N-amidation by copper-mediated cross-coupling of organostannanes or boronic acids with O-acetyl hydroxamic acids

Article abstract of DOI:10.1021/ol8009682

(Chemical Equation Presented) A general nonoxidative N-amidation of organostannanes and boronic acids has been developed. Under nonbasic conditions a wide variety of aryl, alkenyl, and heteroaryl organostannanes and boronic acids couple efficiently with O-acetyl hydroxamic acids in the presence of Cu(I) sources.

Full text of DOI:10.1021/ol8009682

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3005-3008
N-Amidation by Copper-Mediated
Cross-Coupling of Organostannanes or
Boronic Acids with O-Acetyl
Hydroxamic Acids
Zhihui Zhang, Ying Yu,† and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe,
Atlanta, Georgia 30322
chemll1@emory.edu
Received April 27, 2008
ABSTRACT
A general nonoxidative N-amidation of organostannanes and boronic acids has been developed. Under nonbasic conditions a wide variety of
aryl, alkenyl, and heteroaryl organostannanes and boronic acids couple efficiently with O-acetyl hydroxamic acids in the presence of Cu(I)
sources.
Mild methods for the formation of carbon-heteroatom bonds
are of considerable interest to the synthetic organic com-
munity. A great diversity of carbon-nitrogen bonds can now
be easily generated by transition-metal-catalyzed protocols,1
most prominently using the base-promoted conditions de-
veloped by Buchwald and Hartwig2 and the oxidative
couplings of boronic acids and their derivatives with amines
and amides described by Lam, Chan, Evans,3 and Collman
and Batey.4 Complementary protocols that are differentiated
from these C-N bond-forming reactions by providing
nonbasic and nonoxidizing reaction conditions are always
of value in complex synthetic settings. The chemistry
depicted in Scheme 1 suggests that boronic acids could
† Present address: Theravance, 901 Gateway Boulevard, South San
Francisco, CA 94080.
(1) For some recent reviews, see: (a) Beletskaya, I. P Pure Appl. Chem.
2005, 77, 2021–2027. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem.
ReV. 2004, 248, 2337–2364. (c) Ley, S. V.; Thomas, A. W. Angew. Chem.,
Int. Ed. 2003, 42, 5400–5449.
Scheme 1
.
Hydroxylamine-Derived Non-Basic, Non-Oxidative
C-N Bond Formation
(2) (a) Leading reviews: Buchwald, S. L.; Mauger, C.; Mignani, G.;
Scholzc, U. AdV. Synth. Catal. 2006, 348, 23–39. (b) Hartwig, J. F. Synlett
2006, 1283–1294. (c) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131–209. (d) Hartwig, J. F. Compr. Coord. Chem. II 2004, 9, 369–
398. (e) Schlummer, B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 1599–
1626.
couple with derivatives of hydroxylamine and deliver new
chemoselective methods for C-N bond formation through
(3) For some examples, see: (a) Lam, P. Y. S.; Vincent, G.; Bonne, D.;
Clark, C. G. Tetrahedron Lett. 2003, 44, 4927–4931. (b) Chan, D. M. T.;
Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron
Lett. 2003, 44, 3863–3865. (c) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark,
C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694. (d) Lam,
P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001,
42, 2427–2429. (e) Evans, D. A; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937–2940.
(4) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236. (b)
Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66,
1528–1531. (c) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org.
Chem. 2001, 66, 7892–7897. (d) Antilla, J. C.; Buchwald, S. L. Org. Lett.
2001, 3, 2077–2079. (e) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5,
4397–4400. (f) Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008,
47, 2109–2112.
10.1021/ol8009682 CCC: $40.75
Published on Web 06/17/2008
2008 American Chemical Society

