Copper-Catalyzed Amidation of Primary and Secondary Alkyl Boronic Esters

Article abstract of DOI:10.1002/chem.201603677

The oxidative copper-catalyzed cross-coupling of functionalized alkyl boronic esters with primary amides is reported. Through the identification of appropriate diketimine ligands, conditions for efficient coupling of both primary and secondary alkyl boronic esters with diverse primary amides, including acetamide, have been developed.

Full text of DOI:10.1002/chem.201603677

DOI: 10.1002/chem.201603677
Communication
&
Homogeneous Catalysis
Copper-Catalyzed Amidation of Primary and Secondary Alkyl
Boronic Esters
Luis M. Mori-Quiroz+, Kirk W. Shimkin+, Sina Rezazadeh+, Ryan A. Kozlowski, and
Donald A. Watson*[a]
Abstract: The oxidative copper-catalyzed cross-coupling
of functionalized alkyl boronic esters with primary amides
is reported. Through the identification of appropriate dike-
timine ligands, conditions for efficient coupling of both
primary and secondary alkyl boronic esters with diverse
primary amides, including acetamide, have been devel-
oped.
The prevalence of nitrogen-containing molecules in the phar-
Figure 1. Second-generation approach to alkyl boronic ester amidation.
maceutical, agrochemical, and materials industries continues to
fuel the development of methods for the construction of CÀN
bonds. Over the past two decades, transition-metal catalysis,
including Buchwald–Hartwig,[1] Lam–Chan,[2] and Ullman-type[3]
couplings, has revolutionized the way that C(sp2)ÀN bonds are
prepared. However, due to the long-established propensity of
alkylmetal intermediates to undergo b-hydride elimination,
challenges with transmetalation of alkyl nucleophiles, and the
relative reluctance of alkyl electrophiles to participate in oxida-
tive additions,[4] the analogous reactions at alkyl centers have
remained largely undeveloped.
drocarbon or simple ether-containing, primary boronic acids
could be coupled. With regard to secondary systems, only cy-
clopentyl, cyclohexyl, and isopropyl boronic acids could be
coupled, with the latter requiring forcing conditions. In all
three cases, the yields were very modest.
In contrast to alkyl boronic acids, alkyl boronic esters are
both highly accessible and stable, and can be prepared with
a vast range of functional groups.[13] Unfortunately, our prior
catalyst was incapable of coupling the latter reagents in syn-
thetically useful yields.[6,14] Recognizing the practicality and
synthetic accessibility of alkyl boronic esters, we endeavored
to identify catalysts capable of coupling these reagents to pri-
mary amides.
Motivated by recent calls for new technologies for amide
synthesis,[5] we recently reported the copper-catalyzed oxida-
tive N-alkylation of primary amides by using alkyl boronic acids
(Figure 1).[6] This transformation, an alkyl variant of the Lam–
Chan reaction, is a rare example of a transition-metal-catalyzed
CÀN cross-coupling at alkyl centers capable of b-hydride elimi-
nation.[7–10] Importantly, not only does this method access bio-
logically relevant secondary amides from non-canonical start-
ing materials, it completely avoids over-alkylation to the corre-
sponding tertiary amides, which are common by-products
using classical methods employing alkyl electrophiles.[11] This
process also provides a new solution to the difficult conversion
of alkyl boronic acids to alkyl amine derivatives.[12] Despite
these advances, the instability and difficulty of preparation of
the alkyl boronic acids severely limited the functional-group
tolerance of the boron-containing coupling partner; only hy-
We now report two new copper catalysts based on diketi-
mine (NacNac) ligands that effectively couple a wide range of
highly functionalized primary and secondary alkyl boronic
esters to primary amides. These new catalysts allow direct
preparation of secondary amides without over-alkylation or
significant b-hydride elimination. These new catalysts signifi-
cantly advance the ability to prepare highly functionalized
amides through this alkyl Lam–Chan strategy.
We began our study investigating the coupling of pinacol
boronic ester 2, which contains both an aryl ether and a basic
heterocycle, with 4-fluorobenzamide (1, Table 1). Consistent
with prior results, our previously optimized conditions
(10 mol% CuBr, NaOSiMe3, di-tert-butylperoxide (DTBP)) gave
poor yield of the desired product 3 (entry 1). In contrast to the
earlier reactions with alkyl boronic acids, decreasing the base
loading resulted in slightly increased yield of 3 (entry 2). Other
copper salts (e.g., CuI, CuOAc, and Cu(OAc)2) were found to
catalyze the reaction; however, the yields were largely compa-
rable to the use of CuBr.[15] The one exception was Cu(acac)2,
which gave a slightly higher yield (entry 3). An observed side-
[a] Dr. L. M. Mori-Quiroz,+ K. W. Shimkin,+ Dr. S. Rezazadeh,+ R. A. Kozlowski,
Prof. Dr. D. A. Watson
Department of Chemistry and Biochemistry
University of Delaware, Newark, DE, 19716 (USA)
E-mail: dawatson@udel.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603677.
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the use of 1,3-diketimine (NacNac) ligands in combination with
Cu(OAc)2. Several electron-rich ligands from this class resulted
in highly efficient catalysis. For example, the commonly em-
ployed 2,6-dimethylaniline-derived NacNac L1 provides the de-
sired product in 90% yield (Table 1, entry 5). NacNac ligands
with ortho-methoxy groups (L2 and L3, entries 6 and 7) proved
to be even more efficient. Notably, other ligands (such as 2,6-
bipyridine, 1,10-phenanthroline, and 2,2’,2“-tripyridine) that are
commonly employed in aromatic Lam–Chan-type reactions
gave much lower yields.[2e,15] Despite the similar performance
of the NacNac ligands in Table 1, further investigation over
a range of amides and primary boronic esters revealed that L3
was superior in nearly all cases.[15,16]
Table 1. Identification of reaction conditions with primary boronic esters.
The scope of primary boronic esters and primary amides is
outlined in Scheme 1. Numerous heteroaromatic compounds
are compatible, including basic and non-basic indoles (5, 6),
pyridines (3, 8, 23, 26), aminopyrimidines (7), benzimidazoles
(9), benzothiazoles (10), and thiophenes (4, 6, 11). Other toler-
ated groups include protic amine derivatives (17), aryl fluorides
(e.g., 3–5), aryl and heteroaryl chlorides (6, 8, 9, 15), alkenes
(25), aryl ethers (19–22), and carbamates (5, 17, 18). Nitriles
can be used (8, 26), but aliphatic nitriles lead to some attenua-
tion of the yield (16). Interestingly, for primary nitrile 16, ligand
L2 gave higher yield than L3. This is counter to all other exam-
ples we examined and may be related to the donor ability of
the nitrile.
[Cu]
NaOSiMe3 [equiv]
Ligand
Additive
Yield 3[a] [%]
1
2
3
4
5
6
7
CuBr
CuBr
2.2
1.1
1.1
1.1
1.1
1.1
1.1
–
–
–
–
L1
L2
L3
–
–
–
33
48
61
75
90
95
94
Cu(acac)2
Cu(acac)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
4 ꢁ MS
4 ꢁ MS
4 ꢁ MS
4 ꢁ MS
[a] Yields were determined by using 1H NMR analysis against an internal
standard.
product from protodeborylation of 2 was suppressed by the
addition of 4 ꢁ molecular sieves (4 ꢁ MS, entry 4).
Notably, in the previously reported reaction of alkyl boronic
acids, esters were not compatible. However, esters are well tol-
erated in the current transformation (4, 12, 15, 20). Free alco-
hols also can be used, albeit with somewhat suppressed yield
To further optimize the reaction, exogenous ligands were ex-
amined. Based on the superiority of Cu(acac)2, we investigated
Scheme 1. Scope of the coupling reaction with primary pinacol boronic esters. [a] t-BuOLi as base (1.1 equiv).
