Selective formation of secondary amides via the copper-catalyzed cross-coupling of alkylboronic acids with primary amides

Article abstract of DOI:10.1021/ol401004r

For the first time, a general catalytic procedure for the cross-coupling of primary amides and alkylboronic acids is demonstrated. The key to the success of this reaction was the identification of a mild base (NaOSiMe₃) and oxidant (di-tert-butyl peroxide) to promote the copper-catalyzed reaction in high yield. This transformation provides a facile, high-yielding method for the monoalkylation of amides.

Full text of DOI:10.1021/ol401004r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Selective Formation of Secondary Amides
via the Copper-Catalyzed Cross-Coupling
of Alkylboronic Acids with Primary Amides
Steven A. Rossi, Kirk W. Shimkin, Qun Xu,† Luis M. Mori-Quiroz, and
Donald A. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark,
Delaware 19716, United States
dawatson@udel.edu
Received April 10, 2013
ABSTRACT
For the first time, a general catalytic procedure for the cross-coupling of primary amides and alkylboronic acids is demonstrated. The key to the
success of this reaction was the identification of a mild base (NaOSiMe3) and oxidant (di-tert-butyl peroxide) to promote the copper-catalyzed
reaction in high yield. This transformation provides a facile, high-yielding method for the monoalkylation of amides.
Over the past two decades, the preparation of nitrogen-
containing molecules has been revolutionized by the
advent of transition metal-catalyzed cross-coupling proce-
behind. The difficulty in developing alkyl CꢀN bond
forming reactions stems from the lack of reactivity of alkyl
halides and alkylboronic acids with transition metal cata-
lysts, as well as the propensity of intermediate alkylmetal
complexes to undergo competitive β-hydride elimination
(eq 1, Figure 1).6
Traditionally, the conversion of alkyl boronatestoalkyl-
amines has been a challenging process requiring highly
electrophilic boronate reagents and electrophilic nitrogen
sources.7,8 An alkyl variant of the LamꢀChan protocol
2
dures for constructing Csp ꢀN bonds. Both aryl halide/
amine cross-couplings (palladium- and nickel-catalyzed
BuchwaldꢀHartwig1 and copper-catalyzed Ullmann-type
couplings2), as well as arylboronic acid/amine cross-cou-
plings (copper-catalyzed LamꢀChan reactions)3ꢀ5 are
used to an extraordinary extent in preparing biologically
active compounds and pharmaceutical agents. In contrast
to these methods, the development of transition-metal-
3
catalyzed Csp ꢀN bond construction has lagged significantly
(6) A number of CꢀC cross-coupling reactions involving alkyl
reagents have been developed. For a recent review, see: Jana, R.; Pathak,
T. P.; Sigman, M. S. Chem. Rev. 2013, 111, 1417–1492.
(7) (a) Brown, H. C.; Heydkamp, W. R.; Breuer, E.; Murphy, W. S.
J. Am. Chem. Soc. 1964, 86, 3565–3566. (b) Kabalka, G. W.; Sastry,
K. A. R.; McCollum, G. W.; Yoshioka, H. J. Org. Chem. 1981, 46, 4296–
4298. (c) Brown, H. C.; Kim, K. W.; Srebnik, M.; Bakthan, S. Tetra-
hedron 1987, 43, 4071–4078. (d) Matteson, D. S.; Kim, G. Y. Org. Lett.
2002, 4, 2153–2155.
† Separation Sciences R&D, United States Pharmacopeia, 12601 Twin-
brook Parkway, Rockville, MD 20852-1790.
(1) (a) Surry, D.; Buchwald, S. Chem. Sci. 2011, 2, 27–50. (b)
Hartwig, J. Acc. Chem. Res. 2008, 41, 1534–1544. (c) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–6361.
(2) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954–
6971.
(3) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941–2944.
(8) For recent advances in this area, see: (a) Rucker, R. P.; Whittaker,
A. M.; Dang, H.; Lalic, G. J. Am. Chem. Soc. 2012, 134, 6571–6574. (b)
Mlynarski, S. N.; Karns, A. S.; Morken, J. P. J. Am. Chem. Soc. 2012, 134,
16449–16451.
