Monoprotection of triamines with alkyl phenyl carbonates

Full text of DOI:10.1080/00304948.2012.697748

This article was downloaded by: [Massachusetts Institute of Technology]
On: 27 February 2013, At: 02:47
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
Monoprotection of Triamines with Alkyl
Phenyl Carbonates
Amanda B. Sølvhøj a , Christian Tortzen a & Jørn B. Christensen a
a Department of Chemistry, University of Copenhagen,
Universitetsparken 5, DK-2100, Copenhagen Ø, Denmark
To cite this article: Amanda B. Sølvhøj , Christian Tortzen & Jørn B. Christensen (2012):
Monoprotection of Triamines with Alkyl Phenyl Carbonates, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 44:4, 397-400
To link to this article: http://dx.doi.org/10.1080/00304948.2012.697748
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Organic Preparations and Procedures International, 44:397–400, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.697748
Monoprotection of Triamines
with Alkyl Phenyl Carbonates
Amanda B. Sølvhøj, Christian Tortzen, and Jørn B. Christensen
Department of Chemistry, University of Copenhagen, Universitetsparken 5,
DK-2100 Copenhagen Ø, Denmark
Historically we have been interested in developing simple procedures for the partial pro-
tection of polyamines using stoichiometric amounts of reagents and avoiding the use of
chromatographic purification. We previously described the use of alkyl phenyl carbonates
for the monoprotection of diamines and diprotection of triamines in fair to good yields.1,2
Alkyl phenyl carbonates are easy to synthesize on a large scale and have a long shelf-life.1
We were interested in the monoprotection of N1-(2-aminoethyl)-1,2-diaminoethane (1),
N1-(3-aminopropyl)-1,3-diaminopropane (6) and N1-(2-aminoethyl)-1,3-diaminopropane
(9), which are commercially available, inexpensive and interesting as building blocks for a
new family of dendrimers.
The regioselective acylation of polyamines has been the subject of considerable interest
and is undoubtly related to the versatility of the products as well as the chemist’s fascination
with symmetry breaking in molecules. Since polyamines are polybasic, this suggests partial
protonation as one of the strategies for providing temporary protection of some of the
amino groups. However, this strategy requires strict pH control and prior knowledge of
the individual pKb-values. The monoacetylation of acyclic aliphatic α,ω-diamines with
phenyl acetate was studied by Bruice and Willis,3 who showed that the monoacetylation
of 1,3-diaminopropane was twelve times faster than that of 1,2-diaminoethane. This is
interesting considering that 1,2-diaminoethane is a stronger base than 1,3-diaminopropane
and it would be expected that the strongest base should be the strongest nucleophile. The
results were explained as a result of general base catalysis involving the ω-amino group
of the α,ω-diamine, where the cyclic transition state was more favorable in the case of
1,3-diaminopropane than in 1,2-diaminoethane. Sayre and coworkers4 also investigated the
acylation of 1,2-diaminoethane with various acylating reagents and found that either high-
dilution conditions or the use of weaker acylating reagents such as N-hydroxysuccinimide
esters were necessary in order to keep diacylation to a minimum. They also carried out
a kinetic study of the acetylation of a series of α,ω-diamines and derivatives, including
α,ω-dimethylated and monoamides with 4-nitrophenyl acetate, and confirmed the findings
of Bruice and Willis.3 Acylation of one of the amino groups in an α,ω-diamine reduces
Received January 9, 2012.
Address correspondence to Jørn B. Christensen, Department of Chemistry, University of Copen-
hagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark. E-mail: jbc@kiku.dk
397

