Unactivated C(sp3)-H hydroxylation through palladium catalysis with H2O as the oxygen source

Article abstract of DOI:10.1039/c5cc04952k

A novel palladium catalyzed hydroxylation of unactivated aliphatic C(sp³)-H bonds was successfully developed. Different from conventional methods, water serves as the hydroxyl group source in the reaction. This new reaction demonstrates good reactivity and broad functional group tolerance. The C-H hydroxylated products can be readily transformed into various highly valuable chemicals via known transformations. Based on experimental and theoretical studies, a mechanism involving the Pd(ii)/(iv) pathway is proposed for this hydroxylation reaction.

Full text of DOI:10.1039/c5cc04952k

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Unactivated C(sp3)-H Hydroxylation through Palladium Catalysis
with H2O as the Oxygen Source
Jiantao Hua‡, Tianlong Lana‡, Yihua Sunb, Hui Chenb*, Jiannian Yaob and Yu Raoa*
Received 00th January 20xx,
Accepted 00th January 20xx
A novel palladium catalyzed hydroxylation of unactivated aliphatic C(sp3)-H bonds was successfully
developed. Different from conventional methods, water serves as the hydroxyl group source in the reaction.
This new reaction demonstrates good reactivity and broad functional group tolerance. The C-H hydroxylated
products can be readily transformed into various highly valuable chemicals via known transformations. Based
on experimental and theoretical studies, a mechanism involving Pd(II)/(IV) pathway is proposed for this
hydroxylation reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
transition-metal and the heterogeneity of reaction mixture.
Furthermore, molecular water generally is a relatively poor
Introduction
nucleophile in organic reactions.
In the past decade, transition-metal-catalyzed direct
functionalization of C–H bonds has gradually emerged as
valuable and practical tools for organic synthesis.1 Among
these studies, C-H oxygenation2 reactions which introduce a
hydroxyl functional group into molecules have received
much attention owing to its broad application in
pharmaceutical and material industry. In general, the
hydroxyl group can be introduced from three potential
sources: 1) in situ hydrolysis of newly installed acyloxyl
groups,3 such as OAc, OTFA, OBz, etc.; 2) peroxides4,
molecular oxygen5 or ozone5 (Scheme 1); 3) molecular water6.
Compared with the other two common sources, the use of
environmentally benign water as the hydroxyl source is
particularly attractive because of the advantages of high
atom economy, low cost and high safety. However, in
contrast to the other two major approaches, much less
progress has been made in this area. Up to date, there are
only few reported examples7 to involve water as the
hydroxyl source, including well-known Wacker oxidation8,
which involves water as a nucleophile to construct C(sp2)-O
bonds with ethylene. Although the employment of water as
the hydroxyl source may possess great advantages,
transition-metal catalyzed reactions conducted in aqueous
solution are often confronted with great challenges owing to
the potential ‘poisonous’ effect of molecular water to
Inspired by the seminal C(sp3)-H acetoxylation work by
Corey9 and recent advances by Pd(II)/(IV) catalysis with a
bidentate directing group10, we envisioned that Pd(II)/(IV)
may provide a viable solution for the C(sp3)-H hydroxylation
with water. Compared to Pd(II)/(0) pathway, Pd(II)/(IV)
would be more electrophilic and less sensitive to water. In
addition, Pd(II)/(IV) cycle would result in less potential
catalyst precipitation than Pd(II)/(0) catalysis. Our aim was to
identify suitable Pd(II) catalyzed C(sp3)-H hydroxylation
conditions with water via Pd(II)/(IV) cycle for the preparation
of valuable aliphatic alcohols (Scheme 1). Herein, we report
the first example of hydroxylation of unactivated C(sp3)-H
bonds with H2O through palladium catalysis.
Cu, Fe, Mn, Co, Ni, Ru, Pd, etc.
OH
R
Me
R
Common oxygen sources: R'OOH, O2, H2O2
Well studied
Previous works
This work
Rarely reported
O
O
Pd(OAc)2
Me
NHQ
HO
NHQ
Oxygen source: H2O
R
R
Scheme 1 Hydroxylation of unactivated C(sp3)-H bonds by metal
catalysis.