(4) For recent reviews, see: (a) Sanjeeva Rao, K.; Wu, T.-S. Tetra-
hedron 2012, 68, 7735–7754. (b) Qiao, J.; Lam, P. Synthesis 2011,
829–856. (c) Chan, D. M. T., Lam, P. Y. S. In Boronic Acids; Hall,
D. G., Ed.; Wiley-VCH: Weinheim, 2005; pp 205ꢀ240. (d) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
(5) For a related reaction involving ArꢀO bond formation, see:
Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937–2940.
ꢀ
(9) (a) Benard, S.; Neuville, L.; Zhu, J. Chem. Commun. 2010, 46,
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3393–3395. (b) Benard, S. b.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73,
6441–6444. (c) Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki,
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M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653–1655. (d) Gonzalez,
I.; Mosquera, J.; Guerrero, C.; Rodrıguez, R.; Cruces, J. Org. Lett. 2009,
11, 1677–1680. (e) Larrosa, M.; Guerrero, C.; Rodrıguez, R.; Cruces, J.
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Cruces, J. Tetrahedron Lett. 2012, 53, 769–772.
´
´
´
guez, R.;
r
10.1021/ol401004r
XXXX American Chemical Society

molecules and synthetic intermediates.12 Further, although
secondary amides can readily be prepared by acylation of a
primary amine, the complementary monoalkylation of a
primary amide with an alkyl halide remains a difficult
reaction to control and often provides modest selectivity
with respect to overalkylation (eq 2).13
Herein, for the first time, wereporta generalprotocol for
the copper-catalyzed monoalkylation of primary amides
using alkylboronic acids (eq 3). The key to this reaction
is the discovery that the combination of a0 mild base
(sodium trimethylsilanolate, NaOSiMe3, pKa = 12.7)14
and di-tert-butyl peroxide (DTBP) as the oxidant is
uniquely effective in promoting the catalytic cross-coupling
reaction of primary amides and primary boronic acids.11
This reaction is completely tolerant of β-hydrogen atoms
and, in most cases, requires only a small excess of
alkylboronic acid. This protocol offers a simple method
for preparing secondary amides, while providing a rare
example of catalytic alkyl CꢀN cross-coupling.8a,9c,15
We began by examining the reaction of benzamide and
isobutylboronic acid (Table 1). Under typical LamꢀChan
reaction conditions, employing Cu(OAc)2 as the catalyst
and air (or dry oxygen) as the oxidant with a mild base,
only traces of the desired secondary amide 1 were observed
(entries 1 and 2). The use of ligand additives, such as 2,20-
bipyridine, did not positively affect the reaction (not
shown). In contrast, the use of stoichiometric Cu(OAc)2
(4 equiv) under air did lead to a small, but measurable,
increaseinthe yield of the product (upto5%asdetermined
by NMR, not shown). We suspected that this result might
indicate ineffective catalyst turnover. Accordingly, we
examinedthe role of the oxidant in the reactions conducted
under a nitrogen atmosphere. Whereas a range of common
oxidants such as (diacetoxyiodo)benzene, benzoquinone,
hydrogen peroxide, meta-chloroperbenzoic acid, and tert-
butyl hydrogen peroxide (entries 3ꢀ7) were completely
ineffective, the use of di-tert-butyl peroxide (DTBP, entry 8)
provided discernibly more product under catalytic con-
ditions. A stronger base (NaOtBu, entry 9) and optimiza-
tion of the solvent to tBuOH (entry 10) provided further
increases in the yield.16 Interestingly, with the use of
tBuOH as the solvent, the use of NaOSiMe3 provided a
significant increase in yield (87%, entry 11). With this
weaker base, the equilibrium concentration of deproto-
nated amide is expected to be lower, which we suspect
might prevent competitive ligation of the copper catalyst.
Finally, we elected to examine the use of other copper salts
as precatalysts; CuBr proved to be slightly more effective,
leading to a 92% assay yield under optimized conditions.17
Figure 1. Strategies for monoalkylation of primary amides.
