR:
(NaCl) 3291–3209 (NH), 1682 (CO), 1236 (SO2); LRMS
(%) 167 (M, 10), 150 (13), 138 (13), 123 (100), 95 (70), 74
(28), 44 (78). Anal. calcd for C10H11F4NO4S: C, 37.86; H,
3.49; N, 4.41. Found: C, 38.21; H, 3.64; N, 4.15.
1
yield 7b (700 mg, 77%). Mp 648C; H NMR: (300 MHz)
(CDCl3) d TMS: 2.92 (t, 2H, J¼5 Hz), 3.48 (t, 2H, J¼5 Hz),
3.69 (s, 3H); 13C NMR: (74.47 MHz) (CDCl3) d 164.4
(CO), 149.4 (OCON), 53.1 (Me), 37.6, 36.4; IR: (NaCl)
1801 (CO), 1724 (OCON). Anal. calcd for C5H7NO3: C,
46.51; H, 5.46; N, 10.85. Found: C, 46.82; H, 5.64; N,
10.67.
4.1.4. 3-Amino-1-phenyl-propan-1-one trifluoromethyl
sulfonate (4d). 98%; mp 1228C; 1H NMR: (300 MHz)
(d6-DMSO) d TMS: 3.17 (t, 2H, J¼6 Hz), 3.39 (t, 2H,
J¼6 Hz), 7.41 (br-s, 3H), 7.56 (t, 2H, J¼7 Hz), 7.67 (t, 1H,
J¼7 Hz), 7.98 (d, 2H, J¼7 Hz); 13C NMR: (74.47 MHz)
(d6-DMSO) d 198.0 (CO), 136.4, 134.4, 129.5, 128.6, 123.5
4.1.8. 2-Oxo-azetidine-1-carboxylic acid-2,2,2-trichloro-
ethyl ester (7c). In a 100 mL round bottom flask under dry
N2, 2-azetidinone (4.22 mmol, 300 mg) was dissolved in
anhydrous tetrahydrofuran (14 mL). The solution was
then cooled to 2788C (acetone/dry ice bath) causing

K. W. Anderson, J. J. Tepe / Tetrahedron 58 (2002) 8475–8481
8479
precipitation of the insoluble lactams, and then n-butyl
lithium (4.64 mmol, 0.46 mL) was carefully and slowly
added dropwise with stirring. After 30 min of stirring, a
solution of 2,2,2-trichloroethyl chloroformate (4.64 mmol)
in anhydrous tetrahydrofuran (4 mL) was added dropwise.
The reaction mixture was stirred at 2788C for 1.5 h and
allowed to warm to room temperature for 1 h after which it
was quenched with 15 mL aqueous saturated ammonium
chloride. The solution was then washed with diethyl-ether
(3£20 mL), separated, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure to yield a
brown oil. The crude material was further purified by
column chromatography on silica gel (hexanes/ethyl
acetate, 6:4) and re-crystallized with diethyl ether to yield
7b (890 mg, 86%). Mp 988C; 1H NMR: (300 MHz) (CDCl3)
d TMS: 3.14 (t, 2H, J¼5 Hz), 3.73 (t, 2H, J¼5 Hz), 4.83 (s,
2H); 13C NMR: (74.47 MHz) (CDCl3) d 164.0 (CO), 147.0
(OCON), 94.3 (CCl3), 74.7, 38.2, 37.2; IR: (NaCl) 1790
(CO), 1730 (OCON). Anal. calcd for C6H6Cl3NO3: C,
29.24; H, 2.45; N, 5.68. Found: C, 29.60; H, 2.55; N,
5.64.
(OCON), 1684 (CO); HRMS m/e calcd for C11H13NO3 (M)
230.0793, found 230.0791.
