Studies toward the synthesis of cinachyramine. An efficient route to 1,5-diazabicyclo[4.4.0]dec-5-enes Dedicated to the memory of Professor Harry H. Wasserman

Article abstract of DOI:10.1016/j.tetlet.2014.12.071

Hydrogenation (3 atm) of readily available pyrido[1,2-a]pyrimidines 10, 14, and 17 over 5% Rh/Al₂O₃ forms 1,5-diazabicyclo[4.4.0]dec-5-enes 9, 15, and 18 in >95% yield, providing a general route to this little-studied class of compounds. All attempts to form the tetrahydro-1,2,4-triazine moiety of cinachyramine (1) by rearrangement of amidinium dimethylhydrazone 8 using the procedures developed by Kamatori to convert hydrazone 3a to tetrahydro-1,2,4-triazine 4a were unsuccessful.

Full text of DOI:10.1016/j.tetlet.2014.12.071

Tetrahedron Letters 56 (2015) 3151–3154
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies toward the synthesis of cinachyramine. An efficient route
to 1,5-diazabicyclo[4.4.0]dec-5-enes
⇑
Olga V. Barykina-Tassa, Barry B. Snider
Department of Chemistry MS 015, Brandeis University, Waltham, MA 02454-9110, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrogenation (3 atm) of readily available pyrido[1,2-a]pyrimidines 10, 14, and 17 over 5% Rh/Al2O3
forms 1,5-diazabicyclo[4.4.0]dec-5-enes 9, 15, and 18 in >95% yield, providing a general route to this lit-
tle-studied class of compounds. All attempts to form the tetrahydro-1,2,4-triazine moiety of cinachyr-
amine (1) by rearrangement of amidinium dimethylhydrazone 8 using the procedures developed by
Kamatori to convert hydrazone 3a to tetrahydro-1,2,4-triazine 4a were unsuccessful.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 19 November 2014
Revised 11 December 2014
Accepted 12 December 2014
Available online 22 December 2014
Dedicated to the memory of Professor Harry
H. Wasserman
Keywords:
1,5-Diazabicyclo[4.4.0]dec-5-enes
Pyrido[1,2-a]pyrimidines
Hydrogenation
Hydrazones
1,5-Hydrogen shifts
Introduction
was particularly appealing because the conditions are mild enough
for a similar sequence to occur in the biosynthesis of 1. We
Cinachyramine (1), a novel alkaloid possessing a hydrazone and
two aminals, was isolated in 2006 from the Okinawan sponge
Cinachyrella sp. (see Scheme 1).1 The structure was assigned by
spectroscopic analysis and degradation under acidic conditions to
afford azoalkene 2. Cinachyramine trifluoroacetate showed weak
expected that oxidation of the hydroxy group of 9 to a ketone
and hydrazone formation would lead to 8. We thought that
hydroxy amidinium salt 9 should be available by partial hydroge-
nation of the readily available pyrido[1,2-a]pyrimidinium salt
10.3,4
cytotoxic activity against HeLa S3 cells with an IC50 of 6.8 lg/mL.
The structural novelty of cinachyramine and our continuing
interest in amidine- and guanidine-containing natural products
prompted us to attempt its synthesis.
Results and discussion
Reaction of 2-amino-3-hydroxypyridine (11) with 1,1,3,3-tetra-
ethoxypropane in 60% perchloric acid and ethanol at 80 °C by the
literature procedure led to the formation of 10 which precipitated
from solution and was isolated in pure form in 85% yield by
filtration (see Scheme 4).4 We were delighted to find that hydroge-
nation5 of 10 under 3 atm of H2 over 5% Rh/Al2O3 provided 9 as the
Kamatori and co-workers reported an extensive series of stud-
ies on the rearrangements of the dimethylhydrazones of 1,1,1-tri-
fluoro-2,3-diones such as 3a (see Scheme 2).2 Heating 3a absorbed
on silica gel with ammonium acetate (50 equiv) at 60 °C for 2 days
afforded 4a (36%) with the same tetrahydro-1,2,4-triazine ring as
cinachyramine.2c The mechanism probably involves imine forma-
tion and protonation to give 5a, which can also be drawn as the
resonance structure 6a. A 1,5-sigmatropic hydrogen shift will give
iminium salt 7a, which will cyclize to give 4a after deprotonation.
CH3
N
CH3
N
N
N
0.1 M HCl
We hoped that amidinium dimethylhydrazone
8 would
N
N
NH2
undergo a similar 1,5-sigmatropic hydrogen shift followed by
cyclization to give cinachyramine (1) (see Scheme 3). This route
N
cinachyramine (1)
2
⇑
Corresponding author. Tel.: +1 781 736 2550; fax: +1 781 736 2516.
E-mail address: snider@brandeis.edu (B.B. Snider).
