O-acetyl oximes as transformable directing groups for Pd-catalyzed C-H bond functionalization

Article abstract of DOI:10.1021/ol902720d

[Chemical equation presented] O-Acetyl oxlmes serve as effective directing groups for Pd-catalyzed sp² and sp³ C-H functionalization reactions. The C-H functionalization products can be subsequently transformed Into ortho- or β-functionalized ketones, alcohols, amines, and heterocycles.

Full text of DOI:10.1021/ol902720d

ORGANIC
LETTERS
2010
Vol. 12, No. 3
532-535
O-Acetyl Oximes as Transformable
Directing Groups for Pd-Catalyzed C-H
Bond Functionalization
Sharon R. Neufeldt and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan, 48109-1055
mssanfor@umich.edu
Received November 25, 2009
ABSTRACT
O-Acetyl oximes serve as effective directing groups for Pd-catalyzed sp2 and sp3 C-H functionalization reactions. The C-H functionalization
products can be subsequently transformed into ortho- or ꢀ-functionalized ketones, alcohols, amines, and heterocycles.
Over the past decade, palladium-catalyzed ligand-directed
C-H functionalization has been extensively exploited to
convert unactivated carbon-hydrogen bonds into carbon-
heteroatom and carbon-carbon bonds.1 Despite the rapidly
growing arsenal of methods in the field, the synthetic utility
of these transformations is limited by the requirement that a
directing group be built into the substrate. In particular, many
effective directing groups are nitrogen-containing hetero-
cycles that are not easily transformed or removed following
the C-H functionalization event.1
The ideal directing ligand would be sufficiently robust to
tolerate C-H activation/functionalization conditions but then
readily converted into diverse functional groups. Instances
of such directing groups in Pd-catalyzed reactions are
relatively rare. Yu and Shi have independently demonstrated
C-H functionalization of triflamide2a- and dimethyl2b-
protected benzyl amines followed by nucleophilic displace-
ment or reduction of the amine directing group. Oxazolines
have been used for Pd-catalyzed C-I bond forming reactions
followed by H2SO4-catalyzed hydrolysis to afford carboxylic
acids.3 Carboxylic acids have also been directly employed
in Pd-catalyzed C-H arylation and then removed by decar-
boxylation.4 Finally, amides have proven effective for
directing Pd-catalyzed C-C and C-halogen bond formation
and have been subsequently transformed into nitriles5a or
carboxylic acids.5b
Ketones are particularly versatile and widely used synthetic
intermediates.6 However, ketones are poor ligands for PdII
and thus are generally ineffective directing groups for Pd-
catalyzed C-H functionalization.7,8 We thus sought to
temporarily mask ketones as more coordinating imine or
oxime derivatives during C-H functionalization and then
(3) Giri, R.; Wasa, M.; Breazzano, S. P.; Yu, J. Q. Org. Lett. 2006, 8,
5685.
(4) Chiong, H. A.; Pham, Q. N.; Daugulis, O. J. Am. Chem. Soc. 2007,
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(5) (a) Shabashov, D.; Maldonado, J. R. M.; Daugulis, O. J. Org. Chem.
2008, 73, 7818. (b) Wasa, M.; Engle, K. M.; Yu, J. Q. J. Am. Chem. Soc.
2009, 131, 9886.
(6) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed.;
John Wiley & Sons, Inc.: New York, 1999; pp 1197-1620.
(7) For rare examples of ketones or aldehydes serving as directing groups
at Pd, see: (a) Terao, Y.; Kametani, Y.; Wakui, H.; Satoh, T.; Miura, M.;
(1) For reviews, see: (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
62, 2439. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;
Lazareva, A. Synlett 2006, 3382. (c) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174. (d) Li, B. J.; Yang, S. D.; Shi, Z. J. Synlett
2008, 949. (e) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(f) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem., Int. Ed.
2009, 48, 5094.
¨
Nomura, M. Tetrahedron 2001, 57, 5967. (b) Gu¨rbu¨z, N.; Ozdemir, I.;
C¸ etinkaya, B. Tetrahedron Lett. 2005, 46, 2273
.
(8) For reviews on ketone-directed C-H alkylation and arylation
reactions catalyzed by metals other than Pd, see: (a) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (b) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. ReV. [Online early access]. DOI: 10.1021/
cr900005n. Published Online: May 13, 2009. http://pubs.acs.org/doi/pdf/
(2) (a) Wang, X.; Mei, T. S.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131,
7520. (b) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007,
129, 7666.
10.1021/cr900005n (accessed December 10, 2009)
.
10.1021/ol902720d  2010 American Chemical Society
Published on Web 12/30/2009

