Reductive amidation of alkyl tosylates with isocyanates by a Ni/Co-dual catalytic system

Article abstract of DOI:10.1039/c9cc09377j

Reductive amidation of alkyl tosylates with isocyanates using the Ni/Co-dual catalytic system is disclosed. The method proceeds efficiently under mild conditions, giving rise to the corresponding alkyl amides. Notably, the protocol can discriminate the steric environment of two alkyl tosylate moieties, enabling regioselective mono-amidation at the less-bulky site.

Full text of DOI:10.1039/c9cc09377j

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Reductive amidation of alkyl tosylates with isocyanates by Ni/Co-
dual catalyꢀc system†
a
a
a
Takuya Michiyuki, Itaru Osaka and Kimihiro Komeyama *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
■
■
path a: Amidation of alkyl metallic reagents (Bode, Molander)
O
O
M
O
Reductive amidation of alkyl tosylates with isocyanates using the
Ni/Co-dual catalytic system is disclosed. The method proceeds
efficiently under mild conditions, giving rise to the corresponding
alkyl amides. Notably, the protocol can discriminate the steric
environment of two alkyl tosylate moieties, enabling regioselective
mono-amidation at the less-bulky site.
C
R
R
+
C
R
C
N
H
N
path b: Ni-catalysed reductive amidation (Martin)
Br
[Ni]cat.
O
C
+
C
R
Mn reductant
C
N
N
H
N
Alkyl amides are common skeletons found in a broad range of
natural products and pharmaceuticals. 1 Further, the amide
SET-type
OA
0
[
Ni ]
O
C
R
[NiI]
Mn
3
C
group frequently acts as a directing group in C(sp )–H bond
red.
insertion
A
2
functionalisations. Additionally, alkyl amides have allowed us
to access a large variety of organic molecules. 3 Therefore,
development of the route to alkyl amides from readily
accessible starting materials is currently in high demand.
Although dehydrative condensation has been recognised as a
representative strategy for alkyl amide synthesis, the formation
of a large number of by-products attributable to the
condensation reagents is unavoidable. Amidation of alkyl
metallic reagents with isocyanates is an alternative method
■ path c: Ni/Co-catalysed reductive amidation (This work)
O
OTs
[Ni]cat./[Co]cat.
Mn reductant
O
C
R
+
C
R
C
N
N
H
N
0
I
[
CoI]
S 2-type
OA
N
[Ni ] [Co ]
O
C –
[CoIII
C
R
B
[NiI]
OTs
Mn
red.
]
C
trans-
insertion
C
A
alkylation
(
path a, Scheme 1). 4 However, their high reactivity and Scheme 1 Recent progress in alkyl amide synthesis.
availability would restrict substrate scope. Martin and co-
workers have recently demonstrated the Ni-catalysed reductive Co(I) can activate alkyl tosylates and can be applied to nickel-
5
7
amidation of alkyl bromides with isocyanates (path b). The key catalysed couplings. As shown in path c, alkyl tosylates can
intermediate in this amidation is alkyl-Ni(I)
, which is undergo an S 2-type oxidative addition (S 2-type OA) into the
A
N
N
generated from the single electron transfer-type oxidative nucleophilic planar-Co(I) species
B
C
to generate an alkyl-Co(III)
, followed by reduction by
8
9
addition (SET-type OA) of an alkyl bromide into a low-valent
C
. Transalkylation with Ni(0) and
nickel and subsequent reduction with Mn powder. While this Mn, furnishes alkyl-Ni(I) A. Therefore, we speculated that alkyl
approach is efficient, the preparation of alkyl bromides from tosylates could be directly utilised for reductive amidation using
ubiquitous alkyl alcohols can be demanding. In contrast, alkyl the Ni/Co-dual catalytic system without in-situ tosylate–
tosylates, which are tractable carbon-electrophiles that are halogen exchange.10
easily prepared from alkyl alcohols, are readily available.
