A simple one-pot procedure for the iminium salt formation: An efficient route to β-arylethylamines

Article abstract of DOI:10.1016/j.tetlet.2005.01.027

A practical and highly efficient process for the preparation of β-arylethylamines 7 was developed. Benzylic organozinc compounds 10 were reacted with the iminium salts 9 generated in situ from the amine salt 8 and paraformaldehyde in one pot and in a polar and aprotic solvent, such as NMP. A variety of the β-arylethylamines were prepared in 43-91% yields.

Full text of DOI:10.1016/j.tetlet.2005.01.027

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1471–1474
A simple one-pot procedure for the iminium salt formation:
an efficient route to b-arylethylamines
Yi-Yin Ku,* Tim Grieme, Yu-Ming Pu, Ashok V. Bhatia and Steve A. King
R450, Chemical Process Research and Development, Global Pharmaceutical Research and Development,
Abbott Laboratories, North Chicago, IL 60064-4000, USA
Received 17 November 2004; revised 5 January 2005; accepted 7 January 2005
Available online 22 January 2005
Abstract—A practical and highly efficient process for the preparation of b-arylethylamines 7 was developed. Benzylic organozinc
compounds 10 were reacted with the iminium salts 9 generated in situ from the amine salt 8 and paraformaldehyde in one pot
and in a polar and aprotic solvent, such as NMP. A variety of the b-arylethylamines were prepared in 43–91% yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Development of a practical and efficient procedure for
the b-arylethylamines 7 has been the focus of several
recent studies1 because they are the common subunit
of a large variety of biologically active compounds.2
The most common syntheses of the b-arylethylamines
7 are the N-alkylation reactions of the amines with the
corresponding halides 13 or activated alcohols 2.4 The
main drawbacks of this approach are that a substantial
amount of quaternary amine salt could be produced as
well as a styrene by-product formed via E2 elimination.2e
Another common method for b-arylethylamines 7 is the
reductive amination reaction of the corresponding
aldehydes 3.5
to achieve a one-carbon homologation. Specifically, for
the preparation of 2b, the bromides 4 was reacted with
KCN to obtain nitrile 5, which was hydrolyzed to afford
the acid 6, and reduction of 6 led to 2b. Conversion of 2b
to the amines 7 would require two additional steps of
activation and displacement (Scheme 1). It should also
be noted that the reductive amination process would
require the preparation of aryl-acetaldehyde precursors,
which were often difficult to prepare due to their poor
stability.7
The most recent advancement for the preparation of the
b-arylethylamines 7 was reported by Hartwig and co-
workers.1a,b They achieved the anti-Markovnikov
hydroamination of vinylarenes via the rhodium or
ruthenium catalyzed reactions.
R
R
R
OHC
HO
X
The above-mentioned methodologies for the b-aryleth-
ylamines 7 all involve introduction of amines to the
3
1: X = Br, Cl, I
2a: R=2-Br
2b: R=2-i-Pr, 3-Me
Although these approaches appear straightforward,
multiple steps are often required when the precursor
halides, alcohols or aldehydes have some degree of
structural complexity. For example, both alcohols 2a
and 2b were obtained from the corresponding benzyl
bromide6 after undergoing multi-step transformations
HCl
R
KCN
R
R
Br
NC
HO2C
EtOH
4
5
6
LiAlH4
Activation
Displacement
R
R
HO
"RR'N
Keywords: b-Arylethylamines; Iminium salt; Mannich reaction.
Corresponding author. Tel.: +1847 937 4843; fax: +1847 938
5932; e-mail: yiyin.ku@abbott.com
2b
7
*
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.027