4.2.3. [(3-(4-Bromo-phenyl)-3-oxo-propyl)]-carbamic
1
acid-2,2,2-trichloro-ethyl ester (8c). 84%; mp 848C; H
NMR: (300 MHz) (CDCl3) d TMS: 3.26 (t, 2H, J¼6 Hz),
3.68 (q, 2H, J¼6 Hz), 4.72 (s, 2H), 5.70 (br-s, 1H), 7.63 (d,
2H, J¼9 Hz), 7.83 (d, 2H, J¼9 Hz); 13C NMR:
(74.47 MHz) (CDCl3) d 197.8 (CO), 154.6 (OCON),
134.9, 132.0, 129.5, 128.7, 95.4 (CCl3), 74.4, 38.1, 35.9;
IR: (NaCl) 3354 (NH), 1734 (OCON), 1684 (CO); LRMS
(%) 403 (M, 1), 367 (1), 270 (8), 254 (12), 226 (14), 210
(49), 183 (100), 157 (28), 131 (27), 76 (33). Anal. calcd for
C12H11BrCl3NO3: C, 35.72; H, 2.75; N, 3.47. Found C,
35.65; H, 2.69; N, 3.40.
4.2.4. [(3-(4-Chloro-phenyl)-3-oxo-propyl)]-carbamic
1
acid-2,2,2-trichloro-ethyl ester (8d). 87%; mp 878C; H
NMR: (300 MHz) (CDCl3) d TMS: 3.23 (t, 2H, J¼6 Hz),
3.65 (q, 2H, J¼6 Hz), 4.70 (s, 2H), 5.76 (br-s, 1H), 7.44 (d,
2H, J¼9 Hz), 7.87 (d, 2H, J¼9 Hz); 13C NMR:
(74.47 MHz) (CDCl3) d 198.0 (CO), 154.9 (OCON),
140.3, 134.9, 129.7, 129.3, 95.8 (CCl3), 74.7, 38.5, 36.3;
IR: (NaCl) 3352 (NH), 1734 (OCON), 1684 (CO); LRMS
(%) 359 (M). Anal. calcd for C12H11Cl4NO3: C, 40.14; H,
3.09; N, 3.90. Found C, 41.22; H, 3.23; N, 3.81.
4.2. Preparation of (3-oxo-3-phenyl-propyl)-carbamic
acid-2,2,2-trichloro-ethyl ester (8h) from N-(2,2,2-
trichloroethoxycarbonyl)-2-azetidinone and benzene
under trifluoromethanesulfonic acid catalysis (typical
procedure for 8a–8h, 9–12)
4.2.5. [(3-(4-Fluoro-phenyl)-3-oxo-propyl)]-carbamic
1
acid-2,2,2-trichloro-ethyl ester (8e). 85%; mp 818C; H
Trifluoromethanesulfonic acid (0.82 mmol, 222 mg) was
added slowly to a solution of N-(2,2,2-trichloroethoxy-
carbonyl)-2-azetidinone 7c (0.41 mmol, 100 mg) in
benzene (4.4 mmol, 0.4 mL) and 1,2-dichloroethane
(0.4 mL) at 08C under a dry nitrogen atmosphere. The
solution was stirred at room temperature for 15–30 min.
The reaction mixture was then carefully neutralized with
ice-water (10 mL) containing saturated NaHCO3 solution
and extracted with dichloromethane. The organic layer was
separated, washed with brine solution, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to
give crude product, which was re-crystallized in diethyl-
ether to give pure product (121 mg, 91%) or purified by
column chromatography on silica gel (hexane/ethyl acetate,
7:3).
NMR: (300 MHz) (CDCl3) d TMS: 3.24 (t, 2H, J¼6 Hz),
3.64 (q, 2H, J¼6 Hz), 4.72 (s, 2H), 5.74 (br-s, 1H), 7.15 (m,
2H), 7.99 (m, 2H); 13C NMR: (74.47 MHz) (CDCl3) d 197.3
(CO), 167.6, 164.3, 154.6 (OCON), 132.7, 130.7, 130.6,
116.0, 115.7, 95.4 (CCl3), 74.4, 38.1, 36.0; 19F NMR:
(282.35 MHz) (CDCl3) d 229500.42; IR: (NaCl) 3356
(NH), 1734 (OCON), 1684 (CO); LRMS (%) 342 (M). Anal.
calcd for C12H11Cl3FNO3: C, 42.07; H, 3.24; N, 4.09. Found
C, 41.22; H, 3.29; N, 4.07.
