An efficient preparation of 1,2-diamino-1-phenylheptane

Article abstract of DOI:10.3390/70600487

A convenient four-step method for the preparation of the lipophilic vicinal diamine 1,2-diamino-1-phenylheptane is described. Condensation involving octan-2-one, benzaldehyde and ammonia is reported. Regioselective Schmidt rearrangement of 2,6-diphenyl-3-pentyl-piperidin-4-one (1) to 2,7-diphenyl-3-pentyl hexahydrodiazapin-5-one (3) is presented. Hydrolysis of 2,7-diphenyl-3-pentyl hexahydrodiazapin-5-one to 1,2-diamino-1-phenylheptane (4) is also reported for the first time.

Full text of DOI:10.3390/70600487

Molecules 2002, 7, 487-493
molecules
ISSN 1420-3049
http://www.mdpi.org
An Efficient Preparation of 1,2-Diamino-1-phenylheptane
S. Thennarasu* and P. T. Perumal
Organic Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai – 600 020. Tamil
Nadu, India. Phone: (+91) 44 - 4913289 ; Fax: (+91) 44 – 4911589.
* Author to whom correspondence should be addressed; e-mail: sthennarasu@lycos.com
Received: 12 December 2001; in revised form: 24 June 2002 / Accepted: 25 June 2002 / Published: 30
June 2002
Abstract: A convenient four-step method for the preparation of the lipophilic vicinal
diamine 1,2-diamino-1-phenylheptane is described. Condensation involving octan-2-one,
benzaldehyde and ammonia is reported. Regioselective Schmidt rearrangement of 2,6-
diphenyl-3-pentyl-piperidin-4-one (1) to 2,7-diphenyl-3-pentyl hexahydrodiazapin-5-one
(3) is presented. Hydrolysis of 2,7-diphenyl-3-pentyl hexahydrodiazapin-5-one to 1,2-
diamino-1-phenylheptane (4) is also reported for the first time.
Keywords: Piperidinone, Schmidt rearrangement, Hexahydrodiazapinone, Vicinal diamine
Introduction
Vicinal diamines have assumed a significant importance in Organic Synthesis [1] especially in drug
design [2] and in the development of salen complexes for cancer chemotherapy [3,4]. Several
lipophilic amines and diamines have been shown to exhibit antiinflamatory [5] and antimicrobial
activities [6]. They are also useful intermediates in the production of surfactants, resins, drugs,
pesticides and heterocyclic compunds [7]. Previously available methods for the preparation of vicinal
diamines involve (i) reduction of diazides in the presence of Mn (III) salt [8], (ii) catalytic reduction of
dioximes [9], (iii) nucleophilic ring opening of aziridines [10,11], (iv) irradiation of imines [12], (v)
reductive amination of α-amino ketones [13], (vi) reduction of α-amino nitriles [14], (vii) reductive
coupling of aldimines [15], and (viii) reduction of aliphatic α,β-dinitro compounds [16]. The

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Molecules 2002, 7
applicability of these methods is limited by several disadvantages such as the explosive nature of
diazides, requirement for careful selection of reducing agents and the formation of by-products. As a
part of our investigation to identify the biophysical properties governing the antimicrobial activity of
lipophilic vicinal diamines and diamides, this paper describes an efficient and straightforward four-step
synthetic sequence leading in excellent yields to a relatively inaccessible lipophilic vicinal diamine,
1,2-diamino-1-phenylheptane from easily available starting materials, with cinnamic acid being the
only side product. Using this protocol we have prepared a series of vicinal diamines starting from
appropriate methyl ketones. Preparation of some of these vicinal diamines via Beckmann
rearrangement has been reported in the literature [22].
Results and Discussion
Three component condensation involving benzaldehyde, octan-2-one and ammonia proceeded
smoothly in ethanol at higher temperatures (60-70oC) [17-19]. The resultant 2,6-diphenyl-3-pentyl-
piperidin-4-one (1) was stable and obtained in quantitative yield (Scheme 1).
Scheme 1
O
Ethanol/ 70oC
O
2 PhCHO + CH3COONH4 +
N
H
1
Ether/ HCl
O
O
NH
H2SO4/ NaN3
N
H2Cl
N
H
2
3
6N HCl
reflux
COOH
ClH3N
ClH3N
+
5
4

