Reactivity of 5-hydroxy-5,6-dihydro-4H-pyrazines-easy and efficient access to ring-fused polycyclic diazinic systems

Article abstract of DOI:10.1016/j.tetlet.2009.03.152

An efficient synthesis of functionalized 1,4-diazinic hemiaminals starting from methyl-4H-1,4-oxazine-3-carboxylate moiety is reported. Given that various polycyclic heterocyclic frameworks could be easily obtained, this strategy may provide an efficient

Full text of DOI:10.1016/j.tetlet.2009.03.152

Tetrahedron Letters 50 (2009) 3679–3682
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivity of 5-hydroxy-5,6-dihydro-4H-pyrazines—easy and efficient access
to ring-fused polycyclic diazinic systems
*
*
Elise Claveau, Isabelle Gillaizeau , Gérard Coudert
ICOA, UMR CNRS 6005, Université d’Orléans, 45067 Orléans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of functionalized 1,4-diazinic hemiaminals starting from methyl-4H-1,4-oxazine-3-
carboxylate moiety is reported. Given that various polycyclic heterocyclic frameworks could be easily
obtained, this strategy may provide an efficient method to access a library of compounds based on priv-
ileged substructures that are of interest in drug discovery.
Received 9 February 2009
Revised 17 March 2009
Accepted 20 March 2009
Available online 26 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazine
Oxazine
1,4-Diazine
MICHAEL addition
Indole alkaloids
Identifying improved methods for heterocycles synthesis and,
essentially, giving access to new heterocyclic scaffolds are of prime
importance. Accordingly, a wide range of target-directed and
diversity-oriented synthesis activities are devoted to the prepara-
tion of those frameworks.1 In connection with our efforts to devel-
op synthetic routes to nitrogen-containing heterocyclic derivatives
and particularly six-membered ones, we intended to prepare 1,4-
oxazine or 1,4-dihydropyrazine (Fig. 1), and various substituted
derivatives of this kind.2
In some previous work, we reported an efficient method entail-
ing a Michael/retro-Michael reaction which allowed the synthesis
of original 1,4-diazine derivatives 2 (Scheme 1).2g In fact, starting
from methyl-4H-1,4-oxazine-3-carboxylate 12c and in the presence
of primary aliphatic amines, a range of original 1,4-diazinic hemia-
minals 2 were easily isolated in fair to good yields.
introducing molecular diversity into molecules as a result of the
original choice of the starting nucleophile.
The synthesis of the requisite precursors is illustrated in Table 1.
Reaction onto
a,b-unsaturated methyl ester 1 of primary amine
bearing pendent aryl or heteroaryl substituents provided the origi-
nal desired hemiaminals 2a–d in fair to very good yields. As
previously reported,2g the formation of the latter occurred via a
Michael/retro-Michael reaction.
PG
R2
R1
O
R3
R4
R3
R4
R2
R1
N
N
N
PG
PG
1,4-oxazine
1,4-dihydropyrazine
In this paper, we want to highlight the potential of our method
as a synthesizing tool and to explore its scope by taking advantage
of the potential alkyl iminium ion intermediate A (Scheme 2). The
latter does constitute an enabling tool for intermolecular or intra-
molecular reactions that might afford efficient and versatile access
to various substituted 1,4,5,6-tetrahydropyrazines B or C.
Herein, we describe an efficient strategy for the synthesis of
functionalized 1,4-diazinic hemiaminals and its successful applica-
tion to ease the construction of tri- or tetracyclic cores. Direct pre-
cursors or analogs of natural products could then be targeted, and
in addition the method offers the potential advantage of directly
R1, R4 = aryl, heteroaryl, alkenyl, alkynyl, acyl, alkyl, hydroxyalkyl
R2, R3 = alkyl, allyl, hydroxyalkyl
Figure 1. Original 1,4-oxazine or dihydropyrazine derivatives.
R
O
HO
N
RNH2 (1 equiv)
K2CO3 (6 equiv) / CH3CN
N
COOMe
N
COOMe
RT (6h-5d)
(26-100 %)
Boc
1
Boc
R = Alkyl, propargyl
2
* Corresponding authors. Tel.: +33 2 38 49 45 83; fax: +33 2 38 41 72 81 (I.G.).
E-mail address: isabelle.gillaizeau@univ-orleans.fr (I. Gillaizeau).
Scheme 1. Access to diazinic hemiaminals 2.2g
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.152