To test the feasibility of this hypothesis, initial studies on the
Despite these advantages, alkyl tosylates are rarely used in Ni- reductive amidation were performed using the reaction
catalysed transformations such as amidation or cross-couplings between dodecyl tosylate (1a) and t-butyl isocyanate (1.5
6
owing to their low reactivity toward the SET-type OA. On the equiv.). As a result, NiCl
2
bpy (10 mol%) and vitamin B12 (VB12, 5
other hand, we recently demonstrated that nucleophilic planar- mol%. The structure of VB12 was illustrated in Figure S2) in the
presence of Mn reductant (2.0 equiv.) at 30 °C provided alkyl
amide 2a in 12% yield (Table 1, entry 1), wherein most of 1a was
a.
Department of Applied Chemistry, Graduate School of Engineering. Hiroshima
University, 1-4-1 Kagamiyama, Higashi-Hiroshima City, Hiroshima 739-8527,
Japan.
converted into the homo-coupling product, tetracosane. To
improve chemo-selectivity, we investigated certain nickel
catalysts bearing different types of ligands. The screening
†
Electronic Supplementary Information (ESI) available: Experimental procedure for
the amidation and characterisation of products. See DOI: 10.1039/x0xx00000x

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revealed that expansion of ligand π-conjugation and tosylate, 2-butyloctyl tosylate, was not efficiently converted
substituents at the 4,4’-positions of the bipyridine did not affect into amide 2o (35% yield), even under harsh reaction conditions
the selectivity (entries 2 and 3). In contrast, the presence of two (60 °C, 72 h). We anticipated that the low conversion might be
methyl groups at the 6,6’-positions suppressed homo-coupling, attributed to the steric hindrance between the VB12 catalyst and
leading to the desired product 2a in 93% yield (entry 4). The the tosylate because a large amount of unreacted tosylates was
number of methyl substituents was important. Thus, the mono- detected after the reaction.
methylated bipyridine, 6-Mebpy, mainly afforded the homo-
coupling product (entry 5). Further, we confirmed that cobalt
Acceptable conversion was achieved using the less-bulky
catalyst, salcomine [N,N'-Bis(salicylidene)
amidation did not proceed in the absence of nickel or cobalt ethylenediimino cobalt(II)], giving rise to the amide 2o in good
catalysts (entries 6 and 7). yield under mild reaction conditions (Table 3). The NiCl (6,6’-
With optimised conditions in hand, we next explored Me bpy)/salcomine catalyst system well-tolerated other
substrate scope (Table 2). Aromatic isocyanates could be also branched alkyl tosylates, giving rise to the corresponding alkyl
capable in the amidation, providing 2b and 2c in moderate amides 2p 2t in 75–98% yields. Notably, this amidation was
2
2
–
yields. Phenyl, silyl ether, alkene, alkyne and ester functions also utilised for an alkyl tosylate possessing a plurality of
were well tolerated, giving rise to the corresponding alkyl asymmetric carbons, providing the corresponding amide 2u in
amides 2d–2j in good yields. The formation of 2g highlited one 47% yield without epimerisation. Further, the method is not
of the features of the amidation. Thus, the tosylation of alkyl limited to primary alkyl tosylates bound to tertiary carbons; an
diols regioselectively proceeds at the primary alcohol moiety alkyl tosylate bound to quaternary carbon was also available
even in the presence of secondary alcohols. As such, it is (for 2v) and was selectively incorporated with two isocyanates.
considered that this amidation might provide a convenient The reaction was also successful with alkyl tosylate possessing
approach for producing polyfunctionalised alkyl amides from quaternary-carbon at the
polyols.11 The presence of chloro and Bpin groups on the phenyl
-position, generating amide 2w.
rings did not interfere with amidation, affording 2k and 2l. In
addition, five-membered secondary alkyl tosylate was capable
Table 2 Substrate scope of the Ni/Co-catalysed reductive
amidation of alkyl tosylates using VB12
to form amide 2m. Cyclohexyl tosylate was also converted to
amide 2n, albeit in low yield due to the low reactivity for S
a,b
N
2
2 2
NiCl (6,6’-Me bpy) (10 mol%)
H
N
displacement. In contrast, the sterically congested primary alkyl
VB12 (5 mol%)
N
Alkyl
Alkyl OTs +
C
R
R
O
Mn (2.0 equiv.)
