Trifluoroacetic acid-promoted Michael addition-cyclization reactions of vinylogous carbamates

Article abstract of DOI:10.1039/c4ob00437j

A simple and efficient methodology has been developed for the synthesis of pyrrolobenzoxazine and 3-arylamino coumarin derivatives promoted by trifluoroacetic acid. The initial step in the current protocol involves a Michael addition of the 1,4-benzoxazinone derivatives, a novel class of vinylogous carbamates to the Michael acceptors and subsequent cyclization. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00437j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Trifluoroacetic acid-promoted Michael addition–
cyclization reactions of vinylogous carbamates†
Cite this: Org. Biomol. Chem., 2014,
12, 3366
Ram Tilak Naganaboina, Amrita Nayak‡ and Rama Krishna Peddinti*
Received 26th February 2014,
Accepted 18th March 2014
DOI: 10.1039/c4ob00437j
www.rsc.org/obc
A simple and efficient methodology has been developed for the firmed as
a tetracyclic pyrrolobenzoxazine derivative 9a
synthesis of pyrrolobenzoxazine and 3-arylamino coumarin deriva- (Table 1, entry 1). The initial step of the reaction takes place
tives promoted by trifluoroacetic acid. The initial step in the through a Michael addition and undergoes subsequent intra-
current protocol involves a Michael addition of the 1,4-benzoxazi- molecular cyclization and concurrent elimination of the nitro
none derivatives, a novel class of vinylogous carbamates to the functionality to give the pyrrolobenzoxazine 9a. Inspired by
Michael acceptors and subsequent cyclization.
the results obtained, we further proceeded with the screening
of various Brønsted and Lewis acids. Accordingly, when the
reaction was carried out with p-TSA·H2O, the reaction was com-
pleted in 8 h in 73% yield and TFA afforded the corresponding
product 9a in 82% yield in 5 h. Further screening with various
Lewis acids such as ZrCl4, ZnCl2, FeCl3, SnCl4 and BF3·etherate
also afforded the product 9a (Table 1, entries 4–8); neverthe-
less, the results revealed that they were less effective when
compared to that of the trifluoroacetic acid. There was no for-
mation of product in the absence of the reagent (Table 1, entry
Pyrrole fused heterocyclic compounds are widespread in the
nature and extensively found in many of the natural products
and biologically active molecules.1 These compounds possess
a wide range of biological and pharmacological activities like
antioxidant,2 anticancer,3,4 reversal of multidrug resistance
(MDR),5 antimicrobial activity,6 human aldose reductase
(h-ALR2) inhibition,7 HIV-1 integrase inhibition and cell divi-
sion inhibition.8 Pyrrole fused compounds, such as pyrrolo-
benzoxazines and benzothiazines, are found to exhibit
antihypertensive properties and act as central nervous system
depressant agents.9 In our laboratory we have developed novel
methodologies for the synthesis of heterocyclic compounds of
biological significance.10 A green approach for the synthesis of
1,4-benzoxazinone derivatives from the readily available start-
ing materials is among them.10c Further we envisaged that
these 1,4-benzoxazinone derivatives may serve as a new class
of vinylogous carbamates. Herein we report the primary find-
ings of the reactions of these vinylogous carbamates with
Michael acceptors such as nitrostyrene and p-benzoquinones.
In our initial attempts, a mixture of benzoxazinone deriva-
tive 1 and 3,4-dimethoxynitrostyrene in 1,2-dichloroethane
(DCE) in the presence of triflic acid was allowed to reflux for
5 h. The reaction proceeded smoothly and after purification by
Table 1 Optimization of reaction conditionsa
Entry
Reagent
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
TfOH
p-TSA·H2O
TFA
ZrCl4
ZnCl2
FeCl3
SnCl4
BF3·etherate
—
TFA
TFA
TFA
TFA
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
THF
CH3CN
Toluene
5
8
5
5
5
5
5
5
12
8
57
73
82
68
61
72
64
76
—
69
74
71
76
column chromatography
a yellow coloured product was
obtained. Upon careful analysis of the data obtained by 1H,
13C and DEPT NMR spectra, the product obtained was con-
9
10
11
12
13
5
5
5
The Department of Chemistry, Indian Institute of Technology, Roorkee-247667,
Uttarakhand, India. E-mail: rkpedfcy@iitr.ac.in, ramakpeddinti@gmail.com
†Electronic supplementary information (ESI) available. CCDC 982192, 982194
a Reactions were performed with
1 (0.5 mmol), 3,4-dimethoxy
and 982195. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4ob00437j
nitrostyrene (0.6 mmol) and reagent (0.75 mmol) in 4 mL of solvent.
