Simultaneously Electrogenerated Cycloaddition Partners for Regiospecific Inverse-Electron-Demand Diels-Alder Reactions: A Route for Polyfunctionalized 1,4-Benzoxazine Derivatives

Article abstract of DOI:10.1021/jo035614b

A multistep one-pot electrochemical synthesis of a variety of complex 2-alkylamino-1,4-benzoxazine derivatives is described. The reactions are regiospecific and diastereospecific in the case of heterocyclic annulation. This cascade sequence, wherein both cycloaddition partners are generated in situ, at room temperature, under metal-free conditions, allows the inverse-electron-demand Diels-Alder reaction of an o-iminoquinone diene and a secondary alkylenamine dienophile, two chemically nonaccessible unstable entities. To increase the molecular diversity, a variant in which the enamine is separately prepared completes the aforementioned procedure. The extension of this reaction should be useful to generate libraries of heterocycles.

Full text of DOI:10.1021/jo035614b

Sim u lta n eou sly Electr ogen er a ted Cycloa d d ition P a r tn er s for
Regiosp ecific In ver se-Electr on -Dem a n d Diels-Ald er Rea ction s:
A Rou te for P olyfu n ction a lized 1,4-Ben zoxa zin e Der iva tives
Estelle Blattes, Maurice-Bernard Fleury, and Martine Largeron*
UMR 8638 CNRS - Universite´ Rene´ Descartes, Synthe`se et Structure de Mole´cules d’Inte´reˆt
Pharmacologique, Faculte´ des Sciences Pharmaceutiques et Biologiques,
4 Avenue de l’Observatoire, 75270 Paris Cedex 06, France
martine.largeron@univ-paris5.fr
Received November 3, 2003
A multistep one-pot electrochemical synthesis of a variety of complex 2-alkylamino-1,4-benzoxazine
derivatives is described. The reactions are regiospecific and diastereospecific in the case of
heterocyclic annulation. This cascade sequence, wherein both cycloaddition partners are generated
in situ, at room temperature, under metal-free conditions, allows the inverse-electron-demand Diels-
Alder reaction of an o-iminoquinone diene and a secondary alkylenamine dienophile, two chemically
nonaccessible unstable entities. To increase the molecular diversity, a variant in which the enamine
is separately prepared completes the aforementioned procedure. The extension of this reaction should
be useful to generate libraries of heterocycles.
In tr od u ction
diene. In contrast, the scope and frequency of the inverse-
electron-demand Diels-Alder (IEDDA) reaction are
dwarfed by those of the normal DA reaction, the major
limitation of the IEDDA reaction being a lack of ready
accessible simple electron-deficient dienes. It is, however,
well-established that azadienes are effective aromatic
dienes for participation in IEDDA reactions leading to a
plethora of heterocyclic compounds.5
Recently, we showed that electrogenerated 3,4-azaqui-
none 1ox behaved as an efficient catalyst for the autore-
cycling oxidation of aliphatic primary amines under
metal-free conditions.6 The catalytic cycle produced the
reduced catalyst 1r ed and an alkylimine as the product
of amine oxidation (Scheme 1).
The Diels-Alder (DA) reaction constitutes one of the
most powerful synthetic routes for the construction of six-
membered-ring systems,1 and it has been applied to the
synthesis of complex pharmaceutical and biologically
active compounds.2 Since the discovery of natural Diels-
Alderase enzymes,3 this reaction is no longer regarded
as the exclusive domain of synthetic organic chemistry
and there is currently much interest in developing
enzyme-catalyzed DA reactions due to the level of ste-
reocontrol that can be exercised.4 The most commonly
utilized DA reaction is the normal DA reaction which
requires an electron-poor dienophile and an electron-rich
However, in the case of R1R2CHCH2NH2 amines, the
catalytic process ceased after a few turnovers, as the
catalyst was trapped through [4 + 2] cycloaddition
reaction with the simultaneously electrogenerated tau-
tomeric enamine form of the alkylimine extruded during
the catalytic process (Scheme 1). This serendipitous
reaction allowed the rapid and regiospecific construction
of polyfunctionalized 1,4-benzoxazine derivatives through
a cascade transformation wherein both cycloaddition
partners were generated in situ. An expedient investiga-
tion of the reaction led to a preliminary communication.7
Because the reactivity of o-quinone imine as an azadiene
for IEDDA reactions represented uncharted terrain,
though similar reactions with o-quinone monoimides8 and
* To whom correspondence should be addressed. Phone: 33 01 53
73 96 27. Fax: 33 01 44 07 35 88.
(1) For recent reviews, see: (a) Corey, E. J .; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388. (b) J orgensen, K. A., Angew.
Chem., Int. Ed. 2000, 39, 3558. (c) Buonoro, P.; Olsen, J .-C.; Oh, T.
Tetrahedron 2001, 57, 6099. (d) Fringuelli, F.; Taticchi, A. The Diels-
Alder reaction: Selected practical methods; Wiley: New York, 2002.
(e) Corey, E. J . Angew. Chem., Int. Ed. 2002, 41, 1650.
(2) (a) Allen, J . G.; Hentemann, M. F.; Danishefsky, S. J . J . Am.
Chem. Soc. 2000, 122, 571. (b) Tietze, L. F.; Modi, A. Med. Res. Rev.
2000, 20, 304 and references therein. (c) Nicolaou, K. C.; Snyder, S.
A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002,
41, 1668 and references therein. (d) Williams, R. M.; Cox, R. J . Acc.