DMF, 30 ºC, then H+
O
Table 1 Optimisation of the reaction conditions a
1b–1o
2b–2o
2
NiCl bpy (10 mol%)
H
H
N
H
N
VB12 (5 mol%)
N
N
Ph
10 OTs
+
tBu
(
)
C
tBu
(
)
tBu
( )10
R
( )n
10
O
Mn (2.0 equiv.)
DMF, 30 ºC, 24 h
then H+
O
O
O
2a
n = 2: 2d, 80% (24 h)
3: 2e, 76% (24 h)
1a
(1.5 equiv.)
R = Ph: 2b, 48% (24 h)
4
-MeOC
6
H
4
:
2c, 40% (24 h)
4
:
2f, 86% (24 h)
OTBS
Entry
Change from the above conditions
None
Yield (%)b
H
N
H
N
tBu
tBu
Bu
1
2
3
4
5
6
7
12
O
O
NiCl
NiCl
NiCl
NiCl
2
2
2
2
phen instead of NiCl
2
bpy
24
2g, 61% (48 h)
2h, 51% (48 h)
H
N t
t
H
(4,4’- Bu
2
bpy) instead of NiCl
2
bpy
bpy
bpy
24
N t
2
EtO C
Bu
(6,6’-Me
2
bpy) instead of NiCl
2
93 (91)
O
O
(6-Mebpy) instead of NiCl
2
16
0
2j, 69% (24 h)
2
i
, 40% (24 h)
X
without NiCl
2
bpy
H
N
BocN
H
N t
without VB12
0
tBu
Bu
O
tBu
tBu
O
O
X = Cl: 2k, 70% (24 h)
2m, 78% (24 h)
N
Cl
N
Cl
N
Cl
N
Cl
N
Cl
N
Cl
Ni
Ni
Ni
Bpin: 2l, 91% (24 h)
NiCl
2
bpy
NiCl
2
phen
NiCl (4,4’-
t
2
Bu bpy)
2
H
N
H
N
tBu
tBu
N
Cl
N
Cl
N
Cl
N
Cl
Ni
Ni
O
Me
Me
Me
bpy)
O
NiCl
2
(6,6’-Me
2
2n, 20% (48 h)c
2o, 35% (72 h)d
2
NiCl (6-Mebpy)
a
a
Reaction conditions: tosylate (0.25 mmol, 1.0 equiv.); isocyanate (0.375
mmol, 1.5 equiv.); NiCl (6,6’-Me bpy) (0.025 mmol, 10 mol%); VB12 (0.0125
mmol, 5 mol%); DMF (1.5 mL), 30 °C. Isolated yields. NiCl
Reaction conditions: 1a (0.25 mmol, 1.0 equiv.); isocyanate (0.375 mmol, 1.5
bpy (0.025 mmol, 10 mol%); VB12 (0.0125 mmol, 5 mol%); DMF
2
2
equiv.); NiCl
1.5 mL), 30 °C, 24 h. Yields were determined by GC using mesitylene as an
2
b
c
b
2
bpy was used in
(
d
2 2
place of NiCl (6,6’-Me bpy). At 60 °C.
internal standard. The value in the parenthesis is the isolated yield.
