Direct reductive alkylation of amine hydrochlorides with aldehyde bisulfite adducts

Article abstract of DOI:10.1016/j.tetlet.2014.03.046

A mild procedure for the direct reaction of aromatic and aliphatic aldehyde bisulfite adducts with primary and secondary amine hydrochlorides in the presence of sodium cyanoborohydride in methanol is reported.

Full text of DOI:10.1016/j.tetlet.2014.03.046

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct reductive alkylation of amine hydrochlorides with aldehyde
bisulfite adducts
Marta Barniol-Xicota a, Andreea L. Turcu a, Sandra Codony a, Carmen Escolano b, Santiago Vázquez a,
⇑
a Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII s/n,
Barcelona E-08028, Spain
b Laboratori de Química Orgànica, Facultat de Farmàcia, Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII s/n, Barcelona E-08028, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild procedure for the direct reaction of aromatic and aliphatic aldehyde bisulfite adducts with
primary and secondary amine hydrochlorides in the presence of sodium cyanoborohydride in methanol
is reported.
Received 5 February 2014
Revised 4 March 2014
Accepted 7 March 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Bisulfite adducts
Reductive alkylation
Reductive amination
Sodium cyanoborohydride
The reaction of aldehydes with ammonia, primary amines or
secondary amines under reductive conditions (reductive alkylation
of the amines or reductive amination of the aldehydes) is a very use-
ful and versatile method for the synthesis of amines.1 The reaction
involves first the formation of a carbinolamine, which dehydrates
to form an imine/iminium salt that is subsequently reduced to
the product. Although it is possible to perform the reaction in a
stepwise process, with isolation of the imine/iminium salt, usually
the reaction is carried out directly in one step, with the imine/
iminium salt being reduced during formation. In this second, more
common approach, an obvious difficulty is avoiding the reduction
of the aldehyde before its reaction with the amine. The two most
commonly used selective reductor agents are hydrogen, particu-
larly interesting in large scale reactions,2 and several borohydrides
such as sodium cyanoborohydride3 (Borch reaction),4 or sodium
triacetoxyborohydride.5 Numerous alternative reagents have also
been used.6
A widespread problem while working with aldehydes is their
instability (e.g., tendency to epimerize, undergo air oxidation to
the carboxylic acid). Moreover, several liquid aldehydes are difficult
to purify. Bisulfite adducts, are usually crystalline, easy to handle
solids, synthesized simply by mixing the aldehyde with aqueous so-
dium bisulfite. They show desirable physical properties such as fac-
ile isolation and purification and can be stored for prolonged
periods of time.7 Although the most common used counterion in
the preparation of aldehyde bisulfite adducts is sodium, very re-
cently Kissane et al. have reported that, for several aldehydes, the
potassium bisulfite adduct shows more advantageous solid state
properties.8
Surprisingly, the direct use of the bisulfite adducts of aldehydes
in reductive amination reactions has scarcely been reported in the
scientific literature. In a pioneering work, Pandit and Mani reported
in 2009 that secondary amines may be reductively alkylated with
aldehyde bisulfite adducts using NaBH(OAc)3 in anhydrous 1,2-
dichloroethane at room temperature.9 The expected tertiary
amines were isolated in high yields (>80%). Two drawbacks of this
method are that it was limited to secondary aliphatic amines and
that 2 equiv of the amine was needed. It was postulated that the
first equivalent of the amine liberated the aldehyde from the bisul-
fite adduct, while the second one participated in the amination
reaction. In order to avoid the use of an excess of a valuable amine
the authors also reported a method involving prior treatment of the
aldehyde bisulfite adduct with 1 equiv of triethylamine in order to
liberate the aldehyde in situ, followed by the addition of 1 equiv of
the required secondary amine.
In 2013, Vounatsos and co-workers reported a direct reductive
amination reaction of aldehyde bisulfite adducts with primary
amines in methanol at 30 °C using 2-picoline borane as the hydride
source. The expected secondary amines were obtained in medium
yields, although in one particularly interesting example the reac-
tion was further optimized giving yields >80%. The main drawback
⇑
Corresponding author. Tel.: +34 934024533; fax: +34 934035941.
E-mail address: svazquez@ub.edu (S. Vázquez).
http://dx.doi.org/10.1016/j.tetlet.2014.03.046
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Barniol-Xicota, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.03.046

