Terminal alkylation of linear polyamines

Full text of DOI:10.1021/jo952190f

J . Org. Chem. 1996, 61, 3221-3222
3221
Sch em e 1
Ter m in a l Alk yla tion of Lin ea r P olya m in es
J oseph A. Sclafani, Maria T. Maranto,
Thomas M. Sisk, and Scott A. Van Arman*
Department of Chemistry, Franklin and Marshall College,
Lancaster, Pennsylvania 17604-3003
Received December 11, 1995
In tr od u ction
Polyamines, both linear and macrocyclic, have been a
pervasive feature in the literature over the past several
years. They have been studied extensively for their
binding properties with several varieties of non-co-
valently associated guests.1 Spermine and its precursors
(present in all cells2 ) have been widely examined for their
roles in biology. They can influence DNA morphology3
and are likely to be involved in various steps of protein
synthesis.2 They have been shown to participate in
allosteric modulation of the N-methyl-D-aspartate recep-
tor in brain chemistry.4 Many of these functions have
suggested medical applications for compounds based on
these and other linear polyamines and their synthetic
conjugates with other moieties (for NMDA receptor,5
systemic lupus erythematosus,6 and heart disease7 ). In
addition, recent antineoplastic strategies have been
targeted toward polyamine biosynthetic pathways.8
Accordingly, several strategies have been devised to
selectively modify linear polyamines by protection/depro-
tection schemes.8a,9 Reductive amination has been shown
to be a useful method for alkylating the terminal nitro-
gens of polyamines with protected internal amines.10
Martell11 elaborated on the work of Lehn and Pascard
indicating that the protection step may not be necessary.
We are interested in the potential use of bis-terminally
substituted linear polyamines as fluorescence probes for
metal ions. Proper complexation of a metal ion by such
a species may induce a conformation in which intramo-
lecular excimer formation provides a fluorescent signal.
We report here the general use of a simple reductive
amination sequence for the alkylation of terminal amines
in linear polyamines. No products from reaction at
internal (secondary) amine sites are observed. Our
efforts to synthesize these compounds using a simple
substitution reaction on chloromethylarenes,12 or by
substitution on tosylate protected polyamines, were
unsuccessful.
Syn th esis
Two equivalents of the aryl aldehyde are treated with
the polyamine in chloroform solution. For benzaldehyde,
bis-imine formation is complete in less than 2 h. For
anthraldehyde, the addition of molecular sieves is neces-
sary and the mixture must be heated to a gentle reflux
for 2 h or stirred at room temperature overnight. The
imine is not purified13 but is dissolved in alcoholic
solution and treated with an excess of NaBH4. After a
few hours at reflux, the solvent is removed and the HCl
salt of the polyamine can be isolated after a series of
simple extractions (Scheme 1). Further purification by
recrystallization from ethanol or water is necessary for
some adducts. A similar synthesis of the monosubsti-
tuted polyamines (as described by Czarnik12b) can be
effected in high yield by using 1 equiv of the aldehyde
and an excess (5-fold) of the polyamine. All new products
(1) Examples include: (a) Kimura, E. Crown Ethers and Analogous
Compounds; Hiraoka, M., Ed.; Elsevier: Amsterdam, 1992; pp 381-
478. (b) Edwards, M. L.; Snyder, R. D.; Stemerick, D. M. J . Med. Chem.
1991, 34, 2414-2420. (c) Scrimin, P.; Tecilla, P.; Tonellato, U.; Valle,
G.; Veronese, A. J . Chem. Soc., Chem. Commun. 1995, 1163-1164.
(2) (a) Tabor, C. W.; Tabor, H. Ann. Rev. Biochem. 1984, 53, 749-
790. (b) Pegg, A. E. Biochem. J . 1986, 234, 249-262.
(3) Thomas, T. J .; Messner, R. P. Nucleic Acids Res. 1986, 14, 6721-
6733.
(4) (a) Ransom, R. W.; Stec, N. L. J . Neurochem. 1988, 51, 830. (b)
Reynolds, I. J . Neurochem. 1994, 62, 54-62.
