Improved synthesis of an ethereal tetraamine core for dendrimer construction

Article abstract of DOI:10.1021/jo025625p

A new route to a pentaerythritol-based tetra-amine is delineated and subsequently contrasted to a previous report. Access to the pure tetraamine is facilitated by the smooth reduction of its tetraazide precusor. Characterization includes the preparation of a 4:1 Zn-tetraphenylporphyrin/tetraamine complex.

Full text of DOI:10.1021/jo025625p

J . Org. Chem. 2002, 67, 3957-3960
3957
Sch em e 1a
Im p r oved Syn th esis of a n Eth er ea l
Tetr a a m in e Cor e for Den d r im er
Con str u ction
George R. Newkome,* Amaresh Mishra, and
Charles N. Moorefield
Departments of Polymer Science and Chemistry,
Goodyear Polymer Center, The University of Akron,
Akron, Ohio 44325-4717
newkome@uakron.edu
Received February 18, 2002
Ab st r a ct : A new route to a pentaerythritol-based tetra-
amine is delineated and subsequently contrasted to a
previous report. Access to the pure tetraamine is facilitated
by the smooth reduction of its tetraazide precusor. Charac-
terization includes the preparation of a 4:1 Zn-tetraphen-
ylporphyrin/tetraamine complex.
Protocols for precise molecular cores and branched
monomers1-13 underpinning the desired perfection, or
pursuit thereof, in subsequent dendritic constructs have
been reported;14 however, if these cores are not absolutely
perfect, subsequent dendritic growth will be limited to
the degree of initial defects. In a recent publication,15
Hukkama¨ki and Pakkanen described the preparation of
a tetraamine core 6 (Scheme 1), which was accessed from
the tetranitrile precursor 1 (prepared via a simple
Michael-type addition of acrylonitrile to pentaerythritol).
Subsequent nitrile reduction afforded the tetraamine 6,
which was obtained “pure enough to proceed to polyamine
8”; however, based on their analytical and NMR data,15
their sample of the initial core was contaminated due
presumably to a retro-Michael reaction16 or secondary
amine formation17 (or a combination the two) during the
a
Key: (a) concd HCl, MeOH/H2O; (b) BH3‚THF, dry THF, 25
°C, 24 h; (c) MsCl, Et3N, 25 °C, 12 h; (d) NaN3, DMF, 60 °C, 8-9
h; (e) 10% Pd-C, H2, 25 °C, 7 h.
reduction of the starting tetranitrile. Previously, Lellek
and Stibor18a had delineated a procedure to prepare the
tetraamine via a BH3‚THF reduction of its tetranitrile
precusor; however, extended reaction times (i.e., 2 months)
preclude efficient use of this method. We herein report a
high-yield synthesis of the pure ethereal tetraamine core
6 and subsequent reaction with acrylonitrile, followed by
catalytic reduction, to give the polyamine dendrimer 8.
Supportive and comparative data demonstrate the ad-
vantage of this route to this useful core.
It is worth noting that considering the multifunctional
and commercial attributes of the pentaerythrityl starting
point, it is understandable that it has been employed in
a variety of rolls related to dendritic materials. These
include its use as a core component for chiral18a-d and
nonchiral18e-m constructs as well as its use for both a core
and/or branch junctures.18n-q It has also found utility in
the metallodendrimer arena.18r-v
(1) Newkome, G. R.; Gupta, V. K.; Griffin, R. W.; Arai, S. J . Org.
Chem. 1987, 52, 5480-5482.
(2) Newkome, G. R.; Moorefield, C. N.; Theriot, K. J . J . Org. Chem.
1988, 53, 5552-5554.
(3) Newkome, G. R.; Baker, G. R.; Behera, R. K.; J ohnson, A. L.;
Moorefield, C. N.; Weis, C. D.; Cao, W.-J .; Young, J . K. Synthesis 1991,
839-841.
(4) Newkome, G. R.; Arai, S.; Fronczek, F. R.; Moorefield, C. N.; Lin,
X.; Weis, C. D. J . Org. Chem. 1993, 58, 898-903.
(5) Newkome, G. R.; Moorefield, C. N.; Baker, G. R. Aldrichim. Acta
1992, 25, 31-38.
(6) Newkome, G. R.; Childs, B. J .; Rourk, M. J .; Baker, G. R.;
Moorefield, C. N. Biotechnol. Bioeng. 1999, 61, 243-253.
(7) Bashir-Hashemi, A.; Li, J .; Gelber, N. Tetrahedron Lett. 1995,
36, 1233-1236.
