Interaction of β-lactam carbenes with aryl isonitriles: An unprecedented rearrangement of 2-azetidinonylidene indoles to δ-carbolinones

Article abstract of DOI:10.1021/jo0700631

The reaction of/3-lactam carbenes with aryl isonitriles proceeded in a novel [2 + 2] fashion to give high yields of 2-azetidinonylidene indoles 4, which underwent an unprecedented rearrangement to furnish 4-arylimino-(δ- carbolin-2-ones 5 in almost quanti

Full text of DOI:10.1021/jo0700631

Interaction of â-Lactam Carbenes with Aryl Isonitriles: An
Unprecedented Rearrangement of 2-Azetidinonylidene Indoles to
δ-Carbolinones
Ying Cheng* and Lan-Qing Cheng
Chemistry Department, Beijing Normal UniVersity, Beijing 100875, China
ycheng2@bnu.edu.cn
ReceiVed January 11, 2007
The reaction of â-lactam carbenes with aryl isonitriles proceeded in a novel [2 + 2] fashion to give high
yields of 2-azetidinonylidene indoles 4, which underwent an unprecedented rearrangement to furnish
4-arylimino-δ-carbolin-2-ones 5 in almost quantitative yields. Acid catalyzed rearrangement and the
subsequent hydrolysis of 2-azetidinonylidene indoles 4 produced two types of δ-carbolin-2,4-diones 10
and 11, respectively, in good to excellent yields. The photophysical study showed that both δ-carbolin-
2,4-diones 10 and 11 are highly fluorescent with the fluorescent quantum yields being up to 0.43.
Introduction
years3a,4 and showed previously that nucleophilic and ambiphilic
carbenes such as amino(chloro)carbene,4a chloro(oxy)carbine,4b
and diaminocarbene4c served as unique building blocks in the
construction of a variety of novel heterocycles. Our recent
interest in amino substituted carbenes led us to focus on
2-azetidinone-4-ylidenes, a type of â-lactam carbene pioneered
by Warkentin and Zoghbi in the 1990s.5 The cyclopropanation
reactivity toward both electron-rich and -deficient alkenes
labeled â-lactam carbenes as the ambiphilic carbenes.6 Very
recently, however, we have shown that these â-lactam ambi-
Nucleophilic and ambiphilic carbenes are emerging in active
research fields not only because these divalent species are
powerful ligands in the formation of metal complexes1 but also
because they are useful organocatalysts2 and versatile intermedi-
ates in organic synthesis.3 We have been interested in the
chemistry of nucleophilic and ambiphilic carbenes for some
* Corresponding author. Tel.: 86 10 58 80 55 58. Fax: 86 10 58 80 20 75.
(1) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2001, 41, 1290-1309.
(b) Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. ReV. 2000,
100, 39-91.
(2) Examples for organocatalysis with nucleophilic carbenes: (a) Chan,
A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558-4559. (b) Nair, V.;
Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8, 507-
509. (c) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541.
(3) (a) Cheng, Y.; Meth-Cohn, O. Chem. ReV. 2004, 104, 2507-2530.
(b) Warkentin, J. AdV. Carbene Chem. 1998, 2, 245-295.
(4) (a) Cheng, Y.; Yang, H.; Meth-Cohn, O. Chem. Commun. 2003, 90-
91. (b) Cheng, Y.; Zhu, Q.; Li, Q.-S.; Meth-Cohn, O. J. Org. Chem. 2005,
70, 4840-4846. (c) Liu, M. F.; Wang, B.; Cheng, Y. Chem. Commun. 2006,
1215-1217. (d) Cheng, Y.; Wang, B.; Cheng, L.-Q. J. Org. Chem. 2006,
71, 4418-4427.
(5) (a) Zoghbi, M.; Warkentin, J. J. Org. Chem. 1991, 56, 3214-3215.
(b) Zoghbi, M.; Warkentin, J. Can. J. Chem. 1993, 71, 912-918.
10.1021/jo0700631 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/06/2007
J. Org. Chem. 2007, 72, 2625-2630
2625

Cheng and Cheng
TABLE 1. Reaction of â-Lactam Carbene 2a with p-Chlorophenyl
philic carbenes behaved actually as good nucleophiles and
classical nucleophilic carbenes, such as diaminocarbene and
aminooxycarbene species, to react with aryl isocyanates to
produce spiro[azetidine-2-one-4,3′-indole-2′-ones].4d
Isonitrile 3c under Different Conditions
yield (%)
starting materials
entry
R, X, Y
reaction conditions
4a
5a
Isonitriles constitute the other formal divalent species, and
they are able to react with various functional groups.7 Although
alkyl isonitriles have been reported to react with carbenes to
form ketenimines8 that were utilized to trap carbenes and
measure the electrophilicity of a variety of carbenes, the study
on the reaction of free carbenes with isonitriles, especially
aromatic ones,9 is very limited. The synthetic application of the
reaction between carbenes and isonitriles has been largely
unexplored. To explore the synthetic utility and to obtain deep
insight into the unique reactivity of â-lactam carbenes, we
undertook the current study to investigate their reaction with
aryl isonitriles. We were delighted to discover that the reaction
of â-lactam carbenes with aryl isonitriles proceeded in a novel
pathway, which comprised an unprecedented rearrangement of
2-azetidinonylidene indoles to δ-carbolinones.
