The First Example of 3,7-Diazabicyclo[3.3.1]nonane Synthesis by Aminomethylation of Guareschi Imide Salts

Full text of DOI:10.1007/s10593-013-1200-x

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
THE FIRST EXAMPLE OF 3,7-DIAZABICYCLO[3.3.1]NONANE
SYNTHESIS BY AMINOMETHYLATION OF GUARESCHI
IMIDE SALTS
E. A. Chigorina1* and V. V. Dotsenko2
Keywords: bispidines, 3,7-diazabicyclo[3.3.1]nonanes, glutarimides, Guareschi imides, aminomethylation,
Mannich reaction.
2,6-Dioxopiperidine-3,5-dicarbonitriles (also known as Guareschi imides) and their salts are readily
prepared by condensation of ketones, cyanoacetic ester, and ammonia [1-3] and have proved over more than a
century to be convenient reagents for synthesizing derivatives of glutarimide, 3,3-disubstituted glutaric acids [4-
6], azaspiranes [7], etc. A single method has been reported in the literature for the cyclization of Guareschi
imides to bispidines (3,7-diazabicyclo[3.3.1]nonane derivatives) under conditions of acid hydrolysis of the
nitrile groups [4, 8-11]. The compounds obtained are of interest as intermediate products in the preparation of
substances with anti-ischemic activity [12] and of sparteine alkaloids [13].
We have previously reported a convenient method for the synthesis of 4-monosubstituted Guareschi
imide salts by the reaction of 3-aryl-2-cyanoacrylamides with cyanoacetylpyrazole [14, 15]. These compounds,
and other known 2,6-dioxopiperidine-3,5-dicarbonitriles are of general interest (as C-3/C-5 dinucleophilic
reagents) for the preparation of substituted bispidines via a double aminomethylation reaction. The Mannich
reaction of 3,5-dinucleophilic pyridine derivatives is one of the most generally applicable methods of preparing
3,7-diazabicyclo[3.3.1]nonanes [16, 17]. However, to this time there was no published evidence for the
aminomethylation of Guareschi imides. We have found that the reaction of the glutarimide salt 1a with
benzylamine and an excess of formaldehyde occurred under mild conditions to give the 2,4-dioxo-3,7-diaza-
bicyclo[3.3.1]nonane salt ("bispidinate") 2. Reaction of salt 1a with -phenethylamine and salt 1b with
benzylamine proceeded similarly. Acidification gave the expected bispidines 3a,b.
These reactions serve as a first example of the synthesis of 3,7-diazabicyclo[3.3.1]nonane derivatives
1
using Guareschi imides. The structure of compounds 2 and 3a,b was confirmed by IR and H NMR
spectroscopy data, HPLC-MS, and elemental analysis. Optimization of the conditions, limits, and potential uses
of the reaction will be the subject of future investigations.
_______
*To whom correspondence should be addressed, e-mail: echigorina@mail.ru.
1Chemical Diversity Research Institute, 2a Rabochaya St., Khimki 114401, Moscow Region, Russia.
2"ChemEx" Laboratory, Vladimir Dal' East Ukrainian National University, 20-A/7 Molodyozhnyi Kv., Lugansk
91034, Ukraine; e-mail: victor_dotsenko@bigmir.net.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1838-1840, November, 2012.
Original article submitted November 1, 2012.
1722
0009-3122/13/4811-1722©2013 Springer Science+Business Media New York

O
O
O
O
Ar
(from 1а)
PhCH2NH2
HCHO
EtOH
NC
NC
Et3NH+
N
NC
NC
1) RNH2, HCHO
EtOH
NC
O
CN
O
Ar
H
Ar
H
N
NH N
R
2) HCl
Ph
N
H
1a,b
Et3NH+
3a,b
2
1 a Ar = 2-ClC6H4, b Ar = 2-MeC6H4; 2 Ar = 2-ClC6H4;
3 a Ar = 2-ClC6H4, R = CH2CH2Ph; b Ar = 2-MeC6H4, R = CH2Ph
IR spectra were recorded on a Thermo Nicolet Magna IR 750 FTIR spectrometer for KBr pellets.