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Kaele, I. L. J . Pept. Res. 1998, 51, 297-302.
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Lett. 1999, 40, 8985-8988.
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Robert, A. J .; Edwards, C. Bioconjugate Chem. 2001, 12, 980-988.
(14) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendrimers and
Dendrons: Concepts, Syntheses, Applications; Wiley-VCH: Weinheim,
Germany, 2001.
Thus, pentaerythritol has been shown19,20 to react with
acrylonitrile to generate tetranitrile 1, which following
hydrolysis, (HClconcd) gives (98%) tetraacid21 2 confirmed
(13C NMR) by the appearance of peaks at δ 35.14 (CH2-
CO2H) and 173.25 (CO2H) and the disappearance of
peaks at δ 19.0 (CH2CN) and 118.39 (CN). Facile reduc-
tion (BH3‚THF) of tetraacid 2 afforded (97%) the colorless
tetraol 3, which was supported (13C NMR) by the loss of
(16) Smith, M. B.; March, J . March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 5th ed.; Wiley-Interscience:
New York, 2001; p 976.
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174, 205-211.
(17) Gala´n, A.; de Mendoza, J .; Prados, P.; RoJ o, J .; Echavarren, A.
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10.1021/jo025625p CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/26/2002

3958 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Sch em e 2a
a
Key: (a) 12 equiv of acrylonitrile, MeOH, 0.1 equiv of H2O, 0 f 80 °C; (b) Raney Co, EtOH, 600 psi, 60 °C, 12 h.
the signals assigned to the carboxyl moieties and the
appearance of a new signal at δ 58.09 (CH2OH). This
tetraol was readily converted (CH3SO2Cl, Et3N, >90%)
to the corresponding mesylate 4 as confirmed (13C NMR)
by the new signals at δ 66.49 (CH2O) and 37.06 (CH3).
Subsequently, the tetramesylate 4 was converted (NaN3,
DMF; 100%) to azide 5; transformation was supported
by loss of the mesylate signals (13C NMR) and a new
absorption at δ 48.45 attributed to the CH2N3 group as
well as the expected signal in the IR (2152 cm-1) for the
azide moiety and its mass spectrum (m/z 491 for M+
+
Na). Catalytic hydrogenation of azide 5 (10% Pd/C, H2,
MeOH) gave (> 95%) the corresponding tetraamine 6 as
a colorless liquid. Shift (13C NMR) of the CH2N peak to
δ 39.42, loss of the characteristic azide absorption in the
IR, and the mass spectrum confirmed the formation of
tetraamine 6. Thus, this five-step sequence (75% overall)
progressing from the tetranitrile 1 to the desired tet-
raamine 6 afforded a final product purity of 95%, or
greater, based on NMR data.
To make comparisons to the literature, this amine core
was treated25 with an excess (50%) of acrylonitrile to
generate (95%) the colorless, oily octanitrile 7 (Scheme
(18) (a) Lellek, V.; Stibor, I J . Mater. Chem. 2000, 10, 1061-1073.
(b) Kremers, J . A.; Meijer, E. W. J . Org. Chem. 1994, 59, 4262-4266.
(c) Newkome, G. R.; Lin, X.; Weis, C. D. Tetrahedron: Asymmetry 1991,
2, 957-960. (d) Shchepinov, M. S.; Mir, K. U.; Elder, J . K.; Frank-
Kamenetskii, M. D.; Southern, E. M. Nucleic Acids Res. 1999, 27,
3035-3041. (e) Young J . K.; Baker, G. R.; Newkome, G. R.; Morris, K.
F.; J ohnson, C. S. Macromolecules 1994, 27, 3464-3471. (f) Newkome,
G. R.; Woosley, B. D.; He, E.; Moorefield, C. N.; Gu¨ther, R.; Baker, G.
R.; Escamilla, G. H.; Merrill, J .; Luftmann, H. Chem. Commun. 1996,
2737-2738. (g) Halabi, A.; Strumia, M. C. J . Org. Chem. 2000, 65,
9210-9213. (h) Newkome, G. R.; Narayanan, V. V.; Echegoyan, L.;
Pe`rez-Cordero, E.; Luftmann, H. Macromolecules 1997, 30, 5187-5191.