1
have been fully characterized by H and 13C NMR, mass
spectrometry, and elemental analysis or high resolution
mass spectrometry.
(5) (a) Yoneda, Y.; Ogita, K.; Enomoto, R.; Kojima, S.; Shuto, M.;
Shirahata, A.; Samejima, K. Brain Res. 1995, 679, 15-24. (b) Romano,
C.; Williams, K.; DePriest, S.; Seshadri, R.; Marshall, G. R.; Israel,
M.; Molinoff, P. B. Mol. Pharmacol. 1992, 41, 785-792.
(6) Thomas, T. J .; Meryhew, N. L.; Messner, R. P. Arthritis Rheum.
1990, 33, 356-365.
(7) Thomas, R. W.; Cudahy, M. M.; Spilman, C. H.; Dinh, D. M.;
Watkins, T. L.; Vidmar, T. J . J . Med. Chem. 1992, 35, 1233-1245.
(8) (a) Saab, N. H.; West, E. E.; Bieszk, N. C.; Preuss, C. V.; Mank,
A. R.; Casero, R. A., J r.; Woster, P. M. J . Med. Chem. 1993, 36, 2998-
3004. (b) Bergeron, R. J .; McManis, J . S.; Weimar, W. R.; Schreier, K.
M.; Gao, F.; Wu, Q.; Ortiz-Ocasio, J .; Luchetta, G. R.; Porter, C.; Vinson,
J . R. T. J . Med. Chem. 1995, 38, 2278-2285. (c) Lakanen, J . R.; Pegg,
A. E.; Coward, J . K. J . Med. Chem. 1995, 38, 2714-2721.
(9) (a) Edwards, M. L.; Snyder, R. D.; Stemerick, D. M. J . Med.
Chem. 1991, 34, 2414-2420. (b) Mamos, P.; Karigiannis, G.; Atha-
nassopoulos, C.; Bichta, S.; Kalpaxis, D.; Papaioannou, D. Tetrahedron.
Lett. 1995, 36, 5187-5190 and references therein.
Exp er im en ta l Section
Gen er a l. Elemental analyses were performed by Quantita-
tive Technologies, Inc., Whitehouse, NJ . Mass spectral analyses
were performed at the North Carolina State University Mass
Spectrometry Laboratory for Biotechnology. All starting materi-
als were obtained from Aldrich Chemical Co.
Typ ica l E xp er im en t a l. N1,N5-Bis(9-a n t h r ylm et h yl)-
tetr a eth ylen ep en ta a m in ‚5HCl (9). 9-Anthraldehyde (1.00g;
4.85 mmol) was dissolved in 100 mL of CHCl3. To this solution
were added tetraethylenepentamine (0.45g; 2.4 mmol) and 20
g of 3 Å molecular sieves. This mixture was heated at reflux
for 2 h with stirring. Sieves were then removed by vacuum
(10) (a) In polyazamacrocycle synthesis: J azwinski, J .; Lehn, J .-
M.; Me´ric, R.; Vigneron, J .-P.; Cesario, M.; Guilhem, J .; Pascard, C.
Tetrahedron. Lett. 1987, 28, 3489-3492. (b) Overalkylation/deprotec-
tion in linear polyamine elaboration: Cetinkaya, E.; Hitchcock, P. B.;
J asim, H. A.; Lappert, M. F.; Spyropoulos, K. J . Chem. Soc., Perkin
Trans. 1 1992, 561-567.
(12) (a) Wunz, T. P.; Dorr, R. T.; Alberts, D. S.; Tunget, C. L.;
Einspahr, J .; Milton, S.; Remers, W. A. J . Med. Chem. 1987, 30, 1313.
(b) Van Arman, S. A.; Czarnik, A. W. J . Am. Chem. Soc. 1990, 112,
5376-5377.
(13) Both 13C and 1H NMR data for the crude intermediate material
leading to 7 show a symmetrical species that corresponds to the
expected imine structure.
(11) hen, D.; Martell, A. E. Tetrahedron 1991, 47, 6895-6902.