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Molecules 2002, 7
The reaction could be carried out on a large scale in a very simple procedure. Piperidin-4-ones of
type 1 derived from octanone or methyl ketones with a long aliphatic chain have not been reported
before. The structure of compound 1 was identified by comparing its spectral data with those of other
piperidinones of type 1, and confirmed by elemental analysis. The appearance of the strong carbonyl
stretch at 1714 cm-1 is typical of a six member cyclic ketone. The Bohlmann bands [19] at 2700–2850
cm-1 are further evidence in favour of structure 1. Bohlmann bands have been observed earlier in both
piperidinones of type1 and hexahydrodiazapinones of type 2. Analysis of the 1H-and 13C-NMR spectra
also provide evidence in favour of piperidinone 1. The 13C-NMR spectrum of 1 is of particular interest.
The carbonyl carbon resonates at 209 ppm. The quaternary carbons on the two phenyl rings appear at
143.0 and 141.8 ppm indicating the asymmetric nature of the molecule.
Use of the Schmidt rearrangement [20,21] usually results in regioselective formation of lactams.
However, the yields may vary depending on the nature of addition of reactants, temperature and the
mode of neutralization of the reaction mixture. Of the two possible isomers resulting from the Schmidt
rearrangement of the piperidinone hydrochloride 2, only one isomer, 3, was obtained as expected. The
IR spectrum of the diazapinone 3 displays two bands at 3206 cm-1 and 3084 cm-1, corresponding to
amine NH and amide NH, respectively. The strong band at 1674 cm-1 is indicative of the lactam 3.
1
13
Analysis of H and C-NMR spectra of the product revealed that it is the alkyl substituted C3 carbon
which migrates during Schmidt rearrangement producing the hexahydrodiazapinone 3. Whereas the
multiplet corresponding to H3 of 1 appears at 2.6 ppm, the multiplet signal for H3 of 3 resonates at 3.7
ppm. This marked downfield shift of the H3 multiplet provides strong evidence for the regioselective
formation of lactam 3 during the Schmidt rearrangement. The disappearance of the singlets at 5.8 ppm
and 2.05 ppm upon exchange with D2O is attributed to the labile nature of the amide and amine
protons, respectively. The appearance of amide carbonyl peak at 176 ppm and the downfield shift in
the resonance position of C3 (70 ppm) in the 13C-NMR spectrum of 3, provide complementary
evidence suggesting that C3 is adjacent to amide NH and not to the carbonyl group.
Hydrolysis [22] of the 2,7-diphenyl-3-pentyl-hexahydrodiazapin-5-one 3 under reflux for 12h using
6N hydrochloric acid resulted in the quantitative formation of water soluble vicinal diamine 4 and
cinnamic acid (5). The cinnamic acid produced during hydrolysis crystallized readily at room
temperature and was easily separated by filtration, and the residual acid was removed by extraction
with ether, making the procedure very simple. Compound 5 was identified as cinnamic acid by
comparing its spectra with those obtained from the authentic sample. The identity of vicinal diamine 4
was established using physical and spectroscopic data. Unambiguous assignment of the proton and 13C-
NMR spectra of the diamine 4 was accomplished via the corresponding HETCOR spectrum (See
Figure 1). The broad peak at 9.05 ppm in the 1H-nmr of 4 is attributed to the two amino groups in their
hydrochloride form. The singlet at 3.35 ppm is from water impurity. All other assignments are given in
the experimental section. The formation of diamine was confirmed by elemental analysis and by
converting the diamine to lipophilic diamides for further studies.

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Molecules 2002, 7
Figure 1
Conclusions
This paper describes a convenient method for the preparation of lipophilic vicinal diamine 4. The
condensation involving octan-2-one, benzaldehyde and ammonia is reported for the first time. The
regioselective Schmidt rearrangement of piperidin-4-one 2 resulting in the formation of lactam 3 is
presented. Acid hydrolysis of the lactam yields easily separable vicinal diamine.
Experimental Section
General
Melting points were recorded on a Ragaa hot stage capillary melting point apparatus and are
1
uncorrected. The H- (300-MHz) and 13C-NMR (75-MHz) spectra were obtained on a Bruker MSL
1
300P (FT mode) Spectrometer. The 400 MHz H-NMR spectrum for compound 3 was recorded on a
Jeol 400 GSX Spectrometer. The 1H- (400 MHz), 13C- (100 MHz) and HETCOR spectra for compound
4 were obtained on a 400 MHz Avance Bruker spectrometer. Tetramethylsilane was used as an
internal standard. The mass and IR spectra were recorded on a Perkin-Elmer GC-Mass and Perkin
Elmer Spectrum RX I spectrometers, respectively.

