A new manganese-mediated, cobalt-catalyzed threecomponent synthesis of (diarylmethyl)sulfonamides

Article abstract of DOI:10.3762/bjoc.10.39

The synthesis of (diarylmethyl)sulfonamides and related compounds by a new manganese-mediated, cobalt-catalyzed three-component reaction between sulfonamides, carbonyl compounds and organic bromides is described. This organometallic Mannich-like process allows the formation of the coupling products within minutes at room temperature. A possible mechanism, emphasizing the crucial role of manganese is proposed.

Full text of DOI:10.3762/bjoc.10.39

A new manganese-mediated, cobalt-catalyzed three-
component synthesis of (diarylmethyl)sulfonamides
Antoine Pignon, Erwan Le Gall*§ and Thierry Martens
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 425–431.
Électrochimie et Synthèse Organique, Institut de Chimie et des
Matériaux Paris-Est, UMR 7182 CNRS, Université Paris-Est Créteil,
2-8 rue Henri Dunant, 94320 Thiais, France
doi:10.3762/bjoc.10.39
Received: 07 November 2013
Accepted: 20 January 2014
Published: 17 February 2014
Email:
Erwan Le Gall* - legall@icmpe.cnrs.fr
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
* Corresponding author
§ Tel.: +33-149781135; fax: +33-149781148
Keywords:
© 2014 Pignon et al; licensee Beilstein-Institut.
License and terms: see end of document.
carbonyl compounds; cobalt; manganese; multicomponent reaction;
organic bromides; sulfonamides
Abstract
The synthesis of (diarylmethyl)sulfonamides and related compounds by a new manganese-mediated, cobalt-catalyzed three-compo-
nent reaction between sulfonamides, carbonyl compounds and organic bromides is described. This organometallic Mannich-like
process allows the formation of the coupling products within minutes at room temperature. A possible mechanism, emphasizing the
crucial role of manganese is proposed.
Introduction
(Diarylmethyl)amines constitute an important class of pharma- reported for their preparation. Although these methods propose
cologically active compounds, displaying e.g. antihistaminic, complementary approaches to the synthesis of (diaryl-
antiarrhythmic, diuretic, antidepressive, laxative, anesthetic and methyl)amines, their scope might be hampered by functional
anticholinergic activities [1-5]. These attractive properties have group incompatibilities or the number of steps. In addition, no
made them prominent synthetic targets for the organic chemist straightforward and tunable method currently exists for the one-
and various strategies, including for instance arylation of step preparation of (diarylmethyl)amines in N-protected form.
iminium salts [6], displacement of polymer-supported benzotri- Consequently, we felt that a multicomponent procedure
azole [7] with arylmagnesium reagents, addition of phenyl- intended to the synthesis of N-protected (diarymethyl)amines
lithium to selenoamides [8], addition of organometallic species and related compounds would be highly desirable.
[9-21] or arylboronic acids [22-27] to imines, reaction of
organolithium and Grignard reagents with thioformamides [28], In preceding works, we described the Mannich-like multicom-
multistep reactions involving carbonyl compounds [29,30], ponent synthesis of α-branched amines from organic halides,
intramolecular electrophilic arylation of lithiated ureas [31], and aldehydes and amines, using a zinc-mediated process [35-38].
Petasis-type multicomponent reaction [32-34] have been Although the scope of the reaction was demonstrated to be quite
425

