Solvent-free cyclocondensation of lactim ethers with anthranilic acid under microwave irradiation

Article abstract of DOI:10.1055/s-2004-817784

Microwave irradiation greatly improves the results of the cyclocondensation between anthranilic acid and lactim ethers derived from 2,5-piperazinediones in terms of reaction times, yields and stereocenter integrity, leading to pyrazino[2,1-b]quinazoline-3,6-diones. The microwave-assisted reaction was also much better than the thermal one when applied to a bis-lactim ether, leading to the corresponding pentacyclic pyrazino [2,1-b:5,4-b′]diquinazoline-5,13- dione in excellent yield, and it also improved the preparation of compounds containing the ring system of the anti-MDR natural product N-acetylardeemin.

Full text of DOI:10.1055/s-2004-817784

LETTER
803
Solvent-Free Cyclocondensation of Lactim Ethers with Anthranilic Acid
under Microwave Irradiation
I
P
mprove
d
Syn
i
l
f
P
yra
z
a
ino[2,1-
b
]q
r
uinazoline-3,6
C
-diones ledera, J. Domingo Sánchez, Esmeralda Caballero, Carmen Avendaño, M. Teresa Ramos,
J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
E-mail: josecm@farm.ucm.es
Received 12 December 2003
Abstract: Microwave irradiation greatly improves the results of the
9
cyclocondensation between anthranilic acid and lactim ethers de-
rived from 2,5-piperazinediones in terms of reaction times, yields
and stereocenter integrity, leading to pyrazino[2,1-b]quinazoline-
1
0
8
7
N
O
R1
H
1
1
N
N
O
3
,6-diones. The microwave-assisted reaction was also much better
6
1
N
than the thermal one when applied to a bis-lactim ether, leading to
the corresponding pentacyclic pyrazino [2,1-b:5,4-b¢]diquinazol-
ine-5,13-dione in excellent yield, and it also improved the prepara-
tion of compounds containing the ring system of the anti-MDR
natural product N-acetylardeemin.
N 5
O
2
HN
4
3
O
N
H
1
Compound R1 Conf. C-4
Key words: microwave irradiation, iminoethers, cyclizations, anti-
tumor agents, heterocycles
Fiscalin B
Glyantrypine
i-Pr
H
R
Unknown
H C
2
1
N
The pyrazino[2,1-b]quinazoline-3,6-dione system (1) is
H C
H
N
3
H C
the structural core of a small family of natural products
which include glyantrypine, the fiscalins, and the
fumiquinazolines; more complex structures derived from
this parent system can be found in the ardeemins, alant-
3
N
O
2
3
4
CH3
N
H
5
O
O
6
7
rypinone, and spiroquinazoline (Figure 1). Currently the
H3C
8
–10
focus of synthetic efforts by several groups,
some of
N-Acetylardeemin
O
N
these compounds have interesting biological properties.
H
5
b
N
Most notably, ardeemin is a very potent inhibitor of
multi-drug resistance to antitumor drugs (MDR), which is
considered as the main obstacle to antitumor chemothera-
O
HN
H
CH3
NH
CH3
N
1
1
N
py, and it has been shown that the pharmacophore of N-
NH
N
N
acetylardeemin is its pyrazino[2,1-b]quinazoline-3,6-di-
9
b,12
O
O
O
O
one moiety.
Additionally, spiroquinazoline is a com-
Alantrypinone
Figure 1
Spiroquinazoline
petitive inhibitor of the binding of substance P to the
7
human NK-1 receptor.
Two main strategies are currently employed for the
1
preparation of 1. The first of them requires a five-step
by chromatographic removal of the phosphine oxide
formed during the reaction, which is particularly tedious
when the more reactive tributylphosphine is employed be-
cause its oxide tends to co-elute with many of the desired
reaction products. For these reasons, we decided to at-
tempt to improve an earlier procedure, also starting from
diketopiperazines and based on the direct cyclocondensa-
tion of their lactim ethers with anthranilic acid.16 This
method has been relatively neglected in the past because
the cyclocondensation step normally proceeds in low
sequence based on the cyclization of N-amino-
1
3
acylanthranylamides via a benzo[d]oxazine intermedi-
1
4
ate, and involves the use of Fmoc-protected amino acids.
The second strategy involves the use of a four-step proto-
col that starts from cheaper N-Boc amino acids to give
2
,5-piperazinediones, which are submitted to acylation
with o-azidobenzoyl chloride followed by an aza-Wittig
1
5
reaction. In our experience, when both NH groups of the
diketopiperazine system are free, the acylation step is
often troublesome and it is difficult to avoid diacylation.
Additionally, the aza-Wittig cyclization must be followed
yield and sometimes leads to epimerization of stereo-
centers adjacent to carbonyl groups.1
6,17
However, be-
cause it takes place under thermal, solvent-free
conditions, we considered this reaction a good candidate
for optimization by microwave irradiation.
SYNLETT 2004, No. 5, pp 0803–0806
Advanced online publication: 17.02.2004
DOI: 10.1055/s-2004-817784; Art ID: D29603ST
0
2.
0
4.
2
0
0
4
18
©
Georg Thieme Verlag Stuttgart · New York

