Pd-catalyzed intramolecular aminohydroxylation of alkenes with hydrogen peroxide as oxidant and water as nucleophile

Article abstract of DOI:10.1021/ja412023b

A palladium-catalyzed intramolecular aminohydroxylation of alkenes was developed, in which H₂O₂ was applied as the sole oxidant. A variety of related alkyl alcohols could be successfully obtained with good yields and excellent diastereoselectivities, which directly derived from oxidation cleavage of alkyl C-Pd bond by H₂O₂. Facile transformation of these products provided a powerful tool toward the synthesis of 2-amino-1,3-diols and 3-ol amino acids. Preliminary mechanistic studies revealed that major nucleophilic attack of water (S_N2 type) at high-valent Pd center contributes to the final C-O(H) bond formation.

Full text of DOI:10.1021/ja412023b

Communication
pubs.acs.org/JACS
Pd-Catalyzed Intramolecular Aminohydroxylation of Alkenes with
Hydrogen Peroxide as Oxidant and Water as Nucleophile
Haitao Zhu, Pinhong Chen, and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
S
* Supporting Information
30−35% aqueous H2O2 solution is broadly used in industry, and
those processes usually present “green” properties;7 (2) H2O2
ABSTRACT: A palladium-catalyzed intramolecular ami-
has enough oxidative potential to oxidize PdII species. Elegant
nohydroxylation of alkenes was developed, in which H2O2
was applied as the sole oxidant. A variety of related alkyl
alcohols could be successfully obtained with good yields
and excellent diastereoselectivities, which directly derived
from oxidation cleavage of alkyl C-Pd bond by H2O2.
Facile transformation of these products provided a
powerful tool toward the synthesis of 2-amino-1,3-diols
and 3-ol amino acids. Preliminary mechanistic studies
revealed that major nucleophilic attack of water (SN2 type)
at high-valent Pd center contributes to the final C-O(H)
bond formation.
studies from the Vedernikov group demonstrated that H2O2 can
oxidize aryl C-PdII complex with special ligand to yield aryl C-
PdIV(OH) complex.6a,8 We hypothesized that if related alkyl C-
PdIV(OH) could undergo reductive elimination, or external
water could act as a potential nucleophile to react with this PdIV
intermediate, the direct formation of alkyl alcohol product might
be expected (Scheme 1, bottom). In Shilov reaction, water was
reported as a nucleophile to attack carbon center of Me-PtIV
complex (SN2 type), which accounted for the formation of
MeOH.9 But the related water substitution reaction is quite rare
due to its poor nucleophilicity.10 Herein, we report a novel Pd-
catalyzed intramolecular aminohydroxylation of alkenes using
H2O2 as oxidant under mild reaction conditions. Notably, the
final C-O bond formation was mainly achieved through external
water substitution at the carbon center of alkyl C-PdIV (or PdIII)
intermediate via SN2-type nucleophilic attack pathway (Scheme
1, bottom).
Recently, our group revealed that H2O2 can be used as the sole
oxidant to achieve Pd-catalyzed chlorination of alkenes.11
However, acidic solvent (HOAc) is crucial for these trans-
formations. During further studies, we were delighted to find that
an aminohydroxylation product 4a (32% yield) was observed in
the absence of chloride additives, along with aminoacetoxylation
product 3a in 48% yield. Further treatment of 3a under standard
condition could not deliver product 4a (eq 1). Thus, we believed
that 4a should be generated from direct reductive elimination of
alkyl-PdIV(OH) or external water nucleophilic attack at carbon
center of alkyl-PdIV complex.
alladium-catalyzed oxidative reactions are important trans-
P
formation in organic synthesis.1 In the past decade, high-
valent palladium catalysis has been received much attention, and
a number of palladium-catalyzed oxidative C-H functionalization
and alkene difunctionalization reactions have been developed.2
Among these reactions, stoichiometric amount of strong
oxidants are generally required to generate PdIV (or PdIII)
intermediates, which readily undergoes reductive elimination to
yield the new chemical bonds.3,4 For instance, alkyl C-PdII
species, which was generated from C-H activation or
nucleopalladation of alkene, can be efficiently oxidized by
PhI(OAc)2 or other oxidant to deliver alkyl C-OAc,5 which can
be further transformed to related alkyl alcohols (Scheme 1, top).
