Microwave-assisted synthesis of primary amine HX salts from halides and 7 M ammonia in methanol

Article abstract of DOI:10.1016/j.tetlet.2003.10.146

The atom economical synthesis of hydrogen halide salts of primary amines, directly from the corresponding halides, avoids the production of significant amounts of secondary amine side products, and requires only evaporation of the solvent to access the products in yields generally greater than 90%. The procedure uses microwave irradiation in 7 M ammonia in methanol (Aldrich) at 130°C from 0.5 to 2.5h and works on a variety of alkyl halides, as well as mesylates and tosylates. Benzylamines are obtained from benzyl halides without significant amounts of the secondary amine side products that result without microwave heating. Direct isolation of even highly volatile primary amines as their hydrogen halide salts makes the method ideal for use in parallel synthesis.

Full text of DOI:10.1016/j.tetlet.2003.10.146

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 397–399
Microwave-assisted synthesis of primary amine HX salts from
halides and 7 M ammonia in methanol
Mark G. Saulnier,* Kurt Zimmermann,* Charles P. Struzynski, Xiaopeng Sang,
Upender Velaparthi, Mark Wittman and David B. Frennesson
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Received 8 October 2003; accepted 23 October 2003
Abstract—The atom economical synthesis of hydrogen halide salts of primary amines, directly from the corresponding halides,
avoids the production of significant amounts of secondary amine side products, and requires only evaporation of the solvent to
access the products in yields generally greater than 90%. The procedure uses microwave irradiation in 7 M ammonia in methanol
(Aldrich) at 130 °C from 0.5 to 2.5 h and works on a variety of alkyl halides, as well as mesylates and tosylates. Benzylamines are
obtained from benzyl halides without significant amounts of the secondary amine side products that result without microwave
heating. Direct isolation of even highly volatile primary amines as their hydrogen halide salts makes the method ideal for use in
parallel synthesis.
Ó 2003 Elsevier Ltd. All rights reserved.
There are numerous methods for the synthesis of pri-
mary amines from halides.1 While the use of ammonia
for this purpose has certainly been described,2 its rather
poor nucleophilicity tends to demand long reaction
times and can often give significant amounts of sym-
metrical secondary amine side products. For example,
a recent patent3 describes the conversion of (3-chloro-
propyl)triethoxysilane to the corresponding primary
amine using 100 equiv of ammonia in a continuous flow
reactor at 100–120 °C at 50 bar. This method gives 30–
35% secondary amine and a small amount of tertiary
amine in addition to the desired primary amine. A recent
disclosure of the synthesis of tertiary trialkanolamines
by opening of epoxides with ammonia in a microwave
reactor4 prompted our reasoning that similar use of
ammonia might be ideally suited for the synthesis of
primary amines from alkyl halides. Herein we now re-
port a simple, atom economical synthesis of the hydro-
gen halide salts of primary amines, directly from the
corresponding halides, that avoids the production of
significant amounts of secondary amine side products
and requires only evaporation of the solvent to access
the products in yields generally greater than 90%.
Our procedure5 uses microwave irradiation at 100–
130 °C from 0.25 to 2.5 h and works on a variety of alkyl
halides, as well as tosylates and mesylates, as shown in
Table 1. The use of 2 M ammonia in methanol tends to
give substantially more recovered starting halide and
secondary amine side products than 7 M ammonia in
methanol. The preferred reaction concentration is
0.04 M, using 0.25 mmol of substrate in 6.25 mL of 7 M
ammonia in methanol (Aldrich) in a 10 mL microwave
vial, as shown in Scheme 1, for example, 1a to 2a. Using
1 mmol of substrate 1a in 5 mL of 7 M ammonia in
methanol gives somewhat more secondary amine (7%)
and recovered starting material (5%). Several other alkyl
halides also serve as suitable substrates, including those
containing nitro, alkoxy, and halogen substituents.
Table 1 summarizes the range of alkyl halides that were
converted to the corresponding primary amines using
this protocol. All reactions gave 2–4% or less of the
symmetrical secondary amine side product. The scope of
the reaction includes less reactive halides (1h–i) and
branching adjacent to (1g), and at (1o), the reaction
center. Direct isolation of the primary amine products as
Keywords: primary amines; ammonia; microwave-assisted synthesis.
* Corresponding authors. Tel.: +1-203-677-6325; fax: +1-203-677-7702
(M.G.S.), Tel.: +1-203-677-7236; fax: +1-203-677-7702 (K.Z.);
e-mail: mark.saulnier@bms.com; kurt.zimmermann@bms.com
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.146