[a]
J. Hu[‡], T. Lan[‡], Prof. Dr. Y. Rao,
MOE Key Laboratory of Protein Sciences, Department of Pharmacology
and Pharmaceutical Sciences, School of Medicine, Tsinghua University
Beijing, 100084 (China)
To test our hypothesis, 8-aminoquinoline (AQ) protected
2-methylbutyric acid 1 was chosen for the model study
(Table 1). At the beginning of our investigations, a variety of
oxidants, such as PhI(OAc)2, 1,4-benzoquinone (BQ),
Selectfluor, K2S2O8, Na2S2O8, oxone, NaIO4, and Dess-Martin
Periodinane (DMP), etc, were examined in the presence of
Pd(OAc)2 in alcohol/water cosolvent system. After many
fruitless attempts, to our delight, the desired βC-H
E-mail: yrao@mail.tsinghua.edu.cn
[‡]
[b]
These authors contribute equally to this work.
Y. Sun, Prof. Dr. J. Yao, Prof. Dr. H. Chen.
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key
Laboratory of Photochemistry, Institute of Chemistry, Chinese Academy
of Sciences
Beijing, 100190 (China)
E-mail: chenh@iccas.ac.cn
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hydroxylation compound 2 was observed in a NMR yield of yields (50%-72%). In these cases, hydroxylation reactions on
35% along with 60% of unreacted 1 after stirring for 12 hours secondary or tertiary C-H bonds were rarely observed.
at 90 oC with Pd(OAc)2 and DMP11, in the cosolvent of i-
Differently substituted aryl groups, as well as the electron-
rich (3o, 3p) and electron-deficient (3m, 3n) aryl groups,
were also tolerated. Substrates with heteroatoms in the beta
position could be smoothly transformed into corresponding
alcohols (3i-3k). Gratifyingly, our method could be
successfully used to modify two representative
pharmaceutical drugs13 to afford novel hydroxylated
analogues (3v-3w), which were difficult to be obtained by
conventional methods. Phenomenon accompanied with the
moderate to good isolated yields in most cases is partially
remaining of the starting materials with little decomposition.
Additionally, more challenging substrates with sterically
hindered methylene C(sp3)-H bonds were tested and gave
relatively low yields of hydroxylated products along with
greater than 50% recovered starting materials (4a-4d). It is
noteworthy to point out that installing a hydroxyl group on
molecules can serve two general and important purposes: 1)
the hydroxyl group can be further converted into various
functional groups; 2) the water solubility of targeted
molecules can be greatly improved.
PrOH/water (1:1) (entry 1). Meanwhile, a trace amount of
alkoxylated product could be observed by LC-MS analysis.
Considering DMP (I5+) can react with alcohols to in-situ
generate the cyclic hypervalent iodine (I3+) reagent, we
proposed cyclic I3+ reagent might be the true oxidant of this
hydroxylation reaction. Therefore, three readily available
cyclic I3+ reagents12 (for details, seeSupporting Information)
were tried. As expected, these three oxidants gave improved
yields of roughly 50% accompanied with 2-iodobenzoic acid
as the byproduct ( entries 2-4). Encouraged by this initial
findings, we started to optimize the reaction conditions by
screening various organic solvents mixed with H2O (v:v/1:1).
t-BuOH, THF, dioxane, nitromethane and acetone were
found to give the desired product with similar or improved
yields and acetone gave the best result with 55% yield (entry
6). Further investigations indicated that product 2 could be
obtained in an isolated yield of 64% along with 20% of
unreacted 1 at 100 oC (entry 8). Among various Pd(II)
catalysts tested, Pd(OAc)2 proved to give the best yield (see
Supporting Information). Control experiments confirmed the
necessity of palladium catalyst, oxidant and water for this
reaction (entry 9).
