A C-N insertion of β-lactam to benzyne: Unusual formation of acridone

Article abstract of DOI:10.1016/j.tetlet.2012.07.026

Intermolecular insertion of benzyne into the C-N bond of a β-lactam is described. This σ-insertion is followed by ring expansion that produces dihydroquinolinone, which rapidly reacts with an additional benzyne unit to afford an acridone through intramolecular C-C bond formation to the carbonyl group and rapid elimination of ethylene.

Full text of DOI:10.1016/j.tetlet.2012.07.026

Tetrahedron Letters 53 (2012) 4994–4996
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Tetrahedron Letters
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A C–N insertion of b-lactam to benzyne: unusual formation of acridone
⇑
Jimin Kim, Brian M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, California Institute of Technology, Division of Chemistry and Chemical Engineering,
Mail Code 101-20, Pasadena, CA 91125, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Intermolecular insertion of benzyne into the C–N bond of a b-lactam is described. This
r-insertion is fol-
Received 29 June 2012
Revised 4 July 2012
Accepted 6 July 2012
Available online 16 July 2012
lowed by ring expansion that produces dihydroquinolinone, which rapidly reacts with an additional ben-
zyne unit to afford an acridone through intramolecular C–C bond formation to the carbonyl group and
rapid elimination of ethylene.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
b-Lactam
Benzyne
r
-Insertion
Ethylene
Acridone
Recently, Larock and Greaney described
nylamides 2 to arynes generated in situ from 2-(trimethyl-
silyl)phenyl triflate in the presence of fluoride sources
r
-insertion of N-phe-
trace amount of N-phenyl lactam 9 (<5%). We believe that this
mechanistically interesting transformation begins with the nucle-
ophilic attack of the aryne triple bond by the b-lactam nitrogen
to generate intermediate 11 (Scheme 3A). The possibility of fluo-
ride anion deprotonating the b-lactam N–H prior to the nucleo-
philic attack cannot be ruled out. Addition of the aryl anion 11 to
the lactam carbonyl moiety would furnish the highly strained aze-
idinium ion (12), which can rearrange to dihydroquinolinone 13.
Alternatively, the aryl anion in 11 may be quenched via H+-abstrac-
tion to generate N-arylated b-lactam 9. Dihydroquinolinone 13 can
continue to react with another benzyne unit through its nucleo-
philic nitrogen to result in the zwitterionic intermediate 14 fol-
lowed by intramolecular nucleophilic addition of the nascent aryl
anion to the carbonyl group to generate intermediate 15 bearing
a dibenzobicyclo[2.2.2]octane core. The release of ethylene gas
from intermediate 15 through a formal retro Diels–Alder reaction
can unravel acridone 16, which once again can react with benzyne
followed by H+-abstraction to afford N-phenyl acridone 7. It ap-
pears that H+-abstraction in 14 is faster than intramolecular nucle-
ophilic addition to the carbonyl group. The possibility of a formal
[4+2] cycloaddition process between the o-azaxylylenyl tauto-
meric form of 13 (not shown) and benzyne cannot be ruled out
at this point.
1
(Scheme 1).1 Under the mild conditions described by both labora-
tories, aminobenzophenones (i.e., 3) were obtained in overall good
yields. Of particular note, an efficient synthesis of acridones (i.e., 5)
was achieved by employing o-halobenzamides 4 through tandem
insertion and SNAr reactions (Scheme 1). Non-enolizable N-aryl
amides were required in the insertion reactions due to the low
electrophilicity of the amide carbonyl group. Prompted by our
interests in aryne insertion processes,2 we became intrigued in
the possibility of insertion of arynes into the strained C–N bond
of b-lactams.3 Over the years our group has been actively involved
in developing novel applications of arynes toward the synthesis of
nitrogen heterocycles.4 For example, we recently reported methods
that allow access to indolines and isoquinolines from N-acyl enam-
ines through aryne annulation.4,5 Herein, we disclose the first
example of such an aryne insertion and an unexpected secondary
process that leads directly to N-phenyl acridone (Scheme 2).
We initiated our C–N insertion studies by subjecting b-lactam 6
(1.0 equiv) and 2-(trimethylsilyl)phenyl triflate 1 (2.0 equiv) to a
mixture of KF and 18-crown-6 in THF at 23 °C. We were surprised
to find that the major component of the product mixture was acri-
done derivative 7, obtained along with the anticipated dihydro-
quinolinone 8 in 3:2 ratio and 52% overall yield (Scheme 2).1b,6
To the best of our knowledge, insertion of arynes into b-lactams
to give acridones is unprecedented. The reaction also produced
In order to better understand the mechanism of this transfor-
mation we examined N-phenyl and N-benzyl b-lactams (17) as
substrates in reactions with benzyne under otherwise identical
conditions (Scheme 3B). No ring expanded insertion adducts were
observed in these reactions despite complex product mixtures.
Additionally, N-phenyl dihydroquinolinone 8 also failed to react
with benzyne under similar reaction conditions. These results
⇑
Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 395 8436.
E-mail address: stoltz@caltech.edu (B.M. Stoltz).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.026

J. Kim, B. M. Stoltz / Tetrahedron Letters 53 (2012) 4994–4996
4995
R3
O
OTf
TMS
R1
O
R2
F
R1
NH
N
H
R3
solvent
R2
1
2
R2 = CF3, t-Bu, Ph, m-Tol
3
O
N
O
N
TBAT
R3
R1
R2
OTf
TMS
toluene
R1
R3
µwave
H
120 °C
X
R2
4
1
X = F, Cl
5
Scheme 1. Amide insertion into arynes.
O
O
N
KF
O
OTf
O
HN
18-crown-6
N
N
THF, 23 °C
TMS
2 h
Ph
1
6
9
<5% yield
7
8
31% yield
21% yield
Scheme 2. Insertion of benzyne into C–N bond of b-lactam.
9
A
O
O
O
O
O
H
8
N
N
H
N
H
N
N
H
H
10
6
11
12
13
14
O
O
N
O
N
O
N
H
N
H
H
16
15
7
B
C
O
N
O
N
O
R
No insertion products
observed
X
N
17
R = Ph, Bn
8
7
Scheme 3. A plausible reaction pathway.

4996
J. Kim, B. M. Stoltz / Tetrahedron Letters 53 (2012) 4994–4996
O
O
N
A
B
O
OTf
CsF
N
MeCN
TMS
23 °C, 2 h
N
H
13
1
(2.5 equiv)
8
(1.0 equiv)
7
(20%)
(73%)
O
KF
N
Ph
18-crown-6
THF, 23 °C
2 h
O
19
OTf
TMS
(61%)
N
H
(Not observed)
7
1
18
C
O
O
N
KF
OTf
O
HN
18-crown-6
N
THF, 23 °C
2 h
TMS
58%
1
20
(combined yield)
21
7
(3:2 ratio)
Scheme 4. Control experiments for mechanistic elucidation.
provide support to our mechanistic hypothesis wherein the N–H
bond and the nitrogen geometry play a critical role in the
transformation.
References and notes
1. (a) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112–13113; (b) Pintori, D.
G.; Greaney, M. F. Org. Lett. 2010, 12, 168–171; (c) Yoshida, H.; Shirakawa, E.;
Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2002, 41, 3247–3249.
2. (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340–5341; (b)
Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752–
11753; (c) Ebner, D. C.; Tambar, U. K.; Stoltz, B. M. Org. Synth. 2009, 86, 161–
171; (d) Allan, K. M.; Hong, B. D.; Stoltz, B. M. Org. Biomol. Chem. 2009, 7, 4960–
4964; (e) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org.
Lett. 2010, 12, 1224–1227; (f) Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett.
2010, 12, 1612–1614; (g) Allan, K. M.; Gilmore, C. D.; Stoltz, B. M. Angew. Chem.,
Int. Ed. 2011, 50, 4488–4491.
3. For reviews on b-lactams, see: (a) Alcaide, B.; Almendros, P.; Luna, A. In Modern
Heterocyclic Chemistry; Alvare–zBuill, J., Vaquero, J. J., Barluenga, J., Eds.; Wiley-
VCH GmbH&Co. KGaA: Weinheim, 2011. Vol. 4, pp 2117–2173; (b) Alcaide, B.;
Almendros, P. Curr. Org. Chem. 2002, 6, 245–264.
4. (a) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558–
1559; (b) Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 17270–17271.
5. For a recent review on the use of arynes in natural product total synthesis, see:
(a) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550–3577; (b) Gampe, C.
M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3766–3778.
Gratifyingly, subjecting dihydroquinolinone 137 to the reaction
conditions resulted in the formation of N-phenyl acridone (7) and
N-phenyl dihydroquinolinone (8) in 3.7:1 ratio, respectively in 93%
combined yield (Scheme 4A).8 Next, we subjected quinolinone 18
to the aryne insertion conditions, which could be expected to
evolve acetylene based on the ethylene extrusion proposed in the
previous example. However, we observed only N-arylated adduct
19 without the rearrangement product, presumably due to the re-
duced electrophilicity of the carbonyl group in the unsaturated
case (Scheme 4B). Finally, 3-methylazetidione 209 gave products
7 and 21 in 58% yield in a 3:2 ratio, providing further evidence in
support of our proposed mechanism (Scheme 4C).10
In conclusion we have uncovered the unusual reactive combina-
tion of b-lactams and arynes through a mild and one-pot process to
generate useful heterocyclic building blocks. Future efforts will be fo-
cused on detailed mechanistic studies and on the application of this
methodology in the synthesis of complex heterocyclic molecules.
6. For other methods to synthesize acridones from benzynes, see: (a) Zhao, J.;
Larock, R. C. J. Org. Chem. 2007, 72, 583–588; (b) Hellwinkel, D.; Ittemann, P.
Chem. Ber. 1986, 119, 3165–3197.
7. Schmidt, R. G.; Bayburt, E. K.; Latshaw, S. P.; Koening, J. R.; Daanen, J. F.;
McDonald, H. A.; Bianchi, B. R.; Zhong, C.; Joshi, S.; Honore, P.; Marsh, K. C.; Lee,
C.-H.; Faltynek, C. R.; Gomtsyan, A. Bioorg. Med. Chem. Lett. 2011, 21, 1338–
1341.
Acknowledgments
8. For a related reaction of N-Methyl piperidinone, see: Rodier, N.; Pinelli, L.;
Adam, G.; Andrieux, J.; Plat, M. Bull. Soc. Chim. Fr. 1984, 1, 217–221.
9. Nilsson, B. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1990, 33, 580–584.
10. Baraznenok, I. L.; Nenajdenko, V. G.; Churakov, A. V.; Nesterenko, P. N.;
Balenkova, E. S. Synlett 2000, 4, 514–516.
The authors acknowledge Abbott, Amgen, Boehringer Ingel-
heim, the Teva USA Scholars Program, and Caltech for financial
support. We also thank Dr. Pamela Tadross and Mr. Christopher
Haley for helpful discussions and materials.