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Molecules 2002, 7
3-Pentyl-2,6-diphenylpiperidin-4-one (1) .
Benzaldehyde (21.2g, 0.2 mol), octan-2-one (16.0 mL, 0.1 mol; Fluka) and ammonium acetate (7.7
g, 0.1 mol) were added to dehydrated ethanol (100 mL) placed in a conical flask. The contents of the
flask were warmed over a water-bath or hot-plate for about 30-45 minutes with occasional shaking
during which time the solution turned amber coloured. The solution was left standing overnight and the
precipitate formed was separated by filtration. The solid was purified further by crystallization from
o
ethanol or methanol. Yield 16.4g, (51%); mp: 97-98 C; IR (KBr): 3063, 3033, 2923, 2854, 1713
1
(C=O), 1457, 759, 700, 653 cm-1; H-NMR (CDCl3) δ 7.45- 7.26 (m, 10H, Ar.); 4.08 (d, 1H, H6, J=
8.8 Hz); 3.71 (d, 1H, H2, J=10.2 Hz); 2.72-2.62 (dd, 2H, H5 merged with m, 1H, H3); 2.08 (s, 1H,
NH); 1.61 (m, 2H); 1.25 (m, 2H); 1.09 (m, 2H); 0.98 (m, 2H); 0.77 (t, J=7.6 Hz, 3H). 13C-NMR
(CDCl3) δ 209.0, 143.8, 141.8, 128.6, 128.5, 128.0, 127.9, 126.5, 67.2, 61.8, 57.0, 51.5, 31.9, 27.3,
24.6, 22.3, 13.9.; MS (m/z, EI+) 322 (M+1), 321 (M+), 264, 208, 194, 165, 145, 131, 116, 103, 91, 77,
55.; Elemental Analysis [Calculated (Found)]: C: 82.13 (82.42); H: 8.40 (8.51); N: 4.36 (4.35).
3-Pentyl-2,6-diphenylpiperidin-4-one Hydrochloride (2).
Dry powdered compound 1 (16.0 g, 49.8 mmol) was dissolved in ether (300 mL) in a conical flask
and HCl gas was passed through the solution till the precipitation of the white salt was complete. The
precipitated solid was separated by filtration, washed with ether, dried and crystallized from ethanol to
afford colourless flakes of 2. Yield 16.50g (92%); mp: 168-169 oC.
3-Pentyl-2,7-diphenylhexahydro-1,4-diazepin-5-one (3).
Powdered 2 (10.0g, 27.9 mmol ) was added, in small portions, to ice-cold concentrated H2SO4 (50
mL) in a conical flask equipped with a magnetic stirrer. After the addition was complete, the solution
was allowed to equilibrate to room temperature. Sodium azide (3.0 g, 46.15 mmol) was added in
portions over a period of one hour. After the addition was over, the solution was poured into crushed
ice, the pH was adjusted to ~8.0 using 2N NaOH solution and the white solid separated was isolated by
filtration. The solid was further purified by crystallization from benzene. Yield 6.75g (72%); mp: 149-
o
1
150 C; IR (KBr) 3206, 3084, 2958, 1674 (NHC=O), 1428, 1327, 758, 697, 538 cm-1; H-NMR
(CDCl3 ; 400 MHz) δ 7.41-7.29 (m, 10 H, Ar); 5.88 (s, 1H, CONH); 4.13 (d, 1H, H7, J=10.74 Hz);
3
3.77-3.67 (merged d, 1H, H2, J=7.81 Hz and m, 1H, H3); 3.14 (dd, 1H, axial H6, J=10.74 Hz,
2J=14.21 Hz); 2.64 (dd, 1H, equatorial H6, 3J=1.71 Hz, 2J=14.02 Hz); 2.03 (s, 1H, NH); 1.35 (m, 2H);
3
1.16 (m, 2H); 1.08 (m,2H); 1.04 (m,2H); 0.80 (t, J=7.08 Hz, 3H). 13C-NMR (CDCl3) δ 176.0
(CONH), 144.8, 142.0, 128.6,127.9,127.7,127.6,126.4, 70.3, 59.7, 58.9, 47.4, 32.5, 31.1, 24.9, 22.3,
13.8.; MS (m/z, EI+) 338 (M+2), 314, 292, 118, 100, 91, 11, 55.; Elemental Analysis [Calculated
(Found)]: C: 78.46 (78.86); H: 8.32 (8.45); N: 8.32 (8.31).

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Molecules 2002, 7
1,2-Diamino-1-phenylheptane dihydrochloride (4).
Dry solid 3 (5.0g, 14.9 mmol ) was added to 6N HCl (150 mL) in a 250 mL RB Flask and heated
under reflux for 24 h. Upon cooling to RT, colourless crystals separated. The solution was filtered
through a filter paper and washed with ether (3 x 50 mL). The aqueous layer was separated and
evaporated to dryness over a water-bath. The white solid obtained was washed with ether, dried and
o
crystallized from ethanol. Yield 3.30g, (79%); decomposition point: >230 C; IR (KBr) 3129, 3041,
1
2954, 1584, 1488, 1404, 1051, 757, 696, 538 cm-1; H-NMR (DMSO-d6; 400 MHz) δ 9.05 (s, broad,
6H, NH2·HCl); 7.67 (m, 2H, Ar); 7.48 m, 3H, Ar); 4.75 (d, 1H, H1, J=6.38 Hz); 3.82 (m, 1H, H2); 1.58
13
(m, 2H); 1.32 (m, 2H); 1.18 (m, 2H); 1.07 (m, 2H); 0.80 (t, 3H, J= 6.92 Hz); C-NMR (DMSO-d6;
100 MHz) δ 133.12 (Ar), 129.12 (Ar), 128.77 (2C, Ar), 128.29 (2C, Ar3), 55.73 (C1), 52.45 (C2),
30.58 (C6), 28.26 (C3), 23.86 (C4), 21.53 (C5), 13.66 (C7); MS (m/z, EI+) 281 (M+2), 277 (M-2),
207, 149, 128, 118, 106, 100, 91, 77, 55.; Elemental Analysis [Calculated (Found)]: C: 48.92 (49.13);
H: 7.90 (7.98); N: 10.06 (10.22).
References
1. Le Gall, T.; Mioskowski, C.; Lucet, D. Angew. Chem. Int. Ed. 1998, 37, 2580.
2. Kasina, S.; Fritzberg, A. R.; Johnson D. L.; Eshima, D. J. J. Med. Chem. 1986, 29, 1933.
3. Gust, R.; Burgemeister, T.; Mannschreck, A.; Schonenberger, H. J. Med. Chem. 1990, 33, 2535.
4. Khokhar, A. R.; Al-Baker, S.; Shamsuddin, S.; Siddik, Z. H. Bioorg. Med. Chem. Lett. 1997, 40,
112.
5. Kokotos, G.; Constantinou-kokotu, V.; Naoula, C.; Hadjiparlou-litina, D. Lipids, 1999, 34, 307.
6. Telang, A. J.; Ebert, S.; Foght, J. M.; Westlake, D. M. S.; Voordouw, G. Can J. Microbiol. 1998,
44, 1061.
7. Mukoyama, M.; Iwagawa, K.; Hata, E.; Yamada, T. Jpn. Kokai Tokkyo Koho JP 1095753 (1998);
[Chem. Abstr. 1998, 128, 243824n].
8. Jones, D. S.; Srinivasan, A.; Kasina, F.; Fritzbery, A. R.; Wilkening, D. W. J. Org.Chem. 1989,
54, 1940.
9. Nagareda, K. and Susuki, S. Jpn. Kokai Tokkyo Koho JP 10 87573 (1998); [Chem. Abstr.,1998,
128, 257174n].
10. de Sousa, S. E.; O’Briew, P. Tetrahedron Lett. 1997, 38, 4885.
11. Wu J.; Hou X-L.; Dai L-X. J. Org. Chem. 2000, 65, 1344.
12. Katrizky A. R.; Fan, W. Q.; Fu, C. J. Org. Chem. 1990, 55, 3209.
13. Reetz M. T.; Kaysar, F.; Harms, K. Tetrahedron Lett., 1994, 35, 8764.
14. Gutsche, C. D.; Mei, G. C. J. Am. Chem. Soc. 1985, 107, 7964.
15. Dutta, M. P.; Baruah, B.; Boruah, A.; Dipak, P.; Sandhu, J. S. Synlett. 1998, 8, 857.
16. Ji, B.; Chen, H. Huaxue Yanjin Yu Yingyong 1999, 11, 673; [Chem. Abstr., 2000, 132, 264928x].

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Molecules 2002, 7
17. Noller, C. R.; Baliah, V. J. Am. Chem. Soc. 1948, 70, 3853.
18. Baliah, V.; Ekambaram, A.; Govidarajan, T. S. Curr. Sci. 1954, 23, 264.
19. Ravindran, T., Jeyaraman, R., Murray, R. W.; Singh, M. J. Org. Chem. 1991, 56, 4833.
20. Smith, P. A. S. In Molecular Rearrangements; de Mayo, P., Ed.; Interscience: New York, 1963;
Vol. 1, p 507.
21. Senthilkumar, U. P.; Jeyaraman, R.; Murray, R. W.; Singh, M. J. Org. Chem. 1992, 57, 6006.
22. Baliah, V., Lakshmanan, M. R.; Pandiarajan, K. Indian J. Chem. Section B. 1978, 16B, 72.
Sample availability: Samples of compounds 1, 3 and 4 are available from MDPI.
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