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(19). However, a range of protected alcohols, such as silyl
ethers (21–24), pivalates (20), and THP groups (18) can also be
used. Substrates with acetal-protected ketones can be coupled
without incident (12). Significantly, thioethers were tolerated
(14) without evidence (LC/MS) of oxidation of the sulfur atom.
Aromatic (3-5, etc.) heteroaromatic (6, 23), alkyl (11, 13, and
26), and heteroalkyl (18) amides all participate. Electronic (14,
19–21, 23) and steric modulation (26) of the amide has little
effect. A boronic ester with a b-stereogenic center in >99% ee
coupled efficiently without erosion of ee (24), suggesting that
b-hydride elimination and reinsertion does not occur. In some
cases (noted in Scheme 1), LiOtBu proved to be more effective
than NaOSiMe3. In all cases, only minimal b-hydride elimination
of the alkyl coupling partner occurs; at most 8% correspond-
ing alkene was observed.[17] Given the complexity and heteroa-
tom content of the products outlined in Scheme 1, this reac-
tion has remarkably broad scope for a transition-metal-cata-
lyzed transformation.
Table 2. Optimization of the coupling with secondary boronic esters.
Ligand
Yield[a] [%]
33/34
74:26
80:20
74:26
97:3
1
2
3
4
5
6
L3
–
L1
L2
L4
L5
8
10
3
82
36
36
95:5
>95:5
[a] Yield and regiospecificity were determined by 1H NMR analysis of
crude reaction mixtures.
Previously, neither acetamide nor trifluoroacetamide were
suitable coupling partners.[6] However, the increased catalytic
efficiency of the present conditions now allows alkylation of
these low-molecular-weight amides with a range of functional-
ized primary boronic esters (Scheme 2). The ability to cross-
linear product 34.[20] Reactions excluding NacNac ligand
(entry 2), or using dimethylaniline-derived L1 (entry 3) provid-
ed very similar results. But in stark contrast, we found that o-
anisidine-derived ligand L2 gave excellent yield of the product
33, with minimal amounts of rearranged product (entry 4).
Intrigued by these exciting, yet unexpected results, we in-
vestigated two other NacNac ligands. First, we examined
ligand L4 derived from unsubstituted aniline. Although this
ligand did not provide as high yield as L2, it was highly regio-
specific (Table 2, entry 5). This suggests that the rearrangement
observed with ligand L3 and L4 is steric in nature. Next, we ex-
amined the use of L5, which bears p-methoxy substitution
(entry 6). This ligand also provided high regiospecificity, but
low yield of 33. This suggests that the importance of the o-me-
thoxy groups in L2 on the yield of the reaction is not due to
electronic factors but rather that the ether substituents might
participate in metal chelation—possibly modulating or stabiliz-
ing the catalytic center. Further investigations into the coordi-
nation environment of this catalyst are underway.
Scheme 2. Scope of the coupling with acetamide and trifluoroacetamide.
[a] t-BuOLi as base (1.1 equiv).
couple these small amides is of particular importance because
of the relative ease of hydrolysis of the products. In this way,
our method provides mild conditions for the formal conversion
of boronic esters to primary amines that are competitive with
current technologies for this challenging transformation.[12a,e,18]
In the previous work, using boronic acids, only the simplest
secondary substrates (cyclopropyl, cyclohexyl, isopropyl) could
be coupled, and only in very modest yield. Significantly, no
functionality could be tolerated on the secondary alkyl re-
agents. We attributed this to instability of secondary boronic
acids.[13] In sharp contrast, functionalized secondary pinacol
boronic esters are both easily accessible and stable.[19] Thus,
we sought conditions that would allow coupling of these re-
agents as a means of accessing branched amine derivatives.