(i) Chang, J .; Oyelaran, O.; Esser, C. K.; Kath, G. S.; King, G. W.; Uhrig,
B. G.; Konteatis, Z.; Kim, R. M.; Chapman, K. T. Tetrahedron Lett.
1999, 40, 4477-4480. (j) Newkome, G. R.; Lin, X. Macromolecules 1991,
24, 1443-1444. (k) Maltheˆte, J . New J . Chem. 1996, 20, 925-928. (l)
Hanessian, S.; Hoornaert, C.; Vernet, A. G.; Nadzan, A. M. Carbohydr.
Res. 1988, 137, C14. (m) Lin, W.-H.; Clark, W. D.; Lagow, R. J . J . Org.
Chem. 1989, 54, 1990-1992. (n) Bochkov, A. F.; Kalganov, B. E.;
Chernetskii, V. N. Izv. Akad. Nauk. SSSR, Ser. Khim 1989, 10, 2394-
2395. (o) Padias, A. B.; Hall, H. K.; Tomalia, D. A.; McConnell, J . R. J .
Org. Chem. 1987, 52, 5305-5312. (p) Lee, J .-J .; Ford, W. T.; Moore, J .
A.; Li, Y. Macromolecules 1994, 27, 4632-4634. (q) J ayaraman, G. Li,
Y.-F.; Moore, J . A.; Cramer, S. M. J . Chromatogr. A 1995, 702, 143-
155. (r) Newkome, G. R.; Cardullo, F.; Constable, E. C.; Moorefield, C.
N.; Thompson, A. M. W. C. Chem. Commun. 1993, 925-927. (s)
Newkome, G. R.; He, E. J . Mater. Chem. 1997, 7, 1237-1244. (t)
Newkome, G. R.; He. E.; God´ınez, L. A. Macromolecules 1998, 31,
4382-4386. (u) Newkome, G. R.; Gross, J . Moorefield, C. N.; Woosley,
B. D. Chem. Commun. 1997, 515-516. (v) Constable, E. C.; Housecroft
C. E.; Cattalini, M. Phillip, D. New J . Chem. 1998 193-200.
(19) Bruson, H. A. U.S. Pat. 374,603 1946.
F igu r e 1. Proton NMR spectra of (a) the originally reported
octanitrile (reproduced with permission from Elsevier Science:
Hukkama¨ki, J .; Pakkanen, P. T. J . Mol. Catal. A: Chem. 2001,
174, 205-211), and (b) octanitrile 7.
2), which was confirmed by the appearance (13C NMR)
of resonance peaks at δ 17.07 and 118.93 corresponding
to CH2CN and CN, respectively. Reduction25 (Raney Co,
600 psi, 60 °C; 95%) of this octanitrile to the comparative
octaamine 8 was confirmed by the appearance (13C NMR)
of new peaks at δ 39.19 and 25.17 assigned to the R- and
â-aminomethylene groups, respectively. Thus, in contrast
to the previously published15 1H NMR spectrum (Figure
1a) of polynitrile 7, our spectrum (Figure 1b) is devoid of
extra peaks in the region of 3.4-3.7 ppm attributed to
tetraamine impurities.
(22) Reek, J . N. H.; Schenning, A. P. H. J .; Bosman, A. W.; Meijer,
E. W.; Crossley, M. X. Chem. Commun. 1998, 11.
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(24) Derome, A. E. Modern NMR Techniques for Chemistry Research;
Baldwin, J . E., Mangus, P. D., Eds.; Pergamon Press: New York, 1993;
Vol. 6, p 245.
(20) Newkome, G. R.; Weis, C. D.; Lin, X.; Fronczek, F. R. Acta
Crystallogr. C 1993, 49, 998-1000.
(21) Newkome, G. R.; Weis, C. D. Org. Prep. Proced. Int. 1996, 28,
242-246.
(25) Adapted from procedures reported in ref 12.

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3959
F igu r e 2. Idealized representation of the 1:4 complexation of tetraamine 6 with the Zn-tetraphenylporphyrin 9.
69.22 (tCCH2); 1H NMR (CD3OD) δ 1.62 (8H, q), 2.0 (4H, s), 3.3
An ideal way to evaluate the purity of such amino cores
(8H, s), 3.37 (8H, t), 3.53 (8H, t); IR 1125, 2845, 2956, 3464 cm-1
ESI-MS m/z 391 (M + Na)+ (calcd C17H36O8 368.467).
