Effective synthesis of ortho-substituted triphenol amines via reductive amination

Article abstract of DOI:10.1016/j.tetlet.2006.02.091

An efficient synthesis of ortho-substituted triphenolamines via reductive amination is reported. This approach allows access to this increasingly important class of ligands in a structurally systematic way using either commercially or easily synthesizable

Full text of DOI:10.1016/j.tetlet.2006.02.091

Tetrahedron Letters 47 (2006) 2735–2738
Effective synthesis of ortho-substituted triphenol amines
via reductive amination
*
´
´
Leonard J. Prins, Myriam Mba Blazquez, Andrej Kolarovic and Giulia Licini
`
Universita di Padova, Dipartimento di Scienze Chimiche, via Marzolo 1, 35131 Padova, Italy
Received 2 February 2006; accepted 14 February 2006
Abstract—An efficient synthesis of ortho-substituted triphenolamines via reductive amination is reported. This approach allows
access to this increasingly important class of ligands in a structurally systematic way using either commercially or easily synthesiz-
able building blocks.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Recently, a substantial number of publications has
appeared regarding the complexation behavior of
triphenolamines 1a–d with a wide variety of transition
metals (Ti(IV),1–9 Zr(IV),10 In(III),11 Ga(III),11
Fe(III),12 Ta(V),3,13–15 Al(III)9,16) and main group
elements (Si(IV)17–19 and P(V)20), together with some
reports that deal with the catalytic behavior of some
of these complexes, particularly in polymerization reac-
tions.1,3–6,10,15 In these ligands, especially the substitu-
ents in the phenolic ortho-position are important as
these are in close vicinity to the coordination sphere of
the metal center and can therefore be used as control
element.2,7
R
N
N
OH
R
path a
+
N
N
HO
N
R
R
R=Me, t-Bu
R
R
OH
OH
OMe
OMe
path b
R
R
NH2
Br
+ 2
Scheme 1. Reported syntheses for triphenolamines 1a–d. (a) Mannich
reaction with 2,4-dialkylphenol and hexamethylenetetraamine, 100 ꢁC,
2 weeks, 40–70%. (b) Double alkylation of 2-methoxybenzylamine and
subsequent removal of the methyl groups using AlCl3, 56% overall
yield.
R
HO
R'
1a: R=R'=H
R'
1b: R=R'=Me
1c: R=R'=t-Bu
N
R
1d: R=t-Bu; R'=Me
1e: R=Me; R'=H
1f: R=t-Bu; R'=H
1g: R=Ph; R'=H
tuted phenols and affords the products in 40–70% yields
after rather long reaction times (2 weeks), while the sec-
ond requires two different phenolic reagents and protec-
tion of the OH functions as methylethers. It has been
applied to the synthesis of the unsubstituted compound
1a (R = R0 = H) affording the product, after removal of
the protecting groups with AlCl3, in 56% overall yield.
OH
OH
R'
R
The synthesis of triphenolamines 1 is usually performed
either via a one step Mannich reaction of disubstituted
phenols with hexamethylenetetraamine18 (Scheme 1,
path a) or via alkylation of 2-methoxybenzylamine with
2 equiv. of 2-methoxybenzylbromide12 (Scheme 1, path
b). The first synthesis can be applied only to p-substi-
Here we report that a series of ortho-substituted triphe-
nolamines can be easily and effectively prepared via a
different approach: reductive amination of the corre-
sponding salicylic aldehydes. This synthetic approach
allows an easy access to a variety of highly pure ortho-
substituted derivatives under simple and mild reaction
*
Corresponding author. Tel.: +39 0498 275289; fax: +39 0498
275239; e-mail: giulia.licini@unipd.it
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.091

2736
L. J. Prins et al. / Tetrahedron Letters 47 (2006) 2735–2738
conditions, in short reaction times, satisfactory chemical
yields and with easy and efficient purifications. The two
key issues that make this method successful and of gen-
eral application are: (1) the use of NaBH(AcO)3/NH4-
