A convenient method for the preparation of primary amines using tritylamine

Article abstract of DOI:10.1016/j.tetlet.2004.12.098

A simple method for the preparation of primary amines by treating N-tritylamines with trifluoroacetic acid has been established. The N-tritylamines were prepared by the reaction of alkyl halides or alkyl p-toluenesulfonates with tritylamine, or by the reaction of alkyl bromides with lithium tritylamide.

Full text of DOI:10.1016/j.tetlet.2004.12.098

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1357–1360
A convenient method for the preparation of primary amines
using tritylamine
Vassiliki Theodorou,a,* Valentine Ragoussis,b Alexandros Strongilos,c Evangelos Zelepos,b
Argyro Eleftherioub and Maria Dimitrioub
aDepartment of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece
bDepartment of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis,
Zographou, GR-157 71 Athens, Greece
cChemistry Laboratories, Agricultural University of Athens, Iera Odos, GR-118 55 Athens, Greece
Received 25 October 2004; revised 24 November 2004; accepted 17 December 2004
Available online 13 January 2005
This article is dedicated to the memory of Ifig. Photaki, Professor of Organic Chemistry, University of Athens, for her scientific contributions
to peptide science
Abstract—A simple method for the preparation of primary amines by treating N-tritylamines with trifluoroacetic acid has been
established. The N-tritylamines were prepared by the reaction of alkyl halides or alkyl p-toluenesulfonates with tritylamine, or
by the reaction of alkyl bromides with lithium tritylamide.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
amines and the workups require laborious purifications.
Yields are not always satisfactory with ammonia syn-
thons, due to their relatively poor nucleophilicity, which
may lead to elimination products.4 In addition, many of
the above procedures cannot be applied in the presence
of certain functional groups, which react under the reac-
tion conditions.
Primary amines are very important in human life and
the chemical industry. Numerous important methods
for the synthesis of primary amines have been described,
including alkylation of ammonia,1 reductive amination
of carbonyl compounds,2 reduction of azides and of
amides.3 Alkylation of protected ammonia,4 as an
ammonia synthon, by alkyl halides or alkyl tosylates is
one of the most useful methods for the preparation of
primary amino compounds. Potassium phthalimide,
hexamethylenetetramine, guanidine, sodium diphenyl-
phosphinamide, bisarylsulfenimides, silyl derivatives of
amines and sodium diformylamide are among the
ammonia synthons4 reported to react with alkylating
agents to give, after deprotection, primary amines.
Moreover, polymer-bound ammonia equivalents were
introduced5 to afford primary amines, after suitable
cleavage. Most of these methods are versatile reactions
and afford good yields, but often the primary amines
obtained are contaminated1 with secondary and tertiary
In the search for a mild, simple and convenient method
for the conversion of alkyl halides, alcohols or their
derivatives to the corresponding primary amines, the
application of triphenylmethylamine (tritylamine) was
examined as an alternative reagent, with the consider-
ation that the trityl–nitrogen bond is easily cleaved by
acid. The trityl moiety is a valuable acid-labile bulky
protective group for peptide, carbohydrate and nucleo-
tide chemistry, readily introduced as a cation at a nucleo-
philic site, mostly in the form of trityl chloride. It can be
cleaved selectively even in the presence of other acid sen-
sitive protecting groups.6 The extremely mild conditions,
under which the N-trityl group can be removed, and the
benefits of monoalkylation, make tritylamine a very use-
ful aminating agent in organic synthesis. Furthermore,
most of the N-tritylamino compounds obtained in the
reaction mixture, are crystalline solids and can be easily
separated and purified by recrystallization, due to the
Keywords: Primary amines; Tritylamine; Tritylamide; Ammonia syn-
thon; Amination; Aminating agent.
*
Corresponding author. Tel.: +30 26510 98591; fax: +30 2610
98682; e-mail: vtheodor@cc.uoi.gr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.098

