Efficient synthesis of vitamin E amines

Article abstract of DOI:10.1002/ejoc.200900088

A short and efficient synthesis of all VE amines (α-, (β-, γ-, δ- tocopheramines and -tocotrienamines) in enantiopure form is described. These amino analogues of natural vitamin E compounds (β-, γ-, δ--tocopherols and -tocotrienols) can be prepared by Pd-

Full text of DOI:10.1002/ejoc.200900088

FULL PAPER
DOI: 10.1002/ejoc.200900088
Efficient Synthesis of Vitamin E Amines
Francesco Mazzini,*[a] Thomas Netscher,[b] and Piero Salvadori*[a]
Keywords: Amination / Antitumor agents / Palladium / Arylation / Vitamins
A short and efficient synthesis of all VE amines (α-, β-, γ-, δ-
tocopheramines and -tocotrienamines) in enantiopure form is
intermediates deliver the VE amines in high yield and purity
after deprotection. The compounds prepared are key precur-
described. These amino analogues of natural vitamin E com- sors of VE amides, which are of great interest in the search
pounds (α-, β-, γ-, δ-tocopherols and -tocotrienols) can be
prepared by Pd-catalyzed N-arylation reactions on the corre-
sponding triflates, synthesized under controlled conditions
from the phenols. The benzophenone imine or benzylamine
for new therapeutics with antitumoral activity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Vitamin E (VE) is a term that encompasses a group [four
tocopherols and four tocotrienols (Figure 1)] of lipid-solu-
ble, biologically essential compounds derived from 6-chro-
manol that exhibit the biological activity of α-tocopherol.
In 1942, Smith et al. reported that the amino analogue of
(all-rac)-α-tocopherol, (all-rac)-α-tocopheramine, had ap-
proximately the same properties as α-tocopherol itself.[1]
Since that discovery, different racemic tocopheramines have
been found to exhibit biological and antioxidant activities
similar to the corresponding tocopherols and in some cases
even higher activities.[2,3] As tocopheramines are nontoxic,
these properties have made their use as food additives,[4]
polymer stabilizers,[5] and precursors of surfactants and
pharmaceutical excipients[6] effective and thus attractive.
Moreover, VE amides derived from α- and δ-tocopheram-
ines have recently[7] been shown to be potent anticancer
agents, exhibiting higher proapoptotic activity than the
structurally related ester α-tocopheryl succinate, the antitu-
moral activity of which has been well assessed in several
studies.[8,9]
Figure 1. Structures of natural tocopherols and tocotrienols (VE
compounds).
propriate formylamino- or aminophenol with phytol or iso-
phytol.[10] One of the disadvantages of these routes is that
no optical activity can be introduced into the chromane
part, providing only epimeric mixtures of tocopheramines.
Recently, Lambert and Lal[6] described the synthesis of the
optically pure amine 1d in four steps starting from the op-
tically pure (2R,4ЈR,8ЈR)-α-tocopherol (1a; Figure 1). Phe-
nol 1a was converted into the tosylate or triflate ester and
The syntheses of tocopheramines reported up to a few
years ago were low-yielding multistep procedures. They
were basically modifications of the classic route to toco-
pherols, involving the acid-catalyzed condensation of the ap-
[a] Dipartimento di Chimica e Chimica Industriale, Università di deoxygenated by Pd- or Ni-catalyzed hydrogenation or
Pisa,
metal hydride reduction. Nitrogen was then introduced at
Via Risorgimento 35, 56126 Pisa, Italy
C6 by a nitration reaction and finally another catalytic hy-
drogenation step afforded the optically pure α-tocopher-
amine. In particular, the chiral centers present in the start-
ing material and their configurations were maintained
through all the reactions. The possibility of preparing
stereopure VE amines allows the study of the importance
of their stereochemistry in the expression of their biological
Fax: +39-050-2219274
E-mails: lcap@ns.dcci.unipi.it
psalva@dcci.unipi.it
[b] Research and Development, DSM Nutritional Products,
P. O. Box 2676, 4002 Basel, Switzerland
Fax: +41-61-815-8750
E-mail: thomas.netscher@dsm.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 2063–2068
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Mazzini, T. Netscher, P. Salvadori
FULL PAPER
Scheme 1. Preparation of VE amines 1d–7d.
properties, for instance, in the transport protein recognition pheryl triflates has recently been performed by Netscher
pathway, which has already been disclosed for tocopherols and co-workers.[15] A similar approach has also been fol-
and tocotrienols.[11]
lowed by others in the successful preparation of 4d.[12]
Therefore, we have optimized the strategy and extended
it to the synthesis of tocotrienamines (Scheme 1). To intro-
duce a nitrogen function at the 6-position of the chromane
ring we investigated the use of the ammonia equivalent
benzophenone imine (9)[16] and benzylamine (10),[17] which
easily provide the free aniline by acidic hydrolysis (or trans-
amination) and by mild hydrogenolysis with ammonium
formate using Pd/C, respectively.