Scheme 1. Structure and decomposition product of cinachyramine (1).
http://dx.doi.org/10.1016/j.tetlet.2014.12.071
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3152
O. V. Barykina-Tassa, B. B. Snider / Tetrahedron Letters 56 (2015) 3151–3154
R
N
EtO
OEt
OEt OEt
R
N
-
OH
ClO4
OH
NH4OAc,
NH2
N
SiO2, 70 °C
N
CH3
O
N
H
NH
CF3
N
N
Ph
60% HClO4
EtOH, 80 °C, 12 h
Ph
CF3
3a (R = t-Bu)
3b
11
10
(85%)
4a (R = t-Bu) (36%)
4b
(R = Me)
(R = Me)
1) imine formation
5% Rh/Al2O3, H2 (3 atm)
EtOH, 18 h
-H+
-
-
2) H+
ClO4
ClO4
Jones reagent
acetone
4 h, 25 °C
O
H
N
OH
H
N
R
N
R
R
N
N
N
N CH2
N
CH3+
NH2
N
N
CH2
NH2
H
9
12
(97%)
(42%)
NH2
Ph
Ph
Ph
H
Me2NNH2
4 h, 25 °C
CF3
CF3
6
CF3
7
5
-
ClO4
CH3
N
H3C
Scheme 2. Conversion of hydrazone 3 to tetrahydro-1,2,4-triazine 4.
N CH3
N
N
H
N
N
N
-
ClO4
N
H3C
CH3
N
N CH3
1
cinachyramine ( )
N
8 (100%)
N
H
N
N
Scheme 4. Synthesis of amidinium hydrazone 8.
N
N
8
cinachyramine (1)
-
ClO4
-
ClO4
OH
OH
H
N
N
N
N
10
9
Scheme 3. Retrosynthesis of cinachyramine (1).
perchlorate salt in 97% yield. Oxidation of the hydroxy group in 9
with Jones reagent gave oxo amidinium perchlorate salt 12 in
42% yield. Although the amidinium salt is quite stable, deprotona-
tion with K2CO3 or NaOH led to partial hydrolysis of the unproto-
nated amidine. Consistent with this observation, the Swern
oxidation and other neutral or basic oxidation procedures were
unsuccessful. Therefore, Jones oxidation was the method of choice
despite the moderate yield.
The structure of 12 was confirmed by X-ray crystal structure
analysis (see Fig. 1), which also established that the perchlorate
ion was tightly bound and did not exchange with the sulfate ion
from the sulfuric acid in the Jones oxidation.6 It should also be
noted that oxo amidinium cation 12 appeared to slowly equilibrate
with the hemiketal during prolonged storage in CD3OD solution.7
Oxo amidinium perchlorate 12 was stirred in excess 1,
Figure 1. Crystal structure of oxo amidinium perchlorate 12.
tetrahydro-1,2,4-triazine 4b and the analogous tetrahydro oxadi-
azine resulting from a 1,5-sigmatropic hydrogen shift prior to
imine formation. Therefore the facile 1,5-sigmatropic hydrogen
shift that occurs with the trifluoromethyliminium dimethylhyd-
razone cation 5 does not occur under the same conditions with
amidinium dimethylhydrazone 8. Presumably the trifluorometh-
yliminium cation of 5 is much more acidic and therefore more
reactive than the amidinium cation of 8.
We briefly investigated other procedures for the conversion of 8
to cinachyramine (1). No reaction occurred on irradiation with 300
or 350 nm UV light in CD3OD or D2O. Treating 8 with a wide range
of bases either gave recovered 8 or extensive decomposition
without any evidence for the formation of cinachyramine (1).
Although this approach to cinachyramine was not successful,
the hydrogenation of 10 provides a very simple and practical route
1-dimethylhydrazine for 4 h to afford hydrazone salt
8 in
quantitative yield. With the key intermediate 8 in hand we began
to investigate the 1,5-sigmatropic hydrogen shift and cyclization
needed to complete the synthesis of cinachyramine (1). Unfortu-
nately, no reaction occurred on heating 8 in the presence of silica
gel with or without NH4OAc in an oil bath or in a MW oven at
70–100 °C. No reaction occurred in TFA at 25 °C or on microwave
heating with silica gel prior to decomposition at 250 °C.
To verify that we were carrying out the reaction properly,
trifluoroacetyl hydrazone 3b was prepared by the literature
procedure.2a,b Heating 3b with NH4OAc in the presence of silica
in the MW oven for 1 h cleanly afforded a 1.7:1 mixture of

O.V. Barykina-Tassa, B.B. Snider / Tetrahedron Letters 56 (2015) 3151–3154
3153
developed by Kamatori to convert hydrazone 3a to tetrahydro-
1,2,4-triazine 4a. However, we have shown that hydrogenation
(3 atm) of readily available pyrido[1,2-a]pyrimidines 10, 14, and
17 over 5% Rh/Al2O3 forms 1,5-diazabicyclo[4.4.0]dec-5-enes 9,
15, and 18 in >95% yield. Since pyrido[1,2-a]pyrimidines can be
prepared in a single high-yield step from substituted 2-aminopyri-
dines and 1,3-dicarbonyl compounds,10b hydrogenation provides
a general route to a wide variety of novel substituted 1,5-diazabi-
cyclo[4.4.0]dec-5-enes.