8
04
P. Cledera et al.
LETTER
1
We show in Table 1 the comparison between the results was ruled out by H NMR studies in the presence of
obtained using conventional and microwave heating for Eu(hfc) , using racemic tricycle as a reference. Owing to
3
the reaction between anthranilic acid and several imino- the presence of two stereocenters at C-1 and C-4 in most
ethers, which were readily available by treatment of the of the fiscalins and fumiquinazolines, it was considered
corresponding diketopiperazines with Meerwein’s salt in interesting to study a reaction involving a 1,3,6-trisub-
1
9
the presence of K CO . The reactions of 1,3-disub- stituted iminoether such as 2e. As shown in entry 5, its
2
3
stituted lactim ethers 2a–d (entries 1–4) were carried out transformation into the 1,4-disubstituted pyrazino[2,1-
in 3–5 minutes under microwave irradiation at 600 W,20 b]quinazoline-3,6-dione 3e proceeded in 48% yield under
compared to 2 hours at 120–140 °C for the conventional microwave irradiation, which represents a three-fold in-
heating conditions. Yields were also higher, with a more crease in yield with respect to the traditional conditions.
than two-fold increase being observed in the preparation The double condensation of bis-lactim ether 2f was also
of compound 3a from iminoether 2a as compared with the greatly improved by the use of microwave (6 min, 600
1
6
literature method, and smaller, but also very significant, W), leading to pentacyclic 7,15-dihydropyrazino[2,1-
increases in the case of the preparation of compounds b:5,4-b¢]diquinazoline-5,13-dione derivative 3f in 89%
3
b–d. Due to the presence of an adjacent carbonyl group, yield, as compared with the 54% yield described in the
21
the integrity of the stereocenter in these reactions was in literature for a similar reaction at 150–200 °C for 1 hour
doubt, particularly since, as already mentioned, several (entry 6).
examples of epimerization have been described in the
literature for the conventional reaction conditions. This
Table 1 Comparison of the Cyclocondensations Between Iminoethers and Anthranilic Acid under Conventional and Microwave-Assisted
Conditions
Entry
Starting material
Product
Heating
Conditions Yield
Microwave
Conditions
Yield
(
%)
(%)
H3C
O
OEt
H3C
N
N
N
N
3016
600 W, 3 min
63
1
2
3
4
N
120 °C, 2 h
140 °C, 2 h
140 °C, 2 h
140 °C, 2 h
O
CH3
CH3 O
2
a
3a
OEt
N
O
N
N
N
N
N
40
600 W, 5 min
600 W, 5 min
600 W, 3 min
56
58
58
H3CO
O
N
3
H CO
O
CH3
CH3
2b
3b
Ph
Ph
OEt
N
N
N
39
O
O
CH3
CH3 O
3
c
2
2
c
OEt
N
N
N
O
N
N
46
O
CH3
CH3
O
d
3d
3e
CH3
CH3
OEt
N
N
N
5
6
140 °C, 2 h
16
600 W, 3 min
48
89
N
H
N
N
H
N
O
O
CH3
CH3
O
2e
OEt
O
N
N
N
N
EtO
150–200 °C,
1 h
5421
N
600 W, 6 min
N
2f
O
3
f
Synlett 2004, No. 5, 803–806 © Thieme Stuttgart · New York

