Triazenes: A useful protecting strategy for sensitive secondary amines

Article abstract of DOI:10.1055/s-1999-2803

The application of aryl triazene as a protecting group for sensitive secondary amines such as 4-piperidone (2) is described. The triazene protected amine is compatible with oxidative and reductive conditions as well as with lithiating and alkylating reagents. The free amine is regenerated by treatment with trifluoroacetic acid.

Full text of DOI:10.1055/s-1999-2803

1304
LETTER
Triazenes: A Useful Protecting Strategy for Sensitive Secondary Amines
Ryszard Lazny,*a Janusz Poplawski,a Johannes Köbberling,b Dieter Enders,b Stefan Bräse*b
aInstitute of Chemistry, University of Bialystok, Al. Pilsudskiego 11/4, 15-443 Bialystok, Poland
bInstitut für Organische Chemie der Technischen Hochschule, Professor-Pirlet-Straße 1, D-52074 Aachen, Germany
aFax +(48) (0) 58 7457581; E-mail: lazny@noc.uwb.edu.pl; bFax:+(49) (0) 241/8888127; E-mail: Braese@oc.RWTH-Aachen.de
Received 4 June 19998
by treatment with charcoal and chromatography (yields
Abstract: The application of aryl triazene as a protecting group for
60-90%). The triazenes 3 and 12 are stable in contact
with air and at elevated temperatures (boiling ethanol).
sensitive secondary amines such as 4-piperidone (2) is described.
The triazene protected amine is compatible with oxidative and re-
We have also observed that the triazenes were stable to m-
CPBA and ethyl iodide for several hours at r.t. However
carboxylic acids (e.g. m-chlorobenzoic acid) will cause
slow cleavage of the triazene group. Chromatography on
silica gel is possible.
ductive conditions as well as with lithiating and alkylating reagents.
The free amine is regenerated by treatment with trifluoroacetic acid.
Key words: amines, piperidones, protecting groups, triazenes
The secondary amine is a functional group which is often
found in natural products and biologically active sub-
stances (N-methylamino acids, alkaloids). Although many
methods exist for protecting amino groups, few are com-
patible with metal hydride reductions, organolithium
bases and alkylating agents.1,2 During our work with 4-pi-
peridones as potential building blocks for combinatorial
asymmetric drug discovery on solid support we were
faced with the sensitivity of these compounds in deproto-
nation and reduction reactions. Because neither an estab-
lished linker nor a protecting group served our needs for
the planed transformations, our search for unusual pro-
tecting groups led us to the idea of using the diazenyl
group.3 In this letter, we describe our observations on the
preparation, stability and cleavage of triazene moieties
containing the base sensitive amine 4-piperidone (2). Tri-
azenes are well known substances which have been ap-
plied for the protection of primary aromatic amines.4 -9
However, less attention has been focussed on the use of
triazenes as suitable amine protecting groups10 and only
two reports dealt with piperidone or piperidinol based tri-
azenes.4,11
Scheme 2 (a) PhN2BF4, Et3N, -10 °C then r.t., 60%; b) LiAlH4, THF,
95%; c) PDC, CH2Cl2, 75%; d) Me2NNH2, 95%, e) TsNHNH2, EtOH,
70%, f) 1. LDA, THF, -78 °C; 2. BzCN, 65%; g) 1. t-BuLi, THF,
-78 °C, 2. EtI, 85%; h) NaBH4, EtOH, reflux, 70%; i) CuCl2, aq THF,
50%.
Reactions
The triazene protected 4-piperidone 3 was reduced with
LiAlH4 in THF at r.t. in excellent yield (Scheme 2). The
resulting alcohol 4 was oxidized with pyridinium dichro-
mate (PDC) in good yield showing that the triazene pro-
vides suitable protection for amines against chromium
based oxidants and prevents strong coordination of
amines to chromium by-products.13 Ketone 3 was easily
acylated to give dione 7 (LDA, THF, followed by Ph-
COCN at -78 °C). Furthermore, it reacted readily with
dimethylhydrazine or tosylhydrazine to give the corre-
sponding hydrazones 5 and 6, respectively. Dimethyl-
hydrazone 5 was lithiated with t-BuLi in THF at -78 °C
Scheme 1
Protection of amine
The secondary amine functionality was protected by
adoption of the method of Gross et al.5 as the phenyl tria-
zene 1 by mixing a cold solution of phenyl diazonium
salts with a cooled mixture of the secondary amine, trieth-
ylamine and aqueous THF.12 p-Toluidine or p-chloroa-
niline as diazonium precursors are in some cases
beneficial because the resulting products show a higher
tendency to crystallize. The crude products were purified
Synlett 1999, No. 8, 1304–1306 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Triazenes: A Useful Protecting Strategy for Sensitive Secondary Amines
1305
and alkylated with ethyl iodide to give hydrazone 8. from piperazine (20) in 60% yield (1 equiv of diazonium
Cleavage of the hydrazone group in 8 with aqueous CuCl2 salt) or in 93% yield based on PhN2BF4 (10 excess of di-
was clean and gave piperidone 9.14 Reduction of tosylhy- amine).
drazone 6 with NaBH4 in boiling ethanol gave triazene
protected piperidine 10 in good yield. A triazene protected
N-benzylglycine prepared by hydrolysis of the corre-
Similarly, benzyl proline has served as a starting material
for a sequence of protection, reduction and esterification
(Scheme 5). The selective cleavage of the Cbz group in 24
sponding ester 12 with a hydrogen peroxide/lithium hy-
to give the triazene derivative of proline prolinol ester 25
droxide mixture, was coupled with N-benzylglycine using
was achieved under typical hydrogenolysis conditions.
