Catalyst-controlled C-O versus C-N allylic functionalization of terminal olefins

Article abstract of DOI:10.1021/ja405394v

The divergent synthesis of syn-1,2-aminoalcohol or syn-1,2-diamine precursors from a common terminal olefin has been accomplished using a combination of palladium(II) catalysis with Lewis acid cocatalysis. Palladium(II)/bis-sulfoxide catalysis with a silver triflate cocatalyst leads for the first time to anti-2-aminooxazolines (C-O) in good to excellent yields. Simple removal of the bis-sulfoxide ligand from this reaction results in a complete switch in reactivity to afford anti-imidazolidinone products (C-N) in good yields and excellent diastereoselectivities. Mechanistic studies suggest the divergent C-O versus C-N reactivity from a common ambident nucleophile arises due to a switch in mechanism from allylic C-H cleavage/functionalization to olefin isomerization/oxidative amination.

Full text of DOI:10.1021/ja405394v

Article
pubs.acs.org/JACS
Catalyst-Controlled C−O versus C−N Allylic Functionalization of
Terminal Olefins
Iulia I. Strambeanu and M. Christina White*
Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana−Champaign, Urbana, Illinois, 61801, United
States
S
* Supporting Information
ABSTRACT: The divergent synthesis of syn-1,2-aminoalcohol
or syn-1,2-diamine precursors from a common terminal olefin
has been accomplished using a combination of palladium(II)
catalysis with Lewis acid cocatalysis. Palladium(II)/bis-
sulfoxide catalysis with a silver triflate cocatalyst leads for the
first time to anti-2-aminooxazolines (C−O) in good to
excellent yields. Simple removal of the bis-sulfoxide ligand
from this reaction results in a complete switch in reactivity to afford anti-imidazolidinone products (C−N) in good yields and
excellent diastereoselectivities. Mechanistic studies suggest the divergent C−O versus C−N reactivity from a common ambident
nucleophile arises due to a switch in mechanism from allylic C−H cleavage/functionalization to olefin isomerization/oxidative
amination.
Scheme 1. Ambident Nucleophile Reactivity
INTRODUCTION
■
The advent of powerful C−H oxidation reactions1 enables
reactive oxygen and nitrogen functionality to be carried through
synthetic sequences “masked” as inert C−H bonds and
strategically unveiled at late stages to improve efficiency and
increase diversity.2 A powerful approach to increase diversity
would be to take a common hydrocarbon starting material with
an appended ambident nucleophile and, by fully exploiting its
distinguishable reactive centers, selectively transform a C−H
bond into multiple functionalized products. In this regard,
homoallylic ureas could produce either imidazolidinones (cyclic
ureas, C−N functionalization) or 2-aminooxazolines (isoureas,
C−O functionalization), two medicinally important hetero-
cycles3 and precursors to 1,2-diamines or 1,2-aminoalcohols
(Scheme 1).4 While C−O olefin functionalizations with ureas
have been demonstrated using stoichiometric hypervalent
iodine reagents with limited scope,5 in palladium-catalyzed
reactions proceeding through either π-allylPd or amino-
palladated intermediates,6−11 ambident O/N nucleophiles
have reportedly provided primarily8e C−N functionalization
products (Scheme 1).
