N-substituted imines by the copper-catalyzed N-imination of boronic acids and organostannanes with O-acyl ketoximes

Article abstract of DOI:10.1021/ol070561w

Catalytic quantities of copper(I) or copper(II) sources catalyze the N-imination of boronic acids and organostannanes through reaction with oxime O-carboxylates under nonbasic conditions. This method tolerates various functional groups and takes place efficiently using aryl, heteroaryl, and alkenyl boronic acids and stannanes.

Full text of DOI:10.1021/ol070561w

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1947-1950
N-Substituted Imines by the
Copper-Catalyzed N-Imination of Boronic
Acids and Organostannanes with O-Acyl
Ketoximes
Songbai Liu, Ying Yu,† and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe,
Atlanta, Georgia 30322
chemLL1@emory.edu
Received March 6, 2007
ABSTRACT
Catalytic quantities of copper(I) or copper(II) sources catalyze the N-imination of boronic acids and organostannanes through reaction with
oxime O-carboxylates under nonbasic conditions. This method tolerates various functional groups and takes place efficiently using aryl,
heteroaryl, and alkenyl boronic acids and stannanes.
Mild metal-catalyzed methods for the formation of carbon-
heteroatom bonds have revolutionalized the practice of
organic synthesis in both academic and industrial settings.1
Most noteworthy are the palladium- and copper-catalyzed
reactions developed by Buchwald and Hartwig and extended
by many others.2 Important complementary reactions that
oxidatively couple boronic acids with RXH substrates (X )
N, O, S) have been developed by Chan, Evans, Lam, and
others.3
Although C-X bonds can be easily generated under basic
conditions through the Buchwald-Hartwig or oxidative Lam-
like conditions, a nonbasic and nonoxidative metal-catalyzed
protocol could prove highly selective and useful in complex
synthetic settings. In pursuit of this goal, we initiated an
exploration of the metal-catalyzed cross-coupling of nitrogen-
heteroatom reagents (N-O, N-S) explicitly with boronic
acids and organostannanes as mild, nonbasic, and functional
(3) (a) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron
Lett. 2003, 44, 4927. (b) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C.
G.; Combs, A. P. Tetrahedron Lett. 2003, 44, 1691. (c) Chan, D. M. T.;
Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron
Lett. 2003, 44, 3863. (d) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C.
G. Tetrahedron Lett. 2002, 43, 3091. (e) Lam, P. Y. S.; Vicent, G.; Clark,
C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415. (f)
Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan,
D. M. T.; Combs, A. Synlett 2000, 5, 674. (g) Antilla, J. C.; Buchwald, S.
L. Org. Lett. 2001, 3, 2077. (h) Herradura, P. S.; Pendola, K. A.; Guy, R.
K. Org. Lett. 2000, 2, 2019. (i) Collman, J. P.; Zhong, M. Org. Lett. 2000,
2, 1233. (j) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (k) Evans, D. A.; Katz, J. L.; West, T.
R. Tetrahedron Lett. 1998, 39, 2937. (l) 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.
† Present address: Theravance, 901 Gateway Boulevard, South San
Francisco, CA 94080.
(1) (a) Beletskaya, I. P. Pure Appl. Chem. 2005, 77, 2021. (b) Beletskaya,
I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (c) Ley, S.
V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (d) Chan, D.
M. T.; Lam, P. Y. S. Recent Advances in Copper-promoted C-Heteroatom
Bond Cross-coupling Reactions with Boronic Acids and Derivatives. In
Boronic Acids - Preparation, Applications in Organic Synthesis and
Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005; pp 205-240.
(2) (a) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholzc, U. AdV. Synth.
Catal. 2006, 348, 23. (b) Hartwig, J. F. Synlett 2006, 9, 1283. (c) Muci, A.
R.; Buchwald, S. L. Topics in Current Chemistry; 2002; Vol. 219, pp 131.
(d) Hartwig, J. F. Compr. Coord. Chem. II 2004, 9, 369. (e) Schlummer,
B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 1599. (f) Zhang, H.; Cai, Q.;
Ma, D. J. Org. Chem. 2005, 70, 5164.
10.1021/ol070561w CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/20/2007