The acidolysis of triazenyl group was also selective. The
somewhat lower yield of the product is due to unstable na-
ture of the amino esters 25 and 26 which renders isolation
BOP-Cl. Cleavage of the protecting group under usual
acidic conditions furnished the diketopiperazine 14 in
good overall yield.
The triazene-protected products, e.g. 9, could be convert- difficult.
ed back to the corresponding amines under mild acidic
conditions (50% TFA in CH2Cl2, r.t., 1-10 h). The arene
functionality of the protecting group decomposes cleanly
under this conditions to give benzene, which is readily re-
moved by evaporation. The secondary amines were usual-
ly isolated after conversion into acetamides with Ac2O by
an one-pot-procedure.15 Moreover, amides can be ob-
tained directly by treatment of the triazenes with aliphatic
acid chlorides in dichloromethane at room tempera-
ture.16,17 Under these conditions, the arene moiety is con-
verted to the corresponding chloroarene, whereas the Scheme 4 a) PhN2BF4, CH2Cl2, Et3N, -10 °C to r.t.; b) KOH, EtOH,
12 h, D; c) CbzCl, aq K2CO3, CH2Cl2, 12 h; d) 1. TFA, CH2Cl2, -
10 °C to r.t., 1 h; 2. aq K2CO3; e) H2, Pd/C, MeOH, 1h.
amine gives rise to the N,N-dialkyl amide.
Scheme 5 a) PhN2BF4, CH2Cl2, Et3N, -10 °C to r.t.; b) LiAlH4, THF;
c) Cbz-Pro-OH, DCC, DCM; d) H2, Pd/C, MeOH, 1 h; e) 1. TFA,
CH2Cl2, -10 °C to r.t., 1 h; 2. aq K2CO3.
In conclusion, we have demonstrated that the phenyl tria-
zene moiety can serve as a useful protecting group for sec-
ondary amines. This acids cleavable (TFA) protecting
group, combines extreme resistance to basic hydrolysis
with resistance to oxidants (PDC, H2O2, peracids), metal
hydrides (LiAlH4, NaBH4) and hydrogenation (Pd/C in
methanol), alkylating agents (methyl iodide at room tem-
perature), alkyl lithium and lithium amide bases (t-BuLi,
LDA). Moreover Lewis acids such as Ti(Oi-Pr)4 are also
compatible, however, Brønsted acids give rise to cleav-
age.
Scheme 3 a) 50% TFA in CH2Cl2, r.t., 10 h; b) Ac2O, Et3N, r.t., 8 h;
c) 1. LiOH, H2O2, 0 °C; 2. N-BnGlyOMe, BOP-Cl, 3. 50% TFA in
CH2Cl2, r.t., 10 h
In order to determine the potential orthogonality with the
Cbz based protecting group, a sequence of protection/
deprotection steps were conducted on piperazine and pro-
line derivatives (Scheme 4). First, N-butoyl piperazine
(15) was protected with the diazenyl group (16, 89%
yield), the amide hydrolyzed (17, 92% yield) and finally
the free amine functionality protected with the Cbz group
(18, 91% yield). The two different protecting groups
could be cleaved off selectively. The diazenyl group un-
der acidic conditions (to give 19, 80% yield) or the car-
bobenzyloxy group by hydrogenolysis (to give 17, 96%).
Mono protected piperazine 17 were also prepared directly
So far we observed orthogonality with ester, amide, Cbz
and other benzyl based protecting groups. This protecting
group can also serve as a linker for solid-phase organic
synthesis.3
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1306
R. Lazny et al.
LETTER
added to a cooled and stirred solution of triethylamine in aq
THF. Then the mixture was warmed up to rt and stirred for 2
h. Extractive work-up (ether), treatment with charcoal and
chromatography gave 3 (2.45 g, 60% yield). Alternatively, the
reaction can be run in organic solvents: To a stirred mixture of
2•HCl (0.70 g, 4.54 mmol) at rt and wet THF (15 mL) was
added PhN = NBF4 (0.79 g, 4.11 mmol) followed by excess of
triethylamine. Extractive work-up and purification gave 3
(0.54 g, 65%). The triazene protected N-benzylglycine
methylester 12 was prepared by adding a phenyldiazonium
solution to a cooled mixture of substrate and triethylamine.