;
and subsequent dendrimers is to utilize a Zn-tetra-
phenylporphyrin shift reagent, as reported by Reek and
co-workers.22 Hence, treatment of tetraamine 6 with Zn-
tetraphenylporphyrin23 9 (1:4 ratio) in CDCl3 for 5 min
generated complex 10 (Figure 2), which exhibited sig-
nificant upfield shifts [1H NMR δ -2.13 (CH2N), -1.82
(CH2CH2CH2), 0.96 (OCH2CH2), and 1.05 (tCCH2)] of all
the pertinent absorptions related to 6. Notably, for
complexed 6, the R-aminomethylene moiety signal ap-
pears further upfield than the adjacent â-aminomethyl-
ene group in contrast to that observed for uncomplexed
6. A similar switch in 1H NMR chemical shift position
for the resonances attributed to the ethereal methylenes
was also observed. Employing COSY24 NMR on adduct
10 allowed easy assignment of the tetraamine-related 13C
NMR absorptions: δ 27.9 (CH2CH2CH2), 34.86 (CH2N),
42.95 (tC), 67.56 (OCH2CH2), 68.13 (tCCH2).
Tetr akis(5-m esyloxy-2-oxapen tyl)m eth an e (4). To a stirred
solution of tetraol 3 (5 g, 14.2 mM) in THF/CH2Cl2 (1:1, 50 mL)
at 0 °C were added a solution of mesyl chloride (7.28 g, 63.9
mM) and Et3N (6.45 g, 63.92 mM) over 1 h, and then the mixture
maintained at 25 °C for 12 h. The mixture was filtered, giving
a filtrate that was evaporated to dryness, and the residue was
dissolved in CH2Cl2, washed sequentially with water, 10% HCl,
NaHCO3, and brine, dried (MgSO4), filtered, and concentrated
in vacuo to give a white solid. This crude tetramesylate was
column chromatographed (SiO2) eluting with EtOAc/CH2Cl2 (1:
1) to afford (90%) 4, as white solid: 8.7 g; mp 68-70 °C; 13C
NMR δ 28.79 (CH2CH2CH2), 36.49 (CH3), 44.82 (tC), 66.12
(CH2CH2O), 67.31 (tCCH2), 69.2 (CH2OCH2); 1H NMR δ 1.65 (8H,
q), 2.94 (12H, s), 3.29 (8H, s), 3.36 (8H, t), 3.52 (8H, t); IR 1124,
1174, 1348, 2863, 2929 cm-1; ESI-MS m/z 703 (M + Na)+ (calcd
C21H44O16S4 680.831).
Tetr a k is(5-a zid o-2-oxa bu tyl)m eth a n e (5). To a mixture of
mesylate 4 (5 g, 7.35 mM) dissolved in anhydrous DMF (50 mL)
was added excess NaN3 (3 g, 46.1 mM). The mixture was warmed
at 60 °C for 5 h and then cooled. After concentration in vacuo,
the damp residue was washed with brine to remove residual
DMF and then extract with CH2Cl2. The crude tetraazide 5 was
column chromatographed (SiO2), eluting with EtOAc/hexane (5:
95) to give (98%) 5 as a colorless viscous liquid: 3.27 g; 13C NMR
δ 29.02 (CH2CH2CH2), 45.35 (tC), 48.46 (CH2N), 67.81 (OCH2-
CH2), 69.6 (tCCH2); 1H NMR δ 1.5 (8H, q), 2.81 (8H, t), 3.29 (8H,
s), 3.38 (8H, t); IR 1121, 2152, 2871, 2964 cm-1; ESI-MS m/z
491 (M + Na)+ (calcd C17H32O4N12 468.523).
In conclusion, it is essential to have pristine cores and
branched monomeric building blocks in order to ensure
the structural precision demanded for dendritic macro-
molecules.
Exp er im en ta l Section
Gen er a l Meth od s. The melting points were determined in
capillary tubes and are uncorrected. 1H and 13C NMR spectra
were obtained in CDCl3, unless otherwise stated.
