Regiospecific β-lactam ring-opening/recyclization reactions of N-aryl-3-spirocyclic-β-lactams catalyzed by a Lewis-Bronsted acids combined superacid catalyst system: A new entry to 3-spirocyclicquinolin-4(1H)- ones

Article abstract of DOI:10.1039/c1cc15881c

The regiospecific β-lactam ring-opening/recyclization reaction of N-aryl-3-spirocyclic-β-lactams, made by the one-pot cyclization reaction of acetoacetanilides, has been achieved for the first time using a Lewis-Bronsted acids combined superacid catalyst

Full text of DOI:10.1039/c1cc15881c

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COMMUNICATION
Regiospecific b-lactam ring-opening/recyclization reactions of
N-aryl-3-spirocyclic-b-lactams catalyzed by a Lewis–Brønsted
acids combined superacid catalyst system: a new entry to
3-spirocyclicquinolin-4(1H)-onesw
Yinqiao Hu,a Xiaolan Fu,a Badru-Deen Barry,a Xihe Bi*ac and Dewen Dong*ab
Received 22nd September 2011, Accepted 16th November 2011
DOI: 10.1039/c1cc15881c
The regiospecific b-lactam ring-opening/recyclization reaction of
N-aryl-3-spirocyclic-b-lactams, made by the one-pot cyclization
reaction of acetoacetanilides, has been achieved for the first time
using a Lewis–Brønsted acids combined superacid catalyst system,
thus providing an efficient entry to 3-spirocyclicquinolin-4(1H)-
ones. A mechanism involving superacid-catalysis was proposed.
lack of efficient synthetic methods.6 Herein, we wish to report
the first superacid-catalyzed chemoselelctive b-lactam ring-
opening/recyclization of N-aryl-3-spirocyclic-b-lactams,7 which
were prepared by a one-pot cyclization reaction of readily
available acetoacetanilide derivatives, thus providing a new
atom economic approach to 3-spirocyclicquinolin-4(1H)-ones.
The key point in this research is the discovery of a superacid
catalyst system constituting a Lewis acid and Brønsted acid
conjugate, like FeCl3 and HOTf, that can promote the regio-
specific b-lactam ring-opening reaction of 3-spirocyclic b-lactams,
even in the presence of much more strained cyclopropyl unit
(27.5 kcal molꢀ1).
Although most of the current attention is paid to their
renewed biological and medicinal significance as antibiotics
and enzyme inhibitors, b-lactams,1 due to the ring strain
(25 kcal molꢀ1) associated with 2-azetidinones and their
selectivity in bond cleavage (ring-opening), have been recog-
nized as versatile intermediates in the synthesis of a variety of
valuable organic molecules, such as a- and b-amino acids,
alkaloids, other heterocycles, and complex natural products.2
The regioselective N1–C2 ring-opening/recyclization (intra-
molecular acyl migration) reaction of N-aryl-b-lactams,
promoted by Brønsted acids or Lewis acids, remains attractive
since it represents an atom economic approach for the synthesis
of quinolin-4(1H)-ones, an important heterocyclic scaffold.3
Kano and coworkers have done the pioneering work and
firstly surveyed the intramolecular acyl migration of N-aryl-
b-lactams using a Brønsted acid or a Lewis acid.4 Further,
Tepe and coworkers developed this reaction and realized the
synthesis of quinolin-4(1H)-ones under significantly milder
conditions by using equivalent amount of trifluoromethane-
sulfonic acid.5a,b Until now, this transformation has been
exploited to some extent, including the preparation of bioactive
compounds.5c–e On the other hand, the exploration of the
synthetic and medicinal utility of 3-spirocyclicquinolines, an
interesting class of quinoline derivatives, was restrained by the
In the past few years, the study of iron-catalyzed reactions has
received great attention,8 because, compared with precious metal
catalysts such as Pt, Rh, Ru, Pd, Au, and Ag, iron is cheaper,
nontoxic, and above all abundant on earth. As part of our
continuing interest in exploiting iron salts as catalyst in organic
reactions, particular in the synthesis of heterocycles,9 we became
interested in investigating iron-catalyzed ring-opening/recycli-
zation reaction of N-aryl-3-spirocyclic-b-lactams. In this paper,
we disclosed that the combination of an iron salt and a protonic
acid regiospecifically induced b-lactam ring-opening of N-aryl-3-
spirocyclic-b-lactams, featuring well with high reaction efficiency
as well as good regioselectivity for unsymmetrical substrates.
