Chemical generation of o-quinone monoimines for the rapid construction of 1,4-benzoxazine derivatives

Article abstract of DOI:10.1039/c2ob06681e

Highly reactive o-benzoquinone monoimines were chemically generated and successfully trapped with electron-rich olefins that led to the synthesis of hitherto unknown 1,4-benzoxazine derivatives. This unprecedented transformation was achieved by the oxidat

Full text of DOI:10.1039/c2ob06681e

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 1958
www.rsc.org/obc
COMMUNICATION
Chemical generation of o-quinone monoimines for the rapid construction of
1,4-benzoxazine derivatives†
Naganjaneyulu Bodipati and Rama Krishna Peddinti*
Received 4th October 2011, Accepted 5th January 2012
DOI: 10.1039/c2ob06681e
p-quinones. Lectka et al. demonstrated an enantioselective syn-
thesis of 1,4-benzoxazones from o-quinone monoimides and
chiral ketene enolates.9 The demanding task in this area is con-
trolling the reactivity of o-benzoquinone monoimine without
introducing an amide functionality since the removal of an
amide functional group requires harsh reaction conditions.
Recently Fleury discovered an electrochemical method for the
generation of o-benzoquinone monoimines,8 where these reac-
tive species oxidize primary aliphatic amines into enamines to
participate in Diels–Alder reaction.
Highly reactive o-benzoquinone monoimines were chemically
generated and successfully trapped with electron-rich olefins
that led to the synthesis of hitherto unknown 1,4-benzoxazine
derivatives. This unprecedented transformation was achieved
by the oxidation of o-aminophenols bearing appropriate
functionality on the arene residue with less expensive hyper-
valent iodine reagent in the presence of vinylic ethers or
thioethers.
Quinone imines are powerful intermediates for organic synthesis
and constitute potential precursors to a number of natural pro-
ducts.1 The synthetic utility of these intermediates has not been
extensively exploited since they are highly unstable; in particular
o-benzoquinone monoimines are very prone to polymerization.2
The difficulties encountered in handling o-benzoquinone mono-
imines are (i) the dimerization reaction with their precursors i.e.,
o-aminophenols, leading to 2-aminophenoxazones3 and (ii) for-
mation of polymers.4a Hishida4 and co-workers studied, spectro-
photometrically, the reaction between o-benzoquinone
monoimine and o-aminophenol and they obtained 2-aminophe-
noxazones and polymers as the reaction products. However to
stabilize these transient intermediates and to diminish their reac-
tivity and thereby prevent the decomposition, an imide function-
ality (N-acyl or N-benzoyl group) on these o-benzoquinone
monoimines is necessary. Heine et al.5 showed that o-benzoqui-
none monoimines are willing partners in hetero Diels–Alder
reaction6 by introducing an amide functionality and two chlorine
atoms on the ring. Later pioneering work on o-azaquinones was
done by Nicolaou et al.7 and Fleury et al.8
o-Quinone monoimines bearing electron-withdrawing groups
in the ring residue, and o-quinone monoimides being electron-
deficient in nature, react with electron-rich species.7c,e,8e These
reactive intermediates participate as hetero dienes in inverse-
electron demand Diels–Alder reaction with electron-rich dieno-
philes to furnish heterocyclic compounds of biological interest.10
3,4-Dihydro-2H-1,4-benzoxazine is a recurring structural motif
in a number of natural products having important biological
activities. Some of them are central nervous system depres-
sants,10h antipsychotic agents,10d,c antagonists,10f and antibacter-
ial agents,10a,b while others are potential drugs for treating
neurodegenerative,10e cardiovascular,10h and diabetic disor-
ders.10g Although, there are a variety of methods for the syn-
thesis of 3,4-dihydro-2H-1,4-benzoxazine11 most of these
methods involve multistep processes. However, the Diels–Alder
reaction not only provides a single step pathway but also allows
the construction of complex structures.5,7–9 Unfortunately there
has been only one electrochemical method reported for inter-
molecular Diels–Alder reaction of o-quinone monoimines with
enamines.8 In order to explore quinone monoimine chemistry
many features of the reaction system need to be improved,
including the use of less toxic, low-cost catalysts and reagents,
and convenient and mild operating conditions. Herein we report
a novel method for the generation of o-benzoquinone mono-
imines by using diacetoxyiodobenzene, a hypervalent iodine
reagent,12 and successfully trapping with vinyl ethers. To the
best of our knowledge, this reaction is the first example of inter-
molecular inverse-electron demand Diels–Alder reaction of
chemically generated o-quinone monoimines.
