Merging Electron Transfer with 1,2-Metalate Rearrangement: Deoxygenative Arylation of Aromatic Amides with Arylboronic Esters

Article abstract of DOI:10.1002/anie.202104359

Amides are essentially inert carboxyl derivatives in many types of chemical transformations. In particular, deoxygenative C?C bond formation of amides to synthetically important amines is a long-standing challenge for synthetic chemists due to the inertness of the resonance-stabilized amide C=O bond. Herein, it is disclosed that by merging electron-transfer-induced activation with 1,2-metalate rearrangement, a wide range of aromatic amides react smoothly with arylboron reagents, affording a series of biologically relevant diarylmethylamines as deoxygenative C?C bond cross-coupling products. With its simplicity and versatility, this reaction shows great promise in the synthesis of amines from amides, which may open up new avenues in retrosynthetic planning and find widespread use in academia and industry.

Full text of DOI:10.1002/anie.202104359

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Accepted Article
Title: Merging Electron Transfer with 1,2-Metalate Rearrangement:
Deoxygenative Arylation of Inert Amides with Arylboronic Esters
Authors: Xiaoming Wang and Jiwen Jiao
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10.1002/anie.202104359
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RESEARCH ARTICLE
Merging Electron Transfer with 1,2-Metalate Rearrangement:
Deoxygenative Arylation of Aromatic Amides with Arylboronic
Esters
Jiwen Jiao,a Xiaoming Wanga,b*
[a]
J. Jiao, Prof. X. Wang
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032 (China)
xiaoming@sioc.ac.cn
[b]
School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan,
Hangzhou 310024 (China)
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Amides are essentially inert carboxyl derivatives in many
types of chemical transformations. In particular, deoxygenative C-C
bond formation of amides to synthetically important amines is a long-
standing challenge for synthetic chemists due to the inertness of the
resonance-stabilized amide C=O bond. Herein, it is disclosed that by
merging electron transfer induced activation with 1,2-metalate
rearrangement, a wide range of aromatic amides react smoothly with
diaminoalkenes with an α-aminocarbene species as the proposed
initermediate.[16] Therefore, it was envisioned that with the
umpolung of the carbonyl carbon generated in the process of ET
to amides, an active intermediate might be reactive in a
deoxygenative C-C cross-coupling reaction with an appropriate
reagent, providing a means of activating and functionalizing the
inert amide.
arylboron regents, affording
a series of biologically relevant
diarylmethylamines as deoxygenative C-C bond cross coupling
products. With its simplicity and versatility, it shows great promise in
synthesis of amines from amides, which may open up new avenues
in retrosynthetic planning and find widespread use in academia and
industry.
Introduction
The amide, a common functional group in organic chemistry is
characterized by its high chemical stability and the low inherent
reactivity of its carbonyl carbon due to the resonance-stabilized
C-N bond.[1] On the other hand, amides are an under-exploited
class of nitrogen-containing compounds, ubiquitous in the fine
chemical, agrochemical and pharmaceutical industries, and their
transformation to synthetically useful amines by deoxygenative C-
C bond formation is a long-standing challenge for synthetic
chemists (Scheme 1a).[2-7] Several methods involving electrophilic
activation[3] or controlled hydride reduction[4-6] have been
developed to achieve deoxygenative C-C bond forming reactions
of amides. Notwithstanding these advances, multistep
procedures, air/water sensitive organometallic reagents,[8] the use
of strong base/acid[3] or special amides bearing directing
groups,[9] are generally necessary, due to the considerably weak
electrophilicity of the carbonyl carbon.
SmI2, introduced by Kagan in 1977 has emerged as one of the
most important reducing agents available in the laboratory and is
now widely used for the effective reduction of various functional
groups in organic synthesis.[10-12] For examples, electron transfer
(ET) to carboxylic acid derivatives mediated by Sm(II) has been
developed as a powerful strategy to invert the polarity of the
carbonyl group, resulting in the formation of a carbon-centered
radical I and/or a dianion II (Scheme 1b).[13-15] In addition, it has
been revealed that a SmI2/Sm mixed system can promote the
deoxygenative dimerization of amides to provide vic-
Scheme 1. Merging electron transfer with 1,2-metalate rearrangement for the
deoxygenative functionalization of amides.