4.2.6. [(3-(4-Methoxy-phenyl)-3-oxo-propyl)]-carbamic
1
acid-2,2,2-trichloro-ethyl ester (8f). 86%; mp 758C; H
NMR: (300 MHz) (CDCl3) d TMS: 3.20 (t, 2H, J¼6 Hz),
3.64 (q, 2H, J¼6 Hz), 3.87 (s, 3H), 4.71 (s, 2H), 5.81 (br-s,
1H), 6.93 (d, 2H, J¼9 Hz), 7.93 (d, 2H, J¼9 Hz); 13C NMR:
(74.47 MHz) (CDCl3) d 197.4 (CO), 163.8, 154.9 (OCON),
130.3, 129.4, 113.8, 95.5 (CCl3), 74.4, 55.4 (OMe), 37.7,
36.2; IR: (NaCl) 3350 (NH), 1734 (OCON), 1670 (CO);
LRMS (%) 354 (M, 10), 317 (3), 205 (31), 177 (38), 134
(100), 91 (92), 77 (89) 63 (35). Anal. calcd for
C13H14Cl3NO4: C, 44.03; H, 3.98; N, 3.95. Found C,
43.75; H, 3.98; N, 3.92.
4.2.1. N-(3-Oxo-3-p-tolyl-propyl)-benzamide (8a). 70%;
1
mp 1098C; H NMR: (300 MHz) (CDCl3) d TMS: 2.81 (s,
3H), 3.28 (t, 2H, J¼6 Hz), 3.86 (q, 2H, J¼6 Hz), 7.23 (d,
2H, J¼8 Hz), 7.23 (br-s, 1H), 7.34–7.47 (m, 3H), 7.76 (d,
2H, J¼8 Hz), 7.84 (d, 2H, J¼8 Hz); 13C NMR:
(74.47 MHz) (CDCl3) d 199.2 (CO), 167.4 (CON), 144.3,
134.4, 133.9, 131.3, 129.3, 128.4, 128.1, 126.9, 37.9, 34.9,
21.6 (Me); IR: (NaCl) 3333 (NH), 1680 (CO), 1639 (CON);
LRMS (%) 167 (M, 13), 148 (32), 119 (100), 105 (75), 91
(31), 77 (43). Anal. calcd for C17H17NO2: C, 76.38; H, 6.41;
N, 5.24. Found: C, 76.33; H, 6.26; N, 5.18.
4.2.7. (3-Oxo-3-p-tolyl-propyl)-carbamic acid-2,2,2-tri-
chloro-ethyl ester (8g). 85%; mp 988C; 1H NMR:
(300 MHz) (CDCl3) d TMS: 2.42 (s, 3H), 3.23 (t, 2H,
J¼6 Hz), 3.65 (q, 2H, J¼6 Hz), 4.71 (s, 2H), 5.78 (br-s,
1H), 7.27 (d, 2H, J¼8 Hz), 7.85 (d, 2H, J¼8 Hz); 13C
4.2.2. (3-Oxo-3-phenyl-propyl)-carbamic acid methyl
ester (8b). 65%; oil; 1H NMR: (300 MHz) (CDCl3) d
TMS: 3.21 (t, 2H, J¼6 Hz), 3.59 (q, 2H, J¼6 Hz), 3.63 (s,
3H), 5.42 (br-s, 1H), 7.49 (t, 2H, J¼7 Hz), 7.61 (t, 1H,
J¼7 Hz), 7.98 (d, 2H, J¼7 Hz); 13C NMR: (74.47 MHz)
(CDCl3) d 199.4 (CO), 157.4 (OCON), 136.7, 133.7, 128.9,
128.2, 52.3 (Me), 38.7, 36.1; IR: (NaCl) 3350 (NH), 1718
NMR: (74.47 MHz) (CDCl3)
d 198.9 (CO), 154.9
(OCON), 144.8, 134.2, 129.7, 128.4, 95.8 (CCl3), 74.7,
38.3, 36.4; IR: (NaCl) 3356 (NH), 1734 (OCON), 1680
(CO); LRMS (%) 338 (M, 15). Anal. calcd for
C13H14Cl3NO3: C, 46.11; H, 4.17; N, 4.14. Found: C,
46.09; H, 4.20; N, 4.07.