AcO for the reductive amination,21,22 which allows an
effective construction of the ligand skeleton, and (2)
the use of a benzyl moiety as protecting group for the
phenolic OH, which allows an easy and efficacious puri-
fication of the intermediates via chromatography or
crystallization and a quantitative removal even in the
presence of bulky ortho substituents (R = t-Bu).23
R
R
OH
OMe
CHO
MeI, K2CO3
DMF, N2, rt
CHO
NaHB(AcO)3
NH4AcO, THF
3a R=H
3e R=Me (89%)
3f R=t-Bu (90%)
2e R=Me
2f R=t-Bu
N2, rt, overnight
R
BBr3,
CH2Cl2
R
OH
OMe
N
N2,
N
3
-78 oC to rt
3
The general strategy that we set up for the synthesis con-
sists in the protection of the OH function of 3-substi-
1a R=H (60%)
4a R=H (83%)
4e R=Me (78%)
4f R=t-Bu (64%)
1e R=Me (55%)
1f R=t-Bu, no deprotection
tuted salicyl aldehydes, followed by
a threefold
reductive amination under conditions similar as
reported recently in the literature (NH4AcO, NaBH-
(AcO)3, THF).21 Removal of the protective groups gives
triphenol amines 1. Starting 3-substituted salicyl
aldehydes 3 are either commercially available or easily
Scheme 2. Synthesis of triphenol amines 1a,e,f via reductive amination
using an O-Me protecting group.
accessible from the corresponding phenol using parafor-
OH
OMOM
24
NaH
maldehyde and MgCl2
or BuLi and subsequent
+
Br
O
quenching with DMF.25
CHO
DMF, N2, rt
CHO
5a (91%)
2a
Treatment of commercially available ortho-substituted
salicyl aldehydes 2e,f with methyliodide in DMF in the
presence of potassium carbonate resulted in protection
of the phenolic OH in excellent yields (Scheme 2).26
Subsequently, including commercially available 2-meth-
oxybenzaldehyde 3a, the threefold reductive amination
was performed obtaining the O-methyl triphenolamines
4a,e,f in 65–80% yields after purification via column
chromatography (Al2O3 neutral, activity I, EtOAc/
hexane = 1:1).27 However, deprotection of the methyl
groups was only partially successful: reaction with
boron tribromide in dichloromethane afforded crude tri-
phenolamines 1a (R = H) and 1e (R = Me) in 60% and
55% yields, respectively, as confirmed by 1H NMR spec-
troscopy and ESI-MS. On the contrary, deprotection of
compound 4f, substituted with tert-butylgroups, was not
achieved at all, neither using AlCl3 in refluxing toluene.
The absence of reactivity may originate from the
increased size of the R substituent, which prevents coor-
dination of boron or aluminum to the ethereal func-
NaHB(AcO)3
NH4AcO, THF
2, rt, overnight
N
HCl (g)
OMOM
OH
N
N
3
MeOH
0 oC to rt
3
1a (35%)
6a (95%)
Scheme 3. Synthesis of triphenol amine 1a via reductive amination
using an O-MOM protecting group.
mum yield obtained was 35% using the first procedure.
This rather low yield combined with the difficulties in
purifying 6a made us avoid the use of a MOM-ether
as protective group.
1
Finally, the use of a benzylether as protective group was
investigated (Scheme 4). Commonly, this group is con-
veniently and quantitatively cleaved using H2 on Pd/C.31
tions. Furthermore, although the H NMR spectra of
the crude ligands 1a and 1e indicated a relatively high
purity, these were obtained as brown solids. Repetitive
crystallizations from dichloromethane/hexane, with a
concomitant significant drop in yield, were necessary
to obtain pure white solids.
3-Substituted salicylic aldehydes 2a,e–g were benzylated
in 80–90% yield using benzylbromide in acetonitrile in
the presence of K2CO3.32 Subsequent reductive amina-
tion yielded the desired O-benzyl triphenolamines 8 in
yields ranging from 50% to 75% after purification. Puri-
fication was possible both by recrystallization from
either dichloromethane/diethylether or ethanol or col-
umn chromatography. Treatment of 8 with 10% Pd/C
under an H2-atmosphere (1 atm) in EtOAc for 3.5 h
resulted in a quantitative and clean deprotection.