398
Christensen et al.
the reactivity of the remaining amino group, pointing toward the use of acylating reagents
with reduced reactivity as a means to achieve selective discrimination in polyamines. Initial
screening of solvents and conditions indicated the use of methanol at room temperature
gave the best results. On the basis of these experiments, a series of monoprotected triamines
were prepared from the triamines and alkyl phenyl carbonates shown in Eqs. 1–5.
H2N(CH2)2NH(CH2)2NH2 + PhOCO2But −−−−→ H2N(CH2)2NH(CH2)2NH2CO2But
(1)
(2)
(3)
(4)
1
2
3 (47%)
H2N(CH2)2NH(CH2)2NH2 + PhOCO2CH2Ph −−−−→ H2N(CH2)2NH(CH2)2NHCO2CH2Ph
5 (47%)
1
4
H2N(CH2)3NH(CH2)3NH2 + PhOCO2But −−−−→ H2N(CH2)3NH(CH2)3NH2CO2But
6
2
3 (62%)
H2N(CH2)3NH(CH2)3NH2 + PhOCO2CH2Ph −−−−→ H2N(CH2)3NH(CH2)3NHCO2CH2Ph
8 (43%)
6
4
H2N(CH2)2NH(CH2)3NH2 + PhOCO2CH2Ph −−−−→ H ⊕(CH ) ⊕ H (CH ) NHCO CH Ph 2Cꢀl
(5)
3 N
2 N
10 (30%)
2
2
2
3
2
2
9
4
Common to all the selected triamines is the fact that the corresponding monoprotected
derivatives are known. They had been prepared by multi-step sequences with the exception
of 8, which had been obtained by reaction between the corresponding triamine (2) and
Boc-azide.8
The reaction between the unsymmetrical N1-(2-aminoethyl)propane-1,3-diamine (9)
and benzyl phenyl carbonate (2) was expected to give a mixture of the two regioisomers.
However, compound 10 could be isolated in pure form in 30% yield by crystallization of
the mixture of dihydrochlorides from aqueous ethanol. This selectivity fits nicely with the
predicted result based on the work of Bruice and Willis,3 and of Sayre and coworkers,4 pre-
dicting that the 1,3-diaminopropane component of the molecule would react considerably
faster than the 1,2-diaminoethane end. In conclusion, a simple method for monoprotec-
tion of triamines with alkyl phenyl carbonates in methanol that avoids chromatographic
work-up, has been developed.
Experimental Section
The triamines were purchased from Sigma-Aldrich. The alkyl phenyl carbonates were
synthesized as previously described.1,2 NMR Spectra were obtained in CDCl3 or D2O
(TMS as internal standard) on either a Varian 300 MHz or a Bruker 500 MHz spectrometer
equipped with a cryoprobe.
Typical Procedure for the Monoprotection of Triamines
To a solution of triamine (50.0 mmol) in 50 mL methanol was added dropwise a solution of
alkyl phenyl carbonate1,2 (51.5 mmol) in 50 mL methanol) over a period of 25 minutes. The
reaction mixture was stirred at room temperature for 5 days and evaporated to dryness under
reduced pressure. Upon addition of 50 mL CH2Cl2 and 50 ml 2M HCl, the diprotected
triamine hydrochloride which precipitated, was collected on a sintered glass funnel (G3).
The two-phase filtrate was separated (the methylene chloride layer was discarded) and the