Very recently, following the approach outlined by Lam-
bert and Lal,[6] 1d was prepared in 48% yield in four steps
starting from triflate 1b.[12] In agreement with the data re-
ported by these authors, in our trials deoxygenation of 1b
proceeded smoothly by Pd/C hydrogenation in the presence
of Et3N, whereas it proved resistant to the NaBH4/
NiCl2·6H2O and [PdCl2(PPh3)2]/Dppp/Bu3N reduction sys-
tems. However, the subsequent nitration step gave low-to-
moderate yields and its application to the other VE homo-
logues provided complex mixtures.[12]
On the basis of these results and the interest in VE
amines, we decided to look for a simpler and more general
procedure for the synthesis of 1d–7d (Scheme 1) to make
them more easily available. Therefore we turned our atten-
tion to Pd-catalyzed aryl amination. Buchwald[13] and Hart-
wig[14] have independently developed a strategy for the Pd-
catalyzed amination of aryl halides or pseudo-halides that
is a mild and widely applicable alternative to the classic
methods of aryl C–N bond formation. Herein we report its
efficient application to the preparation of VE amines 1d–
7d.
Classic procedures [anhydrous CH2Cl2, triflic anhydride
(Tf2O), base][15,18] were followed for the synthesis of triflates
1b–7b, but unexpected results were obtained in the prepara-
tion of the tocotrienyl triflates. When mixing all the reac-
tants at once, that is, tocotrienol, base (Et3N/DMAP), and
Tf2O in CH2Cl2 at –10 °C, conversion was complete within
3 h, but the product isolated after column chromatography
(n-hexane/EtOAc, 20:1) showed an NMR spectrum with
some inconsistencies, although MS analysis delivered the
expected results. In particular, signals in the olefinic proton
1
region of the H NMR spectrum gave unusually complex
patterns and integral values that account for less than three
protons. Moreover, in the 13C NMR spectrum some signals
were doubled, in particular the signal representing C2 of
the chromane ring. Carrying out the reaction at –20 °C and
using NaH as the base gave the same results. We supposed
Results and Discussion
The synthesis of optically pure as well as racemic toco- that some kind of rearrangement and/or the cyclization of
pheramines by Pd-mediated amination of α-, γ-, and δ-toco- the unsaturated terpenoic side-chain were catalyzed by Tf2O
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Efficient Synthesis of Vitamin E Amines
(or TfOH formed during the reaction), providing toco- Cs2CO3 in place of NaOtBu has been reported to provide
trienyl triflate isomers. In one set of experiments, Tf2O was similarly high efficiency while preventing triflate hydrolysis
added slowly dropwise to a CH2Cl2 solution of tocotrienol in amination reactions.[23] In fact, the formation of 1a was
6a and excess 2,6-lutidine at –60, –30, and –10 °C. Triflate not observed in the coupling reaction of 1b with 9 or 10 in
6b, showing the expected NMR spectrum, was obtained in the presence of Cs2CO3, but the yields of 1c and 1e de-
85% yield in each of the three trials, which suggests that creased dramatically in both toluene and 1,4-dioxane, not
the critical point of the reaction is the rate of Tf2O addition exceeding 37% after prolonged heating. The amination of
rather than the temperature or type of base. The other VE 5b in the presence of Cs2CO3 showed the same trend, and
triflates were obtained in yields of 75–96% (unoptimized) thus 5d was obtained in 73% with respect to 5b by using 9
in 3 h at –20 to –10 °C (Scheme 1).
and NaOtBu as base.
The first amination reaction was performed on 1b.
In contrast, when Cs2CO3 was employed together with 9
Pd(OAc)2 (5 mol-%) and rac-BINAP (6.5 mol-%) were in the synthesis of 2d, 3d, and 6d (with 1,4-dioxane as sol-
stirred in toluene for 30 min[19] at room temp. To this mix- vent), complete conversion was observed after heating at
ture, first a toluene solution of 1b and amine 10 or imine 9 reflux for 5 h. The acidic hydrolysis was faster than for the
was added followed after a few minutes by NaOtBu α series, that is, 30 min at room temp., probably because of
(1.3 equiv.). Complete conversion was obtained at 80 °C in the lower steric hindrance at C6, affording the desired VE
16 h with 10 and in 5 h with 9. Amine 1e was purified by amines 2d, 3d, and 6d in 87, 83, and 82% yields with respect
column chromatography and isolated in a yield of 80% and to the corresponding triflates. Compound 3d was also ob-
then heated at reflux for 30 min in MeOH in the presence tained in a similar yield (88%) in 5 h by using NaOtBu in
of HCOONH4 (3 equiv.) and Pd/C (10%)[20] to give 1d in toluene at 85 °C; the formation of 3a was not observed.
an 84% isolated yield.
Unexpectedly, the triflates of the δ VE series reacted
The benzophenone imine route was easier to perform more slowly than those of the β and γ series when Cs2CO3
from an experimental point of view and more efficient in was used as the base. The amination of 4b under the same
terms of yields. Isolation of imine 1c was carried out by reaction conditions employed for the preparation of 3d pro-
chromatography of the crude mixture on a short column of vided only 50% conversion of the starting triflate after heat-
silica gel, collecting only the eluate corresponding to the ing at reflux for 5 h. Increasing the loading of Pd(OAc)2 to
strong-yellow band. This band contained, besides 1c, only 10 mol-% improved the conversion to 76% after heating at
a small amount of benzophenone, which results from the reflux for 5 h, with further increments in the catalyst load-
cleavage by silica gel of the slight excess of the benzophe- ing changing the outcome of the reaction slightly. In our
none imine used in the reaction. As benzophenone was also hands, changing the catalyst to [Pd2dba3][12] afforded signif-
formed in the following hydrolysis step, better purification icantly worse results. Conversely, 82% conversion was ob-
was unnecessary at this stage. The collected fraction was tained after 5 h by using 5 mol-% of Pd(OAc)2 in toluene
treated with 2  HCl in THF for 2 h at room temp. Alterna- at 85 °C with NaOtBu as the base, whereas complete con-
tively, the rate of hydrolysis could be increased by gentle version was achieved under the same conditions and reac-
warming of the reaction mixture, completion being attained tion time but by starting with 7.5 mol-% of Pd(OAc)2. Fol-
in 30 min at 50 °C. Benzophenone was thus easily separated lowing the latter amination protocol and after acidic hy-
from 1d by column chromatography, affording the amine in drolysis, 4d and 7d were synthesized in yields of 92% with
79% yield with respect to 1b. No cleavage of the imine ad- respect to the starting triflates. The reasons for the different
ducts 1c–7c by silica gel to yield 1d–7d was observed. Race- behaviour of the two series of homologues are not known.
mic α-tocopheramine was prepared by the same protocol One possible explanation could be an inhibition of the cata-
starting from the commercially available (all-rac)-α-tocoph- lytic system caused by the imine adduct of the δ series. Less
erol. As sterically hindered ortho-substituted aryl halides[21] steric hindrance than in the γ or β homologues could result
and nonaflates[22] have been reported to successfully un- in more effective competition with BINAP for palladium.
dergo amination with 9 by using [Pd2dba3], we also used In fact, in a set of experiments carried out using Cs2CO3,
the [Pd2dba3] (3–5 mol-%) and BINAP catalytic system, but we observed a marked slow down of the amination rate of
conversions were significantly lower than those achieved by 4b after 4–5 h. Further addition of only BINAP led to a
Pd(OAc)2-catalyzed amination.
greater conversion than obtained with the addition of
The benzylamine route was then followed to prepare just Pd(OAc)2.
the N-benzyl-γ- and -δ-tocopheramines 3e and 4e as their
Chiral HPLC analysis confirmed that the amines were
antioxidant and biological properties have never been inves- obtained in enantiomerically pure form, as shown by com-
tigated before. Compounds 3e and 4e were obtained in 67 parison of their chromatograms with those of the corre-
and 10% yields, respectively. Several byproducts were sponding racemic products, synthesized according to the
formed in these reactions, likely due to over-arylation of the same amination procedure.
primary amine,[19] a side-reaction not shared by the benzo-
phenone imine adducts.
Conclusions
In one of the experiments, traces of α-tocopherol were
detected by TLC analysis, very likely arising from cleavage
An easy and efficient procedure for the synthesis of
of the corresponding triflate by NaOtBu.[22,23] The use of enantiopure tocopheramines and tocotrienamines has been
Eur. J. Org. Chem. 2009, 2063–2068
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F. Mazzini, T. Netscher, P. Salvadori
FULL PAPER
CH2Cl2 (10 mL) was slowly added over 1 h to a solution of phenol
1a–7a (4 mmol) and 2,6-lutidine (1.29 g, 1.4 mL, 12 mmol, 3 equiv.)
in dry CH2Cl2 (10 mL) at –20 to –10 °C. The mixture was stirred
at –10 °C for a further 2 h and warmed to room temp. Complete
conversion was confirmed by TLC (n-hexane/EtOAc, 10:1). A 5%
NaHCO3 solution was added to the deep-red solution and the
aqueous phase extracted with CH2Cl2 (3ϫ15 mL). The combined
organic phase was washed with 1  HCl, 5% NaHCO3, and brine,
and then dried with anhydrous Na2SO4. After the removal of the
solvent under vacuum, the crude red mixture was purified by col-
developed and optimized. VE amines were obtained in very
good overall yields in three steps (63–88%) with retention
of the configuration of the starting tocopherols/tocotrien-
ols. In particular, the key reaction, N-aryl amination, was
optimized to provide complete conversion of the corre-
sponding tocopheryl/tocotrienyl triflates (prepared with
Tf2O and an excess 2,6-lutidine in CH2Cl2) in 5 h and the
desired compounds in 73–92% yields after acidic hydrolysis,
thus making optically pure VE amines easily available. The
antioxidant and therapeutic properties of the compounds umn chromatography (n-hexane/EtOAc, 10:1).
prepared in this way are currently under investigation. In
(2R,4ЈR,8ЈR)-α-Tocopheryl Trifluoromethanesulfonate (1b): Yield
a preliminary study, 1d showed interesting antiproliferative
effects (IC50 = 150 nm) on the neuroblastoma glioma C6
cancer cell line, that is, it is 100-fold more active than α-
tocopherol in the same test.[24]
1
1.96 g (87%), pale-yellow oil. H NMR[27] (300 MHz, CDCl3): δ =
0.84–1.61 (m, 36 H), 1.72–1.88 (m, 2 H), 2.10 (s, 3 H), 2.19 (s, 3
H), 2.23 (s, 3 H), 2.61 (t, J = 6.9 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.0, 13.2, 14.0, 19.7, 19.8, 20.7, 21.0, 22.6,
22.7, 23.9, 24.5, 24.8, 28.0, 30.9, 32.7, 32.8, 37.3, 37.4, 37.5, 39.4,
40.0, 75.6, 118.4, 118.6 (q, JCF = 318 Hz), 124.3, 126.6, 128.0,
139.6, 150.8 ppm. MS (APCI): m/z
= 563.9 [M +
H]+.
Experimental Section
C30H49F3O4S (562.77): calcd. C 64.03, H 8.78, S 5.70, F 10.13;
found C 63.95, H 8.79, S 5.72, F 10.15.