Scheme 1. Cross-Coupling Concept
Table 1. Optimization Studies
group compatible reaction partners (Scheme 1). Related
cross-couplings have also been studied by Narasaka4 and
Johnson5 and their co-workers using basic organomagnesium
and organozinc reagents. Go¨ttlich and co-workers have
explored metal-mediated reactions of N-halo compounds and
some hydroxylamine derivatives.6
The overall reaction chemistry parallels Lam-like reactions
of boronic acids but replaces the requisite oxidant in those
transformations (stoichiometric CuII or air) with the hetero-
atom-heteroatom bond of the reagent. The unique value of
this additional method for carbon-heteroatom bond forma-
tion becomes apparent if one contemplates hypothetical
synthetic challenges such as the easy and selective manipula-
tion of natural product oximes at the O-N bond for
structure-activity relationship studies or the generation of
transient, highly reactive imines from oximes for subsequent
transformations under mild conditions.
The concept depicted in Scheme 1 led to the disclosure
of Cu(I)-catalyzed couplings of boronic acids with N-
thioimides7 and with nitrosoaromatics.8 Extending these
studies, we report herein a mild method for the N-imination
of boronic acids and organostannanes with oxime O-
carboxylates providing a nonbasic and nonoxidative method
for C-N bond formation leading to N-substituted imines.9
The project was initiated by exploring the cross-coupling
of benzophenone oxime O-acetate with both p-tolylboronic
acid and PhSnBu3. After screening a variety of metal catalysts
(CuTC,10 CuOAc, CuCl, CuI, Pd(PPh3)4), solvents (THF,
DMA, DMF), and reaction temperatures (60, 70, 80 °C), this
initial effort revealed the effectiveness of 20 mol % of CuTC
in DMF at 70 °C for the cross-coupling: after 14 h under
argon, Ph2CdN-OAc and p-tolylboronic acid produced
Ph2CdN-p-tolyl in 81% yield, whereas PhSnBu3 gave
Ph2CdN-Ph in 86% yield.
yield (%)a
HC
entry
R′
solvents
CC
HD
1
2
3
4
5
6
Ac
DMF
DMF
DMF
THF
toluene
dioxane
41
63
86
81
41
39
12
9
0
0
0
9
12
5
12
38
38
COPh
COC6F5
COC6F5
COC6F5
COC6F5
0
1H NMR yield, with para-dimethoxybenzene as the internal standard.
a
O-acetates (Table 1), the boronic acid homocoupling (HC)
side product (1,3-diene) was observed in significant quanti-
ties. Transitioning from O-acetyl- to O-benzoyl- to O-
pentafluorobenzoyl- (used by Narasaka in his studies11)
derived oximes completely suppressed the homocoupling side
reaction (Table 1, compare entries 1-3). The greater
reactivity of the O-pentafluorobenzoyl oximes allowed
efficient coupling to be carried out with lower catalyst
loadings (10 mol % rather than 20 mol % of Cu), at lower
temperature (50 °C rather than 70 °C), and within 3 h.
Another side reaction, competitive hydrolysis (HD) of the
product imines by water generated in situ from the boronic
acid-boroxine equilibrium,12 was problematic, but this was
minimized using DMF as solvent relative to THF, toluene,
and dioxane (Table 1, compare entries 3-6). Although many
different copper sources (CuTC, CuCl, CuBr, CuI, Cu(OAc)2,
CuBr2) were effective catalysts for the cross-coupling of
oxime O-pentafluorobenzoates with aryl and alkenyl boronic
acids, no reaction occurred in the absence of the catalyst.
Interestingly, the reaction can be carried out in the presence
of air using boronic acids as the coupling partners; however,
Cu(I) and an inert atmosphere were required when orga-
nostannanes were employed.
However, upon extending the same reaction conditions to
the cross-coupling of alkenyl boronic acids with oxime
Using the optimized conditions, the scope of this new
methodology was examined as shown in Table 2.13 A variety
of boronic acids and organostannanes react with O-acetyl
and O-pentafluorobenzoyl oximes to generate the N-imina-
(4) (a) Kitamura, M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004,
6, 4619. (b) Narasaka, K. Pure Appl. Chem. 2002, 74, 143.
(5) (a) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219. (b)
Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680.
(6) (a) Noack, M.; Go¨ttlich, R. Chem. Commun. 2002, 536. (b) Helaja,
J.; Go¨ttlich, R. Chem. Commun. 2002, 720. (c) Heuger, G.; Kalsow, S.;
Go¨ttlich, R. Eur. J. Org. Chem. 2002, 1848. (d) Noack, M.; Go¨ttlich, R.
Eur. J. Org. Chem. 2002, 3171.
(11) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 45.
(12) Tokunaga, Y.; Ueno, H.; Shimomura, Y.; Seo, T. Heterocycles 2002,
57, 787.
(7) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309.
(8) Yu, Y.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631.
(9) For the direct reaction of boronic acids with benzophenone imine,
see: Chan, D. M. T.; Lam, P. Y. S. Recent Advances in Copper-promoted
C-Heteroatom Bond Cross-coupling Reactions with Boronic Acids and
Derivatives. In Boronic Acids - Preparation, Applications in Organic
Synthesis and Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005;
p 236.
(13) Typical Experimental Procedure. To benzophenone oxime O-
pentafluorobenzoate (0.1 mmol), E-â-styrylboronic acid (0.12 mmol), and
CuTC (2 mg, 0.01 mmol) in a Schlenk tube flushed with argon was added
dry DMF (2 mL). The reaction mixture was stirred at 50 °C for 3 h and
diluted with EtOAc (30 mL). The copper catalyst was removed by passing
the reaction mixture through a short pad of silica gel that was buffered
with triethylamine. After evaporation of the solvent, the residue was
subjected to flash chromatography (silica gel, buffered by triethylamine,
eluted with 40:1 hexanes/EtOAc) giving the desired product as a yellow
oil in 90% yield.
(10) Cu(I) thiophene-2-carboxylate, see: Allred, G.; Liebeskind, L. S.
J. Am. Chem. Soc. 1996, 118, 2748.
1948
Org. Lett., Vol. 9, No. 10, 2007