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E. Claveau et al. / Tetrahedron Letters 50 (2009) 3679–3682
R'
N
also observed to give unprotected unstable aminonitrile 3c quanti-
tatively isolated. Using this versatile intermediate and via the ami-
nonitrile chemistry, a wide range of synthetic applications could be
envisaged.5
Nu
Nu-
R'
N
R'
N+
N
COOMe
HO
Given these results, our intent, therefore, was turned to synthe-
size ring-fused aminal structures such as 4 in a one-pot procedure
(Scheme 3). In fact, according to the above-described conditions
and starting from unsaturated methyl ester 1, 2-aminobenzylamine
was selected. As first anticipated, the nucleophilic addition of the
primary aliphatic amine function afforded the non-isolated hemia-
minal intermediate. Then addition of BF3ÁEt2O into the crude mix-
ture induced an intramolecular nucleophilic addition of the
pendent primary aromatic amine functionality to the iminium ion
intermediate. Thus, the ring-fused aminal derivative 4 was isolated
in a one-pot procedure from oxazinic methyl ester 1 in high yield
(78%). This strategy provides convenient access to a structural motif,
which is present in many quinazoline alkaloids6 (Fig. 2, i.e. fiscalin
B7). It is worth noting that in each case, the newly formed diazinic
derivative may be further decorated by subsequent nucleophilic
addition onto the remaining unsaturated methyl ester function.
Next, we intended to examine the ability of hemiaminals 2b, 2c,
and 2d to undergo an intramolecular electrophilic cyclization reac-
tion (Table 3). Accordingly, treatment of the azaindole derivative
2b with trifluoroacetic acid in CH2Cl2 at room temperature for
Boc
B
N
COOMe
N
COOMe
N
Boc
Boc
2
A
N
COOMe
Boc
C
Scheme 2.
Having easy access to benzylic hemiaminal 2a, we next exam-
ined the reactivity of the iminium ion intermediate (Scheme 2,
A), generated under acidic conditions, toward nucleophilic addi-
tion4 (Table 2). In the presence of BF3ÁEt2O at room temperature
in dichloromethane, primary and secondary amines were success-
fully tested. Functionalized and stable diazinic derivatives 3a and
3b were thus isolated in good yields. By using TMSCN2g as a nucle-
ophile, the attempted addition quickly occurred (Table 2, entry 3).
However, in this case, concomitant removal of the Boc group was
Table 1
Preparation of diazinic hemiaminal derivatives 2a–d
R
O
HO
N
RNH2 (1 equiv)
N
COOMe
K2CO3 (6 equiv) / CH3CN
RT (5h-22h)
N
COOMe
Boc
1
Boc
2
Entry
Reagents
Time (h)
Productsb (yield %)
Ph
HO
N
1
PhCH2NH2
22
2a (100%)
N
COOMe
Boc
OMe
OMe
N
N
2a,c
5
2b (31%)
HO
N
N
H
NH2
N
N
COOMe
H
Boc
HO
HO
N
N
H
3
17
20
2c (95%)
NH2
H2N
N
N
COOMe
H
Boc
OMe
OMe
OMe
OMe
N
4
2d (100%)
N
COOMe
Boc
a
Reaction performed at 80 °C.
Isolated yield.
See Ref. 3
b
c

E. Claveau et al. / Tetrahedron Letters 50 (2009) 3679–3682
3681
Table 2
Me
HN
Me
N
OMe
MeO
MeO
Nucleophilic addition on benzylic hemiaminal 2a
N
Ph
Ph
N
O
H
N
N
HO
N
N
Nu
N
N
Nu-
O
H
H
H
N
BF3.Et2O
CH2Cl2, RT
H
COOMe
COOMe
HN
OMe
MeOOC
Boc
Boc
2a
3
OMe
Entry
Reagents
Time
Productsa (yield %)
OH
cephaelin
fiscalin B
mitragynine
Ph
H
Figure 2. Structure of some representative alkaloids.
N
N
Ph
O
1
PhCH2NH2
24 h
3a (80%)
N
COOMe
NH2
Boc
1)
Ph
(2 equiv)
NH2
O
N
CH3CN, RT, 6d
N
N
N
HN
N
2
26 h
3b (61%)
O
NH
COOMe
2) BF3.Et2O (1.5 equiv),
CH3CN, RT, 2h30
(78%)
Boc
COOMe
N
COOMe
1
4
Boc
Boc
Ph
Scheme 3. One-pot access from 1 to ring-fused aminal diazinic derivative 4.
NC
N
3
TMSCN
30 min
3c2g (100%)
2 h afforded the desired tetracyclic system 5a in quantitative yield.
Building on our novel efficient approach to diazinic hemiaminal
ring system, rapid and efficient access to various analogs of indo-
N
H
COOMe
a
Isolated yield.
Table 3
Intramolecular cyclization to hemiaminals 5a–c
Ar
Ar
HO
N
N
TFA (2 equiv)
CH2Cl2, RT
N
COOMe
N
COOMe
Boc
Boc
Ar = Aryl or Heteroaryl
2
3
Entry
Reagents
Time (h)
Productsa (yield %)
MeO
OMe
N
N
1
2
5a (100%)
N
N
N
HO
HO
N
H
N
H
N
COOMe
COOMe
2b
Boc
Boc
N
N
N
2b
17
5b (78%)
N
H
N
H
N
COOMe
COOMe
2c
Boc
Boc
OMe
OMe
MeO
MeO
HO
N
N
N
3b
24
5c (33%)
N
COOMe
COOMe
Boc
Boc
2d
a
Isolated yield.
Addition of 1 equiv of pyridine.
b