The 1,2-metalate rearrangement of boronate complexes
possessing an α-leaving group (Scheme 1c) provides a useful
clue for the development of C-C cross-coupling reaction of amides,
1
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10.1002/anie.202104359
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RESEARCH ARTICLE
since intermediate II might be regarded as a carbenoid equivalent
reactivity of SmI2 can be enhanced by co-solvents and various
metal salts,[24] only negative results were obtained from reactions
performed in the presence of the commonly used co-solvents,
such as HMPA, H2O, MeOH or NEt3 (entries 4-7). A range of Fe,
Ni, Rh, Cu and Pd salts and/or complexes were also tested as
additives. To our delight, most of them can obviously improve the
yield of 3aa (entries 9-14) and Pd(PPh3)4 was found to be the best
additive, affording the product 3aa in 86% isolated yield. Catalytic
amount of SmI2 (20 mol%) was also investigated together with Sm
(5.0 eq.) and Pd(PPh3)4 (0.05 eq.) in the reaction. However, only
(α-aminocarbenoid) in the 1,2-metalate rearrangement.[17-20]
A
boronate complex III can be generated from the nucleophilic
addition of anion II to a Lewis acidic organoboron compound
(Scheme 1d). Due to the well-known high oxophilicity of Sm
compounds,[21] 1,2-migration of III following the removal of an [O-
Sm(III)] group and protodeboronation of the C-B bond could afford
the corresponding deoxygenative C-C bond cross coupling
product.[18-20] Herein, we report an unprecedented and highly
efficient SmI2/Sm mediated deoxygenative arylation of
unactivated amides using air- and moisture-stable arylboron
regents by the merging electron transfer with 1,2-metalate
rearrangement (Scheme 1d). This reaction can be used for the
facile reductive conversion of aromatic amides to biologically
Table 1. Optimization of the deoxygenative arylation of amide[a]
important
diarylmethylamines,
a
synthetically
useful
transformation.
Additive
(metal species)
(0.05 eq.)
Additive
Yield
Yield
(%)[b]
Entry
Entry
(co-solvents) (%)[b]
Results and Discussion
1
2[c]
3[d]
4
-
-
-
56
29
0
8
FeCl3
NiI2
30
78
Diarylmethylamines are key constituents in many bioactive
compounds and a variety of methods have been developed to
synthesize these structures.[22,23] However, deoxygenative
arylation of inert amides using bench-stable arylboron regents to
access this important moiety remains a formidable challenge.[8,9]
To implement this proposed reaction, an amide 1a was first
treated with 2.0 eq. of 2-naphthylpinacolboronate ester 2a in the
presence of SmI2 (2.2 eq.) and Sm (2.0 eq.), and the reaction was
continued in THF at 80 oC for 18 h (Table 1, entry 1). The desired
product 3aa was formed in 56% yield, confirming the feasibility of
the transformation. Without Sm powder, the reaction only resulted
in a 29% yield of 3aa (entry 2). Moreover, the reaction failed to
afford 3aa in the absence of SmI2 (entry 3), showing that SmI2 is
essential for the cross coupling. Although it is well known that the
9
10
11
12
13
14
Ni(COD)2/PPh3
Rh2(OAc)4
CuI
74
HMPA (5% V) 42
67
5
H2O (5% V)
MeOH (5% V)
NEt3 (2.0 eq.)
0
0
8
67
6
Pd2(dba)3/PPh3
Pd(PPh3)4
77
7
91 (86)[e]
[a] Reaction conditions: The mixture of 1a (0.1 mmol), 2a (0.2 mmol), SmI2 (2.2
eq., 0.1 M in THF), Sm powder (2.0 eq.) and additive was stirred at 80 oC for 18
h. [b] GC yield. [c] Without Sm. [d] Without SmI2. [e] Isolated yield on 0.2 mmol
scale. HMPA = hexamethylphosphoramide; COD = 1,5-Cyclooctadiene; THF =
Tetrahydrofuran. For more details, see the Supporting Information.
Scheme 2. The scope of aryl boron reagents.
2
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10.1002/anie.202104359
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RESEARCH ARTICLE
34% yield of 3aa was obtained (For details, see the Supporting
Information). In addition, no by-product from pinacol-type coupling
of 1a was detected during this optimization.
