Ru-Catalyzed Selective C(sp3)?H Monoborylation of Amides and Esters

Article abstract of DOI:10.1002/cssc.201902448

A ruthenium-catalyzed method has been developed for the C(sp³)?H monoborylation of various unactivated alkyl and aryl amides and challenging esters, with a low-cost and bench-stable boron source, providing boronates with exclusive selectivity, high efficiency, and high turnover number (up to 8900). This novel strategy may offer a versatile and environmentally friendly alternative to current methods for selective C(sp³)?H borylation that employ even more expensive metals, such as iridium and rhodium.

Full text of DOI:10.1002/cssc.201902448

DOI: 10.1002/cssc.201902448
3
Communications
Ru-Catalyzed Selective C(sp )ÀH Monoborylation of
Amides and Esters
[
a]
Wubing Yao,* Jianguo Yang, and Feiyue Hao
A ruthenium-catalyzed method has been developed for the
3
C(sp )ÀH monoborylation of various unactivated alkyl and aryl
amides and challenging esters, with a low-cost and bench-
stable boron source, providing boronates with exclusive selec-
tivity, high efficiency, and high turnover number (up to 8900).
This novel strategy may offer a versatile and environmentally
3
friendly alternative to current methods for selective C(sp )ÀH
borylation that employ even more expensive metals, such as
iridium and rhodium.
Amido- and alkoxyboronic acids are value-added units in the
structures of pharmaceuticals and biologically active mole-
[
1]
cules, such as Bortezomib and Ixazomib. The frequently used
procedures for the preparation of these important derivatives
involve the reactions of aryllithium or Grignard reagents with
[
2]
organoboron nucleophiles. However, these systems usually
suffer from poor functional group tolerance and require multi-
step syntheses. Therefore, for the synthesis of boronic acids, it
is desirable continue development of synthetic strategies with
high efficiency and atom economy.
An alternative approach for the preparation of amido- and
3
alkoxyboronic acids is to directly catalyze borylation of C(sp )À
H bonds in amides and esters, which is a desirable strategy in
3
Scheme 1. C(sp )ÀH borylation of amides and esters. a) Rhodium-catalyzed
[
3]
terms of high atom efficiency. Despite the impressive ach-
ievements in borylation processes, the selective borylation of
[5]
[6]
borylation of amides. b) Iridium-catalyzed borylation of amides. c) This
work.
3
C(sp )ÀH bonds in unactivated carboxamides still poses chal-
lenges and mainly concerns the use of catalyst systems based
[
4]
on the noble metals Rh and Ir.
and co-workers, who used an iridium catalyst to form a-amido-
[6]
In 2012, Sawamura and co-workers reported an efficient
method that involved a combination of the [{Rh(OMe)(cod)}2]
complex (cod=1,5-cyclooctadiene) with a silica-supported tri-
boronate esters at 1208C (Scheme 1b). However, the system
showed lower catalytic efficiency than the Rh catalyst.
Avoiding the use of organic solvents is clearly an important
3
[7]
arylphosphine ligand to facilitate C(sp )ÀH borylation of alkyl
characteristic of green synthesis. To our knowledge, selective
3
amides to give amidoboronate esters, albeit along with gemi-
C(sp )ÀH borylation of amide derivatives by using eco-friendly
[5]
nal bisborylation products in several cases (Scheme 1a). This
work represented a breakthrough in the borylation of N-adja-
processes has not been reported to date. Furthermore, in con-
3
trast to the borylation of amide derivates, the catalytic C(sp )À
3
cent C(sp )ÀH bonds in carboxamides, but the substrate scope
H borylation of less reactive esters also remains unreported.
The main challenge in this regard is the issue of electronic
properties, given to the different electronic delocalizations in
was restricted to alkyl amides. Moreover, excess amides and
volatile organic solvent were required for good conversions.
Very recently, similar transformations were reported by Clark
[8]
amides and esters (Scheme 2).