selective metal-catalyzed cleavage of the NsO bond fol-
lowed by transmetalation and reductive elimination. Hy-
droxylamine derivatives as coupling reactants provide a
nitrogen moiety “R1NH” for C-N bond formation and an
internal “oxygenate” partner “OR′” to pair with the “B(OH)2”
fragment. In principle, this would allow CsN bond formation
to take place under neutral reaction conditions and avoid the
addition of an oxygenate base that is commonly used in
boronic acid-based cross-couplings. The development of
suitably mild reaction conditions would allow the selective
targeting of reactions at an N-O-bonded functional group
in the presence of other reactive functionalities and facilitate
the development of small molecule therapeutics or provide
a tactic for the chemical modification and/or tagging of more
complex biomolecules.
Using traditional nucleophilic reagents, Narasaka (orga-
nomagnesium)5 and Johnson (organozinc)6 have shown that
hydroxylamine derivatives can be cleaved by organometallic
reagents in the presence of metal catalysts and provide a
general process for C-N bond formation. However, until
recently, boronic acids were not known to participate in
similar N-O cleavage-based cross-coupling with hydroxy-
lamine derivatives.7 Our laboratory disclosed a mild copper-
catalyzed N-imination of boronic acids and organostannanes
using oxime O-carboxylates as iminating agents8 and ex-
tended that chemistry to establish a simple modular synthesis
of substituted pyridines.9 In an extension of this strategy,
we now disclose a new nonbasic method for the preparation
of N-substituted amides by the Cu-mediated cross-coupling
of boronic acids and organostannanes with O-acetyl hydrox-
amic acids (Scheme 2).
transformations on base-sensitive molecules, the use of N-O
moiety-based couplings could also provide useful reaction
chemoselectivities in the presence of Lam-condition-reactive
“NH” moieties.
This investigation was initiated by exploring the cross-
coupling of O-acetyl benzohydroxamic acid with 1.1 equiv
of phenyl boronic acid. A screening of different Cu(I)
sources, solvents, additives, and reaction temperatures re-
vealed the optimum use of 1 equiv of Cu(I) thiophene-2-
carboxylate (CuTC) in THF at 60 °C. Product yields were
compromised using less than 1 equiv of Cu(I), but loadings
in excess of 1 equiv did not lead to improved yields. CuOAc
and CuTC gave similar results, while nonoxygenate Cu(I)
sources such as CuCl, CuI, and CuCN were ineffective.
Solvents such as DMF, DMA, and toluene were not as
effective as THF. The addition of Lewis acids (BF3·Et2O,
Sc(OTf)3, TiCl4, CuPF6(CH3CN)4), or base (Et3N, Cs2CO3)
dramatically reduced the product yield. The influence of the
hydroxamic acid O-substituent on the reaction efficiency was
probed by reacting the O-substituted benzohydroxamic acids
with 1.1 equiv of p-tolylboronic acid and a stoichiometric
amount of CuTC in THF at 60 °C (Table 1).
Table 1. Reaction Survey: Amidation of p-Tolylboronic Acid
with O-Substituted Benzohydroxamic Acids
entry
R′
-COMe
-CO(t-Bu)
-CO(p-tolyl)
-CO(2-thienyl)
-CO(2-pyridyl)
-COC6F5
-Me
amidea (%)
1
2
3
4
5
6
7
8
69
61
40
41
30
36
62
60
Scheme 2. Cu(I)-Mediated Amidation of Boronic Acid/
Organostannane with O-Substituted Hydroxamic Acid
-Ph
a Isolated yield.
This new reaction provides a means of generalizing the
Lam “oxidative” amidation of boronic acids3a,d by substitut-
ing an oxidized form of the amide coupling partner under
neutral reaction conditions in place of an external oxidant-
like stoichiometric Cu(II) or air. In addition to allowing
O-Acetyl benzohydroxamic acid still gave the highest
productyield(69%,entry1).O-(p-methylbenzoyl),O-(thiophene-
2-carbonyl), and O-(2-pyridinylcarbonyl) substitutions re-
sulted in moderate yields of amide (entries 3-5). Surpris-
ingly, O-methyl and O-phenyl benzohydroxamic acid also
generated the N-substituted amide in about 60% yield (entries
6-7).
To probe generality of this reaction various O-acetyl
hydroxamates and boronic acids were reacted with 1 equiv
of CuTC in THF at 60 °C for 16 h producing the
corresponding amides in moderate to good yields in most
cases (Table 2). A 1:1 mixture of hexane and THF was used
as the reaction solvent in some cases to keep the effective
Cu concentrations in solution low and diminish undesired
homocoupling and protodeborylation reactions of the aryl-
(5) (a) Kitamura, M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004,
6, 4619–4621. (b) Narasaka, K. Pure Appl. Chem. 2002, 74, 143–149. (c)
Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 317–318.
(6) (a) Campbell, M. J.; Johnson, J. S. Org. Lett. 2007, 9, 1521–1524.
(b) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219–224. (c)
Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680–5681.
(7) (a) Hydrazines and hydroxyamines are known to undergo Lam-like
oxidative N- and O-arylation with boronic acids without cleavage of the
heteroatom-heteroatom bond: Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W.
Org. Lett. 2001, 3, 139–142. (b) Suzuki, H.; Yamamoto, A. J. Chem. Res.,
Synop. 1992, 8, 280–281.
(8) (a) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947–
1950. (b) See also Cu(I)-catalyzed couplings of boronic acids with
nitrosoaromatics: Yu, Y.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6,
26312634>.
(9) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918–6919.
3006
Org. Lett., Vol. 10, No. 14, 2008

Table 2. CuTC-Mediated Amidation of Arylboronic Acids with
O-Acetyl Hydroxamic Acids10
Table 3. CuDPP-Mediated Amidation of Organostannanes with
O-Acetyl Hydroxamic Acids12
a Isolated yield. b Hexanes/THF (1:1) as solvent. c THF as solvent.
d GC/MS analysis using nonadecane as an internal standard.
boronic acid. Arylboronic acids with electron-donating
substitutions generated amide products as desired (entries 3
and 4), while a low yield of the amide product was obtained
when using an electronic deficient arylboronic acid (entry
5). Only a trace of the enamide product was observed by
GC/MS analysis of the reaction of benzohydroxamic acid
with E-ꢀ-styrylboronic acid (entry 6).
* Isolated yield.
tries 3 and 7). Entries 8-14 show that significant variation
in the nature of the acyl moiety is accommodated by the
reaction system. Heteroaryl O-acetyl hydroxamic acids react
well (entries 11 and 12) and synthetically useful N-alkyl-
substituted amides may also be obtained efficiently by this
method (entries 13-18). Special attention is drawn to entry
14 in which a 4-iodophenyl moiety is tolerated under the
reaction conditions.
Oxidative addition of the O-acetylhydroxamic acid to
Cu(I)13 is a likely first step in the mechanism of the previ-
ously described Cu(I)-catalyzed8,9 as well as in the current
Cu(I)-mediated cross-coupling of hydroxyl amine derivatives
with boronic acids and organostannanes. We note that heating
O-acetyl benzohydroxamic acid with 1 equiv of CuTC in
THF resulted in complete conversion to PhCONH2 after
Organostannanes proved to be excellent reaction partners
in Cu(I)-mediated couplings with O-acetyl hydroxamic acids.
In earlier studies of Cu-mediated cross-couplings involving
organostannanes, the beneficial pairing of Cu(I) diphe-
nylphosphinate (CuDPP) with organostannanes was noted
and ascribed to the precipitation of (n-Bu3SnO(O)PPh2) from
the reaction mixture.11 In the present system involving
organostannane reaction partners, stoichiometric CuDPP
proved equally useful (Table 3). Optimal yields were
achieved with >1 equiv of Cu(I) to 2.0 equiv of CuDPP
was routinely used for convenience. In contrast to the boronic
acid system which appeared limited to electron-rich aryl
substituents, the organostannane system showed significant
generality. Thus, various O-acetyl hydroxamates and orga-
nostannanes were heated with 2 equiv of CuDPP in DMF at
60 °C for 12 h, generating amides in moderate to good yields.
As shown in Table 3, O-acetyl benzohydroxamic acid
coupled efficiently with aryl, heteroaryl, and alkenyl orga-
nostannanes providing the desired amides (entries 1-7),
while slight lower yields of amides were obtained when using
deactivated (electron-deficient) organostannane reagents (en-
(12) Typical experimental procedure: O-Acetyl benzohydroxamic acid
(0.10 mmol), tributyl-p-tolyltin (0.12 mmol), and CuDPP (0.20 mmol) were
added to a Schlenk tube. After flushing with argon, DMF (3 mL) was added
via syringe. The reaction mixture was stirred under argon at 60 °C for 12 h.
Ethyl ether (10 mL) was added to the mixture. The organic layer was washed
with brine, dried over MgSO4, and evaporated. The residue was then
subjected to preparative plate silica chromatography using hexanes/EtOAc
as eluent.
(13) For oxidative addition of the N-O bond to various transition metals
such as Re, Pd, and Cu, see: (a) Kusama, H.; Yamashita, Y.; Uchiyama,
K.; Narasaka, K. Bull. Chem. Soc. Jpn. 1997, 70, 965–975. (b) Ferreira,
C. M. P.; Guedes da Silva, M. F. C.; Kukushkin, V. Y.; Frau´sto da Silva,
J. J. R.; Pombeiro, A. J. L. J. Chem. Soc., Dalton Trans. 1998, 32, 5–326.
(c) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 45–46. (d) Tsutsui, H.;
Narasaka, K. Chem. Lett. 2001, 526–527. (e) Kitamura, M.; Zaman, S.;
Narasaka, K. Synlett 2001, 974–976. (f) Kitamura, M; Narasaka, K. Chem.
Rec. 2002, 2, 268–277. (g) Chiba, S.; Kitamura, M.; Saku, O.; Narasaka,
K. Bull. Chem. Soc. Jpn. 2004, 77, 785–796. (h) Tsutsui, H.; Hayashi, Y.;
Narasaka, K. Chem. Lett. 1997, 317–318. (i) Narasaka, K. Pure Appl. Chem.
2002, 74, 143–149.
(10) Typical experimental procedure: O-Acetyl benzohydroxamic acid
(0.10 mmol), phenylboronic acid (0.12 mmol), and CuTC (0.10 mmol) were
added to a Schlenk tube. After flushing with argon, THF (3 mL) was added
via syringe. The reaction mixture was stirred under argon at 60 °C for 12 h.
Ethyl ether (10 mL) was added to the mixture. The organic layer was washed
with brine, dried over MgSO4,and evaporated. The residue was then
subjected to preparative plate silica chromatography using hexanes/EtOAc
as eluent.
(11) (a) Allred, G.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2748–2749. (b) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org.
Lett. 2003, 5, 3033–3035.
Org. Lett., Vol. 10, No. 14, 2008
3007