2
| J. Name., 2012, 00, 1-3
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Taking advantage of the unique reactivity that the amidation PhSH, giving rise to cyano alkyl amide
is sensitive to the steric environment around the tosyloxy group, thiophenyl alkyl amide (68% yield), respectively.
we attempted regioselective amidation of an alkyl ditosylate, as To gain insight into the possible reaction pathway of the
illustrated in Scheme 2. When the alkyl ditosylate , having two reductive amidation, we carried out two mechanistic studies, as
tosyloxy groups at the different positions, was exposed to the depicted in Scheme 3. First, a radical clock experiment with
amidation conditions, the sterically less-hindered tosyloxy cyclopropylmethyl tosylate ( ) and 4-anisyl isocyanate gave a
group was selectively converted into the amide group to form ring-opening alkyl amide in 20% yield without the formation
5 (82% yield) or
6
3
7
4
8
in 87% yield without lacking another tosyloxy group. Although of any other products bearing the cyclopropylmethyl moieties
traditional reactions of alkyl tosylates using transition metal (Scheme 3a). This indicates alkyl radical generation from alkyl
catalysts have been reported,10 most were triggered by a tosylates. Second, Me-cobalamin also acted as a catalyst in the
sulfonate–halogen exchange of alkyl sulfonates to provide alkyl reductive amidation (Scheme 3b), providing the amide 2a in
halides with the halogen anions of catalysts or additives. 82% GC yield. The result strongly supports the formation of an
Therefore, these traditional methods do not allow alkyl-Co(III) intermediate during amidation.
regioselective mono-functionalisation of ditosylates. In fact, the
Based on these experimental results, we proposed the
5
amidation of
3
using NiBr
2
(6-Mebpy) in the absence of the VB12 catalytic cycle of this reductive amidation, as shown in Scheme
catalyst afforded a complex mixture, wherein we could not 4. An alkyl tosylate
detect the formation of (See Figure S1). The result obviously Co(I) to form an alkyl-Co(III) species
indicates that the bromo anion on the nickel catalyst partially between and Ni(0) gives an alkyl-Ni(II)
performs the tosylate-bromide exchange of alkyl tosylates, generation, followed by reduction with Mn powder, to afford
causing in undesirable side-reactions such as bromination and alkyl-Ni(I) species , which undergoes migratory insertion into
N
1 undergoes S 2-type OA with nucleophilic
1
2
4
B
C
.
Transalkylation
C
D
E through alkyl radical
A

-H elimination. Our approach, on the other hand, achieved the an isocyanate to give Ni-amide
F
. Reduction with Mn releases
regioselective mono-amidation due to the high regioselectivity Mn-amide
G and regenerate D to close the catalytic cycle.
of VB12 and the low nucleophilicity of the chloro anion (See Finally, protonolysis of
Table S1). Finally, the remaining alkyl tosylate unit on could be an acidic workup. However, we cannot rule out the alternative
displaced by traditional nucleophilic substitutions with KCN or pathway proposed by Molander , i.e., the transalkylation of
alkyl-Co(III) with carbamoyl-Ni(I), which was formed upon
G would furnish the desired amide 2 via
4
4
b
C
oxidative addition of an isocyanate to Ni(0) and a sequential
reduction with Mn, would also give a carbamoyl alkyl-Ni(III)
intermediate. The Ni(III) species might produce the same alkyl
amide through reductive elimination.
In conclusion, we have developed a Ni/Co-catalysed direct
reductive amidation of alkyl tosylates with isocyanates. The
amidation proceeded under mild conditions and was able to
tolerate a diverse set of functional groups, thereby offering a
versatile synthetic route to alkyl amides from ubiquitous,
Table 3 Substrate scope of the Ni/Co-catalysed reductive
amidation of alkyl tosylates using salcomine catalyst a,b
2 2
NiCl (6,6’-Me bpy) (10 mol%)
H
N tBu salcomine (5 mol%)
Alkyl
N t
Alkyl OTs +
C
Bu
O
Mn (2.0 equiv.)
O
DMF, 30 ºC, then H+
1o–1w
2o–2w
H
N
H
N
tBu
tBu
BocN
OTBS
TsO
O
O
2
o
, 89% (24 h)
2p, 98% (24 h)
( )3
OTs
H
3
N
H
N
tBu
tBuNCO (1.5 equiv.)
tBu
NiCl
2
(6,6’-Me
2
bpy) (10 mol%)
X
O
Mn (2.0 equiv.)