tion products in good to excellent yields. Electron-neutral
(entries 1 and 2), electron-rich (entries 4-6), and electron-
deficient (entry 7) arylboronic acids participated efficiently
in the reaction. o-Tolylboronic acid and 4-methoxy-2-
formylphenyl boronic acid, the two ortho-substituted aryl-
boronic acids investigated in this study, gave acceptable
yields of the products under the conditions investigated
(entries 3 and 8). Unprotected phenolic and aldehydic
functional groups were well-tolerated using this method
(entries 5, 7, and 8) suggesting that interesting functionalized
imine intermediates could be prepared by this mild synthetic
method. Although providing somewhat lower yields of
N-substituted imine products, heteroaromatic organostan-
nanes and alkenylstannanes were also suitable reaction
partners in this chemistry (entries 9-12). Synthetically useful
2-azadienes14 are easily and efficiently produced when
alkenylboronic acids are the reactants (entries 13-16).
When coupling with boronic acids, the O-pentafluoroben-
zoyl oximes generally gave better results than O-acetyl
oximes probably due to the milder conditions using the
former reactants (lower temperature and shorter reaction
time). However, when using organostannanes as reaction
partners, the O-acetyl oximes performed better than O-
pentafluorobenzoyl oximes because the more reactive O-
pentafluorobenzoyl oximes suffered a competitive Beckmann
rearrangement.15
Table 2. Cu-Catalyzed N-Imination of Boronic Acids and
Organostannanes
The scope of oxime O-carboxylate substrates was also
probed. Oxime O-carboxylates derived from aryl-heteroaryl,
aryl-alkyl, and alkyl-alkyl ketones were suitable substrates,
but the imines derived from alkyl-substituted oximes were
typically unstable to workup and isolation. Rather than
carrying out direct isolation of these imines, a reductive
workup using NaCNBH3 allowed a more convenient isolation
of the corresponding amines (entries 20-23). Unfortunately,
aldoxime O-carboxylates did not produce the desired aldi-
mines; rather, they suffered â-elimination to give the
corresponding nitrile products under the reaction conditions
(Scheme 2).
Scheme 2. Formation of Nitriles from Aldoximes
Under the conditions studied to date, this new reaction is
not appropriate for the stereodefined synthesis of imines,
because separate treatment of each stereoisomeric E- and
Z-oxime O-carboxylate derived from phenyl-2-furyl ketone
with 3-hydroxyphenylboronic acid produces the same 2:1
mixture of product imines (Table 2, entry 18; Scheme 3).
a
20 mol % of CuTC, Ar, 70 °C, 14 h. b 10 mol % of Cu(OAc)2, air, 50
(14) (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron
2002, 58, 379. (b) Boger, D. L. J. Heterocycl. Chem. 1996, 33, 1519. (c)
Gilchrist, T. L.; Rocha Gonsalves, A. M. d’A.; Pinho e Melo, T. M. V. D.
Pure Appl. Chem. 1996, 68, 859.
(15) The Beckmann rearrangement may be facilitated by the organostan-
nane: reaction of the same substrate under the same reaction conditions
with the analogous boronic acid does not cause formation of the Beckmann
product.
°C, 2-3 h. c 20 mol % of Cu(OAc)2, air, 50 °C, 1 h. d 20 mol % of CuTC,
Ar, 50 °C, 2 h. e 20 mol % of CuTC, Ar, 50 °C, 18 h. f 10 mol % of CuTC,
g
Ar, 50 °C, 2-3 h. 10 mol % of CuTC, Ar, 50 °C, 2-3 h; NaBH3CN (3
equiv)/CF3COOH (2 equiv), 0 °C, 2 h. h 10 mol % of CuTC, 4 Å molecular
sieves, Ar, 50 °C, 1-2 h; NaBH3CN (3 equiv)/CF3COOH (2 equiv), 0 °C,
i
2 h. Isolated yield.
Org. Lett., Vol. 9, No. 10, 2007
1949

