Ni-catalyzed direct reductive amidation via C-O bond cleavage

Article abstract of DOI:10.1021/ja5029793

A novel Ni-catalyzed reductive amidation of C(sp²)-O and C(sp³)-O electrophiles with isocyanates is described. This umpolung reaction allows for an unconventional preparation of benzamides using simple starting materials and easy-to-handle Ni catalysts.

Full text of DOI:10.1021/ja5029793

Communication
pubs.acs.org/JACS
Ni-Catalyzed Direct Reductive Amidation via C−O Bond Cleavage
Arkaitz Correa† and Ruben Martin*,†,§
†Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
§Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluïs Companys, 23, 08010 Barcelona, Spain
S
* Supporting Information
Scheme 2. Catalytic Cross-Coupling Routes to Benzamides
ABSTRACT: A novel Ni-catalyzed reductive amidation of
C(sp2)−O and C(sp3)−O electrophiles with isocyanates is
described. This umpolung reaction allows for an
unconventional preparation of benzamides using simple
starting materials and easy-to-handle Ni catalysts.
ithin a few years, C−O electrophiles have emerged as
W
powerful and environmentally friendly alternatives to
the use of organic halides in the arena of cross-coupling.1
Among their advantages are the low toxicity, ready availability,
and natural abundance of phenols together with their unique
pivotal role in organic synthesis, making them particularly
attractive for further applications. Despite formidable advances,
these processes are primarily restricted to the use of
nucleophilic entities such as boronic acids, organozincs, or
Grignard reagents.2,3 Recently, catalytic reductive processes of
organic halides with other electrophilic partners have received
considerable attention.4−6 These methods represent a formal
umpolung or a polarity inversion strategy, employing
unconventional substrate combinations while avoiding the use
of well-defined and stoichiometric organometallic reagents, thus
changing the logic in chemical reactivity and increasing our
ever-growing synthetic toolkit. Strikingly, metal-catalyzed
reductive events employing aryl C−O electrophiles are relatively
scarce.7,8 This might be due to the proclivity of C−O
electrophiles to undesired pathways and site-selectivity issues
with multiple C−O reaction sites, giving the notion that the use
of aryl C−O electrophiles in catalytic reductive protocols
constitutes a notorious difficult challenge. The discovery of new
reactivity within this field would be a highly desirable goal of
utmost synthetic importance.
(Scheme 2, path a),10 carbonylation methods using CO11 or
CO surrogates12 (path b), or C−H functionalization techniques
promoted by suitable ortho-directing groups (path c)13 have
shown to be viable synthetic alternatives to classical methods
for preparing such privileged motifs.14,15 We envisioned that
benzamides would be within reach by a reductive event using
C−O electrophiles and isocyanates, thus providing a unique
opportunity to improve the efficiency and applicability of C−O
electrophiles while offering an innovative bond disconnection
not apparent at first sight (path d).16 As part of our interest in
C−O bond activation,17 we report herein the discovery of a
novel catalytic protocol that deals with such challenge,
exploiting a previously unrecognized opportunity in the field
of C−O bond cleavage. The method is characterized by its wide
scope and excellent chemoselectivity profile, including challeng-
ing substrate combinations. Likewise, the use of readily
available and air-stable compounds represents an additional
benefit from a practical standpoint.