has been recognized as a potential solution to this long-
standing problem.4b To date, however, only a handful of
alkyl LamꢀChan reactions involving alkyl boronates have
been reported,9 and most are limited to the use of methyl
or cyclopropylboronates.9aꢀd Notably, both of these
substrate classes lack hydrogen atoms suitable for
β-elimination.10 Additionally, most of these protocols
require stoichiometric or superstoichiometric copper
promoters.9a,b Only a single report of a catalytic reaction
has been described, and the yields are often inferior com-
pared to reactions employing stoichiometric copper.9c The
Cruces group has recently reported a series of more
general protocols for alkylation of anilines using a range
of alkylboronic acids. These procedures require a large
excess of both copper and boronic acid (up to 4 equiv
each).9e,f The large excess of alkylboronic acid required in
these reactions may be consistent with partial degradation
of the starting material via β-elimination pathways.11
Our interest in developing catalytic alkyl carbonꢀnitro-
gen bond-forming reactions has led us to explore the cross-
coupling of primary amides with alkylboronic acids to
provide secondary amides selectively. Secondary amides
are important functional groups in organic chemistry, as
they comprise the backbones of all natural peptides
and proteins and are widely found in therapeutic small
(10) β-Hydride elimination from metal cyclopropanes has been
shown to be a highly unfavorable process. See: Nuzzo, R. G.; McCarthy,
T. J.; Whitesides, G. M. J. Am. Chem. Soc. 1981, 103, 3404–3410.
(11) During the preparation of this manuscipt, a report describing the
catalytic alkylation of anilines using similar reaction conditions to ours
was published in this journal, see: Sueki, S.; Kuninobu, Y. Org. Lett.
2013, 15, 1544–1547.
(12) (a) Zabicky, J. Amides; Wiley: Weinheim, 1970. (b) Stanley, M.;
Rotrosen, J. The Benzamides: Pharmacology, Neurobiology, and Clinical
Aspects; Raven Press: New York, 1982. (c) Wieland, T.; Bodanszky, M. The
World of Peptides: a Brief History of Peptide Chemistry; Springer-Verlag:
Berlin, 1991. (d) Bioorganic Chemistry: Peptides and Proteins; Hecht,
S. M., Ed.; Oxford University Press: New York, 1998. (e) Greenberg, A.;
Breneman, C. M.; Liebman, J. F. The Amide Linkage: Structural Signifi-
cance in Chemistry, Biochemistry, and Materials Science; Wiley: New
York, 2000. (f) Sinning, C.; Watzer, B.; De Petrocellis, L.; Di Marzo, V.;
Imming, P. ChemMedChem 2008, 3, 1956–1964. (g) McGrath, N. A.;
Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348–1349.
(h) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471–479.
(13) Watanabe, Y.; Ohta, T.; Tsuji, Y. Bull. Chem. Soc. Jpn. 1983, 56,
2647–2651.
(14) Blaschette, A.; Bressel, B. Inorg. Nucl. Chem. Lett. 1968, 4, 175–
178.
(15) (a) Berman, A.; Johnson, J. J. Am. Chem. Soc. 2004, 126, 5680–
5681. (b) Campbell, M.; Johnson, J. Org. Lett. 2007, 9, 1521–1524. (c)
Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed.
2012, 51, 11827–11831.
(16) Other solvents were also examined in this reaction; see Support-
ing Information for details.
(17) Further attempts to optimize the reaction (varied temperature,
time, concentration, and equivalents of reagents) lead to lower yields of 1.
B
Org. Lett., Vol. XX, No. XX, XXXX

The reaction is completely selective for monoalkylation; in
no case was any dialkylated product detected.
Scheme 1. Substrate Scope for Amide Alkylation
Table 1. Identification of Reaction Conditions
entry
catalyst
base
oxidant
air
solvent
yielda
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)
CuCl
Na2CO3
DCE
trace
trace
0%
2
Na2CO3
O2
DCE
3
Na2CO3
PhI(OAc)2
BQ
DCE
4
Na2CO3
DCE
0%
5
Na2CO3
H2O2
DCE
0%
6
Na2CO3
m-CPBA
TBHP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCE
0%
7
Na2CO3
DCE
0%
8
Na2CO3
DCE
5%
9
NatOBu
NatOBu
NaOSiMe3
NaOSiMe3
NaOSiMe3
NaOSiMe3
NaOSiMe3
DCE
31%
36%
87%
71%
70%
88%
92%
10
11
12
13
14
15
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
CuI
CuBr
a Yield determined using NMR. DCE = 1,2-dichloroethane; BQ =
benzoquinone; m-CPBA = meta-chloroperbenzoic acid; TBHP = tert-
butyl hydrogen peroxide; DTBP = di-tert-butyl peroxide.