1
2
3
4
5
6
1a, 3c Me, H, Cl dioxane 100-110 °C, 11 h
1a, 3c Me, H, Cl toluene 110-120 °C, 11 h
81
64
1a, 3c Me, H, Cl propionitrile 100-110 °C, 12 h 77
1a, 3c Me, H, Cl TCEa 110-120 °C, 6 h
80
28
47
1a, 3c Me, H, Cl TCEa 100 °C, 12 h
30
1a, 3c Me, H, Cl xylene 140-150 °C, 40 h
a TCE ) 1,1,2-trichloroethane.
SCHEME 1. Reaction of â-Lactam Carbenes with Aryl
Isonitriles
Results and Discussion
In practice, all â-lactam carbenes 2 are generated in situ by
thermolysis of spiro[â-lactam-4,2′-oxadiazolines] 1 following
Warkentin and Zoghbi’s method.5 Since the optimal temperature
for the generation of carbene 2 was around 100-110 °C,4d the
reaction of 2a with p-chlorophenyl isonitrile 3c was initially
carried out in refluxing 1,1,2-trichloroethane (bp 110-115 °C)
for 6 h. Surprisingly, the reaction gave a totally unexpected
product, 4-arylimino-δ-carbolin-2-one 5a, in 80% yield. Com-
pound 5a was apparently derived from a [2 + 2] addition
reaction between 2a and 3c, although the construction of a
δ-carboline ring from â-lactam species and aryl isonitriles
remained a mystery. During the process of the reaction, it was
noted that an orange compound was initially formed and then
disappeared later. To isolate the intermediate, the reaction of
2a with 3c in trichloroethane was repeated but at a lower
temperature (100 °C). After 12 h, an orange product, 2-azeti-
dinonylidene indole 4a, was isolated in addition to the yellow
δ-carbolin-2-one 5a (Table 1). The reaction was then optimized
using different solvents. Interestingly, in all reactions carried
out in toluene, 1,4-dioxane, and propionitrile, indole 4a was
obtained as the sole product. However, in refluxing 1,1,2-
trichloroethane, 4a was converted completely into 5a
(Scheme 1 and Table 1). As indicated in Table 1, both solvent
and reaction temperatures governed the transformation of 4 to
5. For example, although toluene and 1,1,2-trichloroethane have
very similar boiling points, almost no product (5a) was observed
in refluxing toluene, while 4a was efficiently converted into
5a in refluxing trichloroethane. On the other hand, in trichlo-
roethane, the complete transformation of 4a finished in 6 h at
110-115 °C, while only half the amount of 4a was transformed
into 5a within 12 h at 100 °C. It is worth noting that although
arenes were not good solvents for the formation of product 5,
4a could also be converted into 5a in xylene at elevated
temperatures (140 °C) and in a prolonged reaction time (40 h),
indicating that high reaction temperatures can promote the
conversion of 4 to 5. The smooth and ready transformation of
4 into 5 in refluxing trichloroethane led us to propose that a
trace amount of hydrochloride released from the solvent might
accelerate the reaction. To validate our hypothesis, dry HCl gas
was bubbled into the solution of 2-azetidinonylidene indole 4a
in 1,4-dioxane. Compound 4a was forced to undergo transfor-
mation into δ-carbolinone 5a in 93% yield in 30 min at room
temperature (Table 2, entry 23). Taking all results aforemen-
tioned into consideration, it was concluded that the transforma-
tion of 4 to 5 was an acid catalyzed thermal rearrangement.
To examine the scope of the reaction, â-lactam carbenes 2
bearing different substituents were employed to react with
different aryl isonitriles 3 (Scheme 1). As summarized in
Table 2, in refluxing 1,4-dioxane, all reactions produced indole
4 in 74-95% yields, while 71-85% yields of δ-carbolinone 5
were obtained from the reaction in refluxing trichloroethane.
The substituents on both starting materials have a negligible
effect on the outcome of the reaction. δ-Carbolinone 5 were
also prepared in almost a quantitative yield by refluxing indole
4 in trichloroethane.
