Aminomethylation of organic halides promoted by zinc in protic medium

Article abstract of DOI:10.1016/j.tetlet.2005.08.139

Organic halides undergo smooth aminomethylation by secondary amines and aqueous formaldehyde promoted by metallic zinc under copper(I) catalysis. Good to excellent yields are obtained with primary, secondary, and tertiary iodides, allylic, propargylic, and benzylic bromides and with α-bromoesters. In most cases, DMSO is the best solvent, but dioxane is preferable for some more reactive halides. Additional experiments with radical quenchers and promoters and the use of 'radical clocks' indicate a stepwise reaction mechanism initiated by the attack of an alkyl radical to iminium ion.

Full text of DOI:10.1016/j.tetlet.2005.08.139

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7601–7604
Aminomethylation of organic halides promoted by zinc in
protic medium
a,b
a
a,
*
Id a´ lia H. S. Estevam, Margarete F. da Silva and Lothar W. Bieber
a
Departamento de Qu ı´ mica Fundamental, Universidade Federal de Pernambuco, Cidade Universit a´ ria, 50670-901 Recife, PE, Brazil
b
Departamento de Ci eˆ ncias Exatas e da Terra, Universidade do Estado da Bahia, Cabula, 40000-000 Salvador, BA, Brazil
Received 8 June 2005; revised 16 August 2005; accepted 25 August 2005
Available online 15 September 2005
Abstract—Organic halides undergo smooth aminomethylation by secondary amines and aqueous formaldehyde promoted by metal-
lic zinc under copper(I) catalysis. Good to excellent yields are obtained with primary, secondary, and tertiary iodides, allylic, prop-
argylic, and benzylic bromides and with a-bromoesters. In most cases, DMSO is the best solvent, but dioxane is preferable for some
more reactive halides. Additional experiments with radical quenchers and promoters and the use of Ôradical clocksÕ indicate a step-
wise reaction mechanism initiated by the attack of an alkyl radical to iminium ion.
ꢀ
2005 Elsevier Ltd. All rights reserved.
The classical Mannich reaction is still one of the most
efficient strategies for the synthesis of functionalized ter-
tiary amines. The generally accepted mechanism in-
the first simultaneous in situ generation and coupling
of both iminium ion and allylic intermediate in water
has been accomplished recently in our laboratory. In
1
11
volves iminium ions 1 as reactive intermediates,
generated in acidic medium from secondary amines 2
and formaldehyde 3, which are attacked by suitable
nucleophiles. This in situ procedure is especially efficient
with enolisable carbonyl compounds but has been ex-
the present letter, we describe the generalization of the
method for other types of activated and inactivated
halides.
Already the first experiments with ethyl and isopropyl
iodide under the conditions optimized for allyl bromide
produced the expected tertiary amines 5, but modest
yields and formation of several side products prompted
us to undertake a new systematic search for the best
reaction conditions.
1
2
tended to aromatic compounds and terminal alkynes.
Although preformed stable iminium salts in aprotic sol-
vents allow the use of organometallic nucleophiles, such
complex multistep procedures are much less attractive
3
–5
from the experimental point of view.
The recent
development of mild and efficient Mannich-type three-
component reactions for the synthesis of tertiary prop-
argylamines and the growing number of Barbier-type
In principle, a multicomponent reaction with in situ for-
mation of different intermediates increases the possibil-
ity of undesired side reactions and requires a careful
optimization of all reaction parameters. In the case of
the aminomethylation of alkyl halides promoted by
active metals, several important alternatives must be
considered (Scheme 1): direct Barbier alkylation of the
6
reactions with unconventional electrophiles,7 all per-
formed under protic conditions, suggested the possibil-
ity to combine the generation of iminium ions and
organometallic intermediates in a one-pot reaction.
The validity of this approach has been reinforced by sev-
eral organometallic reactions in aqueous medium: the
aldehyde to 6, S 2 alkylation of amine 2 to 7 and reduc-
N
8
Barbier-type alkylation of benzotriazole derivatives, a
tion of iminium ion to 8 or of organic halide to 9. Only
the reaction of the iminium ion 1 with an intermediate
generated by the action of the metal on the halide 4 will
produce the desired product 5. One of the most impor-
tant factors is the acidity of the medium, for acid catal-
ysis is essential for the rapid formation of the iminium
species and for the activation of the metal surface, but
too acidic conditions can lead to reductions of 1 and 4
source of iminium ions, and the reaction of aldehydes
9
10
and amines with allylic silanes or stannanes. In fact,
Keywords: Mannich reaction; Aqueous formaldehyde; Alkyl halides;
Radical mechanism.
*
Corresponding author. Tel.: +55 81 21268441; fax: +55 81
1268442; e-mail: bieberlothar@hotmail.com
2
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.139