Although for the protecting group removal from deriv-
ative 8 the inherent danger exists that cleavage of the
tertiary benzylic amine also occurs, no sign of disruption
of C–N bonds was observed.33 Cleavage of these bonds
was only observed after a prolonged treatment (15 h)
Alternatively, the use of the MOM protecting group was
attempted. Alkylation of salicylaldehyde 2a28 and subse-
quent reductive amination afforded the crude MOM-
protected tri-phenol amine 6a in high yields (87% two
steps) (Scheme 3).
However, attempts to purify 6a via column chromato-
graphy using similar conditions as for 4a (Al2O3 neutral,
EtOAc/hexane = 1:1) resulted in a very low recovery,
typically around 30%. Deprotection of 6a to give 1a
was attempted using treatment with HCl(g) in MeOH
or 6 N HCl in THF (10 min reflux).25,29,30 The maxi-

L. J. Prins et al. / Tetrahedron Letters 47 (2006) 2735–2738
2737
5. Kim, Y.; Jnaneshwara, G. K.; Verkade, J. G. Inorg. Chem.
2003, 42, 1437–1447.
6. Wang, W.; Fujiki, M.; Nomura, K. Macromol. Rapid
Commun. 2004, 25, 504–505.
7. Ugrinova, V.; Ellis, G. A.; Brown, S. N. Chem. Commun.
2004, 468–469.
8. Fortner, K. C.; Bigi, J. P.; Brown, S. N. Inorg. Chem.
2005, 44, 2803–2814.
R
R
OH
+
CHO
OBn
K2CO3
Br
Ph
CH3CN, N2
reflux
CHO
NaHB(AcO)3
NH4AcO, THF
N2, rt, overnight
2a R=H
7a R=H (89%)
2e R=Me
2f R=t-Bu
2g R=Ph
7e R=Me (77%)
7f R=t-Bu (98%)
7g R=Ph (87%)
9. Kim, Y.; Verkade, J. G. Phosphorus, Sulfur Silicon Relat.
Elem. 2004, 179, 729–732.
10. Davidson, M. G.; Doherty, C. L.; Johnson, A. L.; Mahon,
M. F. Chem. Commun. 2003, 1832–1833.
11. Motekaitis, R.; Martell, A. E.; Koch, S. A.; Hwang, J.;
Quarless, D. A., Jr.; Welch, M. J. Inorg. Chem. 1998, 37,
5902–5911.
12. Hwang, J.; Govindaswamy, K.; Koch, S. A. Chem.
Commun. 1998, 1667–1668.
13. Groysman, S.; Segal, S.; Goldberg, I.; Kol, M.; Goldsch-
midt, Z. Inorg. Chem. Commun. 2004, 7, 938–941.
14. Groysman, S.; Segal, S.; Shamis, M.; Goldberg, I.; Kol,
M.; Goldschmidt, Z.; Hayut-Salant, E. J. Chem. Soc.-
Dalton Trans. 2002, 3425–3426.
R
R
H2, Pd/C
AcOEt, 2-4 hs, rt
OH
OBn
N
3
N
3
8a R=H (50%)
1a R=H (quant.)
8e R=Me (75%)
8f R=t-Bu (75%)
8g R=Ph (50%)
1e R=Me (quant.)
1f R=t-Bu (quant.)
1g R=Ph (quant.)
Scheme 4. Synthesis of triphenol amines 1a,e–g via reductive amina-
tion using an O-benzyl protecting group.
15. Kim, Y. J.; Kapoor, P. N.; Verkade, J. G. Inorg. Chem.
2002, 41, 4834–4838.
16. Kim, Y.; Verkade, J. G. Inorg. Chem. 2003, 42, 4804–
4806.
17. Timosheva, N. V.; Chandrasekaran, A.; Day, R. O.;
Holmes, R. R. Organometallics 2001, 20, 2331–2337.
18. Chandrasekaran, A.; Day, R. O.; Holmes, R. R. J. Am.
Chem. Soc. 2000, 122, 1066–1072.
under the reductive conditions, indicating the lower
reactivity of the benzylic amine versus the benzylic ether.
Triphenolamines 1a,e–g were quantitatively obtained as
pure white solids, which did not require further purifica-
tion. Optionally, the ligands can be recrystallized from
toluene. The overall yields were in the order of 40–70%.