Scheme 1. Oxygenation of Alkyl C-PdII Intermediates
Inspired by the above understanding, we thought replacing an
acidic solvent with another solvent could avoid the formation of
3a, which is beneficial for aminohydroxylation. After extensive
screening of different reaction parameters, the optimized
reaction condition was obtained as follows (Table 1): Pd(OAc)2
(5 mol %), 35% aqueous H2O2 (3 equiv), LiO2CCF3 (2 equiv),
and substrate 1a in acetone at room temperature. The reaction
However, these reactions often produce a large amount of
byproducts due to utilizing above oxidants. In order to avoid
these byproducts, exploration of environmental benign, such as
dioxygen or H2O2 to achieve these oxidative transformations is
an important new trend.6 Among them, 30−35% aqueous H2O2
solution is a preferred oxidant with regard to two aspects: (1)
Received: November 28, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja412023b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Communication
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope
b
yield (%)
entry
reaction condition
standard condition
4a 5a
1
2
3
4
5
6
7
85
0
7
0
no Pd catalyst
Pd(O2CCF3)2 instead of Pd(OAc)2
Pd(CH3CN)2Cl2 instead of Pd(OAc)2
Pd(dba)2 instead of Pd(OAc)2
no CF3CO2Li
75
66
20
80
35
40
33
0
7
5
10
14
23
32
15
40
28
5
CF3CO2Na instead of CF3CO2Li
CH3CO2Li instead of CF3CO2Li
CH3CO2H instead of CH3CO2Li
LiOH instead of CH3CO2Li
urea-H202 instead of aq H202
Na2C03-H202 instead of aq H202
dioxane instead of acetone
THF instead of acetone
c
8
9
10
11
12
13
14
15
16
17
18
50
20
80
67
61
33
trace
trace
9
5
toluene instead of acetone
DMF instead of acetone
9
15
30
trace
NMP instead of acetone
CH3CN instead of acetone
a
b
All the reactions were run at 0.2 mmol scale. Yield obtained by 1H
c
NMR with 1,3,5-trimethoxylbenzene as internal standard. 21%
aminoacetoxylation product.
provided the desired product 4a in 85% yield, along with 7% aza-
Wacker product 5a (entry 1). The structure of 4a was confirmed
by X-ray crystallography. The palladium catalyst was required for
the successful transformation and Pd(OAc)2 gave the best yield
(entry 2−5). The presence of LiO2CCF3 is beneficial to give the
better result (entry 1 vs 6). However, replacing LiO2CCF3 with
LiO2CCH3, NaO2CCF3, or HO2CCF3 diminished the reaction
yields (entries 7−9). Addition of LiOH could inhibit the
aminohydroxylation reaction (entry 10). For the H2O2 source,
aqueous solution is better than urea·H2O2 and Na2CO3·H2O2
complexes (entries 11−12). Finally, screening of solvents
revealed that acetone and dioxane were the best for the
aminohydroxylation; THF and toluene were also suitable to
give the desired product in moderate yields. However, polar
solvents, such as DMF, NMP, and CH3CN, were not compatible
for this reaction (entry 13−18).
With the optimized condition in hand, substrate scope was
further examined (Table 2). The substrates synthesized from
allylic alcohols were first investigated. All those reactions
proceeded very well to provide the desired aminohydroxylation
products (4a−4j) in good yields. For all these γ-substituted
terminal alkenes, excellent diastereoselectivities (>20:1) were
observed to give single trans-isomer products. Interestingly, for
the substrates (1k and 1l) bearing two double bonds, the
reactions selectively occurred at the double bond of allylic moiety
to give products 4k and 4l in excellent yields, and another double
bond remained intact. It is worth noting that products 4g, 4i, and
4j were obtained from corresponding allylic alcohols with two
steps in a one-pot reaction. The 1,1-disubstituted substrate 1m
also afforded product 4m in 64% yield. But internal alkene (1n)
was not compatible to the reaction condition. Furthermore,
substrate 1o which was derived from allylic amine was also good
for this transformation to give product 4o in moderate yield.
a
Reaction condition: substrate (0.2 mmol), H202 (35% aq, 3 equiv),
Pd(OAc)2 (5 mol %), CF3COOLi (2 equiv) in acetone (2 mL) at 0
b
°C. Isolated yield, the data in pharenthesis is the ratio of trans:cis.
c
d
e
Room tempertaure. At −5 °C. Reaction was conducted from allylic
f
alcohol in one pot. Without CF3COOLi.
Beside above allylic alcohol-type substrates, homoallylic
substrates 1p−1s were also compatible for the current reaction
condition to give aminohydroxylation products 4p−4s in good
to excellent yields, albeit with moderate diastereoselectivities (3−
5:1).