a,b
Table 2 Substrate scope
Table 1 Optimization of the reaction conditions
With the optimized conditions in hand, we began to
explore the substrate scope and limitations of this AQ-
directed C(sp3)-H hydroxylation reactions. The scope of this
new C-H hydroxylation reaction was found to be broad. As
illustrated in Table 2, various alkyl (methyl, n-butyl, isopropyl,
tert-butyl, cyclopentyl, benzyl, etc) (3a-3t) at the alpha
position were compatible to the reaction conditions and
most of them afforded desired product in moderate to good
To demonstrate practicality of this synthetic methodology,
large-scale reactions were conducted to give corresponding
hydroxylated product 3l and 3v in satisfactory yields with
partially recovered starting materials ([Eq. (1) and (2)]). As
illustrated in Scheme 2, the hydroxylated products can be
2 | J. Name., 2012, 00, 1-3
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readily converted to various valuable derivatives through
Further studies were performed to gain insights into the
known chemical transformations. For instance, aldehydes 5m, reaction mechanism. One possible reaction pathway would
5n were obtained by oxidation and 3-amino alcohol 5o was involve β-H elimination, which was followed by oxa-Michael
prepared via reduction with LiAlH4. α,β-Unsaturated amide 5l addition to provide the desired product. As depicted in
can be accessed in a yield of 95% via elimination. The acidic Scheme 3, to test this possibility, deuterated water and
deprotection can cleave the directing group and afford acetone were used as the cosolvent in the reactions.
corresponding alcohols 5p and 5q in good yields. Additional However, compound 3f was formed in a good yield of 70%
hydrolysis of 5q would furnish α,β-hydroxyl acid 5r. and none of the corresponding α-deuterated compound was
Mitsunobu reaction with varied nucleophiles can further found, which should exclude the above-proposed
transform the hydroxyl group into different functional mechanism. The use of H218O instead of H216O generated
groups in satisfactory yields, such as aliphatic halides (5a, 5j), compound 6 as the major product, which was confirmed by
β-amino acid 5b, aryl ether 5c, thio ethers (5g, 5h), β-lactam LC-MS and NMR analysis (for details, see Supporting
5d, aliphatic azide 5f, and aryl ester 5k, etc.
Information). These results clearly showed that the oxygen
atom in the hydroxyl group originated from water. Next, the
cyclic palladated complex 7 was prepared and used in the
following reactions. The experimental results showed that no
desired product was observed without cyclic I3+ oxidant,
otherwise roughly 65% of hydroxylated product 4d was
obtained. Therefore, it was suggested that Pd(II) needed to
be oxidized to Pd(IV)14 before affording the C-H
hydroxylation product.
O
O
O
Pd(OAc)2 10 mol %
H18
O
NHQ
HO
NHQ
NHQ
I (III)-OH, OMe or OAc 2.0 equiv,
acetone:H218O/ 3:1, 105 oC, 12 h
"90% 18O atom for H218O"
O
O
O
3f
6
7:3
(70% yield)
H
NQ
Me
Ph
HO
NHQ
OMe
CHO
O
O
O
D
Pd(OAc)2 10 mol %
5o (61%)o
5n (62%)m,n
HO
NHQ
NHQ
HO
NHQ
5m (54%)l
QHN
I (III)-OH 2.0 equiv,
acetone:D2O/ 3:1, 105 oC, 12 h
O
Ph
oxidation
reduction
OMe
3f
O
(70% yield)
not observed
O
HO
5p (95%)m
O
O
elimination
deprotection
Pd(OAc)2 1.05 equiv, pyridine 2.0 equiv
MeCN, 70 oC, 8 h
OH
R
HO
NHQ
N
N
R
Pd
N
N
H
F
N
(80% yield by column purification)
(95% yield by direct filtration)
Mitsunobu
reaction/ SN2
O
OMe
Ph
R = OMe, 5q (97%)m
;
5l (95%)e,k
no oxidant
7
OH, 5r (99%)p.
No reaction happened. All sm remained.
acetone: H2O/ 3:1
90 oC, 8h
O
O
O
7
O
I
O
Ph
NHQ
N
R
NHQ
NQ
H
NHQ
O
N
R = Cl, 5a (94%)a;
NPht, 5b (60%)b.
OH
R
I(III)-OH 2.0 equiv
R = OMs, 5e (95%)e;
N3, 5f (97%)f;
5c (64%)c
5d (57%)d
4d
(65% yield)
SMe, 5g (97%)g;
R
O
O
O
,5h (90%)h.
Scheme 3 Mechanistic studies.
S
NHQ
MeO
O
NHQ
Ph
N
N
MeO
N
N
R = OMs, 5i (94%)e;
I, 5j (84%)i.
O
O
OMe
5k (77%)j
H
O
(kcal mol-1)
∆G
N
IV
N
d
P
28.9
Conditions: a) SOCl2, DCM, reflux, 12h; b) PPh3, DIAD, Phthalimide, THF, 0oC-rt,
1h; c) MsCl, Et3N, DCM, 0oC, 1h; 2-iodophenol, Cu(OAc)2, K2CO3, DMF, 70oC, 2h;
d) MsCl, Et3N, DCM, 0oC, 1h; NaSMe, DMF, 50oC, 1.5h; e) MsCl, Et3N, DCM, 0oC,
1h; f) NaN3, Cu(OAc)2, DMF, 70oC, 2h; g) NaSMe, MeOH/H2O, rt, 2h; h) 1-phenyl-
1H-tetrazole-5-thiol, K2CO3, DMF, 70oC, 2h; i) NaI, acetone, reflux, 48h; j) PPh3,
DIAD, 3,5-dimethoxybenzoic acid, THF, 0oC-rt, 1h; k) K2CO3, acetone, reflux, 48h; l)
TBDBSCl, imidazole, THF, rt, 1h; t-BuOK, MeI, THF, rt, 2h; TBAF, THF, rt, 4h; DMP,
DCM, rt, 1h; m) conc.H2SO4, MeOH, 105oC, 12h; n) DMP, rt, 1h; o) LiAlH4, THF, 0
oC-rt, 6h; p) LiOH, MeOH/H2O, rt, 1h.
O
(CH3)2C
O
I
TSRE
0.0
-10.6
ARE
O
OH
O
BAE
N
N
IV
N
N
d
P
II
HO
O
Pd
(CH3)2C O
O
O
O
O
(CH3)2C
I
I
Scheme 2 Product transformations.
Fig. 1 DFT-calculated reaction profile of intramolecular reductive
elimination (RE) mechanism for the final C-O bond formation of
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hydroxylation.
Notes and references
1
For some recent reviews on transition-metal-catalyzed C-H
After formation of Pd(IV) species, as to the key final C-O
bond formation step, we explored the intramolecular
reductive elimination (RE) process to give the
hydroxylated product and regenerate Pd(II) by using DFT
theoretical calculation. As shown in Figure 1. We can see
that via a transition state TSRE, RE needs to overcome a
reaction barrier of 28.9 kcal mol-1, which implies that RE
mechanism for the final C-O bond formation is a feasible
one in the current reaction system.
functionalization reactions, see: (
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Scheme 4 Plausible mechanism.
Although some details of the mechanism remain to be
ascertained, based on our experimental and computational
studies, a plausible mechanism was proposed (Scheme 4).
The first step involves AQ-directed C(sp3)-H activation by
Pd(OAc)2 to form a bicyclic five-membered cyclopalladated
intermediate, which was then oxidized by ligand exchanged
cyclic I3+ reagent to generate Pd(IV) complex. Reductive
elimination afforded Pd(II) coordinated hydroxylated product, Jr., J. Am. Chem. Soc., 2001, 123, 6327.
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which reacts with another substrate to afford final product
and restart the catalytic cycle.
In summary, we have developed the first Pd(II)-catalyzed Chem. Soc., 2010, 132, 12550.
hydroxylation of C(sp3)-H bonds with water as a unique
hydroxyl group source. The prepared hydroxylated products
are highly valuable building blocks for further chemical
transformations and this new hydroxylation reaction can also
be employed to modify drugs efficiently. This new reaction
demonstrates good reactivity and broad functional group
tolerance. Further studies on the application and mechanism
of this new reaction are in progress in our laboratory.
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Acknowledgements
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This work was supported by the national ‘973’ grant from the
Ministry of Science and Technology (grant # 2011CB965300),
National Natural Science Foundation of China (grant #
21302106, 21290194, 21221002, 21473215) and Tsinghua
University Initiative Scientific Research Program.
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