Chem. Res. 2003, 36, 127 and references therein.
(3) (a) Auclair, K.; Sutherland, A.; Kennedy, J .; Witter, D. J .; Van
der Heever, J . P.; Hutchinson, C. R.; Vederas, J . C. J . Am. Chem. Soc.
2000, 122, 11519. (b) Watanabe, K.; Mie, T.; Ichihara, A.; Oikawa, M.;
Honma, H. J . Biol. Chem. 2000, 275, 38393. (c) Pohnert, G. ChemBio-
Chem 2001, 2, 873. (d) Stuhlmann, F.; J a¨schke, A. J . Am. Chem. Soc.
2002, 124, 3238. (e) Ose, T.; Watanabe, K.; Mie, T.; Honma, M.;
Watanabe, H.; Yao, M.; Oikawa, H.; Tanaka, I. Nature 2003, 422, 185.
(4) For a recent review on biosynthetically catalyzed Diels-Alder
reactions, see: (a) Stocking, E. M.; Williams, R. M. Angew. Chem., Int.
Ed. 2003, 42, 3078 and references therein. See also: (b) Oikawa, H.;
Kobayashi, T.; Katayama, K.; Suzuki, Y.; Ichihara, A. J . Org. Chem.
1998, 63, 8748. (c) J ohansson, M.; Ko¨pcke, B.; Anke, H.; Sterner, O.
Angew. Chem., Int. Ed. 2002, 41, 2158. (d) Zhang, X.; Deng, Q.; Yoo,
S. H.; Houk, K. N. J . Org. Chem. 2002, 67, 9043.(e) Schlatterer, J . C.;
Stuhlmann, F.; J a¨schke, A. ChemBioChem 2003, 4, 1089.
(5) For reviews, see: (a) Boger, D. L. Tetrahedron 1983, 39, 2869.
(b) Boger, D. L. J . Heterocycl. Chem. 1998, 35, 1003 and references
therein. (c) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259.
(d) J ayakuman, S.; Iskar, M. P. S.; Mahajan, M. P. Tetrahedron 2002,
58, 379.
(6) (a) Largeron, M.; Fleury, M.-B. J . Org. Chem. 2000, 65, 8874.
(b) Largeron, M.; Neudorffer, A.; Fleury, M.-B. Angew. Chem., Int. Ed.
2003, 42, 1026.
(7) Largeron, M.; Neudorffer, A.; Vuilhorgne, M.; Blattes, E.; Fleury,
M.-B. Angew. Chem., Int. Ed. 2002, 41, 824.
10.1021/jo035614b CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004
882
J . Org. Chem. 2004, 69, 882-890

Simultaneously Electrogenerated Partners for [4 + 2] Cycloadditions
SCHEME 1. Ca ta lytic Oxid a tion of P r im a r y
Alip h a tic Am in es Med ia ted by Electr ogen er a ted
3,4-Aza qu in on e 1ox
never reached unity (iPc/iPa ∼ 0.8) and the value of EPa
-
EPc (E being the peak potential) was found to be higher
than 30 mV. Note that, in the reverse sweep, a second
reduction peak Pc′ was recorded at a more negative
potential (-1770 mV vs SCE) due to the irreversible two-
electron reduction of the carbonyl group of the benzophe-
none skeleton.6a
When the controlled potential of the mercury pool was
fixed at +50 mV vs SCE, which is at a potential for which
1r ed could be oxidized to the iminoquinone form 1ox (Fig-
ure 1), the anodic current remained unchanged for a cer-
tain time, consistent with steady-state catalytic behavior.
Accordingly, a value of 16 was found for the total
number of electrons (n) transferred per molecule of 1r ed
in the catalytic process (eight turnovers). These results
indicated that the 1r ed /1ox system behaved as a redox
mediator for the indirect electrochemical oxidation of
aminomethylcyclohexane to the corresponding alkylimine
(Scheme 1), according to the transamination mechanism
previously reported.6a Further, the catalytic process
ceased and close inspection of the exhaustively oxidized
solution revealed that electrogenerated 3,4-azaquinone
1ox was trapped with the tautomeric enamine form of the
alkylimine produced during the catalytic process (Scheme
2), to give the substituted 2-alkylamino-1,4-benzoxazine
2a in 77% yield, along with 3% of the accompanying
2-hydroxy byproduct 2b resulting from the conversion of
2a on silica gel10 (Table 2, entry 1). At this point, it should
be mentioned that the workup and isolation procedures
were crucial to the success of this reaction (see the
Experimental Section). In particular, under acidic work-
up conditions, the 2-alkylamino chain was removed and
the 2-alkylamino-1,4-benzoxazine derivative 2a was con-
verted to the corresponding 2-hydroxy compound 2b. This
ease of transformation was confirmed by treatment of
benzoxazine 2a under various acidic conditions which
yielded hemiacetal 2b in high yields (Table 3, entries
1-4).
The progress of the electrolysis was simultaneously
followed by monitoring the UV-vis absorption spectrum.
After application of the potential (E ) +50 mV vs SCE),
no spectral changes were observed for a time, consistent
with steady-state catalytic behavior (Figure 2). After the
consumption of 5 F mol-1, a decrease in the UV-vis
absorption band shown by the monoanionic form of 1r ed
at 350 nm (ꢀ/mol-1 L cm-1 ) 19 000) was observed, while
new bands at 320 and 259 nm developed. Spectral
changes showed three isosbestic points at 330, 245, and
230 nm, indicating that a simple equilibrium between
two species was shifted. The new bands at 320 and 259
nm could be assigned to the 2-alkylamino-1,4-benzox-
azine 2a , as corroborated after recording the UV-vis
absorption spectrum of the isolated product.
o-quinone monooximes9 are known, we then decided to
explore further its potential for [4 + 2] cycloaddition
reactions with variously substituted enamines. In this
paper, we present a full account of the 1ox-mediated
cascade reactions leading to the construction of complex
1,4-benzoxazine derivatives in a regiospecific manner and
allowing diastereospecific heterocyclic annellation.
Resu lts a n d Discu ssion
Op tim iza tion of th e 1ox-Med ia ted Ca sca d e Rea c-
tion s. First, we have performed optimization studies of
the 1ox-mediated cascade reactions using aminomethyl-
cyclohexane as the amine substrate. As shown in Table
1, we found that the optimum conditions required a
mercury anode, methanol as the solvent, and tetraethyl-
ammonium perchlorate (TEAP) as the supporting elec-
trolyte. One equivalent of 1r ed and 20.0 equiv of amine
substrate were an ideal reagent combination for the
reaction (Table 1, entry 2). Under these conditions, the
cyclic voltammogram of compound 1r ed (2 mM), in de-
aerated MeOH containing an excess of aminomethylcy-
clohexane (40 mM), at a dropping mercury electrode,
showed an oxidation peak Pa due to a diffusion-controlled
two-electron process at -50 mV vs SCE, the sweep rate
being 0.5 V s-1. As can be seen in Figure 1, a cathodic
peak Pc appeared on the reverse sweep at -150 mV vs
SCE, illustrating the partial reversibility of the two-
electron transfer that could be assigned to the 3,4-
aminophenol 1r ed /3,4-iminoquinone 1ox redox couple.
However, the redox potential E′° could not be accurately
evaluated under our experimental conditions, as the
system (Pa, Pc) did not fulfill all the diagnostic criteria
required for a reversible process, at least when v was
e500 V s-1: the ratio of the height of Pa over that of Pc
Scop e of th e 1ox-Med ia ted Ca sca d e Rea ction s.
With the reliable set of conditions in hand, we probed
the generality of the IEDDA reaction with a variety of
electrogenerated enamines. Table 2 shows some examples
of the molecular diversity that is accessible through this
reaction which is an inverse-electron-demand controlled
Diels-Alder reaction between the electron-poor o-aza-
quinone heterodiene and the electron-rich enamine di-
(8) (a) Heine, H. W.; Barchiesi, B. J .; Williams, E. A. J . Org. Chem.
1984, 49, 2560. (b) Heine, H. W.; La Porte, M. G.; Overbaugh, R. H.;
Williams, E. A. Heterocycles 1995, 40, 743 and references therein. (c)
Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. Angew. Chem., Int. Ed. 2000,
39, 622. (d) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y. L.
Angew. Chem., Int. Ed. 2001, 40, 207. (e) Nicolaou, K. C.; Baran, P.
S.; Zhong, Y. L.; Sugita, K. J . Am. Chem. Soc. 2002, 124, 2212. (f)
Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y. L. J . Am. Chem.
Soc. 2002, 124, 2221.
(9) (a) Nicolaides, D. N.; Awad, R. W.; Varella, E. A. J . Heterocycl.
Chem. 1996, 33, 633. (b) Nicolaides, D. N.; Bezergiannidou-Balouctsi,
C.; Awad, R. W.; Litinas, K. E.; Malanidou-Xenikaki, E.; Terzis, A.;
Raptopoulou, C. P. J . Org. Chem. 1997, 62, 499 and references therein.
(10) For a similar behavior, see: J uhl, K.; J orgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 1498.
J . Org. Chem, Vol. 69, No. 3, 2004 883

Blattes et al.
TABLE 1. Op tim iza tion of th e 1ox-Med ia ted Ca sca d e Rea ction
supporting
electrolytea
initial concn
of 1r ed (mM)
aminomethyl
cyclohexane (mM)
entry
anode
solvent
nb
yieldc (%)
1
2
3
4
5
6
7
8
9
Hg
Hg
Hg
Hg
Hg
Hg
Hg
Hg
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCNe
MeOH
MeOH
TEAP
TEAP
TEAP
TEAP
TEAP
LiClO4
TEATFB
TEAP
2.0
2.0
2.0
1.0
0.5
2.0
2.0
2.0
2.0
2.0
20.0
40.0
100.0
40.0
40.0
40.0
40.0
40.0
40.0
40.0
11
16
17
14
15
12
15
15
25
15
66
77
51
68
52
76
56
10
47
10
d
Pt
Carbon
TEAP
TEAP
10
a
b
TEAP ) tetraethylammonium perchlorate, TEATFB ) tetraethylammonium tetrafluoroborate, rt, 8h. Total number of electrons
transferred per molecule of 1ox.
c Yields refer to chromatographically pure isolated products. TEAP is preferred over LiClO4, due to the
d
potentially explosive hazard character of the latter. e MeCN is not a suitable solvent probably because strong solvation of methanol to the
azaquinone 1ox may be required to enhance the electrophilicity of the quinonoid moiety of 1ox, making it capable of participating in
IEDDA reaction.
heterodiene system 1ox (Scheme 2). Accordingly, alkylen-
amines with a pronounced electron-rich character led to
the formation of the expected cycloadduct in high yields
(Table 2, entries 1-4), whereas the enamine that bore
phenyl substituents resulted in somewhat lower yield
(Table 2, entry 5).
Interestingly, when we used a cyclic alkylenamine
generated from the 1ox-mediated catalytic oxidation of
2-methylcyclohexylamine, we found that the cascade
sequence led to heterocyclic annulation in a diastereospe-
cific manner, as established on the basis of NOE experi-
ments (see the Experimental Section). Nevertheless, the
5a-alkylaminophenoxazine 7a was isolated in modest
yield (25%) for two reasons. First, it was easily hydro-
lyzed by silica gel to afford the hemiacetal byproduct 7b
in 15% yield (Table 2, entry 6). Second, the concomitant
formation of the less substituted cyclic alkylenamine
isomer, which could not be avoided,11 did not afford the
F IGURE 1. Cyclic voltammogram of 1r ed (2 mM) at a dropping
mercury electrode in deaerated MeOH containing tetraethyl-
corresponding phenoxazine derivative. This was sup-
ammonium perchlorate (20 mM) and aminomethylcyclohexane
ported by the attempt to react cyclohexylamine, where
(40 mM). Arrowheads indicate the direction of the potential
no product was formed.
sweep; v ) 0.5 V s-1. The vertical arrow indicates the initial
potential point.
In the specific case of ring-substituted phenylethyl-
amines as the amine starting material, the catalytic
process ceased rapidly (two to five turnovers), while a
yellow solid precipitated in the electrolysis solution. This
was collected by filtration and identified as a 2-alkyl-
amino-1,4-benzoxazine derivative. As described above,
the electrogenerated 3,4-azaquinone 1ox was trapped
through [4 + 2] cycloaddition with alkylenamines, leading
to unstable aryl-2H-3,4-dihydro-1,4-benzoxazine inter-
mediates (Scheme 3, step 1). However, these compounds
could be isolated as stable products 8-13 in yields
ranging from 58 to 76% (Table 4, entries 1-6), after a
SCHEME 2. Regiosp ecific IEDDA Rea ction of
En a m in e Dien op h ile w ith o-Aza qu in on e Dien e 1ox
Electr ogen er a ted Sim u lta n eou sly, To Give
P olyfu n ction a lized 1,4-Ben zoxa zin e Der iva tives
,
(11) The preparation of enamines from unsymmetrically ketones
gives rise to the formation of two regiochemically distinct isomers
whose the ratio depends on the relative reactivity of the two enamines.
As a general rule, the more substituted the enamine, the slower it
undergoes reaction. (a) Gurowitz, W. D.; J oseph, M. A. J . Am. Chem.
Soc. 1967, 3289. (b) Whitesell, J . K.; Whitesell, M. A. Synthesis 1983,
517 and references therein.
enophile. This uncatalyzed cycloaddition reaction occurs
at room temperature, within 8-10 h, with complete
regiospecificity. The more electron-rich carbon atom of
the enamine dienophile adds to the nitrogen atom of the
884 J . Org. Chem., Vol. 69, No. 3, 2004

Simultaneously Electrogenerated Partners for [4 + 2] Cycloadditions
TABLE 2. [4 + 2] Cycloa d d ition Rea ction of Sim u lta n eou sly Electr ogen er a ted O-a za qu in on e Dien e 1ox a n d En a m in e
Dien op h ilea
a
b
Reagents and conditions: (1r ed ) ) 2 mM, (amine) ) 40 mM, MeOH, rt, Hg anode (E ) +50 mV vs SCE), 8-10 h. Yields refer to
chromatographically pure isolated products. c Obtained as a mixture of two unassigned diastereoisomers (ca. 1:1 ratio). A cis-trans
mixture of 2-methylcyclohexylamine was used as the starting amine, so that two diastereoisomers were isolated which differed by the
position (axial or equatorial) of the methyl group on the 5a-alkylamino side chain.
d
subsequent two-electron oxidation step (Scheme 3, step
2). Note that the yield of the benzoxazine derivative 14
decreased to 20% when a methoxy group was introduced
in ortho position of the phenyl ring, probably for steric
reasons (Table 4, entry 7).
we attempted to generate enamines in which the sub-
stituents on the amino group were different from those
linked to the double bond. For this purpose, the amine
(12) For examples, see: (a) Danishefsky, S. J .; Cavanaugh, R. J . J .
Org. Chem. 1968, 33, 2959 and references therein. (b) South, M. S.;
Terri, L.; J akuboski, M. D.; Westmeyer, M. D.; Dukersherer, D. R. J .
Org. Chem. 1996, 61, 8921. (c) Koyama, J .; Toyokuni, I.; Tagahara, K.
Chem. Pharm. Bull. 1998, 46, 332. (d) Boruah, R. C.; Ahmed, S.;
Sharma, U.; Sandhu, J . S. J . Org. Chem. 2000, 65, 922. (e) J ones, R.
M.; Selenski, C.; Pettus, T. R. R. J . Org. Chem. 2002, 67, 6911. (f)
Kozhevnikov, V. N.; Kozhevnikov, D. N.; Nikitina, T. V.; Rusinov, V.
L.; Chupakhin, O. N.; Zabel, M.; Ko¨nig, B. J . Org. Chem. 2003, 68,
2882. (g) Soenen, D. R.; Zimpleman, J . M.; Boger, D. L. J . Org. Chem.
2003, 68, 3593. (h) Bodwell, G. J .; Hawco, K. M.; Satou, T. Synlett 2003,
6, 879 and references therein.
