N -Boc amines to oxazolidinones via Pd(II)/bis-sulfoxide/br?nsted acid Co-catalyzed allylic C-H oxidation

Article abstract of DOI:10.1021/ja506036q

A Pd(II)/bis-sulfoxide/Br?nsted acid catalyzed allylic C-H oxidation reaction for the synthesis of oxazolidinones from simple N-Boc amines is reported. A range of oxazolidinones are furnished in good yields (avg 63%) and excellent diastereoselectivities (avg 15:1) to furnish products regioisomeric from those previously obtained using allylic C-H amination reactions. Mechanistic studies suggest the role of the phosphoric acid is to furnish a Pd(II)bis-sulfoxide phosphate catalyst that promotes allylic C-H cleavage and π-allylPd functionalization with a weak, aprotic oxygen nucleophile and to assist in catalyst regeneration.

Full text of DOI:10.1021/ja506036q

Article
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N‑Boc Amines to Oxazolidinones via Pd(II)/Bis-sulfoxide/Brønsted
Acid Co-Catalyzed Allylic C−H Oxidation
Thomas J. Osberger and M. Christina White*
Roger Adams Laboratory, University of Illinois Urbana−Champaign, Champaign, Illinois 61801, United States
*
S Supporting Information
ABSTRACT: A Pd(II)/bis-sulfoxide/Brønsted acid catalyzed
allylic C−H oxidation reaction for the synthesis of oxazolidinones
from simple N-Boc amines is reported. A range of oxazolidinones
are furnished in good yields (avg 63%) and excellent
diastereoselectivities (avg 15:1) to furnish products regioisomeric
from those previously obtained using allylic C−H amination
reactions. Mechanistic studies suggest the role of the phosphoric
acid is to furnish a Pd(II)bis-sulfoxide phosphate catalyst that
promotes allylic C−H cleavage and π-allylPd functionalization
with a weak, aprotic oxygen nucleophile and to assist in catalyst
regeneration.
INTRODUCTION
Scheme 1. Pd/Bis-Sulfoxide Catalyzed Allylic C−H
Oxidations To Form 1,2-Amino Alcohol Motifs
■
Brønsted acid catalysis is increasingly being recognized as a
powerful strategy for electrophile activation. Such organo-
1
catalytic modes of activation hold tremendous potential for
cooperative catalysis with organometallic systems, as has been
2
,3
4
recently demonstrated in Pd and Ir /phosphoric acid catalyzed
allylic functionalizations and C−H activation/rearrangement
reactions. We reasoned that for C−H activation reactions that do
not tolerate exchangeable, dative ligands that are often used in
Lewis acid catalysis, this mode of electrophile activation may be
especially powerful. Herein we report the successful application
of this concept toward the synthesis of oxazolidinones from
simple N-Boc-amines.
Palladium(II)/bis-sulfoxide catalysis has emerged as a general
5
6
platform for allylic C−H esterification, alkylation, dehydrogen-
7
8
9
ation, fluorination, and amination. Common to these C−H
functionalization reactions is the use of acidic, protic pro-
nucleophiles that become deprotonated in situ and activated
toward functionalization while concomitantly acting as proton
tions wherein these aprotic moieties are able to functionalize
13
highly activated iodonium electrophiles, we endeavored to
discover an activation mode to generate a highly electrophilic π-
allylPd intermediate while providing a source of exogenous
proton for efficient catalyst regeneration. Herein we describe the
merging of C−H activation catalysis with Brønsted acid catalysis
to effect the synthesis of anti-oxazolidinones from simple N-Boc
homoallylic amines.
10
sources for Pd(0) → Pd(II) reoxidation. In many cases, aprotic
nucleophiles are desirable because of their ease of preparation
and potential as surrogates for highly unstable protic analogues.