(base-promoted deprotonation at nitrogen) and thermody-
namic preference for C−N alkylation [Pd(0)-catalyzed
equilibration].14 Given that Pd(II)/sulfoxide catalysis proceeds
under acidic, oxidative conditions that do not favor nitrogen
deprotonation or promote reversible functionalization, O-
alkylation may compete with N-functionalization using urea
terminal olefin substrates. Additionally, O-alkylation may be
further promoted by the addition of an azaphilic Lewis acid
additive that binds to the nitrogen and retards nucleophilic
attack. Significantly, the 1,2-aminoalcohol products furnished
by this method would have the regiochemistry opposite to that
of products previously obtained from carbamate nucleophiles
Design Principles. Palladium(II)/sulfoxide catalysis has
proven itself to be a general platform for allylic C−H to C−O12
and C−N13 reactions of terminal olefins under mildly acidic,
oxidative conditions. For example, 1,2- and 1,3-aminoalcohol
precursors are readily accessible from homoallylic and bis-
homoallylic carbamates, respectively (Scheme 1). Under similar
conditions, homoallylic ureas could furnish either valuable 1,2-
diamine (C−N) precursors or 1,2-aminoalcohol (C−O)
precursors. Under the reductive, basic conditions of Pd(0)-
catalyzed allylic substitutions, ambident urea nucleophiles have
provided exclusively C−N products in the form of
imidazolidinones.6 This is thought to be due to both a kinetic
Received: May 29, 2013
© XXXX American Chemical Society
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(Scheme 1). With the goal of increasing diversity by tuning the
reactivity of an ambident urea nucleophile, herein we show that
readily accessible homoallylic N-nosyl urea substrates can be
transformed into 2-aminooxazolines (C−O) or imidazolidi-
nones (C−N) by a simple switch in the Pd(II) catalyst in the
presence of azaphilic Lewis acid cocatalysts.
have azaphilic properties with amides, increased the overall
selectivity favoring the formation of the desired 2-aminooxazo-
line (4.9:1 and 7:1, respectively) furnishing 4 in 50% and 76%
yield, respectively. In contrast, inclusion of an oxophilic Lewis
acid cocatalyst [Cr(salen)Cl],13a previously shown to activate
intermediate π-allylPd(BQ) electrophiles toward functionaliza-
tion, led to diminished yields and did not change the C−O to
C−N selectivity (entry 5). As had been previously observed
with carbamate nucleophiles, N-tosyl ureas are less reactive
(entry 6). Catalytic triflic acid (TfOH) additive promotes
reactivity but with lower selectivity for anti-aminooxazoline 4
(entry 7). This result is consistent with experimental
observations that water, which may form triflic acid in situ,
erodes C−O:C−N ratios. Deletion experiments showed that
the Pd/bis-sulfoxide catalyst 1 was critical for reactivity (entries
8 and 9). To the best of our knowledge, this represents the first
example of successfully tuning the reactivity of an ambident O/
N nucleophile under palladium catalysis to favor C−O bond
formation.
RESULTS AND DISCUSSION
■
Reaction Discovery: C−O Functionalization. We began
our study by subjecting N-nosyl urea 3 to our standard Pd(II)/
sulfoxide catalysis. Interestingly, we found that, although C−N
(5) product was formed in slight excess, an appreciable amount
of C−O (4) product was present (Table 1, entry 1). As
expected, inclusion of a Brønsted base cocatalyst (Table 1,
entry 2) completely shut down the C−O functionalization
pathway and resulted in a strong preference for C−N
15
functionalization. However, we found that catalytic B(C6F5)3
(entry 3) or silver triflate16,17 (entry 4), previously shown to
Reaction Discovery: C−N Functionalization. We were
intrigued by our discovery of a selective C−O bond-forming
reaction using Pd(II)/sulfoxide catalysis and questioned
whether the sulfoxide ligand was critical for the observed
selectivity. After removing the ligand from a standard reaction,
we made the unexpected observation of the exclusive formation
of C−N alkylated product anti-imidazolidinone 5 in 46% yield
(entry 10). Upon optimization, synthetically useful yields and
excellent diastereoselectivity (>20:1 dr) were obtained using
either silver triflate (entry 11, 59% yield) or B(C6F5)3 (entry
12, 62% yield). Notably, omission of the Lewis acid cocatalyst
resulted in lower product formation (32% yield) due to an
oxidative amination pathway (aminopalladation/β-hydride
elimination) of the terminal olefin (entry 13). Additionally,
omission of the palladium catalyst gave no reactivity (entry 14).
Collectively, these two processes represent the first examples
of transforming readily accessible ambident urea nucleophiles
into either C−O or C−N alkylated products by simply
switching the Pd(II) catalyst.
