Pd(II)-catalyzed primary-C(sp3)-H acyloxylation at room temperature

Article abstract of DOI:10.1021/ol301579q

With the aid of a novel S-methyl-S-2-pyridyl-sulfoximine (MPyS) directing group (DG), the unactivated primary β-C(sp³)-H bond of MPyS-N-amides oxidizes at room temperature. The catalytic conditions are applicable to the diacetoxylation of primary β,β′-C(sp ³)-H bonds, and the carboxylic acid solvent is pivotal in the formation of the C-O bond. The MPyS-DG cleaves from the oxidation products and is recovered. This method provides convenient access to α,α′- disubstituted-β-hydroxycarboxylic acids.

Full text of DOI:10.1021/ol301579q

ORGANIC
LETTERS
Pd(II)-Catalyzed Primary-C(sp3)ꢀH
2012
Vol. 14, No. 14
3724–3727
Acyloxylation at Room Temperature
Raja K. Rit, M. Ramu Yadav, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad, India
akhilchemistry12@gmail.com; akssc@uohyd.ernet.in
Received June 7, 2012
ABSTRACT
With the aid of a novel S-methyl-S-2-pyridyl-sulfoximine (MPyS) directing group (DG), the unactivated primary β-C(sp3)ꢀH bond of MPyS-N-
amides oxidizes at room temperature. The catalytic conditions are applicable to the diacetoxylation of primary β,β0-C(sp3)ꢀH bonds, and the
carboxylic acid solvent is pivotal in the formation of the CꢀO bond. The MPyS-DG cleaves from the oxidation products and is recovered. This
method provides convenient access to R,R0-disubstituted-β-hydroxycarboxylic acids.
Transition-metal-catalyzed, directing-group (DG) as-
sisted oxidation of an unactivated C(sp3)ꢀH bond has
emerged as an elegant and powerful tool for the construc-
tion of chemo- and regioselective CꢀO bonds in aliphatic
chains.1 This unique strategy allows the creation of a hydroxy
functional group within a complex molecule, therefore giving
it broad application in synthetic chemistry.2 However, owing
to the high bond dissociation energy of the C(sp3)ꢀH bond
and lack of π-participation, direct oxidation of an unacti-
vated alkane CꢀH bond is a challenging problem.1b Among
the known processes for CꢀH bond oxidation,3ꢀ5 the
inherently reactive and relatively weaker alkane CꢀH bonds
are more amenable to oxidation.6 Sanford and co-workers
demonstrated an elegant approach for the transformable
oximes or pyridine-directed 1°/2°-C(sp3)ꢀH oxidation of
alkanes (eq 1).5e,j The Yu group employed a chiral oxazoline
to accomplish the otherwise challenging diastereoselective
oxidation of a methyl group (eq 1).5i However, the use of
nonremovable and nonmodifiable DGs limit the applications
of alkane CꢀH oxidation methods to synthetic chemistry.7
Therefore, the development of a new synthetic pathway for the
direct oxidation of C(sp3)ꢀH bonds with the aid of reusable
DG under mild catalytic conditions is highly desirable.1b,8
(1) For reviews on sp3 CꢀH functionalization, see: (a) Newhouse, T.;
Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 3362. (b) Li, H.; Li, B. J.;
Shi, Z. J. Catal. Sci. Technol. 2011, 1, 191. (c) Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010,
16, 2654. (d) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q.
Chem. Soc. Rev. 2009, 38, 3242. (e) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439. (f) Crabtree, R. H. J. Organomet. Chem.
2004, 689, 4083.
(2) For sp3 CꢀH functionalization in organic synthesis, see: (a)
Stang, E. M.; White, M. C. Angew. Chem., Int. Ed. 2011, 50, 2094. (b)
Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976 and
references cited therein. (c) McMurray, L.; O’Hara, F.; Gaunt, M. J.
Chem. Soc. Rev. 2011, 40, 1885. (d) Stang, E. M; White, M. C. Nature
2009, 1, 547. (e) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(f) Godula, K.; Sames, D. Science 2006, 312, 67.
(3) For oxidation of an sp3 CꢀH bond using a stoichiometric amount
of Pd-catalyst, see: (a) Carr, K.; Saxton, H. M.; Sutherland, J. K.
