1,n-Diamines. Part 4: Synthesis of 1-aryl-2-alkyl-1,4,5,6,7,8-hexahydro-1, 3-diazocines

Article abstract of DOI:10.1016/j.tetlet.2011.09.097

In this Letter we present the synthesis of hitherto unreported 1-aryl-2-alkyl-1,4,5,6,7,8-hexahydro-1,3-diazocines 1. Cyclic amidines 1 were synthesized by PPSE promoted ring closure of N-acyl-N'-arylpen- tamethylenediamines 2. The cyclodehydration reacti

Full text of DOI:10.1016/j.tetlet.2011.09.097

Tetrahedron Letters 52 (2011) 6443–6445
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1,n-Diamines. Part 4: synthesis of 1-aryl-2-alkyl-1,4,5,6,7,8-hexahydro-1,
3-diazocines
⇑
Jimena E. Díaz, Nadia Gruber, Liliana R. Orelli
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Junín 956, (1113) Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we present the synthesis of hitherto unreported 1-aryl-2-alkyl-1,4,5,6,7,8-hexahydro-1,3-
diazocines 1. Cyclic amidines 1 were synthesized by PPSE promoted ring closure of N-acyl-N0-arylpen-
tamethylenediamines 2. The cyclodehydration reaction was performed under microwave irradiation in
solvent-free conditions. Precursors 2 were prepared by selective functionalization of N-arylcadaverines 3.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 20 August 2011
Revised 14 September 2011
Accepted 20 September 2011
Available online 28 September 2011
Keywords:
Polyamine analogs
Cyclic amidines
Medium size heterocycles
PPSE
Microwaves
Introduction
acid esters are mild irreversible dehydrating reagents of the Lewis
acid type that activate oxygen and nitrogen functionalities toward
Cyclic amidines represent a heterocyclic core of wide pharmaco-
logical interest. Among them, dihydroimidazoles1 and tetrahydro-
pyrimidines2 are found in many biologically active compounds.
Due to their broad spectrum of biological activity, such heterocycles
have received a great deal of attention in connection to their syn-
thesis. Tetrahydro-1,3-diazepines have been studied owing to the
biological properties of some members, acting as diuretics, hypo-
glycemiants, anti-inflammatories, and antispasmodics.3 More re-
cently, some derivatives have been investigated as NMDA
antagonists4 and dopamine D41b or muscarinic agonists.5 Literature
data on the higher homologs, namely 1,4,5,6,7,8-hexahydro-1,3-
diazocines, are very scarce. This may be due to the intrinsic difficul-
ties in ring closure reactions leading to medium size heterocycles.6
Mirskova et al. reported the reaction of cadaverine with alkylthio-
chloroacetylenes leading to 2-alkylthiochloromethyl-hexahydro-
1,3-diazocines.7 Other literature examples involve treatment of
the parent diamine or its N-alkyl derivatives with carboxylic acids
or their derivatives.8 Due to the considerably lower nucleophilicity
of the arylamino group, application of such procedures to N-aryl
derivatives would involve drastic reaction conditions, which may
result in the decomposition of sensitive substrates.
nucleophilic attack and, at the same time, react chemically with
water. Ethyl polyphosphate (PPE) and trimethylsilylpolyphosphate
(PPSE) have been used as dehydrating agents for the synthesis of N-
aryl five to seven membered cyclic amidines.10
Reactions performed under microwave irradiation proceed in
general faster, more cleanly, and with higher yields than with con-
ventional heating.11 Cyclocondensation is one of the most impor-
tant methods for the synthesis of heterocycles, and microwave
heating has found interesting applications in this area.12 In previ-
ous work, we investigated the use of microwave irradiation to en-
hance the PPE-promoted synthesis of cyclic amidines.13
N-Acyl-N0-arylpentamethylenediamines are the synthetic pre-
cursors of 1,2-disubstituted hexahydrodiazocines and other acyclic
cadaverine derivatives. All these compounds are of biochemical
and pharmacological interest as natural polyamine analogs.14–16
The reported synthetic method for N-benzoyl-N0-aryl pentamethy-
lenediamines involves the reaction of N-acylpiperidines with PCl5
followed by aminolysis.17 The overall yields are moderate, and the
procedure is restricted to N-acyl derivatives without a
-hydrogens.18
In the context of our research,19 functionalization of N-arylcadaver-
ines 3 seemed an interesting alternative for the preparation of selec-
tively N,N0-disubstituted 1,5-diamines and related heterocyclic
amidines.