LETTER
Improved Synthesis of Pyrazino[2,1-b]quinazoline-3,6-diones
805
OEt
H
N
H
N
N
N
H
N
H
N
+
H
H
H N
2
N
O
N
O
CH3
+
N
H
CO2H
O
CH3
CH3
CH3
N
H
N
H
O
O
O
4
CH3
CH3
O
O
5
6
N
O
Conditions
40 °C, 6 h
µW, 600 W, 3 m
% 5
% 6
% 7
H
N
H
N
O
1
23
41
8
7
3
0
+
CH3
N
H
CH3
O
7
Scheme 1
Finally, we examined the applicability of our microwave
conditions to the synthesis of more complex structures re-
lated to biologically relevant natural products. Thus, treat-
ment of the known tetracyclic ardeemin fragment 4 with
anthranilic acid at 600 W for 3 minutes gave a 6:1 mixture
of the diastereoisomeric de-prenylardeemins 5 and 6, in
(4) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto,
T.; Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi,
H.; Shingu, T. Tetrahedron Lett. 1992, 33, 1621.
(
b) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.;
17
Shingu, T.; Kumeda, Y.; Numata, A. J. Chem. Soc., Perkin
Trans. 1 1995, 2345.
(
5) (a) Karwowski, J. P.; Jackson, M.; Rasmussen, R. R.;
Humphrey, P. E.; Poddig, J. B.; Kohl, W. L.; Scherr, M. H.;
Kadam, S.; McAlpine, J. B. J. Antibiotics 1993, 46, 374.
4
8% overall yield (Scheme 1). Besides the improved yield
and shorter reaction time, this result was also much better
in terms of stereochemical integrity than that obtained
under conventional conditions (compounds 5, 6 and 7 in
(
b) Hochlowski, J. E.; Mullally, M. M.; Spanton, S. G.;
Whittern, D. N.; Hill, P.; McAlpine, J. B. J. Antibiotics 1993,
6, 380. (c) Chou, T. C.; Depew, K. M.; Zheng, Y.-H.; Safer,
4
1
7
3
4% overall yield and ca. 7:2:1 ratio), proving again the
M. L.; Chan, D.; Helfrich, B.; Zatorska, D.; Zatorski, A.;
Bornmann, W.; Danishefsky, S. J. Proc. Natl. Acad. Sci.
USA 1998, 95, 8369.
mildness of the microwave-enhanced conditions.
In conclusion, microwave irradiation significantly im-
proves the reaction of lactim ethers with anthranilic acid,
providing a useful alternative for the preparation of
pyrazino[2,1-b]quinazoline-3,6-diones.
(
6) Larsen, T. O.; Frydenvang, K.; Frisvad, J. C.;
Christophersen, C. J. Nat. Prod. 1998, 61, 1154.
7) Barrow, C. J.; Sun, H. H. J. Nat. Prod. 1994, 57, 471.
8) Fiscalins, fumiquinazolines and glyantrypine: (a) He, F.;
Snider, B. B. Synlett 1997, 483. (b) Snider, B. B.; Busuyek,
M. V. Tetrahedron 2001, 57, 3301. (c) Snider, B. B.; Zeng,
H. Org. Lett. 2000, 2, 4103. (d) Wang, H.; Ganesan, A. J.
Comb. Chem. 2000, 2, 186. (e) Cledera, P.; Avendaño, C.;
Menéndez, J. C. J. Org. Chem. 2000, 65, 1743.
(
(
Acknowledgment
We thank CICYT for financial support (projects SAF 97-0143 and
SAF 2000-0130).
(f) Hernández, F.; Lumetzberger, A.; Avendaño, C.;
Söllhuber, M. M. Synlett 2001, 1387. (g) Snider, B. B.;
Zeng, H. Org. Lett. 2002, 4, 1087. (h) Snider, B. B.; Zeng,
References
1
3,14
H. J. Org. Chem. 2003, 68, 545; see also refs.
.
(
(
(
1) For a review, see: Avendaño, C.; Menéndez, J. C. Curr. Org.
Chem. 2003, 7, 149.
2) Penn, J.; Mantle, P. G.; Bilton, J. N.; Sheppard, R. N. J.
Chem. Soc., Perkin Trans. 1 1992, 1495.
3) (a) Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.;
Gillum, A. M.; Cooper, R. J. Antibiotics 1993, 46, 545.
(
9) Ardeemins: (a) Marsden, S. P.; Depew, K. M.; Danishefsky,
S. J. J. Am. Chem. Soc. 1994, 116, 11143. (b) Depew, K.
M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann,
W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,
11953.
(
10) Alantrypinone and its enantiomer: (a) Hart, D. J.;
Magomedov, N. Tetrahedron Lett. 1999, 40, 5429. (b)Hart,
D. J.; Magomedov, N. J. Am. Chem. Soc. 2001, 123, 5892.
(
b) Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.;
Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1843.
(
2
c) Kende, A. S.; Fan, J. F.; Chen Chen, Z. C. Org. Lett.
003, 5, 3205. (d) Chen, Z.; Fan, J.; Kende, A. S. J. Org.
Chem. 2004, 69, 79.
Synlett 2004, No. 5, 803–806 © Thieme Stuttgart · New York