For example, we previously reported that allylic N-tosyl
carbamates undergo C−H amination to furnish N-tosyl 5-alkyl-
11
4
-vinyloxazolidinones (Scheme 1), important pharmacophores
in their unprotected form and precursors to amino-alcohols
motifs. The only method to furnish the regioisomeric N/O
9
d
RESULTS AND DISCUSSION
■
Reaction Development. At the outset of our investigation,
we evaluated the reaction of homoallylic Boc-amine 2a with
Pd(II)/bis-sulfoxide catalyst 1 under standard allylic amination
conditions and observed low conversion to the desired product
motif starts with N-nosyl ureas and gives 2-aminooxazoline
1
2
heterocycles (Scheme 1). We considered that a direct
regiodivergent C−H oxidation method may be possible from
readily accessible N-Boc amines (Scheme 1, this work). In
addition to being a common protecting group for amines, the N-
tert-butoxycarbonyl (N-Boc) group is an aprotic surrogate for
highly unstable carbamic acids. Inspired by iodofunctionaliza-
Received: June 16, 2014
Published: July 7, 2014
©
2014 American Chemical Society
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Article
a
Table 1. Reaction Development
10). An iterative addition of DBP (3 times 17 mol %) over 3 h
was found to only marginally increase the yield of 3a (entry 11);
however, with lower converting substrates we observed that this
protocol increases reactivity, possibly by extending the catalyst
lifetime (vida infra). Deleting catalyst 1 from the reaction
resulted in no observed product and 97% recovered starting
material after 24 h, indicating that no deprotection of the Boc
group occurs under these mildly acidic conditions in the absence
of catalyst (entry 12). Substituting the sterically hindered 2,6-
dimethylbenzoquinone for 1,4-benzoquinone resulted in low
conversion and no observable 3a, suggesting that the
functionalization step of this reaction is quinone dependent
5b−e
(
entry 13).
Lewis acid additives, known to promote reactivity
with protic nucleophiles under Pd(II)/bis-sulfoxide catal-
9
a,d,12
ysis,
salen)Cl
were also investigated. Oxophilic Lewis acid Cr-
9a,d
(
minimally converted starting material with no
product formation (entry 14). Azaphilic Lewis acids AgOTf and
1
2
B(C F ) , also hypothesized to promote reactivity by
6
5 3
enhancing the electrophilicity of the π-allylPd intermediate,
15
were less effective than Brønsted acids. This is consistent with
our hypothesis that when using nonacidic pronucleophiles a
source of exogenous proton is necessary for effective catalyst
regeneration (entries 15 and 16). Interestingly, copper(II)
triflate promoted the reaction (entry 17); however, even after
extensive optimization, yields and diastereoselectivities of
oxazolidinone product 3a remained moderate.
Scope and Applications. We next sought to explore the
substrate scope of the reaction (Table 2). N-Boc homoallylic
amine substrates possessing varying degrees of steric congestion
a
Conditions: 0.3 mmol (1.0 equiv) 2a, 10 mol % 1, acid (indicated
and functionality were prepared using Ellman’s sulfinamine
b
equiv), 1.5 equiv BQ, 2 M 1,4-dioxane, 45 °C, 24 h. Determined by
14,16
auxiliary or other standard methods.
Substrates having at
1
c
H NMR of the crude reaction mixture. Obtained 20% isolated yield
least one branching element adjacent to the amine afforded good
yields of oxazolidinones as one diastereomer (3b, 3c, 3d).
Significantly, small substituents like isobutyl and even methyl
gave useful diastereoselectivities (3e, 3f). Such high diastereo-
selectivities are rare for allylic C−H oxidation processes and may
be attributed to the conformational rigidity of the carbamate
tether resulting from amide A(1,3) strain. Oxygen- and nitrogen
containing functionality (e.g., ethers, esters, amides) may also be
present on the substrates, furnishing densely functionalized
products with functional group handles for further elaboration
(3g, 3h, 3i, 3j). It is significant to note that acid labile
functionality such as primary silyl ethers, tert-butyl esters, and
even a distal Boc-amino group are all stable under these mildly
acidic conditions. Notably, aryl substitution in the homoallylic
position gave product in good yields and excellent diastereo-
selectivities: previous allylic C−H functionalization reactions did
not tolerate such substitution due to formation of stable diene
products (3k). Benzyl-substituted amines furnished products in
good yields as one diastereomer (3l, 3p). Significantly, substrate
2m containing an indole moiety, was well-tolerated under these
acidic, oxidative conditions providing 3m. Indoles have been
previously reported to undergo oxidation on the ring with Pd(II)
d
of allylic p-nitrobenzoate (see Supporting Information). Obtained
1% isolated yield of allylic o-nitrobenzoate (see Supporting
5
e
Information). DBP added in three 0.17 mmol portions at t = 0,
f
1
.5, and 3 h. Reaction run without 1; 97% recovered starting material.
g
2
,6-Dimethylbenzoquinone (1.5 equiv) employed as oxidant; 94%
h
recovered starting material. 87% recovered starting material.
(Table 1, entry 1). We reasoned that Brønsted acids may activate
the π-allylPd species by protonating anionic ligands (e.g.,
acetate) and/or promoting breakdown of the N-Boc pro-
nucleophile and provide the necessary protons required for
catalyst regeneration (vide infra). We first evaluated carboxylic
acid additives that are known to be compatible with the Pd(II)/
bis-sulfoxide reaction manifold. The addition of acetic acid
provided a significant increase in reactivity with excellent
diastereoselectivity (entry 2). Increasing the acidity of the
carboxylic acid increased reactivity; however, it led to significant
formation of linear allylic ester byproducts (entries 3−5). For
example, ortho-nitrobenzoic acid, (entry 5), led to 78% overall
conversion but only 27% yield of oxazolidinone 3a and 51% yield
of the linear allylic benzoate. We hypothesized that phosphoric
acids may similarly promote reactivity with minimized linear
functionalization byproducts. Dibutylphosphate (DBP), a
phosphoric acid with a comparable pK to ortho-nitrobenzoic
acid, furnished a promising 54% yield of 3a with excellent
14
17
salts under acidic conditions. Finally, we probed the reaction
tolerance of high levels of steric bulk on the amine-bearing center
given that stereocontrolled methods for efficient access to β,β-
a
18
diastereoselectivity and no observable allylic phosphate by-
products (entry 6). Phosphoric acids with lower pK values gave
diminished yields (entry 7). Lowering the loading of DBP to
substoichiometric amounts, we found 50 mol % to be optimal
disubstituted amino alcohol motifs are scarce. Gratifyingly, the
reaction proved to be tolerant of highly congested stereocenters,
providing oxazolidinones 3n, 3o, and 3p in good yield and
diastereoselectivity.
a
(
63% yield, entry 8) and highly scalable up to nearly 20-fold the
In addition to providing a direct and highly selective route to
oxazolidinones, we recognized that such compounds could be
readily elaborated to valuable α-hydroxy-β-amino acid com-
typical scale with little change in efficiency (entry 9). Lower DBP
loadings (e.g., 20 mol %) reduced reactivity (45% yield, entry
1
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II
Table 2. Pd /Bis-sulfoxide/Phosphoric Acid-Catalyzed
Scheme 2. Application to Hydroxyamino Acid Motifs
a
Allylic C−H Oxidation
a
Conditions and Reagents: RuCl ·xH O, H IO , CCl /H O/MeCN,
3
2
5
6
4
2
b
c
rt, 5h, 89%; 6 M HCl, 100 °C, 16 h, 97%. Conditions: 1.0 equiv
substrate (-)-5, 10 mol % 1, 50 mol % DBP (3 × 17 mol % at 0 h, 1.5
h, and 3 h), 1.5 equiv BQ, 2.0 M in 1,4-dioxane, 45 °C, 24 h. dr
determined by H NMR of crude reaction mixture.”
d
1
Powerful features of this allylic C−H oxidation reaction are its
predictably high diastereo- and site-selectivity. When coupled
with our previously reported intramolecular allylic C−H
11
amination, these two Pd(II)bis-sulfoxide catalyzed methods
function as regiodivergent synthetic transforms for the synthesis
of oxazolidinones and 1,2-amino alcohols starting from a
common aldehyde precursor (Scheme 3). For example, starting
Scheme 3. Regiodivergent Synthesis of 1,2-Amino Alcohols
a
Conditions: 1.0 equiv substrate 2, 10 mol % 1, 50 mol %
(
BuO) PO H, 1.5 equiv BQ, 2.0 M in 1,4-dioxane, 45 °C, 24 h.
2 2
1
b
Diastereomeric ratio (dr) determined by H NMR of crude reaction
c
mixtures. Iterative addition of 17 mol % DBP at 0 h, 1.5 h, 3 h.
d
Optical rotation measured on material in >20:1 dr after additional
e
purification. Isolated as a 15:1 dr mixture after 1 flash chromato-
graphic purification.
pounds, such as those found in the biologically active molecules
18b
Taxol, Bestatin, and Amastatin (Scheme 2). Vinyloxazolidin-
one 3a can be readily transformed into syn-3-amino-2-hydroxy-4-
phenylbutyric acid (AHPBA, 4), the hydroxyamino acid
19
component of the dipeptide aminopeptidase inhibitor Bestatin,
from aldehyde (−)-7, derived from commercially available (L)-
ethyl lactate, conversion to homoallylic, Boc-amine (+)-8 was
achieved via Ellman’s auxiliary. Cyclization via Pd(II)bis-
sulfoxide/DBP catalyzed CH oxidation proceeded smoothly,
affording oxazolidinone (−)-9 in 63% yield as a single
diastereomer. N-methylation and hydroboration/oxidation of
the terminal olefin yielded (−)-10, a known synthetic
via a sequence of olefin oxidation and oxazolidinone hydrolysis to
the free amino alcohol (Scheme 2A). Additionally, the high
functional group tolerance of this method enables the direct C−
H amination of Boc-protected β-allylglycine residues within a
peptide setting. For example, the dipeptide leucine-β-allylglycine
(
−)-(5) underwent Pd(II)bis-sulfoxide/phosphoric acid cata-
lyzed C−H amination to afford a 57% yield of oxazolidinone 6
Scheme 2B).
2
0
intermediate to perosamine, an aminosugar found in
21
(
pyrrolosporin A, an antitumor antibiotic. Alternatively, starting
1
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from (−)-7, the previously reported Pd(II)bis-sulfoxide
Finally, we investigated our hypothesis that the phosphoric
acid acts as Brønsted acid cocatalyst to generate an electrophilic
π-allylPd(phosphate) intermediate highly activated toward
nucleophilic attack. A Pd(II)bis-sulfoxide-phosphate complex
11
mediated allylic C−H amination route efficiently provides
the regioisomeric oxazolidinone which is an intermediate in the
synthesis of (−)-N-methylacosamine, a sugar found in
2
2
epirubicin.
was generated in situ via metathesis of Pd(II)bis-sulfoxide-Cl 12
2
Mechanistic Investigations. An important question raised
by these studies relates to the mechanism by which catalytic
phosphoric acids promote allylic C−H oxidation with N-Boc
amines. The phosphoric acid additive may promote loss of t-
butyl cation from the Boc group, forming a transient carbamic
acid species that functionalizes the π-allyl. However, we have
observed the preservation of distal Boc groups under the reaction
conditions (Table 2, 3j and 3m), as well as greater than 90%
recovery of starting material in the absence of Pd(II)/bis-
sulfoxide catalyst or 2,6-dimethylbenzoquinone as oxidant
with AgO P(OBn) and the resulting solution was used as a
catalyst under otherwise identical conditions (Scheme 5A). The
2
2
Scheme 5. In Situ Formation and Reactivity of
II
Pd (phosphate) (bissulfoxide) Complex
2
(
Table 1, entries 12 and 13), suggesting that the reaction does
not proceed by simple acid promoted decomposition of Boc
groups.
The second mechanistic possibility is that phosphate anion
generated in equilibrium concentrations with acetateacts as a
23
nucleophilic catalyst to form a transient allylic phosphate via
intermolecular π-allylPd substitution. The allylic phosphate may
then undergo carbamate displacement to furnish oxazolidinone
and regenerate the phosphate catalyst. A competition experiment
between independently synthesized allylic phosphate 11 and
terminal olefin substrate 2a resulted in preferential reactivity of
the olefin (Scheme 4A). Consistent with this, initial rate studies
reaction proceeded in comparable yields, reaction times, and
selectivities as that using acetate catalyst 1. In the absence of
silver phosphate under otherwise identical conditions, 12 is
Scheme 4. DBP as a Possible Nucleophilic Catalyst
14
inactive toward allylic oxidation. Prior to this, only Pd(II)bis-
sulfoxide complexes having carboxylate counterions have shown
competence for allylic C−H cleavage. Consistent with a
Pd(II)bis-sulfoxide-phosphate complex being a competent
catalyst, a stoichiometric study under mock catalytic conditions
showed the Pd(II)bis-sulfoxide−phosphate complex effects C−
H cleavage (Scheme 5B). Significantly, the role of the Brønsted
acid cocatalysis extends beyond generation of a Pd(II)bis-
sulfoxide-phosphate complex; removal of phosphoric acid from
the reaction results in significantly diminished yields (19%, 5A).
This may be due to the requirement for acid to assist in catalyst
regeneration (Scheme 6, vide infra).
Scheme 6. Plausible Catalytic Cycle
on isopropyl olefin substrate 2c versus 11 under standard
reaction conditions show a faster reaction rate for olefin 2c (k ≈
rel
1
.8, Scheme 4B). In view of this, taken together with the fact that
allylic phosphates are not observed under these reaction
conditions, leads us to conclude that it is unlikely the reaction
proceeds primarily via a phosphate nucleophile-catalyzed
pathway.
1
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We present a plausible catalytic cycle that is consistent with
our studies in Scheme 6. Catalyst 1 may undergo equilibrium
acetate/phosphate exchange to form an intermediate of type A
having acetate and/or phosphate ligands (denoted X).
Intermediate A binds substrate 2 and subsequently performs
C−H cleavage, producing π-allylPd complex B and 1 equivalent
of proton source (HX). The weakly coordinating ligand (X) on B
may then dissociate to afford cationic complex C, which
undergoes functionalization. Loss of the tert-butyl group during
functionalization may proceed by loss of isobutylene gas with
concomitant generation of a second equivalent of proton and/or
by loss of t-butyl cation and subsequent trapping by DBP or
acetate (forming t-BuX products). We have observed (n-
Taylor for preliminary studies with Lewis acids, Mr. Rulin Ma for
Table 2 repeats, Ms. Jennifer Griffin for checking the procedure
in Table 1, entry 8, and Dr. Jennifer Howell for checking Scheme
5A. We thank Sigma-Aldrich for a generous gift of catalyst 1 and
Johnson Matthey for a gift of Pd(OAc)2.
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■
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CONCLUSION
■
We describe a Pd(II)/bis-sulfoxide/phosphoric acid catalyzed
intramolecular allylic C−H oxidation of simple homoallylic, Boc-
protected amine substrates to furnish anti-vinyl oxazolidinones.
This method provides unprecedented direct access to these
important heterocycles with outstanding stereoselectivities and
novel regioselectivities. Mechanistic studies suggest the in situ
generation of a Pd(II)/bis-sulfoxide/phosphate complex that is
capable of promoting both C−H cleavage and π-allylPd
functionalization with the weak, aprotic N-Boc amine pro-
nucleophile. These findings have important future implications
for effecting asymmetric induction under this general allylic C−
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26
H oxidation manifold.
(
1
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EXPERIMENTAL PROCEDURES
■
General Procedure for the Allylic C−H Oxidation Reaction
Table 2). A 1-dram vial was sequentially charged with substrate 2 (1.0
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(
equiv, 0.3 mmol), benzoquinone (48.6 mg, 1.5 equiv, 0.45 mmol), and
catalyst 1 (15.1 mg, 0.1 equiv, 0.03 mmol). A stir bar was added to the
vial, then 1,4-dioxane (0.15 mL, 2.0 M with respect to substrate) was
added to the vial via syringe, followed by dibutyl phosphate (28 μL, 0.5
equiv, 0.15 mmol). The vial was capped with a Teflon cap and stirred at
̈
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4
5 °C for 24 h. The reaction was diluted with CH Cl and transferred to
2 2
a separatory funnel. The mixture was washed with H O, the layers were
2
separated, and the aqueous layer was extracted with CH Cl (3 × 20
mL). Combined organics were dried over MgSO , filtered through a pad
of Celite, and concentrated. H NMR spectroscopy was performed on
the crude mixture to determine the diastereomeric ratio. Flash
2
2
4
(15) Significant amounts of olefin isomerization are also observed with
AgOTf and B(C F ) .
1
6
5 3
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9
84.
(
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data, and H and C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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■
*
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AUTHOR INFORMATION
Corresponding Author
white@scs.uiuc.edu
■
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The authors declare no competing financial interest.
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observation of apparent t-Bu scavenging by solvent acetonitrile in a
ACKNOWLEDGMENTS
Financial support was provided by the NIH/NIGMS (2R01 GM
76153B). T.J.O. thanks the University of Illinois for a
■
0
+
Springborn Graduate Fellowship. We thank Mr. Christopher
1
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related bromofunctionalization reaction. See: Yeung, Y.-Y.; Gao, X.;
Corey, E. J. J. Am. Chem. Soc. 2006, 128, 9644. (b) Direct generation of
isobutylene has also been proposed for a bromofunctionalization
process. See: Agami, A.; Couty, F.; Venier, O. Synlett 1995, 1027.
+
(
25) Our studies suggest that DBP does not simply play the role of tBu
scavenger. Superstoichiometric amounts of DBP were not optimal
compared to substoichiometric loadings. See Table 1, entry 6 vs entry 8.
(
26) (a) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4,
6
2
03. (b) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.Eur. J.
010, 16, 9350. (c) Ohmatsu, K.; Ito, M.; Kunieda, T.; Ooi, T. Nat.
Chem. 2012, 4, 473.
1
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