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E. Claveau et al. / Tetrahedron Letters 50 (2009) 3679–3682
lo[2,3-a]quinolizidine alkaloids8 (Fig. 2, i.e., mitragynine9) could be
envisioned.
References and notes
1. For diversity-oriented synthesis, see: (a) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74–
84; (b) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58; (c)
Schreiber, S. L. Science 2000, 287, 1964–1969.
When experimenting on tryptamine derivative 2c (Table 3, en-
try 2), a concomitant cleavage of the Boc group was observed
inducing the decomposition of the unstable intermediate enamine
in acidic medium. So as to buffer the reaction medium as did the
pyridinic nitrogen in 2b, 1 equiv of pyridine was added. In this
case, the desired tetracyclic indolyl derivative 5b was recovered
in 78% yield. An electrophilic cyclization also occurred when start-
ing with dimethoxyphenyl derivative 2d. The original tetracycle 5c,
isolated in moderate yield,10 might allow an easy way to diazinic
analogs of isoquinoline alkaloids (Fig. 2, i.e. cephaelin11).
To sum up, this method allowed an efficient transformation of
one type of heterocycles, the 1,4-oxazine ring, into another, namely
the 1,4-diazine system. As various polycyclic heterocyclic frame-
works could be easily obtained, this strategy may efficiently pro-
2. (a) Mousset, D.; Gillaizeau, I.; Sabatié, A.; Bouyssou, P.; Coudert, G. J.
Org. Chem. 2006, 71, 5993–5999; (b) Mousset, D.; Gillaizeau, I.; Hassan,
J.; Lepifre, F.; Bouyssou, P.; Coudert, G. Tetrahedron Lett. 2005, 46, 3703–
3705; (c) Claveau, E.; Gillaizeau, I.; Blu, J.; Bruel, A.; Coudert, G. J. Org.
Chem. 2007, 72, 4832–4836; (d) Cottineau, B.; Gillaizeau, I.; Farard, J.;
Auclair, M.-L.; Coudert, G. Synlett 2007, 1925–1929; (e) Chaignaud, M.;
Gillaizeau, I.; Ouhamou, N.; Coudert, G. Tetrahedron 2008, 64, 8059–
8066; (f) Claveau, E.; Gillaizeau, I.; Coudert, G. Synlett 2009, 2, 263–267;
(g) Claveau, E.; Gillaizeau, I.; Kalinowska, J.; Bouyssou, P.; Coudert, G.
2009 (ASAP) doi:10.1021/jo900291f.
3. The necessary primary amine was prepared from 4-azamelatonin by
deprotection of the corresponding acetamide by KOH/EtOH. See: Jeanty, M.;
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vide access to
a library of compounds based on privileged
substructures that are of interest in drug discovery. The application
of this methodology to the synthesis of more complex heterocyclic
structures is currently under investigation in our laboratory and
will be described in due course.
8. (a) Brown, R. T. Indoles. The Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.
In The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.;
Wiley: New York, 1983; Vol. 25, Part 4, Chapter 3.; (b) Szántay, C.; Blaskó, G.;
Honty, K.; Dörnyei, G. In The Alkaloids; Brossi, A., Ed.; Academic Press: London
UK, 1986; Vol. 27, Chapter 2; (c) Lounasmaa, M.; Tolvanen, A. In Monoterpenoid
Indole Alkaloids; Saxton, J. E., Ed. In The Chemistry of Heterocyclic Compounds;
Taylor, E. C., Ed.; Wiley: Chichester, UK, 1994; Vol. 25, Part 4, Chapter 3.; (d)
Amat, M.; Gòmez-Esqué, A.; Escolano, C.; Santos, M. M.; Molins, E.; Bosch, J. J.
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Acknowledgments
We are grateful to the CNRS and the Region Center for their
financial support.
Supplementary data
9. Ma, J.; Yin, W.; Zhou, H.; Liao, X.; Cook, J. M. J. Org. Chem. 2009, 74, 264–273.
and references cited herein.
10. Compound 5c was isolated in low yield as the sole product. No regioisomer
could be detected by NMR analysis. The low yield might have been partially
due to the degradation of the starting compound.
11. Muhammad, I.; Dunbar, D. C.; Khan, S. I.; Tekwani, B. L.; Bedir, E.; Takamatsu,
S.; Ferreira, D.; Walker, L. J. Nat. Prod. 2003, 66, 962–967.
Supplementary data (experimental procedures and full spec-
troscopic data for all new compounds) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2009.03.152.