‡Carried out crystallographic studies.
b Yields of pure and isolated product 9a.
3366 | Org. Biomol. Chem., 2014, 12, 3366–3370
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
9). Subsequently, we have also tested various solvents such as entries 3, 9 and 15) which may be attributed to the steric bulk
toluene, CH3CN, CH2Cl2 and THF. However, DCE was found to of the ortho substituent.11
be the better solvent for the current transformation (Table 1,
We then focused on investigating the reactivity of these 1,4-
entries 3 and 10–13). With the optimized conditions in hand, benzoxazinone derivatives with other common Michael accep-
we further explored the scope and generality of the current pro- tors, p-benzoquinone derivatives. Initially we started our inves-
tocol with diversely substituted 1,4-benzoxazinones 1–3 and tigation with the reaction of benzoxazinone
1
and
nitrostyrene derivatives. Accordingly, a variety of aryl substi- p-benzoquinone (12). In a typical reaction procedure 1,4-benzo-
tuted nitroalkenes such as 3,4-dimethoxy, 4-methyl, 4-chloro, xazinone 1 and p-benzoquinone were dissolved in 4 mL of
and 2-chloro substituted phenyl nitrostyrenes, were prepared CH2Cl2, then trifluoroacetic acid was added and allowed to stir
and subjected to the Michael addition–cyclization strategy at room temperature for 3 h. As the reaction proceeded the
with vinylogous carbamate 1–3. The desired products were product started precipitating out of the reaction mixture. After
obtained in high yields in all cases. The reaction of naphthyl completion of the reaction, as shown by TLC, the reaction
and phenyl nitrostyrenes with 1,4-benzoxazinone 1 also pro- mixture was filtered to get the coumarin derivative 14a as
ceeded smoothly to afford the corresponding products in 81% yellow precipitate (Table 3, entry 1).
and 84% yields, respectively. The 1,4-benzoxazinone 2, bearing
Encouraged by the results obtained, we have chosen the
a methyl substituent, also reacted well with the diversely sub- reaction of 1 and 12 as our model reaction and proceeded for
stituted nitrostyrenes to furnish pyrrolobenzoxazines 10 in the optimization of reaction conditions. When the reaction
high yields (Table 2, entries 7–12). Under similar reaction con- was carried out with p-TSA·H2O the desired product was
ditions, when benzoxazinone 3, bearing an ester (CO2Me) obtained in 68% yield. However, no product was observed
moiety, was reacted with the nitrostyrene derivatives, the when the reaction was carried out with TfOH. Further screen-
corresponding products were obtained in slightly diminished ing of various Lewis acids such as ZrCl4, FeCl3, SnCl4, and
yields when compared to those of other two benzoxazinone BF3·etherate afforded the desired product in moderate yields
derivatives 1 and 2 (Table 2, entries 13–18). The reason might be (Table 3, entries 2–7). Screening of various reagents disclosed
the moderate nucleophilicity of 3, due to presence of an electron- that the trifluoroacetic acid affords the coumarin derivative
withdrawing ester group. It is noteworthy that the reactions of 14a in higher yield. Successive screening of various solvents
1,4-benzoxazinones 1–3 with 2-chlorophenyl nitrostyrene furn- such as CH2Cl2, DCE, toluene, THF and CH3CN, suggests that
ished the products in lower yields (Table 2, entries 4, 10 and 16) CH2Cl2 was the optimal solvent (Table 3, entries 8–11).