8480
K. W. Anderson, J. J. Tepe / Tetrahedron 58 (2002) 8475–8481
4.2.8. (3-Oxo-3-phenyl-propyl)-carbamic acid-2,2,2-tri-
chloro-ethyl ester (8h). 91%; mp 758C; 1H NMR:
(300 MHz) (CDCl3) d TMS: 3.27 (t, 2H, J¼6 Hz), 3.67 (q,
2H, J¼6 Hz), 4.71 (s, 2H), 5.74 (br-s, 1H), 7.48 (t, 2H,
J¼7 Hz), 7.59 (t, 1H, J¼7 Hz), 7.96 (d, 2H, J¼7 Hz);
13C NMR: (74.47 MHz) (CDCl3) d 198.9 (CO), 154.6
(OCON), 136.3, 133.6, 128.7, 127.9, 95.5 (CCl3), 74.4,
38.1, 36.0; IR: (NaCl) 3427 (NH), 1716 (OCON), 1678 (CO);
LRMS (%) 224 (M). Anal. calcd for C12H12Cl3NO3: C,
44.40; H, 3.73; N, 4.32. Found: C, 44.45; H, 3.78; N, 4.25.
1H, J¼9, 3 Hz); 13C NMR: (74.47 MHz) (CDCl3) d 193.1
(CO), 157.0, 153.9, 148.8, 123.3, 122.9, 120.3, 119.3, 119.2,
117.4, 117.3, 112.2, 111.9, 42.3, 37.8; IR: (NaCl) 3341
(NH), 1651 (CO). Anal. calcd for C9H8FNO: C, 65.45; H,
4.88; N, 8.48. Found C, 65.57; H, 5.19; N, 7.99.
4.2.14. 2,3-Dihydro-4(1H)-quinolone (14c). 96%; mp
1
448C; H NMR: (300 MHz) (CDCl3) d TMS: 2.66 (t, 2H,
J¼7 Hz), 3.53 (t, 2H, J¼7 Hz), 4.79 (br-s, 1H), 6.69 (d, 2H,
J¼9 Hz), 7.26 (t, 1H, J¼7 Hz), 7.81 (d, 1H, J¼8 Hz); 13C
NMR: (74.47 MHz) (CDCl3) d 194.0 (CO), 152.3, 135.2,
127.4, 119.0, 117.6, 115.9, 42.0, 37.9; IR: (NaCl) 3348
(NH), 1660 (CO). Anal. calcd for C9H9NO: C, 73.45; H,
6.16; N, 9.52. Found C, 72.22; H, 6.08; N, 9.16.
4.2.9. (3-Naphthalen-1-yl-3-oxo-propyl)-carbamic acid
2,2,2-trichloro-ethyl ester (9a) and (3-naphthalen-2-yl-
3-oxo-propyl)-carbamic acid 2,2,2-trichloro-ethyl ester
1
(9b). 47% 9a; 37% 9b; H NMR: (500 MHz) (CDCl3) d
TMS: 3.33 (t, 2H, J¼6 Hz), 3.36 (t, 2H, J¼6 Hz), 3.70 (4H,
q, J¼6 Hz), 4.72 (s, 2H), 4.73 (s, 2H), 5.78 (br-s, 2H), 7.45–
7.62 (m, 5H), 7.85–7.88 (m, 4H), 7.93 (d, 1H, J¼8 Hz),
7.98–7.99 (m, 2H), 8.43 (s, 1H), 8.71 (d, 1H, J¼9 Hz); 13C
NMR: (74.47 MHz) (CDCl3) d 202.9 (CO), 199.1 (CO),
154.9 (OCON), 136.0, 134.9, 134.3, 134.0, 133.7, 132.7,
130.4, 130.2, 129.9, 128.9, 128.84, 128.8, 128.7, 128.5,
128.0, 127.2, 126.8, 125.9, 124.6, 123.7, 95.9 (CCl3), 74.8,
41.4, 38.5, 36.9, 36.6; IR: (NaCl) 3352 (NH), 1736
(OCON), 1676 (CO); HRMS m/e calcd for C16H14Cl3NO3
(M) 373.0039, found 373.0030.