(6) (a) Zoghbi, M.; Warkentin, J. Can. J. Chem. 1992, 70, 2967-2971.
(b) Zoghbi, M.; Horne, S. E.; Warkentin, J. J. Org. Chem. 1994, 59, 4090-
4095.
(7) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.
(8) (a) Holinga, G.; Platz, M. S. Tetrahedron Lett. 2005, 46, 8245-
8247. (b) Ciganek, E. J. Org. Chem. 1970, 35, 862. (c) Emig, N.; Tejeda,
J.; Re´au, R.; Bertrand, G. Tetrahedron Lett. 1995, 36, 4231-4234. (d)
Merceron, N.; Miqueu, K.; Baceiredo, A.; Bertrand, G. J. Am. Chem. Soc.
2002, 124, 6806-6807. (e) Krysiak, J.; Lyon, C.; Baceiredo, A.; Gornitzka,
H.; Mikolajczyk, M.; Bertrand, G. Chem.sEur. J. 2004, 10, 1982-1986.
(f) Gillette, G. R.; Igau, A.; Baceiredo, A.; Bertrand, G. New J. Chem.
1991, 15, 393-400. (g) Bertrand, G. Heteroatom Chem. 1991, 2, 29-38.
(h) Despagnet-Ayoub, E.; Gornitzka, H.; Bourissou, D.; Bertrand, G. Eur.
J. Org. Chem. 2003, 11, 2039-2042. (i) Sole´, S.; Gornitzka, H.; Schoeller,
W. W.; Bourissou, D.; Bertrand, G. Science 2001, 292, 1901-1903.
(9) Obata, N.; Mizuno, H.; Koitabashi, T.; Takizawa, T. Bull. Chem.
Soc. Jpn. 1975, 48, 2287-2293.
The structures of all products were fully characterized by
spectroscopic data and microanalysis, which indicated 4 and 5
2626 J. Org. Chem., Vol. 72, No. 7, 2007

â-Lactam Carbene Interaction with Aryl Isonitriles
TABLE 2. Preparation of 2-Azetidinonylidene Indoles 4 and δ-Carbolin-2-ones 5
entry
1 and 3
R, X, Y
reaction conditions
4
yield (%)
5
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1a, 3c
1b, 3a
1b, 3b
1b, 3c
1b, 3d
1b, 3e
1c, 3c
1d, 3c
1e, 3c
1f, 3c
1g, 3c
1h, 3c
1i, 3c
1j, 3c
1k, 3c
1a, 3c
1b, 3d
1e, 3c
1f, 3c
1g, 3c
1h, 3c
4a
Me, H, Cl
Me, Me, Me
Me, Me, OMe
Me, Me, Cl
Me, Me, Br
Me, Me, F
Me, OMe, Cl
Me, Cl, Cl
Me, Br, Cl
Et, OMe, Cl
Et, Cl, Cl
Et, Br, Cl
Ph, Me, Cl
Ph, Cl, Cl
Ph, Br, Cl
Me, H, Cl
Me, Me, Br
Me, Br, Cl
Et, OMe, Cl
Et, Cl, Cl
dioxane, reflux, 11 h
dioxane, reflux, 9 h
dioxane, reflux, 12 h
dioxane, reflux, 9 h
dioxane, reflux, 11 h
dioxane, reflux, 11 h
dioxane, reflux, 10 h
dioxane, reflux, 12 h
dioxane, reflux, 10 h
dioxane, reflux, 10 h
dioxane, reflux, 11 h
dioxane, reflux, 11 h
dioxane, reflux, 11 h
dioxane, reflux, 11 h
dioxane, reflux, 11 h
TCE, reflux, 6 h
TCE, reflux, 8 h
TCE, reflux, 4 h
TCE, reflux, 8 h
TCE, reflux, 8 h
TCE, reflux, 8 h
TCE, reflux, 3 h
dry HCl, dioxane r.t., 0.5 h
TCE, reflux, 3 h
TCE, reflux, 6 h
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
81
78
83
84
85
74
82
77
81
82
80
83
95
94
95
5a
5e
5i
5j
5k
5l
5a
5a
5e
5k
5m
80
85
77
78
71
82
98
93
99
97
94
Et, Br, Cl
Me, H, Cl
Me, H, Cl
Me, Me, Br
Et, Cl, Cl
4a
4e
4k
4m
Ph, Me, Cl
dry HCl, dioxane r.t., 1 h
SCHEME 2. Proposed Mechanism for Formation of
2-Azetidinonylidene Indole 4 and δ-Carbolinone 5
to be two isomeric products. To identify the isomers beyond
doubt, the structures of 4d and 5i were determined unambigu-
ously by single-crystal X-ray diffraction analysis (see
Figure S1 in the Supporting Information). It is worth addressing
the characteristics of the 1H NMR spectra of δ-carbolinones 5.