We began our investigations by examining the reactivity of 1a
with n-butyl isocyanate using Ni precatalysts (Table 1), and the
effects of all reaction parameters were systematically exam-
ined.18 As for other catalytic reductive processes,4−7 we
anticipated that the nature of the ligand would play a critical
role for success. As shown in entries 1−5, this was indeed the
case: while dppf provided promising results in DMA with Mn
as reducing agent (entry 1), the use of other related ligands was
rather unsatisfactory, not affording even traces of 2aa and
invariably resulting in 2-naphthol or reduced naphthalene
(entries 2−5).18 Interestingly, the replacement of Mn by Zn
under otherwise identical reaction conditions significantly
improved the yield of 2aa (entry 6).19 Although different Ni
sources could be utilized (entries 6−11), the best results were
Benzamides are key structural units in a wide variety of
compounds that display important biological properties, such as
Atorvastatin, Fluopicolide, and Balsalazide, among others
(Scheme 1).9 Recently, metal-catalyzed amidation protocols
using well-defined and stoichiometric organometallic species
Scheme 1. Biological Significance of Benzamides
Received: March 27, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
a
isocyanate motif. Gratifyingly, minor modifications on the
reaction conditions allowed for effecting the Ni-catalyzed
reductive amidation of benzylic C(sp3)−O bonds at room
temperature (2d, 2e). Of significant interest is the successful
preparation of 2e; in this particular case, we found that the
reductive amidation event occurred exclusively at the C(sp3)−
O motif by leaving the proximal C(sp2)−O bond intact, an
observation that is in line with the higher propensity of benzylic
positions toward oxidative addition.21,22 As for many other C−
OPiv bond-cleavage processes,23 however, we found that our
protocol was restricted to the use of π-extended systems, an
observation that is tentatively attributed to the intermediacy of
η2-arene or Meisenheimer-type complexes.24
Table 1. Optimization of the Reaction Conditions
b
entry
Ni catalyst
L (x mol%)
reductant
yield 2aa (%)
1
NiCl2(dppf)
NiCl2(dppp)
NiCl2(PMe3)2
NiCl2(PPh3)2
NiBr2(bpy)2
NiCl2(dppf)
Ni(acac)2
dppf (10)
dppp (10)
PMe3 (10)
PPh3 (10)
bpy (10)
Mn
Mn
Mn
Mn
Mn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
18
0
2
3
0
4
0
5
0
6
dppf (10)
dppf (20)
dppf (20)
dppf (20)
dppf (20)
dppf (20)
dppf (10)
dppf (20)
dppf (20)
38
28
21
46
42
55
4
Challenged by the limitation to π-extended systems, we
envisioned a further extension of the scope of this novel
method to accommodate simple phenyl derivatives. We
hypothesized that the use of slightly more activated C−O
electrophiles such as aryl tosylates would be ideal for our
purposes.25 Owing to their higher reactivity, however, we
anticipated a certain degree of undesired dimerization events
using aryl tosylates. Indeed, this turned out to be the case for
most of the ligands analyzed;18 while the use of 2,2′-bipyridine
provided homocoupling products quantitatively, the use of dppf
as the ligand was found to be critical to effect the rather
challenging amidation of phenyl derivatives in high yields at 60
°C. Interestingly, the inclusion of NaI as additive totally
suppressed the competitive dimerization event, an observation
that is in line with other reports recently described in the
literature.26 Under these reaction conditions, a wide variety of
substituted phenyl tosylates smoothly underwent the desired
reductive amidation process (Table 3). Control experiments in
the absence of NaI clearly confirmed its beneficial effect on
reactivity (4c, 4f). The chemoselectivity profile is nicely
illustrated by the fact that ethers (4b), thioethers (4e), ester
(4g), nitriles (4k), pivalates (4h), and tosylates (4i, 4n) were
perfectly accommodated. Of remarkable interest is the
selectivity pattern observed for 4h and 4i, thus leaving ample
opportunities for manipulation via common cross-coupling
techniques. As shown for 4c, the reaction was not hampered by
ortho substituents. Importantly, the presence of nitrogen-
containing heterocycles such as pyrazole (4d), pyrrole (4l),
and carbazole (4m) posed no problems, delivering the
corresponding amides in good to excellent yields. Even more
instructive was the successful preparation of 4n, evidencing the
selectivity profile among different C−OTs bonds as well as the
practical utility of our method for late-stage modification of
biologically relevant compounds. It is worth noting that the
catalytic reductive amidation of aryl chlorides (4ja, 4jb, 4k, and
4l), particularly challenging substrates in the cross-coupling
arena,27 could be conducted at room temperature under
otherwise identical reaction conditions, an observation that
clearly highlights the robustness and generality of our
protocol.28,29
7
8
Ni(OTf)2
9
NiBr2·glyme
NiBr2·H2O
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
10
11
12
cd
,
f
13
70
de
,
f
14
81
a
Reaction conditions: 1a (0.50 mmol), nBuNCO (2.0 equiv), [Ni]
(10 mol%), L (x mol%), reductant (2.0 equiv), DMA (0.25 M) at 80
°C for 24 h. HPLC yield using anisole as internal standard. K2HPO4
(1.0 equiv) was added. DMF as solvent. K2HPO4 (2.0 equiv) was
b
c
d
e
f
added. Isolated yield.