(13) To the best of our knowledge, only two syntheses of 1,4-
benzoxazine derivatives bearing either a 2-imidazoline or a 3-ami-
nomethyl substituent have been reported until now: (a) Touzeau, F.;
Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer, B.; Rettori, M.-C.;
Renard, P.; Me´rou, J .-Y. J . Med. Chem. 2003, 46, 1962 and references
therein. (b) Banzatti, C.; Heidempergher, F.; Melloni, P. J . Heterocycl.
Chem. 1983, 20, 259.
All the above results showed that, under our experi-
mental conditions, no subsequent elimination of the
alkylamino chain was observed, in contrast to what has
been previously reported for similar cycloaddition reac-
tions of enamines with heterodienes.12 This feature is of
synthetic interest since the multistep one-pot electro-
chemical procedure we describe represents the first
synthesis of 1,4-benzoxazine derivatives that bear alkyl-
amino substituents on the oxazine ring.13
Ca ta lytic Oxid a tion of Am in e R1R2CHCH2NH2
Med ia ted by th e 3,4-Aza qu in on e 1ox in th e P r esen ce
of a Secon d Am in e R3NH2. In a second series of
experiments aimed at increasing the molecular diversity,
J . Org. Chem, Vol. 69, No. 3, 2004 885

Blattes et al.
TABLE 3. Hyd r olysisa of 2-Alk yla m in oben zoxa zin es 2a -6a to 2-Hyd r oxyben zoxa zin es 2b-6b
a
b
Reactions were carried out on a 2 mM solution of substrate in solvent/acid (ca. 70/30 ratio). Yields refer to chromatographically
pure isolated products. c 30% of the recovered substrate were obtained also.
SCHEME 3.
1ox-Med ia ted Ca sca d e Sequ en ce
Lea d in g to 2-Alk yla m in o-1,4-ben zoxa zin e
Der iva tives 8-14
F IGURE 2. Spectrophotometric changes accompanying the
electrochemical oxidation of 1r ed (2 mM) at a mercury pool (E
) +50 mV vs SCE), in deaerated MeOH containing tetraethyl-
ammonium perchlorate (20 mM) and aminomethylcyclohexane
(40 mM): (a) 0 (before electrolysis); (b) 6; (c) 10; (d) 12; (e) 16
mol of electrons. Cell thickness, 0.1 cm.
except when prevented by steric hindrance (Table 5,
entries 1-8). Concerning the low yield of the 1,4-
benzoxazine derivative 23 (Table 5, entry 9), it was due
to the concomitant formation of another enamine which
afforded the unwanted benzoxazine 6a (Table 2, entry
5) as the major product.
Another limitation of our electrochemical procedure
that uses both in situ generated diene and dienophile was
illustrated by the catalytic oxidation of a primary amine
R1R2CHCH2NH2 mediated by the o-azaquinone 1ox in the
presence of a secondary amine R3NHR4, which failed to
produce the expected tertiary alkylenamine, whereas the
secondary alkylenamine continued to be generated lead-
R1R2CHCH2NH2 was catalytically oxidized by o-aza-
quinone 1ox in the presence of a second primary aliphatic
amine R3NH2. Table 5 gives some examples of 1,4-
benzoxazine derivatives produced in this way. Efforts
were made to optimize the yield of benzoxazines and led
to the conclusion that the optimum conditions required
roughly equimolar quantities of both reacting amines.
However, the choice of amines proved to be important
for the outcome of the reaction which was affected by
steric and electronic effects exerted by the substituents
R1, R2, and R3: the most nucleophilic amine was oxidized,
886 J . Org. Chem., Vol. 69, No. 3, 2004

Simultaneously Electrogenerated Partners for [4 + 2] Cycloadditions
TABLE 4.
1
ox-Med ia ted Ca sca d e Sequ en ce Affor d in g 2-Alk yla m in o-1,4-ben zoxa zin e Der iva tives 8-14a
a
b
Reagents and conditions: (1r ed ) ) 2 mM, (amine) ) 40 mM, MeOH, rt, Hg anode (E ) +50 mV vs SCE), 6-8 h. Yields refer to
chromatographically pure isolated products.
ing to the benzoxazine derivatives reported in Table 2.
Therefore, to avoid these limitations, we envisioned some
modifications of the aforementioned procedure.
electrogenerated o-azaquinone 1ox was examined. Our
initial attempts to prepare the expected 2-alkylamino-
1,4-benzoxazine derivatives were disappointing, leading
to low yields of the desired products. We attributed these
results to the instability of both 3,4-azaquinone 1ox and
secondary enamines which prohibited their efficient use
in IEDDA reactions. So, to circumvent this problem,
compound 1r ed was added by small portions to the
electrolysis solution, which contained the separately
prepared enamine. In the meantime, the anodic potential
was maintained at +50 mV vs SCE (see the Experimental
Section). Thus, the continuously low concentration of the
electrogenerated o-azaquinone 1ox, together with the
large excess of enamine, should promote the cycloaddition
reaction at the expense of the dimerization, or polymer-
Cycloa d d ition Rea ction of th e Electr ogen er a ted
Aza qu in on e 1ox w ith a Sep a r a tely P r ep a r ed En a m -
in e. To extend the scope of the reaction, we focused on
the [4 + 2] cycloaddition of a separately prepared
enamine with the electrogenerated 3,4-azaquinone 1ox
.
Thus, the cycloaddition would no longer be limited to the
enamine part that originates from the more nucleophilic
amine and it could be performed with tertiary alkylen-
amines. To explore this novel prospect, a series of sec-
ondary and tertiary enamines was synthesized by con-
densation of the appropriate aldehyde (or ketone) and
amine. Then, their reactivity in IEDDA reactions with
J . Org. Chem, Vol. 69, No. 3, 2004 887

Blattes et al.
a
TABLE 5.