7602
I. H. S. Estevam et al. / Tetrahedron Letters 46 (2005) 7601–7604
4/Zn
Zn/H+
control of reactivity are the temperature and the nature
R NCH3
R N=CH
R NCH R'
2 2
2
2
2
and active surface of the metal.
8
1
5
As a result of extensive optimization experiments with
representative halides of different structural types, sev-
eral common features could be observed. Probably for
solubility reasons, the best results were obtained in polar
organic solvents mixed with a small excess of aqueous
formaldehyde. In all cases, greater excess of formalde-
hyde or higher amounts of water increased the forma-
tion of side products 8 by reductive methylation.
Copper iodide was essential for good yields, but its
amount could be reduced, in comparison to the previous
conditions, to 0.1 equiv; other Cu(I) or Cu(II) com-
pounds were much less effective. The addition of a pro-
ton source (4 equiv) was necessary to suppress direct N-
alkylation to 7. A general observation was the superior-
ity of granulated zinc over zinc dust and other metals
R NH
2
2
H CO
3
2
Zn/H O
2
R NR'
7
R'X
4
2
R'CH OH
6
2
Zn H O
2
1
1
R'H
9
Scheme 1.
(Sn, Al, Mn, Mg, In, or Bi). Formation of alcohol 6
and dissolution of the metal. On the other hand, basic
conditions can promote direct substitution by free
amine. A protic solvent, ideally water, will assure rapid
equilibration, but favors also reducing side reactions
whereas an organic solvent may be necessary to solubi-
lize the organic reagents. Other important factors for the
by Barbier addition to 3 was observed only in the reac-
tion of allyl bromide with tin. In general, an excess of
halide (2 equiv) is indicated in order to assure complete
conversion of 2; alternatively, in the case of halides of
higher molecular weight or synthetic value, the amine
may be used in excess.
a
Table 1. Aminomethylation of alkyl halides
Entry
Amine 2
Halide 4
Solvent
Acid
Temp. (ꢁC)
Yield 5 (%)
1
2
3
4
5
6
7
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Me-I
Et-I
i-Pr-I
t-Bu-I
Allyl-Br
Propargyl-Br
1-Br-2-butyne
Benzyl-Br
Et-I
i-Pr-I
t-Bu-I
n-Bu-I
Cyclohexyl-I
PhCH
Benzyl-Br
Br-CMe
i-Pr-I
Cyclohexyl-I
Adamantyl-I
Allyl-Br
i-Pr-I
t-Bu-I
Benzyl-Br
1-Br-2-butyne
Et-I
i-Pr-I
t-Bu-I
Et-I
MeOH
DMSO
DMSO
Dioxane
DMSO
Dioxane
DMSO
Dioxane
DMSO
DMSO
Dioxane
DMSO
DMSO
DMSO
Dioxane
DMSO
DMSO
DMSO
Dioxane
DMSO
DMSO
Dioxane
Dioxane
DMSO
DMSO
DMSO
Dioxane
DMSO
DMSO
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
30
30
30
0
0
0
40
95
84
66
75
76
b
0
0
60
c
8
9
68
71
71
55
60
77
59
68
65
91
69
69
76
79
57
30
30
0
30
30
30
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
F
F
F
3
CCO
3
CCO
3
CCO
2
2
2
H
H
H
c
c
c
2 2
CH -I
HOAc
CCO
2
CO
2
Et
F
3
2
H
0
Me
Me
Me
Me
2
2
2
2
NH · HCl
NH · HCl
NH · HCl
NH · HCl
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
30
30
0
0
30
0
c
c
Et
2
Et
2
Et
2
Et
2
NH
NH
NH
NH
b
0
0
80
57
68
64
59
75
63
Pyrrolidine
Pyrrolidine
Pyrrolidine
Dibenzylamine
Dibenzylamine
30
30
0
30
30
i-Pr-I
a
General procedure: To a solution of free amine or hydrochloride (5 mmol), acid (20 mmol), and halide (10 mmol) in 5 ml of the indicated solvent
were added, at rt or 0 ꢁC, aqueous formaldehyde (1 ml, 35%), CuI (100 mg), and granulated zinc (15 mmol). After 2 h of stirring, the reaction was
hydrolyzed by the addition of 50 ml of aqueous NaOH (10%) and extracted with ether. The solvent was removed and the free bases were purified by
short-path distillation or crystallization as picrates.
b
c
The rearranged allenic compound was isolated.
10 mmol of amine and 5 mmol of halide were used.