2
M. Barniol-Xicota et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Mani's work
p-methoxybenzaldehyde bisulfite adduct, 1b, in the presence of
NaCNBH3 in methanol at room temperature. After an extractive
work-up, the expected tertiary amine, 12, was isolated in 90% yield
(Table 1, entry 1). An excellent yield, 91%, was also obtained when
the reaction was conducted with dimethylamine hydrochloride
and p-chlorobenzaldehyde bisulfite adduct, 1d (Table 1, entry 2).
The generality of the method was further evaluated by perform-
ing the reaction with various aldehyde bisulfite adducts and the
hydrochlorides of several primary and secondary amines. Specifi-
cally, five different aromatic benzaldehydes, cinnamaldehyde and
two aliphatic aldehydes were used (Scheme 2). Regarding the
amines, three secondary amine hydrochlorides, including
R'
N
Et3N
R''
+
R
N
1 equivalent
H
R''
R'
1 equivalent
secondary amine
R', R''= alkyl
RNH2
Vounatsos' work
OH
SO3Na
2 equivalents
primary amine
R
NHR'
R
R' = alkyl, aryl
R'(H)
·HCl
R''
This work
N
H
R''
1 equivalent
R
N
R'
primary/secondary
amine
Table 1
Amines 12–24 produced via Scheme 3
R' = alkyl
c
Aminea
Aldehyde
Productb
%
R'' = H or alkyl
Entry
N
Scheme 1. Processes for the direct reductive amination of aldehyde bisulfite
adducts.
1
6
1b
90
CH3O
Cl
12
N
2
3
6
7
1d
1b
91
61
of this approach was that again, 2 equiv of the starting primary
amine was required.10 This recent Letter prompted us to disclose
our own progress in this field.
We reasoned that the salt break may be brought about by using
only 1 equiv of the amine if it was added to the reaction as its cor-
responding hydrochloride. In this way, the use of a second equiva-
lent of the amine may be avoided (Scheme 1).
In order to investigate the use of bisulfite adducts in the direct
reductive alkylation of amine hydrochlorides, a series of aromatic
and aliphatic aldehyde bisulfite adducts were first prepared. Thus,
an ethanolic solution of the aldehyde at 30–35 °C was treated with
an aqueous solution of sodium bisulfite.11 The resulting solid was
filtered, dried under vacuum and used directly in the reductive
amination experiments (Scheme 2).12
With the structurally different aldehyde bisulfite adducts in
hand, the direct reductive alkylation reaction with amine hydro-
chlorides was attempted (Scheme 3).
13
N
F
CH3O
14
OCH3
N
4
5
8
8
1b
2
74
65
CH3O
15
16
OCH3
OCH3
O
O
N
OCH3
OCH3
N
6
7
8
9
4
80
95
17
OCH3
CO2CH3
N
H
1b
CH3O
18
After some preliminary experiments, we carried out the reac-
tion of dimethylamine hydrochloride with 1.12 equiv of the
8
9
10
11
11
11
11
11
1b
1a
1b
1c
4
58
67
N
H
19
CH3O
O
NaHSO3
,
30-35ºC
OH
SO3H
N
H
R
H
R
EtOH/H2O, 16 h
20
OH
SO3Na
OH
SO3Na
OH
SO3Na
N
H
O
10
11
12
13
60
CH3O
21
O
R
2
3
1a
1b
, R = H; , R = OCH3
N
1c, R = N(CH3)2; 1d, R = Cl
H
92
OH
SO3Na
N
22
N
H
67
5
4
CF3
HO
SO3Na
23
Scheme 2. Synthesis of bisulfite adducts. Reagents and conditions: (a) NaHSO3
(1 equiv), EtOH, H2O, 30–35 °C, 16 h. Yields: 1a, 98%; 1b, 94%; 1c, 90%; 1d, 76%; 2,
97%; 3, 94%; 4, 88%; 5, 91%.
F3C
N
H
5
90d
24
OH
SO3H
NaCNBH3
MeOH, rt
R'(H)
R'(H)
a
R
N
R''
All the starting amines were used as hydrochlorides.
All final products were isolated as hydrochlorides, except compounds 12, 18
·HCl
+
N
b
R
H
R''
and 19.
c
The yields are unoptimized.
91% yield using Et3NÁBH3.
Scheme 3. Direct reductive alkylation of amine hydrochlorides with aldehyde
d
bisulfite adducts.
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M. Barniol-Xicota et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
F
molecular weight, such as dimethylamine, are usually commercially
available as salts. Thus, our approach is particularly interesting for
this kind of amine. The reductive amination conditions described
fulfil the principle of atom economy because equimolecular
amounts of bisulfite adduct and amine hydrochloride are used.
OCH3
·HCl
OCH3
HCl·NH(CH3)2
HN
N
H
7
·HCl
6
8
CO2CH3
H2N
Acknowledgements
H2N
·HCl
·HCl
H2N
SV thanks the Spanish Ministerio de Ciencia e Innovación (Grant
CTQ2011-22433) and the Generalitat de Catalunya (Grant SCG-
2009-294) for financial support.
·HCl
11
9
10
Supplementary data
Figure 1. Primary and secondary amine hydrochloride tested.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
046.
dimethylamine hydrochloride, 6, a pyrrolidine derivative, 7 and the
tetrahydroisoquinoline derivative 8, and three primary amine
hydrochlorides, the methyl ester of phenylalanine, 9, the sterically
hindered 2-adamantanamine, 10 and the enantiopure (R)-1-(1-
naphthyl)ethylamine, 11, were investigated (Fig. 1).
References and notes
1. Smith, M. B. March’s Advanced Organic Chemistry, 7th ed.; John Wiley & Sons:
New Jersey, 2013; pp 1096–1099.
2. Tripathi, R. P.; Verma, S. S.; Pandey, J.; Tiwari, V. K. Curr. Org. Chem. 2008, 12,
1093–1115.
3. (a) Lane, C. F. Synthesis 1975, 135–146; (b) Hutchins, R. O.; Natale, N. R. Org.
Prep. Proced. Int. 1979, 11, 201–246.
4. Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673–1674.
5. Abdel-Magid, A. F.; Mehrman, S. J. Org. Process Res. Dev. 2006, 10, 971–1031.
6. Kumar, N. U.; Reddy, B. S.; Reddy, V. P.; Bandichhor, R. Tetrahedron Lett. 2012,
53, 4354–4356.
7. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford
University Press: New York, 2012; pp 138–139.
8. Kissane, M. G.; Frank, S. A.; Rener, G. A.; Ley, C. P.; Alt, C. A.; Stroud, P. A.; Vaid,
R. K.; Boini, S. K.; McKee, L. A.; Vicenzi, J. T.; Stephenson, G. A. Tetrahedron Lett.
2013, 54, 6587–6591.
9. Pandit, C. R.; Mani, N. S. Synthesis 2009, 4032–4036.
10. Faul, M.; Larsen, R.; Levinson, A.; Tedrow, J.; Vounatsos, F. J. Org. Chem. 2013,
78, 1655–1659.
11. General procedure for the synthesis of the aldehyde bisulfite adducts. To a stirred
solution of the aldehyde (50 mmol) in ethanol (100 mL) at room temperature
was added dropwise (15 min) a solution of NaHSO3 (5.3 g, 50 mmol) in water
(10 mL). The resulting suspension was stirred at 30–35 °C for 16 h and
subsequently at 4–5 °C for 4 h. Then, the product was filtered, washed with
hexane (3 Â 50 mL) and dried in vacuo to afford the bisulfite adduct as a white
powder.
12. General procedure for the reductive amination of bisulfite adducts with amine
hydrochlorides. To a solution of amine hydrochloride (1 mmol) in methanol
(10 mL) was added the aldehyde bisulfite adduct (1.12 mmol). To the resulting
suspension NaCNBH3 (2.5 mmol) was slowly added, and the mixture was
stirred for 20 h at rt. Then, the evaporation of the mixture furnished a residue
which was partitioned between a 5 N NaOH solution and EtOAc. The aqueous
phase was extracted with EtOAc and the combined organic phases were dried
and evaporated to give a residue which was dissolved in Et2O and treated with
Et2O–HCl (0.6 N). The resulting suspension was cooled down for 13 h at 0 °C
and the precipitated white solid was filtered and dried in vacuo to afford the
amine 12–24.
All the reactions worked well with the sole exception of the reac-
tion of 11 with the bisulfite adduct of cinnamaldehyde, 3, that fur-
nished a mixture of products, probably arising from the competitive
reduction of the carbon–carbon double bond. Table 1 summarizes
the different examples including the starting amine hydrochloride,
the bisulfite adduct, the final products and the yields. Typically, the
yields (unoptimized) ranged from 58% to 92%. Notably, this novel
methodology has permitted the synthesis of the calcimimetic drug
cinacalcet hydrochloride, 24ÁHCl, in 90% yield (entry 13).6
The data from the NMR spectra of all the known compounds
matched with the reported values, while all new compounds have
been fully characterized.
Although NaCNBH3 is a widely used reagent for laboratory pur-
poses, its use on a large scale may raise concerns. For this reason,
we have also briefly evaluated the alternative use of other reductor
agents. While the use of triethylamine borane complex worked
well, unfortunately, the lower priced NaBH4 gave the expected
products in much lower yield and an unpleasant odour was ob-
served. Of note, while acetic acid is usually added in the sodium
cyanoborohydride-mediated reductive aminations, in the present
procedure no acetic acid is required.
In summary, we have developed a mild, efficient and general
reaction procedure for the direct reductive amination of bisulfite
aldehyde adducts with amine hydrochlorides using sodium cyano-
borohydride in methanol. The described methodology avoids the
use of rather unstable amines that are usually stabilized by
formation of a salt (e.g., hydrochlorides). Moreover, amines of low
Please cite this article in press as: Barniol-Xicota, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.03.046