2-Amino-1,3-diol is an important moiety in natural products
and bioactive compounds. For instance, safingol, which contains
2-amino-1,3-diol backbond, has been considered as a valuable
candidate for antineoplastic and antipsoriatic drugs and is
extensively investigated for its role in cell regulation signal
transduction and inhibition of protein kinase C.12 With the
current transformation, safingol could be efficiently synthesized
from simple allylic alcohol 6t. As shown in eq 2, the single isomer
of trans-4t was provided from the reaction of 6t in high yield and
excellent diastereoselectivity in one pot, and further deprotection
B
dx.doi.org/10.1021/ja412023b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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and ring-opening processes delivered racemic safingol in 90%
yield. In addition, chiral allylic alcohol (2R,3S)-6u could also be
converted to the product (2R,3S,4R)-4u in 83% yield with high
dr selectivity. Final deprotection steps provided chiral amino-
tetraol carbamate (2R,3S,4R)-7u in good yields (two steps, 85%
overall yields, eq 3). It is worth noting that the core of
Scheme 2, addition of extra water resulting in highly selective
trans-4a-d1 formation was consistent with SN2 nucleophilic
pathway b. Furthermore, the reaction rate was significantly
enhanced by increasing the concentration of H2O2 (see the SI),
implying that oxidation of PdII should contribute to the rate-
limiting step.
Interestingly, when the reaction was conducted in HOAc, the
opposite stereoconfiguration products were obtained (Scheme
3). The reaction of trans-1a-d1 gave the mixture of cis-4a-d1 and
Scheme 3. Mechanism in HOAc
(2R,3S,4R)-7u is an enantiomer of the core of natural products
bathymodiolamides A and B, which exhibit the potential activity
to inhibit the growth of two cancer cell lines (cervical and breast
cancer).13
In order to gain insights into the stereochemical course of the
C-N and C-O bond forming steps, trans-1a-d1 (80% D) was
subjected to the standard condition with different additives
(Scheme 2). First, only a single isomer trans-5a-d1 was obtained
cis-3a-d1 in high diastereoselectivities (>20:1), combined with a
small amount of cis-5a-d1. The formation of cis-5a-d1 indicated
that the reaction should be initiated by trans-aminopalladation to
give int-III.16 After oxidation by H2O2, high-valent palladium
complex int-IV possibly reacts with solvent HOAc to give
complex int-V. The selective formation of cis-4a-d1 and cis-3a-d1
revealed that the C-O bond formation undergoes SN2
nucleophilic attack by H2O or HOAc at the carbon center of
high-valent palladium complex int-IV or int-V.
Scheme 2. Mechanism in Standard Condition
Critical evidence was obtained in the isotope labeling
experiments by using H2O2 in H2O18 solution.17 The reaction
in dioxane led to the formation of [18O]-4a and 4a with the ratio
of 1.3:1 (eq 4), and this result was unequivocally confirmed by
mass spectrometry. In addition, the mixture of [18O]-4a and 4a
with the similar ratio was obtained in the same reaction in AcOH
(eq 5). Interestingly, this reaction afforded product 3a without
18O incorporation, which also implied the formation of 4a was
not derived from product 3a.
as a side product in ∼10% yield in the above reactions, which
suggest the reaction involved a cis-aminopalladation process to
give alkyl C-Pd(II) species (int-I). Meanwhile, these reactions
also afforded the mixture of two isomers cis-4a-d1 and trans-4a-d1,
in which the trans-isomer is predominant. And the ratio of cis-
and trans-isomer varied significantly according to the different
additives. For instance, the ratio of trans/cis-4a-d1 was increased
from 1.7:1 to 4.7:1 by removal of CF3CO2Li and further
increased to 7.6:1 by adding exogenous water.
With the above results, we believe the high-valent palladium
complex int-II might be involved to account for C-OH bond
forming (Scheme 2):14 (1) cis-4a-d1 was delivered from the direct
reductive elimination of PdIV complex int-II, resulting the
retention of the C(sp3) center (path a); and this process could be
promoted by addition of CF3CO2Li (see above). (2) For the case
of trans-4a-d1, the reaction should involve a SN2 type nucleophilic
attack pathway due to the inversion of the C(sp3) center, and
external water acts as a nucleophile (path b).15 As shown in
Vedernikov has reported that the C-O reductive elimination of
LPtIV(OH)2Me in H2O18 via water nucleophilic substitution is
much faster than that of 16OH/18OH exchange in Pt center. In
addition, there is no oxygen exchange between H2O2 and H2O18
in the absence or presence of palladium catalyst.16 Thus, the
formation of [18O]-4a implied that H2O18 should act a
nucleophile to attack the high-valent Pd complex to construct
a C-O18H bond via a favorable SN2-type substitution. To the best
C
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Journal of the American Chemical Society
Communication
J. Am. Chem. Soc. 2006, 128, 7179. (e) Desai, L. V.; Sanford, M. S. Angew.
Chem., Int. Ed. 2007, 46, 5737. (f) Wang, A.; Jiang, H. J. Org. Chem. 2010,
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132, 6284.
(6) For some reviews: (a) Vedernikov, A. N. Acc. Chem. Res. 2012, 45,
803. (b) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851.
(c) Piera, J.; Backvall, J.-E. Angew. Chem., Int. Ed. 2008, 47, 3506.
(d) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977.
(7) For safety guideline on H2O2: (a) http://en.wikipedia.org/wiki/
Hydrogen_peroxide. (b) http://h2o2.evonik.com/product/h2o2/en/
pages/h2o2-safety-training-video.aspx.
of our knowledge, this is a rare example of oxidative cleavage of a
C-Pd bond involving water as the nucleophile to give an alcohol
product. However, the above mechanism could not address the
formation of [16O]-4a.18 We assumed that alkyl Pd(IV)16OH
complex19 could also act as a nucleophile to compete with water,
allowing for nucleophilic attack of another alkyl Pd(IV)16OH to
give [16O]-4a.20
In conclusion, we have developed a simple catalytic system to
achieve intramolecular aminohydroxylation of alkenes with Pd
catalyst under mild reaction conditions. In this transformation,
aq H2O2 solution plays two roles to achieve C-OH bond
formation via a favorable SN2-type substitution pathway: H2O2 as
oxidant and water as nucleophile reacting with high-valent
palladium intermediate to give a C-O bond. Further application
of this aminohydroxylation reaction is in progress.
(8) Oxidation of stoichiometric amount of Pd(II) by H2O2: Oloo, W.;
Zavalij, P. Y.; Zhang, J.; Khashin, E.; Vedernikov, A. N. J. Am. Chem. Soc.
2010, 132, 14400.
(9) For Shilov reaction: (a) Shilov, A. E.; Shul’pin, G. B. Activation and
Catalytic Reactions of Saturated Hydrocarbons in the presence of Metal
Complexes, Kluwer, Dordrecht, 2000. (b) Shilov, A. E.; Shul’pin, G. B.
Chem. Rev. 1997, 97, 2879. (c) Kushch, K. A.; Lavrushko, V. V.;
Misharin, Y. S.; Moravshky, A. P.; Shilov, A. E. New. J. Chem. 1983, 7,
729. (d) Stahl, S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed.
1998, 37, 2180. Mechanistic studies on C-O bond formation:
(e) Vedernikov, A. N. Top. Organomet. Chem. 2010, 31, 101. (f) Luinstra,
G. A.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 1993, 115, 3004.
(g) Labinger, J. A.; Herring, A. M.; Bercaw, J. E. J. Am. Chem. Soc. 1990,
112, 5628. (h) Vedernikov, A. N.; Binfield, S. A.; Zavalij, P. Y.;
Khusnutdinova, J. R. J. Am. Chem. Soc. 2006, 128, 82. (i) Khusnutdinova,
J. R.; Zavalij, P. Y.; Vedernikov, A. N. Organometallics 2007, 26, 3466.
(10) Recently, only a few cases were reported with water acting as a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
gliu@mail.sioc.ac.cn
■
Notes
nucleophile in allylic substitutions: Ir catalyst (a) Gartner, M.; Mader, S.;
̈
The authors declare no competing financial interest.
Seehafer, K.; Helmchen, G. J. Am. Chem. Soc. 2011, 133, 2072. Ru
catalyst (b) Kanbayashi, N.; Onitsuka, K. Angew. Chem., Int. Ed. 2011,
50, 5197. Organocatalyst (c) Zhu, B.; Yan, L.; Pan, Y.; Lee, R.; Liu, H.;
Han, Z.; Huang, K.-W.; Tan, C.-H.; Jiang, Z. J. Org. Chem. 2011, 76,
6894.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Basic
Research Program of China (973-2011CB808700), the National
Nature Science Foundation of China (nos. 21225210, 21202185,
and 21121062), the Science and Technology Commission of the
Shanghai Municipality (11JC1415000), and the CAS/SAFEA
International Partnership Program for Creative Research Teams.
(11) (a) Yin, G.; Liu, G. Angew. Chem., Int. Ed. 2008, 47, 5442. (b) Yin,
G.; Wu, T.; Liu, G. Chem.Eur. J. 2012, 18, 451.
(12) (a) USP Dictionary of USAN and International Drug Names, US
Pharmacopoeis: Rockville, MD, 2000; P636. (b) Hannun, Y. A.; Bell, R.
M. Science 1989, 243, 500. (c) Schewartz, G. K.; Jiang, J.; Kelsen, D.;
Albino, A. P. J. Natl. Cancer. Inst. 1993, 85, 402.
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D
dx.doi.org/10.1021/ja412023b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX