Copper-catalyzed reductive coupling of tosylhydrazones with amines: A convenient route to α-branched amines

Article abstract of DOI:10.1039/c1ob05664f

A general procedure for the reductive coupling of N-tosylhydrazones with amines in the presence of Cu(acac)₂ and Cs₂CO₃ has been developed. The protocol is very effective and chemoselective with various primary and secondary aliphatic amines, aminoalcohols as well as azole derivatives to give α-branched amines in good yields.

Full text of DOI:10.1039/c1ob05664f

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Copper-catalyzed reductive coupling of tosylhydrazones with amines: A
convenient route to a-branched amines†
Abdallah Hamze,* Bret Tre´guier, Jean-Daniel Brion and Mouaˆd Alami*
Received 28th April 2011, Accepted 6th July 2011
DOI: 10.1039/c1ob05664f
A general procedure for the reductive coupling of N-
tosylhydrazones with amines in the presence of Cu(acac)2 and
Cs2CO3 has been developed. The protocol is very effective and
chemoselective with various primary and secondary aliphatic
amines, aminoalcohols as well as azole derivatives to give a-
branched amines in good yields.
of carbon nucleophiles to imines7 or related derivatives,8 dis-
placement of polymer-supported benzotriazole using Grignard
reagents,9 addition of organo-lithium and -magnesium reagents to
selenoamides10 and thioformamides,11 or acid-catalyzed reaction
of diarylmethanols with phenyl carbamate followed by an extra
cleavage step under alkaline media.12 Systems related to three-
component coupling of aromatic zinc reagents, secondary amines
and aromatic aldehydes has also been reported.13 Although the
aforementioned transformations are suitable procedures, however,
most of them require the use of stoichiometric amounts of
organometallic compounds or metal hydrides, thus generating
waste from reagents. Therefore, the development of alternative
and general protocols for the preparation of a-branched amines,
which operate under environmentally friendly conditions, is still
desirable.14
In recent years, N-tosylhydrazones have attracted extensive
attention because of their various useful applications in organic
synthesis.15 In particular, they are valuable and readily available
reagents in C–C,16 C–O,17 and C–S18 bond-forming reactions
through metal-catalyzed and metal-free processes. Although sig-
nificant progress has been achieved on the aforementioned trans-
formations, application in C(sp3)–N bond-forming reactions is still
a relatively unexplored process. To our knowledge, the formation
of amines from tosylhydrazones had been previously reported by
Cuevas-Yan˜ez and co-workers19 by employing Cu(acac)2 as the
catalyst and a large excess of tetra-n-butylammonium bromide.
In their study, the C(sp3)–N bond coupling reaction was only
described with imidazole and benzimidazole derivatives, and
therefore, its scope seems to be very limited. A supplementary
drawback of this methodology was the need to pre-form a THF-
solution of tosylhydrazone sodium salts with NaH, followed by
a change of the reaction solvent to toluene, thus limited the
practicality of the process.
a-Branched amines, including aryl- and diarylmethylamine
derivatives represent an important class of organic compounds
regarding their various biological and pharmacological activities
(Fig. 1).1 For instance, the diarylmethylamine moiety is a common
pharmacophore for multiple drug classes such as histamine
H1 receptor antagonists (cetirizine),2 calcium channel blockers
(lomerizine),3 and aromatase inhibitors (letrozole).4 In addition,
these structural motifs are highly valuable intermediates in organic
synthesis.5 Thus, efficient syntheses of a-branched amines are
of interest in medicinal chemistry and for the synthesis of
screening libraries. The most common route for their preparation
is undoubtedly the reductive amination of carbonyl compounds
with metal hydrides.6 Alternative procedures consist of addition
As part of our continuing studies on the Pd-catalyzed coupling
of N-tosylhydrazones with aryl halides,20 combined with our
interest in C–N bond forming reactions,21 we decided to explore
the ability of N-tosylhydrazones to participate in metal-catalyzed
C–N coupling reactions with various nitrogen nucleophiles. In this
study, we report our success in achieving the reductive coupling of
tosylhydrazones with amines in the presence of Cs2CO3 as the base
and a catalytic amount of easily available Cu(acac)2 in dioxane.
Under these simple and general reaction conditions, various
arylsulfonylhydrazones 1 derived from ketones and aldehydes
reacted with primary and secondary aliphatic amines as well as
Fig. 1 a-Branched drugs with aryl- and diarylmethylamine moieties.
Univ Paris-Sud 11, CNRS, BioCIS UMR 8076, Laboratoire de Chimie
The´rapeutique, Faculte´ de Pharmacie, 5 rue J.-B. Cle´ment, Chaˆtenay-
Malabry, F-92296, France. E-mail: abdallah.hamze@u-psud.fr, mouad.
alami@u-psud.fr; Fax: +33-1-46835828; Tel: +33-1-46835887
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05664f
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Table 1 Cu-catalyzed synthesis of a-branched amines 3 from tosylhydra-
zones 1a
azole derivatives to give aryl- and diarylmethylamine derivatives 3
in reasonable to good yields.
In our initial study, tosylhydrazone 1a and morpholine 2a
were chosen as model substrates for the C(sp3)–N bond-
forming process. The reaction was first investigated according
to the conditions described by Cuevas-Yan˜ez and co-workers19
(NaH/Cu(acac)2/Bu4NBr/THF/Toluene, 85 ◦C for 36 h). How-
ever, this transformation was inefficient and resulted in concomi-
tant formation of the expected amine 3a and products derived from
the evolution of the diazo compound generated from 1a, sulfone
4a,18a,b the homocoupling product 5a and Bamford–Stevens alkene
6a22 (Scheme 1). After a tedious separation, 3a was isolated in a low
17% yield. To promote the formation of 3a, an extensive screening
of various reaction parameters (base, copper source, solvent,
temperature) was conducted (for more details, see ESI†). Optimal
conditions for the reaction of 1a with morpholine required the
use of 10 mol% Cu(acac)2 as the catalyst and Cs2CO3 as the base
(2.2 equiv) in dioxane at 100 ◦C for 3 h. Under this protocol, the
desired amine 3a was isolated in a good yield (80%, Table 1, entry
1). A control experiment revealed that the copper catalyst plays
an important role for this coupling reaction. Attempts to carry
out the reaction in the absence of Cu(acac)2 failed to provide any
cross-coupled product 3a, and by-product alkene 6a was formed
mainly. It should be noted that this reductive coupling of 1a with
morpholine is not limited to a small scale (0.25 mmol) as it could
be conveniently performed on a 2 g scale (5.7 mmol; 20-fold scale
up) in 72% yield.
Entry
1
1
Amine 2
Compound 3
Yield (%)b
80c,d
1a
3a
3b
2
1a
75
3
4
1a
1a
3c
3d
82
55
5
6
1b
1c
2a
2a
3e
3f
67
84
Scheme 1 Cu-catalyzed reductive coupling of 1a with morpholine 2a.
To establish the generality of this protocol, a series of hydra-
zones 1a–h were coupled with various amines, including azole
derivatives. As summarized in Table 1, the transformation seems to
be general, as tosylhydrazones derived from ketones or aldehydes
were converted into corresponding amines 3 by using the above-
mentioned optimized conditions. Satisfactory to good yields were
obtained with secondary aliphatic amines (entries 1–10) as well
as with primary aliphatic amines (entries 11 and 12), including
benzylic amines 2h and 2i (entries 13 and 14). Unfortunately, with
aniline 2j, none of the desired product 3o was detected; instead
alkene 6a was formed (entry 15).
7
8
1d
1e
2a
2a
3g
3h
40e
61
To broaden the scope of substrates, we further investigated
the reaction selectivity with respect to functionalized amines. We
found that primary and secondary aliphatic amino alcohols 2k–
m proved to be suitable substrates in this transformation leading
exclusively to C–N bond-forming products 3p–r in satisfactory
to good yields (entries 16–18). Under our selective protocol, no
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Table 1 (Contd.)
Table 1 (Contd.)
Entry
9
1
Amine 2
Compound 3
Yield (%)b
71
Entry
17
1
Amine 2
Compound 3
Yield (%)b
1f
2a
3i
3j
1a
3q
3r
84
18
1a
61
10
1f
60
19
20
1a
1c
3s
3t
65
64
11
12
1a
1a
3k 50
3l
62
13
14
1a
1c
3m 53
21
22
1c
1g
3u
3v
70
63
3n
42
2n
2n
23
1h
3w 40
15
16
1a
1a
3o
3p
0
a Reactions conditions: tosylhydrazone 1 (0.25 mmol), amine 2 (2 equiv),
Cu(acac)2 (10 mol%), Cs2CO3 (2.2 equiv), dioxane (2.5 mL) in a sealed
tube at 100 ◦C. b Isolated yield of 3. c A 72% yield was obtained when the
reaction was carried out on a 2 gram scale of tosylhydrazone 1a. d Using
open-vessel reaction conditions, a 71% yield was obtained within 3 h
heating at 100 ◦C. e Reaction conducted in the presence of 20 mol% N,N¢-
dimethylethylenediamine (DMEDA); less than 10% of 3g was obtained in
the absence of DMEDA.
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ether products resulting from C–O bond-forming reaction was
observed, although tosylhydrazones have been recently reported
to provide reductive etherification with alcohols.17
Finally, extending this chemistry to include azoles 2n–p as
substrates proved to be quite successful, with tosylhydrazones
derived from aromatic ketones (entries 19–21) as well as aliphatic
aldehydes (entry 22) and ketones (entry 23). Thus, imidazole,
benzimidazole and pyrazole also underwent a C–N bond forming
reaction providing coupling products 3s–w in satisfactory to good
yields.
Although there is no clear experimental evidence, we suppose
that the reaction proceeds as shown in Scheme 2. Initially, N-
tosylhydrazone 1 in basic media undergoes thermal decompo-
sition through the Bamford–Stevens reaction to generate diazo
compound II followed by in situ reduction of Cu(II) by II into the
active catalytic Cu(I) species III.23 This latter would react with II to
give the copper(I) carbene complex24 IV. Further copper carbene
N–H insertion might proceed with attack of the nitrogen atom on
the electrophilic carbene to generate copper species V, followed by
hydrogen transfer25 to produce amine 3.
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Scheme 2 Proposed mechanism for the Cu-catalyzed reductive coupling
of N-tosylhydrazones 1 with amines.
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In summary, we have demonstrated that the reductive coupling
of tosylhydrazones with amines in presence of Cs2CO3 and a
catalytic amount of Cu(acac)2 represents a general, operationally
simple, inexpensive and efficient approach for the synthesis of
aryl- and diarylmethylamine derivatives. A variety of amines,
including primary and secondary aliphatic amines as well as azole
derivatives were used successfully. It is particularly noteworthy that
this protocol is chemoselective allowing amino alcohols to react
with hydrazones to give exclusively C–N bond forming products.
Further development of this coupling methodology is under way.
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