Scheme 3. Stereochemistry of the Cross-Coupling
Scheme 4. Suggested Mechanism
A reasonable mechanistic pathway for the copper-catalyzed
coupling of ketoxime O-carboxylates with boronic acids or
organostannanes is shown in Scheme 4. Oxidative additions
to N-O bonded species are precedented.11,16 In the current
study, strong support for oxidative addition of the oxime
O-carboxylate to Cu(I) comes from the formation of ben-
zophenone imine in 90% yield after a mixture of benzophe-
none oxime O-acetate and 1 equiv of CuTC in DMF was
subjected to workup after 30 min. Transmetalation of either
the boronic acid or the organostannane to the putative Cu-
(III) intermediate followed by reductive elimination would
produce the desired C-N bond and regenerate a catalytically
active Cu(I). The requisite Cu(I) catalyst is either added to
the reaction system or generated in situ through reduction
of a Cu(II) precatalyst by the coupling agent.
boronic acids and organostannanes has been developed. The
reaction uses oxime O-carboxylates as iminating agents and
proceeds under nonbasic and nonoxidizing conditions, thus
complementing existing C-N bond forming reactions. A
simple, modular synthesis of highly substituted pyridines, a
powerful extension of this new method, will be reported
shortly.
Acknowledgment. The National Institutes of General
Medical Sciences, DHHS, supported this investigation
through grant No. GM066153. We thank Dr. Paul Reider of
Amgen for his support of our work and Dr. Gary Allred of
Synthonix for providing boronic acids and organostannanes
for our studies.
In summary, a general copper-catalyzed N-imination of
(16) For the oxidative addition of oxime derivatives to metals such as
Re, Pd, and Cu, see: (a) Kusama, H.; Yamashita, Y.; Uchiyama, K.;
Narasaka, K. Bull. Chem. Soc. Jpn. 1997, 70, 965. (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, 325. (c) Tsutsui, H.;
Narasaka, K. Chem. Lett. 2001, 526. (d) Kitamura, M.; Zaman, S.; Narasaka,
K. Synlett 2001, 974. (e) Kitamura, M.; Narasaka, K. Chem. Rec. 2002, 2,
268. (f) Chiba, S.; Kitamura, M.; Saku, O.; Narasaka, K. Bull. Chem. Soc.
Jpn. 2004, 77, 785. (g) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett.
1997, 317. (h) Narasaka, K. Pure Appl. Chem. 2002, 74, 19.
Supporting Information Available: Complete descrip-
tion 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.
OL070561W
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Org. Lett., Vol. 9, No. 10, 2007