19. Timosheva, N. V.; Chandrasekaran, A.; Day, R. O.;
Holmes, R. R. Organometallics 2000, 19, 5614–5622.
20. Timosheva, N. V.; Chandrasekaran, A.; Day, R. O.;
Holmes, R. R. J. Am. Chem. Soc. 2002, 124, 7035–7040.
21. Hajela, S. P.; Johnson, A. R.; Xu, J.; Sunderland, C. J.;
Cohen, S. M.; Caulder, D. L.; Raymond, K. N. Inorg.
Chem. 2001, 40, 3208–3216.
22. George, J. P.; Britovsek, G. J.; England, J.; Andrew, J. P.;
White, A. J. P. Inorg. Chem. 2005, 44, 8125–8134.
23. Removal of the commonly used methylether protecting
group using Lewis acids such as BBr3 or AlCl3 appears not
to be effective when bulky substituents in the phenolic
ortho-position are present.
24. Verner, E.; Katz, B. A.; Spencer, J. R.; Allen, D.; Hataye,
J.; Hruzewicz, W.; Hui, H. C.; Kolesnikov, A.; Li, Y.;
Luong, C.; Martelli, A.; Radika, K.; Rai, R.; She, M.;
Shrader, W.; Sprengeler, P. A.; Trapp, S.; Wang, J.;
Young, W. B.; Mackman, R. L. J. Med. Chem. 2001, 44,
2753–2771.
25. Antonisse, M.; Snellink-Rue¨l, B. H. M.; Ion, A. C.;
Engbersen, J. F. J.; Reinhoudt, D. N. J. Chem. Soc.,
Perkin Trans. 2 1999, 1211.
In conclusion, the reported method allows the synthesis
of highly pure ortho-substituted triphenolamines 1 with
very satisfactory yield. This approach allows, for the
first time, access to this increasingly important class of
ligands in a structurally systematic way using either
commercially or easily synthesizable building blocks.
Currently, we are employing this methodology for the
synthesis of a large library of this class of ligands for
application in coordination chemistry and catalysis.
Acknowledgments
L.J.P., M.M.B., and A.K. acknowledge the financial
support provided through the European Community’s
Human Potential Programme under contract HPRN-
CT-2001-00187 [AC3S]. The support and sponsorship
by MIUR, FIRB-2003 CAMERE-RBNE03JCR5
project and COST, Action D24 ‘Sustainable Chemical
Processes: Stereoselective Transition Metal-Catalysed
Reactions’ (WG D24/0005/2001) are also kindly
acknowledged.
26. Boger, D. L.; Hong, J.; Hikota, M.; Ishida, M. J. Am.
Chem. Soc. 1999, 121, 2471–2477.
27. A typical procedure for the reductive amination is as
follows: Salicyl aldehyde (3 equiv) and ammonium acetate
(1 equiv) were mixed in THF (ꢀ0.05 N) and sodium
triacetoxy borohydride (4.5 equiv) was added under a N2-
atmosphere. The mixture was stirred overnight at room
temperature and evaporated to dryness. The residue was
dissolved in AcOEt and washed twice with 5% KOH aq
(making sure that the aqueous layer remains basic) and
brine. Drying over Mg2SO4 and evaporation of the solvent
gave a crude product that was purified by recrystallization
or column chromatography.
References and notes
1. Bull, S. D.; Davidson, M. G.; Johnson, A. L.; Robinson,
D. E. J. E.; Mahon, M. F. Chem. Commun. 2003, 1750–
1751.
2. Kol, M.; Shamis, M.; Goldberg, I.; Goldschmidt, Z.; Alfi,
S.; Hayut-Salant, E. Inorg. Chem. Commun. 2001, 4, 177–
179.
28. Fkyerat, A.; Dubin, G.-M.; Tabacchi, R. Helv. Chim. Acta
1999, 82, 1418–1422.
3. Michalczyk, L.; De Gala, S.; Bruno, J. W. Organometallics
2001, 20, 5547–5556.
29. Wang, Q.; El Khoury, M.; Schlosser, M. Chem. Eur. J.
2000, 6, 420–426.
4. Kim, Y.; Verkade, J. G. Organometallics 2002, 21, 2395–
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30. Winfield, C. J.; Al-Mahrizy, Z.; Gravestock, M.; Bugg, T.
D. H. J. Chem. Soc., Perkin Trans. 1 2000, 3267–3276.
31. Protective groups in Organic Synthesis, 3rd ed.; Green, T.
W., Wuts, P. G. M., Eds.; Wiley: New York, 1999.
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3H, J = 7.4 Hz, ArH), 6.33 (br s, 3H, OH), 3.73 (s, 6H,
NCH2), 2.26 (s, 9H, CH3). 13C NMR (62.9 MHz, CDCl3):
d 153.7 (C), 131.3 (CH), 128.9 (CH), 125.5 (C), 121.4 (C),
120.2 (CH), 56.4 (CH2), 16.2 (CH3). ESI-MS: m/z
378.2038 (M+H+), calcd 378.2069.
Tri-(2-hydroxy-3-tert-butylbenzyl)amine 1f. Compound 1f
was obtained as a white solid (92%). Mp = 166.4–
166.7 ꢁC. 1H NMR (250 MHz, CDCl3): d 7.27 (d, 3H,
J = 7.2 Hz, ArH), 7.00 (d, 3H, J = 7.2 Hz, ArH), 6.81 (t,
3H, J = 7.2 Hz, ArH), 6.55 (br s, 3H, OH), 3.66 (s, 6H,
NCH2), 1.41 (s, 27H, CH3). 13C NMR (62.9 MHz,
CDCl3): d 153.9 (C), 137.6 (C), 129.3 (CH), 127.4 (CH),
122.6 (C), 120.0 (CH), 56.4 (CH2), 34.8 (C), 29.7
(3 · CH3). ESI-MS: m/z 504.3504 (M+H+), calcd
504.3478.
Tri-(2-hydroxy-3-phenylbenzyl)amine 1g. Compound 1g
was obtained as a white solid (95%). Mp = 157.7–
158.5 ꢁC. 1H NMR (300 MHz, CDCl3): d 7.49–7.32 (m,
15H, ArH), 7.16 (m, 6H, ArH), 6.88 (m, 3H, ArH), 3.89
(s, 6H, CH2N). 13C NMR (62.9 MHz, CDCl3): d 152.5
(C), 137.7 (C), 130.4 (CH), 130.0 (CH), 129.5 (CH),
128.9 (CH), 128.8 (C), 127.6 (CH), 123.5 (C), 120.1
(CH), 55.9 (CH2). ESI-MS: m/z 564.2552(M+H+), calcd
564.2539.
33. A typical procedure for O-benzyl groups deprotection is as
follows: Compound 8 was dissolved in degassed AcOEt
(ꢀ0.05 N) and a catalytic amount of 10% Pd/C was added
under a N2-atmosphere. Next, a H2-atmosphere (1 atm)
was applied and the reaction was stirred for 3.5 h at room
temperature. The reaction mixture was filtered over Celite
and evaporated to dryness, yielding the final product 1.
Tri-(2-hydroxybenzyl)amine 1a. Compound 1a was
obtained as a white solid (98%). Mp = 151.3–151.7 ꢁC.
1H NMR (250 MHz, CDCl3): d 8.62 (s, 3H, OH), 7.3–7.1
(m, 6H, ArH), 6.8–6.7 (m, 6H, ArH), 3.86 (s, 6H, CH2N).
13C NMR (62.9 MHz, CDCl3): d 156.3 (C), 131.1 (CH),
129.8 (CH), 122.2 (C), 119.8 (CH), 116.7 (CH), 56.7
(CH2). ESI-MS: m/z 336.1592 (M+H+), calcd 336.1600.
Tri-(2-hydroxy-3-methylbenzyl)amine 1e. Compound 1e
was obtained as a white solid (96%). Mp = 153.6–
153.9 ꢁC. 1H NMR (250 MHz, CDCl3): d 7.05 (d, 3H,
J = 7.4 Hz, ArH), 6.96 (d, 3H, J = 7.4 Hz, ArH), 6.76 (t,