We next sought to explore the scope of various carboxamides
in
the
deoxygenative
arylation
reactions
with
2-
naphthylpinacolboronate ester 2a, obtaining the results in
Scheme 3. The reactions of amides derived from different
secondary cyclic amines (1b-1g) proceeded well under the
standard conditions, affording the products (3ba-3ga) with yields
The substrate scope of the arylboron reagents in the
deoxygenative cross-coupling reactions of the amide 1a was
examined. As shown in Scheme 2, with the β-naphthyl boron
reagent replaced by a phenyl boron reagent, the reaction
proceeded in good yield (3ab, 84%). Arylboron reagents bearing
electron-withdrawing substituents such as Cl- or CF3- on the
arene subunit were converted smoothly to the corresponding
products 3ac (88%) or 3ad (65%). Electron-rich arylboron
reagents with methyl-, TMS-, MeO- and Ph2N- at the para position
of the arene produced the corresponding arylation products (3ae-
3ai) in yields of 66-80%. Synthetically versatile vinyl and
cyanomethyl groups were well tolerated in these reaction
conditions, giving moderate yields of the products 3aj and 3ak.
The reaction also proceeded smoothly with meta-substituted
arylboron reagents, affording products 3al and 3am in 91% and
59% yield, respectively. Arylpinacolboronates with a disubstituted
aryl group are also effective substrates, as exemplified by the
reactions of diversely disubstituted boronates 2n, 2o and 2p,
which gave the corresponding densely substituted products 3an,
3ao and 3ap respectively, with yields of 67-77%. The reaction is
compatible with heteroaryl boronate esters, affording 3aq (91%)
and 3ar (83%) in good yields. Several boronate esters (2s-2w)
with a highly conjugated arene unit were also investigated in this
reaction, and gave the products (3as-3aw), possibly valuable in
material science, in yields of 68-89%. However, the using of n-
butyl boron reagent (nBu-BPin) in the reaction with 1a failed to
afford any of the desired product.
of
58-94%.
Remarkably,
the
sterically
congested
diarylmethylamine 3ea was isolated in 58% yield. An amine
product with a strained ring 3ga can also be obtained in good yield
(77%), and an amide bearing a benzo[d]isothiazole unit can be
tolerated in the reaction, giving the product 3ha with the intact
heterocyclic structure, in 52% yield. For amides 1ia and 1ja,
derived from bis(2-methoxyethyl)amine and dimethylamine
respectively, the reactions gave the corresponding products in 83%
and 87% yield, respectively. These results indicate that the
reaction proceeds well with aryl amides derived from either cyclic
or acyclic amines. Aryl amides (1ka-1ua) with either electron
withdrawing groups (such as Cl-, F-, CF3-, and NC-) or electron-
donating groups (MeO-, 3,4-dimethoxy-) on the phenyl ring are
good substrates for the reaction, affording the corresponding
benzhydryl amines (3ka-3ua) in moderate to good yields. The
cross-coupling product 3la was obtained with a yield of 66%,
indicating that this protocol can tolerate an aryl chloride subunit
on the amide. The synthetically versatile cyano group is well
tolerated in this reaction conditions, as demonstrated by the 50%
yield of the cyano substituted benzhydryl amine 3oa. Amides
bearing a 2-naphthoyl, 3-benzofuroyl, 2-furoyl or 2-thiophene-
carbonyl moiety undergo the transformation smoothly, giving the
corresponding products (3va-3ya) in 51-93% yields. For the
amide derived from hexanoic acid and pyrrolidine, no desired
product was detected in the reaction with 2a.
Scheme 3. The scope of aryl amides.
Alkylamine motifs are ubiquitous structural motifs found in a
wide range of small-molecule drugs and preclinical drug
candidates. Late-stage functionalization of such molecules
(Scheme 4) is a compelling demonstration of the utility of this
reaction and may be a unique way to access new pools of
functionalized alkylamine analogues. To demonstrate the
applicability of the protocol, amide 4, derived from norquetiapine
and 6, from desloratadine, were subjected to the reaction with 2n
and 2a, respectively, under optimized conditions. Both
deoxygenative arylation reactions proceeded smoothly affording
5 and 7 in 62% and 90% yield, respectively. In these reactions,
functional groups such as amidine, thioether and pyridine are
tolerated better than in typical metal- mediated reactions. The
present protocol therefore represents a practical alternative
method for the conversion of structurally complex dialkylamines
to their biologically important benzhydryl amine derivatives.
