Reductive amination with zinc powder in aqueous media

Article abstract of DOI:10.3762/bjoc.7.125

Zinc powder in aqueous alkaline media was employed to perform reductive amination of aldehydes with primary amines. The corresponding secondary amines were obtained in good yields along with minor amounts of hydrodimerization byproducts. The protocol is a green alternative to the use of complex hydrides in chlorinated or highly flammable solvents.

Full text of DOI:10.3762/bjoc.7.125

Reductive amination with zinc powder
in aqueous media
Giovanni B. Giovenzana*1, Daniela Imperio1, Andrea Penoni2
and Giovanni Palmisano2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1095–1099.
1DiSCAFF, Università degli Studi del Piemonte Orientale “A.
Avogadro”, Via Bovio 6, I-28100 Novara, Italy; Fax:
+39-(0)321-375821, Tel: +39-(0)321-375846 and 2Dipartimento di
Scienze Chimiche e Ambientali, Università dell’Insubria, Via Valleggio
11, I-22100 Como, Italy; Fax: +39-(0)31-2386449, Tel:
+39-(0)31-2386234
doi:10.3762/bjoc.7.125
Received: 14 March 2011
Accepted: 12 July 2011
Published: 10 August 2011
Associate Editor: B. Stoltz
Email:
Giovanni B. Giovenzana* - giovenzana@pharm.unipmn.it
© 2011 Giovenzana et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aldehydes; amines; reductive amination; water; zinc
Abstract
Zinc powder in aqueous alkaline media was employed to perform reductive amination of aldehydes with primary amines. The
corresponding secondary amines were obtained in good yields along with minor amounts of hydrodimerization byproducts. The
protocol is a green alternative to the use of complex hydrides in chlorinated or highly flammable solvents.
Introduction
Reductive amination is the name usually employed to indicate a unaffected the potentially reducible carbonyl compound. In ad-
synthetic protocol for the preparation of amines that involves a dition, the desired reduction of the C=N bond may be acceler-
two-step reaction between a carbonyl compound and a primary ated by working in the presence of weak acids, thus allowing
or secondary amine (or even ammonia or ammonium salts), in protonation of the C=N nitrogen atom but not of the carbonyl
the presence of a selective reducing agent [1,2]. The carbonyl oxygen; the reducing agent, usually a hydride, should then be
compound and the nitrogen derivative undergo a dehydrative reasonably stable in the presence of acidic additives. Several
condensation to give an imine or an iminium ion, the latter reagents and combinations have been reported through the
being formally hydrogenated to the final amine product. The years; among them a predominant role has been played by
selectivity of the reducing agent is crucial as it should effi- modified borohydride reagents, such as NaBH3CN [3] and
ciently reduce the C=N bond of the intermediate while leaving NaBH(OAc)3 [4,5]. Additional reducing agents may be exem-
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Beilstein J. Org. Chem. 2011, 7, 1095–1099.
plified by H2/cat [6,7], pyridine·BH3 [8] and picoline·BH3 [9], formation may be slower than zinc oxidation by water; iii) car-
Zn(BH4)2/ZnCl2 [10], NaBH4/Mg(ClO4)2 [11], electrochem- bonyl compounds are well-known to undergo different transfor-
istry [12], 1,4-dihydropyridines [13,14], Ti(OiPr)4-PMHS [15], mations under basic aqueous conditions, which may lead to
NaBH4-CoCl2 [16], iPrOH/RuCl(PPh3)2 [17], BH3·Me2S [18], extensive formation of byproducts.
PhSiH3-Bu2SnCl2 [19], and Zn/HCOONH4 [20].
