Cobalt-Catalyzed 1,4-Aryl Migration/Desulfonylation Cascade: Synthesis of α-Aryl Amides

Article abstract of DOI:10.1002/chem.202005129

A cobalt-catalyzed 1,4-aryl migration/disulfonylation cascade applied to α-bromo N-sulfonyl amides was developed. The reaction was highly chemoselective, allowing the preparation of α-aryl amides possessing a variety of functional groups. The method was used as the key step to synthesize an alkaloid, (±)-deoxyeseroline. Mechanistic investigations suggest a radical process.

Full text of DOI:10.1002/chem.202005129

Accepted Article
Accepted Article
Title: Cobalt-catalyzed 1,4-aryl migration/desulfonylation cascade:
synthesis of α-aryl amides.
Authors: Nicolas Gillaizeau-Simonian, Etienne Barde, Amandine
Guérinot, and Janine Cossy
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To be cited as: Chem. Eur. J. 10.1002/chem.202005129
Link to VoR: https://doi.org/10.1002/chem.202005129
01/2020

10.1002/chem.202005129
Chemistry - A European Journal
COMMUNICATION
Cobalt-catalyzed 1,4-aryl migration/desulfonylation cascade:
synthesis of α-aryl amides.
Nicolas Gillaizeau-Simonian,[a] Etienne Barde,[a] Amandine Guérinot*,[a] Janine Cossy*.[a]
[a]
N. Gillaizeau-Simonian, Dr. E. Barde, Dr. A. Guérinot, Prof. J. Cossy
Molecular, Macromolecular Chemistry and Materials-UMR 7167 ESPCI Paris, CNRS, PSL Research University
10, rue Vauquelin 75231 Paris Cedex 05, France
janine.cossy@espci.fr; amandine.guerinot@espci.fr
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Access to α-aryl amides- previous work
Abstract: A cobalt-catalyzed 1,4-aryl migration/desulfonylation
cascade applied to α-bromo N-sulfonyl amides is described. The
reaction is highly chemoselective allowing the preparation of
α-aryl amides possessing a variety of functional groups. The
method was used as the key step to synthesize an alkaloid,
(±)-deoxyeseroline. Mechanistic investigations suggest a radical
process.
Aryl migration/desulfonylation sequence 11,12,13
α-Arylation of amides enolates 6,7,8,9
O
O
O
O
[Pd] cat.
R1
R2
R1
R1
" Z "
R1
R2
NR2R3
NR2R3
N
N
ArX, base
H
Z
Ar
Ar
Ar
SO2Ar
A
(eq. 3)
(eq. 1)
X = Br, Cl
Z = R, RC(O), CF3, RO, RSO2, P(O)R2, N3
O
O
[Ni], [Pd], [Co]
cat.
R1
R1
O
O
[Cu] (2 equiv.)
or [Ir] cat.
R1
NR2R3
NR2R3
R1
ArM
N
X
N
M = B, Zn, Si, Mg
(eq. 2)
H
Br SO2Ar
X = Br, Cl
Ar
(eq. 4)
B
As ubiquitous pharmacophores, α-aryl amides constitute a
class of attractive compounds in medicinal chemistry.1 They
are present in a range of marketed drugs such as atenolol,2
which is used in the treatment of cardiovascular diseases, or
in many β-lactam antibiotics such as amoxicilline,3 which is
the most frequently employed antibiotic for children. α-Aryl
amides are also analogs of α-aryl carboxylic acids that are
key motifs in several non-steroidal anti-inflammatory agents.4
In addition, they can be easily reduced to β-aryl amines that
can be found in a variety of biologically active molecules.5 As
a consequence of their outstanding importance, several
methods have been developed to access α-aryl amides, the
most popular one being the metal-catalyzed arylation of
amides enolates (Scheme 1, eq. 1).6 Since its discovery by
Hartwig et al. in 1998,7 this reaction has known numerous
developments but still suffers from some drawbacks such as
the need for a strong base to generate the amide enolate.8 As
an alternative, metal-catalyzed cross-couplings between α-
halo amides and organometallics have been studied, most of
them relying on Ni-, Pd- or Co- catalysts (Scheme 1, eq. 2).9
A third way to access α-aryl amides is based on an aryl
migration/desulfonylation process applied to N-sulfonyl
amides of type A or B (Scheme 1, eq. 3 and 4).10,11 In both
cases, a radical generated in the α position of the amide
moiety is able to perform a 5-ipso cyclization triggering, after
a desulfonylation step, a 1,4-aryl migration. Numerous radical
addition/aryl migration cascade applied to acrylamides have
been reported, resulting in α-aryl amides that incorporate a Z
group in their final structure coming from the radical precursor
(Scheme 1, eq. 3).12 To avoid this first intermolecular addition
Scheme 1. Access to α-aryl amides: previous work.