S0022-3263(95)02190-6 CCC: $12.00 © 1996 American Chemical Society

3222 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
filtration, ground a with mortar and pestle, and washed with
CHCl3. The CHCl3 solutions were pooled, and the solvent was
removed by rotary evaporation to give an orange residue
(presumably the bis imine). This residue was dissolved in 100
mL of hot methanol. NaBH4 (0.31g; 8.0 mmol) was dissolved in
15 mL of methanol and added to the methanolic imine solution.
This solution was stirred at reflux for 1.5 h and then at room
temperature overnight. The solvent was removed by rotary
evaporation to give an oily orange residue which was partitioned
between 75 mL of CHCl3 and 25 mL of 1 M NaOH. The aqueous
phase was discarded. The organic layer was further extracted
with 100 mL of 1M NaOH. Again, the aqueous phase was
discarded. The organic layer was treated with 3 mL of concen-
trated HCl, and a sticky orange solid formed in the separatory
funnel. H2O (20 mL) was added, and after a few minutes the
solid turned yellow. The organic layer remained yellow (prob-
ably 9-anthrylmethanol). The CHCl3 layer was discarded, and
the solid suspended in the aqueous layer was collected by
vacuum filtration. This solid was dried over P2O5 in vacuo at
50 °C to give a yellow solid (1.16 g; 64%). This solid was easily
purified by recrystallization from DMSO to give a pale yellow
solid with clean NMR spectra or by recrystallization from H2O
(80% recovery): mp 195-210 °C (dec); 1H NMR (300 MHz,
DMSO-d6) δ 10.0 (bs, 10NH), 8.76 (s, 2H), 8.59 (d, 4H), 8.16 (d,
4H), 7.62 (m, 8H), 5.31 (s, 4H), 3.76 (t, 4H), 3.55 (t, 4H), 3.46 (s,
8H); 13C NMR (300 MHz, DMSO-d6) δ 130.63, 130.44, 129.60,
128.68, 126.80, 125.13, 124.11, 122.30, 43.63, 42.70, 42.35, 42.24;
MS (FAB, NBA/DMSO) m/ z (relative intensity) 571 (100.00, [M
+ H]+ free base, C38H43N5), 528 (17.84); high resolution FAB
MS, m/ z calcd for C38H43N5 [M + H]+ for free amine 570.3597,
measured, 570.3602 ( 3σ.
adequately soluble in standard NMR solvents. To obtain the
free base, 600 mg of solid was partitioned between 50 mL pf
CHCl3 and 15 mL of 3 M NaOH. The organic was dried over
Na2SO4 and evaporated to a pale yellow oily residue: mp (salt)
280+ °C (dec); 1H NMR (300 MHz, CDCl3) δ 7.56-7.72 (m, 8H),
7.26-7.38 (m, 6H), 3.75 (s, 4H), 2.50-2.65 (m, 12H), 1.45 (s,
4NH); 13C NMR (300 MHz, CDCl3) δ 137.43, 132.71, 131.90,
127.21, 126.95, 126.91, 125.87, 125.58, 125.20, 124.72, 53.22,
48.65, 48.61, 48.18; MS (FAB, DEA/DMSO) m/ z (relative
intensity) 428 (100.00, [M + H]+ free base, C28H34N4), 396 (12.7),
404 (9.15), 390 (7.57), 388 (12.70), 360 (9.61), 312 (9.81). Anal.
Calcd for C28H34N4‚3.9HCl‚1H2O: C, 57.31; H, 6.85; N, 9.55; Cl,
23.56. Found: C, 57.62; H, 6.59; N, 9.55; Cl, 23.53.
N1,N5-Bis(2-n a p h t h ylm et h yl)t et r a et h ylen ep en t a m in e‚
5HCl (6): yield 55%, recrystallized from H2O (74% recovery).