Perillo et al . reported the cyclodehydration of N-(4-nitro-
phenyl)-N0-aroyl-1,5-diaminopentanes to the corresponding hexa-
hydrodiazocines by conventional heating of the substrates with
neat ethyl polyphosphate (PPE) for 2 h at 120 °C.9 Polyphosphoric
Results and discussion
N-acyl-N0-arylpentamethylenediamines 2 were synthesized by
the sequence shown in Scheme 1.
⇑
Corresponding author. Tel./fax: +54 11 4964 8250.
E-mail address: lorelli@ffyb.uba.ar (L.R. Orelli).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.097

6444
J. E. Díaz et al. / Tetrahedron Letters 52 (2011) 6443–6445
ArNH2
Cl
ArHN
CN
CN
Cs2CO3
4
BH3/THF
H
(RCO)2O/aq. Na2CO3 (0°C) or
N
ArHN
R
ArHN
NH2
4-NO2C6H4OCHO/THF (-5ºC)
(R=H)
O
2
3
Scheme 1. Synthesis of N-acyl-N0-arylcadaverines 2.
Table 2
R
Synthesis of compounds 1 via Scheme 2
Ar
N
N
Compound 1
Ar
R
Yielda (%)
H
PPSE
ArHN
N
R
O
a
b
e
f
g
j
k
l
m
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
C6H5
C2H5
iso-C3H7
CH3
C2H5
iso-C3H7
CH3
C2H5
iso-C3H7
H
58
60
50
61
84
52
61
81
27b
µW
2
1
Scheme 2. Synthesis of compounds 1.
a
Table 1
Yields correspond to pure compounds.
The reported yield is approximate and was estimated by integration of suitable
Synthesis of N-acyl-N0-aryl-1,5-pentanediamines 2
b
1H NMR signals (see Supplementary data).
Compound 2
Ar
R
Yielda (%)
useful organic transformations, including heterocycles syntheses.21
This prompted us to investigate the use of PPSE for the synthesis of
1-aryl-2-alkyl-1,4,5,6,7,8-hexahydro-1,3-diazocines 1.
Reaction of compound 2a with PPSE in dichloromethane under
microwave irradiation at reflux (15 min at 70 °C) led to the corre-
sponding cyclic amidine 1a in 42% yield. Working in solvent-free
conditions in an open vessel, the reaction was completed in
40 min. at 90 °C. In such conditions, aminoamides 2a,b,e–g,j–m
were converted into the corresponding hexahydrodiazocines 1.
Isolated yields are shown in Table 2.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
C6H5
C2H5
iso-C3H7
C6H5
H
CH3
75
95
Quant.
80
87
Quant.
95
90
Quant.
78
76
C2H5
iso-C3H7
tert-C4H9
C6H5
CH3
C2H5
iso-C3H7
H
iso-C3H7
85
70
Quant.
The expected reactivity of the amide moiety present in precur-
sors 2 follows the order R = H > methyl > ethyl > iso-propyl. Con-
versely, amidines with sterically hindering C2 substituents are
less reactive toward hydrolysis. Analysis of the results shows that,
in general, yields increase along with the steric hindrance of the R
substituent (Table 2). We might therefore conclude that stability of
the reaction products is the main factor that conditions the exper-
imental yields. This is in line with our previous results on 1,2-
diarylhexahydro-1,3-diazocines,13a which are further stabilized
C6H5
a
Yields correspond to pure compounds.
Precursors 3 were prepared using the method previously devel-
oped by our group.20 Aminoamides 2a–c,e–l,n were synthesized
by selective acylation of diamines 3 with carboxylic acid anhy-
drides,19g while the reaction of diamines 3d,m with 4-nitrophenyl
formate led selectively to N-aryl-N0-formyl-1,5-pentanediamines
2d,m (Table 1).
by the p
-conjugating 2-aryl substituent.22 In fact, such compounds
were obtained in high yields employing a less reactive dehydrating
agent, and in milder reaction conditions (PPE/chloroform).13a
Cyclodehydration reactions leading to eight membered cyclic
amidines require prolonged reaction times and harsh conditions
under conventional heating. As already mentioned, reaction condi-
tions described in the literature for 1,2-diaryl derivatives involve
heating the substrate for 2 h in neat PPE.9 In a previous report,
we showed that the microwave irradiation of N-aryl-N0-benzoyl-
pentamethylenediamines with a chloroform solution of PPE under
reflux drastically reduces the reaction times and leads to high
yields of 1,2-diarylhexahydro-1,3-diazocines.13a In connection to
this, we recently reported the cyclodehydration of N-aryl-N0-acyl-
1,4-butanediamines with a chloroformic solution of PPE as an effi-
cient method for the preparation of 1-aryl-2-alkyl-1H-1,4,5,6-tet-
rahydrodiazepines.19g In such conditions, however, considerably
lower yields of a homologous hexahydrodiazocine were obtained.