Based on our previous studies on the synthetic utility of
acetoacetanilide derivatives,10 the preparation of N-aryl-3-
spirocyclic-b-lactams was started from the stepwise cyclization
reaction of cyclopropane-containing acetoacetanilide 1a by
sequential reduction of carbonyl with NaBH4, esterification of
hydroxyl reacting with p-toluenesulfonyl chloride, and finally
intramolecular nucleophilic substitution (Scheme 1). Further, the
stepwise reaction was optimized into an operation economic one-
pot procedure, which afforded 3-spirocyclic-b-lactam 2a in 75%
yield. The structure of 2a was unambiguously confirmed by X-ray
crystallography (CCDC 816903). Under the one-pot conditions,
we next investigated the scope for the preparation of 3-spirocyclic-
b-lactams 2. As shown in Table 1, substituted 3-spirocyclic-
b-lactams 2b–2m were prepared in good to high yields, even with
a size variation of the 3-spirocyclic unit from 3-spirocyclopropyl
(entries 1–10) to 3-spirocyclopentyl (entries 11–12). Even though
many methods are presently available for the synthesis of
a Department of Chemistry, Northeast Normal University, Changchun,
130024, China. E-mail: bixh507@nenu.edu.cn, dwdong@ciac.jl.cn
b Changchun Institute of Applied Chemistry, Chinese Academy of
Sciences, Changchun, 130022, China
c State Key Laboratory of Fine Chemicals, School of Chemical
Engineering, 158 Zhongshan Road, Dalian University of Technology,
Dalian 116012, China
w Electronic supplementary information (ESI) available: experimental
procedures, analytical data, and spectra copies of all compounds.
CCDC 816903. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc15881c
c
690 Chem. Commun., 2012, 48, 690–692
This journal is The Royal Society of Chemistry 2012

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Table 2 Conditions optimization
Scheme 1 Reagents and Conditions: (a) 1a (5 mmol), NaBH4 (6 mmol),
EtOH (25 mL), at room temperature, 1 h, 95% yield. (b) KOH (25 mmol),
TsCl (7.5 mmol), CH2Cl2 (25 mL), 40 1C, 4 h, 87% yield.
BAa
Entry [Fe] (30 mol%) (mol%)
Temp. Time
Solvent (1C) (h) Yield (%)b
1
2
3
4
5
6
7
8
FeCl3
FeCl3 (1 eq)
FeCl3
Fe (OTf)3
FeBr3
FeCl2
Fe
FeCl3
FeCl3
FeCl3
FeCl3
—
—
—
toluene 100
toluene 100
3
1
2
2
2
2
2
9 : 91 : 0c
61 : 26 : 13c
82
Table 1 One-pot synthesis of 3-spirocyclic N-aryl-b-lactams 2a
TFA (300) toluene 100
TFA (300) toluene 100
TFA (300) toluene 100
TFA (300) toluene 100
TFA (300) toluene 100
HOTf (100) toluene 100
HOTf (20) toluene 100
HOTf (20) toluene 80
HOTf (20) toluene 60
HOTf (20) toluene 80
83
86
75 : 25 : 0c
0
0.2 87
0.5 92
9
10
11
12
13
14
15
1
3
1
1
2
2
91
46 : 38 : 16c,d
48 : 28 : 24c
68 : 23 : 9c
0
Entry
R1
R2
n
Time (h)
2
Yield (%)b
FeCl3
FeCl3
FeCl3
HOTf (20) DCE
HOTf (20) DMF
HOTf (20) MeOH 80
80
80
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
COOEt
H
H
4-MeO
H
2-Me
4-Me
2,4-diMe
2-Cl
3-Cl
4-Cl
1-Naphthyl
H
1
1
1
1
1
1
1
1
1
1
3
3
5
5
3
3
5
3
4
3
2b
2c
2d
2e
2f
2g
2h
2i
65
75
73
71
66
68
87
70
75
82
77
66
trace
a
b
Brønsted acid. Isolated yield. The ratio of 3a : 2a : 4a was
c
determined by the 1H-NMR spectra analysis of crude product.
d
The trans- configuration of 4a was determined by NOE experiment.