Table 1. Reaction Development
Reaction Scope. As outlined in Tables 2 and 3, a range of
N-nosyl urea olefin substrates were effectively oxidized and
aminated using these heterobimetallic catalytic systems to
furnish either anti-2-aminooxazolines or anti-imidazolidinones
in good yields and selectivities. Substrates containing moderate
to high levels of steric bulk adjacent to the urea tether (R =
ethyl, isopropyl, t-Bu) furnished the corresponding products in
high yields and selectivities with both systems (4, 5, 6, 14, 15).
anti-2-Aminooxazolines (7 and 8) and anti-imidazolidinones
(16 and 17), derived from common tertiary amines, can also be
accessed in excellent yields and selectivities. These represent a
class of sterically challenging vicinal diamine and aminoalcohol
precursors that are difficult to access otherwise in optically
enriched form. In each case, a single starting material was
converted selectively into either C−O or C−N functionalized
products simply by using the appropriate palladium catalyst.
Substrates containing proximal benzylated diols capable of
catalyst deactivation via metal chelation are also tolerated under
both reaction manifolds [(−)-11, (−)-18, (−)-19]. Aryl
moieties were evaluated and the products generated displayed
excellent selectivities for either the C−O or the C−N
functionalized products [12, (−)-13, 21]. The diastereoselec-
tivity for both processes appears to be very high; in most cases
examined, only the anti-aminooxazolines and anti-imidazolidi-
nones are observed by 1H NMR of the crude reaction mixtures.
a
All reactions were run using THF (1.0 M) as solvent, MeBQ
(methyl-p-benzoquinone, 1.5 equiv) as terminal oxidant and 8 mol %
Lewis acid (LA) cocatalyst for 6 h unless otherwise noted. Reactions
with cat. 1 were run with an additional 5 mol % Bis-SO ligand [1,2-
b
c
d
bis(phenylsulfinyl)ethane]. Average of two runs. Observed diaster-
eoselectivities in crude reaction mixtures: >20:1 dr anti:syn for 4 for all
entries; dr for 5: entry 1, 1.3:1 dr anti:syn; entry 2, 4.4:1 dr; entry 4,
1:1 dr; entry 7, 2.5:1 dr; entries 3, 5, 10, 11, 12, 13 >20:1 dr; dr
determined by 1H NMR analysis of the crude reaction mixture.
e
Reactions run to complete conversion: entry 1, 24 h; entry 3, 2 h;
f
entry 10, 72 h. Reaction stopped at 18 h (37% rsm); no improved
conversion was observed at 48 h or 72 h. DCM (dichloromethane,
g
1.0 M) used as solvent; for entry 4, 1 equiv of DMA was added.
h
Reaction stopped before complete conversion at 2 h. Increased
i
reaction times resulted in product decomposition. >99% rsm, 0% E-
internal olefin. Reaction run using THF (1.66 M) as solvent, BQ (p-
benzoquinone, 1.05 equiv) as terminal oxidant and 10 mol % LA
cocatalyst for 72 h.
j
B
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Table 2. PdII/Bis-sulfoxide/Ag-Catalyzed Allylic C−O Bond
Formation
Table 3. PdII/B-Catalyzed Allylic C−N Bond Formation
a
1
Diastereoselectivities and C−N:C−O ratios were measured by H
a
NMR of the crude reaction mixtures; >20:1 dr and >20:1 C−N:C−O
unless otherwise noted. 14: 9.8:1 dr; 20: 7:1 dr; 21: 12:1 dr. 16: 10:1
C−N:C−O; 17: 10:1 C−N:C−O.
Diastereoselectivities and C−O:C−N = anti-2-aminooxazoline:anti-
b
c
1
imidazolidinone ratios were measured by H NMR analysis of the
crude reaction mixtures; >20:1 dr unless otherwise noted. All yields are
b
reported for the major diastereomer. 7: 5.6:1 dr anti:syn 2-
c
amination methods furnished either the corresponding amino-
oxazoline ( )-8 or imidazolidinone ( )-20 in excellent yields
and selectivities (Tables 2, 3). Elaboration of the vinyl moiety
of aminooxazoline ( )-8 via ruthenium tetraoxide-catalyzed
oxidative cleavage affords carboxylic acid ( )-22 in 86% yield.