During the course of our studies in sustainable metal-
catalyzed reactions, we developed a cobalt-catalyzed cross-
coupling of α-halo amides with Grignard reagents.9i While
using sulfonamide 1.1 under our optimized conditions, we
observed the formation of α-tolyl amides 1.2 as the major
product instead of the expected α-phenyl amide. We
hypothesized that this product could arise from a low-valent
cobalt-catalyzed 1,4-aryl migration/desulfonylation process
initiated by the formation of a radical in the α position of the
amide moiety. Intrigued by this result, the conditions were
optimized, particularly with the objective of avoiding the use of
Grignard reagent as the reducing agent. Herein, we report a
cobalt-catalyzed, manganese-mediated intramolecular aryl
migration/desulfonylation sequence applied to the arylation of
α-bromo N-sulfonyl amides (Scheme 2). As it is not restricted
to tertiary bromides, this chemoselective transformation
allows the access to a great diversity of α-aryl amides. The
rearrangement was used as the key step in the synthesis of
(±)-deoxyeseroline and mechanistic investigations have been
conducted.
Ÿ
of a Z radical on A derivatives, radicals can be generated
from α-halo sulfonamides (Scheme 1, eq. 4).13 However,
examples of such rearrangements are scarce in the literature.
All of them require the use of tertiary bromides and either
stoichiometric amount of copper complexes or expensive
iridium photocatalyst.
1
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10.1002/chem.202005129
Chemistry - A European Journal
COMMUNICATION
Initial observation
Bis(diphenylphosphino)-9,9-dimethylxanthene. DPEPhos= (Oxydi-2,1-
phenylene)bis(diphenylphosphine).
PhMgBr (2 equiv.)
CoCl2 (5 mol%)
XantPhos (5 mol%)
O
O
Bn
Bn
N
Table 1. Optimization of the reaction conditions.
N
H
2 h, rt, THF
p-Tol
Br SO2p-Tol
With the optimized conditions in hand, the scope of the
reaction was investigated, first focusing on the influence of
α-substituent of the amide (R1) and nitrogen substituent (R2).
The reaction outcome was not affected when the n-propyl
1.1
1.2 (48%)
[Co]
"H
"
O
O
N
O
5-ipso
cyclization
Bn
O
Bn
Bn
N
S
group was changed for
a methyl substituent as the
N
O
O
S
- SO2
corresponding α-aryl amide was isolated in an excellent yield
of 85%. The reaction was scalable under the optimized
conditions as 1 mmol of 1.2 were efficiently transformed in 2.2
with a good yield (80%). Interestingly, the reaction could be
performed on an α-chloro N-sulfonyl amide and, after 48 h,
the desired α-tolyl amide was isolated in an excellent yield
(87%).17 Changing the N-Bn substituent for a N-Me did not
modify the reactivity and the corresponding N-Me amide was
obtained selectively (79%). The presence of a silyl ether was
well tolerated and α-aryl amide 2.4 was formed with a good
yield of 68%. However, when α-bromo β-amido ester 1.5 was
involved in the reaction, a mixture composed of the desired
compound, the dehalogenated product and the primary
sulfonamide 4 was obtained and 2.5 could not be isolated.18,19,
20 This result can be obtained by the presence of the electron-
withdrawing group which could stabilize the putative radical
intermediate, favoring the formation of a cobalt enolate (vide
infra). This cobalt enolate could provide a transient ketene
upon elimination of the observed sulfonamide. 21 , 22 When
tertiary bromides were used, moderate yields in the
rearranged product 2.6 and 2.7 (38% and 30% respectively)
were obtained, due to the formation of a substantial amount
of the non-desired dehalogenated compound. We
hypothesized that the stabilization of the radical may favor an
hydrogen abstraction to THF over the 5-ipso cyclization. Even
disappointing, this result highlights the difference of our
method with the existing aryl migration/desulfonylation
cascades that generally required tertiary bromides. Primary
bromide cannot be used in this rearrangement as a mixture of
starting bromide and sulfonamide 4 was obtained (Scheme 3).