9
3
2.5
4
2j
2k
2l
10c
11
12
ineffective (entries 6 and 7). Following these observations, we
unambiguously inferred that the combination of a trivalent iron
salt with a Brønsted acid was the key factor for the chemo-
selective lactam ring-opening of 3-spirocyclic-b-lactam 2a, and
thereafter envisioned that use of a much stronger Brønsted acid
(BA) such as trifluoromethanesulfonic acid (HOTf) instead of
TFA could reduce the loading amount of BA and lower the
reaction temperature. The results shown in entries 8–11 confirmed
this hypothesis, and so the combined utility of 30 mol% FeCl3
and 20 mol% HOTf as catalyst, offered a single and smooth
transformation from 2a to 3a in high yield within 1 h at a little
lower temperature (80 1C) (entry 10). The necessity of an iron salt
in the combined catalyst system was verified by the fact that a
mixture of 3a, 2a and 4a was produced when only using 20 mol%
HOTf (entry 12). Under otherwise the same conditions in
entry 10, the solvent was varied and the products obtained were
mixtures (entry 13), trace (entry 15) or absolutely no conversion
(entry 14). In comparison, the solvent types significantly influ-
enced the reaction. For example, aprotic solvents such as DCE
and DMF as well as protic solvent such as EtOH all proved
inapplicable in this reaction (entries 13–15). Consequently, the
conditions in entry 10 proved optimal, and were then chosen for
further investigations.
4-Me
4-Cl
7
2m
a
Reactions were performed with 1 (5.0 mmol) under one-pot operation
of (a) NaBH4 (6.0 mmol), THF (25 mL), at room temperature, 1.0–1.5 h,
b
and (b) KOH (25 mmol), TsCl (10 mmol), 40 1C, 4.0–6.0 h. Isolated
yields. The configuration of 2k was determined with NOE experiment.
c
3-spirocyclic-b-lactams,11 yet specific procedures for the synthesis
of 3-spirocyclopropyl b-lactams are still limited.12 The one-pot
procedure described here represents a highly efficient approach to
this kind of transformations.
Next, we decided to screen reaction conditions for the
selective lactam ring-opening of 3-spirocyclic-b-lactams 2, that
lead to 3-spirocyclicquinolin-4(1H)-ones. The ring-opening
reaction of compound 2a was used as a model, and represen-
tative data are summarized in Table 2. The use of FeCl3 alone
as catalyst in toluene at 100 1C only resulted in a slight
conversion of 2a into the desired product 3a (entry 1). Inter-
estingly, an increase in the FeCl3 catalyst to one equivalent
amount dramatically influenced the transformation by offering
61% of 3a, along with a 13% of cyclopropane ring-opening/
oxidized product 4a and 26% of unreacted substrate 2a, in
which the ratio of 3a, 4a and 2a was determined by 1H-NMR
spectra analysis of crude product (entry 2). Further, when
three equivalents of trifluoroacetic acid (TFA) was employed
as an additive, the desired 3-spirocyclicquinoline 3a was
obtained in 82% yield within 2 h, with notably no by-product
of 4a detected (entry 3). Other iron sources swapped with
FeCl3 by varying anion and oxidation state were also examined,
and results revealed that all the trivalent iron salts, irrespective of
the anions attached, offered a single transformation product of
3a with high yields (entries 4 and 5), while FeCl2 and metallic
iron (Fe) either produced a mixture of 3a and 2a or proved
With the optimal conditions in hand, we began to study the
scope for the chemoselective b-lactam ring-opening reactions
of 3-spirocyclic-b-lactams 2. As shown in Table 3, 3-spiro-
cyclic-b-lactams 2 were subjected to the optimized conditions
described above, and correspondingly 3-spirocyclopropyl
quinolin-4(1H)-ones 3a–3j were obtained in good to high
yields within a short time (entries 1–9). For the unsymmetrical
substrate 2h, a good ratio of para- to ortho-selective products
was produced (entry 7). Unexpectedly, when R1 was ethoxy-
carbonyl (COOEt), no reaction occurred even within a longer
reaction time (2.5 h), only with the recovery of starting
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 690–692 691

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Table 3 Preparation of 3-spirocyclicquinolin-4(1H)-ones 3 through
FeCl3/HOTf co-catalyzed chemoselective ring-opening/recyclization of 2
a superacid species like H[Fe(OTf)Cl3] is proposed (Scheme 2).