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V. Theodorou et al. / Tetrahedron Letters 46 (2005) 1357–1360
ROTs
n. r.
TrNHLi
n-BuLi
TrNH2
2
RBr
RX
3
1
1. TFA
TrNH2 HBr
RNH2 HCl
TrNHR
TrOCH3
2. HCl/ CH3OH
5
4
X: Cl, Br, I, OTs
Scheme 1. General reaction pathway.
high symmetry of the crowded trityl group. However,
despite the wide use of the N-trityl moiety, only few
references have been reported on the applications of
tritylamine in organic synthesis.7–9
The TrNHR can also be prepared from alkyl bromides
and lithium tritylamide (2), formed by the reaction of
TrNH2 and n-BuLi in THF (Scheme 1). Alkyl tosylates
do not react with the tritylamide to obtain TrNHR, pos-
sibly because tritylamide, as a strong base, abstracts an
acidic proton from the p-methyl group of the tosyl ester
to give a stabilized benzylic anion11 (Eq. 1).
In the present work, a simple and mild method for the
synthesis of primary amines is described, including the
amination of alkyl halides and alkyl tosylates by
the use of tritylamine, as an ammonia synthon, and
the subsequent detritylation with trifluoroacetic acid at
room temperature. The synthetic route is outlined in
Scheme 1.
Deprotection of TrNHR was achieved very simply, after
treatment with TFA for a few minutes or after refluxing
with 1 N HCl in MeOH for some hours. The trityl cat-
ion was removed as TrOMe, while the hydrochloride
salts of the primary amines RNH2ÆHCl 5 were obtained
after vacuum distillation of TFA and subsequent treat-
ment of the residue with HCl in CH3OH, followed by
dry ether.
2. Results and discussion
Primary alkyl bromides and iodides react smoothly in
acetonitrile with tritylamine TrNH2 (1), behaving both
as a base and as the aminating agent, to give N-tritylam-
ines TrNHR 4 and the salt of TrNH2ÆHBr, which is re-
moved by filtration and recycled. n-Alkyl chlorides react
very slowly. Chain extension or branching of the alkyl
group reduces the reactivity of the halide, which must
be used in excess in order to increase the reaction rate.
The reaction is more sluggish with secondary halides,
and fails with tertiary halides. Allylic, propargylic and
benzylic halides react faster than the alkyl ones and give
almost pure crystalline TrNHR, which are detritylated
much easier than the alkyl derivatives. Alkyl tosylates10
ROTs react faster in refluxing toluene, than in acetoni-
trile, in the presence of triethylamine, which reduces
the reaction time, giving the desired TrNHR 4.
This method was applied for the amination of geranyl
chloride, which was prepared from geraniol, with minor
modifications of the reported procedure12 and without
further purification. Although geranyl chloride failed
to react with TrNH2, N-geranyl tritylamine (TrNH-
Ger)13 was obtained easily in the presence of KBr in ace-
tone, after a halogen exchange reaction (Eq. 2), in high
yield (Table 1).
It is worthy to note that this amination reaction was also
applied to the preparation of cross-linked polymeric
amines from the corresponding chloromethylated resins
(Eq. 3), which are useful supporting materials, especially
for peptide synthesis. The results of the present work are
summarized in Table 1.
TrNH2
+
+
ð1Þ
ð2Þ
Li
TrNHLi
CH3
SO2 OR
CH2
SO2 OR
OH
Cl
NHTr
n-BuLi, TsCl, LiCl
HMPA, Et2O, 0oC
1. KBr/ Acetone
2. TrNH2/ CHCl3
1.TFA
P
P
P
CH2 Cl
CH2 NHTr
CH2 NH2
ð3Þ
TrNH2
2. DIEA