Beilstein J. Org. Chem. 2014, 10, 425–431.
broad, some limitations were noticed, especially in reactions tical and environmental reasons, we chose to keep 10 equiv of
involving aryl halides. For instance, primary amines and enoliz- manganese for the rest of the study. In general, the reaction
able aldehydes were unusable in this process. As a part of our proceeded very quickly and came to completion within 10 min
ongoing efforts to improve reliability and versatility of multi- at room temperature. An extended reaction time (20 min) did
component procedures, we describe herein a new manganese- not result in a notably improved reaction yield (Table 1, entry
mediated, cobalt-catalyzed three-component reaction, which 14).
circumvents the above-mentioned limitations by allowing the
synthesis of an extended range of (diarylmethyl)sulfonamides Bromides proved to be the most efficient halides. Indeed, while
(and related compounds) within minutes at room temperature. the reaction also worked with iodides (Table 1, entry 15), albeit
To the best of our knowledge, this constitutes the first in lower yield, it did not work with chlorides (Table 1, entry
manganese-mediated multicomponent reaction involving aryl 16). A decrease of the amount of cobalt salts to 10 mol %
halides as the source for nucleophilic species.
(Table 1, entry 17) or 1.5 mol % (Table 1, entry 18) resulted in
a significant decrease of the reaction efficiency, thus indicating
the prevalent role of the catalyst. This was confirmed by the
Results and Discussion
We previously reported that primary amines are not active in a absence of the coupling product when the reaction was
Mannich-like multicomponent reaction with aldehydes and conducted in the absence of cobalt bromide (Table 1, entry 19).
arylzinc compounds [37]. It was assumed that the imine, which Another nickel-based catalyst, e.g., NiBr2bpy, was not active
is initially formed by a condensation of the aldehyde and the under standard conditions (Table 1, entry 20), and solvents
amine, is not sufficiently electrophilic to undergo a coupling other than acetonitrile did not allow the reaction to proceed
with the arylzinc compound. Considering the increased elec- (Table 1, entries 21 to 24).
trophilicity of sulfonylimines, we aimed to use sulfonamides as
potential synthetic equivalents of ammonia in a procedure that The scope of the reaction was then investigated by using
additionally avoids the preformation of an imine and/or an various sulfonamides 1, aldehydes 2 and organic bromides 3,
organometallic compound. Thus, we turned our attention to a and the results are presented in Table 2.
multicomponent reaction between aldehydes, aryl halides and
sulfonamides, which involves an in situ activation (Barbier Results indicated a rather broad functional tolerance of the reac-
conditions) of the aryl halide by cobalt salts in the presence of a tion, although some yields are limited and might be likely im-
reducing metal. Initial experiments employed zinc as the proved under more specific conditions. In all cases, the organic
reducing agent and were carried out under standard conditions. bromide was completely consumed and the main side-products
However, only trace amounts of the coupling product were were the imine and the biaryl. The imine results from the reac-
detected in the reaction mixture. A screening of the reducing tion of the tosylamide with the aldehyde, and the biaryl was
metal was then performed and revealed that only manganese is formed by reductive coupling of the starting halide. A
active in the process. Other reaction conditions such as the preformed imine can be used in the process (Table 2, entry 3,
amount of reagents and catalyst, the solvent, the reaction time, result in brackets), indicating that this species might be the reac-
the temperature and the nature of the halogen atom were also tive electrophilic intermediate of the reaction. Aryl halide is
examined. The results are reported in Table 1.
generally prone to dimerization under such reductive condi-
tions. Thus, we assume that if the imine is formed slowly or is
As mentioned above, metals other than manganese did not work less reactive, the more rapid consumption of the halide results
in the reaction (Table 1, entries 1–7). In accordance with previ- in the lack of a nucleophilic partner in the reaction medium. In
ously reported works, a minimum of two equiv of the halide this case, the imine remains partly unconsumed at the end of the
were required for the reaction to take place. However, yields process. Nevertheless, we were pleased to observe that the reac-
were noticeably improved by using 3 equiv of the halide tion works with enolizable aldehydes (Table 2, entries 4 and 5),
(Table 1, entry 8) or 2.5 equiv (Table 1, entry 9) instead of a notable result considering the acidity of the protons α to the
2 equiv (Table 1, entry 10). The amount of manganese was also carbonyl. Logically, Ms-containing sulfonamides (Table 2,
of crucial importance. Indeed, whereas an increase to 15 equiv entries 12–15) worked in the same fashion as their
(Table 1, entry 11) led to a slightly improved yield, a decrease Ts-containing counterparts.
to 7.5 (Table 1, entry 12) or even 5 equiv (Table 1, entry 13)
resulted in a dramatic decrease of the yield, which dropped to Considering the crucial importance of the reducing metal in the
32% in the latter case. However, the usage of an increased synthetic process and the probable involvement of an imine as
amount of manganese led to a more challenging work-up and the electrophilic intermediate, we were able to propose a
the generation of more metallic waste. Consequently, for prac- possible reaction mechanism (Scheme 1).
426