Acknowledgement
This work was supported by the Deutscher Forschungsgemein-
schaft (Leibniz prize to D. E., Sonderforschungsbereich 380, Trans-
ferbereich 11, BR1750/1) and the Fonds der Chemischen Industrie
(Liebig stipend to St. B.). We are also grateful to the University of
Bialystok for financial support (BW-173) and thank the companies
Degussa AG, BASF AG, Hoechst AG, Bayer AG, Wacker Chemie
and Grünenthal GmbH for donations of chemicals.
References and Notes
All new compounds have been characterized by 1H and 13
C
NMR, MS, IR and elemental analysis or HRMS, respectively.
Selected NMR data: 3:1H NMR: 2.50-2.68 (m, 4 H), 4.05-
4.20 (m, 4 H), 7.10-7.25 (m, 1 H), 7.28-7.55 (m, 4 H).13C
NMR: 40.08, 45.61 br, 120.83, 126.60, 128.93, 149.94,
207.17. 5:1H NMR: 2.45 (s, 6 H), 2.50-2.59 (m, 2 H),
2.75-2.83 (m, 2 H), 3.85-4.01 (m, 4 H) 7.08-720 (m, 1 H),
7.25-7.50 (m, 4 H).13C NMR: 27.70, 33.64, 45.86 br, 46.96 br,
47.31, 47.35, 120.70, 126.18, 128.84, 150.25, 165.45. 6:1H
NMR: 2.44 (d, 3 H), 2.48-2.57 (m, 2 H), 2.58-2.70 (m, 2 H),
7.18-7.45 (m, 4 H), 7.80-7.90 (m,1 H).
(1) Greene, T.; Wuts, G. M. P. Protecting groups in Organic
Synthesis; Wiley: New York, 1991.
(2) Kocienski, P. J. Protecting Groups; Thieme Verlag Stuttgart:
1994, p. 195-199.
(3) For the use of triazenes as a linker in SPOS, see: Bräse, S.;
Köbberling, J.; Enders, D.; Lazny, R.; Wang, M.; Brandtner,
S.; Tetrahedron Lett. 1999, 40, 2105-2108.
(4) Stevens, M. F. G.; Philipp, K. S., Rathbone, D. L.; O’Shea,
D.M.; Queener, S. F. J. Med. Chem. 1997, 40, 1886-1893.
(5) Gross, M. L.; Blank, D. H.; Welch, W. M. J. Org. Chem. 1993,
58, 2104-2109.
(13) Lyle, R. E.; Maloney, J. R.; White, R. J. Org. Prep. Proced.
1980, 12, 255.
(14) Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976, 3667 and
4687.
(6) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T. Y.;
Li, H.; Bräse, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997,
119, 3421-3422.
(15) Typical procedure for the deprotection of amines and
subsequent acylation: To a cooled (0 °C) solution of the
triazene in dichloromethane (1.0 mmol), trifluoroacetic acid
(10 mmol, 10 equiv) was added. After 5 h, the excess of TFA
and solvent were removed under vacuum. The residue was
dissolved in a CH2Cl2/Et3N mixture and treated with Ac2O
(16) Strict exclusion of moisture is not necessary. Water reacts
with acid chlorides yielding the corresponding acid and as
well as HCl. Both acids increase the cleavage rate of the
triazene prior to acylation rather than disturbing the reaction
sequence.
(17) Typical procedure for the deprotection of amines and in situ
acylation: To a cooled (0 °C) solution of the triazene in
dichloromethane (1.0 mmol), the acid chloride (4.0 mmol, 4
equivalents) was added. After 24 h, the excess of acid chloride
and the solvent were removed under vacuum.
(7) Nicolaou K. C.; Takayanagi, M., Jain, N. F.; Natarajan, S.;
Koumbis, A. E.; Bando, T.; Ramanjulu, J. M. Angew. Chem.
1998, 110, 2881-2883.
(8) For recent publication on bistriazenes and triazenes see:
Hooper, D. L.; Pottier, I. R.; Vacheresse, M.; Vaughan, K.
Can. J. Chem. 1998, 76, 125.
(9) Bräse, S.; Enders, D.; Köbberling, J.; Avemaria, F. Angew.
Chem. 1998; 110, 3614-3616; Angew. Chem. Int. Ed. Engl.
1998, 37, 3413-3415.
(10) CAUTION: Triazenes are potential carcinogenic and some
members are reported to be active towards biological systems.
Therefore we recommend special caution during handling.
(11) Gescher, A.; Turnbull, C. P.; Stevens M. F. G. J. Chem. Soc.
Perkin Trans. I 1977, 2078-2082.
(12) Procedure for the protection of the secondary amine group to
give 3: To a cooled (0 °C) solution of aniline (1.86 g, 20
mmol) in a mixture of conc. HCl (12 mL) and water (10 mL)
was added cold solution of NaNO2 (1.38 g, 20 mmol). After
stirring for 30 min at 0 °C 4-piperidone hydrochloride (25
mmol) was added, the mixture was cooled to -10 °C and
Article Identifier:
1437-2096,E;1999,0,08,1304,1306,ftx,en;G15199ST.pdf
Synlett 1999, No. 8, 1304–1306 ISSN 0936-5214 © Thieme Stuttgart · New York