Results and Discussion
Although the choice of reagents for reductive amination is quite We investigated the reaction between benzaldehyde and benzyl-
large, a closer look from the viewpoint of green chemistry amine (Scheme 1, R = Ph R' = Bn) in 5% aqueous NaOH solu-
reveals that few of the above cited alternatives meet the require- tion in the presence of zinc dust under vigorous stirring at room
ments for sustainable processes [21,22]. Modified borohydride temperature. The reaction was complete within 24 h and stan-
reagents are efficient and their activity spans a large array of dard work up afforded the desired secondary amine 1a in
substrates, but their atom economy is far from optimal; 69–72% yield along with hydrodimers 2a as byproducts (0–8%)
NaBH(OAc)3 offers a single hydride at the “price” of a molec- (Scheme 1).
ular weight of 212, while NaBH3CN is plagued by the high
toxicity of the cyanide that is potentially liberated during
workup procedures. Moreover their use is nearly always limited
to undesirable solvents: Carcinogenic 1,2-dichloroethane is the
suggested first choice for NaBH(OAc)3 followed by the highly
flammable tetrahydrofuran. Catalytic hydrogenation is an
interesting alternative to modified borohydrides in terms of
atom economy, but its application is unfortunately not general
as many chemical groups must be avoided (e.g., double and
triple bonds, nitro groups, benzyl–O and benzyl–N groups,
Scheme 1: Reductive amination with zinc in aqueous base solution.
etc.). Even electrochemistry, where the reducing agent (i.e., the
electron) is the lightest, suffers from a limited case history and
requires dedicated equipment.
The use of an alkaline aqueous medium was necessary in order
to fulfill the requirements of the reduction step, while the dehy-
Owing to the popularity of reductive amination in the prepara- drative condensation leading to aldimine is possible even in a
tion of amines, and its growing exploitation in industrial prepa- neutral medium. Acidic pH is detrimental as the protonation of
rations, greener alternatives are required in order to reduce the amine precludes imine formation; moreover, zinc dissolution is
environmental impact of the processes involving this useful too fast under these conditions. The same reaction was then
reaction. Clearly, the use of water as a solvent is to be preferred performed in the presence of alternative bases (LiOH, Na2CO3,
and we were prompted to explore whether the elementary steps NaHCO3, KOH, CaO), the best results being obtained with
involved in reductive amination are compatible with aqueous KOH (1a, 82%). Higher base concentrations (10% w/v) did not
conditions. A literature search revealed that imine formation is lead to significant improvements, while lower ones (1–2% w/v)
possible in water [23] and other green solvents [24]. The reduc- strongly reduced the reaction yields. Finally, the effect of the
tion of imine in aqueous conditions is reported for selected reductant was studied: zinc dust (<10 μm, 98+% Sigma-
reagents. We were interested in the use of zinc metal in view of Aldrich) was effective while other forms of zinc (foil, wire,
several factors promoting its use as a green reductant: i) atom mossy or shots) gave only minute yields, showing the surface-
economy, ii) low toxicity, iii) relative stability in air and water, related nature of the reduction step, likely dependent on
and iv) low cost. Examples of the reduction of imines by zinc the extent of the imine adsorption. This was additionally
metal are reported, either in organic solvents [25-29] or in basic supported by the fact that 15 equiv of Zn was the minimum
aqueous medium [30]. We recognized that this process could be excess needed to reach satisfactory yields, even though the
considerably simplified by the development of a one-pot proce- recovery of unreacted zinc by filtration averaged about 80%.
dure involving the combination of a primary amine, aldehyde, The recovered zinc powder was used for additional runs (after
and zinc in water, thereby avoiding the isolation of the inter- washing with water and drying in vacuo) and the consumed
mediate imine. Although this combination appears to be plau- fraction replenished with “fresh” zinc powder. No difference in
sible, its success is far from obvious: i) the reaction system is the reducing activity was noted in two reactions run with such
triphasic, resulting in complex and unpredictable phase recycled zinc powder. The scope of the reaction was assessed
dynamics of the involved chemical species; ii) the kinetics of using different combinations of aldehydes and primary amines
the single processes may be mismatched, for example, imine (Table 1).
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Beilstein J. Org. Chem. 2011, 7, 1095–1099.
Conclusion
Table 1: Results of the reductive amination with zinc in aqueous base
solution.
In summary, zinc dust in 5% aqueous KOH solution was found
to be an environmentally friendly alternative to the large array
of reagent/solvent combinations used for reductive amination.
The attractive features of this method are high selectivity and
ease of operation using cheap and safe reductants. Although the
reaction is not as general as that with modified hydride
reagents, a careful screening of the many variables involved in
the reaction conditions will allow us to extend this protocol to a
wider selection of substrates.