1
ox-Med ia ted Oxid a tion of Am in e R1R2CHCH2NH2 in th e P r esen ce of a Secon d Am in e R3NH2
a
Reagents and conditions: (1r ed ) ) 2 mM, (R1R2CHCH2NH2) ) (R3NH2) ) 20 mM, MeOH, rt, Hg anode (E ) +50 mV vs SCE), 8-10
b
h. Yields refer to chromatographically pure isolated products. c Obtained as a mixture of two unassigned diastereoisomers (ca. 1:1 ratio).
d
Besides benzoxazines 20, 21, 22, and 23, benzoxazines 4a , 5a , 2a , and 6a were isolated as byproducts, in yields of 5, 10, 20, and 40%,
respectively, as a consequence of the concomitant production of another unwanted enamine.
ization, of both cycloaddition partners. As shown in Table
6 (entry 1), the reaction proved to be efficient since the
yield of the benzoxazine derivative 23 was markedly
improved (55%), when compared to that of the aforemen-
tioned electrochemical procedure (5%) (Table 5, entry 9).
Similarly, the desired products 24-26 could be isolated
within 4 h, in yields ranging from 45 to 61% (Table 6,
entries 2-4).
As confirmed by NMR experiments, condensation of
2-methylcyclohexanone and appropriate amine produced
the corresponding imine, which tautomerized to enamine
in the course of the anodic electrolysis, yielding two
regiochemically distinct isomers. As already reported, the
most substituted enamine and the electrogenerated o-
azaquinone 1ox cyclized with complete diastereospecificity
to give the 2-alkylamino-1,4-benzoxazine derivatives 27
and 28 in 25% yield (Table 6, entries 5 and 6).
Despite its aromaticity, commercially available 2,3-
dihydro-1H-cyclopent[b]indole with latent enamine func-
tionality participated in the IEDDA reaction with the
electrogenerated o-azaquinone diene 1ox affording the
expected indolobenzoxazine ring system 29 in 16% yield
(Table 6, entry 7).14
As for the secondary enamines (Table 2), tertiary
alkylenamines with a pronounced electron-rich character
led to the formation of the expected cycloadduct in high
yields (Table 6, entries 8-10), whereas introduction of
phenyl substituents resulted in lower yields (Table 6,
entries 12 and 13). Surprisingly, with 1-piperidino-2-
methyl-1-propene (Table 6, entry 11), the yield of the
888 J . Org. Chem., Vol. 69, No. 3, 2004

Simultaneously Electrogenerated Partners for [4 + 2] Cycloadditions
TABLE 6. [4 + 2] Cycloa d d ition Rea ction of th e Electr ogen er a ted o-Aza qu in on e Dien e 1ox a n d Sep a r a tely P r ep a r ed
En a m in e Dien op h ilea
a
Reagents and conditions: (1r ed ) ) 2 mM, (enamine) ) 6-10 mM, MeOH, rt, Hg anode (E ) +50 mV vs SCE), 4 h; 1 equiv of amine
engaged in the synthesis of the enamine was added to the bulk solution for producing the monoanionic species of 1r ed , which is the sole
form that can be oxidized to 1ox
7b was isolated as the byproduct in roughly 10% yield. 1 equiv of tert-butylamine was added to the bulk solution for producing the
b
.
Yields refer to chromatographically pure isolated products. c Besides benzoxazines 27 and 28, hemiacetal
d
monoanionic species of 1r ed
.
desired cycloadduct 33 was found to be low (26%). This
result presumably reflected the particular instability of
the alkylenamine in the course of the anodic electrolysis.
strated its synthetic utility for the construction of poly-
functionalized 1,4-benzoxazine derivatives. The reactions
are regiospecific and diastereospecific in the case of
heterocyclic annulation. The electrochemical procedure,
wherein both cycloaddition partners are generated in
situ, allows the systematic study of the IEDDA reaction
of an o-iminoquinone and a secondary alkylenamine, two
chemically non accessible unstable materials.11b,15 The
methodology that uses a separately prepared secondary
or tertiary enamine nicely completes the initial electro-
chemical procedure in terms of increasing the molecular
diversity. Interestingly, the reactions can be conducted
at room temperature, under metal-free conditions. The
extension of this cascade reaction should be useful to
Con clu sion
In this paper, we have described a cascade transforma-
tion traversing through an o-iminoquinone and demon-
(14) Indole has often served as a dienophile, especially for intramo-
lecular IEDDA reaction. For a review, see: (a) Lee, L.; Snyder, J . K.
Adv. Cycloaddit. 1999, 6, 119. For very close examples using indoles,
see: (b) Omote, Y.; Tomotake, A.; Kashima, C. Tetrahedron Lett. 1984,
25, 2993. (c) Omote, Y.; Harada, K.; Tomotake, A.; Kashima, C. J . Het-
erocycl. Chem. 1984, 21, 1841. (d) Black, D. St C.; Craig, D. C.; Heine,
H. W.; Kumar, N.; Williams, E. A. Tetrahedron Lett. 1987, 28, 6691.
J . Org. Chem, Vol. 69, No. 3, 2004 889

Blattes et al.
occurred leading to a 2/3 vs 1/3 mixture of diastereoisomers,
as already reported for similar derivatives.19 The NOE effect
was no more observed with the minor isomer: H NMR (500
MHz, CDCl3) δ 1.20 (s, 3H), 1.45-2.12 (m, 8H), 4.23 (s, 1H),
4.30 (s, 1H), 6.45 (d, J ) 9 Hz, 1H), 7.10 (d, J ) 9 Hz, 1H),
7.50 (m, 3H), 7.67 (d, J ) 7 Hz, 2H), 12.81 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.6, 22.0, 22.9, 30.8, 35.6, 53.9, 99.8,
109.4, 113.6, 120.7, 125.8, 128.7, 129.4, 132.0, 138.7, 148.1,
153.3, 201.2.
generate libraries of heterocycles which constitute the
molecular framework of medicinally relevant compounds.