O
This work
CoCl2 cat.
DPEPhos cat.
Mn
O
O
R1
Bn
R1
N
NHBn
(Het)Ar
Br SO2(Het)Ar
Scheme 2. Access to α-aryl amides through cobalt-catalyzed 1,4-aryl
migration/desulfonylation cascade. XantPhos= 4,5-Bis(diphenylphosphino)-
9,9-dimethylxanthene.
The first objective of our optimization study consisted of
finding an alternative reductive agent preventing the waste of
the Grignard reagent.14 The same catalytic system [CoCl2,
XantPhos] was used and, among the reductive metals tested
(Mg, Zn, Mn), the most promising one was Mn powder (2.5
equiv.). Under these conditions, the starting bromo N-sulfonyl
amide was fully consumed to give a mixture of the desired
α-aryl amide 2.1 together with the dehalogenated compound
3.1 (2.1/3.1 = 32:68), allowing the isolation of the targeted
molecule with a moderate yield of 31% (Table 1, entry 1) but
this reaction revealed hardly reproducible. However,
increasing the temperature to 100 °C revealed to be the key
feature to address this issue and also to significantly improve
the selectivity in favor of the α-aryl amide (Table 1, entry 2). A
range of amine, phosphine and phosphite ligands has then
been screened and the best result was obtained with 10
mol% of the bidentate DPEPhos (Table 1, entry 3). Several
solvents were examined but moderate conversion of the
starting bromo amide and/or formation of the dehalogenated
compound as the major product were observed in all cases.
Among the commercially available cobalt complexes tested,
CoCl2 was the most powerful one to provide α-aryl amide
2.1.15,16
CoCl2 (10 mol%)
O
DPEPhos (10 mol%)
Mn (2.5 equiv.)
O
O
R1
R2
R2
R1
R1
R2
H
NHR2
+
+
N
N
N
24 h, 100 °C, THF
Br SO2p-Tol
1.2-1.8
SO2p-Tol
p-Tol
SO2p-Tol
3.2-3.8
2.2-2.8
4
O
O
O
O
O
Me
Me
NHBn
TBDPSO
NHBn
NHMe
MeO
NHBn
CoCl2 (5-10 mol%)
L (x mol%)
Mn (2.5 equiv.)
p-Tol
p-Tol
p-Tol
2.3 (79%)
O
p-Tol
O
O
O
2.2 (85%)(80%)[a]
2.4 (68%)
2.5 (traces)
Bn
Bn
Bn
+
N
N
N
O
H
O
20 h, T °C, THF
p-Tol
SO2p-Tol
Me
Me
Br SO2p-Tol
1.1
H
NHBn
NHBn
NHBn
2.1
3.1
p-Tol
p-Tol
p-Tol
2.8 (0%)
2.6 (38%)
[a] On 1 mmol scale.
2.7 (30%)
L (x mol%)
2.1, yield
entry
1[c],[d]
T °C
rt
τc (%)[a]
2.1/3.1
[b]
Scheme 3. Variation of the R1 side chain and R2 nitrogen substituent.
DPEPhos= (Oxydi-2,1-phenylene)bis(diphenylphosphine).
XantPhos (5)
XantPhos (5)
> 95
32:68
31%
2[c]
3[e]
100
58
90:10
90:10
45%
80%
N-sulfonyl amides bearing various para-substituents on the
aryl ring was then evaluated in this cobalt-catalyzed aryl
migration/desulfonylation cascade. Pleasingly, the reaction
was not sensitive to electronic effects as the migration of aryl
rings displaying both p-OMe and p-CF3 substituents was
efficient. These results differentiate our method from the
reported iridium-catalyzed aryl migration,13d which does not
tolerate the presence of strong electron-rich or electron-
DPEPhos (10)
100
> 95
[a] Ratio (2.1+3.1)/(1.1+2.1+3.1) calculated from 1H NMR spectra of the
crude. [b] Isolated yield. [c] 5 mol% of CoCl2 was used. [d] The reaction
was not reproducible. [e] 10 mol% of CoCl2 was used. XantPhos= 4,5-
2
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10.1002/chem.202005129
Chemistry - A European Journal
COMMUNICATION
withdrawing groups on the migrating aryl ring. A limitation was
noticed in the presence of a nitro substituted aryl as no traces
of the rearranged product could be detected. The poisoning of
the cobalt catalyst upon coordination to the nitro substituent
as well as the undesired reduction of the nitro group could
explain this result. Interestingly, the reaction revealed to be
highly chemoselective in the presence of an aryl bromide or
electrophilic substituents including nitrile, ketone and highly
reactive aldehyde moiety. In addition, the presence of a free
hydroxyl group did not interfere with the catalytic system.
Thus, this aryl migration process appeared as an attractive
mild alternative to metal-catalyzed cross-coupling between
α-bromo amides and nucleophilic reactive organometallics
(Scheme 4a).
amides, which are challenging to obtain by using other
methods (Scheme 4c).
The developed rearrangement could be used as a key step in
the synthesis of the (±)-deoxyeseroline, a pyrrolidino-indoline
alkaloid featuring a benzylic all carbon quaternary center.23
The aryl migration was performed on α-bromo N-sulfonyl
amide 724 under our optimized conditions and the resulting
crude α-aryl amide was directly engaged in an Ullmann
coupling [CuI (10 mol%), 1,2-dimethylethylenediamine
(DMEDA, 40 mol%), t-butyl acetoacetate (TBAA, 2 equiv)]
affording oxindole 9 with a decent 50% yield for the two
consecutive steps. Treatment of oxindole 9 with a base
followed by addition of bromoacetonitrile allowed the
construction of the quaternary center. Concomitant reduction
of the nitrile and amide moieties (LiAlH4, THF, 65 °C) was
then performed delivering (±)-deoxynorseroline, which was
CoCl2 (10 mol%)
DPEPhos (10 mol%)
Mn (2.5 equiv.)
O
O
Me
Bn
Me
Bn
N
N
24 h, 100 °C, THF
H
(Het)Ar
2.9-2.24
Br SO2(Het)Ar
1.9-1.24
readily transformed into (±)-deoxyeseroline through
a
reductive amination. Overall, the alkaloid was prepared in 7
steps from 2-bromobenzenesulfonyl chloride with an overall
yield of 16%. Given the chemical tolerance of the developed
method, a panel of substituents on the aryl ring could be
envisioned, leading to the possible synthesis of various
pyrrolidino-indoline analogs.
(a) para-substituted
O
O
O
O
Me
Bn
Me
Bn
Me
Bn
Me
Bn
N
H
N
H
N
N
H
H
2.9 (97%)
2.10 (74%)
2.11 (0%)
2.12 (80%)
OMe
CF3
NO2
O
Br
O
N
O
CuI (20 mol%)
DMEDA (40 mol%)
Me
TBAA (2 equiv.)
O
CoCl2 (10 mol%)
DPEPhos (10 mol%)
Mn (2.5 equiv.)
Me
O
O
O
Me
Me
Me
Me
Bn
Me
Bn
Me
Bn
Me
Bn
N
N
Me
N
H
N
H
N
H
N
H
H
Br O2S
24 h, 80 ° C, DMF
50% (2 steps)
24 h, 100 ° C, THF
Br
2.13 (79%)
2.14 (79%)
2.15 (76%)
2.16 (75%)
9
7
8
Br
(not isolated)
NaH (1.4 equiv.)
CN
O
H
O
OH
(1.5 equiv.)
53%
Br
CN
1 h, 0 °C to rt, DMF
(b) meta- and ortho-substituted
O
O
NC
Me
Me
Bn
Me
H
Me
Bn
NH
H
O
N
N
N
N
N
H
formaldehyde (10 equiv.)
0.5 h, 0 °C, MeOH/H2O
H
LiAlH4
(10 equiv.)
Me
Me
N
2.18 (62%)
Me
2.17 (57%)
Me
Me
1 h, 65 °C
THF
then NaBH4 (10 equiv)
rt, 3 h
68%
95%
10
(±)−Deoxyeseroline
(±)−Deoxynoreseroline
O
O
O
Me
Bn
Me
Br
Bn
Me
Bn
N
N
N
H
H
H
Scheme 5. Synthesis of (±)-deoxyeseroline. DPEPhos= (Oxydi-2,1-
phenylene)bis(diphenylphosphine). DMEDA= N,N’-dimethylethylene-
diamine. TBAA= Bis(tetrabutylammonium) adipate.