DMF, 30 ºC, 24 h, then H+
O
VB12 (5 mol%)
nBu
X = CH
2
:
2q, 97% (48 h)
NTs: 2r, 91% (24 h)
O: 2s, 75% (24 h)
2t, 90% (24 h)
OTBS
H
N
O
TsO
H
H
tBu
( )
3
tBu
N t
H
N
O
Bu
O
N
tBu
4, 87%
H
O
OBz
O
O
O
2
u
, 47% (24 h)
2v, 84% (24 h)c
DMSO
NaOH (1.5 equiv.) EtOH
KCN (2.0 equiv.)
OTBS
60 ºC, overnight
PhSH (1.5 equiv.) 40 ºC, overnight
H
N
tBu
OTBS
NC
OTBS
H
O
H
N
PhS
N
, 63% (48 h)d
tBu
tBu
2
w
( )
3
( )
3
O
O
a
5, 82%
6, 68%
Reaction conditions: tosylate (0.25 mmol, 1.0 equiv.); isocyanate (0.375
mmol, 1.5 equiv.); NiCl (6,6’-Me bpy) (0.025 mmol, 10 mol%); salcomine
0.0125 mmol, 5 mol%); DMF (1.5 mL), 30 °C. Isolated yields. BuNCO (3.0
2
2
Scheme
2 Regioselective amidation and sequential
nucleophilic substitutions starting from alkyl ditosylate
b
c t
(
3
.
d
equiv.) was used. At 60 °C.
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J. Name., 2013, 00, 1-3 | 3
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a) Radical clock experiment.
readily available, and stable alkyl tosylates. The amidation was
strongly affected by the steric interaction between alkyl
tosylates and nucleophilic Co(I) catalysts. Thus, the amidation of
sterically more congested alkyl tosylates could be accelerated
using the smaller cobalt catalyst, salcomine. The most
interesting synthetic feature of this amidation is the
regioselectivity in the reaction using alkyl ditosylates; that is,
the less-bulky alkyl tosylate moiety could be selectively
converted into the amide while keeping the bulky alkyl tosylate
moiety. Further investigations of the mechanisms and synthetic
applications of the regioselective functionalisation of polyol
derivatives are ongoing in our laboratory.
OTs
H
N
7
+
see Table 1
N
C
O
O
OMe
8
, 20%
OMe
b) Amidation of 1a using Me-cobalamin catalyst.
(
)
10 OTs
2 2
NiCl (6,6’-Me bpy) (10 mol%)
1a
H
N
Me-cobalamin (5 mol%)
Mn (2.0 equiv.)
+
tBu
(
)
10
N tBu
This work was supported by a JSPS KAKENHI (Grant Number
JP18K05106).
C
O
O
(
DMF, 30 ºC, 24 h
2
a, 82% (GC)
1.5 equiv.)
then H+
Conflicts of interest
There are no conflicts to declare.
Scheme 3 Mechanistic investigations.
O
H+
C
OTs
R
C
CoIII
C
–OTs
Notes and references
C
N
1
Mn1/2
G
S
N
2-type
OA
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N
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,
4
| J. Name., 2012, 00, 1-3
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Reductive amidation of alkyl tosylates with isocyanates by Ni/Co-dual cataly
D
t
O
icI: 1
s
0
y
.1
s
0
t
39/C9CC09377J
e
m
Takuya Michiyuki, Itaru Osaka and Kimihiro Komeyama*
Co
N
N
O
Me
Ni
Me
C
OTs
R
O
C
N
H
Mn powder
C
R
alkyl tosylate
N
up to 97% yield
New strategy for functionalisation of poly-tosylates
classical substitution
amidation by Ni/Cocat.
OTBS
TsO
OTs
Reductive amidation of alkyl tosylates with isocyanates using the Ni/Co-dual catalytic system is disclosed. The method
proceeds efficiently under mild conditions, giving rise to the corresponding alkyl amides. Notably, the protocol can
discriminate the steric environment of two alkyl tosylate moieties, enabling regioselective mono-amidation at the less-bulky
site.