Ruthenium is an attractive alternative to established iridium
and rhodium catalysts, because it is approximately ten times
[
a] Dr. W. Yao, Prof. J. Yang, Dr. F. Hao
School of Pharmaceutical and Materials Engineering
Taizhou University
Jiaojiang 318000, Zhejiang (P.R. China)
E-mail: icyyw2010@yeah.net
[9]
less expensive. Although a large number of Ru complexes
have been used in versatile catalytic transformations, to our
knowledge there are no reports on Ru-catalyzed borylation of
amides and esters. On the basis of our interest in exploring the
Supporting Information (including experimental details) and the ORCID
identification number(s) for the author(s) of this article can be found
under:
[10]
selectivity,
we report herein the Ru-catalyzed exclusive
3
C(sp )ÀH borylation of inert amides (Scheme 1c). Importantly,
3
https://doi.org/10.1002/cssc.201902448.
the ruthenium catalyst is also effective for C(sp )ÀH borylation
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DME, Et O, and PhMe (Table 1, entries 7–10, 45–68%). Further
2
optimization revealed that extending the reaction time to 24 h
further improved the yield to 95% with only 0.05 mol% of
iPr
[
( POCOP)Ru] (Table 1, entry 11). However, when the reaction
temperature (Table 1, entry 12), the catalyst loading (entry 13),
or the amount of B pin (entry 14) was lowered, the yield of 2a
2
2
decreased as well.
Utilizing the optimized reaction conditions, we examined
the substrate scope with respect to various amides for the
monoborylation reaction (Scheme 3). The catalytic system
3
mediated C(sp )ÀH borylation of both linear and cyclic alkyl
Scheme 2. Electronic properties of amides (a) and esters (b).
amides with B pin (1a–g), delivering the corresponding isolat-
2
2
ed monoborylated products in good to excellent yields with
iPr
of challenging alkyl and aryl esters with bis(pinacolato)diboron
only 0.05 mol% loading of [( POCOP)Ru]. Interestingly, bisbor-
(
B pin ).
ylation products were not formed in the reactions of ureas
2
2
Our initial study of the catalytic activity of several ruthenium
(1h, 1i), even when 2.0 equivalents of B pin were used. Signif-
2
2
complexes focused on the controlled reduction of dimethyl-
icantly, our catalyst system enabled, for the first time, the
highly efficient and selective monoborylation of N,N-dimethyl-
benzamide derivatives in useful yields (1j, 1k). The bisboryla-
tion processes did not occur at the second N-methyl group in
amides or ureas, which may indicate that intramolecular coor-
dination of the carbonyl oxygen to the B atom may disturb
acetamide (1a) with B pin (Table 1). The most effective cata-
2
2
iPr
lyst was [( POCOP)Ru], which gave a good yield of the mono-
borylated product 2a under the standard conditions (Table 1,
iPr
entry 1).The highly catalytic activity of the pincer [( POCOP)Ru]
[11]
catalyst is partly attributed to its high thermal stability. In
contrast, when the reaction was performed with [Ru(acac)3],
[
Ru (CO) ], [(Cp*RuCl ) ] [{Ir(cod)Cl} ] or even [Rh(PPh ) Cl], the
3 12 2 2 2 3 3
process was inefficient (Table 1, entries 2–6). Notably, [{Ir-
cod)Cl} ] and [Rh(PPh ) Cl] were previously reported to be
(
2
3 3
3
highly efficient catalysts for the C(sp )ÀH borylation of unacti-
[
3]
iPr
vated alkanes. The [( POCOP)Ru]-catalyzed borylation of 1a
also proceeded efficiently in organic solvents, such as THF,
[
a]
Table 1. Optimization of reaction conditions.