aqueous workup.14 Why at least a full equivalent of Cu(I) is
required during cross-coupling reactions of O-acetylhydrox-
amic acids but is required in only catalytic quantities for
cross-couplings with O-acyloximes8,9 must reside in the
nature of the two different amido Cu intermediates A and B
shown in Scheme 3.
amic acids do not participate in the Cu(I)-mediated cross-
coupling, generating instead (after aqueous workup) the
product of N-O bond reduction, suggesting that transmeta-
lation is prevented by steric encumbrance in these cases.
Interesting chemoselectivity of this new N-O-based cross-
coupling is seen in the two reactions depicted in Scheme 4
Scheme 4. Examples of Chemoselectivity
Scheme 3. Mechanistic Speculations
(where DMF was used as solvent to ensure solubility of both
Cu sources, rather than THF/hexanes as described in Table
2). Upon exposure of a mixture of O-acetyl benzohydroxamic
acid and p-tolylboronic acid to Cu(II), Lam-like N-arylation
reactivity is predominantly observed. In contrast, the use of
Cu(I) allows divergence of this chemistry from Lam-like
reactivity to exclusive formation of the product of cross-
coupling at the N-O bond.
In summary, a general copper-mediated cross-coupling of
O-acetyl hydroxamic acids with boronic acids and orga-
nostannanes under nonbasic and nonoxidizing conditions has
been developed. This methodology allows a variety of amides
to be easily prepared and is a useful complement to existing
metal-catalyzed methods for C-N bond formation. Given
the mild reaction conditions and its inherent chemoselectivity,
this new method might be useful as a novel bioorthogonal
peptide ligation protocol of use in the construction of peptides
and peptidomimetics. Additional studies are ongoing.
Although the detailed mechanism of these Cu-mediated
couplings of hydroxylamine derivatives with boronic acids
and organostannanes is not known, we speculate that the
imido intermediates R2CdNCuX2 are sufficiently electro-
philic to engage in a fast transmetalation with boronic acids
and organostannanes, while the amido RCONHCuX2 species
are likely to form relatively stable and less electrophilic
amido bridging dimeric structures that would be more
sluggish at transmetalation. This would rapidly consume a
full equivalent of Cu(I) and could give the appearance of a
noncatalytic process. In fact N-substituted O-acetyl hydrox-
Acknowledgment. The National Institutes of General
Medical Sciences, DHHS, supported this investigation
through Grant No. GM066153. Dr. Gary Allred of Synthonix
provided the boronic acids and organostannanes used in our
studies.
Supporting Information Available: Complete description
of experimental details and product characterization and
photocopies of spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) This reduction has been commonly found with various O-substituted
hydroxamic acids, even with O-methyl hydroxamic acid. A Ti(III)-mediated
reduction of O-methyl hydroxamic acid has been reported: Fisher, L. E.;
Caroon, J. M.; Jahangir; Russell Stabler, J. S.; Lundberg, S.; Muchowski,
J. M. J. Org. Chem. 1993, 58, 3643–3647.
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Org. Lett., Vol. 10, No. 14, 2008