when compared to that of 4-chlorophenyl nitrostyrene (Table 2,
With the optimized protocol, we next set out to explore the
substrate scope and limitation of the reaction. When the reac-
tion of diversely substituted 1,4-benzoxazinone derivatives 1–2
and 4–8 was carried out with p-benzoquinone, all the reactions
proceeded smoothly to give the coumarin derivatives 14a–g in
excellent yields. The current methodology also tolerates a
variety of functional groups. Further, the reaction of 1,4-ben-
Table 2 Substrate scopea
Table 3 Optimization of reaction conditionsa
Entry R1
R2
Ar
Product Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
H
H
3,4-Dimethoxy-phenyl 9a
82
77
75
71
81
84
76
75
71
66
78
82
68
66
62
56
71
75
4-Methylphenyl
4-Chlorophenyl
2-Chlorophenyl
1-Naphthyl
9b
9c
9d
9e
9f
Entry
Reagent
Solvent
Yieldb (%)
Phenyl
Me 3,4-Dimethoxy-phenyl 10a
1
2
3
4
5
6
7
8
TFA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
88
—
68
71
76
62
79
85
84
80
78
Me 4-Methylphenyl
Me 4-Chlorophenyl
Me 2-Chlorophenyl
Me 1-Naphthyl
10b
10c
10d
10e
10f
TfOH
p-TSA·H2O
ZrCl4
FeCl3
SnCl4
BF3·etherate
TFA
TFA
TFA
TFA
9
10
11
12
13
14
15
16
17
18
Me Phenyl
H
H
H
H
H
H
3,4-Dimethoxy-phenyl 11a
4-Methylphenyl
4-Chlorophenyl
2-Chlorophenyl
1-Naphthyl
11b
11c
11d
11e
11f
9
10
11
Toluene
THF
CH3CN
Phenyl
a Reactions were performed with 1 (0.5 mmol), p-benzoquinone 12
(0.6 mmol) and TFA (0.6 mmol) in 4 mL of solvent. b Yields of pure
and isolated product 14a.
a Reactions were performed with benzoxazinone derivative (1–3,
0.5 mmol), nitrostyrene derivative (0.6 mmol) and TFA (0.75 mmol) in
4 mL of DCE. b Yields of pure and isolated products.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 3366–3370 | 3367

View Article Online
Communication
Organic & Biomolecular Chemistry
Scheme 1 Substrate scope. Reactions were performed with 1 (0.5 mmol), p-benzoquinone (12)/naphthoquinone (13) (0.6 mmol) and TFA
(0.6 mmol) in 4 mL of CH2Cl2.
zoxazinone derivatives 1–2 and 4–8 with 1,4-naphthoquinone initially the Michael addition of the activated vinylogous carba-
(13) also delivered the corresponding coumarin derivatives mate takes place at the α-position of β-nitrostyrene, which
15a–g in high yields (Scheme 1). The single crystal X-ray analysis further undergoes intramolecular cyclization. The aromatiza-
of the compound 14f, corroborated the assigned structure to tion to the pyrrole ring and concomitant exclusion of HNO
this coumarin derivative (Fig. 1). Coumarin derivatives exhibit and H2O from species A results in the formation of a pyrrolo-
prominent biological activities,12 and exclusively, the 3-amino benzoxazine derivative. In a similar fashion, the 1,4-benzoxazi-
substituted coumarins are found in naturally occurring anti- none derivative undergoes Michael addition with
biotics such as novobiocin,13 chlorbiocin,14 and coumermycin p-benzoquinone in the presence of trifluoroacetic acid. The
A1.15 Moreover, the reported methods for the synthesis of 3-ami- species B undergoes subsequent rearomatization and succes-
nocoumarin derivatives involves the multi-step procedures and sive intramolecular ring opening of oxazinone ring and cycliza-
expensive reagents.16 Herein we reported a simple and efficient tion to pyranone ring to generate 3-arylamino coumarin
protocol for the synthesis of diversely substituted 3-amino cou- derivative.
marin derivatives from the readily available starting materials.