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M. G. Saulnier et al. / Tetrahedron Letters 45 (2004) 397–399
Table 1. Microwave-assisted synthesis of primary amine HX salts from halides and 7 M ammonia in methanola
Halide
Productb
Yield (%)c
95
Halide
Productb
Yield (%)c
93
NH2
HI
NH2
I
Cl
N
N
N
N
1a
.
HCl
.
2a
2k
1k
Cl
Br
Cl
NH2
NH2
Cl
Br
Cl
Cl
N
N
95
95
96
96
.
N
HCl
N
1b
.
.
HCl
F
F
2b
1l
2l
Cl
Br
NH2
NH2
HCl
N
N
N
N
MeO
O2N
.
HCl
MeO
1c
2c
1m
2m
NH2
Br
NH2
HBr
75d
N
94
95
N
N
N
.
.
O2N
HBr
1d
2d
2n
1n
Br
NH2
HBr
98
MeO
MeO
NH2
Br
.
.
HBr
1e
2e
2o
1o
I
NH2
Cl
NH2
.
70
90
97
95
95
95
HI
N
N
.
.
HCl
HCl
1f
2f
1p
2p
Br
NH2
HBr
Cl
NH2
.
.
.
HCl
N
HCl
N
2g
1g
2q
1q
O
F3C
O
F3C
Br
NH2
HCl
NH2
Cl
.
Br
.
Br
HBr
CF3
1r
CF3
2h
.
1h
2r
Br
NH2
HBr
O
O
95
95
Br
NH2
.
HBr
1i
2i
1s
2s
Br
NH2
HBr
Br
Br
NO2
NH2
88
94
NO2
.
.
1j
HBr
2j
1t
2t
a All reactions gave 2–4% or less of the symmetrical secondary amine side product.
b Reaction conditions: 130 °C for 2.5 h, for example, 2a–e, 2g–j, 2l–n; 130 °C for 0.5 h, for example, 2f, 2k, 2o–q; 100 °C for 0.25 h, for example, 2r–t.
All reactions used 0.25 mmol substrate in 6.25 mL of 7 M ammonia in methanol in a 10 mL microwave vial.
c Yields refer to weight of product obtained after evaporation of the solvent. All of the examples in the table were >95% pure as determined by
1H NMR (except example 2n).
d For 2n, the p-nitrostyrene elimination side product (20%) was present as indicated by 1H NMR.