Using the coupling of 4-fluorobenzamide and 2-octylboronic
acid pinacol ester as a model, we found that the optimized
conditions for the coupling of primary boronic esters using L3
provided very little cross-coupled product (Table 2, entry 1).
Alarmingly, the small amount of product was observed as a 3:1
mixture of the desired product 33 along with the rearranged
With optimized conditions in hand for the coupling of
amides with secondary boronic esters, the scope was exam-
ined (Scheme 3). Gratifyingly, this process provided convenient
and selective access to highly functionalized a-branched
amides. Secondary boronic esters bearing ethers (37), carba-
mates (38), heterocyclic amides (39), imides (40), alkenes (44),
and acetals (45) underwent smooth coupling with various alkyl
and aryl amides. Like with the primary substrates, this reaction
showed the remarkable ability to tolerate heterocyclic scaf-
folds. In no case was isomerization to the linear amide ob-
served.
The present reaction appears to be stereoconvergent
(Scheme 4). Boronic esters cis-46 and trans-46 were prepared
and independently subjected to the cross-coupling. Identical
diastereomeric ratios were observed (determined by 19F NMR
spectroscopy of crude mixture). This lack of stereospecificity
suggests a mechanism that does not involve simply invertive
or retentive transmetallation.[21] Studies are underway to fur-
ther investigate the mechanism of this transformation.
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CHE1229234,
and
CHE0840401;
NIH
P20GM104316,
P30GM110758, S10RR026962 and S10OD016267).
Keywords: alkyl boronic esters · amides · copper · cross-
coupling · NacNac ligand
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Scheme 4. Stereoconvergence in the cross-coupling reaction.
In conclusion, we have developed a mild, selective synthesis
of secondary amides through the cross-coupling of alkyl bor-
onic esters and primary amides using non-canonical starting
materials. This cross-coupling is a rare example of a transition-
metal-catalyzed CÀN bond construction at an alkyl center, and
both primary and secondary alkyl boronic esters participate.
Key to the high heterocycle and functional group tolerance
was identification of diketimine ligands to support the copper
center. Investigations to understand the role of ligand struc-
ture, as well as the expansion to other heteroatomic coupling
partners, is currently underway.
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[15] See the Supporting Infomation.
[16] It should be noted that the commercially available catalyst Cu(acac)2
was effective for some simple, minimally functionalized substrates.
[17] In some cases, a small amount (ca. 5%) of the corresponding N-methyl
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Acknowledgements
We thank Mr. Steven Rossi for initial investigation in this area.
The University of Delaware (UD) and the NIH (P20GM104316)
are gratefully acknowledged for support. NMR, MS, and other
data were acquired at UD on instruments obtained with the
assistance of NSF and NIH funding (NSF CHE0421224,
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[20] We speculate that 34 was formed through a pathway involving b-hy-
dride elimination and subsequent reinsertion of the CuÀH into the
alkene.
[21] For a possibly relevent discussion on mechanism, see: E. S. Jang, C. L.
McMullin, M. Kꢅß, K. Meyer, T. R. Cundari, T. H. Warren, J. Am. Chem. Soc.
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Received: August 2, 2016
Published online on && &&, 0000
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COMMUNICATION
&
Homogeneous Catalysis
L. M. Mori-Quiroz, K. W. Shimkin,
S. Rezazadeh, R. A. Kozlowski,
D. A. Watson*
&& – &&
Copper-Catalyzed Amidation of
Primary and Secondary Alkyl Boronic
Esters
NacNac time! The oxidative copper-cat-
alyzed cross-coupling of functionalized
alkyl boronic esters with primary amides
is reported. Through the identification
of appropriate diketimine ligands, con-
ditions for efficient coupling of both pri-
mary and secondary alkyl boronic esters
with diverse primary amides, including
acetamide, have been developed (see
scheme).
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