In further investigations to evaluate the substrate scope, we
A possible mechanism for the formation of pyrrolobenzoxa- have also carried out the reaction of 1,4-benzoxazinone 16
zine derivatives and 3-arylamino coumarin derivatives is with ortho-naphthoquinone monoketal 17 in presence of TFA
depicted in Scheme 2. In the presence of trifluoroacetic acid, at room temperature for 4 h. The reaction proceeded smoothly
and after purification by column chromatography the product
18 was obtained in 78% yield (Scheme 3). The structure of
product 18 was assigned by the collective information
obtained from 1H, 13C NMR, DEPT, HRMS and single crystal
X-ray analysis.
In conclusion, we have demonstrated a simple and efficient
methodology for the synthesis of pyrrolobenzoxazine derivatives
from readily available starting materials and we have also deve-
loped a novel synthetic route for the synthesis of 3-amino cou-
marin derivatives from a new class of vinylogous carbamates.
The current protocol obviates the purification by column
chromatography and provides an easy access for the synthesis
of diversely substituted 3-amino coumarin derivatives.
Fig. 1 Single crystal X-ray structure of 14f.
3368 | Org. Biomol. Chem., 2014, 12, 3366–3370
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Scheme 2 A plausible mechanism for the formation of pyrrolobenzoxazine and 3-arylamino coumarin derivatives.
D. Chandrasekar, S. Ramakrishna and Y. Venkateswarlu,
J. Nat. Prod., 2004, 67, 1168.
3 (a) C. Rochais, V. Lisowski, P. Dallemagne and S. Rault,
Bioorg. Med. Chem., 2006, 14, 8162; (b) S. Han, D. S. Siegel,
K. C. Morrison, P. J. Hergenrother and M. Movassaghi,
J. Org. Chem., 2013, 78, 11970.
Scheme 3 Reaction of bezoxazinone 16 with naphthoquinone
monoketal 17.
4 (a) J. Ham and H. Kang, Bull. Korean Chem. Soc., 2002, 23,
163; (b) A. Fürstner, H. Krause and O. R. Thiel, Tetrahedron,
2002, 58, 6373; (c) R. Kumar and J. W. Lown, Eur. J. Med.
Chem., 2005, 40, 641; (d) S. M. Reddy, M. Srinivasulu,
N. Satyanarayana, A. K. Kondapi and Y. Venkateswarlu,
Tetrahedron, 2005, 61, 9242; (e) D. L. Boger, C. W. Boyce,
M. A. Labroli, C. A. Sehon and Q. Jin, J. Am. Chem. Soc.,
1999, 121, 54.
The authors thank the Science & Engineering Research
Board, New Delhi [Research Grant SR/S1/OC-38/2011] for
financial support, DST for providing the HRMS facility in the
DST-FIST Program, and Prof. V. R. Pedireddi, IIT Bhubaneswar,
for X-ray crystallographic assistance. R.T.N. thanks CSIR, New
Delhi for a research fellowship.
5 (a) A. R. Quesada, M. D. G. Grávalos and J. L. F. Puentes,
Br. J. Cancer, 1996, 74, 677; (b) D. R. Soenen, I. Hwang,
M. P. Hedrick and D. L. Boger, Bioorg. Med. Chem. Lett.,
2003, 13, 1777; (c) H. Tao, I. Hwang and D. L. Boger, Bioorg.
Med. Chem. Lett., 2004, 14, 5979; (d) T.-C. Chou, Y. Guan,
D. R. Soenen, S. J. Danishefsky and D. L. Boger, Cancer
Chemother. Pharmacol., 2005, 56, 379.
6 (a) M. Biava, R. Fioravanti, G. C. Porretta, D. Deidda,
C. Maullu and R. Pompei, Bioorg. Med. Chem. Lett., 1999, 9,
2983; (b) M. V. Raimondi, S. Cascioferro, D. Schillaci and
S. Petruso, Eur. J. Med. Chem., 2006, 41, 1439.
Notes and references
1 (a) H. Fan, J. Peng, M. T. Hamann and J.-F. Hu, Chem. Rev.,
2008, 108, 264; (b) J. C. Morris and A. J. Phillips, Nat. Prod.