1H NMR spectra were recorded on a Bruker DPX-400 (400 MHz) instrument using DMSO-d6 with TMS as
internal standard. HPLC-MS analysis was carried out on a Shimadzu LC-10AD chromatograph with Shimadzu
SP D-10A UV-Vis (254 nm) and Sedex 75 ELSD detectors combined with a PE SCIEX API 150EX mass
spectrometer using ES-API ionization. Elemental analysis was performed on a Carlo Erba 1106 Elemental
Analyzer instrument. Melting points were determined on an Electrothermal Mel-Temp 3.0 apparatus.
Monitoring of the purity of the compounds obtained was carried out using TLC on Sorbfil PTSCh-AF-V-UV
plates with acetone–hexane (1:1) as eluent and visualized with iodine vapor and UV radiation. The starting
tetrahydropyridin-2-olates 1a [15] and 1b [14] were prepared by known methods.
Triethylammonium Salt of 7-Benzyl-9-(2-chlorophenyl)-2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane-
1,5-dicarbonitrile (2). Tetrahydropyridin-2-olate 1a (Caution, irritant!) (400 mg, 1.07 mmol), benzylamine
(0.12 ml, 1.1 mmol), and 96% EtOH (10 ml) were placed in a 50 ml-beaker, and 37% formalin (1.00 ml, 13.3
mmol, free from paraformaldehyde) was added with stirring. The mixture was boiled for 1 min and then stirred
for 1 h at about 20°C. The product precipitated upon cooling, and it was maintained for 24 h. The precipitate
was filtered off, washed with EtOH and Et2O. Yield 375 mg (69%). Colorless crystals; mp 225-227°C. IR
1
spectrum, , cm-1: 3441 (N–H), 2240 (C≡N), 1718, 1661 (C=O), 1608 (C=C). H NMR spectrum, , ppm (J,
Hz): 1.07 (9H, t, 3J = 7.1, 3СH2CH3); 2.81 (6Н, q, 3J = 7.1, 3СH2CH3); 2.99 (2Н, d, 2J = 10.8) and 3.33 (2Н, d,
2J = 10.8, 6,8-СН2); 3.72 (2Н, br. s, СН2Ph); 4.36 (1H, s, 9-СН); 7.22-7.45 (8Н, m, H Ar); 7.60-7.62 (1Н, m,
H Ar). The NH+ signal was not observed due to deuterium exchange. Mass spectrum, m/z: 102.3 [Et3NH]+,
405.3 [М-Et3N+H]+, 809.0 [2(М-Et3N)+H]+. Found, %: C 66.50; H 6.49; N 13.92. C28H32ClN5O2. Calculated, %:
C 66.46; H 6.37; N 13.84.
9-(2-Chlorophenyl)-2,4-dioxo-7-(2-phenylethyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile
(3a). Tetrahydropyridin-2-olate 1a (Caution, irritant!) (166 mg, 0.44 mmol), -phenylethylamine (0.06 ml,
0.48 mmol), 96% EtOH (6 ml), and 37% formalin (0.50 ml, 6.66 mmol) were placed in a 25 ml-beaker. The mixture
was boiled for 1 min, left for 48 h at 25°C, 96% EtOH (3 ml) was added, and then 10% HCl was added dropwise to
pH 2. After 48 h, the precipitate was filtered off and washed with 50% EtOH and Et2O. Yield 109 mg (59%). White
powder; mp 251-253°C (decomp.). IR spectrum, , cm-1: 3183 (N–H), 2262 (C≡N), 1734 sh, 1704 (C=O). 1H NMR
spectrum, , ppm (J, Hz): 2.69-2.73 (2H, m, NCH2CH2Ph); 2.79-2.83 (2H, m, NCH2CH2Ph); 3.34-3.38 (2H, m) and
3.59 (2H, d, 2J = 11.0, 6,8-CH2); 4.93 (1H, s, 9-CH); 7.19-7.29 (6H, m, H Ar); 7.51-7.53 (2H, m, H Ar); 7.69-7.71
(1H, m, H Ar); 12.76 (1H, s, NH). Mass spectrum, m/z: 419.0 [M+H]+, 837.3 [2M+H]+. Found, %: C 65.82; H 4.68;
N 13.43. C23H19ClN4O2. Calculated, %: C 65.95; H 4.57; N 13.38.