V. Theodorou et al. / Tetrahedron Letters 46 (2005) 1357–1360
1359
Table 1. Synthesis of primary amine HCl salts
Entry Reagent TrNH2/RX RX
Time, temp
TrNHR yield% (mp °C) RNH2ÆHCl (mp °C)a
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1:5
1:5
1:10
1:2
1:2
1:10
1:10
1:2
1:2
1:5
2:1
1:5
2:1
2:1
2:1
CH3I
C2H5Br/I
1 day, rt
2–5 days, rt
90 (93–94)
92 (78–9)
227–9 (227–8)4j
2
107–9 (964h, 79-814e
)
3
n-C4H9Br
n-C4H9OTs
iso-C4H9OTs
n-C5H11Br
n-C7H15Br
n-C7H15OTs
C12H25OTs
10 days, rt (or 2 days, 40 °C) 88 (oily)
194–5 (1944e
See entry 3
)
4
5 h, reflux
8 h, reflux
12 days, rt
90 (oily)
70 (oily)
85 (oily)
5
167–9 (168–713b
)
6
215–7 (217–83c
)
7
15 days, rt (or 3 days, 40 °C) 75 (oily)
10 h, reflux
15 h, reflux
234–7 (2404d, 2464h
See entry 7
)
8
80 (oily)
78 (oily)
9
183–5 (1854d
)
10
11
12
13
14
15
CH2@CH–CH2Br/Cl 3 days, rt
>90 (83–4)
>90 (oily)
>90 (166)
>90 (92–3)
>90 (143)
>90 (168)
108–9 (1064h, 104–94e)
118–20 (1184h
178–9 (177–803b
243–4 (243–44e
Ger-Cl, KBr
CH„C–CH2Br
Ph–CH2Br/Cl
2 h, 40 °C
3 days, rt
1 day, rt
2 days, rt
2 days, rt
)
)
)
p-Br–C4H4CH2Br
p-O2N-C4H4CH2Br
285–7 (281–315
)
255–7(258–603c
)
16
1
4:1
-C6H4CH2Cl
3–4 days, 40 °C
>90
P
n-C4H9Br
17
18
19
2
2
2
1:2
1:2
1:2
ꢀ15–0 °C, 1 h, then 4 h, rt
ꢀ15–0 °C, 1 h, then 4 h, rt
ꢀ15–0 °C, 1 h, then 4 h, rt
65 (oily)
62 (oily)
No reaction
See entry 3
See entry 7
n-C7H15Br
ROTs (R: alkyl)
a Literature melting points are given in parentheses.
1
In summary, we describe a simple, mild and convenient
method for the synthesis of primary amines, in the form
of HCl salts, from the corresponding alkyl, allyl, propar-
gyl and benzylic halides or alkyl tosylates and the
ammonia equivalent, tritylamine, in high overall yields,
after mild detritylation of the initially formed N-trityl-
amines with trifluoroacetic acid. This procedure is envi-
ronmentally friendly and economic, the starting
materials are readily available and the by-products pro-
duced can be easily separated and recycled. We are cur-
rently exploring the preparation of primary amides
using tritylamine.
TrNHRꢀs in the Table 1 were identified by IR and H
NMR spectroscopy and by elementary analysis.
3.2. Detritylation/RNH2ÆHCl (5)
TrNHR (1 mmol) in a solution of 5 ml 60% TFA in CH2
Cl2 was stirred for 10 min at rt, then 2 ml of CH3OH
were added and the yellow colour immediately disap-
peared. After stirring for about 1 h, the solvent was
evaporated in vacuo and the hydrochloride salt
RNH2ÆHCl was precipitated by the addition of 10 ml
1 N HCl in CH3OH and subsequent concentration to
dryness. The salt was washed with dry ether.
3. Typical experimental procedure
3.1. Synthesis of TrNHR (4)
3.3. Preparation of cross-linked polymeric amines
One millimole of 1% cross linked Merrifield resin and
1.04 g (4 mmol) of TrNH2 were suspended in a solution
of 20 ml of 30% DMF/CH2Cl2 and the mixture was
warmed to 40 °C for 3 days, then cooled to rt, filtered
and washed thoroughly with DMF, MeOH, CH2Cl2.
The detritylation was effected by treating with 40%
TFA/CH2Cl2 for 15 min, then adding 5 ml of CH3OH
and stirring for further 10 min, filtering, and washing
with CH2Cl2, 10% DIEA/CH2Cl2, CH2Cl2, MeOH,
CH2Cl2.
(a) To a solution of 1 mmol tritylamine14 in 5 ml of
CH3CN 1–10 mmol RBr were added and the resulting
solution was either left at rt for several days or refluxed
for several hours (see Table 1). The precipitated salt
TrNH2ÆHBr was removed by filtration and recycled,
and the solvent was concentrated in vacuo. The residue
was purified by recrystallization from ethanol, or by col-
umn chromatography (ether/petroleum ether). Total
yield: 70–93% of TrNHR. (b) A solution of 5 mmol
TrNH2, 10 mmol Et3N and 5–10 mmol ROTs in 5 ml
of toluene was refluxed for 5–15 h. The precipitate was
removed and the organic layer, after water extraction,
was concentrated in vacuo. The residue was purified
by column chromatography Yield: 70–90% of TrNHR.
(c) To a stirred solution of 5 mmol of TrNH2 in abs.
THF, cooled to ꢀ15–0 °C, 5 mmol of n-BuLi in hexane
were added dropwise under N2. After 30 min, 10 mmol
of RBr in 5 ml THF were added, and the stirring was
continued for about 2 h at ꢀ10 to 0 °C and about 4–
5 h at rt. The reaction was quenched with water at
0 °C under N2 and the product was extracted with ether
and purified as above. Yield: 60% of TrNHR. All the
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