For compounds 5a, 5e, and 5i that were derived from 3,3-
dimethyl-2-azetidinone-4-ylidenes, when the spectra were re-
corded at room temperature (298 K), the signals of partial methyl
protons, the â-lactam proton, and some aromatic protons
1
appeared as broad peaks. On the other hand, however, the H
NMR spectra of compounds 5j, 5k, and 5l that were yielded
from 3,3-diethyl substituted carbene species exhibited sharpened
proton signals with good resolution. We rationalized that in the
case of geminally dimethylated compounds 5a, 5e, and 5i, the
â-lactam moiety might slowly rotate along the N5-C4′ single
bond, yielding a number of rotamers on the NMR time scale,
whereas with 5j, 5k, and 5l, the same rotation was prohibited
due to the steric bulkiness of a pair of the geminally substituted
ethyl groups. The rotamers were frozen when the temperature
decreased, as the variant temperature 1H NMR showed that all
broad signals observed at room temperature became very well-
resolved, and three sets of the â-lactam proton were observed
at 248 K (see Figure S2 in the Supporting Information).
The formation of 2-azetidinonylidene indole 4 can be best
explained by a reaction pathway depicted in Scheme 2. The
reaction was initiated by coupling of the carbene with isonitrile
to form a ketenimine intermediate 6. Nucleophilic addition of
a second isonitrile to 6 followed by intramolecular aromatic
electrophilic cyclization led to the indole derivative 8. Finally,
N-H insertion of â-lactam carbene to 8 afforded product 4.
The rearrangement of indole 4 to δ-carbolinone 5 proceeded
most probably through a novel acid catalytic N-to-N′ [1,5]-acyl
migration. In the presence of an acid catalyst, indole 4 was
protonated into 9A, which rearranged its π system, giving rise
to resonance form 9B. Intramolecular nucleophilic attack led
to [1,5]-acyl migration of 9B to form δ-carbolinone 5
(Scheme 2). Theoretically, nucleophilic attack of isonitrile to
ketenimine 6 might take place at either face of the imine carbon
and lead to the formation of both Z- and E-isomers of 4.
However, only the Z-isomer was detected. The structure of
ketenimine intermediate 6a (Figure 1) optimized with the
B3LYP/6-31G method (Gaussian 98)10 clearly shows that
(10) See Supporting Information.
J. Org. Chem, Vol. 72, No. 7, 2007 2627

Cheng and Cheng
SCHEME 3. Preparation of δ-Carbolin-2,4-dione
Derivatives 10 and 11 from 2-Azetidinonylidene Indoles 4
and 4-Arylimino-δ-carbolinones 5
FIGURE 1. Gaussian 98 optimized structure of ketenimine intermedi-
ate 6a.
isonitrile can only attack on one face of the imine double bond
of 6 and form the Z-configuration of the carbon-carbon double
bond since the other face of the imine is hindered by the N-aryl
group of the carbene moiety.
Carbolines and their derivatives comprise an important family
of heterocyclic compounds owing to their unique biological
properties. Some δ-carboline derivatives, for example, have
shown antiplasmodial,11a antitrypanosomal,11b antimalarial,11b
and antineoplastic11c activities. In addition, a few δ-carboline
derivatives exhibit interesting photophysical behaviors. The
fluorescence and phosphorescence spectra of δ-carbolines are
influenced by the polarity, hydrogen-bonding property, and
acidity of the solvents.12 The advantage of their fluorescent
property has been applied to localize a δ-carboline derivative
inside the human cell.11a In the literature, studies on the
construction of a δ-carboline unit were very limited. All of the
known syntheses were based on either the intramolecular
coupling of phenylpyridine or anilinopyridine compounds13 or
cyclic condensation of 2 or 3 substituted indole derivatives.14
Having considered the easy rearrangement of indole 4 to
δ-carbolin-2-one 5 and the possible hydrolysis of the imine
group of compound 5, we envisioned that our â-lactam carbene
approach would provide a very simple and efficient method for
the preparation of δ-carbolin-2-one and δ-carbolin-2,4-dione
derivatives. Thus, upon the treatment of indole 4 with different
acids including p-toluenesulfonic acid monohydrate, boron
trifluoride, and aqueous hydrochloride, two types of novel
δ-carbolin-2,4-diones were obtained, respectively, under dif-
ferent reaction conditions. When compound 4 was warmed with
hydrated p-toluenesulfonic acid, boron trifluoride, or aqueous
hydrochloride in trichloroethane or in dioxane for 0.5-1 h, N-â-
lactam-δ-carbolin-2,4-dione 10 was obtained in excellent yield.