Similarly, several drug molecules containing aryl amide motifs,
including CX-546 8, Trocimine 9 and Trimetozine 10 were also
3
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10.1002/anie.202104359
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RESEARCH ARTICLE
Scheme 4. Late-stage functionalization, the synthesis of drug molecules and gram scale synthesis.
Preliminary mechanistic studies were conducted in an effort to
understand the mechanism of the reaction (Scheme 5). The
reaction of preformed iminium triflate 17 with 2a was explored in
the presence or absence of Sm/SmI2 under otherwise identical
conditions. Neither of these reactions gave the desired product
3ma, suggesting that the iminium intermediate is unlikely to be
responsible for the formation of the deoxygenative cross-
coupling product of the reaction.[23c] Addition of D2O to quench
the reaction of 1a and 2a led to 100% deuteration at the
benzhydryl position in the isolated product 3aa-D, suggesting
protonation should be involved in the formation of the final
deoxygenative product. In the absence of the boronic ester 2a,
the reaction of the amide 18 under standard conditions gave the
deoxygenative cyclopropanation product 19 in 23% yield,
suggesting the involvement of an α-aminocarbene species.[16,17]
Under the standard conditions, the reaction of amide 18 with 2a
afforded the desired product 20 in 50% yield without any
detectable cyclopropanation product 19, indicating that the
boronic ester may intercept the α-aminocarbenoid equivalent II
prior to the generation of the α-aminocarbene. The possible
Scheme 5. Preliminary mechanistic studies.
submitted to this late-stage modification and were efficiently
transformed into the corresponding benzhydryl amines (11-13)
in 51-75% yields. This methodology was successfully applied to
the synthesis from the corresponding amides of some drug
molecules containing a diarylmethylamine unit. Buclizine 14,
Meclizine 15 and Cinnarizine 16 were obtained in good yields
with this deoxygenative arylation procedure, providing a valuable
alternative route to these small drug molecules. The late-stage
functionalization of drug molecules, including secondary amines
and aryl amides, together with the synthesis of drug molecules
demonstrates the wide synthetic utility of this reaction. Finally,
the reaction of 1d and 2a was performed directly using the in situ
generation of Sm/SmI2 mixture from Sm (4.2 eq.) and CH2I2 (2.2
eq.) in THF, and 3da was successfully achieved in 89% isolated
yield (1.35 g) using this operationally simple protocol (Scheme
4d).
involvement of
a
free α-aminocarbene or metal α-
aminocarbenoid species in the reaction cannot be totally ruled
out and the details regarding the significantly enhanced reactivity
for metal additive in this reaction system are unclear at
present.[24] Considering that the reaction can proceed smoothly
without any co-metal additive (albeit giving a lower yield of the
product), it was tempting to tentatively propose that
a
conceivable role of co-metal might be to increase the reactivity
of SmI2, e.g., via facilitating the single electron transfer process
from the SmI2/Sm mixed system to organic species.[24,25]
4
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10.1002/anie.202104359
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RESEARCH ARTICLE
Hu, H. Chen, P.-Q. Huang, Angew. Chem. Int. Ed. 2018, 57, 11354-11358;
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Conclusion
In summary, we have developed a direct deoxygenative
arylation of amides using SmI2/Sm mixed system. The reactions
are operationally simple and proceed under mild conditions,
affording a series of biologically important diarylmethylamines in
moderate to good yields. The key to this success is the merging
of ET induced activation of amide with boron 1,2-metalate
rearrangement. The utility of the present methodology was
demonstrated in the late-stage diversification of some marketed
drugs, and in the synthesis of drugs from corresponding amides.
This transformation is an extremely simple way to carry out the
challenging deoxygenative transformation of amides, a long-
standing goal for organic chemists.
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This work was generously supported by the National Natural
Science Foundation of China (21821002) and Shanghai Pujiang
Program (19PJ1411500). We thank X.-L. Hou, G.-S. Liu, Z.
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Keywords: Amides
•
Electron transfer
•
1,2-Metalate
Rearrangement • Deoxygenative Arylation • SmI2
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Entry for the Table of Contents
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A mild and efficient protocol for deoxygenative C-C bond cross coupling of aromatic amides with air- and moisture-stable arylboronic
esters is achieved, affording a series of biologically important diarylmethylamines in moderate to good yields. The key to this success
is proposed to be the merging of electron transfer induced activation of amide with boron 1,2-metalate rearrangement.
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