The superacid H[Fe(OTf)Cl3] is first formed and then reacts
with substrate 2a to give protonated intermediates I–III.
Following the C–N bond cleavage, which is consistent with
previously reported acid-catalyzed, N-protonated, unimolecular
(AN1) mechanism that might be involved in the rate-limiting
step,13 an acylium ion IV is formed. The AN1 mechanism is
favoured due to the enhanced rate of C–N bond cleavage that
occurs in 2-azetidinones, resulting from the relief in ring strain.
The highly reactive acyl carbonium ion IV then reacts with the
aromatic unit, providing the desired 3-spirocyclicquinolin-
4(1H)-one 3a through an intramolecular acyl migration, with
the release of catalyst H[Fe(OTf)Cl3] for the next reaction.
Financial support by NSFC (20902010, 21172029) and
FRFCU (10JCXK005) is gratefully acknowledged.
Entry
2
Time (h)
3
Yield (%)a
1
2
3
4
5
6
7
8
9
10
2b
2c
2d
2e
2f
2g
2h
2i
1.0
1.0
0.5
0.5
1.0
1.5
1.0
0.5
0.5
2.5
3b
3c
3d
3e
3f
3g
3h
3i
88
92
89
90
81
87
93
85
90
0
2j
2k
3j
3k
Notes and references
1 For a general review on ‘b-Lactams’, see: Heterocyclic Scaffolds I:
b-Lactams, in Top. Heterocycl Chem, ed. B. K. Banik,
Springer-Verlag, Berlin Heidelberg, 1st edn, 2010, vol. 22.
2 For a review on the synthetic application of b-lactams, see:
B. Alcaide, P. Almendros and C. Aragoncillo, Chem. Rev., 2007,
107, 4437.
a
Isolated yields.
3 S. Okamoto, M. Iwakubo, K. Kobayashi and F. Sato, J. Am.
Chem. Soc., 1997, 119, 6984.
4 (a) S. Kano, T. Ebata and S. Shibuya, Heterocycles, 1976, 4, 1649;
(b) S. Kano, T. Ebata and S. Shibuya, J. Chem. Soc., Perkin Trans.
1, 1980, 2105.
5 (a) K. W. Anderson and J. J. Tepe, Org. Lett., 2002, 4, 459;
(b) K. W. Anderson and J. J. Tepe, Tetrahedron, 2002, 58,
8475; (c) J. Lange, A. C. Bissember, M. G. Banwell and
I. A. Cade, Aust. J. Chem., 2011, 64, 454; (d) R. G. Schmidt,
E. K. Bayburt, S. P. Latshaw, J. R. Koenig, J. F. Daanen,
H. A. McDonald, B. R. Bianchi, C. Zhong, S. Joshi, P. Honore,
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6 V. V. Kouznetsov, J. Heterocycl. Chem., 2005, 42, 39.
7 G. A. Olah, G. K. S. Prakash, J. Sommer and A. Molnar,
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ed. B. Plietker, Wiley-VCH, Weinheim, 2008.
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Scheme 2 A plausible reaction mechanism.
material 2k (entry 10). Similar to cyclopropyl-containing
substrates, the cyclopentyl counterparts 2l and 2m were also
subjected to the optimal reaction conditions and afforded the
3-spirocyclopentyl quinolin-4(1H)-ones 3l and 3m in 85% and
83% yields, respectively (eqn (1)).
ð1Þ
11 S. S. Bari and A. Bhalla, Spirocyclic b-Lactams: Synthesis,
Biological Evaluation of Novel Heterocycles, Top. Heterocycl.
Chem., 2010, 22, 49–99.
Superacid can be prepared in situ by the combination of two
components, a strong Lewis acid and a strong Brønsted acid.6
The combination of FeCl3 and HOTf is necessary for the
chemoselective b-lactam ring-opening of N-aryl-3-spirocyclic-
b-lactams, therefore, a possible reaction mechanism involving
12 (a) A. Zanobini, A. Brandi and A. de Meijere, Eur. J. Org. Chem.,
2006, 1251; (b) S. Gurtler, M. Johner, S. Ruf and H. H. Otto, Helv.
Chim. Acta, 1993, 76, 2958.
13 M. V. Roux, P. Jimenez, J. Z. Davalos, O. Castano, M. T. Molina,
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c
692 Chem. Commun., 2012, 48, 690–692
This journal is The Royal Society of Chemistry 2012