On the other hand, in the presence of 10 equiv of hydrated
p-toluenesulfonic acid, the N-unsubstituted δ-carbolin-2,4-dione
11 was obtained generally in good yield in a prolonged time
(2-4 h) (Scheme 3 and Table 3, see the Supporting Information
for X-ray data of 10a and 11a). Hydrochloric acid was not an
efficient catalyst for the preparation of δ-carbolin-2,4-dione 11
because compound 10 did not undergo further hydrolysis to 11,
even in the presence of a large excess of hydrochloric acid
(about 100 equiv) for 6 h. Transformation of indole 4 to
δ-carbolin-2,4-diones 10 and 11 can be easily explained by
isomerization of 4 to δ-carbolinone 5 followed by hydrolysis
of 5 into 10 and then to 11. This mechanism was further
supported by the hydrolysis of 5 to 10 or 11 using hydrated
p-toluenesulfonic acid (Table 3, entries 11 and 17).
Both δ-carbolin-2,4-diones 10 and 11 were found to be
fluorescent. To study the photophysical properties of compounds
10 and 11, their fluorescent quantum yields were measured. To
examine the solvent effects on the fluorescent property, the
fluorescent spectra of 10a and 11a were first measured in
different solvents. As indicated in Table 4, the solvents have a
larger effect on the emission maximum (λemmax) and quantum
yield (ΦF) of 11a than that of 10a. Since δ-carbolin-2,4-dione
11 can form intramolecular and intermolecular hydrogen bonds,
the influence of the solvents on the fluorescence of 11 was most
probably due to the formation of a hydrogen bond between 11
and solvents. The fluorescence spectra of other δ-carbolin-2,4-
diones 10 and 11 were then recorded in the optimal solvent
(Table 5). It was noted that the substituents bearing the carboline
ring and lactam moiety have a significant influence on the
fluorescence of compounds 10 and 11. The N substituted
carbolin-2,4-dione 10 generally has stronger fluorescence than
its N-unsubstituted analogue 11. For example, the ΦF value of
10a was 0.35 measured in ethyl acetate, while that of 11a was
only 0.25 in the same solvent (Table 4, entries 2 and 7). The
halogen substituted carbolin-2,4-diones 10 (ΦF ) 0.32-0.43)
and 11 (ΦF ) 0.23-0.25) have higher fluorescent quantum
yields than the electron-donating methoxy and methyl substituted
analogues (see Table 5).
(11) (a) Arzel, E.; Rocca, P.; Grellier, P.; Labaeied, M.; Frappier, F.;
Gueritte, F.; Gaspard, C.; Marsais, F.; Godard, A.; Queguiner, G. J. Med.
Chem. 2001, 44, 949-960. (b) Goerlitzer, K.; Kramer, C.; Meyer, H.;
Walter, R. D.; Jomaa, H.; Wiesner, J. Pharmazie 2004, 59, 243-250. (c)
Suvorov, N. N.; Chernov, V. A.; Velezheva, V. S.; Ershova, Y. A.; Simakov,
S. V.; Sevodin, V. P. Khim.-Farm. Zh. 1981, 15, 27-34.
(12) (a) Balon, M.; Carmona, C.; Munoz, M. A. Chem. Phys. 2004, 302,
13-20. (b) Balon, M.; Munoz, M. A.; Carmona, C. Chem. Phys. 2004,
299, 67-77. (c) Balon, M.; Angulo, G.; Carmona, C.; Munoz, M. A.;
Guardado, P.; Galan, M. Chem. Phys. 2002, 276, 155-165. (d) Angulo,
G.; Carmona, C.; Pappalardo, R. R.; Munoz, M. A.; Guardado, P.; Sanchez
Marcos, E.; Balon, M. J. Org. Chem. 1997, 62, 5104-5109.
(13) (a) Abramovitch, R. A.; Adams, K. A. H.; Notation, A. D. Can. J.
Chem. 1960, 38, 2152-2160. (b) Arzel, E.; Rocca, P.; Marsais, F.; Godard,
A.; Queguiner, G. Heterocycles 1999, 50, 215-226. (c) Iwaki, T.; Yasuhara,
A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 11, 1505-1510.
(14) (a) Velezheva, V. S.; Nevskii, K. V.; Suvorov, N. N. Khim.
Geterotsikl. Soedin. 1985, 2, 230-235. (b) Yaroslavskii, I. S.; Velezheva,
V. S.; Suvorov, N. N. Zh. Org. Khim. 1985, 21, 432-436. (c) Sevodin, V.
P.; Velezheva, V. S.; Suvorov, N. N. Khim. Geterotsikl. Soedin. 1981, 3,
368-371.