4.2.15. 3-Methoxy-2,3-dihydro-4(1H)-quinolone (14d).
1
97%; mp 1118C; H NMR: (300 MHz) (CDCl3) d TMS:
2.66 (t, 2H, J¼7 Hz), 3.51 (t, 2H, J¼7 Hz), 4.41 (br-s, 1H),
3.74 (s, 3H), 6.63 (d, 1H, J¼9 Hz), 6.95 (dd, 1H, J¼9,
3 Hz), 7.29 (d, 1H, J¼3 Hz); 13C NMR: (74.47 MHz)
(CDCl3) d 193.7 (CO), 151.9, 147.4, 125.2, 119.1, 117.6,
107.6, 55.6 (Me), 42.7, 38.0; IR: (NaCl) 3331 (NH), 1647
(CO). Anal. calcd for C10H11NO2: C, 67.78; H, 6.20; N,
7.90. Found C, 67.81; H, 6.22; N, 7.83.
4.2.16. 3-(4-Chloro-phenylamino)-1-phenyl-propan-1-
1
one (15a). 10%; mp 1358C; H NMR: (300 MHz) (CDCl3)
4.2.10. (3-Oxo-3-ferrocenyl-propyl)-carbamic acid-
2,2,2-trichloro-ethyl ester (10). 89%; mp 948C; 1H
NMR: (300 MHz) (CDCl3) d TMS: 2.97 (t, 2H, J¼6 Hz),
3.58 (q, 2H, J¼6 Hz), 4.16 (m, 5H), 4.50 (s, 2H), 4.69 (m,
2H), 4.76 (m, 2H), 5.78 (br-s, 1H); 13C NMR: (74.47 MHz)
(CDCl3) d 203.2 (CO), 154.6 (OCON), 95.5 (CCl3), 78.3,
74.4, 72.6, 69.9, 69.2, 38.9, 36.1; IR: (NaCl) 3341 (NH),
1734 (OCON), 1660 (CO); LRMS (%) 432 (M). Anal. calcd
for C16H16Cl3FeNO3: C, 44.43; H, 3.73; N, 3.24. Found C,
44.44; H, 3.59; N, 3.14.
d TMS: 3.29 (t, 2H, J¼6 Hz), 3.60 (t, 2H, J¼6 Hz), 4.10 (br-s,
1H), 6.58 (d, 2H, J¼9 Hz), 7.14 (d, 2H, J¼9 Hz), 7.49 (t, 2H,
J¼8 Hz), 7.58 (t, 1H, J¼8 Hz), 7.96 (d, 2H, J¼8 Hz); 13C
NMR: (74.47 MHz) (CDCl3) d 199.1 (CO), 146.2, 136.5,
133.4,129.1,128.6,127.9,122.0,114.0,38.7, 37.3;IR:(NaCl)
3370 (NH), 1672 (CO). Anal. calcd for C15H14ClNO: C,
69.36; H, 5.43; N, 5.39. Found C, 69.02; H, 5.69; N, 5.21.