Nicolaou and his co-workers synthesized N-acetyl o-azaqui-
none derivatives from easily accessible anilides and carried out
intermolecular Diels–Alder cycloaddition. However, this reaction
procedure is limited to ortho-substituted anilides and involves
the use of excess amount of oxidizing reagent (Dess–Martin per-
iodinane); the oxidation of para-substituted anilides leads to
Department of Chemistry, Indian Institute of Technology, Roorkee-247
667, Uttarakhand, India. E-mail: rkpedfcy@iitr.ernet.in, ramakpeddinti@
gmail.com; Fax: + (91) 133 227 3560; Tel: +(91) 133 228 5438
†Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data, copies of 1H NMR (500 MHz), crystallo-
graphic data (CIF) and computational details. CCDC reference number
815224. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob06681e
Inspired by the protocols harnessing the reactive ortho-benzo-
quinone monoketals13 generated by oxidation of 2-methoxyphe-
nols with hypervalent iodine reagents, we became interested
in extending this strategy for the generation of o-quinone
1958 | Org. Biomol. Chem., 2012, 10, 1958–1961
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 1 Optimization of the Diels–Alder reaction of in situ generated
o-quinone monoimines 2a and 2b with butyl vinyl ethera
Table 2 Cycloaddition of o-quinone monoimines with vinyl ethers
and phenyl vinyl sulfidea
o-Aminophenol
Entry
1
R
Dienophile
Product
Yield (%)b
Yield
(%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
1e
1f
5-NO2
5-NO2
5-NO2
5-NO2
4-CN
4-CN
4-CN
4-CN
4-CN, 6-OMe
4-CN, 6-OMe
4-CN, 6-OMe
4-CN, 6-OMe
5-CN
5-CN
5-CN
3
4
5
6
3
4
5
6
3
4
5
6
3
4
5
6
3
4
5
6
3
4
5
6
7a
8a
9a
10a
7b
8b
9b
10b
7c
64
69
52c
78
66
68
61c
76
68
72
59c
71
61
63
51c
64
66
71
56c
75
54
60
49c
64
Entry
Solvent
Base
Temp.
Time
Product
1c
2d
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
—
—
—
—
—
—
—
Et3N
Et3N
KHCO3
—
RT
RT
RT
RT
40 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
1 h
2 h
2 h
2 h
3 h
3 h
6 h
6 h
3 h
3 h
2 h
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b +
N-Ac 7b
7b
7b
7b
19
21
40
42
38
64
51
0
4e
5
6
7
8
9
10
11
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
8c
9c
0
10c
7d
8d
9d
10d
7e
8e
9e
10e
7f
8f
THF
CH2Cl2
0
53f
12
13
14
CH2Cl2
THF
THF
KHCO3
Et3N
KHCO3
0 °C
0 °C
0 °C
3 h
3 h
3 h
52
Trace
66
5-CN
4-COOMe
4-COOMe
4-COOMe
4-COOMe
4-CF3
4-CF3
4-CF3
a Reactions were carried out with 5 equiv. of butyl vinyl ether and 1.2
equiv. of DAIB, unless otherwise mentioned. b Yield of isolated
products. c 1 equiv. of DAIB was used. d 1 equiv. of butyl vinyl ether
was used. e 1.5 equiv. of DAIB was used. f Combined yield.
1f
1f
1f
9f
10f
4-CF3
a All reactions were carried out with 5 equiv. of vinyl ether, entries 1–4
were carried out in CH2Cl2; and entries 5–24 were carried out in THF
and in presence of KHCO3. b Yield of isolated products. c Reactions
were carried out with 2 equiv. of phenyl vinyl sulfide and slow addition
of DAIB.
monoimines as electrophilic intermediates by oxidative dearoma-
tization of o-aminophenols. Considering the stability of o-benzo-
quinone monoimides, we reasoned that electron-withdrawing
group(s) on the arene moiety of the o-aminophenols would
impart considerable stability to the corresponding oxidized o-
benzoquinone monoimines. To test this hypothesis, 2-amino-
phenol was oxidized with diacetoxyiodobenzene (DAIB) in
dichloromethane in the presence of butyl vinyl ether (3).