In summary, we have shown that the reaction of â-lactam
carbenes with aryl isonitriles proceeded in a [2 + 2] fashion to
give high yields of functionalized 2-azetidinonylidene indoles.
2628 J. Org. Chem., Vol. 72, No. 7, 2007

â-Lactam Carbene Interaction with Aryl Isonitriles
TABLE 3. Preparation of δ-Carbolin-2,4-dione Derivatives 10 and 11
entry
4 or 5
reaction conditions
10: R, X, Y
yield (%)
11: R, Y
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
5g
4a
4b
4e
4f
3 × TsOH‚H2O, TCE reflux, 0.5 h
2 × BF3‚Et2O, TCE, reflux, 1 h
10 × HCl (aq), dioxane, reflux, 0.5 h
10 × HCl (aq), dioxane, reflux, 0.5 h
3 × TsOH‚H2O, TCE, reflux, 0.5 h
10 × HCl (aq), dioxane, reflux, 0.5 h
10 × HCl (aq), dioxane, reflux, 0.5 h
3 × TsOH‚H2O, TCE, reflux, 0.5 h
3 TsOH‚H2O, TCE, reflux, 0.5 h
3 × TsOH‚H2O, TCE, reflux, 0.5 h
3 × TsOH‚H2O, TCE, reflux, 0.5 h
10 × TsOH‚H2O, TCE, reflux, 3 h
10 × TsOH‚H2O, TCE, reflux, 3 h
10 × TsOH‚H2O, TCE, reflux, 3 h
10 × TsOH‚H2O, TCE, reflux, 4 h
10 × TsOH‚H2O, TCE, reflux, 4 h
10 × TsOH‚H2O, TCE, reflux, 2 h
6 × TsOH‚H2O, TCE, reflux, 2 h
10a: Me, H, Cl
10a: Me, H, Cl
91
87
98
89
94
97
98
94
97
90
95
10b: Me, Me, Me
10c: Me, Me, OMe
10d: Me, Me, Cl
10e: Me, Me, Br
10f: Me, Me, F
10g: Me, OMe, Cl
10h: Me, Cl, Cl
10i: Me, Br, Cl
10g: Me, OMe, Cl
11a: Me, Cl
11b: Me, Me
11e: Me, Br
11f: Me, F
11j: Et, Cl
11a: Me, Cl
11c: Me, OMe
83
62
75
83
77
82
49
4j
5a
10c
TABLE 4. Emission Maxima and Fluorescent Quantum Yields of
applications in advanced functional organic materials and
medicinal chemistry.
δ-Carbolin-2,4-diones 10a and 11a Measured in Different Solvents
a
entry
compound
solvent
λ
emmax (nm)
ΦF
Experimental Section
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
11a
11a
11a
11a
11a
CH3CN
CH3CO2C2H5
THF
CH2Cl2
PhCH3
CH3CN
CH3CO2C2H5
THF
452
448
449
454
449
447
441
444
448
437
0.32
0.35
0.35
0.36
0.31
0.11
0.25
0.21
0.16
0.18
General Procedure for the Reaction of â-Lactam Carbenes
with Aryl Isonitriles. Under nitrogen atmosphere, a mixture of
spiro[â-lactam-4,2′-oxadiazoline] 1 (1.5 mmol) and aryl isonitrile
3 (1.5 mmol) was refluxed in 1,4-dioxane (30 mL) for 9-12 h or
in 1,1,2-trichloroethane (30 mL) for about 6-8 h. After removal
of the solvent, the residue was chromatographed on a silica gel
column eluting with a mixture of petroleum ether (30-60 °C) and
ethyl acetate (petroleum ether/ethyl acetate from 12:1 to 6:1). The
product 2-azetidinonylidene indole 4 was obtained in 74-95% yield
from the reaction in 1,4-dioxane, while 4-arylimino-δ-carbolin-2-
one 5 was obtained in 71-85% yield from reaction in 1,1,2-
trichloroethane. The δ-carbolin-2-one 5 could also be prepared in
93-99% yield by refluxing the indole 4 in 1,1,2-trichloroethane
for 3-6 h or by bubbling the dry HCl gas into the solution of indole
4 in 1,4-dioxane for 0.5-1 h at room temperature.
CH2Cl2
PhCH3
10
a The quantum yields (ΦF) were determined with reference to perylene
(1.2 × 10-6 M in toluene) excited at 395 nm for 10 and 376 nm for 11.