accomplished using NiCl2·glyme (entry 11). Intriguingly, the
inclusion of K2HPO4 in anhydrous DMF had a dramatic effect
on reactivity, providing 2aa in 81% isolated yield while
minimizing undesired reaction pathways such as formation of
carbamate or isocyanurates by trimerization of nBuNCO (entry
14). To put these results into perspective, control experiments
revealed that NiCl2·glyme, dppf, and Zn were absolutely
required to promote the reductive coupling event.18
Encouraged by our initial results, we sought to examine the
preparative scope and generality of our Ni-catalyzed reductive
amidation event using naphthyl pivalates as substrates (Table
2).20 As shown for 2aa−2ag, moderate to good yields were
obtained regardless of the substitution pattern on the
a b
,
Table 2. Catalytic Reductive Amidation of Pivalates
Although a detailed mechanistic picture requires further
studies, several experiments were performed to gain insights
into the reaction mechanism. We found that the catalytic
reductive coupling of 1a, 3a, and 3k was completely inhibited
by the addition of TEMPO.18 While such observation might
indicate that single electron transfer processes come into play,
care must be taken when generalizing this, as other radical
scavengers such as BHT or galvinoxyl followed an opposite
reactivity pattern.18 Interestingly, we found no reaction of 1a or
3a when replacing n-butyl isocyanate with butyraldehyde or
a
b
Reaction conditions as for Table 1, entry 14. Isolated yields, average
c
d
e
of at least two independent runs. 2.50 mmol scale. 90 °C. Mn (2.0
equiv) at rt.
B
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Journal of the American Chemical Society
Communication
a b
,
Table 3. Reductive Amidation of ArOTs and ArCl
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
rmartinromo@iciq.es
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank ICIQ Foundation, European Research Council
(ERC-277883), and MICINN (CTQ2012-34054) for financial
support. Johnson Matthey, Umicore, and Nippon Chemical
Industrial are acknowledged for gifts of metal and ligand
sources. A.C. thanks MICINN for a JdC fellowship.
REFERENCES
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a
Reaction conditions: ArOTs (0.50 mmol), R2NCO (1.0 mmol),
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Journal of the American Chemical Society
Communication
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́
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(18) See Supporting Information for more details. The optimal Ni:L
ratio was found to be 1:2; little conversion was observed at lower Ni:L
ratio and lower catalyst loading. In all cases, reduced arenes and free
alcohols were observed as byproducts.
(19) The difference in reactivity when using Zn and Mn is in analogy
with recent literature data on reductive coupling events. See, for
example, refs 5, 6a, and 6c.
(20) The use of other related C(sp2)−O electrophiles such as
naphthyl acetates, carbamates, or benzoates provided amide 2aa in
comparatively much lower yields. See ref 18.
(21) The higher reactivity of benzylic C(sp3)−O bonds is illustrated
by the observation that a mixture of 1a and 1d (1:1 ratio) with
cyclohexyl isocyanate at rt using Mn as reductant resulted in 2ag and
2dg (1:10 ratio). This result is in agreement with the higher reactivity
of benzylic over aromatic moieties in related reductive coupling events.
See for example, refs 6a and 7a.
(22) Competitive reduced arene was found in the reaction mixture.
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Chem., Int. Ed. 2010, 49, 4566.
D
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