I. H. S. Estevam et al. / Tetrahedron Letters 46 (2005) 7601–7604
7603
All other parameters—solvent, temperature, and
employed acid—varied for different types of halides.
Primary and secondary alkyl iodides are best reacted
in commercial DMSO at rt (30 ꢁC); for small halides
catalytic copper(I) species improves the yields signifi-
cantly in the case of iminium ions.
In order to get a better understanding of these differ-
ences, a series of competition reactions was performed
using morpholine, formaldehyde, and allyl bromide in
all cases and adding various additives or catalysts (Table
2). The uncatalyzed reaction produced a moderate yield
of 5 (39%, entry 1). When the same reaction was con-
ducted in the presence of one equivalent of benzalde-
hyde as a competitive electrophile, the yield of 5 was
slightly reduced to 36%, but 60% of homoallylic alcohol
13 was also formed (entry 2). This latter product was
significantly reduced to 26% in the presence of catalytic
copper iodide, whereas the yield of tertiary amine in-
creased to 60%; exactly the same yield of 5 was obtained
in the absence of benzaldehyde (entries 3 and 4). In the
presence of a radical quencher, 2,6-di-tert-butyl-4-meth-
ylphenol (BHT), the yield of 5 was also decreased to
33% (entry 5). These few experiments demonstrate
clearly that carbonyl and iminium addition follow differ-
ent and competitive mechanisms: the first predominates
in the absence of any catalyst and is severely suppressed
by CuI; the second process is enhanced by the same cat-
alyst, but inhibited by BHT. These observations are best
explained by a first single electron transfer (SET) to the
halide producing a radical intermediate 10 which can
add directly to iminium ion 1, but not to benzaldehyde,
generating radical cation 11 (Scheme 2). A further SET
to 10 produces a carbanionic species 12, capable to react
with benzaldehyde to 13 (R = allyl) and, in minor de-
gree, with iminium ion 1. The role of the catalyst can
be to stabilize the radical 10 or to prevent the second
SET.
(
(
R = Et, i-Pr) acetic acid is sufficient as proton source
Table 1, entries 2, 3, 9, 10, 17, 21, 25, 26, 28, and 29),
for those of higher molecular weight trifluoracetic acid
is more effective (entries 12–14 and 18). Tertiary iodides,
benzyl, and propargyl bromide (entries 4, 6, 11, 15, 19,
2
2, 23, and 27) were too reactive under these conditions
and required a less polar solvent, dioxane, at lower tem-
perature (0 ꢁC) in the presence of acetic acid. Allyl bro-
mide and 1-bromo-2-butyne gave best results in DMSO
at 0 ꢁC (entries 5, 7, 22, and 24). Only for methyl iodide
we were unable to obtain preparative yields, the best
result (40%) was achieved in methanol at rt (entry 1).
Various cyclic secondary amines 2 were used with good
6
,11
results. As already observed in previous papers,
steric
hindrance in acyclic amines causes loss of reactivity, but
even with dibenzylamine we obtained satisfactory yields
of 5 (entries 28 and 29).
1
In analogy to the classical Mannich reaction, the mech-
anism can be explained as a nucleophilic attack of an
organozinc intermediate to the highly electrophilic imin-
ium ion. There are also parallels to the aqueous Barbier
1
2
addition to aldehydes and ketones. However, several
important differences can be observed. First, the aque-
1
2
ous Zn-Barbier reaction is essentially limited to allylic,
1
3
14
propargylic, and benzylic halides, all capable of
producing resonance stabilized intermediates; saturated
primary alkyl iodides react only partially with highly
electron-deficient benzaldehydes. By contrast, in the
present reaction, all types of halides, including primary,
secondary, and tertiary alkyl iodides, give comparable
yields. Second, no catalyst is necessary for the aqueous
allylation of carbonyl compounds, but the presence of
1
5
Further confirmation of this type of mechanism was
obtained by use of different radical quenchers in the
aminomethylation of iodocyclohexane. The presence of
Table 2. Reaction of morpholine and formaldehyde with different halides promoted by zinc in the presence of additives
0
Entry
Halide R X (4)
Acid
Temp. (ꢁC)
Additives (equiv)
Products (yield [%])
1
2
3
4
5
6
7
8
9
Allyl-Br
Allyl-Br
Allyl-Br
Allyl-Br
HOAc
HOAc
HOAc
HOAc
HOAc
0
0
0
0
0
30
30
30
30
30
30
30
30
30
30
None
5 (39)
PhCHO (1.0)
PhCHO (1.0) + CuI (0.1)
CuI (0.1)
CuI (0.1) + BHT (1.0)
None
Galvinoxyl (0.1)
TEMPO (0.1)
(BzO)
CuI (0.1)
CuI (0.1) + BHT (1.0)
CuI (0.1) + (BzO)
CuI (0.1)
CuI (0.1)
5 (36) + 13 (60)
5 (60) + 13 (26)
5 (60)
5 (33)
5 (49)
5 (32)
5 (19)
5 (26)
5 (77)
5 (64)
5 (57)
15 (36) + 16 (4)
18 (9) + 19 (21)
21 (25)
Allyl-Br
Cyclohexyl-I
Cyclohexyl-I
Cyclohexyl-I
Cyclohexyl-I
Cyclohexyl-I
Cyclohexyl-I
Cyclohexyl-I
Cyclobutyl-CH
CF
CF
CF
CF
CF
CF
CF
3
3
3
3
3
3
3
COOH
COOH
COOH
COOH
COOH
COOH
COOH
2
O (0.1)
10
11
12
13
14
15
2
O (0.1)
2
-I 14
HOAc
HOAc
HOAc
6-Iodo-1-hexene 17
Cyclopropyl-CH -I 20
2
CuI (0.1)
NR
2
NR
2
NR
2
NR2
NR2
1
5
16
18
19
21

7604
I. H. S. Estevam et al. / Tetrahedron Letters 46 (2005) 7601–7604
Zn
SET
1
with preformed iminium ions and organometallic Zn or
Mg reagents under anhydrous conditions, restricted to
R'X
4
R'
10
2 2
R NCH R'
[CuI]
11
4
,5
aromatic and benzylic groups,
the present radical
reaction works equally well with allyl, benzyl, propargyl,
primary, secondary, and tertiary alkyl halides and
a-bromoesters.
Zn SET
Zn
SET
PhCHO
1
R'ZnX
R NCH R'
2 2
PhCHOHR'
1
2
5
1
3
Acknowledgments
Scheme 2.
This work was supported by CNPq (Brasilia). We thank
Mr. Ricardo O. Da Silva, for GC/MS analyses.
stable free radicals—galvinoxyl and TEMPO—or a rad-
ical source—dibenzoyl peroxide—led to a significant de-
crease of the yield of 5 in comparison to the uncatalyzed
reaction (Table 2, entries 6–9). On the other hand, addi-
tion of CuI caused an important improvement which is
only partially lost in the presence of BHT or dibenzoyl
peroxide (entries 10–12).
References and notes
1
2
3
4
5
6
7
. Review: Arend, M.; Westermann, B.; Risch, N. Angew.
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1
6
. Millot, M.; Piazza, C.; Avolio, S.; Knochel, P. Synthesis
as a Ôradical clockÕ were reacted with morpholine and
formaldehyde under non-optimized conditions. Iodo-
methylcyclobutane (14) gave a mixture of two morphol-
ines with isomeric N-substituents, the unrearranged
cyclobutylethyl (15) and the linear 5-hexenyl group
2
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8
(
15) in a 9:1 ratio (Table 2, entry 13). A similar reaction
with 6-iodo-1-hexene (17) produced the unrearranged
linear (18) and the cyclized compound (19) in a ratio
of 3:7 (entry 14). Finally, iodomethylcyclopropane (20)
led to 21 under complete ring opening with no trace of
the cyclic product. These findings are in good agreement
with the relative rates of rearrangement of the three rad-
2
8. Katritzky, A. R.; Hong, Q.; Uang, Z. J. Org. Chem. 1995,
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ꢀ1 16
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1
1
7
Wurtz coupling of the same iodides.
4
1
The described experiments corroborate the participation
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2
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1
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