subsequently remove this group to reveal the ketone func-
tionality (Scheme 1). This communication describes the
catalyzed imine-directed acetoxylation of an sp2 C-H bond
has been reported;9a however, imines have proven too labile
for analogous sp3 C-H functionalizations. For example,
reaction of 5 under standard acetoxylation conditions affords
the hydrolyzed ketone 6 as the major identifiable product
(39% yield, eq 2).
Scheme 1. Approach to ꢀ-C-H Functionalization of Ketones
development of O-acetyl oximes as versatile and readily
transformable directing groups for Pd-catalyzed C-H func-
tionalization.
Two key challenges exist in the design of a ketone
surrogate for Pd-catalyzed C-H functionalization. First, the
protecting group must be stable to the catalytic conditions.
Second, the group must be readily removed in high yield
without affecting the newly installed functional group.
Previous studies have shown that oxime ethers such as 1
(eq 1) are effective directing groups for Pd-catalyzed sp2 and
sp3 C-H acetoxylation reactions with PhI(OAc)2.9,10 How-
ever, removal of the oxime ether protecting group from
ꢀ-functionalized products like 2 is problematic. Acid-
catalyzed hydrolysis11 is sluggish and produces significant
quantities of elimination products 3 and 4 (eq 1).12 The use
of superstoichiometric TiIIICl3 is effective in some cases,13
but this expensive, air-sensitive reagent is not practical for
general application.
Simple hydroxyl (OH) oximes are another attractive ketone
surrogate. These readily available, stable, often crystalline
starting materials are known to direct stoichiometric cyclo-
palladation at both sp2 and sp3 C-H sites14 and are much
more readily cleaved than their oxime ether counterparts.15
In addition, they are prepared from NH2OH·HCl, which is
nearly 100-fold less expensive than NH2OMe·HCl.16 Despite
these advantages, oximes are known to undergo rapid
oxidative cleavage in the presence of oxidants like PhI(O-
Ac)2.17 For example, subjecting oxime 7 to Pd(OAc)2 and
PhI(OAc)2 in AcOH resulted in a nearly instantaneous color
change from colorless to blue-green, concomitant with
regeneration of the parent ketone 6. However, encouragingly,
a similar color change was not observed when the solvent
was changed from AcOH to AcOH/Ac2O (1:1). Under these
conditions, only traces of ketone 6 (4% by GC) were formed;
instead the major product (68% by GC) was the O-acetylated/
C-H acetoxylated compound 9 (eq 3).
This initial result suggested that the in situ reaction of 7
with Ac2O affords a stable O-acetyl oxime (8) that can direct
C-H acetoxylation. Further study showed that this in situ
O-acetylation occurred quantitatively upon stirring the oxime
starting material in AcOH/Ac2O for 2 h at 25 °C. Subsequent
addition of Pd catalyst and oxidant, followed by heating the
reaction mixture at 100 °C for 12 h, afforded 8 in 70% GC
yield (49% isolated).
Imines would be a versatile alternative to oxime ethers,
as they are readily hydrolyzed under mild conditions. Pd-
(9) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300. (b) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 9542. (c) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett.
2006, 8, 3387. (d) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem.
Soc. 2008, 130, 13285
.
(10) For related C-H acetoxylation reactions of other substrates, see:
(a) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149. (b) Giri, R.; Liang,
J.; Lei, J. Q.; Li, J. J.; Wang, D. H.; Chen, X.; Naggar, I. C.; Guo, C.;
Foxman, B. M.; Yu, J. Q. Angew. Chem., Int. Ed. 2005, 44, 7420. (c) Wang,
D. H.; Hao, X. S.; Wu, D. F.; Yu, J. Q. Org. Lett. 2006, 8, 3387. (d) Reddy,
B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (e) Wang,
G. W.; Yuan, T. T.; Wu, X. L. J. Org. Chem. 2008, 73, 4717. (f) Zhang,
J.; Khaskin, E.; Anderson, N. P.; Zavalij, P. Y.; Vedernikov, A. N. Chem.
Commun. 2008, 3625. (g) Stowers, K. J.; Sanford, M. S. Org. Lett. 2009,
As summarized in Table 1, a number of dialkyl oximes
underwent in situ acetylation/ꢀ-acetoxylation in modest to
(13) (a) Desai, L. V. Palladium-Catalyzed Functionalization of C-H
Bonds and Alkenes. Ph.D. Thesis, University of Michigan, April 2008. (b)
Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada, Y.
Tetrahedron Lett. 1986, 27, 2199.
11, 4584
(11) For example, see: Shipe, W. D.; Sorensen, E. J. Org. Lett. 2002, 4,
2063.
.
(14) For selected examples, see: (a) Baldwin, J. E.; Jones, R. H.; Na´jera,
C.; Yus, M. Tetrahedron 1985, 41, 699. (b) Baldwin, J. E.; Na´jera, C.;
Yus, M. J. Chem. Soc., Chem. Commun. 1985, 126. (c) Carr, K.; Saxton,
H. M.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 1 1988, 1599.
(15) Corsaro, A.; Chiacchio, U.; Pistara`, V. Synthesis 2001, 1903.
(16) Cost calculated on a molar basis using: Aldrich Catalog Handbook
of Fine Chemicals; Aldrich Chemical: Milwaukee, WI, 2009.
(17) Moriarty, R. M.; Prakash, O.; Vavilikolanu, P. R. Synth. Commun.
1986, 16, 1247.
(12) Conversion of oxime ethers to ketones has been reported using
Amberlyst 15 at temperatures ranging from 25 to 110 °C. See: (a)
Sakamoto, T.; Kikugawa, Y. Synthesis 1993, 563. (b) Mears, R. J.; Sailes,
H. E.; Watts, J. P.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2000, 3250.
In our hands, 2 and derivatives were unreactive to the reported conditions
at room temperature. At elevated temperatures (80 °C), 2 reacted to form
a complex mixture of products that did not include the expected ꢀ-acetoxy
or ꢀ-hydroxy ketone.
Org. Lett., Vol. 12, No. 3, 2010
533

alkyl chlorides (entry 4) and protected amines (entry 3);
furthermore, remote benzylic C-H bonds were well tolerated
under the oxidizing reaction conditions (entries 1, 9, and
14).18
Table 1. O-Acetyl Oxime-Directed Acetoxylation of C-H
Bondsa
O-Acetyl ketoximes were also effective directing groups
for Pd-catalyzed acetoxylation at sp2 C-H sites. Both
electron-poor and electron-rich aryl rings underwent mono-
ortho-oxygenation in high yields (entries 7 and 11). Further,
aryl bromides (entry 8) and silyl-protected phenols (entry
12) were compatible with the reaction conditions. One
notable limitation of this method is that O-acetyl aldoximes
(for example, entry 10) were susceptible to elimination of
AcOH to generate nitriles.19
The C-H acetoxylation products in Table 1 were obtained
in yields comparable to those previously reported with oxime
ether derivatives.9b,d However, the O-acetyl oxime directing
group is significantly more readily deprotected. In general,
ꢀ-hydroxy ketones are accessible via alcoholysis of both
acetate groups (to afford ꢀ-hydroxy oximes) followed by
removal of the oxime functionality. The first step can be
accomplished by treatment of starting materials like 9 with
K2CO3 in MeOH to afford 10 in 91% isolated yield.
While numerous methods exist for the second step
(conversion of an oxime to a ketone), many of our substrates
are susceptible to competing formation of side products (e.g.,
via alcohol oxidation, isoxazoline formation, or elimination).
After extensive experimentation, we identified the use of
NaHSO3 in EtOH/H2O20 as the most general and high
yielding method to transform these oximes into ꢀ-hydroxy
ketones while circumventing undesired side reactions and
persistent byproducts. Under these conditions, substrate 10
was converted cleanly to 11 in 80% yield. Compound 11
was obtained in pure form by a simple extraction, obviating
the need for chromatography.
The two deprotection steps could also be combined to
provide an operationally simple, high-yielding, one-pot route
from O-acetyl oxime C-H oxidation products to ꢀ-hydroxy
ketones (eq 4). For example, treatment of 9 with K2CO3 in
MeOH, followed by addition of NaHSO3 and H2O, provided
11 in 80% yield after a simple extractive workup (eq 4). As
shown in Table 2, this one-pot deprotection could also be
achieved with other substrates. Under these conditions,
elimination products were not observed, and isoxazoline
formation was limited to e5%.
a Conditions: 0.12 M in AcOH/Ac2O (1:1), 2 h, 25 °C; then 5 mol %
Pd(OAc)2, 1-3 equiv of PhI(OAc)2, 80 or 100 °C, 4-12 h. b The remaining
mass balance (as determined by GC of the crude reaction mixtures) was
generally unreacted O-acetyloxime (analogous to 8 in eq 3). c Starting
material and product consisted of a mixture of oxime E/Z stereoisomers.
d GC yield. e Product consisted of a mixture of oxime E/Z stereoisomers.
An important characteristic of the O-acetyl oxime directing
group is that it enables access to a variety of additional
good yields (entries 1-6). The observed trends in reactivity
and selectivity were similar to those in sp3 C-H function-
alization reactions of related oxime ethers.9b For example,
oxidation occurred selectively at 1° ꢀ-sp3 C-H bonds versus
the analogous 2° sites (entries 1-4). Acetoxylation of a 2°
C-H bond could be achieved in modest yield in the rigid
trans-decalone system (entry 6). The reaction conditions were
compatible with a number of functional groups, including
(18) The acetoxylated products were typically isolated as mixtures of
E/Z oxime stereoisomers, which rapidly interconvert under the catalytic
reaction conditions.
(19) For an example under similar conditions, see: Waring, P. Aust.
J. Chem. 1988, 41, 667.
(20) Pines, S. H.; Chermerda, J. M.; Kozlowski, M. A. J. Org. Chem.
1966, 31, 3446.
534
Org. Lett., Vol. 12, No. 3, 2010

rearrangement21 followed by intramolecular condensation),
to amino phenol 16 (via reduction),22 and to diol 17 (via
oxime hydrolysis followed by reduction).23
Table 2. Deprotection to ꢀ- and ortho-Hydroxy Ketonesa
Preliminary results indicate that these O-acetyl oximes are
also effective directing groups for other Pd-catalyzed C-H
functionalization reactions. For example, as shown in Scheme
3, the Pd-catalyzed iodination of 18 and chlorination of 19
Scheme 3
.
Other Pd-Catalyzed C-H Functionalization
Reactions of O-Acetyl Oximes
a Conditions in entries 1-3 (one pot): K2CO3 (3 × 0.15 equiv/2.5 h),
MeOH, 25 °C, then 3.5 equiv of NaHSO3, H2O, 80 °C, 3 h. Conditions in
entry 4 (two steps): (i) 0.15 equiv of K2CO3, MeOH, 25 °C, 1 h, then (ii)
3.5 equiv of NaHSO3, H2O, EtOH, 90 °C, 12 h.
proceeded to form aryl halides 20 and 21 in modest to good
yields.24 Interestingly, under standard Pd-catalyzed C-H
arylation conditions with PhI and AgOAc in TFA,25 19
underwent in situ Beckmann rearrangement/C-H phenyla-
tion to afford acetamide 22.
structural motifs from a common synthetic intermediate. As
exemplified with 12 in Scheme 2, K2CO3-catalyzed metha-
In conclusion, this letter describes the use of in situ
generated O-acetyl oximes as effective directing groups in
Pd-catalyzed C-H functionalization reactions. These direct-
ing groups are stable under the catalytic reaction conditions
but can then be readily manipulated to afford ketones,
alcohols, amines, and heterocycles.
Scheme 2
.
Diverse Transformations on C-H Functionalization
Product 12
Acknowledgment. We thank the NIH NIGMS (GM-
073836) for support of this research. Additional support from
Dupont, AstraZeneca, Merck, Amgen, Abbott, GlaxoSmith-
Kline, Roche, Eli Lilly, and Bristol Myers Squibb is
gratefully acknowledged.
Supporting Information Available: Experimental details
and spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
nolysis of the acetyl groups provided oxime 13 in quantitative
yield. Product 13 could then be converted to the correspond-
ing acetophenone 14, to oxazoline 15 (via Beckmann
OL902720D
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Org. Lett., Vol. 12, No. 3, 2010
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