General: All reactions were performed under an inert atmosphere
(Ar or N2). NMR spectra were obtained at 300 (1H) and 75 MHz
(13C) using CDCl3 as internal standard. Chemical shifts are ex-
pressed on the δ scale (ppm). Toluene was dried with Na, and 1,4-
dioxane and CH2Cl2 with CaH2 before use. All other commercial
reagents were used without further purification. Column
chromatography was performed on silica gel 60 (70–230 and 230–
400 mesh). TLC was performed on silica gel (Macherey–Nagel Alu-
gram Sil G/UV254, 0.20 mm). UV spectra were measured with a
Perkin-Elmer Lambda 650 spectrophotometer. MS (APCI) spectra
were recorded using CH3CN sample solutions. All yields given refer
to isolated yields. Conversions were determined by HPLC on a
LUNA Silica(2) column (250ϫ4.6 mm, 5 µm, from Phenomenex);
eluent: n-hexane/THF (100:1), flow: 1 mL/min, λ = 220 nm.
(R,R,R)-α-Tocopherol (1a) was obtained from Henkel (from natu-
ral sources, Covitol F1490). (all-rac)-γ-Tocopherol and rac-α-toco-
trienol were synthesized at DSM Nutritional Products (former
Roche Vitamins and F. Hoffmann-La Roche). Tocopherols 2a–4a
were obtained by flash chromatographic purification (n-hexane/Ac-
OEt, 88:12) of tocopherol concentrate, “d-Mixed Tocopherols”
from Bizen Chemical Co., Ltd. (Okayama, Japan), as described by
us in a previous paper.[25] Tocotrienols 5a–7a were obtained by
flash chromatographic purification (n-hexane/Et2O, 10:1 to 2:1) of
“Natural tocopherol-free tocotrienol concentrate (min. 97%)” from
Davos Life Sciences. The stereopurity was determined by HPLC
on a Chiralcel OD-H column (eluent: 0.5% EtOH in n-hexane,
flow: 1.0 mL/min, λ = 220 nm). Racemic α-tocotrienamine, and α-
and γ-tocopheramine were prepared according to the procedures
described for the preparation of 5d, 1d, and 3d, respectively. Ac-
cording to our experience of VE chemistry, the procedures used for
VE amine synthesis are not expected to alter the configuration of
the chiral centers in the starting tocopherols/tocotrienols, in par-
ticular, the chiral centers in the aliphatic side-chains. Thus, the con-
figurations were assigned on the basis of the latter considerations,
the order of elution of the VE compounds on the OD-H column
under the same conditions,[26] and a comparison of the HPLC chro-
matograms of the amines of racemic and enantiopure tocopherols/
tocotrienols.
(2R,4ЈR,8ЈR)-β-Tocopheryl Trifluoromethanesulfonate (2b): Yield
2.06 g (94%), pale-yellow oil. 1H NMR (300 MHz, CDCl3): δ =
0.84–1.65 (m, 36 H), 1.85–1.92 (m, 2 H), 2.19 (s, 3 H), 2.24 (s, 3
H), 2.62 (t, J = 6.9 Hz, 2 H), 6.92 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.4, 16.1, 19.7, 19.8, 20.8, 21.0, 22.7, 22.8,
23.9, 24.6, 24.9, 28.1, 30.8, 32.8, 32.9, 37.4, 37.5, 37.6, 39.5, 40.0,
75.8, 118.9 (q, JCF = 320 Hz), 120.6, 121.0 125.6, 126.8, 140.6,
151.5 ppm. MS (APCI): m/z = 549.8 [M + H]+. C29H47F3O4S
(548.74): calcd. C 63.47, H 8.63, S 5.84, F 10.39; found C 63.55, H
8.62, S 5.81, F 10.32.
(2R,4ЈR,8ЈR)-γ-Tocopheryl Trifluoromethanesulfonate (3b): Yield
1.80 g (82%), pale milky oil. 1H NMR (300 MHz, CDCl3): δ =
0.85–1.65 (m, 36 H), 1.71–1.82 (m, 2 H), 2.13 (s, 3 H), 2.22 (s, 3
H), 2.73 (t, J = 6.6 Hz, 2 H), 6.81 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.1, 13.1, 19.6, 19.7, 20.9, 21.0, 22.2, 22.6,
22.7, 24.1, 24.4, 24.8, 28.0, 30.7, 32.6, 32.8, 37.3, 37.4, 37.5, 39.4,
40.2, 76.3, 118.7 (q, JCF = 319 Hz), 118.5, 119.1, 127.0, 127.8,
141.0, 151.2 ppm. MS (APCI): m/z
= 549.8 [M +
H]+.
C29H47F3O4S (548.74): calcd. C 63.47, H 8.63, S 5.84, F 10.39;
found C 63.70, H 8.59, S 5.79, F 10.35.
(2R,4ЈR,8ЈR)-δ-Tocopheryl Trifluoromethanesulfonate (4b): Yield
2.05 g (96%), pale-yellow oil. 1H NMR (300 MHz, CDCl3): δ =
0.83–1.62 (m, 36 H), 1.69–1.85 (m, 2 H), 2.18 (s, 3 H), 2.76 (t, J =
6.3 Hz, 2 H), 6.81 (d, J = 3 Hz, 1 H), 6.85 (d, J = 3 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 16.1, 19.6, 19.7, 20.9, 22.4, 22.6,
22.7, 24.1, 24.4, 24.8, 28.0, 30.7, 32.7, 32.8, 37.3, 37.4, 37.5, 39.4,
40.2, 76.6, 118.8 (q, JCF = 315 Hz), 119.0, 120.7, 121.7, 128.3,
141.5, 151.7 ppm. MS (APCI): m/z
= 535.8 [M +
H]+.