4.2.17. 3-(4-Fluoro-phenylamino)-1-phenyl-propan-1-
1
one (15b). 5%; mp 1158C; H NMR: (300 MHz) (CDCl3)
d TMS: 3.29 (t, 2H, J¼6 Hz), 3.59 (t, 2H, J¼6 Hz), 4.05
(br-s, 1H), 6.61 (dd, 2H, J¼4, 9 Hz), 6.91 (t, 2H, J¼9 Hz),
7.49 (t, 2H, J¼8 Hz), 7.60 (t, 1H, J¼8 Hz), 7.97 (d, 2H,
J¼8 Hz); 13C NMR: (74.47 MHz) (CDCl3) d 199.2 (CO),
157.4, 154.3, 144.0, 136.6, 133.4, 128.6, 127.9, 120.3,
115.8, 115.5, 113.9, 39.4, 37.4; IR: (NaCl) 3366 (NH), 1672
(CO). Anal. calcd for C15H14FNO: C, 74.06; H, 5.80; N,
5.76. Found C, 74.83; H, 5.50; N, 4.85.
4.2.11. [3-Oxo-3-(1-trityl-1H-pyrrol-3-yl)-propyl]-car-
bamic acid-2,2,2-trichloro-ethyl ester (11). 63%; mp
518C; H NMR: (300 MHz) (CDCl3) d TMS: 2.94 (t, 2H,
1
J¼6 Hz), 3.56 (q, 2H, J¼6 Hz), 4.68 (s, 2H), 5.71 (br-s,
1H), 6.58 (m, 2H), 7.13 (m, 6H), 7.3 (m, 10H); 13C NMR:
(74.47 MHz) (CDCl3) d 194.5 (CO), 154.6 (OCON), 142.4,
129.8, 128.0, 127.7, 125.4, 123.9, 108.1, 95.6 (CCl3), 76.9
(CPh3), 74.4, 38.5, 36.2; IR: (NaCl) 3337 (NH), 1736
(OCON), 1657 (CO); LRMS (%) 554 (M). Anal. calcd for
C29H25Cl3N2O3: C, 62.66; H, 4.53; N, 5.04. Found C, 61.51;
H, 4.55; N, 4.83.
Acknowledgements
The authors gratefully acknowledge the financial support
provided by the Petroleum Research Fund, administered by
the American Chemical Society, and Michigan State
University.
4.2.12. 3-Chloro-2,3-dihydro-4(1H)-quinolone (14a).
1
97%; mp 1268C; H NMR: (300 MHz) (CDCl3) d TMS:
2.67 (t, 2H, J¼7 Hz), 3.56 (t, 2H, J¼7 Hz), 4.70 (br-s, 1H),
6.64 (d, 1H, J¼9 Hz), 7.20 (dd, 1H, J¼8, 3 Hz), 7.75 (d, 1H,
J¼3 Hz); 13C NMR: (74.47 MHz) (CDCl3) d 192.7 (CO),
150.5, 134.9, 126.6, 122.9, 119.7, 117.5, 41.9, 37.6; IR:
(NaCl) 3356 (NH), 1647 (CO). Anal. calcd for C9H8NOCl:
C, 59.52; H, 4.44; N, 7.71. Found C, 59.74; H, 4.43; N, 7.46.
References
1. (a) Olah, G. A. Friedel–Crafts and Related Reactions; Wiley-
Interscience: New York, 1965; Vols. I–IV. (b) Olah, G. A.
Friedel–Crafts Chemistry; Wiley-Interscience: New York,
1973.
4.2.13. 3-Fluoro-2,3-dihydro-4(1H)-quinolone (14b).
98%; mp 718C; 1H NMR: (300 MHz) (CDCl3) d TMS:
2.66 (t, 2H, J¼7 Hz), 3.54 (t, 2H, J¼7 Hz), 4.58 (br-s, 1H),
6.65 (dd, 1H, J¼9, 3 Hz), 7.02 (td, 1H, J¼3, 9 Hz), 7.46 (dd,
2. (a) Effenberger, F.; Steegmuller, D. Chem. Ber. 1988, 121,

K. W. Anderson, J. J. Tepe / Tetrahedron 58 (2002) 8475–8481
8481
117. (b) Mukaiyama, T.; Suzuki, K.; Han, J. S.; Kobayashi, S.
