The first intermolecular Friedel-Crafts acylation with β-lactams

Article abstract of DOI:10.1021/ol010291w

(Equation Presented) The first intermolecular Friedel-Crafts acylation of a variety of aromatic substrates with azetidinones is described. The Friedel-Crafts acylations are performed under very mild conditions, using trifluoromethanesulfonic acid to produce β-amino aromatic ketones in excellent yields.

Full text of DOI:10.1021/ol010291w

ORGANIC
LETTERS
2002
Vol. 4, No. 3
459-461
The First Intermolecular Friedel−Crafts
Acylation with â-Lactams
Kevin W. Anderson and Jetze J. Tepe*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
tepe@cem.msu.edu
Received December 11, 2001
ABSTRACT
The first intermolecular Friedel−Crafts acylation of a variety of aromatic substrates with azetidinones is described. The Friedel−Crafts acylations
are performed under very mild conditions, using trifluoromethanesulfonic acid to produce â-amino aromatic ketones in excellent yields.
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, including AlCl3, SnCl4, and
BF3‚OEt2 have been shown to be very successful for the
acylation of aromatic substrates with acid chlorides or
anhydrides.2 Surprisingly, to our knowledge, no intermo-
lecular Friedel-Crafts acylations utilizing â-lactams as
substrates have been reported to date. The highly strained
â-lactam was anticipated to be a good substrate for acylating
aromatics to produce â-amino aromatic ketone derivatives.
Considering the proven generality and usefulness of Friedel-
Crafts acylations in organic synthesis, as well as the easy
access to a wide range of substituted â-lactams, we herein
report a significant expansion of the arsenal of Friedel-Crafts
reactions with the use of azetidinones as substrates (Figure
1).
reaction with various aromatic compounds (both electron-
rich and electron-poor) produced benzophenone derivatives
in good yields.3 In light of these results, we envisioned that
under similar superacid activating conditions the strained
â-lactam was anticipated to be a good substrate for acylating
aromatics to produce the â-amino aromatic ketone deriva-
tives. Herein we report a very mild procedure for the
acylation of aromatic substrates with 2-azetidinones and
N-substituted azetidinones with trifluoromethanesulfonic acid
to give the corresponding â-amino aromatic ketones in good
to excellent yields (Table 1).
The efficacy of 2-azetidinone as a Friedel-Crafts substrate
for a variety of aromatic compounds, including toluene,
chlorobenzene, anisole, and nitrobenzene, is illustrated in
Table 1. With the exception of nitrobenzene, all reactions
provided the â-amino aromatic ketone derivatives 2 as the
triflate salt in excellent yields (Table 1). By contrast, the
less strained â-butyrolactam 3 failed to undergo the Friedel-
(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.
(2) (a) Benkeser, R. A.; Krysiak, H. R. J. Am. Chem. Soc. 1954, 76,
599. (b) Olah, G. A.; Kobayashi, S. J. Am. Chem. Soc. 1971, 93, 6964. (c)
Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533. (d) Effenberger, F.;
Steegmuller, D. Chem. Ber. 1988, 121, 117. (e) Mukaiyama, T.; Suzuki,
K.; Han, J. S.; Kobayashi, S. Chem. Lett. 1992, 435. (f) Takagi, K.;
Shimoishi, Y.; Sasaki, K. Chem. Lett. 1994, 2055. (g) Evans, P. A.; Nelson,
J. D.; Stanley, A. L. J. Org. Chem. 1995, 60, 2298. (h) Kim, S.-H.; Hanson,
M. V.; Rieke, R. D. Tetrahedron Lett. 1996, 37, 2197. (i) Desmurs, J. R.;
Labrouillere, M.; Le Roux, C. L.; Gaspard, H.; Laporterie, A.; Dubac, J.
Tetrahedron Lett. 1997, 38, 8871.
Figure 1. Intermolecular Friedel-Crafts acylation with azetidi-
nones.
Recently, it was reported that aromatic esters can be
activated with trifluoromethanesulfonic acid, which upon
(3) Hwang, J. P.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 2000, 56,
7199.
10.1021/ol010291w CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/03/2002