C28H45F3O4S (534.71): calcd. C 62.89, H 8.48, S 6.00, F 10.66;
found C 62.75, H 8.50, S 6.05, F 10.65.
(2R,3ЈE,7ЈE)-α-Tocotrienyl Trifluoromethanesulfonate (5b): Yield
1.94 g (87%), pale-yellow oil. 1H NMR (300 MHz, CDCl3): δ =
1.26 (s, 3 H), 1.63–1.85 (m, 16 H), 1.94–2.15 (m, 13 H), 2.20 (s, 3
H), 2.23 (s, 3 H), 2.61 (t, J = 6.6 Hz, 2 H), 5.12 (m, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 12.1, 13.1, 15.9, 16.0, 17.6, 22.1, 22.2,
24.1, 25.7, 26.6, 26.8, 30.8, 39.7, 39.8, 39.9, 75.4, 118.4, 118.7 (q,
JCF = 315 Hz), 124.1, 124.2, 124.4, 126.7, 128.1, 131.2, 135.0,
135.3, 139.7, 150.8 ppm. MS (APCI): m/z = 557.8 [M + H]+.
C30H43F3O4S (556.72): calcd. C 64.72, H 7.79, S 5.76, F 10.24;
found C 64.69, H 7.74, S 5.85, F 10.29.
General Procedure for VE Triflate Synthesis: The general procedure
described below was used for the synthesis of all triflates, including
for racemic ones. The characterization data and yields of the latter
were the same as the optically pure triflates. In a general procedure,
a solution of Tf2O (1.46 g, 0.87 mL, 5.2 mmol, 1.3 equiv.) in dry
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Efficient Synthesis of Vitamin E Amines
(2R,3ЈE,7ЈE)-γ-Tocotrienyl Trifluoromethanesulfonate (6b): Yield
1.84 g (85%), pale milky oil. 1H NMR (300 MHz, CDCl3): δ = 1.31
General Procedure for Pd-Catalyzed Amination Using Benzo-
phenone Imine: Dry toluene and dry 1,4-dioxane were used in the
(s, 3 H), 1.60–1.90 (m, 16 H), 1.94–2.20 (m, 13 H), 2.24 (s, 3 H), amination reactions carried out in the presence of NaOtBu and
2.77 (t, J = 6.6 Hz, 2 H), 5.11 (m, 3 H), 6.82 (s, 1 H) ppm. 13C
Cs2CO3 as base, respectively. The reaction temperature was 85 °C
NMR (75 MHz, CDCl3): δ = 12.1, 13.1, 15.9, 16.0, 17.6, 22.1, 22.2, using toluene and 100 °C using 1,4-dioxane. There were no other
24.1, 25.7, 26.6, 26.8, 30.8, 39.7, 39.8, 39.9, 76.5, 118.7 (q, JCF
=
differences in the reaction protocol employing Cs2CO3 or NaOtBu.
315 Hz), 118.6, 119.1, 124.0, 124.1, 124.4, 127.0, 127.8, 131.2,
Increasing the loading of Cs2CO3 from 1.6 to 3 equiv. did not pro-
135.0, 135.4, 141.1, 151.1 ppm. MS (APCI): m/z = 543.9 [M +H]+. vide a substantial improvement in yield. The representative amina-
C29H41F3O4S (542.69): calcd. C 64.18, H 7.61, S 5.91, F 10.50;
found C 64.15, H 7.64, S 5.99, F 10.55.
tion procedure given below was used for the synthesis of all the
imine adducts 1c–7c, and also for the racemic ones. In a typical
procedure, Pd(OAc)2 (12 mg, 0.05 mmol) and rac-BINAP (41 mg,
0.065 mmol) in dry toluene (3 mL) were stirred under argon for
about 30 min at room temp. Then, first a solution of 1b–7b
(1 mmol) and 9 (217 mg, 0.2 mL, 1.2 mmol) in dry toluene (3 mL)
was added to the catalyst mixture at room temp. followed after a
few minutes by NaOtBu (125 mg, 1.3 mmol). The resulting mixture
was heated at 80 °C for 5 h. Complete conversion of the starting
triflate was confirmed by HPLC analysis. The reaction mixture was
cooled to room temp., diluted with diethyl ether, (40 mL) and fil-
tered through a plug of Celite. The crude product was concentrated
and partially purified by chromatography through a short column
(SiO2, n-hexane/EtOAc, 7:1), collecting the eluate from the strong-
yellow band. This fraction contained mainly the imine adducts 1c–
7c and only a small amount of benzophenone. After removal of
the solvent under vacuum, an orange-yellow crude mixture was ob-
tained ready for the subsequent hydrolysis step. Pure fractions of
1c–7c were isolated by a more accurate column chromatographic
purification procedure to allow their characterization (see the Sup-
porting Information).