Finally, as a result of their structural similarity with a
series of topologically different 1,4-benzoxazine deriva-
tives reported earlier,16 the biological evaluation of these
new benzoxazine derivatives as neuroprotective agents
is currently in progress and will be reported elsewhere.
1
[(R,S)-5-Hydr oxy-3-ph en yl-2-ph en yleth ylam in o-2H-1,4-
ben zoxa zin -6-yl](p h en yl)m eth a n on e 8. 3,4-Aminophenol
1r ed (114.5 mg, 0.5 mmol) and phenylethylamine (1.3 mL, 10
mmol) were added to a 0.02 M solution of TEAP (1.15 g, 5
mmol) in MeOH (250 mL). The resulting solution was then
oxidized under nitrogen, at room temperature, at a mercury
pool whose potential was fixed at +50 mV vs SCE (initial
current 45 mA). After exhaustive electrolysis (6 h, n ) 10),
the electrolysis solution was concentrated until the 1,4-
benzoxazine derivative precipitates in full. Then, the yellow
solid was collected by filtration, washed with small fractions
of MeOH, and dried in a vacuum desiccator (130 mg, 0.29
mmol, 58% yield): mp 193-195 °C; 1H NMR (300 MHz, CDCl3)
δ 2.35 (m, 1H), 2.85 (m, 2H), 3.20 (m, 1H), 3.28 (m, 1H), 5.95
(d, J ) 11 Hz, 1H), 6.58 (d, J ) 9 Hz, 1H), 7.15 (d, J ) 7 Hz,
2H), 7.25 (m, 3H), 7.40-7.60 (m, 7H), 7.70 (d, J ) 7 Hz, 2H),
8.00 (d, J ) 7 Hz, 2H), 13.10 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 37.2, 46.6, 81.8, 108.8, 114.7, 123.1, 126.8, 127.9, 128.8, 128.9,
129.0, 129.2, 129.5, 131.4, 132.2, 134.2, 135.6, 138.6, 139.7,
151.4, 155.4, 161.1, 200.9; MS DCI m/z 449 (MH+). Anal. Calcd
for C29H24N2O3: C, 77.68; H, 5.36; N, 6.25. Found: C, 77.59;
H, 5.46; N, 6.24.
[(R,S)-2-(2,2-Dim eth oxy)eth yla m in o-3,3-d ip h en yl-5-h y-
d r oxy-3,4-d ih yd r o-2H-1,4-ben zoxa zin -6-yl](p h en yl)m eth -
a n on e 23. Freshly distilled enamine (425 mg, 1.5 mmol) was
dissolved in methanol (250 mL) that contained TEAP (1.15 g,
5 mmol), along with 2,2-dimethoxyethylamine (55 µL, 0.5
mmol). The addition of the latter was necessary to produce
the monoanionic species of 1r ed , which was the sole form that
can be oxidized to o-azaquinone 1ox. Then, 3,4-aminophenol
1r ed (114.5 mg, 0.5 mmol) was added by small portions (22.9
mg, 0.1 mmol) to the solution which was oxidized at a mercury
pool whose potential was fixed at +50 mV vs SCE, under
nitrogen, at room temperature. After exhaustive electrolysis
(4 h, n)2), the solvent was removed under reduced pressure.
The brown oil residue was then poured into diethyl ether (20
mL). Insoluble TEAP was filtered off and the filtrate was
evaporated under reduced pressure, at 30 °C. Flash chroma-
tography of the residue on silica gel with toluene/acetone 98/2
v/v as the eluent afforded the expected 1,4-benzoxazine 23 in
55% yield (140 mg, 0.274 mmol) as a yellow solid which was
recrystallized from ether: mp 154-156 °C; 1H NMR (300 MHz,
CDCl3) δ 2.45 (m, 1H), 2.95 (m, 2H), 3.30 (s, 3H), 3.35 (s, 1H),
4.30 (t, J ) 6 Hz, 1H), 5.20 (s, 1H), 5.80 (d, J ) 11 Hz, 1H),
6.35 (d, J ) 9 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.10-7.55 (m,
13H), 7.70 (d, J ) 8 Hz, 2H), 12.85 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 46.9, 53.4, 54.0, 62.3, 89.4, 104.1, 108.7, 112.7, 120.7,
124.5, 126.6, 126.8, 127.0, 128.0, 128.1, 128.3, 128.8, 131.2,
138.3, 143.0, 144.1, 147.0, 152.3, 201.5; MS DCI m/z 511
(MH+). Anal. Calcd for C31H30N2O5: C, 72.94; H, 5.88; N, 5.49.
Found: C, 72.87; H, 5.95; N, 5.47.