However, no identifiable products were observed under these
conditions.
Upon treatment of the parent 2-aminophenol with DAIB in
the presence of butyl vinyl ether, neither 2-aminophenol nor any
isolable product was observed from TLC analysis. It was pre-
sumed that o-quinone monoimine, if formed, could not undergo
Diels–Alder reaction as it is not sufficiently electron-deficient to
drive the reaction. Keeping the required electronic nature for the
reactants of inverse-electron demand Diels–Alder reaction in
mind and to amplify the probability of the heterodiene participat-
ing in the Diels–Alder event, we introduced a nitro group onto
the aromatic ring of o-aminophenol. The oxidation of nitro-
aminophenol 1a was carried out with varying amounts of DAIB
at different temperatures in the presence of butyl vinyl ether. The
use of 1.2 equiv. of DAIB and 5 equiv. of butyl vinyl ether in
dichloromethane at 0 °C afforded the benzoxazine derivative 7a
in 64% yield (Table 1, entry 6). The yield of the product can be
further improved with an additional amount of enol ether (72%
with 20 equiv.). The treatment of cyano-aminophenol 1b with
DAIB and butyl vinyl ether in the absence of base provided the
desired product 7b along with its N-acetylated derivative in a
combined yield of 53% (Table 1, entry 11). We then probed the
reactivity of 4-cyano-2-aminophenol (1b) under oxidative dearo-
matization Diels–Alder conditions in the presence of KHCO3 to
provide the heterocycle 7b in similar yield (Table 1, entry 14).
With a consistent set of conditions in hand, we extended the
protocol for the reactions of 5-nitro-2-aminophenol (1a) in the
presence of electron-rich enol ethers such as ethyl vinyl ether
(4), dihydrofuran (6), and phenyl vinyl sulfide (5) (Table 2). The
reactions proceeded smoothly at 0 °C to furnish the benzoxa-
zines 8a–10a in good yields. However, the reaction of 4-nitro-2-
aminophenol, under the same conditions, provided the corre-
sponding products in moderate yields.
To determine the scope and to test the generality of this novel
synthetic technology, a range of aminophenols 1b–1f bearing
different withdrawing groups at different positions of the arene
moiety were probed (Scheme 1, Table 2). Since the reaction of
1b with butyl vinyl ether furnished clean product in the presence
of KHCO3, the reactions of 1b–1f were performed under the
same conditions. The introduction of methoxy substituent in
position-6 of cyano-aminophenol as shown in 1c also exhibited
very good reactivity in this methodology. These current con-
ditions were also employed for 5-cyano derivative 1d and as
seen in Table 2, the reactivity of 2d towards Diels–Alder
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1958–1961 | 1959

View Article Online
sulfide with complete regioselectivity, to afford N-unsubstituted-
1,4-benzoxazine derivatives of diverse functionalities. Conse-
quently these heterocycles could be considered as target struc-
tures for medicinal use since they have a 1,4-benzoxazine
nucleus. The significant discovery of the current study is the
incorporation of electron-withdrawing substituent on the aryl
ring to disfavor polymerization and allow for the described inter-
molecular reaction to proceed. The present protocol demon-
strated here may be helpful for expanding the horizons of o-
quinone monoimine chemistry. Further studies are currently
underway in this direction.
Acknowledgements
The authors thank Council for Scientific and Industrial Research
[CSIR 01(2297)/09/EMR-II], New Delhi for financial support.
We thank Prof V. R. Pedireddi, IIT Bhubaneswar for X-ray crys-
tallographic assistance. N. B. thanks CSIR for a research
fellowship.
Scheme 1 [4 + 2] Cycloaddition of o-quinone monoimines 2a–f with
electron-rich dienophiles.
Notes and references
1 Naturally Occurring Quinones IV: Recent Advances, ed. R. H. Thomson,
Blackie, London, 4th edn, 1997, p. 746..
2 For a review on the synthesis of quinones, see: W. M. Owton, J. Chem.
Soc., Perkin Trans. 1, 1999, 2409–2420, and references therein.
3 C. E. Barry, P. G. Nayar and T. P. Begley, Biochemistry, 1989, 28, 6323–
6333.
4 (a) T. Nogami, T. Hishida, M. Yamada, H. Mikawa and Y. Shirota, Bull.