(2R,3ЈE,7ЈE)-δ-Tocotrienyl Trifluoromethanesulfonate (7b): Yield
1.59 g (75%), pale-yellow oil. 1H NMR (300 MHz, CDCl3): δ =
1.25 (s, 3 H), 1.57–1.90 (m, 16 H), 1.94–2.19 (m, 13 H), 2.78 (t, J
= 6.6 Hz, 2 H), 5.11 (m, 3 H), 6.81 (d, J = 2.7 Hz, 1 H), 6.86 (d, J
= 2.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.9, 16.0,
16.1, 17.6, 22.1, 22.4, 24.1, 25.7, 26.6, 26.8, 30.7, 39.7, 39.8, 39.9,
76.6, 118.8 (q, JCF = 315 Hz), 119.0, 120.7, 121.7, 123.9, 124.1,
124.4, 128.4, 131.2, 135.0, 135.4, 141.5, 151.6 ppm. MS (APCI):
m/z = 529.7 [M + H]+. C28H39F3O4S (528.67): calcd. C 63.61, H
7.44, S 6.07, F 10.78; found C 63.72, H 7.51, S 6.10, F 10.71.
General Procedure for Pd-Catalyzed Amination Using Benzylamine:
In a typical procedure, Pd(OAc)2 (12 mg, 0.05 mmol) and rac-BI-
NAP (41 mg, 0.065 mmol) in dry toluene (3 mL) were stirred for
about 30 min at room temp. Then, first a solution of 1b (or 3b or
4b, 1 mmol) and 10 (217 mg, 0.2 mL, 1.2 mmol) in dry toluene
(3 mL) was added to the catalyst mixture at room temp. followed
after a few minutes by NaOtBu (125 mg, 1.3 mmol). The resulting
mixture was heated at 80 °C for 16 h. Complete conversion of the
starting triflate was confirmed by HPLC analysis. The reaction
mixture was cooled to room temp., diluted with diethyl ether
(40 mL), and filtered through a plug of Celite. After removal of the
solvent under vacuum, the crude mixture was purified by column
chromatography (n-hexane/EtOAc, 95:5).
General Procedure for the Hydrolysis of 1c–7c: In a general pro-
cedure, a 2  HCl solution (3 mL) was added to a solution in THF
(5 mL) of the crude product isolated after the amination reaction
of 1b–7b with 9. After 30 min at room temp. (for 1c and 5c 2 h at
room temp. or 30 min at 50 °C) the orange solution turned to pale
yellow and complete conversion was confirmed by TLC (n-hexane/
EtOAc, 6:1). A 1  NaOH solution (10 mL) was added and the
aqueous phase extracted with Et2O (3ϫ10 mL). The combined or-
ganic phases were washed with brine and dried with anhydrous
Na2SO4. After removal of the solvent under vacuum, the crude
yellow-orange mixture was purified by column chromatography
(SiO2, n-hexane/EtOAc, 5:1 to 2:1).
(2R,4ЈR,8ЈR)-N-Benzyl-α-tocopheramine (1e): Yield 416 mg (80%),
1
amber oil. H NMR (300 MHz, CDCl3): δ = 0.84–0.88 (m, 12 H),
1.05–1.45 (m, 24 H), 1.75–1.83 (m, 2 H), 2.12 (s, 3 H), 2.18 (s, 3
H), 2.23 (s, 3 H), 2.40 (br. s, 1 H), 2.63 (t, J = 6.8 Hz, 2 H), 3.91
(s, 2 H), 7.24–7.44 (m, 5 H) ppm. [α]2D0 = +6.1 (c = 1.04, CH2Cl2).
MS (APCI): m/z = 520.8 [M + H]+. C36H57NO (519.84): calcd. C
83.18, H 11.05, N 2.69; found C 83.13, H 10.99, N 2.75.
(2R,4ЈR,8ЈR)-N-Benzyl-γ-tocopheramine (3e): Yield 339 mg (67%),
1
amber oil. H NMR (300 MHz, CDCl3): δ = 0.83–0.88 (m, 12 H),
(2R,4ЈR,8ЈR)-α-Tocopheramine (1d): Yield 340 mg (79% with re-
spect to 1b), amber oil. UV (EtOH): ε (λmax) = 3780 dm3 mol–1 cm–1
(301 nm).[28] 1H NMR (300 MHz, CDCl3): δ = 0.81–1.68 (m, 36
H), 1.76–1.86 (m, 2 H), 2.08 (s, 3 H), 2.14 (s, 3 H), 2.17 (s, 3 H),
1.04–1.60 (m, 24 H), 1.65–1.79 (m, 2 H), 2.06 (s, 3 H), 2.14 (s, 3
H), 2.66 (t, J = 6.4 Hz, 2 H), 3.00 (br. s, 1 H), 4.26 (s, 2 H), 6.26
(s, 1 H), 7.23–7.42 (m, 5 H) ppm. [α]2D0 = +17.3 (c = 1.06, CH2Cl2).
MS (APCI): m/z = 506.6 [M + H]+. C35H55NO (505.82): calcd. C 2.66 (t, J = 6.6 Hz, 2 H), 3.28 (br. s, 2 H) ppm. 13C NMR (75 MHz,
83.11, H 10.96, N 2.77; found C 83.14, H 10.85, N 2.82.
CDCl3): δ = 11.9, 12.6, 13.6, 19.7, 19.8, 21.1, 22.7, 22.8, 23.8, 24.5,
24.9, 28.0, 31.9, 32.8, 32.9, 37.4, 37.5, 37.6, 39.4, 39.9, 74.3, 117.1,
117.7, 120.4, 122.3, 134.9, 144.8 ppm. [α]2D3 = +3.7 (c = 1.0, EtOH).
MS (APCI): m/z = 430.9 [M + H]+. C29H51NO (429.72): calcd. C
81.05, H 11.96, N 3.26; found C 81.24, H 11.94, N 3.21.