Under preparative conditions, amide 1 was isolated in
84% yield (1 mmol scale, Scheme 1).18 Significantly, the
reaction conditions developed for this substrate proved
highly general with respect to both amide and alkylboronic
acid. As shown inScheme 1, a variety of substituents on the
amide were well tolerated, including alkyl groups (2),
aromatic ethers (3), and tertiary amides (7 and 9), as well
as alkyl nitriles (16), alcohols (17), and silyl ethers (18). As
expected from the high selectivity for monoalkylation,
secondary amides were inert under the alkylation condi-
tions (8). Electron-rich (3), as well as mildly electron-
deficient (4 and 9), amides were highly effective substrates.
However, benzamides bearing electron-withdrawing
groups stronger than p-dialkylamides failed to react. While
aryl fluorides (4) and chlorides (5 and 6) were well toler-
ated, we found that reactions involving aromatic bromides
were less effective, providing only low yields of the desired
product. Unfortunately, esters (both aromatic and alkyl)
proved incompatible with the reaction conditions due to
competitive hydrolysis.19 In contrast, aliphatic amides
were excellent substrates for the reaction. This includes
linear amides such as hexanoamide (10), as well as those
containing branching R to the carbonyl, such as in 11 and
benzylic amide 12. Amides containing carbocyclic rings
were also were well tolerated, including those containing
cyclopropyl, cyclobutyl, and cyclohexyl units (13ꢀ15).
Significantly, heterocyclic amides were also suitable sub-
strates in the reaction. This includes both heteroaromatic
compounds, such as those leading to 19 and 20, as well as
(18) All reported isolated yields are the average of at least two runs.
(19) The incompatibility of ester under the reaction conditions
appears to be due to the combination of the mildly basic conditions
with the Lewis acidic catalyst. Control experiments showed that esters
decomposed only when base and catalyst were present.
Org. Lett., Vol. XX, No. XX, XXXX
C

nonaromatic heterocycles (21 and 22). The latter two
examples demonstrate that both protic and protected
amines can also be tolerated in the reaction. Finally, the
reaction also proved to be highly scalable; amide 5 was
prepared on a 3-g scale (ca. 20 mmol) in 81% yield, which
was nearly identical to that obtained on a 1-mmol scale.
The copper-catalyzed alkylation reaction is not limited
to the use of isobutylboronic acid. As demonstrated by the
preparation of amides 23ꢀ31, a wide range of boronic
acids can be utilized as alkylating reagents. This includes
those bearing functional groups, such as arenes, ethers,
and alkenes (24ꢀ27), as well as more sterically demanding
primary alkylboronic acids, such as neopentylboronic acid
(28). Takentogetherwiththe examples above, the coupling
reaction displays wide functional group tolerance.
Finally, we have examined the scope with respect to
more substituted boronic acids. Whereas tertiary boronic
acids (such as tert-butylboronic acid, not shown) were not
successful substrates for the cross-coupling reaction, some
secondary boronic acids did undergo coupling. For exam-
ple, cyclopropyl- and cyclohexylboronic acids both under-
went coupling, giving rise to 29 and 30 in modest yield.
However, other similar secondary boronic acids were less
successful. For example, the use of isopropylboronic acid
required excess reagent and catalyst to afford a modest
yield. We believethatthisdifferencein yield correspondsto
the low stability of isopropylboronic acid relative to the
others.
In conclusion, we have developed a mild, inexpensive,
functional group tolerant method for the synthesis
of secondary amides via the cross-coupling of primary
amides with alkylboronic acids. We demonstrated that the
LamꢀChan-type reaction can be carried out efficiently using
a catalytic amount of copper, and for the first time,11 DTBP
was discovered as an effective oxidant for the process. More-
over, the application of alkylboronic acids in the cross-
coupling significantly broadens the scope of LamꢀChan-type
reactions in organic synthesis. Further efforts will be directed
toward investigation of the detailed reaction mechanism20 and
expansion of the generality of the transformation.
Acknowledgment. The University of Delaware (UD)
and the ACS Petroleum Research Fund (51706-DNI1)
are gratefully acknowledged for funding and other research
support. NMR and other data were acquired at UD on
instruments obtained with the assistance of NSF and NIH
funding (NSF MIR CHE0421224 and CHE1229234, NSF
CRIF MU CHE0840401, NIH P20 GM103541, NIH S10
RR02692).
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For mechanistic studies on aryl Lam-Chan reactions, see: King,
A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044–
5045.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX