Pd(II)-catalyzed o-C-H acetoxylation of phenylalanine and ephedrine derivatives with MeCOOOtBu/Ac2O

Article abstract of DOI:10.1021/ol1007108

Pd(II)-catalyzed ortho C-H acetoxylation of triflate protected phenethyl- and phenpropylamines has been achieved with tert-butyl peroxyacetate as the stoichiometric oxidant and either DMF or CH₃CN as the promoter. The reaction was found to tolerate a large variety of functional groups and could be combined with subsequent intramolecular amination to afford functionalized indoline derivatives.

Full text of DOI:10.1021/ol1007108

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2511-2513
Pd(II)-Catalyzed o-C-H Acetoxylation of
Phenylalanine and Ephedrine Derivatives
with MeCOOOtBu/Ac2O
Chris J. Vickers, Tian-Sheng Mei, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037
yu200@scripps.edu
Received March 26, 2010
ABSTRACT
Pd(II)-catalyzed ortho C-H acetoxylation of triflate protected phenethyl- and phenpropylamines has been achieved with tert-butyl peroxyacetate
as the stoichiometric oxidant and either DMF or CH3CN as the promoter. The reaction was found to tolerate a large variety of functional
groups and could be combined with subsequent intramolecular amination to afford functionalized indoline derivatives.
Pd(II)- and Cu(II)-catalyzed C-H activation/C-O bond
forming reactions have received increased attention recently,
and major efforts have been directed toward discovering new
oxidants and conditions that enhance catalytic turnover.1-5
Consequentially, a number of new oxidation systems with
Pd and Cu catalysts for activation of inert C-H bonds have
been reported during the past decade, namely, Pd(II)/
K2S2O8,6 Pd(II)/PhI(OAc)2,7 Pd(II)/MeCOOOtBu/Ac2O,8a
Pd(II)/IOAc,8b Pd(II)/O2,9 and Cu(II)/O2.10 In contrast to the
rapid improvement of Pd-catalyzed C-H activation/C-C
bond forming reactions,11 in terms of both practicality and
scope, oxidation of C-H bonds by Pd(II) and Cu(II) catalysts
remains underdeveloped, which has limited the application
of these potentially powerful reactions in making molecules
that are relevant to medicinal chemistry or total synthesis.
Herein, we report a new transformation that effects ortho-
acetoxylation of C-H bonds in phenethyl- and phenpropy-
ltriflamide substrates (including amino acid derivatives)12
using palladium acetate as the catalyst, tert-butyl peroxyac-
etate as the stoichiometric oxidant, and either DMF or
(1) For reviews, see: (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
62, 2439. (b) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4,
(6) (a) Gretz, E.; Oliver, T. F.; Sen, A. J. Am. Chem. Soc. 1987, 109,
8109. (b) Muehlhofer, M.; Strassner, T.; Herrmann, W. A. Angew. Chem.,
Int. Ed. 2002, 41, 1745. (c) Desai, L. V.; Malik, H. A.; Sanford, M. S.
Org. Lett. 2006, 8, 1141. (d) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org.
Chem. 2008, 73, 4717.
4041
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(2) For recent examples of Pd-catalyzed allylic peroxidation, see: (a)
Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727. (b) Yu, J.-Q.; Corey, E. J.
J. Am. Chem. Soc. 2003, 125, 3232. For a recent example on Rh-catalyzed
allylic peroxidation, see: (c) Catino, A. J.; Forslund, R. E.; Doyle, M. P.
J. Am. Chem. Soc. 2004, 126, 13622. For a new development of Pd-catalyzed
allylic acetoxylation of terminal olefins, see: (d) Chen, M. S.; Prabagaran,
(7) (a) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A: Chem. 1996,
108, 35. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
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Soc. 2004, 126, 9542.
N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970
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(8) (a) Giri, R.; Liang, J.; Lei, J.-G.; 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. (b) Wang, D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J,-Q. Org.
Lett. 2006, 8, 3387.
(3) For dioxirane and radicals, see: (a) Yang, D.; Wong, M. K.; Wang,
X. C.; Tang, Y. C. J. Am. Chem. Soc. 1998, 120, 6611. (b) Curci, R.;
D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2005, 39, 1. (c) Baran, P. S.;
Chen, K. Nature 2009, 459, 824. (d) Kasuya, S.; Kamijo, S.; Inoue, M.
(9) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
(10) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790.
Org. Lett. 2009, 11, 3630
.
(4) For a single example of oxaziridine-promoted C-H oxidation, see:
Litvinas, N. D.; Brodsky, B. H.; Du Bois, J. Angew. Chem., Int. Ed. 2009,
(11) (a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2009, 48, 5094.
48, 4513
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(5) For benzylic C-H acetoxylation, see: (a) Zhang, J.; Khaskin, E.;
Anderson, N. P.; Zavalij, P. Y.; Vedernikov, A. N. Chem. Commun. 2008,
(12) For an example of acetoxylation of amino acids, see: Reddy,
B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391.
3625. (b) Vedernikov, A. N. Chem. Commun. 2009, 4781
.
10.1021/ol1007108  2010 American Chemical Society
Published on Web 05/06/2010

CH3CN additive as the crucial promoter. The reaction was
found to proceed under relatively mild temperatures (70 °C)
and could be used with a variety of functional groups, such
as alcohols and ketones, as well as with both electron-rich
and electron-deficient arenes. A sequential o-C-H activation/
intramolecular amination of the products was also carried
out to synthesize 4-oxygenated indolines, demonstrating
additional synthetic utilities. Another attractive feature of this
method is its potential application toward the derivation of
natural amino acids tyrosine and phenylalanine as well as
other biologically active molecules such as ephedrine, which
together with its analogues comprise a family of important
hormones and neurotransmitters in biological systems13
(Figure 1).
Table 1. DMF versus CH3CN as an Additive
Figure 1. Examples of biologically active molecules that can be
modified by this method.
a Substrate (0.5 mmol), Pd(OAc)2 (10 mol %), tert-butyl peroxyacetate
(1.0 mmol), Ac2O (1.0 mmol), AcOH (0.5 mmol), ClCH2CH2Cl (0.19 mL),
70 °C, 24 h. The yields were determined by 1H NMR analysis of the crude
reaction mixture with CH2Br2 as the internal standard. b As in footnote a,
but with CH3CN (3.0 mmol). c As in footnote a, but with DMF (3.0 mmol),
ClCH2CH2Cl (0.32 mL), 70 °C, 48 h. d 48 h. e tert-Butyl peroxyacetate
(1.25 mmol), Ac2O (1.25 mmol).
We have previously developed a Pd(II)-catalyzed C-H
oxidation reaction using MeCOOOtBu as the stoichiometric
oxidant and Ac2O as the crucial promoter.8 Since MeCOOOt-
Bu is inexpensive and easy to use ($37 per mol), we began
our study by investigating whether this oxidation system can
be applied to the oxidation of phenethyltriflamide sub-
strates.14 Through extensive screening and optimization, we
discovered new conditions to effect ortho-acetoxylation of
this type of substrates (Table 1).
A number of important observations are worth noting.
First, the use of 6 equiv of DMF or CH3CN as an additive
increases the yields significantly (Table 1, entries 1 and 2).
The highest reactivity was achieved when CH3CN was used;
thus these conditions were useful with ortho-substituted or
electron-poor substrates (entries 2 and 4). However, in the
case of substrates lacking ortho-substitution, the high reactiv-
ity proved to be detrimental to the mono-/diselectivity (entry
3). Thus, in cases where substrates are electron-rich or lack
ortho-substitution, DMF was found to offer better control
and higher overall yields. Second, the presence of 1 equiv
of HOAc was found to increase the yield further by ∼15%.
Finally, it is important to note that running the oxidation
reaction under relatively dilute conditions results in the
formation of indolines (∼25%) via the intramolecular C-H
amination pathway14c along with ∼35% of the desired
products.
With the established reaction conditions, we proceeded
to examine the substrate scope (Figure 2). The acetoxylation
of unsubstituted and para-substituted substrates are best
performed with DMF as the additive to avoid significant
formation of diacetoxylated products (2a, 5a). DMF is also
the additive of choice when substrates contain electron-rich
arene rings (6a, 7a, 8a). Ortho- and meta-substituted
substrates work well in the presence of 6 equiv of CH3CN,
giving yields of 93% and 63%, respectively (1a, 4a). The
tolerance of a wide range of halides on the arenes is a
synthetically useful feature (9a-14a). Substrate 3 containing
an electron-withdrawing CF3 group is also acetoxylated to
give 3a in 72% yield; however, NO2 and acetyl groups
decrease the yields significantly (15a, 16a).
As anticipated from our previous understanding based on
the Thorpe-Ingold effect,15 substitutions at the benzylic
position, or the R-position of the triflamide enhance the
reactivity (17a-23a). Notably, a wide range of functional
groups at these positions are tolerated, such as ketal, OTBS,
triflate, and ester groups (17a, 19a-21a). This versatile
reactivity has allowed acetoxylation of a number of biologi-
cally important compounds such as derivatives of phenyla-
lanine, tyrosine, and ephedrine. By using our more reactive
CH3CN conditions, the acetoxylation of phenpropyltriflamide
derivative 23 was also possible, albeit in relatively low yield
(13) For studies on the biochemical role of ephedrine, see: (a) Astrup,
A.; Lundsgaard, C.; Madsen, J.; Christensen, N. J. Am. J. Clin. Nutr. 1985,
42, 83. (b) Vansal, S. S.; Feller, D. R. Biochem. Pharmacol. 1999, 58, 807.
(c) Rothman, R. B.; Vu, N.; Partilla, J. S.; Roth, B. L.; Hufeisen, S. J.;
Compton-Toth, B. A.; Birkes, J.; Young, R.; Glennon, R. A. J. Pharmacol.
Exp. Ther. 2003, 307, 138.
(14) For triflamide-directed o-C-H activation, see: (a) Li, J.-J.; Mei,
T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452. (b) Wang, X.;
Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520. (c) Mei, T.-S.;
Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806.
(15) Bachrach, S. M. J. Org. Chem. 2008, 73, 2466.
Org. Lett., Vol. 12, No. 11, 2010
2512