(2R,4ЈR,8ЈR)-N-Benzyl-δ-tocopheramine (4e): Yield 50 mg (10%),
1
amber oil. H NMR (300 MHz, CDCl3): δ = 0.83–0.90 (m, 12 H),
1.04–1.45 (m, 24 H), 1.67–1.79 (m, 2 H), 2.10 (s, 3 H), 2.66 (t, J =
6.7 Hz, 2 H), 3.05 (br. s, 1 H), 4.23 (s, 2 H), 6.21 (d, J = 2.6 Hz, 1
H), 6.36 (d, J = 2.6 Hz, 1 H), 7.30–7.38 (m, 5 H) ppm. [α]2D0 = +12.1
(c = 1.06, CH2Cl2). MS (APCI): m/z = 492.4 [M + H]+. C34H53NO
(491.79): calcd. C 83.04, H 10.86, N 2.85; found C 83.19, H 10.80,
N 2.89.
(2R,4ЈR,8ЈR)-β-Tocopheramine (2d): Yield 362 mg (87% with re-
spect to 2b), amber oil. UV (EtOH): ε (λmax) = 3127 dm3 mol–1 cm–1
(302 nm).[28] 1H NMR (300 MHz, CDCl3): δ = 0.79–0.97 (m, 12
H), 1.08–1.69 (m, 24 H), 1.74–1.92 (m, 2 H), 2.07 (s, 3 H), 2.17 (s,
3 H), 2.67 (t, J = 6.6 Hz, 2 H), 3.23 (br. s, 2 H), 6.47 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.2, 15.9, 19.7, 19.8, 21.0, 22.7,
22.8, 23.8, 24.5, 24.8, 28.0, 31.7, 32.7, 32.8, 37.3, 37.5, 39.4, 39.7,
74.2, 116.5, 118.6, 119.7, 124.1, 136.0, 145.3 ppm. [α]2D3 = +5.6 (c
= 1.0, EtOH). MS (APCI): m/z = 416.7 [M + H]+. C28H49NO
(415.69): calcd. C 80.90, H 11.88, N 3.37; found C 81.02, H 11.91,
N 3.44.
Preparation of 1d by the Hydrogenolysis of 1e: HCOONH4 (190 mg,
3 mmol) was added to a suspension of 1e (520 mg, 1 mmol) and
10% Pd/C (530 mg) in MeOH (10 mL), and the resulting black
suspension was stirred at reflux for 1 h. After filtering through Ce-
lite and removal of the solvent under vacuum, the crude product
was purified by column chromatography (n-hexane/EtOAc, 9:1) to
afford 1d (360 mg, 84% yield) as an amber oil.
Eur. J. Org. Chem. 2009, 2063–2068
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2067

F. Mazzini, T. Netscher, P. Salvadori
FULL PAPER
(2R,4ЈR,8ЈR)-γ-Tocopheramine (3d): Yield 345 mg (83% with re-
spect to 3b), amber oil. UV (EtOH): ε (λmax) = 3345 dm3 mol–1 cm–1
(304 nm).[28] 1H NMR (300 MHz, CDCl3): δ = 0.83–0.98 (m, 12
H), 1.12–1.70 (m, 24 H), 1.75–1.88 (m, 2 H), 2.11 (s, 3 H), 2.18 (s,
3 H), 2.70 (t, J = 6.3 Hz, 2 H), 3.24 (br. s, 2 H), 6.34 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 11.8, 13.0, 19.6, 19.7, 20.9, 22.2,
22.5, 22.6, 24.0, 24.4, 24.7, 27.9, 31.5, 32.6, 32.7, 37.2, 37.4, 37.5,
39.3, 40.0, 75.1, 113.1, 118.2, 121.0, 124.8, 136.5, 144.9 ppm. [α]2D3
= +1.8 (c = 1.0, EtOH). MS (APCI): m/z = 416.6 [M + H]+.
C28H49NO (415.69): calcd. C 80.90, H 11.88, N 3.37; found C
81.05, H 11.90, N 3.31.
Acknowledgments
We are grateful to Dr. A. Cuzzola for MS analyses and Dr. A.
Mandoli and Prof. B. A. Salvatore for useful discussions. Financial
support from the Ministero dell’Università e della Ricerca (MIUR)
(Project FIRB RBPR05NWWC) is gratefully acknowledged.
[1] L. I. Smith, W. B. Renfrow, J. W. Opie, J. Am. Chem. Soc. 1942,
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references cited therein.
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1994, 29, 799–802.
(2R,4ЈR,8ЈR)-δ-Tocopheramine (4d): Yield 370 mg (92% with re-
spect to 4b), dark-amber oil. UV (EtOH):
ε (λmax) =
[4] W. Schlegel, U. Schwieter, R. Tamm (Hoffmann-La Roche,
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[5] M. Tokuwame (Mitsui Petrochemical Industries, Ltd.), JP
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2863 dm3 mol–1 cm–1 (304 nm).[28] 1H NMR (300 MHz, CDCl3): δ
= 0.81–0.96 (m, 12 H), 1.05–1.59 (m, 24 H), 1.69–1.83 (m, 2 H),
2.11 (s, 3 H), 2.66 (t, J = 6.6 Hz, 2 H), 3.13 (br. s, 2 H), 6.28 (d, J
= 2.4 Hz, 1 H), 6.38 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR (75 MHz, [6] K. J. Lambert, M. Lal (Sonus Pharmaceuticals, Inc.), WO
2002076937, 2002 [Chem. Abstr. 2002, 137, 263202].