Solid is not adequately soluble in standard NMR solvents. To
obtain the free base, 80 mg of solid was partitioned between 50
mL of CHCl3 and 10 mL pf 3 M NaOH. The organic was dried
over Na2SO4 and evaporated to a white solid residue: mp (salt)
1
242-253 °C (dec); H NMR (300 MHz, CDCl3) δ 7.68-7.82 (m,
8H), 7.38-7.48 (m, 6H), 3.90 (s, 4H), 2.72 (s, 8H), 2.68 (s, 8H),
1.92 (s, 5NH); 13C NMR (300 MHz, CDCl3) δ 137.85, 133.36,
132.53, 127.92, 127.57, 127.53, 126.50, 126.33, 125.88, 125.41,
53.92, 49.24, 49.20, 48.76, 48.72; MS (FAB, NBA/CH2Cl2) m/ z
(relative intensity) 470 (7.66), [M + H]+ free base, C30H39N5),
427 (28.14), 424 (19.14), 261 (100.00); high resolution FAB MS,
m/ z calcd for C30H40N5 [M + H]+ for free amine 470.3284,
measured 470.3265 ( 3σ.
N1,N3-Bis(9-a n th r ylm eth yl)d ieth ylen etr ia m in e‚3HCl (7):
yield 73% recrystallized from H2O (71% recovery); mp 220+ °C
1
N1,N3-Diben zyld ieth ylen etr ia m in e3HCl (1): yield 66%, no
recrystallization necessary; mp dec 280+ °C; 1H NMR (300 MHz,
D2O) δ 7.40 (s, 10H), 4.22 (s, 4H), 3.42 (s, 8H); 13C NMR (300
MHz, D2O) δ 130.05, 130.00, 129.88, 129.41, 51.69, 43.58, 42.57;
MS (CI, methane) m/ z (relative intensity) 284 (100.00, [M +
H]+ free base, C18H25N3), 206 (10.92), 177 (49.87), 163 (30.78),
151 (37.64), 134 (31.67), 120 (17.28), 91 (46.88). Anal. Calcd
for C18H25N3‚3HCl: C, 55.04; H, 7.19; N, 10.70; Cl, 27.08.
Found: C, 54.83; H, 7.25; N, 10.54; Cl, 27.17.
(dec) H NMR (300 MHz, DMSO-d6, T ) 80 °C) δ 8.78 (s, 2H),
8.58 (d, 4H), 8.16 (d, 4H), 7.62 (m, 8H), 5.30 (s, 4H), 3.74 (s,
4H), 3.48 (s, 4H); 13C NMR (300 MHz, DMSO-d6, T ) 80 °C) δ
130.88, 130.69, 129.94, 129.04, 127.09, 125.54, 124.57, 122.85,
43.77, 42.95, 42.83; MS (FAB, NBA/DMSO) m/ z (relative
intensity) 485 (100.00, [M + H]+ free base, C34H33N3), 381 (2.62),
307 (4.84). Anal. Calcd for C34H33N3‚3HCl‚1.5H2O: C, 65.86;
H, 6.34; N, 6.78. Found: C, 65.95; H, 6.32; N, 6.78.
N1,N4-Bis(9-a n t h r ylm et h yl)t r iet h ylen et et r a m in e ‚4H Cl
(8): yield 69% recrystallized from H2O/EtOH (80% recovery):
mp 232-244 °C (dec) 1H NMR (300 MHz, DMSO-d6, T ) 80 °C)
δ 8.75 (s, 2H), 8.59 (d, 4H), 8.14 (d, 4H), 7.61 (m, 8H), 5.31 (s,
4H), 3.78 (t, 4H), 3.58 (t, 4H), 3.48 (s, 4H); 13C NMR (300 MHz,
DMSO-d6, T ) 80 °C) δ 130.61, 130.45, 129.58, 128.65, 126.77,
125.11, 124.17, 122.31, 43.61, 42.70, 42.62, 42.17; MS (FAB,
NBA/DMSO) m/ z (relative intensity) 528 (100.00, [M + H]+ free
base, C36H38N4). Anal. Calcd for C34H33N3‚3.9HCl‚2H2O‚
2CH3CH2OH: C, 61.05; H, 6.77; N, 7.70; Cl, 18.99. Found: C,
60.76; H, 6.54; N, 7.77; Cl, 18.75.
