A one-pot, solid-phase synthesis of secondary amines from reactive alkyl halides and an alkyl azide

Article abstract of DOI:10.1055/s-2007-990927

A one-pot, two-step, polymer-bound, triphenylphosphine-supported synthesis of secondary amines from the corresponding azide and a reactive alkyl halide is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990927

LETTER
97
A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl
Halides and an Alkyl Azide
Synthesis of
S
u
e
condary Am
s
ines ana Ayesa, Bertil Samuelsson, Björn Classon*
Medivir AB, P.O. Box 1088, 141 22 Huddinge, Sweden
Fax +46(8)54683199; E-mail: bjorn.classon@medivir.se
Received 28 August 2007
R
Abstract: A one-pot, two-step, polymer-bound, triphenylphos-
phine-supported synthesis of secondary amines from the corre-
sponding azide and a reactive alkyl halide is described.
N
P
N
N
Ph
P+
Ph
PPh3
Ph
N
N–
RN3
Ph
Ph
N
R
Ph
Key words: secondary amines, azides, phosphinimine, polymer-
supported triphenylphosphine, alkylation
– N2
H2O
Ph3PO
Ph3P NR
RNH2
+
The most widely used methods for the preparation of sec-
ondary amines employ either reductive aminations or
alkylation procedures on primary amines. In most cases
they result in good yields of the corresponding secondary
amine. However, when using reactive alkyl halides, over-
alkylation is generally observed and difficult to avoid,
leading to the formation of the corresponding tertiary or
quaternary ammonium salts. In an attempt to circumvent
these issues and to deliver only secondary amines from
alkylation of reactive alkyl halides, the alkylation of the
corresponding solid-phase iminophosphorane was inves-
tigated and found to provide a promising alternative pro-
cedure. Furthermore a solid-phase protocol offers
significant advantages over the corresponding solution-
phase methodologies in terms of ease of purification by
use of simple filtration and often avoidance of chromatog-
raphy. An additional advantage of using a solid-phase re-
action is its potential utility in combinatorial library
synthesis of secondary amines from readily available
alkyl azides. We were attracted by the operational sim-
plicity of the Staudinger reaction (Scheme 1),1 a reaction
which involves the treatment of an alkyl azide with triph-
enylphosphine to produce a phosphoazide which rapidly
eliminates nitrogen to deliver an iminophosphorane, an
intermediate useful for the synthesis of a variety of nitro-
gen-containing compounds,2 including imines,3 and for
aza-Wittig reactions. Iminophosphoranes are also readily
hydrolyzed to give the corresponding primary amines and
triphenylphosphine oxide in a protic solvent, a process
that has been transferred to polymer support.4
Scheme 1
In a publication describing the use of a phosphonium di-
aza-diylides or a phosphonium aza-yldiide as reagent for
the synthesis of primary and secondary amines8
(Scheme 2) by a stepwise solution-phase dialkylation of
an aza-yldiide, good yields were reported of N-alkyl phos-
phimines or disubstituted aminophosphonium salts,
which by hydrolysis provided the corresponding primary
or secondary amines. However, this methodology re-
quires the use of strong base.
Use of the Staudinger reaction to accomplish alkylations
of N-alkyl phosphimines or N-aryl phosphimines with re-
active alkyl halides seemed an attractive new methodolo-
gy for the synthesis of secondary amines.
R1
NH3
H2N R1
HN
R2
HO–/H2O
R1I, THF, 65 °C
HO–/H2O
R1
3 steps
R1I, THF, r.t.
+
Ph3P
N
Li
Ph3P NR1
I –
Ph3P
N
R2
Scheme 2
Ph
P
R2X
R1N3
PPh2
N
R1
4
2
Ph
3
1
X –
X –
Methods for the conversion of azides into secondary
amines which do not involve iminophosphorane or imine
intermediates are known.5 However, while solid- and so-
lution-phase methods via intermediary iminophospho-
ranes have been reported,6,7 they describe aza-Wittig
reactions starting from azides and aldehydes.
Ph
Ph
P
R1
R1
(a)
P+ NH
Ph
+
N
R2
R2
Ph
5
5
H
N
(b)
78–87%
R1
R2
6
SYNLETT 2008, No. 1, pp 0097–0099
x
x.
x
x.
2
0
0
7
Advanced online publication: 03.12.2007
DOI: 10.1055/s-2007-990927; Art ID: D26807ST
Scheme 3 Reagents and conditions: (a) filtration and washing of the
© Georg Thieme Verlag Stuttgart · New York
resin; (b) KOH–MeOH, 65 °C; filtration.

98
S. Ayesa et al.
LETTER
The solid-phase protocol developed (Scheme 3) proceeds secondary amines from the solid support was performed
via a Staudinger reaction employing polymer-supported using one equivalent of methanolic KOH. The cleavage
triphenylphosphine 19 and an azide 2 to give the corre- time was optimized to three to four hours at 65 °C to fur-
sponding iminophosphorane 3. The resulting suspension nish the corresponding secondary amine 6 in solution and
was subsequently agitated at room temperature for three the resin-bound triphenylphosphine oxide, which was re-
to four hours. During protocol development the reactions moved by filtration. After concentration, the resulting sec-
were conveniently monitored by FT-IR where the disap- ondary amines were obtained by extraction of the aqueous
pearance of the signal corresponding to the azide in the so- phase containing the potassium salts with dichlo-
lution phase was followed by a new P=N absorption band romethane and ethyl acetate. Polymer-supported triphen-
in the solid phase. Iminophosphorane 3 was alkylated in ylphosphine can be regenerated by the reduction of
situ with alkyl, allyl, or benzyl halides 4 to afford the cor- polymer-supported phosphine oxide with trichlorosi-
responding disubstituted aminophosphonium salts 5. Best lane.10
results were obtained when the alkylation was allowed to
Table 1 shows the azides and the alkylating agents used,
proceed for 16 hours at ambient temperature. Prolonged
as well as the isolated yields of products and their purities.
reaction times or heating did not improve the overall
All products were characterized by LC-MS, NMR, and
yields. After washing the resin, hydrolytic cleavage of the
HRMS.11–13 No primary amine byproducts from incom-
Table 1 Preparation of Secondary Amines 6 from Azides and Reactive Halides12
Entry Azide 2
R2X 4
Product 6
Yield (%)a
81
Purity (%)b
95/95
1
MeI
N
H
N3
N3
2
3
82
87
95/95
94/95
CN
Br
NC
HN
N3
Br
HN
HN
4
78
21
97/95
97/95
Br
N3
5
N3
Br
O
O
H
N
O
O
6
MeI
85
82
97/94
O
O
O
O
HN
HN
N
H
N3
7
96/95
Br
O
O
O
O
HN
HN
N3
N
H
a Yield of pure compound fully characterized by LCMS, NMR, and HRMS, with respect to the initial loading of the resin.
b Purity determined by LCMS/NMR, except for entry 6 which was determined by ELSD/NMR.
Synlett 2008, No. 1, 97–99 © Thieme Stuttgart · New York

LETTER
Synthesis of Secondary Amines
99
Senenayake, C. H. Tetrahedron Lett. 2002, 43, 8620.
(c) Entry 4: Barluenga, J.; Canteli, R.-M.; Flórez, J. J. Org.
Chem. 1994, 59, 602.
plete alkylation or other byproducts were observed. The
yields obtained were good in all cases (78–87%) except
for the phenylazide (entry 5), and with excellent purities
(>95%). A possible explanation for the low yield obtained
in entry 5 could be that of slower reaction kinetics be-
tween the phenylazide and the polymer-supported triphen-
ylphosphine as has previously been reported in a study
concerning the reduction of phenyl azide to aniline.14 The
advantage of avoiding dialkylation in the present method-
ology is most clearly observed in the cases where MeI was
used (entries 1 and 6), where in contrast to other methods
for methylation, no dimethylated products were observed.
(12) General Procedure for the Synthesis of Secondary
Amines 6
Anhyd THF (5 mL) was added to polymer-supported Ph3P9
(2.15 mmol/g, 200 mg, 0.43 mmol). The mixture was left to
stand for 5 min, whereupon a solution of the azide (0.215
mmol) in anhyd THF (1 mL) was added. The suspension was
agitated at r.t. for 4 h. To the mixture was added a solution
of the alkylating reagent (0.645 mmol) in anhyd THF (500
mL). The mixture was agitated at r.t. for 16 h, filtered and the
resin washed with anhyd THF (5 × 10 mL) and anhyds
CH2Cl2 (5 × 10 mL). The resin was suspended in MeOH (2
mL) and transferred to a 4 mL screw-lock vial, and a solution
of KOH (2% in MeOH, 2.15 mmol) was added. The
suspension was agitated at 65 °C for 4 h, cooled to r.t.,
filtered and the resin washed with CH2Cl2 (4 × 3 mL) and
MeOH (2 × 3 mL). The filtrate and washings were combined
and concentrated to dryness. The crude product was
partitioned between CH2Cl2 and 10% aq NaHCO3, and the
aqueous layer extracted with EtOAc. The combined organic
extracts were dried over anhyd Na2SO4, filtered, and
concentrated to give the amine. Yields and purities of
isolated amines are shown in Table 1.
In summary, we have described a convenient and efficient
polymer-supported protocol for the synthesis of second-
ary amines in good overall yields and purities from the
corresponding azides and reactive alkyl halides, without
the necessity of isolation or purification of any intermedi-
ates. This procedure complements existing methods of
amine alkylation, reductive alkylation, and aza-Wittig
procedures.7,15,16 Current work is focused on the optimiza-
tion of the method for phenylazides as starting materials
and the development of a protocol for adapting this meth-
od to solution-phase parallel synthesis employing a fluo-
rous-tethered Ph3P in combination with FluoroFlashTM
SPE.
(13) Spectral Data for Table 1
Entry 3: 1H NMR (400 MHz, CDCl3): d = 1.25 (s, 9 H), 1.55
(br s, 1 H), 3.78 (s, 2 H), 3.83 (s, 2H), 7.25–7.39 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 31.1, 34.6, 49.5, 49.8,
126.0, 127.3, 128.9, 129.3, 129.7, 129.9, 130.5, 152.5. MS
(ES+): m/z = 254.39 [H + M]+. HRMS (ES+): m/z calcd for
C18H23N: 254.1903; found: 254.1904 [H + M]+.
References and Notes
Entry 5: 1H NMR (400 MHz, CDCl3): d = 1.32 (s, 9 H), 3.84
(s, 3 H), 4.34 (s, 2 H), 4.44 (br s, 1 H), 6.50 (d, J = 8.7 Hz, 2
H), 7.28 (d, J = 7.6 Hz, 2 H), 7.38 (d, J = 7.6 Hz, 2 H), 7.84
(d, J = 8.7 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 31.4,
34.6, 47.5, 51.5, 111.6, 118.6, 125.7, 127.3, 131.6, 135.3,
150.6, 151.8, 167.3. MS (ES+): m/z = 298.23 [H + M]+.
HRMS (ES+): m/z calcd for C19H23NO2: 298.1801; found:
298.1802 [H + M]+.
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Entry 6: 1H NMR (400 MHz, CDCl3): d = 0.88–0.94 (m, 6
H), 1.20–1.30 (m, 1 H), 1.41 (s, 9 H), 1.58–1.70 (m, 2 H),
2.70 (s, 3 H), 2.96–3.10 (m, 2 H), 3.90–4.00 (m, 1 H), 5.20–
5.28 (br s, 1 H), 5.48–5.50 (br s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 21.8, 22.8, 28.2, 33.2, 41.9, 46.2, 50.8, 80.1,
156.2. MS (ES+): m/z = 231.35 [H + M]+. HRMS (ES+): m/z
calcd for C12H26N2O2: 231.2073; found: 231.2074 [H + M]+.
Entry 7: 1H NMR (400 MHz, CDCl3): d = 0.84–0.86 (m, 6
H), 1.21–1.23 (m, 1 H), 1.25 (s, 9 H), 1.43 (s, 9 H), 1.58–1.63
(m, 2 H), 3.85–3.90 (m, 2 H), 3.84–4.03 (m, 3 H), 5.65 (br s,
1 H), 5.80 (br s, 1 H), 7.31 (d, J = 7.6 Hz, 2 H), 7.36 (d,
J = 7.6 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 21.9,
22.7, 28.3, 31.1, 34.6, 41.9, 46.1, 50.0, 50.4, 79.7, 125.9,
129.4, 152.1, 156.3, 168.6. MS (ES+): m/z = 363.56 [H +
M]+. HRMS (ES+): m/z calcd for C22H38N2O2: 363.3006;
found: 363.3007 [H + M]+.
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Synlett 2008, No. 1, 97–99 © Thieme Stuttgart · New York

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