J. Chem. Soc., Prekin Trans. 1 1988, 1599. (b) Baldwin, J. E.; Jones,
R. H.; Najera, C.; Yus, M. Tetrahedron 1985, 41, 699. (c) Carr, K.;
Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1984, 1227.
(4) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001,
123, 8149.
(5) For Pd-catalyzed sp3 CꢀH oxidation, see: (a) He, G.; Zhao, Y.;
Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (b) Novak,
P.; Correa, A.; Donaire, J. G.; Martin, R. Angew. Chem., Int. Ed. 2011,
50, 12236. (c) Hou, X. F.; Wang, Y. N.; Schnetmann, I. G. Organome-
tallics 2011, 30, 6053. (d) Zhang, S.; Luo, F.; Wang, W.; Jia, X.; Hu, M.;
Cheng, J. Tetrahedron Lett. 2010, 51, 3317. (e) Neufeldt, S. R.; Sanford,
M. S. Org. Lett. 2009, 12, 532. (f) Reddy, B. V. S.; Reddy, L. R.; Corey,
E. J. Org. Lett. 2006, 8, 3391. (g) Wang, D. H.; Hao, X. S.; Wu, D. F.; Yu,
J. Q. Org. Lett. 2006, 8, 3387. (h) Lee, J. M.; Chang, S. Tetrahedron Lett.
2006, 47, 1375. (i) 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. (j) Desai, L. V.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 9542.
(6) (a) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2011, 133,
12584. (b) McNeill, E.; Du Bois, J. J. Am. Chem. Soc. 2010, 132, 10202.
(c) Chen, M. S.; White, M. C. Science 2010, 327, 566. (d) Litvinas, N. D.;
Brodsky, B. H.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 4513. (e)
Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247.
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2112.
r
10.1021/ol301579q
Published on Web 07/05/2012
2012 American Chemical Society

(0.5 mmol) in the presence of Pd(OAc)2 (5 mol %) and
PhI(OAc)2 (0.75 mmol) in AcOH (1.50 mL) was found to
be optimal.14 Other N,N- or N,S-bicoordinated direct-
ing groups,16 such as 8-aminoquinoline (8-AQ),16a,b,e
2-methylthioaniline (2-MTA),16e and 2-pyridin-ylmethyl-
amine (2-PMA)16c in 5, 6, and 7, were found to be ineffec-
tive under the optimized conditions (Scheme 1).
To investigate the effect of the MPyS-DG for the
unactivated primary β-C(sp3)ꢀH oxidation, a wide variety
of MPyS-N-amides having a 1°-β-CꢀH bond were sub-
jected to the optimized catalytic conditions at rt. Table 1
summarizes the scope and limitations of these studies. The
desired monoacetoxylation product 3a was obtained in
80% yield from 2a in 14 h. The β-C(sp3)ꢀH bond was
exclusively oxidized leaving the γ-C(sp3)ꢀH unaffected,15
producing 3b in 82% yield. Interestingly, chloro and
bromo substitutions on an aliphatic chain survived, deli-
vering 3c and 3d effectively; in contrast oxidation of β,β0-
dichloro containing amide 2e proceeded sluggishly even at
60 °C. The 2°-benzylic β-C(sp3)ꢀH bonds and the more
reactive aromatic CꢀH bonds were inert to the reaction
conditions; the desired oxidation products 3fꢀj were furn-
ished in good yields. Functional groups on the aromatic
ring, including nitro (3g), bromo (3h), and ether (3i), were
unaffected. Amides derived from 2-methylcyclohexane
carboxylic acids underwent β-acetoxylation successfully
(3k). The ester functional group did not affect the reaction
productivity, furnishing 3l in an appreciable yield in Ac2O.
Pleasingly, a good amount of β,β0-diacetoxylation product
4a resulted from 3a, when the reaction was performed in an
AcOH and Ac2O mixture.
A recent report by Simmons and Hartwig describes a
conceptually interesting method for the primary γ-CꢀH
functionalization of aliphatic alcohols/ketones in the pre-
sence of an iridium-phenanthroline catalyst and a dihydri-
dosilane reagent at 120 °C.9 We recently reported our preli-
minary observation on the Pd-catalyzed direct 1°-β-C(sp3)ꢀ
H acetoxylation of S-methyl-S-phenylsulfoximine-N-amide
at 100 °C.10 This result inspires us to envision a new
S-methyl-S-2-pyridylsulfoximine (MPyS)11 bidented
reusable DG to carry out the oxidation of an alkane
CꢀH bond. Presumably the facile coordination of
pyridyl12 and sulfoximine nitrogens of MPyS-DG to a
Pd-catalyst would trigger activating the β-C(sp3)ꢀH
bond of MPyS-N-amides with the involvement of a
[5,5]-fused-Pd-bridged system (eq 2), a concept that was
first reported by Daugulis.12c Moreover, the oxidation
of C(sp3)ꢀH bonds of amides and the use of a bicoor-
dinated DG for the CꢀH oxidation of alkane are rare.5f
Recently, Chen et al. demonstrated the picolinamide-
directed alkoxylation of a C(sp3)ꢀH bond at 110 °C.13
We report herein a Pd-catalyzed highly selective direct
acetoxylation of a 1°-β-C(sp3)ꢀH bond of MPyS-N-
amides at room temperature (rt).
The catalytic conditions were next surveyed to examine the
oxidation of β-C(sp3)ꢀH bonds of MPyS-N-amides bearing
R-CꢀH bonds. In general, the R-CꢀH is prone to undergo
the βꢀH elimination with the involvement of either the
Saegusa-type process or the cyclopalladated intermediates.17
However, the decrease in R-substitutions causing a sluggish
reaction and poor product yield was observed. To overcome
this problem, oxidations of 2mꢀ2o were therefore conducted
at 60 °C. Moderate to good yields of the desired β-CꢀH
acetoxylated products 3mꢀ3o were isolated. The β-H elim-
ination products, possibly obtained from the cyclopalladated
intermediates, were not detected.17a
Scheme 1. Acetoxylation of N-Pivaloyl-MPyS
The β,β0-dihydroxycarboxylic acids are valuable precur-
sors to the functionalized cyclic carbonates.18a These cyclic
carbonate monomers are used for the production of
To probe this hypothesis, compound 2a was exposed to
catalytic conditionscomprisingofvarious combinations of
Pd-catalysts, oxidants, and solvents.14 The reaction of 2a
(15) Oxidations of the 1°-acidic-R-H of 8 and the 1°-γ-H of 9 were
unsuccessful.
(9) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70.
(10) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Chem.;Eur. J 2012, 18,
5541.
~
(11) Mancheno, O. G.; Bolm, C. Chem.;Eur. J. 2007, 13, 6674.
(16) (a) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7.
(b) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133,
12984. (c) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani,
N. J. Am. Chem. Soc. 2011, 133, 8070. (d) He, G.; Chen, G. Angew.
Chem., Int. Ed. 2011, 50, 5192. (e) Shabashov, D.; Daugulis, O. J. Am.
Chem. Soc. 2010, 132, 3965.
ꢀ
(12) (a) Rubia, A. G.; Urones, B.; Arrayas, R. G.; Carretero, J. C.
Angew. Chem., Int. Ed. 2011, 50, 10927. (b) Emmert, M. H.; Cook, A. K.;
Xie, Y. J.; Sanford, M. S. Angew. Chem., Int. Ed. 2011, 50, 9409. (c)
Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 13154.
(13) Zhang, S. Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen,
G. J. Am. Chem. Soc. 2012, 134, 7313.
(14) For more details, see the Supporting Information.
(17) (a) Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.-Q. Organome-
tallics 2008, 27, 1667. (b) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem.
1978, 43, 1011.
Org. Lett., Vol. 14, No. 14, 2012
3725

Table 1. Acetoxylation of 1°-β-C(sp3)ꢀH Bonds of Amidesa,b
Table 2. Direct β,β0-Di-acetoxylation of Primary β,β0-C(sp3)ꢀH
Bonds of Amidesa,b
a Reaction conditions: 2 (0.25 mmol), Pd(OAc)2 (10 mol %), PhI-
(OAc)2 (0.75 mmol), AcOH/Ac2O (1:1, 1.5 mL) at 70 °C. b Isolated
yields. Yield of the monoacetoxylation product is given in parentheses.
presence of Pd(OAc)2 in AcOH. No trace of the ꢀOPiv
1
containing CꢀH oxidation product was detected by H
NMR; rather 3a was exclusively formed in 81% yield
(entry 1, Table 3). In contrast, this reaction did not proceed
inthe absenceofoxidant.14 The effectof variouscarboxylic
acid solvents was next examined. The carboxylate groups
Table 3. Acyloxylation of 1°-β-C(sp3)ꢀH Bond of Amidesa
t
R2
yield
(%)b
entry
R1
R2
(h)
(major)
3/10
1
2
3
4
5
t-Bu
CH3
CH3
CH3
CH3
CH3
30
12
32
30
26
CH3
CD3
Et
3a
81(13)
a Reaction conditions: 2 (0.5 mmol), Pd(OAc)2 (5 mol %), PhI(OAc)2
(0.75 mmol), AcOH (1.5 mL) at rt. b Isolated yields. Recovered starting
material is indicated in parentheses. c Reaction was carried out at 60 °C.
d 2e (100 mg) was employed. e Bulk scale reaction of 2j (1.50 g) was
performed. f 10 mol % of Pd(OAc)2 was introduced; Ac2O was used as
solvent. g Mixture of AcOH and Ac2O (1:1) was used.
c
CD3
Et
10a
10b
10c
10d
68(20)
59(26)
n-Pr
iso-Pr
n-Pr
iso-Pr
58(21)d,e
54(30)d,e
a Reaction conditions: 2a (100 mg, 0.42 mmol), Pd(OAc)2 (5 mol %),
PhI(OAc)2 (0.63 mmol), R2COOH (1.25 mL) at rt. b Isolated yields.
Yield of the recovered 2a shown in parentheses. c CD3COOD was used
as solvent. d Reaction performed at 65 °C. e Yield of the nonseparable
mixture of 10 and 2a.
biodegradable and biocompatible polymers.18b Hydrolysis
of 4a would generate β,β0-dihydroxycarboxylic acids. To
obtain 4a from 2a, the diacetoxylation of the primary
β,β0-C(sp3)ꢀH bonds of amides was therefore investigated.
Excellent conversion of 2a to 3a and 4a was observed under
the modified conditions [Pd(OAc)2 (10 mol %), PhI(OAc)2
(3.0 equiv) in AcOH/Ac2O at 70 °C] as shown in Table 2.
Following this method, 4b, 4c, 4h, and 4j were isolated in
56ꢀ78% yields.
CD3COOꢀ, EtCOOꢀ, n-PrCOOꢀ, and iso-PrCOOꢀ
from the corresponding carboxylic acids were successfully
incorporated into the oxidation products, producing 10aꢀd
in good yields (entries 2ꢀ5).5d,i It appeared that the
(18) (a) Sanders, D. P.; Fukushima, K.; Coady, D. J.; Nelson, A.;
Fujiwara, M.; Yasumoto, M.; Hedrick, J. L. J. Am. Chem. Soc. 2010,
132, 14724. (b) Jerome, C.; Lecomte, P. Adv. Drug Delivery Rev. 2008,
60, 1056.
(19) (a) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev.
2010, 110, 824. (b) See also ref 1d.
It was speculated that the acetate moiety from the PhI-
(OAc)2 or AcOH was involved in the formation of the
CꢀO bond. To study the role of the oxidant in this
transformation, 2a was reacted with PhI(OPiv)2 in the
3726
Org. Lett., Vol. 14, No. 14, 2012

Facile cleavageofthe directinggroupfrom the oxidation
products and the successful recovery of the MPyS-moiety
would broaden the synthetic versatility of this strategy.16b,23
Pleasingly, the MPyS-containing amide 3a was hydro-
lyzed with HCl (2 N) at 50 °C in 3 h (entry 1, Table 4). The
desired 3-hydroxy-2,2-dimethyl-propanoic acid 13a (215
$/1 g; Aldrich)24 was extracted from the crude reaction
mixture in 88% yield. Following this procedure, various
β-hydroxycarboxylic acids 13j and 13k were obtained with
ease (entries 2 and 3). The precious MPyS-DG was readily
isolated from the acidic mother liquor in excellent yields.14
Finally, potential synthetic application of this strategy
was demonstrated performing Pd-catalyzed unactivated
primary β-C(sp3)ꢀH acetoxylation of drug derivatives
(Figure 1). The fibrate-based drugs gemfibrozil and clofi-
brate are effective in reducing the cardiovascular risk
factors associated with type 2 diabetics.25 Gratifyingly,
reaction of MPyS-bearing amides derived from gemfibro-
zil and clofibrate, under the optimized conditions, furn-
ished the desired β-C(sp3)ꢀH acetoxylation products 14
and 15 in 66% and 51% yield, respectively.14
Scheme 2. Proposed Catalytic Cycle
carboxylic acid solvent was responsible for the CꢀO bond
formation, while the oxidant kept the catalytic cycle active.
Based on the discussed Pd-catalyzed alkane CꢀH oxida-
tion and the results of the β-C(sp3)ꢀH acyloxylation shown
in Table 3, the catalytic cycle in Scheme 2 is proposed with
the involvement of the PdII and PdIV species.19 The biche-
lated PdII species, generated in situ via the chelation of
pyridine and the sulfoximine N-atom to Pd(OAc)2, activates
the 1°-β-C(sp3)ꢀH of MPyS-N-amide at rt and produces the
[5,5]-fused bicyclic cyclopalladated intermediate 11. Follow-
ing this, oxidation of the PdII-species of 11 with PhI(OAc)2
or PhI(OCOR)2, obtained through the ligand exchange
between PhI(OAc)2 and carboxylic acid, delivers the PdIV
species 12.20,21 Finally reductive elimination of 12 delivers
Table 4. Recovery of the MPyS Directing Groupa,b
Figure 1. 1°-β-C(sp3)ꢀH Acetoxylation of drug derivatives.
In conclusion, we have developed a novel MPyS directing
group that is functional in the highly selective acetoxylation
of the unactivated 1°-β-C(sp3)ꢀH of MPyS-N-amides at rt.
The catalytic conditions are able to tolerate various func-
tional groups with a broad reaction scope, making them
suitable for use in the synthesis of drug derivatives. The
process also allows the formation of the β,β0-diacetoxylation
products. The facile cleavage and easy recovery of the robust
MPyS-DG makes the present protocol highly useful. Gen-
eralization of MPyS-DG for other CꢀH functionaliza-
tions, unraveling of mechanistic details, diastereoselective
C(sp3)ꢀH functionalizations, and investigation of the novel
synthetic applications are being actively pursued.
t
yield
yield
entry
3
(h)
of 1
of 13
1
2
3
3a, R1 = R2 = Me
3j, R1 = Bn, R2 = Me
3k, R1--R2 = cyclohexyl
3
6
5
87
87
89
88 ($215/1 g)
90
91
a Reaction conditions: 3 (0.25 mmol), 1 mL of 2 N HCl at 50 οC.
b Isolated yields. Bn = benzyl.
the desired β-acyloxylated product 3 and the active PdII
species. Alternatively the oxidation could also proceed with
the involvement of a Pd(III) intermediate.22
Acknowledgment. This research was supported by the
DST (Grant No. SR/S1/OC-34/2009). R.K.R. and M.R.Y.
thank CSIR, India for fellowship. We thank Mr. P.
Sanphui (University of Hyderabad) for the X-ray crystal-
lographic analysis.
(20) (a) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(b) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 12790.
(21) Koposov, A. Y.; Boyarskikh, V. V.; Zhdankin, V. V. Org. Lett.
2004, 6, 3613.
(22) (a) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T.
J. Am. Chem. Soc. 2009, 131, 17050. (b) Deprez, N. R.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 11234.
Supporting Information Available. Detailed experimen-
tal procedures, spectra, and X-ray data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(23) (a) Ihara, H.; Koyanagi, M.; Suginome, M. Org. Lett. 2011, 13,
2662. (b) Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 7502.
(24) CAS No for 14a: 4835-90-9; Aldrich Catalogue 2011ꢀ2012.
(25) (a) Jun, M.; Foote, C.; Lv, J.; Neal, B.; Patel, A.; Nicholls, S. J.;
Grobbee, D. E.; Cass, A.; Chalmers, J.; Perkovic, V. Lancet 2010, 375,
1875. (b) Steiner, G. Diabetes Vasc. Dis. Res. 2007, 4, 368.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3727