TABLE 5. Selected Fluorescent Properties of
δ-Carbolin-2,4-diones 10 and 11
entry 10: R, X, Y or 11: R, Y
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
λ
emmax (nm)
ΦF
(Z)-5-Chloro-1-(3,3-dimethyl-1-phenylazetidin-2-one-4-yl)-2-
(3,3-dimethyl-1-phenylazetidin-2-one-4-ylidene)-3-(p-chlorophe-
nyl)imino-2,3-dihydroindole (4a). 81%, mp 229-230 °C; IR V
1
2
3
4
5
6
7
8
9
10
11
12
13
14
10a: Me, H, Cl
10b: Me, Me, Me
10c: Me, Me, OMe
10d: Me, Me, Cl
10e: Me, Me, Br
10f: Me, Me, F
10g: Me, OMe, Cl
10h: Me, Cl, Cl
10i: Me, Br, Cl
11b: Me, Me
454
466
470
456
458
458
456
454
453
449
452
441
441
443
0.36
0.28
0.14
0.32
0.41
0.43
0.13
0.37
0.37
0.13
0.11
0.25
0.23
0.23
(cm-1) 1800, 1772, 1677, 1615; H NMR (500 MHz, C6D6) δ
1
(ppm): 7.46 (d, J ) 7.9 Hz, 2H), 7.30 (d, J ) 7.8 Hz, 2H), 7.21
(d, J ) 8.4 Hz, 2H), 7.10 (brs, 4H), 6.91-6.96 (m, 4H), 6.64 (d,
J ) 8.3 Hz, 2H), 6.57 (d, J ) 8.8 Hz, 1H), 5.11 (s, 1H), 1.80 (s,
3H), 1.72 (s, 3H), 1.06 (s, 3H), 0.85 (s, 3H); 13C NMR (125 MHz,
C6D6) δ (ppm): 174.1, 170.2, 157.7, 149.8, 149.6, 138.2, 136.2,
135.1, 132.7, 130.0, 129.8, 129.2, 127.4, 127.2, 126.8, 125.9, 124.4,
124.3, 122.1, 121.4, 119.8, 117.6, 117.1, 76.0, 61.2, 57.5, 22.1,
18.3, 18.2, 16.0. MS (APCI): 621 (M + 1)/623. Anal. Calcd for
C36H30Cl2N4O2: C 69.57, H 4.87, N 9.01. Found: C 69.68, H 4.90,
N 8.87.
CH2Cl2
CH2Cl2
CH3CO2C2H5
CH3CO2C2H5
CH3CO2C2H5
CH3CO2C2H5
CH3CO2C2H5
11c: Me, OMe
11a: Me, Cl
11e: Me, Br
11f: Me, F
8-Chloro-1-(p-chlorophenyl)-3,3-dimethyl-4-phenylimino-5-
(3,3-dimethyl-1-phenylazetidin-2-one-4-yl)-δ-carbolin-2-one (5a).
The resulting azetidinonylidene indoles underwent a novel N-to-
N′ [1,5]-acyl migration in an enamino imine system to furnish
δ-carbolinones in almost quantitative yields. Acid catalyzed
rearrangement and the subsequent hydrolysis of 2-azetidi-
nonylidene indoles 4 produced two types of novel δ-carbolin-
2,4-diones 10 and 11, respectively, in good to excellent yields.
2-Azetidinonylidene indoles, δ-carbolin-2-ones, and δ-carbolin-
2,4-diones obtained from the current study are new chemical
entities of potential biological properties. They are also valuable
intermediates subject to further elaborations owing to their
multifunctional structures. The high fluorescence emission
efficiencies of δ-carbolin-2,4-diones suggest their potential
80% from 1a and 3c, 98% from 4a, mp 241-242 °C; IR V (cm-1
)
1
1764, 1693, 1626. H NMR (500 MHz, CDCl3) δ (ppm) 7.58 (d,
J ) 8.1 Hz, 2H), 7.35-7.40 (m, 6H), 7.28 (brs, 4H), 7.08-7.10
(m, 2H), 7.02 (d, J ) 9.1 Hz, 1H), 6.84 (brs, 2H), 6.06 (brs, 1H),
1.70 (s, 3H), 1.54 (brs, 3H), 1.49 (brs, 3H), 1.15 (brs, 3H); 13C
NMR (125 MHz, CDCl3) δ (ppm) 173.8, 170.8, 158.3, 149.5, 137.6,
136.2, 135.1, 130.1, 130.0, 129.5, 129.0, 126.9, 126.4, 125.4, 124.7,
122.9, 120.7, 120.1, 117.4, 116.3, 115.1, 115.0, 73.8, 58.1, 53.2,
27.5, 25.9, 22.1, 16.2. MS (MALDI-TOF): 621 (M + 1). Anal.
Calcd for C36H30Cl2N4O2: C 69.57, H 4.86, N 9.01. Found: C
69.35, H 4.60, N 8.88.