Hydrolysis of the N-nosyl-2-aminooxazoline ( )-22 under
acidic conditions afforded the α-hydroxy-β-amino acid ( )-23
in 80% yield (see Scheme 2). Imidazolidinone ( )-20 could
aminooxazoline; 12: 4:1 dr. Reaction run at 45 °C with a 0.12:1
d
DMA:DCM solvent mixture. Reaction run at 40 °C with a 0.12:1
e
DMA:DCM solvent mixture. Unable to determine crude selectivity
due to peak overlap; isolated selectivity reported.
For substrates that contain multiple stereogenic centers, the
diastereomeric outcome is predictable and controlled entirely
by the stereocenter containing the urea ((+)-9, (−)-10, (−)-11,
(−)-13, (−)-18, (−)-19). Taken together, these results
demonstrate the selective, catalyst-controlled allylic installation
of either the O or N functionality using a bifunctional urea
nucleophile. It is significant to note that alternative methods to
generate these products require de novo syntheses of separate
starting materials.5−11,18 Reactions such as these that take a
common intermediate and obtain divergent outcomes based on
catalyst control have the potential to significantly advance
synthetic efficiency and flexibility.
Scheme 2. Diversification to Biologically Relevant Motifs
α,β-Diamino Acids and α-Hydroxy-β-Amino Acids. The
vinyl imidazolidinones (ureas) and aminooxazolines (isoureas)
generated via these methods are precursors to valuable 1,2-
diamines and 1,2-aminoalcohols. For example, the α-olefin
moiety can be easily elaborated to furnish α,β-diamino acids
and α-hydroxy-β-amino acids, nonproteinogenic amino acids
found in numerous biologically active compounds and synthetic
peptides.19
Beginning with readily accessible homoallylic N-nosyl urea
precursors (four steps from commercial starting materials, see
Supporting Information), application of Pd(II)/bis-sulfoxide/
Lewis acid (LA)-catalyzed oxidation or Pd(II)/LA-catalyzed
C
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also be readily elaborated to α,β-diamino acid ( )-25 via a
three-step sequence involving oxidative cleavage of the olefin
(78%), mild PhSH/K2CO3 removal of the N-nosyl group, and
acidic hydrolysis (90% over two steps) (see Scheme 2). These
methods enable the selective and efficient generation of
heterocyclic and acyclic polyoxidized pharmacophores and
may expedite discovery of new medicinal agents.
Scheme 4. Mechanistic Experiments for C−O
Functionalization
Mechanistic Considerations. Data from the reaction
discovery studies suggested that the C−O versus C−N
selectivities obtained with the ambident urea nucleophile are
dictated by the choice of PdII catalyst (Table 1). In order to
confirm that it is a switch in palladium catalyst alone that is
causing the selectivity for C−O vs C−N bond formation in
these two reactions, we subjected a common starting material
26 to either 10 mol % Pd(II)/bis-sulfoxide catalyst 1 or
Pd(OAc)2 2 under otherwise identical reaction conditions of
azaphilic Lewis acid cocatalyst, solvent, oxidant, and temper-
ature (Scheme 3). Remarkably, both Lewis acid cocatalysts
(a) Stoichiometric formation and functionalization of a π-allylPd
intermediate. (b) Functionalization of a pre-oxidized N-nosyl urea
under Pd(0) conditions.
Scheme 3. Ligand Effects on Selectivity
hypothesis, we evaluated the rate of functionalization for
terminal olefin substrate 3 and the corresponding E-internal
olefin substrate 33, which would lead to the observed anti-
stereochemistry via an aminopalladation mechanism. Consis-
tent with our hypothesis, both substrates formed the anti-
imidazolidinone product with comparable overall kinetic
profiles, yields, and selectivities (Scheme 5).
Scheme 5. Mechanistic Experiments for C−N
Functionalization
a
Isolated yield, average of 2 runs at 0.3 mmol. bThe ratios were
1
determined by H NMR analysis of crude reaction mixture.