Chem. Soc. Jpn., 1975, 48, 3709–3714; (b) T. Hishida, T. Nogami,
Y. Shirota and H. Mikawa, Chem. Lett., 1974, 293–296.
5 (a) H. W. Heine, B. J. Barchiesi and E. A. Williams, J. Org. Chem.,
1984, 49, 2560–2565; (b) H. W. Heine, C. Olsson, J. D. Bergin,
J. B. Foresman and E. A. Williams, J. Org. Chem., 1987, 52, 97–101;
(c) H. W. Heine, J. A. Suriano, C. Winkel, A. Burik, C. M. Taylor and E.
A. Williams, J. Org. Chem., 1989, 54, 5926–5930; (d) H. W. Heine, M.
G. La Porte, R. H. Overbaugh and E. A. Williams, Heterocycles, 1995,
40, 743–752.
6 For reviews on hetero Diels–Alder reaction: (a) K. A. Jørgensen, Angew.
Chem., Int. Ed., 2000, 39, 3558–3588, and references therein
(b) S. Reymond and J. Cossy, Chem. Rev., 2008, 108, 5359–5406, and
references therein (c) H. Pellissier, Tetrahedron, 2009, 65, 2839–2877,
and references therein.
7 (a) K. C. Nicolaou, Y.-L. Zhong and P. S. Baran, Angew. Chem., Int. Ed.,
2000, 39, 622–625; (b) K. C. Nicolaou, P. S. Baran, R. Kranich, Y.-
L. Zhong, K. Sugita and N. Zou, Angew. Chem., Int. Ed., 2001, 40, 202–
206; (c) K. C. Nicolaou, K. Sugita, P. S. Baran and Y.-L. Zhong, Angew.
Chem., Int. Ed., 2001, 40, 207–210; (d) K. C. Nicolaou, P. S. Baran, Y.-
L. Zhong and K. Sugita, J. Am. Chem. Soc., 2002, 124, 2212–2220;
(e) K. C. Nicolaou, K. Sugita, P. S. Baran and Y.-L. Zhong, J. Am.
Chem., Soc., 2002, 124, 2221–2232.
8 (a) M. Largeron and M.-B. Fleury, J. Org. Chem., 2000, 65, 8874–8881;
(b) M. Largeron, A. Neudorffer, M. Vuilhorgne, E. Blattes and M.-
B. Fleury, Angew. Chem., Int. Ed., 2002, 41, 824–827; (c) M. Largeron,
A. Neudorffer and M.-B. Fleury, Angew. Chem., Int. Ed., 2003, 42,
1026–1029; (d) E. Blattes, M.-B. Fleury and M. Largeron, J. Org. Chem.,
2004, 69, 882–890; (e) D. Xu, A. L. Chiaroni, M.-B. Fleury and
M. Largeron, J. Org. Chem., 2006, 71, 6374–6381; (f) M. Largeron,
C. Angèle and M.-B. Fleury, Chem. Eur. J., 2008, 14, 996–1003.
9 J. Wolfer, T. Bekele, C. J. Abraham, C. Dogo-Isonagie and T. Lectka,
Angew. Chem., Int. Ed., 2006, 45, 7398–7400.
Fig. 1 Crystal structure of benzoxazine 7a.
cycloaddition was found to be slightly reduced in comparison to
its regio isomer 2b. This remarkable protocol is also tolerant for
functionalities such as 4-CO2Me and 4-CF3. The efficient reac-
tivity of ester derivative 2e is evident from Table 2. Surprisingly,
the aminophenol with 3-CO2Me substitution failed to give the
corresponding cycloadducts under the reaction conditions. The
yields of 1,4-benzoxazine derivatives shall be seen as overall
yields of two steps i.e., oxidation/Diels–Alder reaction. The
yields are comparable with those of 1,4-benzoxazine derivatives
derived from o-quinone monoimides/monoimines.7,8
The more electron-rich carbon atom of the dienophilic enol
ether added to the nitrogen atom of the o-quinone monoimine.
This can be attributed to the electron-deficiency on the nitrogen
atom due to the presence of more electronegative oxygen atom at
the other end of the heterodiene. The regiochemistry of benzoxa-
zine derivative 7a was confirmed by its single crystal X-ray
analysis (Fig. 1).† To evaluate the origin of the regioselectivity
observed in this study, we have computed the energies of the
transition-state structures for the reaction between o-quinone
monoimine 2b and ethyl vinyl ether (4) by the B3LYP/6-31G(d)
method. It was found that the transition-state structure of the
product 8b is favored by 7.7 kcal mol−1 over the transition-state
structure of its regioisomer.