EtO
OEt
OEt OEt
-
ClO4
NH2
N
N
N
60% HClO4
EtOH, 80 °C, 2 h
13
14
(86%)
5% Rh/Al2O3
H2 (3 atm)
EtOH, 18 h
-
DOWEX 550A
(OH- form)
CH2Cl2
ClO4
H
N
Acknowledgments
N
We thank the NIH (R01 GM-50151) for partial support of this
research.
N
N
16
(90%)
15
(95%)
Supplementary data
Scheme 5. Synthesis of 1,5-diazabicyclo[4.4.0]dec-5-ene (DBD, 16).
Supplementary data (experimental details and spectra) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.12.071.
to 7-hydroxy-1,5-diazabicyclo[4.4.0]dec-5-ene (9). 1,8-Diazabicy-
clo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-
ene are readily available and widely used as bases,8 but the
intermediate compound 1,5-diazabicyclo[4.4.0]dec-5-ene (DBD,
16) has been reported only a few times.9 We therefore decided to
explore the generality of this route to DBD derivatives. Condensa-
tion of 2-aminopyridine (13) with 1,1,3,3-tetraethoxypropane
by the literature procedure10 in EtOH and 60% HClO4 at 80 °C for
2 h provided 14 in 86% yield (see Scheme 5). Hydrogenation
(3 atm) of a suspension of 14 in EtOH over 5% Rh/Al2O3 for 18 h
afforded amidinium salt 15 in 95% yield. We did not determine
the minimum amount of rhodium needed, but note that the hydro-
genation was efficient with 0.5% Rh (10 mg of 5% catalyst per mmol
of 14). Amidinium salts such as 15 are stable, but free amidines
such as 16 hydrolyze very readily to the N-aminopropyl lactam
as has also been noted for DBU.8b,11,12 Free amidine 16 was
prepared by passing a solution of 15 in CH2Cl2 through DOWEX
550A (OHÀ form) resin and concentration.12 Evaporative distilla-
tion gave 16 in 90% yield and >95% purity.
References
1. Shimogawa, H.; Kuribayashi, S.; Teruya, T.; Suenaga, K.; Kigoshi, H. Tetrahedron
Lett. 2006, 47, 1409–1411.
2. (a) Kamitori, Y.; Hojo, M.; Masuda, R.; Fujitani, T.; Ohara, S.; Yokoyama, T. J. Org.
Chem. 1988, 53, 129–135; (b) Kamitori, Y.; Hojo, M.; Msuda, R.; Yoshida, T.;
Ohara, S.; Yamada, K.; Yoshikawa, N. J. Org. Chem. 1988, 53, 519–526; (c)
Kamitori, Y.; Hojo, M.; Masuda, R.; Takahashi, T.; Wada, M.; Hiyama, T.;
Mimura, Y. Heterocycles 1994, 38, 803–809; (d) Kamitori, Y.; Sekiyama, T.
Heterocycles 2005, 65, 2139–2150; (e) Kamitori, Y.; Sekiyama, T.; Okada, E.
Heterocycles 2007, 71, 2219–2226.
3. For reviews of pyrido[1,2-a]pyrimidinium salts, see: (a) Hermecz, I.; Mészáros,
Z. Adv. Heterocycl. Chem. 1983, 33, 242–330; (b) Hermecz, I. Adv. Heterocycl.
Chem. 2003, 85, 173–285; (c) Hajós, G. Curr. Org. Chem. 2006, 10, 319–322.
4. (a) LeonPalomino, M. I.; Zaitsev, B. E.; Gashev, S. B.; Nikitin, S. V.; Smirnov, L. D.;
Koval’chukova, O. V. Chem. Heterocycl. Compd. 1991, 27, 1110–1115. Chem.
Abstr. 1992, 117, 48471; (b) Dennin, F.; Blondeau, D.; Sliwa, H. Tetrahedron Lett.
1991, 32, 4307–4308.
5. Hydrogenation of 2-aminopyridines over Rh/Al2O3 affords amidines. See, for
instance: Hansen, D. W. Jr.; Currie, M. G.; Hallinan, E. A.; Fok, K. F.; Hagen, T. J.;
Bergmanis, A. A.; Kramer, S. W.; Lee, L. F.; Metz, S.; Moore, W. M.; Peterson, K.
B.; Pitzele, B. S.; Spangler, D. P.; Webber, R. K.; Toth, M. V.; Trivedi, M.; Tjoeng, F.
S. U.S. Patent 6,046,211, 2000; Chem. Abstr. 2000, 132, 265104.
6. Analysis of the X-ray crystal structure data suggests that the counterion is a
perchlorate, not a sulfate: (a) There is no evidence for a longer SAO single bond
corresponding to a SAOAH bisulfate group. (b) There is no evidence for any
plausible OAHÁ Á ÁO hydrogen bonds based on OÁ Á ÁO contacts. (c) The Cl@O
distances should be slightly shorter than S@O distances as is observed. (d)
Condensation of 2-aminopyridine (13) with 3,3-dimethoxyb-
utan-2-one by the literature procedure10b,13 in MeOH and 70%
HClO4 at 25 °C for 24 h provided 17 in 61% yield (see Scheme 6).
Hydrogenation (3 atm) of
a suspension of 17 in EtOH over
5% Rh/Al2O3 for 18 h afforded methyl-substituted amidinium
salt 18 in 95% yield.14
There are no likely
H peaks near the perchlorate oxygens, but this last
In conclusion, we were unable to convert amidinium dim-
ethylhydrazone 8 to cinachyramine (1) using the procedures
argument is weak owing to a minor disorder in that region. Crystallographic
data (excluding structure factors) for the structure in this Letter (12) have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no CCDC 1033656. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax:
+44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.UK.
MeO
O
-
ClO4
7. The 1H NMR spectrum of a freshly prepared solution of 12 shows a single
compound. The spectrum becomes more complex over time. The 13C NMR
spectrum shows a mixture of both the ketone and the hemi-ketal formed from
CD3OD. MS analysis of a methanolic solution of 12 shows cations with m/z of
153.1 (MH+) and 185.1 (MH++MeOH).
NH2
N
OMe Me
N
N
70% HClO4
MeOH, 25 °C, 24 h
13
Me
8. (a) Oediger, H.; Möller, F.; Eiter, K. Synthesis 1972, 591–598; (b) Nakatani, K.;
Hashimoto, S. Yuki Gosei Kagaku Kyokai 1975, 33, 925–935. Chem. Abstr. 1976,
84, 164644; (c) Hermecz, I. Adv. Heterocycl. Chem. 1987, 42, 83–202.
9. (a) Möhrle, H.; Seidel, C.-M. Arch. Pharm. 1976, 309, 471–479; (b) Rokach, J.;
Hamel, P.; Hunter, N. R.; Reader, G.; Rooney, C. S.; Anderson, P. S.; Cragoe, E. J.,
Jr.; Mandel, L. R. J. Med. Chem. 1979, 22, 237–247; (c) Birman, V. B.; Li, X.; Han,
Z. Org. Lett. 2007, 9, 37–40.
10. (a) Pollak, A.; Stanovnik, B.; Tišler, M. J. Org. Chem. 1971, 36, 2457–2462; (b)
Sawyer, J. R. H.; Wibberly, D. G. J. Chem. Soc., Perkin Trans. 1 1973, 1138–1143;
(c) Fischer, G. W. J. Prakt. Chem. 1974, 316, 474–484; (d) Tamura, S.; Ono, M.
Chem. Pharm. Bull. 1978, 26, 3167–3177.
17
(61%)
5% Rh/Al2O3
H2 (3 atm)
EtOH, 18 h
-
ClO4
H
N
11. Heidelberger, C.; Guggisberg, A.; Stephanou, E.; Hesse, M. Helv. Chim. Acta
1981, 64, 399–406.
N
12. Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43, 478–
482.
13. (a) Nesmeyanov, A. N.; Rybinskaya, M. I.; Bel’skii, N. K. Dokl. Akad. Nauk SSSR
1957, 113, 343–346. Chem. Abstr. 1957, 51, 81441; (b) Nesmeyanov, A. N.;
Me
18
(95%)
Scheme 6. Synthesis of 2-methyl-1,5-diazabicyclo[4.4.0]dec-5-enium perchlorate.

3154
O. V. Barykina-Tassa, B. B. Snider / Tetrahedron Letters 56 (2015) 3151–3154
Rybinskaya, M. I. Dokl. Akad. Nauk SSSR 1958, 118, 297–298. Chem. Abstr. 1958,
52, 55911.
14. Hydrogenation of 17 over platinum black in EtOH was reported to give the
saturated aminal based on the absorption of 5 equiv of hydrogen and
elemental analysis for nitrogen.13a However, we found that hydrogenation of
14 (1 mmol) over PtO2 (10 mg) in EtOH under 3 atm gave only amidinium
perchlorate 15 resulting from the absorption of 4 equiv of hydrogen, although
the hydrogenation was not as clean as that run over Rh/Al2O3.