Exp er im en ta l Section
Chemicals were commercial products of the highest avail-
able purity and were used as supplied. Reduced catalyst 1r ed
was synthesized as previously reported.17 All apparatus, cells,
and electrodes were identical with those described previously.18
[(R,S)-2-Cycloh exylm eth yla m in o-5-h yd r oxy-3-sp ir o-1′-
cycloh exyl-3,4-d ih yd r o-2H-1,4-ben zoxa zin -6-yl](p h en yl)-
m eth a n on e 2a . 3,4-Aminophenol 1r ed (114.5 mg, 0.5 mmol)
and aminomethylcyclohexane (1.3 mL, 10 mmol) were added
to a 0.02 M solution of tetraethylammonium perchlorate
(TEAP) (1.15 g, 5 mmol) as the supporting electrolyte in MeOH
(250 mL). The resulting solution was then oxidized under
nitrogen, at room temperature, at a mercury pool whose
potential was fixed at +50 mV vs SCE (initial current 50 mA).
After exhaustive electrolysis (8 h, n ) 16), that is, when a
negligible current was recorded (1 mA), the solution was
neutralized with dry ice and the solvent was removed under
reduced pressure. The brown oil residue was then poured into
diethyl ether (20 mL). Insoluble TEAP was filtered off, and
the filtrate was evaporated under reduced pressure at 30 °C.
Flash chromatography of the residue on silica gel with toluene
as the eluent afforded the expected 1,4-benzoxazine 2a in 77%
yield (167 mg, 0.385 mmol) as a yellow solid which was
recrystallized from pentane/ether (60/40): mp 129-131 °C; 1H
NMR (300 MHz, CDCl3) δ 0.85-1.80 (m, 21H), 1.95 (s, 1H),
2.55 (m, 1H), 2.75 (m, 1H), 4.30 (s, 1H), 4.75 (s, 1H), 6.35 (d,
J ) 9 Hz, 1H), 7.00 (d, J ) 9 Hz, 1H), 7.50 (m, 3H), 7.70 (d, J
) 8 Hz, 2H), 12.75 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 21.2,
21.4, 25.5, 26.0, 26.6, 31.2, 33.2, 33.5, 38.5, 51.6, 51.9, 91.8,
108.7, 112.6, 120.6, 123.8, 128.0, 128.8, 131.1, 138.5, 147.2,
152.1, 203.0; MS DCI m/z 435 (MH+). Anal. Calcd for
C
27H34N2O3: C, 74.65; H, 7.83; N, 6.45. Found: C, 74.56; H,
8.11; N, 6.42.
[(5a R ,9a S )-1,5a -Dih yd r oxy-9a -m e t h yl-6,7,8,9,9a ,10-
h exa h yd r o-5a H-p h en oxa zin -2-yl](p h en yl)m eth a n on e 7b.
Isolated as a single diastereoisomer with cis configuration:
yellow solid recrystallized in ether; mp ) 192-194 °C; 1H NMR
(500 MHz, CDCl3) δ 1.40 (s, 3H), 1.45-1.90 (m, 7H), 2.12 (d,
J ) 14.5 Hz, 1H), 3.54 (s, 1H), 4.02 (s, 1H), 6.43 (d, J ) 9 Hz,
1H), 7.02 (d, J ) 9 Hz, 1H), 7.50 (m, 3H), 7.67 (d, J ) 7 Hz,
2H), 12.72 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.6, 22.0,
22.8, 33.2, 35.1, 53.9, 99.3, 108.8, 113.5, 120.1, 124.5, 128.7,
129.4, 131.9, 138.8, 147.2, 152.5, 201.2; MS DCI m/z 340
(MH+). Anal. Calcd for C20H21NO4: C, 70.79; H, 6.19; N, 4.13.
Found: C, 70.54; H, 6.41; N, 4.14. The cis junction of the
bicyclic system was established on the basis of NOE experi-
ments (mixing time: 250 ms): a NOE effect was observed
between the 9a-angular methyl substituent (1.40 ppm) and
the 5a-hydroxy group (3.54 ppm). The stereochemical assign-
ment was confirmed when the hemiacetal cycloadduct 7b was
exposed for 48h in CDCl3; then, a cis-trans equilibrium
Ack n ow led gm en t. We thank the Servier Co. for
financial support of this research.
(15) It is known that secondary alkylenamines are thermodynami-
cally unstable at room temperature and that the imino form is the
sole detectable species; see: B. De J eso, J .-C. Pommier J . Chem. Soc.,
Chem. Commun. 1977, 565 and references therein.
(16) (a) Largeron, M.; Lockhart, B.; Pfeiffer, B.; Fleury, M.-B. J . Med.
Chem. 1999, 42, 5043. (b) Largeron, M.; Mesples, P.; Gressens, P.;
Cechelli, R.; Spedding, M.; Le Ridant, A.; Fleury, M.-B. Eur. J .
Pharmacol. 2001, 424, 189.
(17) Larget, R.; Lockhart, B.; Pfeiffer, B.; Neudorffer, A.; Fleury, M.-
B.; Largeron, M. Bioorg. Med. Chem. Lett. 1999, 9, 2929.
(18) Largeron, M.; Neudorffer, A.; Fleury, M.-B. J . Chem. Soc.,
Perkin Trans. 2 1998, 2721.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal methods, H/13C NMR and MS spectral data, CHN analy-
ses, and melting points for substituted benzoxazine derivatives
2b-7a , 9-22, and 24-35. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O035614B
(19) (a) Levine, S. G.; Gragg, C.; Bordner, J . J . Org. Chem. 1976,
41, 4026. (b) Herzig, C.; Gasteiger, J . Chem. Ber. 1981, 114, 2348.
890 J . Org. Chem., Vol. 69, No. 3, 2004