2.20 (97%)
2.21 (78%)
2.19 (76%)
(c) heteroaromatics
O
O
S
O
Me
Bn
Me
Bn
Me
Bn
To get some insights into the mechanism of the
transformation, some experiments were conducted. At first,
with the objective of confirming the formation of a transient
radical species, α-bromo N-sulfonyl amide 1.25 featuring a
N
N
N
H
H
H
N
2.22 (50%)
2.23 (68%)
2.24 (64%)
N
Scheme 4. Migration of para-, meta-, ortho-substituted aryl groups and
N-cyclopropyl ring was treated under the optimized conditions.
After 48 h, primary α-aryl amide 2.25 was isolated with a yield
of 42% (55% NMR yield). The absence of the cyclopropyl ring
in the final product may confirm the formation of an amidyl
radical producing a ring-opening of the strained 3-membered
ring leading to an unstable imine that finally delivered 2.25.
heteroaromatics.
DPEPhos=
(Oxydi-2,1-
phenylene)bis(diphenylphosphine).
α-Aryl amides incorporating a 1- or 2-naphthyl susbtituents
were efficiently synthesized from the starting α-bromo amides
(62% and 57% yields respectively). More interestingly, the
reaction proved to be not sensitive to steric hindrance as an
ortho-methyl or ortho-bromide aryl rings efficiently migrated to
give the corresponding α-aryl amides with good yields (76%
and 97% respectively). Even the migration of a sterically
hindered mesityl group successfully delivered the α-arylated
product with a good yield (78%). These results are highly
valuable as only few methods allow the easy preparation of
such hindered α-aryl amides (Scheme 4b). Gratifyingly,
several heteroaromatics such as pyridine, thiophene and
indole successfully migrated to furnish the α-heteroaryl
3
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10.1002/chem.202005129
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COMMUNICATION
CoCl2 (10 mol%)
To confirm the ability of Co(I) catalyst in activating the C-Br
bond of 1.2, the stable Co(I)(PPh3)3Cl was prepared and a
stoichiometric amount was added to 1.2 in the absence of Mn.
The reaction was heated at 100 °C and high conversion of 1.2
into the rearranged and dehalogenated products was
obtained, thus confirming the reactivity of Co(I) complex
towards C-Br bond (Scheme 7b). In addition, when a kinetic
study was conducted in the presence of a catalytic amount of
Co(I)(PPh3)3Cl, no clear induction period was observed
compared to the one observed using CoCl2. This observation
could be due to the absence of required preliminary reduction
step when a Co(I) complex is involved in the reaction
(Scheme 7a). Several factors may explain the observed
acceleration, such as the progressive activation of Mn or the
non-innocent role of generated MnX2 salts. Indeed, no
induction period was observed when the reaction was
conducted in the presence of CoCl2 (10 mol%) and 50 mol%
of MnCl2 (Scheme 7a).26From these experiments and based
on literature reports, the following mechanism was
hypothesized (Scheme 8). At first, a slow reduction of CoCl2
by Mn into a Co(I) complex would occur delivering the active
catalyst of the reaction.27 In the presence of an α-bromo N-
sulfonyl amide, a fast single electron transfer (SET) would
provide alkyl radical II and a Co(II) complex in equilibrium with
Co(III) complex III. This latter could be favored in the
presence of a R1 electron-withdrawing group leading to a
ketene and a sulfonamide. Alkyl radical II could undergo a 5-
ipso cyclization followed by SO2 extrusion to give the α-aryl
amidyl radical that could then abstract an hydrogen to the
solvent. Alternatively, radical II could abstract directly a
hydrogen to the solvent providing the dehalogenated product.
In both cases, the Co(II) complex would be reduced by Mn to
regenerate the active catalyst.
O
O
DPEPhos (10 mol%)
Mn (2.5 equiv.)
Me
Me
N
NH2
24 h, 100 °C, THF
Br SO2p-Tol
p-Tol
55% (NMR yield)
42% (isolated yield)
1.25
2.25
[Co(n)]
"H " then H2O
O
O
O
-SO2
Me
N
Me
Me
N
N
p-Tol
p-Tol
SO2p-Tol
[Co(n+1)]
Scheme 6. Rearrangement of radical clock 1.25.
Kinetic studies were then conducted and the consumption of
α-bromo N-sulfonyl amide 1.2 was measured at different
reaction times. Interestingly, an induction period of ca. 3 h
was observed followed by an acceleration of the reaction.