[7] A. Tomic-Vatic, J. Eytina, J. Chapman, E. Mahdavian, J. Neu-
zil, B. A. Salvatore, Int. J. Cancer 2005, 117, 188–193.
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[10] H. Mayer, O. Isler, Methods Enzymol. 1971, 18, 241–348.
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1155.
CDCl3): δ = 16.0, 19.6, 19.7, 20.9, 22.4, 22.6, 22.7, 24.1, 24.4, 24.8,
27.9, 31.4, 32.6, 32.7, 37.2, 37.4, 39.3, 39.8, 75.2, 113.2, 116.4,
121.0, 126.9, 138.0, 145.1 ppm. [α]2D3 = +5.7 (c = 1.0, EtOH). MS
(APCI): m/z = 402.6 [M + H]+. C27H47NO (401.67): calcd. C 80.74,
H 11.79, N 3.49; found C 80.89, H 11.82, N 3.43.
(2R,3ЈE,7ЈE)-α-Tocotrienamine (5d): Yield 310 mg (73% with re-
spect to 5b), amber oil. UV (EtOH): ε (λmax) = 3435 dm3 mol–1 cm–1
(301 nm).[28] 1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.58–
1.96 (m, 16 H), 2.00–2.29 (m, 19 H), 2.72 (t, J = 6.6 Hz, 2 H), 3.33
(br. s, 2 H), 5.20 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
12.0, 12.5, 13.6, 16.0, 16.1, 17.8, 21.1, 22.4, 23.8, 25.8, 26.7, 26.9,
32.0, 39.7, 39.8, 74.1, 117.1, 117.6, 120.4, 122.3, 124.3, 124.6, 124.7,
131.2, 134.9, 135.0, 144.8 ppm. [α]2D3 = –5.8 (c = 1.0, EtOH). MS
(APCI): m/z = 424.7 [M + H]+. C29H45NO (423.67): calcd. C 82.21,
H 10.71, N 3.31; found C 82.33, H 10.72, N 3.37.
[12] E. Mahdavian, S. Sangsura, G. Landry, J. Eytina, B. A. Salva-
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[13] B. H. Yang, S. L. Buchwald, J. Organomet. Chem. 1999, 576,
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[14] J. F. Hartwig in Handbook of Organopalladium Chemistry for
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Abstracts of the International Symposium on Homogeneous Ca-
talysis, ISHC-XVI, Florence (Italy), 6–11th July, 2008, poster
P 450.
(2R,3ЈE,7ЈE)-γ-Tocotrienamine (6d): Yield 336 mg (82% with re-
spect to 6b), amber oil. UV (EtOH): ε (λmax) = 3175 dm3 mol–1 cm–1
(302 nm).[28] 1H NMR (300 MHz, CDCl3): δ = 1.22 (s, 3 H), 1.48–
1.84 (m, 16 H), 1.90–2.21 (m, 16 H), 2.69 (t, J = 6.6 Hz, 2 H), 3.21
(br. s, 2 H), 5.13 (m, 3 H), 6.33 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 11.9, 13.1, 15.8, 16.0, 17.6, 22.1, 22.3, 24.0, 25.6, 26.6,
26.7, 31.5, 39.7, 39.8, 75.0, 113.2, 118.3, 121.1, 124.2, 124.4, 124.5,
125.0, 131.1, 134.8, 134.9, 136.6, 145.0 ppm. [α]2D3 = –6.8 (c = 1.0,
[16] J. P. Wolfe, J. Ahman, J. P. Sadighi, R. A. Singer, S. L. Buch-
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EtOH). MS (APCI): m/z = 410.6 [M + H]+. C28H43NO (409.65): [20] S. Ram, L. D. Spicer, Tetrahedron Lett. 1987, 28, 515–516.
[21] G. A. Grasa, M. S. Viciu, J. Huang, S. P. Nolan, J. Org. Chem.
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calcd. C 82.09, H 10.58, N 3.42; found C 82.22, H 10.52, N 3.47.
(2R,3ЈE,7ЈE)-δ-Tocotrienamine (7d): Yield 364 mg (92% with re-
spect to 7b), dark-amber oil. UV (EtOH):
ε (λmax) =
2796 dm3 mol–1 cm–1 (304 nm).[28] 1H NMR (300 MHz, CDCl3): δ
= 1.23 (s, 3 H), 1.52–1.88 (m, 16 H), 1.92–2.20 (m, 13 H), 2.68 (t,
J = 6.6 Hz, 2 H), 3.19 (br. s, 2 H), 5.12 (m, 3 H), 6.28 (d, J =
2.7 Hz, 1 H), 6.39 (d, J = 2.7 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 15.8, 15.9, 16.0, 17.6, 22.1, 22.3, 24.0, 25.6, 26.5, 26.7,
31.5, 39.6, 75.0, 113.2, 116.5, 121.0, 124.1, 124.3, 124.4, 126.9,
131.1, 134.8, 134.9, 138.0, 145.0 ppm. [α]2D3 = –1.6 (c = 1.0, EtOH).
MS (APCI): m/z = 396.7 [M + H]+. C27H41NO (395.62): calcd. C
81.97, H 10.45, N 3.54; found C 82.12, H 10.51, N 3.62.
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Supporting Information (see also the footnote on the first page of
this article): Characterization data, including data for 1c–7c, and
chromatograms obtained by chiral HPLC.
[28] H. Mayer, O. Isler, Methods Enzymol. 1971, 18, 241–348.
Received: January 26, 2009
Published Online: ᭿
2068
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Eur. J. Org. Chem. 2009, 2063–2068