Beilstein J. Org. Chem. 2014, 10, 425–431.
Table 1: Optimization of the reaction conditionsa.
Entry
PhX
(equiv)b
X
Reducing metal Amount
(equiv)c
Cat.
(mol %)d
Solvent
Time
(min)
Yield
(%)e
1
3
3
3
3
3
3
3
3
2.5
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
Mg
Al
10
10
10
10
10
10
10
10
10
10
15
7.5
5
–
THF
60
60
60
60
60
60
60
5
–
2
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (10)
CoBr2 (1.5)
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
–
3
Ti
–
4
Cr
–
5
Fe
–
6
Sn
Zn
–
7
–
8
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
68
52
44
76
50
32
70
40
-
9
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
5
5
5
5
10
10
10
10
10
10
10
10
10
10
10
20
5
Cl
Br
Br
Br
Br
Br
Br
Br
Br
5
5
52
21
–f
–
20
60
60
60
60
60
60
NiBr2bpy (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
CoBr2 (15)
–
DMF
–
Dioxane
Toluene
–
–
aReactions were conducted at room temperature with 5 mL of solvent, 0.43 g (2.5 mmol) of p-toluenesulfonamide (1a), 0.25 mL (2.5 mmol) of
benzaldehyde (2a), 7.5 mmol of phenyl halide 3, 1.125 mmol of the catalyst, and 25 mmol of the reducing metal, preactivated by using 0.1 mL
BrCH2Ch2Br and 0.1 mL TFA. bCalculated relative to the sulfonamide. cCalculated relative to the sulfonamide. dCalculated relative to the halide. eGC
yield. f1 h at room temperature, then heating 5 h under reflux.
Table 2: Scope of the reactiona.
Entry
R1
R2
Ph
Ar
Product
Yield
(%)b
1
p-Tol
Ph
4a
68
427

Beilstein J. Org. Chem. 2014, 10, 425–431.
Table 2: Scope of the reactiona. (continued)
2
3
p-Tol
p-Tol
4-MeO-C6H4
Ph
Ph
4b
4c
60
3-thienyl
15 (35c)
4
5
p-Tol
p-Tol
iPr
Bn
Ph
Ph
4d
4e
45
32
6
7
8
9
p-Tol
p-Tol
p-Tol
p-Tol
Ph
Ph
Ph
Ph
4-Cl-C6H4
4f
39
32
46
20
3-CF3-C6H4
4-EtO2C-C6H4
4-iPr-C6H4
4g
4h
4i
10
11
p-Tol
p-Tol
4-Cl
3-Me-C6H4
4j
25
34
4-F-C6H4
4-MeO-C6H4
4k
428

Beilstein J. Org. Chem. 2014, 10, 425–431.
Table 2: Scope of the reactiona. (continued)
12
13
Me
Me
Ph
Ph
Ph
4l
65
27
4-F-C6H4
4m
14
15
Me
Me
4-MeS-C6H4
4-CF3-C6H4
Ph
4n
4o
36
39
4-Me-C6H4
aReactions were conducted with 5 mL of acetonitrile, 2.5 mmol of sulfonamide 1, 2.5 mmol of aldehyde 2, 7.5 mmol of aryl bromide 3, 0.25 g
(1.125 mmol) of cobalt bromide, and 1.4 g (25 mmol) of manganese dust (preactivated by using 0.1 mL BrCH2Ch2Br and 0.1 mL TFA), for 10 min at
room temperature. bIsolated yield. cReaction conducted with the preformed sulfonyl imine.
Scheme 1: Possible reaction mechanism.
It was previously established that zinc is able to reduce [39]. It can thus be assumed that a reductive metal other than
cobalt(II) in the presence of an aryl halide to promote the for- zinc, e.g., manganese, can also promote a similar process. The
mation of a transient arylcobalt(II) species, which undergoes a first reaction step is the manganese-mediated formation of the
fast transmetallation with zinc to furnish an organozinc species organocobalt intermediate I. Depending on the kinetics of the
429

Beilstein J. Org. Chem. 2014, 10, 425–431.
transmetallation of I by manganese salts, two different The organic fractions were dried over Na2SO4 and concen-
scenarios may be envisaged featuring either an organocobalt or trated under reduced pressure. The crude product was purified
an organomanganese species as the key organometallic II.
by silica-gel chromatography by using a solvent gradient
(pentane/diethyl ether 90:10 to pentane/diethyl ether 70:30) to
In the first scenario, manganese undergoes a slow transmetalla- yield the three-component coupling product 4 as a generally
tion with the organocobalt species I. It has been shown earlier white solid.
that zinc salts undergo rapid transmetallations with
organocobalt(II) species to furnish organozinc compounds. Acknowledgements
However, as mentioned above, the usage of zinc does not allow Financial support of this work by the CNRS and the University
the reaction to proceed, so that we assume that the active Paris-Est (Ph.D. grant) is gratefully acknowledged.
organometallic species II could not be an organozinc com-
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