Entry
[Ru]
[Ru]
mol%]
Solvent
Yield
2a [%]
Yield
2a’ [%]
[
iPr
1
2
3
4
5
6
7
8
9
[( POCOP)Ru]
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.05
0.05
0.01
0.05
neat
neat
neat
neat
neat
neat
THF
73
trace
trace
trace
trace
trace
68
45
57
48
95
0
0
0
0
0
0
0
0
0
0
0
0
0
0
[Ru(acac)
[Ru (CO)12
[(Cp*RuCl
[{Ir(cod)Cl}
[Rh(PPh Cl]
3
]
3
]
2
)
2
]
2
]
3
)
3
iPr
[( POCOP)Ru]
iPr
[( POCOP)Ru]
DME
iPr
[( POCOP)Ru]
Et
2
O
iPr
10
[( POCOP)Ru]
PhMe
neat
neat
neat
neat
[
b]
iPr
1
1
[( POCOP)Ru]
[
b,c]
iPr
1
1
1
2
3
4
[( POCOP)Ru]
56
39
69
[
[
b]
iPr
[( POCOP)Ru]
b,d]
iPr
[( POCOP)Ru]
[
0
[
a] Reaction conditions: 1a (1.0 mmol), B
.2 mol%), 1208C, 10 h. Yields refer to isolated products. [b] t=24 h.
c] T=808C. [d] B pin (0.75 equiv.).
2 2
pin (1.0 equiv.) and [Ru] (0.01–
Scheme 3. Substrate scope for monoborylation of amides. Reaction condi-
tions: 1 (1–10 mmol), B pin (1.0 equiv.), [( POCOP)Ru] (0.05 mol-1.0%), neat,
2 2
iPr
2
2
1208C, 12–24 h. Yields shown refer to isolated products.
&
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the binding of the Ru center to the carbonyl. Unfortunately, in-
creasing the size of the substituents at N or by using acyl-,
alkene-, or ester-substituted amides destroyed the catalytic ef-
ficiency of the borylation (1l and Scheme S1 in the Supporting
Information).
forded the desired products in good yields with exclusive se-
lectivity. Notably, the heterocyclic ester 3j was also a suitable
substrate for this reaction and a series of linear and cyclic alkyl
esters (3k–q) could also undergo selective monoborylation.
However, some limitations of the scope were observed; boryla-
tion of acyl-, nitrile-, and nitro-containing amides could not
proceed (Scheme S2). Furthermore, the attempted borylations
of alkyne-, alkene-, bromo- or iodo-substituted amides also re-
sulted in no product, even when the reaction was carried out
at high temperature.
iPr
In light of the high activity of [( POCOP)Ru] in the catalytic
borylation of amides and ureas, we next tested the catalytic
systems applicability to the less reactive ester species
(
Scheme 2). Compared with carboxamides, the selective mono-
3
borylation of O-adjacent C(sp )ÀH bonds in esters is more diffi-
3
cult, which is due to the lower activity of these C(sp )ÀH
With the highly active catalyst in hand, we sought to dem-
onstrate the synthetic utility of the borylation process
(Scheme 5). In the presence of only 100 ppm (0.01 mol%) of
catalyst, the borylation of 1h (25 mmol) could proceed at
1208C, and afforded 2h in 89% yield after 72 h. This result cor-
responded to a turnover number (TON) of 8900, which, to our
knowledge, represents the highest turnover number for any
bonds.
With the optimized reaction conditions in hand (see the
Supporting Information), we explored the scope of reactions
with respect to ester species (Scheme 4). Most reactions were
conducted at 1208C with catalyst loadings of 1.0 mol% and
the low-cost B pin as boron source. Reactions of substrates
2
2
3
[12]
bearing methyl (3b), ether (3c), amino (3d), fluoro (3e), and
trifluoromethyl (3 f) functional groups proceeded in a chemo-
and site-selective manner. In addition, substituents at the ortho
position on the aromatic ring (3g–i) were all tolerated and af-
metal-catalyzed C(sp )ÀH borylation of 1h with B pin .
2
2
Scheme 5. Large-scale reaction.
Following the borylation, boronic ester 4d could be smooth-
ly converted into the corresponding organotrifluoroborate by
treatment with KHF (Scheme 6). Moreover, a mild protocol for
2
the cross coupling of 4d with bromobenze was also devel-
oped and gave the isolated product 6 in good yield.
Scheme 6. Functionalization of boronic ester 4d.
3
The time courses of the C(sp )ÀH monoborylations of 1a
iPr
and 3a catalyzed by [( POCOP)Ru] are shown in Figure 1.