10 Selected papers for the medicinal use of benzoxazine derivatives, see:
(a) I. Hayakawa, T. Hiramitsu and Y. Tanaka, Chem. Pharm. Bull., 1984,
32, 4907–4913; (b) L. A. Mitscher, P. N. Sharma, D. T. W. Chu,
L. L. Shen and A. G. Pernet, J. Med. Chem., 1987, 30, 2283–2286;
(c) T. Taverne, O. Diouf, P. Depreux, J. H. Poupaert, D. Lesieur, B.
G. Lemaître, P. Renard, M. C. Rettori, D. H. Caignard and B. Pfeiffer,
J. Med. Chem., 1998, 41, 2010–2018; (d) A. M. Birch, P. A. Bradley,
In summary, we have described a novel method for the chemi-
cal generation of o-quinone monoimines, which underwent [4 +
2] cycloaddition reaction with vinyl ethers and phenyl vinyl
1960 | Org. Biomol. Chem., 2012, 10, 1958–1961
This journal is © The Royal Society of Chemistry 2012

View Article Online
J. C. Gill, F. Kerrigan and P. L. Needham, J. Med. Chem., 1999, 42,
3342–3355; (e) M. Largeron, B. Lockhart, B. Pfeiffer and M. B. Fleury,
J. Med. Chem., 1999, 42, 5043–5052; (f) T. M. Bohme, C. E. A. Szafran,
H. Hallak, T. Pugsley, K. Serpa and R. D. Schwarz, J. Med. Chem., 2002,
45, 3094–3102; (g) P. J. Rybczynski, R. E. Zeck, J. Dudash Jr,
D. W. Combs, T. P. Burris, M. Yang, M. C. Osborne, X. Chen and K.
T. Demarest, J. Med. Chem., 2004, 47, 196–209; (h) W. Yang, Y. Wang,
Z. Ma, R. Golla, T. Stouch, R. Seethala, S. Johnson, R. Zhou, T. Güngör,
J. H. M. Feyen and J. K. Dickson Jr., Bioorg. Med. Chem. Lett., 2004,
14, 2327–2330; (i) E. Blattes, B. Lockhart, P. Lestage, L. Schwendimann,
P. Gressens, M.-B. Fleury and M. Largeron, J. Med. Chem., 2005, 48,
1282–1286.
12 For reviews on hypervalent iodine reagents, see: (a) V. V. Zhdankin,
Chem. Rev., 2008, 108, 5299–5358, and references therein (b) T. Wirth,
Top. Curr. Chem., 2003, 224, 1–264, and references therein
(c) L. Pouysegu, D. Deffieux and S. Quideau, Tetrahedron, 2010, 66,
2235–2261, and references therein (d) L. F. J. Silva and B. Olofsson, Nat.
Prod. Rep., 2011, 28, 1722–1754, and references therein
(e) R. M. Moriarty, J. Org. Chem., 2005, 70, 2893–2903, and
references therein (f) V. Satam, A. Harad, R. Rajule and H. Pati, Tetra-
hedron, 2010, 66, 7659–7706, and references therein (g) S. F. Kirsch and
A. Duschek, Angew. Chem., Int. Ed., 2011, 50, 1524–1552, and refer-
ences therein.
13 (a) C.-C. Liao and R. K. Peddinti, Acc. Chem. Res., 2002, 35, 856–866;
(b) Y.-K. Chen, R. K. Peddinti and C.-C. Liao, Chem. Commun., 2001,
1340–1341; (c) S. R. Surasani, V. S. Rajora, N. Bodipati and
R. K. Peddinti, Tetrahedron Lett., 2009, 50, 773–775; (d) S. R. Surasani
and R. K. Peddinti, Tetrahedron Lett., 2011, 52, 4615–4618.
11 (a) B. Achari, S. B. Mandal, P. K. Dutta and C. Chowdhury, Synlett,
2004, 2449–2467, and references therein (b) J. Ilaš, P. S. Anderluh, M.
S. Dolenc and D. Kikelj, Tetrahedron, 2005, 61, 7325–7348, and refer-
ences therein.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1958–1961 | 1961