Monoprotection of Triamines with Alkyl Phenyl Carbonates
399
aqueous layer was made alkaline (pH 11) with 12M NaOH and extracted with methylene
chloride (4 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered and
evaporated under reduced pressure to give the monoprotected triamines.
t-Butyl 2-(2-Aminoethylamino)ethyl Carbamate (3).6,7
Pale yellow oil. Yield: 47%. 1H NMR (300 MHz; CDCl3): δ 1.43 (s, 9 H); 1.56 (s, 3 H);
2.65–2.81 (m, 6 H); 3.18–3.24 (m, 2 H); 4.99 (s, 1 H). 13C NMR (75 MHz; CDCl3): δ
28.54; 41.76; 49.16; 52.04; 79.05; 156.5.
Benzyl 2-(2-Aminoethylamino)ethyl Carbamate (5).5
Pale yellow oil. Yield: 49%. 1H NMR (300 MHz, CDCl3): δ 1.82 (s, 3 H); 2.63–2.80 (m, 6
H); 3.28 (s, 2 H); 5.09 (s, 2 H); 5.40 (s, 1 H); 7.26 - 7.37 (m, 5 H). 13C NMR (125 MHz,
CDCl3): δ 40.76; 41.56; 48.83; 51.78; 66.68; 128.06; 128.11; 128.51; 136.55; 156.37.
t-Butyl 3-(3-Aminopropylamino)propyl Carbamate (7).7,8
Pale yellow oil. Yield: 62%. 1H NMR (500 MHz, CDCl3): δ1.37 (s, 9 H); 1.57 (m, 4 H);
1.69 (broad s, 3 H); 2.59 (m, 4 H); 2.71 (t, J = 2.7 Hz, 2 H); 3.14 (m, 2 H); 5.17 (broad
s, 1 H). 13C NMR (125 MHz, CDCl3): δ 28.44; 29.82; 33.57; 39.20; 40.40; 47.75; 47.82;
78.96; 156.14.
Benzyl 3-(3-Aminopropylamino)propyl Carbamate (8).9
Pale yellow oil. Yield: 43%. 1H NMR (300 MHz; CDCl3): δ 1.51–1.68 (m, 4 H); 2.61–2.77
(m, 6 H); 3,27 (d, 2 H); 5.08 (s, 2 H); 7.26–7.35 (m, 5 H). 13C NMR (125 MHz, CDCl3): δ
29.54; 33.68; 40.05; 40.42; 47.73; 48.01; 66.44; 127.26; 128.04; 128.47; 136.82; 156.52.
N1-[3-(Benzyloxycarbonylamino)propyl]-1,2-diaminoethane Dihydrochloride (10).10
Reaction of 9 with benzyl phenyl carbonate (2) according to the general procedure
gave a pale yellow oil containing mainly N1-(3-(benzyloxycarbonylamino)propyl)-1,2-
diaminoethane. This crude material was converted to the dihydrochlorides by addition of
a solution of HCl in EtOH (generated by cautious addition of 5 mL CH3COCl to 50 mL
EtOH). Evaporation of the solution to dryness in vacuo gave a mixture of the two hy-
drochlorides which was crystallized from 96% EtOH (cooling only to room temperature!)
1
to afford white crystals (30% yield) of 10, mp. 229–230◦C (lit.6: 230–231◦C). H NMR
(D2O, 500 MHz): δ 1.83 (m, 2 H); 3.05 (t, 2 H, J = 7.5 Hz); 3.17 (t, 2 H, J = 6.5 Hz); 3.30
(br s, 4 H); 5.05 (s, 2 H); 7.37 (m, 5 H). 13C NMR (D2O, 125 MHz): δ 26.84; 35.91; 38.12;
44.76; 45.29; 65.99; 128.41; 128.47; 129.06; 137.78; 156.82.
Acknowledgements
This work was made possible through support from the Lundbeck Foundation and the
Danish Council for Independent Research/ Natural Sciences.

400
Christensen et al.
References
1. M. Pittelkow, R. Lewinsky and J. B. Christensen, Synthesis, 2195 (2002).
2. M. Pittelkow, R. Lewinsky and J. B. Christensen, Org. Syn., 84, 209 (2007).
3. T. C. Bruice and R. G. Willis, J. Am. Chem. Soc., 87, 531 (1965).
4. A. R. Jacobson, A. N. Makris and L. M. Sayre, J. Org. Chem., 52, 2592 (1987).
5. A. R. Jacobson, S. Tam and L. M. Sayre, J. Med. Chem., 34, 2816 (1991).
6. D. D. N’Da and E. W. Neuse, South African J. Chem., 59, 65 (2006); Chem. Abstr., 146, 63186
(2006).
7. S. Fixon-Owoo, F. Levasseur, K. Williams, T. N. Sabado, M. Lowe, M. Klose, A. J. Mercier, P.
Fields and J. Atkinson, Phytochemistry, 63, 315 (2003).
8. J. B. Hansen, M. C. Nielsen, U. Ehrbar and O. Buchardt, Synthesis, 404 (1982).
9. Y. Nakamura, Heterocycles, 27, 1873 (1988).
10. H. H. Lee, B. D. Palmer, B. C. Baguley, M. Chin, W. D. McFadyen, G. Wickham, D. Thorsbourne-
Palmer, L. P. G. Wakelin and W. A. Denny, J. Med. Chem., 35, 2983 (1992).