Previous results of our group indicated that PPSE is capable of
efficiently promoting cyclodehydration of certain substrates, which
could not be achieved with PPE.10b,d PPSE is a mild aprotic dehy-
drating agent which has been employed in various synthetically
Conclusions
In conclusion, we have developed a novel method to hitherto
unreported 1-aryl-2-alkyl-1,4,5,6,7,8-hexahydro-1,3-diazocines 1,
by microwave-assisted cyclodehydration of N-acyl-N0-aryl-1,5-
pentanediamines 2 with PPSE in solvent-free conditions. The pro-
posed synthetic route allows for the preparation of derivatives
with primary and secondary 2-alkyl substituents, not accessible
through previously reported methods. Moreover, this is one of
the few examples of ring closure reactions leading to eight mem-
bered heterocyclic systems described in the literature.
The precursor aminoamides 2 were synthesized by the func-
tionalization of N-arylcadaverines 3. Such acyclic and heterocyclic
N-arylcadaverine derivatives are potentially bioactive compounds
as synthetic polyamine analogs, and some of them represent useful
precursors of selectively N,N0-disubstituted 1,5-pentanediamines.23

J. E. Díaz et al. / Tetrahedron Letters 52 (2011) 6443–6445
6445
Chem. 2000, 37, 1431–1438; (d) Perillo, I. A.; Caterina, M. C.; López, J.; Salerno,
A. Synthesis 2004, 6, 851–856. and references therein.
Acknowledgments
11. (a)Among others: Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Winheim, 2002; (b) Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Disc. 2006, 5, 51–
63; (c) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (d) Shipe, W. D.;
Wolkenberg, S. E.; Lindsley, C. W. Drug Discovery Today: Technol. 2005, 2, 155–
161; (e) Leadbeater, N. B. Chem. Commun. 2005, 2881–2902; (f) Lindström, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–9283; (g)
Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223; (h) Caddick, S.
Tetrahedron 2005, 51, 10403–10432; (i) Kappe, C. O.; Dallinger, D. Mol.
Divers. 2009, 13, 71–193.
This work was supported by the University of Buenos Aires and
by the CONICET. We are also grateful to Fernando J. Durán (PhD)
and Pablo Di Chenna (PhD) for their helpful collaboration.
Supplementary data
12. (a) Van der Eicken, E.; Kappe, C. O. Microwave-Assisted Synthesis of Heterocycles;
Distribution Center, GmbH, 2006; (b) Bougrin, K.; Loupy, A.; Soufiaoui, M. J.
Photochem. Photobiol. C: Photochem. Rev. 2005, 6, 139–167.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.097.
13. (a) García, M. B.; Torres, R. A.; Orelli, L. R. Tetrahedron Lett. 2006, 47, 4857–
4859; (b) Díaz, J. E.; García, M. B.; Orelli, L. R. J. Mol. Struct. 2010, 982, 50–56.
14. Burns, M. R. US Patent 2005 6,872,852.
References and notes
15. (a) Frydman, B.; Valasinas, A. Exp. Opin. Ther. Patents 1999, 9, 1055–1068; (b)
Aizencang, G.; Harari, P.; Buldain, G.; Guerra, L.; Pickart, M.; Hernández, P.;
Frydman, B. Cell Mol. Biol. 1998, 44, 615–625.
16. (a) Stemberg, P.; Ljunggreth, C.; Nilsson, J. L. G.; Lundén, R.; Eriksson, O. J. Med.
Chem. 1972, 15, 674–675; (b) Ahmad, P.; Fyfe, C. A.; Mellors, A. Biochem.
Pharmacol. 1975, 24, 1103–1110; (c) Hoffmann, K.-J.; Stemberg, P.; Ljunggren,
C.; Svensson, U.; Nilsson, J. L. G. J. Med. Chem. 1975, 18, 278–284.
17. Ramírez, M. A.; Corona, M. V.; Blanco, M. M.; Perillo, I. A.; Porcal, W.; Salerno, A.
Tetrahedron Lett. 2010, 38, 5000–5002.