(Scheme 7a). The combination of a Co(II) pre-catalyst with
Mn has been described in the literature,25 particularly for the
catalysis of reductive cross-coupling between two
electrophiles. A reduction of Co(II) pre-catalyst using Mn into
a Co(I) is generally proposed as the initiation step to generate
the active catalyst. Once formed, the Co(I) catalyst is able to
react with halides, generally through a single electron transfer
(SET). We hypothesized that the induction period may be due
to a slow reduction of CoCl2 into a Co(I) active catalyst that
then would be able to transfer one electron to the α-bromo
N-sulfonyl amide.
(a)
[Co] (10 mol%)
DPEPhos (10 mol%)
Mn (2 or 2.5 equiv.)
O
O
O
MnCl2 (0 or 50 mol%)
Me
Bn
Me
Me
Bn
+
N
NHBn
N
t, 100 °C, THF
Br SO2p-Tol
p-Tol
SO2p-Tol
3.2
2.2
[Co(II)]Cl2
1/2 Mn
1.2
reduction
slow
1/2 MnCl2
O
R1
R
O
N
1/2 MnX2
[Co(I)]X
R1
R
Br SO2Ar
N
H
I
reduction
1/2 Mn
Ar
SET
VII
"H
"
O
O
R1
R
R1
R
N
N
O
II
SO2Ar
[Co(III)]
SO2Ar
R1
R
R
[Co(II)]X2
+
N
+ [Co(II)]X2
III
X
X
Ar V
when
R1 = EWG
"H
"
aryl migration
SO2
H abstraction
R1
O
O
R1
N
O
R
N
R1
R
N
Ar[Co(III)]
+
SO2Ar
IV
X
X
SO2Ar
Co(PPh3)3Cl
(1 equiv.)
O
O
O
[Co(III)X2]+
(b)
VI
+ [Co(II)]X2
Me
Bn
Me
Bn
N
Me
+
N
NHBn
1 h, 100 °C, THF
Ligand has been omitted for seak of clarity
SO2p-Tol
Br SO2p-Tol
p-Tol
(55%)
1.2/2.2/3.2 = 11:55:34
1.2
2.2
3.2
Scheme 8. Hypothetical mechanism.
Scheme 7. Mechanistic investigations: (a) Kinetic studies: comparison of
CoCl2, Co(PPh3)3Cl and CoCl2/MnCl2 catalytic activity. (b) Experiment with
stoichiometric amount of Co(I)(PPh3)3Cl. DPEPhos= (Oxydi-2,1-
phenylene)bis(diphenylphosphine).
In summary, we have developed a cobalt-catalyzed 1,4-aryl
migration/desulfonylation cascade allowing the synthesis of a
wide variety of α-aryl amides from α-bromo N-sulfonyl amides.
The reaction is highly chemoselective and appears as a
flexible strategy to prepare α-aryl amides. The efficient
4
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10.1002/chem.202005129
Chemistry - A European Journal
COMMUNICATION
synthesis of the alkaloid (±)-deoxyeseroline using the aryl
migration as a key step illustrates the potential of the
developed reaction. Mechanistic studies suggest the
formation of a radical through a SET from a Co(I) complex to
α-bromo N-sulfonyl amide. To the best of our knowledge, it is
the first cobalt-catalyzed aryl migration with SO2 extrusion and
this reactivity pave the way to numerous further
developments.
Barde, S. Bräse, J. Cossy, Org. Lett. 2019, 16, 6241. k) M. M.
Lorion, V. Koch, M. Nieger, H.-Y. Chen, A. Lei, S. Bräse, J. Cossy,
Chem. Eur. J. 2020 DOI: 10.1002/chem.202001721
10
11
For pioneering work in aryl migration/desulfonylation sequence, see:
a) R. Loven, W. N. Speckamp, Tetrahedron Lett. 1972, 16, 1567. b)
J.-C.Arnould, J. Cossy, J.-P. Pète, Tetrahedron Lett. 1976, 43, 3919.
c) J. Cossy, J.-P. Pète, Tetrahedron 1981, 37, 2296.
For selected general reviews on radical aryl migration, see: a) A.
Studer, M. Bossart Tetrahedron 2001, 57, 9649. b) Z.-M. Chen, X.-
M. Zhang, Y.-Q. Tu Chem. Soc. Rev. 2015, 44, 5220. c) C. M.
Holden, M. F. Greaney Chem. Eur. J. 2017, 23, 8992. d) W. Li, W.