Treatment of the N-Troc (2,2,2-trichloroethoxycarbonyl)-
protected â-lactam 4b with 1.1 equiv of trifluoromethane-
sulfonic acid at 0 °C in the presence of an excess of
naphthalene (10 equiv) for 15 min at 0 °C provided a 1:0.78
mixture of the 1- and 2-substituted naphthalene isomers in
good yields (Table 3). The â-lactams also proved to be
Table 1. Friedel-Crafts Acylation with
Trifluoromethanesulfonic Acid on Various Aromatic Substrates
substrate 1
R
nucleophile
yield (%) of 2
Table 3. Friedel-Crafts Acylation of Naphthalene and
Pyrroles
1
1
1
1
1a
1
3b
H
Me
Cl
MeO
Br
NO2
H
benzene
toluene
98
93
92
95
92
0
chlorobenzene
anisole
bromobenzene
nitrobenezene
benzene
0
a Optimal yields obtained when heated to 80 °C for 2 h. b Reaction was
heated to reflux in benzene with no desired product isolated.
Crafts reaction even under more vigorous conditions. A
possible mechanism consistent with previous reported studies
could involve N-protonation of the â-lactam, followed by
C-N bond fission resulting in the relief of ring strain.4 The
highly reactive acyl carbonium ion then further reacts with
the aromatic substrate, providing the acylated product (Figure
1).
a Isolated as an inseparable mixture of 1- and 2-substituted naphthalene
derivatives.
substrates for the acylation of aromatic heterocycles, il-
lustrated here with the phenylsulfonyl- and triisopropyl-
protected pyrroles (Table 3). The phenylsulfonyl- and the
silyl-protected pyrroles provided the 2- and 3-acylated
substrates, respectively.
The Friedel-Crafts acylation of various N-acylated 2-aze-
tidinones 4 with benzene in 1,2-dichloroethane was subse-
quently investigated (Table 2). Treatment of 2-azetidinone
In addition, we examined the N-aryl 2-azetidinones (p-
NO2, p-Cl, p-F, H, p-OMe) 6a-e under the same mild
condition because of their high propensity to suffer CO-N
bond cleavage under both acidic and basic conditions.5 The
N-aryl 2-azetidinones were prepared by standard protocols.6
N-Aryl 2-azetidinones have previously been shown to
undergo a Fries-type rearrangement, resulting in the corre-
sponding 2,3-dihydro-4(1H)-quinolones 7 under forcing
conditions (reflux in trifluoroacetic acid for 2 h).7 We report
here a significantly milder method for the preparation of
quinolones 7 by trifluoromethanesulfonic acid (1.0 equiv)
Table 2. Friedel-Crafts Acylation with
Trifluoromethanesulfonic Acid
substrate 4
R
acid
yield (%) of 5
4a
4b
4b
4b
4b
CO2Me
CF3SO3H
CF3SO3H
AlCl3
BF3‚OEt2
SnCl4
65
85
npa
npa
npa
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
(4) (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) Roux, M. V.;
Jimenez, P.; Davalos, J. Z.; Castano, O.; Molina, M. T.; Notario, R.;
Herreros, M.; Abboud, J.-L. M. J. Am. Chem. Soc. 1996, 118, 12735. (e)
Wan, P.; Modro, T. A.; Yates, K. Can. J. Chem. 1980, 58, 2423.
(5) (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.
(6) (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.
(7) (a) Kano, S.; Ebata, T.; Shibuya, S. Heterocycles 1976, 4(10), 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(2), 1011.
a No products isolated.
4a or 4b with 1.0 equiv of trifluoromethanesulfonic acid at
0 °C in a 1:1 mixture of benzene and 1,2-dichloroethane
provided the corresponding products 5 in good yields.
Treatment of the 2-azetidinones 4b with traditional Lewis
acids did not result in any Friedel-Crafts acylation of
benzene.
460
Org. Lett., Vol. 4, No. 3, 2002

In summary, we report the first Friedel-Crafts acylations
of aromatic substrates using â-lactams with trifluoromethane-
sulfonic acid. Further studies of this methodology and the
potential applications to the total synthesis of natural products
are currently under investigation in these laboratories and
will be reported in due course.
Table 4. Fries-Type Rearrangement of Aryl â-Lactams
Acknowledgment. The authors gratefully acknowledge
the financial support provided by the Petroleum Research
Fund, administered by the American Chemical Society, and
Michigan State University.
substrate 6
R
time
yield (%) of 7
6a
6b
6c
6d a
6ea
NO2
Cl
15 min
15 min
15 min
15 min
15 min
0
97
98
96
97
F
H
OMe
Supporting Information Available: Experimental pro-
cedures and IR, 1H and 13C NMR data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Two equivalents of trifluoromethanesulfonic acid were required for
optimal yields.
in 1,2-dichloroethane (0 °C to room temperature over 15 min)
in excellent yields (Table 4).
OL010291W
Org. Lett., Vol. 4, No. 3, 2002
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