Rep., 2008, 25, 95; (c) F. Bellina and R. Rossi, Tetrahedron,
2006, 62, 7213; (d) H. Kang and W. Fenical, J. Org. Chem.,
1997, 62, 3254; (e) X.-G. Tong, L.-L. Zhou, Y.-H. Wang,
C. Xia, Y. Wang, M. Liang, F.-F. Hou and Y.-X. Cheng, Org.
Lett., 2010, 12, 1844; (f) J.-L. Guo, Z.-M. Feng, Y.-J. Yang,
Z.-W. Zhang and P.-C. Zhang, Chem. Pharm. Bull., 2010, 58,
983.
7 S. Manzanaro, J. Salvá and J. Á. de la Fuente, J. Nat. Prod.,
2006, 69, 1485.
8 (a) R. J. Andenen, D. J. Faulkner, H. Cun-heng, G. D. Van
Duyne and J. Clardy, J. Am. Chem. Soc., 1985, 107, 5492;
2 P. Krishnaiah, V. L. N. Reddy, G. Venkataramana,
K. Ravinder, M. Srinivasulu, T. V. Raju, K. Ravikumar,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 3366–3370 | 3369

View Article Online
Communication
Organic & Biomolecular Chemistry
(b) M. V. R. Reddy, M. R. Rao, D. Rhodes, M. S. T. Hansen,
K. Rubins, F. D. Bushman, Y. Venkateswarlu and
D. J. Faulkner, J. Med. Chem., 1999, 42, 1901;
and L. M. Neckers, J. Biol. Chem., 2000, 275, 37181;
(c) J. A. Burlison, L. Neckers, A. B. Smith, A. Maxwell and
B. S. J. Blagg, J. Am. Chem. Soc., 2006, 128, 15529.
(c) C. P. Ridley, M. V. R. Reddy, G. Rocha, F. D. Bushman 13 (a) I. Raad, R. Darouiche, R. Hachem, M. Sacilowski and
and D. J. Faulkner, Bioorg. Med. Chem., 2002, 10, 3285.
9 M. Kato, S. Nishino and H. Takasugi, PCT Int. Appl, WO
9306108 A1 19930401, 1993.
G. P. Bodey, Antimicrob. Agents Chemother., 1995, 39, 2397;
(b) I. I. Raad, R. Y. Hachem, D. Abi-said, K. V. I. Rolston,
E. Whimbey, A. C. Buzaid and S. Legha, Cancer, 1998, 82,
403.
10 (a) R. T. Naganaboina and R. K. Peddinti, J. Org. Chem.,
2013, 78, 12819; (b) N. Bodipati and R. K. Peddinti, Org. 14 U. Galm, S. Heller, S. Shapiro, M. Page, S.-M. Li and
Biomol. Chem., 2012, 10, 1958; (c) G. Choudhary and
R. K. Peddinti, Green Chem., 2011, 13, 3290.
11 For a recent report of synthesis of pyrrolobenzoxazines
from o-aminophenols and acetylenedicarboxylates, see:
L. Moradi, M. Piltan and H. Rostami, Chin. Chem. Lett.,
2014, 25, 123.
L. Heide, Antimicrob. Agents Chemother., 2004, 48, 1307.
15 (a) B. R. Kusuma, L. B. Peterson, H. Zhao, G. Vielhauer,
J. Holzbeierlein and B. S. J. Blagg, J. Med. Chem., 2011,
54, 6234; (b) L. Vozzolo, B. Loh, P. J. Gane, M. Tribak,
L. Zhou, I. Anderson, E. Nyakatura, R. G. Jenner,
D. Selwood and A. Fassati, J. Biol. Chem., 2010, 285,
39314.
12 (a) L. Santana, E. Uriarte, H. G. Diaz, G. Zagotto, R. Soto-
Otero and E. Mendez-Alvarez, J. Med. Chem., 2006, 49, 16 M. A. Soussi, D. Audisio, S. Messaoudi, O. Provot,
1149; (b) M. G. Marcu, A. Chadli, I. Bouhouche, M. Catelli
J.-D. Brion and M. Alami, Eur. J. Org. Chem., 2011, 5077.
3370 | Org. Biomol. Chem., 2014, 12, 3366–3370
This journal is © The Royal Society of Chemistry 2014