Tet r a k is(5-a m in o-2-oxa p en t yl)m et h a n e (6). The tetra-
azide 5 (2 g) with 10% Pd/C (1 g) in MeOH (50 mL) was reduced
in basic condition to give (100%) the desired amine 6, as a
colorless liquid: 1.5 g; 13C NMR δ 33.08 (CH2CH2CH2), 39.42
Tet r a k is(5-ca r b oxy-2-oxa b u t yl)m et h a n e (2). Tetrani-
trile16,17 1 (5 g, 14.0 mM) was refluxed for 2 h in dry HCl
saturated MeOH (20 mL) solution. The solvent was evaporated
and dried to give the methyl ester of tetraacid as yellowish oil,
which was hydrolyzed with NaOH at 70 °C for 24 h. The crude
material was then crystallized from acetonitrile to afford (90%)
the tetraacid 2, as white solid: mp 107-109 °C (lit.18 mp 104-
106 °C); 13C NMR (DMSO-d6) δ 35.14 (CH2CO), 45.55 (tC), 67.23
(OCH2CH2), 69.47 (tCCH2), 173.25 (CO2H); 1H NMR (DMSO-
d6) δ 2.4 (8H, t), 3.24 (8H, s), 3.52 (8H, t), 12.14 (4H, br, s); IR
1
(CH2N), 44.81 (tC), 69.16 (OCH2CH2), 69.5 (tCCH2); H NMR δ
0.95 (2H, s), 1.37 (8H, q), 2.47 (8H, t), 3.06 (8H, s), 3.15 (8H, t);
IR 1125, 2867, 2982, 3320 cm-1; ESI-MS m/z 365 (M + H)+ (calcd
C17H40O4N4 364.531). The tetraamine was stored under an inert
atmosphere under refrigeration, until use.
Syn th esis of th e F ir st-Gen er a tion Octa n itr ile 7. To a
solution of tetraamine 6 (200 mg, 549 µmol) in MeOH (3 mL)
and water (1-2 drops) at 5 °C was added acrylonitrile (349 mg,
6.59 mM) dropwise. After being stirred for 1 h at 5 °C, the
resulting mixture was heated at 80 °C for 6 h. After cooling, the
solvent and the excess acrylonitrile were removed in vacuo to
give a residue that was dissolved in CH2Cl2, washed with water,
dried (MgSO4), and concentrated in vacuo. The crude material
was column chromatographed (SiO2), eluting with EtOAc/hexane
(80:20), to afford (90%) the colorless octanitrile 7: 410 mg; 13C
NMR δ 17.07 (CH2CN), 27.68 (CH2CH2CH2), 45.4 (tC), 49.76
(CH2CH2CN), 49.95 (NCH2), 68.65 (CH2CH2O), 70.07 (tCCH2),
118.93 (CN); 1H NMR δ 1.66 (8H, q), 2.46 (16H, t), 2.59 (8H, t),
1125, 1745, 2845, 2956 cm-1
.
Tetr a k is(5-h yd r oxy-2-oxa p en tyl)m eth a n e (3). To a stirred
solution of tetrakis(5-carboxy-2-oxabutyl)methane19 (2; 10 g, 23.6
mM) in THF (100 mL), under N2, was added a BH3‚THF solution
(1 M; 110.42 mL, 113.7 mM) dropwise at 0 °C for 1 h. After the
mixture was stirred for 12 h, MeOH (20 mL) was added to
quench the reaction, followed by water. The solvents were
evaporated in vacuo, aqueous HCl was added, and the mixture
was warmed to 60 °C for 1 h. The solution was concentrated to
dryness and extract with warm absolute EtOH to give (95%) 3,
as colorless viscous liquid: 7.7 g; 13C NMR (CD3OD) δ 32.66
(CH2CH2CH2), 45.04 (tC), 58.09 (CH2OH), 67.98 (OCH2CH2),

3960 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
2.82 (16H, t), 3.35 (8H, s), 3.43 (8H, t); IR 1095, 1365, 1461, 2244,
2852, 2919 cm-1; ESI-MS m/z 811 [M + Na]+ (calcd C41H64N12O4
788).
Syn th esis of th e F ir st-Gen er a tion Octa a m in e 8. A stirred
MeOH/H2O (9:1) suspension of octanitrile 7 (100 mg, 127 µM)
and Raney Co (H2, 600 psi) was maintained at 65 °C for 7 h.
The solution was filtered and evaporated in vacuo and then
extracted with CH2Cl2 to give (95%) octaamine 8: 95 mg; 13C
NMR (D2O) δ 25.17 (CH2CH2NH2), 28.21 (CH2CH2N), 39.19
(CH2NH2), 44.98 (tC), 50.15 and 50.88 (CH2NCH2), 69.45
(CH2CH2O), 70.22 (tCCH2); 1H NMR δ 1.63 (16H, m), 1.75 (8H,
br m), 2.53 (24H, m), 2.64 (16H, t), 3.41 (8H, s), 3.52 (8H, t); IR
1106, 1330, 1484, 1575, 2805, 2861, 2940, 3343 cm-1; ESI-MS
m/z 821.8 (M + H)+ (calcd C41H96N12O4 820.77).
Ack n ow led gm en t. We gratefully thank the Na-
tional Science Foundation (DMR 0196231) and the
Office of Naval Research (N00014-99-1-0082).
J O025625P