7-Benzyl-9-(2-methylphenyl)-2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile (3b) was
prepared similarly to the bispidine 3a from salt 1b (300 mg, 0.85 mmol), benzylamine (0.1 ml, 0.93 mmol), and
37% formalin (1.0 ml, 13.3 mmol). Yield 126 mg (39%). Colorless crystals; mp 262-264°C. 1H NMR spectrum,
2
2
, ppm (J, Hz): 2.48 (3Н, s, Me); 3.31 (2Н, d, J = 10.9) and 3.42 (2Н, d, J = 10.9, 6,8-СН2); 3.78 (2Н, br. s,
СН2Ph); 4.38 (1H, s, 9-СН); 7.08 (1Н, d, 3J = 6.8, Н Ar); 7.24-7.36 (8Н, m, H Ar); 12.80 (1H, br. s, NH). Mass
spectrum, m/z: 385.1 [М+H]+, 769.8 [2М+H]+. Found, %: C 71.68; H 5.37; N 14.70. C23H20N4O2. Calculated, %:
C 71.86; H 5.24; N 14.57.
1723

REFERENCES
1.
2.
3.
4.
5.
I. Guareschi, Chem. Zbl., 69 Pt. II, 544 (1898).
I. Guareschi and E. Grande, Chem. Zbl., 70 Pt. 2, 439 (1899).
I. Guareschi, Chem. Zbl., 72 Pt. I, 579 (1901).
G. J. Handley, E. R. Nelson, and T. C. Somers, Austr. J. Chem., 13, 129 (1960).
R. W. Holder, J. P. Daub, W. E. Baker, R. H. Gilbert III, and N. A. Graf, J. Org. Chem., 47, 1445
(1982).
6.
7.
P. Jimonet, Y. Ribeill, G. A. Bohme, A. Boireau, M. Cheve, D. Damour, A. Doble, A. Genevois-
Borella, F. Herman, A. Imperato, S. Le Guern, F. Manfre, J. Pratt, J. C. R. Randle, J.-M. Stutzmann, and
S. Mignani, J. Med. Chem., 43, 2371 (2000).
A. M. Badger, D. A. Schwartz, D. H. Picker, J. W. Dorman, F. C. Bradley, E. N. Cheeseman,
M. J. DiMartino, N. Hanna, and C. K. Mirabelli, J. Med. Chem., 33, 2963 (1990).
J. F. Thorpe and A. S. Wood, J. Chem. Soc., Trans., 103, 1586 (1913).
S. M. McElvain and D. H. Clemens, J. Am. Chem. Soc., 80, 3915 (1958).
L. M. Rice, C. F. Geschickter, and C. H. Grogan, J. Med. Chem., 6, 388 (1963).
Y. Xu, L. Xie, B. Han, G. D. Maynard, B. L. Chenard, and A. J. Staab, WO Pat. Appl. 2009/097405.
U. Schön, J. Antel, R. Brückner, J. Messinger, R. Franke, and A. Gruska, J. Med. Chem., 41, 318
(1998).
8.
9.
10.
11.
12.
13.
14.
N. R. Norcross, J. P. Melbardis, M. Ferris Solera, M. A. Sephton, C. Kilner, L. N. Zakharov,
P. C. Astles, S. L. Warriner, and P. R. Blakemore, J. Org. Chem., 73, 7939 (2008).
E. Chigorina and V. Dotsenko, in: Proceedings of the 15th Int. Electron. Conf. Synth. Org. Chem.,
1-30 November 2011, Sciforum Electronic Conferences Series (2011). Avail. URL:
http://www.sciforum.net/presentation/702/.
15.
E. A. Chigorina, V. V. Dotsenko, and S. G. Krivokolysko, Khim. Geterotsikl. Soedin., 1108 (2011).
[Chem. Heterocycl. Compd., 47, 913 (2011)].
16.
17.
N. S. Zefirov and S. V. Rogozina, Usp. Khim., 42, 423 (1973).
R. Jeyaraman and S. Avila, Chem. Rev., 81, 149 (1981).
1724