General Procedure for the Preparation of 5-(Azetidin-2-one-
4-yl)-δ-carbolin-2,4-dione 10. The mixture of 2-azetidinonylidene
J. Org. Chem, Vol. 72, No. 7, 2007 2629

Cheng and Cheng
indole 4 (0.5 mmol) with hydrated p-toluenesulfonic acid
(1.5 mmol) in trichloroethane (40 mL), or with aqueous HCl (36%
w/v, 10 mmol) in 1,4-dioxane (40 mL), refluxed for 0.5 h. After
removal of the solvent, the residue was chromatographed on a silica
gel column eluting with a mixture of petroleum ether (30-60 °C)
and ethyl acetate (petroleum ether/ethyl acetate 6:1) to give
5-(azetidin-2-one-4-yl)-δ-carbolin-2,4-dione 10 in 87-98% yield.
8-Chloro-1-(p-chlorophenyl)-3,3-dimethyl-5-(3,3-dimethyl-1-
phenylazetidin-2-one-4-yl)-δ-carbolin-2,4-dione (10a). 91%, mp
187-188 °C; IR V (cm-1) 1777, 1701, 1650; 1H NMR (500 MHz,
CDCl3) δ (ppm): 7.61 (t, J ) 6.4 Hz, 2H), 7.41 (d, J ) 9.3 Hz,
1H), 7.37 (d, J ) 8.1 Hz, 2H), 7.30-7.33 (m, 4H), 7.19 (s, 1H),
7.10-7.13 (m, 2H), 6.03 (d, J ) 1.5 Hz, 1H), 1.74 (s, 3H), 1.68
(s, 3H), 1.66 (s, 3H), 1.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
(ppm): 189.9, 175.4, 170.5, 137.4, 137.2, 135.8, 135.6, 132.2,
130.4, 130.3, 129.6, 129.5, 126.8, 124.9, 121.5, 118.1, 117.6, 116.3,
115.2, 73.2, 58.2, 54.6, 25.2, 24.4, 21.9, 16.0. MS (ESI): 546 (M
+ 1), 568 (M + Na+). Anal. Calcd for C30H25Cl2N3O3: C 65.94,
H 4.61, N 7.69. Found: C 65.91, H 4.51, N 7.52.
General Procedures for the Preparation of δ-Carbolin-2,4-
diones 11. The mixture of 2-azetidinonylidene indole 4 (0.5 mmol)
with hydrated p-toluenesulfonic acid (5 mmol) in trichloroethane
(50 mL) refluxed for 2-4 h. After removal of the solvent and
p-toluenesulfonic acid, the residue was chromatographed on silica
gel eluting with a mixture of petroleum ether (30-60 °C) and ethyl
acetate (petroleum ether/ethyl acetate 4:1) to give δ-carbolin-2,4-
dione 11 in 62-83% yield.
8-Chloro-1-(p-chlorophenyl)-3,3-dimethyl-δ-carbolin-2,4-di-
one (11a). 83%, mp 282-283 °C; IR V (cm-1) 3216, 1699, 1688,
1
1625; H NMR (500 MHz, CDCl3) δ (ppm): 10.01 (s, 1H), 7.62
(d, J ) 8.5 Hz, 2H), 7.41 (d, J ) 8.9 Hz, 1H), 7.37 (d, J ) 8.5 Hz,
2H), 7.31 (dd, J ) 8.9, 1.7 Hz, 1H), 6.13 (s, 1H), 1.70 (s, 6H); 13
C
NMR (125 MHz, CDCl3) δ (ppm): 189.7, 175.9, 137.3, 135.8,
135.5, 131.2, 130.3, 130.2, 129.0, 126.2, 121.0, 118.7, 116.9, 114.4,
53.7, 25.1. MS (EI): 84 (100)/86 (60), 372 (25%, M+)/374 (15).
Anal. Calcd for C19H14Cl2N2O2: C 61.14, H 3.78, N 7.51. Found:
C 61.46, H 3.83, N 7.49.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China for Distinguished Young
Scholars (20525207), Program for New Century Excellent
Talents in University (NCET-04-0143), and the “PCSIRT”.
Supporting Information Available: Experimental procedures
for the preparation of 2-azetidinonylidene indoles 4, δ-carbolinones
5, δ-carbolin-2,4-diones 10 and 11; full characterization for
1
compounds 4, 5, 10, and 11; copies of H NMR and 13C NMR
spectra of products 4, 5, 10, and 11; single-crystal data of 4d, 5i,
10a, and 11a (CIF); as well as the computational calculated data
for intermediate 6a. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0700631
2630 J. Org. Chem., Vol. 72, No. 7, 2007