M. G. Saulnier et al. / Tetrahedron Letters 45 (2004) 397–399
399
H
N
6.25 mL 7 M NH3
NH
2
Cl
in MeOH
N
N
N
N
N
N
N
.
HCl
.
N
HCl
microwave
130 oC / 2.5 h
2a (>95%)
<5%
1a (0.25 mmol)
Scheme 1. Optimal conditions for microwave-assisted synthesis of 2a using 7 M ammonia in methanol.
F C
3
F C
3
F C
3
CF
3
NH
Cl
NH
2
7 M NH3 / CH3OH
.
.
HCl
HCl
CF
CF
3
3
A
. microwave
100 oC / 15 min
or
CF
3
CF
3
1r
A.
<4%
2r (>96%)
B
. 23 oC / 2 h
B.
2r (75-80%)
20-25%
Scheme 2. Dramatic improvement in the synthesis of benzyl amines from benzyl halides using microwave irradiation.
their hydrogen halide or sulfonate6 salts by simple
evaporation allows very volatile primary amines (1e–f)
to be obtained in good yield as well.7
Voelter, W. Tetrahedron Lett. 2001, 42, 2435; (d) Kaylor, J.
J.; Risley, J. M. Carbohydr. Res. 2001, 439; (e) Morini, G.;
Pozzoli, C.; Adam, M.; Poli, E.; Coruzzi, G. Farmaco 1999,
54, 740; (f) Nugiel, D. A.; Vidwans, A.; Etzkorn,
A.-M.; Rossi, K. A.; Benfield, P. A.; Burton, C. R.; Cox,
S.; Doleniak, D.; Seitz, S. P. J. Med. Chem. 2002, 45,
5224.
The results with benzyl halides (1r–t) are noteworthy
since reaction of these substrates with 7 M ammonia in
methanol proceeds to completion in 2 h at room tem-
perature. However, 20–25% of the bisalkylated second-
ary amine is produced as side product. We were
surprised to discover that under conditions of micro-
wave irradiation at 100 °C for 15 min, there was less than
4% of secondary amine formed as shown in Scheme 2.
3. Balduf, T.; Wieland, S.; Lortz, W.; Pohlisch, J.; Gobel, T.;
Grethe, H. Continuous Process for Preparing Aminopropyl
Trialkoxysilanes. EP 0849271B1, granted 8-07-2002.
4. Favretto, L.; Nugent, W. A.; Licini, G. Tetrahedron Lett.
2002, 43, 2581.
5. General experimental procedure: A solution of 7 M ammo-
nia in methanol (Aldrich; 6.25 mL) was added to 0.25 mmol
of the alkyl halide (or sulfonate) in a 10 mL microwave vial.
The reaction mixture was heated with stirring at 100–130 °C
in a Smith synthesizer auto-sampling microwave from 0.25
to 2.5 h as indicated in Table 1. The solvent was evaporated
under a stream of dry nitrogen to give the primary amine
HX salts as solids. All of the examples in the table were
>95% pure as determined by 1H NMR and LC/MS and
were used directly as obtained in a parallel synthesis
fashion.
In summary, we have described a practical and atom
economical synthesis of hydrogen halide salts of primary
amines, directly from the corresponding halides, using
microwave irradiation in 7 M ammonia in methanol,
commercially available from Aldrich. This procedure
avoids the production of significant amounts of sec-
ondary amine side products, and requires only evapo-
ration of the solvent to access the products in yields
generally greater than 90%. Benzylamines are obtained
from benzyl halides, avoiding significant amounts of the
secondary amine side products that result without
microwave heating. Direct isolation of the primary
amine products as their hydrogen halide salts by simple
evaporation is ideal for their subsequent use in parallel
synthesis. The fact that hydrogen halide salts of the
primary amine products are obtained directly, allows
even very volatile primary amines to be accessed in good
yield as well.
6. Both ethyl methanesulfonate and 3-butynyl p-toluenesulf-
onate are similarly converted to their corresponding
primary amine sulfonate salts in high yield.
7. The yield for ethyl iodide 1f is only 70% due to the high
volatility of ethylamine. In fact, if the product of this
reaction (ethylamine HI salt, obtained after evaporation) is
redissolved in 7 M ammonia in methanol and evaporated
under nitrogen again, further loss occurs. Presumably
ammonium iodide is formed as ethylamine is lost. Using
ethyl methanesulfonate instead of ethyl iodide gives an
identical result with the caveat that the anion, methane-
sulfonate, can be identified by 1H NMR (CD3OD). The
integration of the methanesulfonate signal at 2.70 ppm is
almost 50% greater than the methyl triplet for the ethyl-
amine, indicating about a 2:1 mixture of ethylamine
methanesulfonate to ammonium methanesulfonate. Redis-
solving this material in 7 M ammonia in methanol followed
by evaporation under a stream of nitrogen leads to the
integration of the methanesulfonate signal at 2.70 ppm
being 100% greater than the methyl triplet for the
ethylamine. This result confirms some loss of ethyl amine
due to equilibration with ammonia.
References and Notes
1. Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989, pp 397–410.
2. (a) Zimmerman, H. E.; Paskovich, D. H. J. Am. Chem. Soc.
1964, 86, 2149; (b) Millan, D. S.; Prager, R. H. Aust. J.
Chem. 2000, 53, 615; (c) Abdel-Jalil, R. J.; Saeed, M.;