Ra
R'a
Yield
(1)b
Yield
(2)b
a
b
c
d
e
f
Ph
PhCH2
PhCH2
PhCH2
PhCH2
n-C4H9
Allyl
82%
65%
48%
55%
58%
60%
43%
33%
70%
65%
68%
55%
8%
7%
—
2-Furyl
1-Naphthyl
2-Naphthyl
Ph
2%
7%
6%
—
Ph
Experimental
Typical experimental procedure
g
h
i
n-C5H11
n-C5H11
3-OH-Ph
3-OH-Ph
4-OH-Ph
4-OH-Ph
PhCH2
n-C4H9
4-OH-Ph
3-OH-Ph
4-OH-Ph
3-OH-Ph
—
<2%
<2%
<2%
<2%
In a round-bottomed flask the aldehyde (5 mmol) and the amine
(5 mmol) were suspended in 25 mL of an aq. solution of potas-
sium hydroxide (5% w/v), and zinc dust (<10 μm, 98+% Sigma-
Aldrich) (15 equiv) was added. The mixture was vigorously
stirred at rt for 24 h. Ethyl acetate (20 mL) was added and the
residual zinc powder was filtered and washed with ethyl acetate.
The filtrate and wash solutions were pooled and the organic
layer was separated. The aqueous layer was extracted with ethyl
acetate (2 × 20 mL), the combined organic layers were washed
with water (2 × 20 mL), dried over sodium sulfate and evapo-
rated under vacuum. The crude secondary amine was purified
by column chromatography using petroleum ether/ethyl acetate.
j
k
l
aSee Scheme 1; bYields of isolated compounds.
In the first entries, benzylamine was chosen and fixed as the
amine component, then different aromatic and heterocyclic
aldehydes were employed, giving good yields of secondary
amines along with minor percentages of coupling byproducts
(except with 1-naphthalenecarboxaldehyde, where coupling is
likely plagued by steric hindrance). These diamines likely arise
from a mechanism involving dimerization of an intermediate
aminoalkyl radical that is generated by electron transfer from
the metal to the imine; this process is well-known and under
different experimental conditions may predominate [31] and be
useful for the preparation of 1,2-diamines [32]. Similar results
were obtained upon reacting benzaldehyde with aliphatic
amines (entries e and f). The reaction with allylamine allows us
to appreciate the chemoselectivity of this protocol, leaving the
C=C double bond untouched. Entries g and h rely on the combi-
nation of aliphatic substrates; the yields are lower and coupling
byproducts were not detected, probably due to minor stabiliza-
tion of aminoalkyl–radical intermediates involved in the reduc-
tion step. Additional examples (entries i to l) were explored
with different combinations of isomeric hydroxybenzaldehydes
and amines showing the successful reactivity of anilines and the
compatibility of phenolic hydroxy groups.
Characterization data
Dibenzylamine (1a)
1H NMR (300 MHz, CDCl3) δ 7.40–7.30 (m, 10H), 3.86 (s,
4H), 1.90 (bs, 1H); 13C NMR (75.4 MHz, CDCl3) δ 140.5,
128.6, 128.4, 127.2, 53.3; ESIMS m/z: calcd for C14H15N,
197.1; found, 198.2 (M + H)+.
N-Benzyl(furan-2-ylmethyl)amine (1b)
1H NMR (300 MHz, CDCl3) δ 7.40–7.24 (m, 6H), 6.34 (dd, J =
3.1, 1.8 Hz, 1H), 6.21 (dd, J = 3.4, 0.6 Hz, 1H), 3.80 (bs, 4H),
2.13 (bs, 1H); 13C NMR (75.4 MHz, CDCl3) δ 153.8, 142.0,
139.9, 128.6, 128.4, 127.2, 110.3, 107.2, 52.9, 45.4; ESIMS
m/z: calcd for C12H13NO, 187.1; found, 188.1 (M + H)+.