After 24 and 12 h, the yields of 2a and 4a were 95% and
72%, respectively. However, a substantial decrease in the reac-
tion time was detrimental in both cases, and the yields of the
two products were significantly diminished. These results clear-
ly suggest that the reaction time has a significant impact on
these borylation transformations.
Scheme 4. Substrate scope for monoborylation of esters. Reaction condi-
tions: 3 (1.0 mmol), B pin (1.0 equiv.), [( POCOP)Ru] (1.0 mol%), 1208C,
2 2
iPr
12 h. Yields shown refer to isolated products. [a] [Ru] (2.0 mol%). [b] [Ru]
(4.0 mol%).
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II
metathesis through the Ru transition state were reported pre-
[15]
viously. Further in-depth tests and computational studies are
currently underway to distinguish the two pathways.
[5]
11
Based on the previous report and the signal of the B NMR
[16]
spectrum, the intramolecular coordination of the carbonyl
oxygen to the B atom (G) may disturb the binding of the Ru
center to the carbonyl (H or I), which will lead to the failure in
bisborylation processes at the second N-ethyl group of amides
or ureas. This suggests that the exclusive selectivity in the
3
C(sp )ÀH monoborylation of amides is likely.
In conclusion, we have developed a new approach for the
3
selective monoborylation of inert C(sp )ÀH bonds in alkyl and
even aryl carboxamides, using a thermally robust and active
pincer Ru complex in the absence of additives and solvents.
Featuring environmentally benign utility, high efficiency, and
exclusive selectivity, this catalytic strategy has also been ap-
plied to selective ester monoborylations to form the corre-
sponding aryl and alkyl boronates.
3
Figure 1. Time courses of the C(sp )ÀH monoborylations of 1a and 3a. Reac-
iPr
2 2
tion conditions: 1a (10.0 mmol), B pin (1.0 equiv.), [( POCOP)Ru]
0.05 mol%), neat, at 1208C, 1–24 h. 3a (1.0 mmol), B
( POCOP)Ru] (1.0 mol%), neat, at 1208C, 1–24 h. Yields shown are of isolat-
(
[
2
pin
2
(1.0 equiv.),
iPr
ed products.
[
13]
Based on the previous works and free-radical control ex- Acknowledgements
periments (see the Supporting Information), we propose the
mechanism of the borylaton process depicted in Scheme 7. Ac-
We gratefully acknowledge financial support from the China
II
cording to reports on Ru systems, the Ru complexes are not
Postdoctoral Science Foundation (2017M621972), Zhejiang Post-
Doctoral Preferential Fund Project (zj20180084), Natural Science
Foundation of Zhejiang Province (LQ19B020001), Science and
Technology Plan Project of Taizhou (1803gy04), and Project of
Taizhou University Fund for Excellent Young Scholars. We also
thank Lanzhou University for support.
[
14]
6
prone to two-electron oxidation. The d [Ru]H center is not
8
isoelectronic with the d [Ir] center. Thus, these results indicate
that oxidative addition of BÀB/CÀH bonds to A/D via discrete
IV
Ru intermediates C/F is unlikely. Therefore, we propose that
BÀB/CÀH bond activation proceeds by s-bond metathesis
II
through two four-coordinate, 14-electron Ru species B and E.
Following dissociation from the resulting E regenerate A and
the desired borate. Similar CÀN bonds activation by s-bond
Conflict of interest
The authors declare no conflict of interest.
Keywords: amides · borylation · CÀH activation · ester ·
ruthenium
[
[
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Scheme 7. Proposed mechanism.
&
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Version of record online: && &&, 0000
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COMMUNICATIONS
W. Yao,* J. Yang, F. Hao
&& – &&
3
Ru-Catalyzed Selective C(sp )ÀH
Monoborylation of Amides and Esters
Plan B: A ruthenium-catalyzed method
esters with a low-cost and bench-stable
boron source, providing boronates with
exclusive selectivity, high efficiency, and
turnover numbers of up to 8900.
3
has been developed for the C(sp )ÀH
monoborylation of various unactivated
alkyl and aryl amides and challenging
&
ChemSusChem 2019, 12, 1 – 6
www.chemsuschem.org
6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!