8
06
P. Cledera et al.
LETTER
(20) Representative Procedure: A 10 mL flask containing a
(
11) For selected reviews on MDR modulators, see: (a) Wiese,
1
6
M.; Pajeva, I. K. Curr. Med. Chem. 2001, 8, 685.
b) Teodori, E.; Dei, S.; Scapecchi, S.; Gualtieri, F. Il
Farmaco 2002, 57, 385. (c) Avendaño, C.; Menéndez, J. C.
Curr. Med. Chem. 2002, 9, 159.
mixture of (3S)-5-ethoxy-1,3-dimethylpiperazin-2-one
(100 mg, 0.59 mmol) and anthranilic acid (88 mg, 0.65
mmol) was submerged in alumina, contained in a beaker,
and irradiated for 1 min at 600 W in a domestic microwave
oven. The reaction was left to cool for 2 min and submitted
to two additional irradiation-cooling cycles. The solid thus
obtained was purified by chromatography on silica gel,
eluting with 6:1 petroleum ether-EtOAc mixture to yield 90
mg (63%) of compound 3a, as an off-white solid. Mp 150–
(
(
(
(
(
(
12) Méndez-Vidal, C.; Rodríguez de Quesada, A. Cancer Lett.
1
998, 132, 45.
13) (a) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432.
b) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022.
14) (a) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397.
b) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545.
15) See, for instance, refs. 9a,b and: Cledera, P.; Avendaño, C.;
Menéndez, J. C. Tetrahedron 1998, 54, 12349.
16) (a) Rajappa, S.; Advani, B. G. Tetrahedron 1973, 29, 1299.
(
1
6b
25
(
152 °C; lit. 153–156 °C. [a] +142.9 (c = 0.135 g/100
16b
D
mL in CHCl ); lit. +149.2 (c = 2 g/100 mL, EtOH). IR
3
(KBr): 1673 (CO) cm . H NMR (250 MHz, CDCl ) d =
–
1 1
3
8.27 (dd, J = 8.0, 1.3 Hz, 1 H, H-7), 7.76 (td, J = 7.8, 1.3 Hz,
1 H, H-8), 7.62 (d, J = 7.6 Hz, 1 H, H-10), 7.49 (td, J = 8.1,
1.2 Hz, 1 H, H-9), 5.45 (q, J = 7.1 Hz, 1 H, H-4), 4,75 (d,
J = 16.8 Hz, 1 H, H-1 pseudoequatorial), 4.37 (d, J = 16.8
(
1
b) Rajappa, S.; Advani, B. G. J. Chem. Soc., Perkin Trans.
1974, 2122.
(
17) Caballero, E.; Avendaño, C.; Menéndez, J. C. Tetrahedron:
Asymmetry 1998, 9, 3025.
18) For representative reviews on microwave-assisted organic
synthesis, see: (a) Caddick, S. Tetrahedron 1995, 38,
Hz, 1 H, H-1 pseudoaxial), 3.12 (s, 3 H, NCH ), 1.59 (d, J =
3
1
3
(
7.2 Hz, 3 H, C -CH ). C NMR (63 MHz, CDCl ) d = 167.7
4
3
3
(C-3), 160.1 (C-6), 147.8 (C-11a), 147.3 (C-10a), 134.9 (C-
9), 127.4 (C-7), 127.0 (C-8 and C-10), 120.1 (C-6a), 52.2 (C-
4), 51.6 (C-1), 33.9 (N-CH ), 17.0 (C -CH ). Anal. Calcd for
1
0403. (b) de la Hoz, A.; Díaz-Ortiz, A.; Moreno, A.; Langa,
F. Eur. J. Org. Chem. 2000, 22, 3659. (c) Perreux, L.;
Loupy, A. Tetrahedron 2001, 57, 9199. (d) Lidstrom, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57,
3
4
3
C H N O (243): C, 64.19; H, 5.39; N, 17.27. Found: C,
1
3
13
2
3
63.91; H, 5.61; N, 16.98.
9
225. (e) Santagada, V.; Perissutti, E.; Caliendo, G. Curr.
(21) Gompper, R.; Breitschaft, W. Angew. Chem., Int. Ed. Engl.
1983, 22, 717.
Med. Chem. 2002, 9, 1251.
(19) Fukuyama, T.; Frank, R. K.; Laird, A. A. Tetrahedron Lett.
1985, 26, 2955.
Synlett 2004, No. 5, 803–806 © Thieme Stuttgart · New York