1. Among others: (a) Prisinzano, T.; Dukat, M.; Law, H.; Slassi, A.; McLean, N.;
DeLannoy, I.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2004, 14, 4697–4699; (b)
Einsiedel, J.; Hübner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2003, 13, 851–854;
(c) Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y. Tetrahedron Lett.
2005, 46, 2197–2199. and references therein; (d) Giorgioni, G.; Ambrosini, D.;
Vesprini, C.; Hudson, A.; Nasuti, C.; Di Stefano, A.; Sozio, P.; Ciampi, O.; Costa,
B.; Martini, C.; Carrieri, A.; Carbonara, G.; Enzensperger, C.; Pigini, M. Bioorg.
Med. Chem. 2010, 18, 7085–7091.
18. Hedrera, M. E.; Salerno, A.; López, J.; Niemevz, F.; Perillo, I. A. Trends Org. Chem.
2008, 12, 61–66.
2. (a) Austin, W. C.; Courtney, W.; Danilewicz, J. C.; Morgan, D. H.; Conover, L. H.;
Howes, H. L.; Lynch, J. E.; McFarland, J. W.; Cornwell, R. L.; Theordorides, V. J.
Nature 1966, 212, 1273–1274; (b) McFarland, J. W.; Conover, L. H.; Howes, H. L.
J. Med. Chem. 1969, 12, 1066–1079; (c) McFarland, J. W.; Howes, H. L. J. Med.
Chem. 1969, 12, 1079–1086; (d) Weinhardt, K.; Wallach, M. B.; March, M. J.
Med. Chem. 1985, 28, 694–698; (e) Langis, A. L.; Pilkington, C. A. U. S. Patent,
3,126,381 Chem. Abstr. 1964, 60, 14517.; (f) Faust, J. A.; Mori, A.; Sahyun, M. J.
Am. Chem. Soc. 1959, 81, 2214–2219; (g) Dunbar, P. G.; Durant, G. J.; Fang, Z. J.
Med. Chem. 1993, 36, 842–847; (h) Dunbar, P. G.; Durant, G. J.; Rho, T. J. Med.
Chem. 1994, 37, 2774–2782; (i) Messer, W. S.; Abuh, Y. F.; Liu, Y.; Periyasamy,
S.; Ngur, D. O.; Edgar, M. A. N.; El Assadi, A. A.; Sbeih, S.; Dunbar, P.; Nagy, P. J.
Med. Chem. 1997, 40, 1230–1246.
3. (a) Faust, J.; Mori, A.; Sahyun, M. J. Am. Chem. Soc. 1959, 81, 2214–2219; (b)
Faust, J.; Sahyun, M. U. S. Patent, 2,953,565 Chem. Abstr. 1961, 55, 7449; (c)
White, A. C.; Black, R. M. U. S. Patent 3,926,994 Chem. Abstr. 1976, 85, 21505p;
(d) Bailey, D.; De Grazia, C. G.; Wood, D.; Siggins, J.; Harding, H. R.; Potts, G. O.;
Skulan, T. W. J. Med. Chem. 1974, 17, 702–708.
4. Nguyen, K. T.; Clairborne, C. F.; McCauley, J. A.; Libby, B. E.; Claremon, D. A.;
Bednar, R. A.; Mosser, S. D.; Gaul, S. L.; Connolly, T. M.; Condra, C. L.; Bednar, B.;
Stump, G. L.; Lynch, J. J.; Koblan, K. S.; Liberton, N. J. Bioorg. Med. Chem. Lett.
2007, 17, 3997–4000.
5. Plate, R.; Jans, C. J. G. M.; Plaum, M. J. M.; de Boer, T. Biorg. Med. Chem. 2002, 10,
1143–1152.
6. (a) Woodburn, H. M.; Fischer, J. R. J. Org. Chem. 1957, 22, 895–899; (b) Johnson,
R. N.; Woodburn, H. M. J. Org. Chem. 1962, 27, 3958–3962.
7. Mirskova, A. N.; Seredkina, S. G.; Kallikhman, I. D.; Bannikova, O. B.; Voronkov,
M. G. Russ. Chem. Bull. 1989, 38, 815–818.
19. (a) García, M. B.; Grilli, S.; Lunazzi, 1; Mazzanti, A.; Orelli, L. R. J. Org. Chem.