B(C6F5)3 and Ag(OTf) furnished imidazolidinone product anti-
15 and 2-aminooxazoline product anti-6 in comparable yields
with excellent C−O vs C−N selectivities of >20:1 that are
dependent solely on the nature of the palladium catalyst.
A critical question raised by these studies relates to the
means by which a switch in palladium catalyst results in
divergent product outcomes from a common urea starting
material. We hypothesized that the observed difference in the
reactivity of the urea nucleophile when switching from Pd(II)/
bis-sulfoxide 1 to Pd(OAc)2 2 arises from a change in
mechanism from allylic C−H oxidation that furnishes anti-2-
aminooxazoline products to olefin isomerization/oxidative
olefin amination that generates anti-imidazolidinones. Pd(II)/
sulfoxide catalysis with terminal olefins has been well
established to proceed via an allylic C−H cleavage/π-allylPd
functionalization mechanism with a wide range of oxygen and
nitrogen nucleophiles under varying reaction conditions.12,13
Consistent with C−O alkylation proceeding via such a
mechanism, stoichiometric π-allyl intermediate 28 affords
anti-aminooxazoline 29 as the major product in the presence
of AgOTf (Scheme 4a).
Given that the sulfoxide ligand is known to retard olefin
isomerization,12b we envisioned that its exclusion allows
Pd(OAc)2/B(C6F5)3 to effect isomerization of the terminal
olefin starting material to the internal E-olefin; subsequently,
the internal olefin would be capable of undergoing an oxidative
amination pathway (aminopalladation/β-hydride elimination).
Isomerizations of terminal olefins catalyzed by Pd(II)-salts20 are
well documented, and the addition of Lewis acid additives21 has
been shown to promote these processes. To test our
a
(a) Terminal vs internal olefin functionalization under PdII/B
catalysis. (b) Overall kinetic profile of the terminal olefin and the
internal olefin under the standard C−N functionalization conditions
1
Additionally, H NMR analysis of the reaction with terminal
olefin substrate 3 revealed complete conversion to the
corresponding E-internal olefin 33 after only 1 h.22 Our studies
demonstrate that a change in mechanism from allylic C−H
oxidation to isomerization/aminopalladation led to catalyst-
controlled, divergent C−O and C−N allylic functionalization
reactions using tethered urea nucleophiles.
Interestingly, while inclusion of a Lewis acid results in O-
functionalization from a π-allylPd intermediate, exclusive N-
D
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equiv), 1,2-bis(phenylsulfinyl)ethane (0.05 equiv), and freshly
recrystallized AgOTf (0.08 equiv) were added to the 1/2 dram vial
in the glovebox, in the order specified. The vial was securely sealed
with the Teflon-lined cap and taken out of the glovebox. Dry
dichloromethane (1.0 M) (and DMA, if specified in Table 2) was
quickly added to the 1/2 dram vial outside of the glovebox, under a
flow of argon gas. The vial was then sealed and placed in an aluminum
block to stir at 45 °C for exactly 6 h. If the reaction is allowed to run
longer than 6 h, an erosion of the C−O:C−N selectivity is observed.
The solution was allowed to cool to room temperature and then
transferred using dichloromethane to a 250 mL separatory funnel. The
solution was diluted with 15 mL of dichloromethane and rinsed with 1
× 15 mL aqueous NH4Cl (sat.). The organic layer was collected and
dried over MgSO4, filtered, and concentrated in vacuo. The crude
reaction mixture was purified using flash column chromatography (in
general, gradient 25−30% EtOAc/hexanes was used).
functionalization is observed via an aminopalladation pathway.