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Y.-Y. Ku et al. / Tetrahedron Letters 46(2005) 1471–1474
corresponding pre-established two-carbon side unit. On
the other hand, direct one-carbon homologation and
concurrent introduction of amine functionality from
the benzylic organometallic and Mannich reagents could
provide an attractive alternate route for the b-arylethyl-
amines 7. In fact, this approach to b-arylethylamines 7
has not been well recognized.8 Herein, we would like
to report a highly efficient procedure for the preparation
of the b-arylethylamines 7 via a one-pot direct a-amino-
methylation of the benzylic organozinc reagents 10 with
the iminium 9 generated in situ.
A variety of b-arylethylamines 7 were prepared from the
reaction of the organozinc reagent 10 and the Mannich
reagents 9 generated in situ (Table 1, Scheme 3). The
organozinc reagents are readily accessible by direct
insertion of zinc15 to the readily available benzyl bro-
mides, and in fact, many benzylic organozinc reagents
are commercially available. The Mannich reagents were
typically prepared by heating a mixture of 1equiv of
amine salt (HCl, CF3CO2H) and 1.2–2.0 equiv of para-
formaldehyde in a polar aprotic solvent, such as NMP
at 40–60 °C for >10 h. Several other polar aprotic sol-
vents, such as DMF, DMA, DMSO and CH3CN could
also be used to generate the Mannich reagents. The
resulting reaction mixture was used directly without fur-
ther processing. The Mannich reagents obtained from
either chloride or trifluoroacetate salts produced similar
results in the subsequent reaction with the organozinc
reagents, although when the trifluoroacetate salt was
used, the Mannich reagents could be prepared at lower
temperatures (ꢀ40 °C). Typically, the reactions between
the organozinc reagents and the Mannich reagents were
carried out at ambient temperature and reached comple-
tion within 10 min to produce the b-arylethylamines 7.
When the bulky amine, 2,2,6,6-tetramethylpiperidine,
was used in the reaction (entry 15), a lower yield was
obtained, which presumably is caused by the steric
hindrance of the amine.
The Mannich reaction is one of the most important
methods for the a-aminomethylation of acidic CH com-
pounds.9 In practice, enolizable carbonyl compounds
serving as the acidic CH substrate are heated with aque-
ous formaldehyde and an amine hydrochloride in a pro-
tic solvent to produce the b-aminocarbonyl compound.
One of the limitations of these reaction conditions
is the use of formaldehyde10 in an aqueous media.
Recently, significant improvements have been made in
the field,11 the key success has come from the use of
pre-formed Mannich reagents. For example, iminium
salts can be prepared by cleavage of aminals with acetyl
chloride, iodotrimethylsilane or trifluoroacetic anhy-
dride;12 by cleavage of aminol ethers with trichloro-
methylsilane or chlorotrimethylsilane13 in an aprotic
solvent. The availability of these pre-formed Mannich
reagents having good electrophilicity in aprotic solvents
allowed for the use of more reactive nucleophiles such as
enolates, Grignard and organozinc reagents.8
It is noteworthy that when a chiral amine, R-2-methyl-
pyrrolidine, was used in the synthesis of b-arylethyl-
amines 7e–g, no racemization occurred throughout the
process. The enantiomeric purities of the products are
consistent with the enantiomeric purity of the starting
amine, R-2-methylpyrrolidine. Chiral HPLC analysis
was used to determine the enantiomeric purities of the
b-arylethylamines products 7e–g, while the chiral
derivatization using Cbz valine anhydride to prepare
the diastereomeric derivatives was used to determine
the enantiomeric purity of the starting material,
R-2-methylpyrrolidine.
The main disadvantages involved in the synthesis of pre-
formed Mannich reagents are that it requires an addi-
tional synthetic step to prepare the aminal or aminol
ether and the reagents are typically distilled (Scheme
2).14 In the case when aminal was used,8 1equiv of
amine is consumed to form the amide (Scheme 2), wast-
ing 1equiv of amine. It is undesirable when a valuable
amine such as chiral amine is used.
We have now demonstrated that the iminium reagents
can be generated efficiently in a single step under the
conditions compatible with the organozinc reagents,
by simply reacting the amine salt (HCl, CF3CO2H)
and paraformaldehyde in a polar and aprotic solvent
such as NMP. The iminium reagents generated can be
used directly to react with organozinc reagents under
mild conditions, thus further extending the scope of
the application of the Mannich reaction.
The major by-product formed in the reaction was from
hydrolysis of the corresponding benzylic organozinc
reagents. All other minor by-products were also neutral
species. All the by-products were easily removed from
the desired amine product by an acid/base extractive
work-up procedure. Thus, analytically pure b-arylethyl-
amines 7 can be obtained without the need of column
chromatographic purification. It should be noted that
HPLC analysis of the aqueous washes indicated the loss
(CF3CO)2O
N+
F3C
H
N
R: CH2CH=CH2
NR2
O
O
H
-OCOCF3
aq. CH2O
R2N
R2NH
Ph
Ph
Distillation
F3C
N
Ph
(CF3CO)2O
R: CH2C6H5
N+
Ph
H
H
-OCOCF3
Scheme 2.

Y.-Y. Ku et al. / Tetrahedron Letters 46(2005) 1471–1474
Table 1. Preparation of the terminal amines
1473
Entry
Organozinc reagent
Amine
Product type
Yielda (%)
Br
Br
1
8d
7a
7b
83
87
N
BrZn
O
2
3
8d
8d
CN
N
BrZn
CN
O
7c1a
91
86
CF3
N
ClZn
CF3
O
BrZn
N
4
5
8d
8a
7d
O
BrZn
N
7e
81
6
7
8a
8a
7f
73
68
CN
Br
BrZn
N
N
CN
Br
7g
BrZn
Br
Br
8
9
8b
8b
7h
7i
70
70
N
N
ClZn
CN
BrZn
CN
10
11
8b
8b
7j
71
77
CF3
N
N
BrZn
CF3
BrZn
7k
Br
Br
12
8c
7l2c
66
BrZn
N
Br
Br
N
13
14
8e
8e
7m
7n
65
59
O
BrZn
O
CN
N
O
BrZn
CN
O
N
Br
Br
15
8f
7o
43
BrZn
O
O
O
HN
N
H
N
H
N
N
H
N
H
8d
H
8e
8f
8b
8a
8c
a The HPLC assay yields of the reaction mixture were determined using quantitative HPLC analysis by comparison to a know amount of analytical
pure reference standards. The yields were not optimized.

1474
Y.-Y. Ku et al. / Tetrahedron Letters 46(2005) 1471–1474
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NH2
N+ CH2
R''
R''
X = Cl, OCOCF3
9
8
R
R
BrZn
10
"RR'N
7
Scheme 3.
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tion of the work-up procedure could reduce the product
losses.
The good reactivity exhibited by the Mannich reagents
generated in situ directly from paraformaldehyde and
the amine salts coupled with the simplicity of the isola-
tion and purification procedure provide a viable synthe-
sis for the b-arylethylamines 7. The reactions were
carried out under mild conditions and they are compat-
ible with a variety of functional groups such as bromo,
nitrile and acetal, all of which can be further function-
alized to obtain structurally more diverse b-arylethyl-
amines 7.
In conclusion, we have demonstrated a practical and
efficient process for the preparation of various b-aryleth-
ylamines 7 containing a wide range of substitution
patterns under mild reaction conditions from readily
accessible benzyl organozinc reagents and easily pre-
pared Mannich reagents. The methodology should be
easily applicable to a large number of biologically active
compounds contain the subunit of b-arylethylamines.
The process is highlighted by the development of a sin-
gle-step procedure to generate the pre-formed Mannich
reagents in situ. It further extends the spectrum of the
application of the Mannich reaction.
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Supplementary data
The supplementary data is available online with the
paper in ScienceDirect. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.01.027.
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