Chem. Lett. 1992, 435. (c) Takagi, K.; Shimoishi, Y.; Sasaki,
K. Chem. Lett. 1994, 2055. (d) Evans, P. A.; Nelson, J. D.;
Stanley, A. L. J. Org. Chem. 1995, 60, 2298. (e) Kim, S.-H.;
Hanson, M. V.; Rieke, R. D. Tetrahedron Lett. 1996, 37, 2197.
(f) Desmurs, J. R.; Labrouillere, M.; Le Roux, C. L.; Gaspard,
H.; Laporterie, A.; Dubac, J. Tetrahedron Lett. 1997, 38, 8871.
3. Cho, H.; Matsuki, S.; Mizuno, A.; Annoura, H.; Tatsuoka, T.
J. Heterocycl. Chem. 1997, 34, 87.
M. T.; Notario, R.; Herreros, M.; Abboud, J.-L. M. J. Am.
Chem. Soc. 1996, 118, 12735.
11. (a) Ohwada, T.; Yamagata, N.; Shudo, K. J. Am. Chem. Soc.
1991, 113, 1364. (b) Saito, S.; Ohwada, T.; Shudo, K. J. Am.
Chem. Soc. 1995, 117, 11081. (c) Olah, G. A.; Hartz, N.;
Rasul, G.; Burrichter, A.; Prakash, G. K. S. J. Am. Chem. Soc.
1995, 117, 6421.
12. (a) Fischer, M.; Mattheus, A. Chem. Ber. 1969, 102, 342.
(b) Blackburn, G. M.; Plackett, J. D. J. Chem. Soc., Perkin
Trans. 2 1972, 1366. (c) Bird, P. G.; Irwin, W. J. J. Chem. Soc.,
Perkin Trans. 1 1973, 2664. (d) Blackburn, G. M.; Plackett,
J. D. J. Chem. Soc., Perkin Trans. 2 1973, 981.
13. (a) Takahata, H.; Ohnishi, Y.; Takehara, H.; Tsuritani, K.;
Yamazaki, T. Chem. Pharm. Bull. 1981, 29, 1063. (b) Manhas,
M. S.; Jeng, S. J. J. Org. Chem. 1967, 32, 1246.
14. (a) Kano, S.; Ebata, T.; Shibuya, S. Heterocycles 1976, 4,
1649. (b) Kano, S.; Ebata, T.; Shibuya, S. J. Chem. Soc.,
Perkin Trans. 1 1980, 2105. (c) Kano, S.; Shibuya, S.; Ebata,
T. Heterocycles 1981, 15, 1011.
4. Mizuno, A.; Miya, M.; Kamei, T.; Shibata, M.; Tatsuoka, T.;
Nakanishi, K.; Takiguchi, C.; Hidaka, T.; Yamaki, A.;
Inomata, N. Chem. Pharm. Bull. 2000, 48, 1129.
5. Yamato, T.; Hideshima, C.; Prakash, G. K. S.; Olah, G. A.
J. Org. Chem. 1991, 36, 3955.
6. Hwang, J. P.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 2000,
56, 7199.
7. Anderson, K. W.; Tepe, J. J. Org. Lett. 2002, 4, 459.
8. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
9. (a) Page, M. I. Acc. Chem. Res. 1984, 17, 144. (b) Cox, R. A.;
Yates, K. Can. J. Chem. 1981, 59, 2853. (c) Abboud, J.-L. M.;
Canada, T.; Homan, H.; Notario, R.; Cativiela, C.; Diaz de
Villegas, M. D.; Bordeje, M. C.; Mo, O.; Yanez, M. J. Am.
Chem. Soc. 1992, 114, 4728. (d) Wan, P.; Modro, T. A.; Yates,
K. Can. J. Chem. 1980, 58, 2423.
15. Chadwick, D. J.; Hodgson, S. T. J. Chem. Soc., Perkin Trans. 1
1983, 93.
16. Zelikin, A.; Shastri, V. R.; Langer, R. J. Org. Chem. 1999, 64,
3379.
17. Freihammer, P. M.; Detty, M. R. J. Org. Chem. 2000, 65,
7203.
10. Roux, M. V.; Jimenez, P.; Davalos, J. Z.; Castano, O.; Molina,