N-Benzyl(naphthalen-1-ylmethyl)amine (1c)
1H NMR (300 MHz, CDCl3) δ 8.19–8.16 (m, 1H), 7.96–7.92
(m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60–7.33 (m, 9H), 4.31 (s,
The list illustrates the significant applicability of this one-pot 2H), 3.99 (s, 2H), 1.87 (bs, 1H); 13C NMR (75.4 MHz, CDCl3)
zinc-mediated reductive amination. Nevertheless the protocol δ 140.5, 136.1, 134.1, 132.1, 128.9, 128.6, 128.5, 128.0, 127.2,
showed some limitations with selected substrates: i) Secondary 126.3, 126.2, 125.8, 125.6, 124.0, 53.8, 51.0; ESIMS m/z: calcd
amines failed to give tertiary amines; ii) hindered primary for C18H17N, 247.1; found, 248.4 (M + H)+.
amines (e.g., tert-butylamine and 1-aminoadamantane) did not
react; iii) aminoesters reacted giving low yields of the corres- N-Benzyl(naphthalen-2-ylmethyl)amine (1d)
ponding carboxylic acid derivative (ester hydrolysis occurring 1H NMR (300 MHz, CDCl3) δ 7.91–7.88 (m, 4H), 7.57–7.49
even with tert-butyl esters).
(m, 3H), 7.44–7.38 (m, 4H), 7.36–7.30 (m, 1H), 4.01 (s, 2H),
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Beilstein J. Org. Chem. 2011, 7, 1095–1099.
3.89 (s, 2H), 2.16 (bs, 1H); 13C NMR (75.4 MHz, CDCl3) δ N-(4-Hydroxybenzyl)-4-aminophenol (1k)
140.4, 137.9, 133.6, 132.9, 128.7, 128.4, 128.3, 127.9, 127.8, 1H NMR (300 MHz, CD3OD) δ 7.16 (d, J = 8.6 Hz, 2H), 6.72
127.2, 126.8, 126.7, 126.2, 125.7, 53.4, 53.3; ESIMS m/z: calcd (d, J = 8.6 Hz, 2H), 6.63–6.52 (m, 4H), 4.08 (s, 2H); 13C NMR
for C18H17N, 247.1; found, 248.4 (M + H)+.
(75.4 MHz, CD3OD) δ 156.9, 150.1, 142.6, 131.5, 129.6,
116.24, 116.21, 115.6, 49.8; ESIMS m/z: calcd for C13H13NO2,
215.1; found, 216.1 (M + H)+.
N-Butylbenzylamine (1e)
1H NMR (300 MHz, CDCl3) δ 7.37–7.20 (m, 5H), 3.78 (s, 2H),
2.63 (t, J = 7.2 Hz, 2H), 1.98 (bs, 1H), 1.56–1.45 (m, 2H), N-(4-Hydroxybenzyl)-3-aminophenol (1l)
1.41–1.28 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (75.4 1H NMR (300 MHz, CD3OD) δ 7.14 (d, J = 8.6 Hz, 2H), 6.90
MHz, CDCl3) δ 140.4, 128.5, 128.3, 127.0, 54.1, 49.2, 32.2, (td, J = 7.6, 0.9 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.19–6.09 (m,
20.6, 14.1; ESIMS m/z: calcd for C11H17N, 163.1; found, 164.1 3H), 4.09 (s, 2H); 13C NMR (75.4 MHz, CD3OD) δ 157.7,
(M + H)+.
155.9, 150.3, 130.9, 129.6, 128.6, 114.9, 105.5, 104.1, 99.9,
47.2; ESIMS m/z: calcd for C13H13NO2, 215.1; found, 216.1
(M + H)+.
N-Allylbenzylamine (1f)
1H NMR (300 MHz, CDCl3) δ 7.38–7.08 (m, 5H), 5.89 (ddt, J
= 17.2, 10.4, 6.1 Hz, 1H), 5.21–5.10 (m, 2H), 3.74 (s, 2H), 3.21
(d, J = 6.1 Hz, 2H), 3.00 (bs, 1H); 13C NMR (75.4 MHz,
CDCl3) δ 139.6, 136.2, 128.6, 128.1, 127.2, 116.8, 53.0, 51.5;
ESIMS m/z: calcd for C10H13N, 147.1; found, 148.1 (M + H)+.
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