Monoalkylation of primary amines and N-sulfinylamides

Article abstract of DOI:10.1039/b816846f

An efficient monoalkylation of primary amines with primary or secondary alcohols catalyzed by Ra-Ni under mild conditions is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b816846f

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COMMUNICATION
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Monoalkylation of primary amines and N-sulfinylamidesw
a
a
a
b
´ ´ ´
´
Jose Luis Garcıa Ruano,* Alejandro Parra, Jose Aleman, Francisco Yuste
and Virginia M. Mastranzob
Received (in Cambridge, UK) 25th September 2008, Accepted 31st October 2008
First published as an Advance Article on the web 24th November 2008
DOI: 10.1039/b816846f
An efficient monoalkylation of primary amines with primary or
secondary alcohols catalyzed by Ra–Ni under mild conditions is
described.
Scheme 1 Monoalkylation of R–NH2 and N-sulfinyl derivatives.
The amine moiety has played a central role in chemothera-
peutics of numerous diseases due to its unique biological
properties.1 The synthesis of secondary amines has long been
of interest because of their potential as robust pharmaco-
phores and as useful synthetic intermediates.2
of these sulfinamides into N-alkylamines requires a two-step
sequence involving N-desulfinylation and the monoalkylation
of the resulting free amines (with the drawbacks mentioned
above). In our program dealing with the addition of g-sulfinyl-
carbanions to N-sulfinylimines,9 we observed a different
evolution for the desulfinylation processes of the resulting
sulfinamides 1a,b with Ra–Ni depending on the solvent. Thus,
reaction of 1a,b with TFA provided 4a,b, which could be
desulfinylated in THF (top equation, Scheme 2), giving the
optically pure amines 2a,b. However, when EtOH is used
instead of THF as the solvent for the C-desulfinylation, the
N-ethyl derivatives 3a,b were obtained in almost quantitative
yield as a consequence of a simultaneous desulfinylation–
alkylation process (middle, Scheme 2). The direct reaction of
compounds 1a,b with Ra–Ni in EtOH provided compounds
3a,b in good yields (bottom equation, Scheme 2), which
indicated that N-desulfinylation, C-desulfinylation, and
N-alkylation took place in only one step. We have checked
that using optically pure 4b, we obtained 3b with de 4 98%,
indicating that racemization has not occurred during the
alkylation process. These results prompted us to investigate
the scope of the reactions of both N-sulfinyl amines (sulfina-
mides) and amines, with Ra–Ni in ethanol as an alternative
method for the synthesis of N-alkylamines.
General synthetic methods for the preparation of dialkyl-
amines3 are usually included in some of these three strategies:
reductive amination of aldehydes and ketones,4 alkylation of
primary amines with alkyl halides,5 and alkylation reactions
using transition metals.6 All of them have disadvantages which
determine that they cannot be considered as a general method.
Thus, reductive amination requires the use of strong reducing
reagents that are not compatible with the presence of certain
functions in the substrates, whereas reactions of RNH2 with
R0–X are sometimes undesirable from an environmental point
of view, due to generation of wasteful salts as by-products.
Finally the successful N-alkylations reactions catalyzed by
transition metals are usually restricted to anilines. Moreover,
one additional problem limiting the usefulness of the
N-alkylation processes is the mono-versus-dialkylation. In
consequence, the search for new procedures of wide scope
for obtaining monoalkylated amines, avoiding the commented
drawbacks, is therefore important.
The use of alcohols instead of alkyl halides for achieving the
N-alkylation of amines is an attractive method because it does
not generate harmful by-products and alcohols are more
readily available than the corresponding halides. Some of
these reactions have been reported using transition metals
and high temperatures by homogeneous catalysis6 (usually
with Ru and Rh at 100–150 1C, or Ir at 90–110 1C). Therefore,
it seems highly desirable to find a simple, efficient, and
economical method for the monoalkylation of amines under
milder and environmentally friendly conditions.
Reactions of sulfinamides 5a,b and 5d,e, which are obtained
by reaction of amines with methyl p-toluenesulfinate,10 with
Ra–Ni in EtOH at rt provided the corresponding N-ethyl-
amines 6 in good yields and short reaction times (entries 1–4,
Table 1). Interestingly, benzylamine derivative 5f gave only
decomposition products (entry 5), despite other benzyl amino
derivatives such as N-sulfinyl benzhydrylamine (entry 3)
evolved satisfactorily into the alkylated product. The
In this communication we describe the monoalkylation of
primary amines and N-sulfinyl derivatives with the inexpensive
Ra–Ni in alcohols at room temperature (Scheme 1).
Reactions of N-sulfinylamines (sulfinamides)7,8 have achieved
a notorious significance in the past years. The transformation
a Departamento de Quı´mica Orga´nica, Universidad Auto´noma de
Madrid, Cantoblanco, 28049-Madrid, Spain.
E-mail: joseluis.garcia.ruano@uam.es; Fax: +34 914973966
b
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´
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico,
´
´
Circuito Exterior, Cd. Universitaria, Coyoacan 04510, Mexico D. F.
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/b816846f
Scheme 2 Monoalkylation of 1,2-diarylethylamines.
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Table 1 Monoalkylation of N-sulfinylamides using Ra–Ni with
EtOHa
Table 3 Monoalkylation of primary amines and N-sulfinylamides
with different alcoholsa
Starting material (R1)
Product
Yield (%)
t/min
Alcohol
Entry
Entry Starting material (R1/X) (R2OH) Product Yield (%) t/h
1
2
3
4
5
5a (Ph)
6a
6b
6d
6e
6f
81
83
77
89
20c
15c
40
15
—
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
7e (PhCH2CH2/H)
7e (PhCH2CH2/H)
7e (PhCH2CH2/H)
7e (PhCH2CH2/H)
7e (PhCH2CH2/H)
7f (PhCH2/H)
7f (PhCH2/H)
7f (PhCH2/H)
5f (PhCH2/SOTol)
5f (PhCH2/SOTol)
MeOH
EtOH
n-BuOH 8e
i-PrOH
t-BuOH
EtOH
—
6e
—
—
0.2
5b (p-MeOC6H4)
5d (Ph2CH)
5e (PhCH2CH2)
5f (PhCH2)
70
74
80
3
20
72
—
3
26
—
6
b
—
9e
—
6f
NRc
a
b
All the reactions were performed on a 0.20 mmol scale. Decom-
b
—
c
position products were observed in the crude mixture. Longer reac-
tion times determine the formation of dialkylated products.
n-BuOH 8f
72
70
i-PrOH
EtOH
i-PrOH
9f
6f
9f
b
—
65
89
formation of diethylamines is observed for 5a, 5b and 5e when
longer reaction times than those indicated in Table 1 are
applied, except for sec-alkylamine 5d, for which dialkylation
has not been detected.
5e (PhCH2CH2/SOTol) EtOH
5e (PhCH2CH2/SOTol) i-PrOH
6e
9e
6g
0.25
5
0.40
8
48
72
76
78
7g (PhCHCH3/H)
7g (PhCHCH3/H)
7g (PhCHCH3/H)
EtOH
n-BuOH 8g
i-PrOH 9g
75
80
NRc
We assume that the desulfinylation should take place as a
step previous to the alkylation and therefore we investigated
the behavior of the free amines with Ra–Ni in ethanol. The
alkylation of the amines had been reported in harsher condi-
tions such as refluxing in different solvent for several hours11
or by using different additives such as aluminium tert-
butoxide.12 Results obtained in reactions of the amines 7a–f
with Ra–Ni in EtOH are depicted in Table 2. Aromatic
primary amines 7a–c, bearing electron-donating and
electron-withdrawing groups, were monoalkylated in short times
(15–30 min) in good yields (entries 1–3, Table 2). Similar good
results were obtained from alkyl amines 7d,e (entries 4–5,
Table 2). As in the previous case (entry 5, Table 1), benzyl-
amine could not be transformed into the N-ethyl derivative
under the same conditions (entry 6, Table 2), and decomposi-
tion products were also obtained.
7h (t-BuCH2C(Me)2/H EtOH
6h
a
b
All the reactions were performed on a 0.20 mmol scale. Decom-
c
position products were observed in the crude mixture. No reaction.
decomposed in EtOH (entry 6), however it reacts without
problems with n-BuOH and i-PrOH (entries 7 and 8). A
similar behaviour takes place with N-sulfinylamine 5f (entries
9 and 10). The dialkylated products were never observed in the
reactions with n-BuOH and i-PrOH. All the reactions in
MeOH were unsuccessful (entry 1), it not being possible to
isolate the N-methyl derivatives. Finally, reactions did not
proceed when t-BuOH was used (entry 5) as well with the
tert-alkyl amines with EtOH (entry 16).
One of the advantages of our method derives from the fact
that Raney-nickel is a non-expensive reagent and a hetero-
geneous (and therefore easily separable) catalyst. Nevertheless,
the need to use a large amount of Raney-nickel is a clear
disadvantage. This inconvenience could be diminished if the
recovering and reusing of the catalyst were possible, which
would also be desirable from the environmental point of view.
Consequently, we investigated the monoalkylation of aniline
with ethanol under standard conditions and we used the
catalyst, recovered by filtration, in three consecutive reactions.
Raney-nickel maintains the efficiency after four cycles with
almost identical isolated yields and only slightly longer reac-
tion times (see results in Table ESI-1 of ESIw).
In order to explain the experimental results, we have
considered different reaction mechanisms. The first one in-
volves the reductive amination of the aldehydes, obtained by
dehydrogenation of the alcohol used as solvent (eqn (a),
Scheme 3). Despite that the oxidation of the alcohols with
Ra–Ni is not easy to assume, this hypothesis was proposed by
Rice and Kohn11b and supported by some experimental evi-
dence, to explain similar processes taking place in harsh
conditions (longer reaction times and higher temperatures).
Although the mild conditions used in our case would suggest a
lower probability for the oxidation, we unequivocally excluded
this route by using aldehyde instead of the alcohol as solvent
and checking that the reaction does not take place at room
temperature. We consider, as a second alternative mechanism,
the hydroamination catalyzed by Ra–Ni of the double bond
The monoalkylation of primary amines and N-sulfinyl-
amides could be carried out with different alcohols (Table 3).
Thus, the reaction with primary alcohols, such as EtOH,
n-BuOH, and secondary alcohols, such as i-PrOH, provides
the corresponding monoalkylated products in good yields
after reasonable periods of time (Table 3). In addition, for
amines 7e (entries 2–4) and 7g (entries 13–15) it could be
established that the reaction time is longer when the size of
the alcohol chain (EtOH o n-BuOH o i-PrOH) or the
amine (PhCH2CH2NH2 o PhCH(CH3)NH2) is larger. This
tendency is also observed in other alkylations of amines and
N-sulfinylamines collected in Table 3. Interestingly, amine 7f
Table 2 Monoalkylation of primary amines with Ra–Ni and EtOHa
Entry
Starting material (R1)
Product
Yield (%)
t/min
1
2
3
4
5
6
7a (Ph)
6a
6b
6c
6d
6e
6f
83
86
81
82
79
20
15
30
15
20
—
7b (p-MeOC6H4)
7c (p-ClC6H4)
7d (Ph2CH)
7e (PhCH2CH2)
7f (PhCH2)
b
—
a
b
All the reactions were performed on a 0.20 mmol scale. Decom-
position products were observed in the crude mixture.
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Looking for some experimental support for the formation
of the aminyl radicals as intermediates, we have performed the
reaction of aniline with Ra–Ni in EtOH in the presence of a
radical inhibitor TEMPO (1 equiv.). Under these conditions,
aniline is recovered unaltered after long periods of time,
showing that N-alkylation has been inhibited and suggesting
that radical intermediates are involved in the reaction.
This work was supported by grants from the Ministerio de
Educacio
Ministerio de Educacio
fellowship.
´
n y Ciencia (CTQ2006-06741/BQU). A. P. thanks the
´
n y Ciencia of Spain for a predoctoral
Scheme 3 Different pathways to explain the alkylated product.
Notes and references
generated by dehydration of the alcohol in the reaction
conditions (eqn (b), Scheme 3). Taking into account the high
reactivity of norbornene in hydroamination processes, we
performed the reaction of aniline with EtOH and Ra–Ni (large
excess) in the presence of norbornene. N-Ethylaniline was
obtained along with the unaltered starting norbornene.
The third possibility involves a radical mechanism in which
the substrate is homolytically cleaved after absorption on the
metal surface. According to this route, the N–H (from amines)
and N–S (from N-sulfinylamines) bonds would act as precur-
sors of the nitrogenated radicals, which would attack the
hydroxylic carbon of the alcohol, also absorbed on the metal
surface, collapsing into the N-alkylamines (eqn (3), Scheme 3),
according to a radical substitution mechanism. The negative
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explain the strong increase in the reaction times observed for
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the low reactivity of t-BuOH. Regarding the size of the amine,
the influence on the reaction rate could be due mainly to the
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reactivity of 7e (entries 2–4, Table 3) compared to 7g (entries
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alkylamine (entry 16) are in agreement with this explanation.
The slower evolution of the secondary amines into the tertiary
ones, which is crucial in controlling the mono-versus-dialkyl-
ation, should also be a consequence of the more difficult
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The absence of dialkylated products using n-BuOH and
i-PrOH suggests that the resulting N-monoalkyl amines can-
not be easily fixed again on the metal surface whereas N-ethyl
amines could be. On this basis, we could assume that N-ethyl
benzylamine, after the absorption on the metal surface, is
decomposed (probably by homolytic breaking of the benzylic
C–N bond) and therefore the isolation cannot be carried out.
By contrast, other secondary benzylamines with larger size at
any of the two groups joined to the nitrogen (N-ethyl deriva-
tives 3a, 3b, 6d, and 6g, as well as 8f and 8g (N-n-butyl
derivatives) and 9f and 9g (N-isopropyl derivatives), with
presumably scarce tendency to the absorption, are not decom-
posed and can be easily isolated.
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This journal is The Royal Society of Chemistry 2009
406 | Chem. Commun., 2009, 404–406