Scheme 1. Acetoxylation of Hydroxyl-Containing Substrate
moiety via intramolecular C-H amination to form a new
indoline ring system that can subsequently be oxidized to
the corresponding indole.14c In principle, this two-step C-H
acetoxylation/C-H amination sequence could be used to
synthesize an array of indolines and indoles adorned with
diverse substitution patterns. To demonstrate this approach,
we converted one of the acetoxylated products (22a) to 22b
(Scheme 2). All told, this represents a net conversion of
phenylalanine to 4-acetoxy-2-carbomethoxyindoline deriva-
tive (22b) in three steps: amine triflation, ortho-acetoxylation,
and intramolecular amination.
Scheme 2. Tandem C-H Acetoxylation/Indoline Formation
Figure 2. C-H acetoxylation of phenethyltriflamides: (a) isolated
yields; (b) substrate (0.5 mmol), Pd(OAc)2 (10 mol %), Ac2O (1.0
mmol), AcOH (0.5 mmol), tert-butyl peroxyacetate (1.0 mmol),
DMF (3.0 mmol), ClCH2CH2Cl (0.32 mL), 70 °C, 48 h; (c) as in
b, but with CH3CN (3.0 mmol), ClCH2CH2Cl (0.19 mL), 24 h; (d)
as in b, but with Ac2O (1.25 mmol), tert-butyl peroxyacetate (1.25
mmol), 48 h.
In summary, we have developed a mild protocol for
o-C-H acetoxylation of a wide range of phenyethyltrifla-
mides with varying electronic and steric properties on the
aryl rings. This technology enables the site-specific oxidation
of biologically important amines, using a synthetically
versatile directing group capable of undergoing further
synthetic manipulations, including intramolecular C-H ami-
nation to give 4-acetoxyindolines.
(23a). Notably, this reaction presumably proceeds through
a seven-membered palladacycle intermediate and as such
represents a rare example of remote directed C-H activa-
tion.16 A hydroxyl-containing substrate was also smoothly
acetoxylated under the standard conditions. It is possible that
the free hydroxyl is acetylated by Ac2O in situ prior to the
C-H oxidation reaction (Scheme 1).
Acknowledgment. We thank The Scripps Research In-
stitute and the U.S. National Science Foundation (NSF CHE-
0910014), Amgen, and Lilly for financial support.
This method also lends itself to the preparation of
4-acetoxyindoline derivatives using a transformation recently
described by our group to cyclize the phenethyltriflamide
Supporting Information Available: Experimental pro-
cedure and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) For a definition of remote C-H functionalizations, see: Breslow,
R. Acc. Chem. Res. 1980, 13, 170.
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