Xu, J. Xie, S. Yu, C. Zhu Chem. Soc. Rev. 2018, 47, 654.
Selected examples: a) W. Kong, M. Casimiro, N. Fuentes, E. Merino,
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W. Kong, N. Fuentes, A. Garcìa-Domíguez, M. Estíbaliz, C. Nevado,
Angew. Chem. Int. Ed. 2015, 54, 2487-2491. e) J.-K.Qiu, W.-J. Hao,
L.-F. Kong, W. Ping, S.-J. Tu, B. Jiang, Tetrahedron Lett. 2016, 57,
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Org. Chem. 2016, 81, 1277-1284. g) K. Liu, L.-C. Sui, Q. Jin, D.-Y.
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Acknowledgements
12
We thank the French Ministère de l’Enseignement Supérieur et de la
Recherche (MESR) for financial support (N.G.S and E.B).
The authors declare no conflict of interests.
Keywords: cobalt • α-aryl amide • aryl migration • N-sulfonyl
amide
13
a) A. J. Clark, R. C. Stuart, A. Collis, T. Debure, C. Guy, N. P.
Murphy, P. Wilson, Tetrahedron Lett. 2009, 50, 5609-5612. b) A. J.
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1
Selected book and reviews: a) A. Greenberg, L. M. Breneman, J. F.
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14
15
See the supporting information for a detailed optimization study.
The robustness of the reaction was assessed by the addition of 1
equiv of water to the reaction mixture. Under these modified
conditions, the α-aryl amide was isolated with a correct yield of 54%,
see SI for details.
2
a) J. Akisanya, A. W. Parkins, J. W. Steed, Org. Proc. Res. Dev.
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16
17
Using NiCl2 (10 mol%) associated to DPEPhos (10 mol%) also led
to 2.1 in good yield (78%).
This result is of importance as α-bromo amides can sometimes be
prepared as mixtures of α-bromo and α-chloro derivatives when
using acyl chloride precursors due to halogen exchange. The
rearrangement is compatible with the use of such mixtures as
starting materials.
A 2.5/3.5/4 ratio of 15:21:64 was determined on the 1H NMR
spectrum of the crude material.
3
a) H. H. Handsfield, H. Clark, J. F. Wallace, K. K. Holmes, M. Turck
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4
5
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18
19
20
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When a diethylphosphonate was present instead of the ester group,
the exclusive formation of sulfonamide 4 was observed.
For R1= Ph, a mixture of expected, dehalogenated products and
sulfonamide was obtained preventing the isolation of the α-aryl
amide.
6
For enolate arylation using Bi, Pb or Cr derivatives, see: a) R. A.
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19
22
Unfortunately, we were not able to isolate by-products resulting from
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7
8
K. H. Shaughnessy, B. C. Hamann, J. F. Hartwig, J. Org. Chem.
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references therein.
23
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9
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24
25
Prepared from the corresponding sulfonamide and α-bromo
propionyl bromide (94%, 2 steps, see SI for details).
Selected articles: a) M. Amatore, C. Gosmini, J. Périchon, Eur. J.
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5
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10.1002/chem.202005129
Chemistry - A European Journal
COMMUNICATION
26
In that experiment 50 mol % of MnCl2 were added to the classical
conditions and only 2 equiv of Mn were used. The conversion of 1.2
was fast but led to a mixture of 2.2 and 3.2 (1.2/2.2/3.2 = 10:37:53
after 5 h). Very low conversion of 1.2 was observed using MnCl2 (10
mol %) in the absence of cobalt catalyst. See SI for details.
27
Reduction to a Co(0) complex cannot be fully excluded.
6
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10.1002/chem.202005129
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
CoCl2 cat.
DPEPhos cat.
Mn
O
O
R1
Bn
R1
N
NHBn
(Het)Ar
Br SO2(Het)Ar
The synthesis of α-aryl amides through a cobalt-catalyzed 1,4-aryl migration/desulfonylation cascade applied to α-bromo N-sulfonyl
amides is reported. The combination of a cobalt catalyst together with a phosphine ligand and a metal reductive agent results in soft
conditions that proved to be compatible with a wide range of functional groups. The cascade reaction was used as a key step in a
flexible synthesis of (±)-deoxyeseroline, a pyrrolidino-indoline alkaloid. Mechanistic investigations suggest the formation of a transient
radical.
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