2001, 66, 6679–6684; (b) García, M. B.; Grilli, S.; Lunazzi, 1; Mazzanti, A.;
Orelli, L. R. Eur. J. Org. Chem. 2002, 23, 4018–4023; (c) García, M. B.; Orelli, L. R.;
Magri, M. L.; Perillo, I. A. Synthesis 2002, 23, 2687–2690; (d) Magri, M. L.;
Vanthuyne, N.; Roussel, C.; García, M. B.; Orelli, L. R. J. Chromat. A 2005, 1069,
203–208; (e) Lavaggi, M. L.; Aguirre, G.; Boiani, L.; Orelli, L. R.; García, M. B.;
Cerecetto, H.; González, M. Eur. J. Med. Chem. 2008, 43, 1737–1741; (f)
Bisceglia, J. A.; Mollo, M. C.; Orelli, L. R. J. Mol. Struct. 2010, 966, 79–84; (g) Díaz,
J. E.; Bisceglia, J. A.; Mollo, M. C.; Orelli, L. R. Tetrahedron Lett. 2011, 52, 1895–
1897; (h) Bisceglia, J. Á.; Díaz, J. E.; Torres, R. A.; Orelli, L. R. Tetrahedron Lett.
2011, 52, 5238–5240.
20. Link, N. P.; Díaz, J. E.; Orelli, L. R. Synlett 2009, 751–754.
21. (a) Imamoto, T.; Yokohama, H.; Yokohama, M. Tetrahedron Lett. 1981, 22, 1803–
1804; (b) Imamoto, T.; Yokohama, H.; Yokohama, M. Tetrahedron Lett. 1982, 23,
1467–1470; (c) Imamoto, T.; Matsumoto, T.; Yokohama, M. Synthesis 1983, 460;
(d) Yamamoto, K.; Watanabe, H. Chem. Lett. 1982, 1225–1228; (e) Marquart, A.
L.; Podlogar, B. L.; Huber, E. W.; Demeter, D. A.; Peet, N. P.; Weintraub, H. J. R.;
Angelastro, M. R. J. Org. Chem. 1994, 59, 2092–2100; (f) Coleman, A. C.; Kerr, R. G.
Tetrahedron 2000, 56, 9569–9574; (g) Shimizu, H.; Okada, N.; Yoshimatsu, M.
Tetrahedron Lett. 2001, 42, 4183–4186; (h) Li, W.; Fuchs, P. L. Org. Lett. 2003, 5,
4061–4064; (i) Yildiz-Oren, I.; Yalcin, I.; Aki-Sener, E.; Ucarturk, N. Eur. J. Med.
Chem. 2004, 39, 291–298; (j) Zanirato, V.; Pollini, G. P.; De Risi, C.; Valente, F.;
Melloni, A.; Fusi, S.; Barbettib, J.; Olivucci, M. Tetrahedron 2007, 63, 4975–4982;
(k) Lopez, S. E.; Perez, Y.; Restrepo, J.; Salazar, J.; Charris, J. J. Fluorine Chem. 2007,
128, 566–569; (l) Bourderioux, A.; Routier, S.; Bénéteau, V.; Mérour, J.
Tetrahedron 2007, 63, 9465–9475; (m) Messali, M.; Christiaens, L. E.;
Alshahateet, S. F.; Kooli, F. Tetrahedron Lett. 2007, 48, 7448–7451; (n) Lei, Y.;
Chen, F.; Luo, Y.; Xu, P.; Wang, Y.; Zhang, Y. Inorg. Chim. Acta 2011, 368, 179–186.
22. Brown, D. J.; Evans, R. F. J. Chem. Soc. 1962, 4039–4045.
8. (a) White, A. C.; Black, R. M. US Patent 1975 3,926,994.; (b) Miller, G. A.;
Pridgen, L. N. US Patent 1984 4,428,948.
9. Perillo, I. A.; Fernández, B. M.; Lamdan, S. J. Chem. Soc. 1976, Pt 2, 2068–2072.
10. (a) Orelli, L. R.; Niemevz, F.; García, M. B.; Perillo, I. A. J. Heterocycl. Chem. 1999,
36, 105–112. and references therein; (b) Orelli, L. R.; García, M. B.; Perillo, I. A.
Heterocycles 2000, 53, 2437–2450; (c) Hedrera, M. H.; Perillo, I. A. J. Heterocycl.
23. Orelli, L. R.; Salerno, A.; Hedrera, M. E.; Perillo, I. A. Synth. Commun. 1998, 28,
1625–1639.