This outcome may be explained by considering that π-allylPd
N-functionalization proceeds via external attack that requires an
anionic, nucleophilic nitrogen (Scheme 6). In accord with this,
Scheme 6. Proposed Mechanisms
General Procedure for the Allylic Amination (Table 3). A 1/2
dram borosilicate vial containing a Teflon stir bar was flame-dried,
sealed with a Teflon-lined cap, and taken inside a glovebox. The
homoallylic N-nosyl urea starting material (1 equiv, dried over P2O5),
sublimed benzoquinone (1.05 equiv), Pd(OAc)2 (0.1 equiv), and
B(C6F5)3 (0.1 equiv) were added to the 1/2 dram vial in the glovebox,
in the order specified. The vial was securely sealed with the Teflon-
lined cap and taken out of the glovebox. Dry tetrahydrofuran (1.66 M)
was quickly added to the 1/2 dram vial outside of the glovebox, under
a flow of argon gas. The vial was then sealed and stirred in an
aluminum block at 45 °C for 72 h, unless otherwise noted in Table 3.
The solution was allowed to cool to room temperature, and the crude
reaction mixture was directly purified using flash column chrom-
atography (in general, gradient 20−30% EtOAc/hexanes was used).
we have observed that Pd(0)-catalyzed allylic substitution of an
analogous allylic acetate substrate, known to proceed via a π-
allylPd intermediate, does not proceed without inclusion of
stoichiometric base (Scheme 4b). The Lewis acid cocatalysts
used in this study may coordinate to the urea nosyl nitrogen
and block its attack on the Pd/π-allyl complex and/or generate
highly electrophilic π-allylPd intermediates that are preferen-
tially attacked by the hard oxygen urea nucleophile (Scheme 6).
In contrast, aminopalladation is a process that has been noted
to proceed under both acidic and basic reaction conditions.23
Future studies will seek to better understand the divergent
reactivity of ambident nucleophiles with π-allylPd and olefin
intermediates.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
white@scs.uiuc.edu
■
Notes
The authors declare no competing financial interest.
CONCLUSION
■
In conclusion, we have developed a novel process that uses
palladium catalysis in combination with Lewis acid cocatalysis
for the formation of either anti-2-aminooxazolines or anti-
imidazolidinone products from common ambident urea
precursors. The inclusion of Lewis acid promotes O-alkylation
in reactions proceeding with ambident O/N nucleophiles via π-
allylPd intermediates, thereby offering a strategy for expanding
the scope of nucleophiles subject to palladium catalysis.
Moreover, the discovery of facile isomerization/olefin pallada-
tion under LA/Pd(II) conditions may broaden the scope of
allylic functionalization reactions available from terminal
olefins. We anticipate that the general strategy of taking a
common hydrocarbon starting material and selectively trans-
forming it into multiple useful products will find immediate use
in streamlining and diversifying the synthesis of medicinal
agents and natural products.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH/NIGMS (2R01
GM 076153B) and ARRA supplemental funding. We thank Mr.
C. Taylor and Dr. G. Rice for preliminary studies on these
systems. We thank Dr. M. A. Bigi for assistance with spectral
data analysis and Dr. D. Covell for checking the experimental
procedure in Table 1, entry 10. We thank Johnson Matthey for
a generous gift of Pd(OAc)2.
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■
General Procedure for the Allylic Oxidation (Table 2). A 1/2
dram borosilicate vial containing a Teflon stir bar was flame-dried,
sealed with a Teflon-lined cap, and taken inside a glovebox. The
homoallylic N-nosyl urea starting material (1 equiv, dried over P2O5),
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(15) For the complexation of B(C6F5)3 with a wide range of
nitrogen-containing compounds see: Focante, F.; Mercandelli, P.;
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(16) Ag+ was shown to lower the rotational barrier in amides, see:
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(17) For a general review on Ag-catalyzed reactions see: Naodovic,
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(18) There are no direct, catalytic methods to make 4,5-disubstituted
2-aminooxazolines; syntheses require lengthy sequences from amino-
alcohols. (See Supporting Information.)
(19) (a) Viso, A.; Fernandez de la Pradilla, R.; Garcia, A.; Flores, A.
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(22) It is significant to note that, while it takes just four steps to
furnish the terminal olefin starting material 3, it requires five steps
including a challenging metal/ammonia reduction to generate the
stereochemically defined E-olefin 33.
(23) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
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̃
̈
Gom
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F
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