N1,N4-Diben zyltr ieth ylen etetr a m in e‚4HCl (2): yield 43%,
no recrystallization necessary; mp 221-258 °C dec; 1H NMR (300
MHz, D2O) δ 7.71 (s, 10H), 4.46 (s, 4H), 3.52-3.58 (m, 12H);
13C NMR (300 MHz, D2O) δ 131.69, 131.20, 131.13, 130.65, 52.42,
45.09, 44.58, 44.30; MS (CI, methane) m/ z (relative intensity)
327 (100.00, [M + H]+ free base, C20H30N4), 249 (6.32), 237 (7.05),
206 (22.07), 177 (26.09), 151 (21.34). Anal. Calcd for C20H30N4‚
4HCl: C, 50.86; H, 7.26; N, 11.86; Cl, 30.02. Found: C, 50.87;
H, 7.34; N, 11.72; Cl, 29.74.
N1,N5-Diben zyltetr a eth ylen ep en ta m in e‚5HCl (3): yield
31%, recrystallized from H2O (84% recovery); mp 248-281 °C
1
(dec); H NMR (300 MHz, D2O/DMSO-d6, T ) 80 °C) δ 7.37 (s,
Ack n ow led gm en t. Mass spectral analyses were
obtained at the North Carolina State University Mass
Spectrometry Laboratory for Biotechnology. Partial
funding for the facility was obtained from the North
Carolina Biotechnology Center and the National Science
Foundation Grant 9111391. We thank Beth Buckwalter
for her time and efforts managing the NMR spectro-
scopy. We also heartily thank Research Corporation,
the Hackman Scholars program at Franklin and Mar-
shall College, and the Franklin and Marshall College
committee on grants for their generous support of this
research.
10H), 4.14 (s, 4H), 3.31 (d, 16H); 13C NMR (300 MHz, D2O/
DMSO-d6, T ) 80 °C) δ 131.31, 130.80, 130.74, 130.27, 52.25,
44.74, 44.48, 44.34, 43.72; MS (FAB, DEA/DMSO) m/ z (relative
intensity 371 (100.00, [M + H]+ free base, C22H35N5), 280 (3.38),
261 (3.34), 249 (4.19), 247 (7.38). Anal. Calcd for C22H35N5‚
5HCl: C, 47.88; H, 7.31; N, 12.69; Cl, 32.12. Found: C, 47.95;
H, 7.30; N, 12.58; Cl, 31.97.
N1,N3-Bis(2-n aph th ylm eth yl)dieth ylen etr iam in e‚3HCl (4):
yield 56% no recrystallization necessary. Solid is not adequately
soluble in standard NMR solvents. To obtain the free base, 60
mg of solid was partitioned between 10 mL of CHCl3 and 10 mL
of 3 M NaOH. The organic was dried over Na2SO4 and
evaporated to a white solid residue: mp (salt) 230-280+ °C
(dec); 1H NMR (300 MHz, CDCl3) δ 7.7-7.82 (m, 8H), 7.38-
7.48 (m, 6H), 3.94 (s, 4H), 2.75 (octet, 8H), 1.72 (s, 3NH); 13C
NMR (300 MHz, CDCl3) δ 137.14, 132.65, 131.86, 127.26, 126.90,
126.85, 125.80, 125.65, 125.19, 124.73, 53.25, 48.48, 48.04; MS
(FAB, DEA/DMSO) m/ z (relative intensity) 385 (100.00, [M +
H]+ free base, C26H29N3), 249 (21.73), 247 (63.27), 207 (19.10);
high resolution FAB MS, m/ z calcd for C26H29N3 [M + H]+ for
free amine 384.2440, measured 384.2443 ( 3σ.
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
spectra for compounds 4, 6, and 9 for proof of purity where
adequate elemental analyses were not available (3 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
N 1,N 4-B is (2-n a p h t h y lm e t h y l)t r ie t h y le n e t e t r a m in e ‚
4HCl (5): yield 52% no recrystallization necessary. Solid is not
J O952190F