Palladium(II)-Catalyzed Allylic C H Oxidation of Hindered Substrates Featuring Tunable Selectivity Over Extent of Oxidation

Article abstract of DOI:10.1002/anie.201504007

The use of Oxone and a palladium(II) catalyst enables the efficient allylic C H oxidation of sterically hindered α-quaternary lactams which are unreactive under known conditions for similar transformations. This simple, safe, and effective system for C H activation allows for unusual tunable selectivity between a two-electron oxidation to the allylic acetates and a four-electron oxidation to the corresponding enals, with the dominant product depending on the presence or absence of water. The versatile synthetic utility of both the allylic acetate and enal products accessible through this methodology is also demonstrated.

Full text of DOI:10.1002/anie.201504007

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International Edition: DOI: 10.1002/anie.201504007
German Edition: DOI: 10.1002/ange.201504007
Allylic Compounds
À
Palladium(II)-Catalyzed Allylic C H Oxidation of Hindered
Substrates Featuring Tunable Selectivity Over Extent of Oxidation
Xiangyou Xing, Nicholas R. O’Connor, and Brian M. Stoltz*
Abstract: The use of Oxone and a palladium(II) catalyst
À
enables the efficient allylic C H oxidation of sterically
hindered a-quaternary lactams which are unreactive under
known conditions for similar transformations. This simple,
À
Scheme 1. Enantioselective synthesis of a-quaternary lactams by palla-
dium-catalyzed decarboxylative allylic alkylation. PHOX=phosphino-
oxazoline, pmdba=4,4’-methoxydibenzylideneacetone.
safe, and effective system for C H activation allows for
unusual tunable selectivity between a two-electron oxidation to
the allylic acetates and a four-electron oxidation to the
corresponding enals, with the dominant product depending
on the presence or absence of water. The versatile synthetic
utility of both the allylic acetate and enal products accessible
through this methodology is also demonstrated.
tion,[9] the utility of allyl groups as functional handles, and the
À
known status of allylic C H bonds as a privileged motif in the
À
C H activation literature, we investigated the use of several
À
À
R
ecent developments in C H functionalization have made
reported procedures for the C H functionalization of our
major contributions to organic chemistry and are beginning to
change the way chemists approach synthetic transforma-
lactam products (Scheme 2). Interestingly, the use of either
classical[5,10] or modern[3a,i] conditions for allylic oxidations
resulted in decomposition, low conversion, or undesired
reactivity.
[2,3]
tions.[1] Allylic C H acetoxylation
and other functionali-
À
zations[4] of terminal olefins have received considerable
interest over the past decade as allyl groups are versatile
and widespread in synthetic organic chemistry. After the
seminal report by White and co-workers of allylic acetox-
ylation,[3a] numerous research groups have developed alter-
native conditions for this transformation, mainly differing in
the terminal oxidant used.[3]
Complementing reports of the two-electron oxidation of
allyl groups to allylic acetates, the four-electron oxidation of
allyl groups to enones or enals has also been described. While
the oxidation of olefins, particularly cycloalkenes, to enones is
well precedented,[5] there exist few examples of the trans-
formation of allyl groups to enals.[6,7] Of these limited cases,
most produce the enals in low yield and with poor selectivity
over other oxidation products, and/or require activated allylic
À
C H bonds (i.e., allylbenzenes). None of these methods are
reported to be effective on complex or sterically hindered
substrates.
Our research group has had a longstanding interest in the
asymmetric synthesis of a-quaternary carbonyl compounds by
palladium-catalyzed decarboxylative enantioselective allylic
alkylation.[8] In 2012 we reported the construction of quater-
nary a-allyl lactams (2), in excellent yield and ee using this
Scheme 2. Investigation into the allylic oxidation of lactam 3. For
experimental details see the Supporting Information. BQ=1,4-benzo-
quinone, DMSO=dimethylsulfoxide, TBHP=tert-butyl hydroperoxide.
strategy (Scheme 1).[8c] Given our interest in C H activa-
À
We attribute the absence of the desired reactivity to the
sterically demanding quaternary center at the homoallylic
position. This hypothesis is corroborated by the paucity of
sterically encumbered examples of such allylic oxidations in
the methods literature. Realizing the amide moiety could act
as an internal ligating group, we chose to develop reaction
conditions for the substrate-directed palladium-catalyzed
[*] Dr. X. Xing,[+] N. R. O’Connor,[+] Prof. Dr. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology
1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
E-mail: stoltz@caltech.edu
[+] These authors contributed equally to this work.
À
allylic C H acetoxylation of these molecules. We hoped
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504007.
À
that the use of a directing group, largely unknown in allylic C
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H oxygenation reactions,[11] would enable reactivity even in
the most sterically hindered substrates.
We began our studies by screening various palladium(II)
catalysts, oxidants, and solvents in the allylic acetoxylation of
an N-benzoyl lactam (Table 1, entry 1), itself accessed by our
allylic alkylation chemistry.[8c] Gratifyingly, exposure of the
substrate to palladium(II) acetate and Oxone in a mixture of
Table 1: Optimization of the allylic acetoxylation.
Entry
R
Catalyst
(mol%)
Oxone
t
Conv. Yield 4/6[d]
(equiv) [h] [%][b]
[%][c]
1
2
Bz Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Bn Pd(OAc)2 (7.5)
Bn Pd(TFA)2 (7.5)
Bn [Pd(acac)2] (7.5)
1.5
1.5
2.5
2.5
2.5
96 31
trace 6:1
H
3
100
41
62
62
55
65
8:1
8:1
9:1
7:1
8:1
3[e]
4[e]
5[e]
6[e]
10 100
10 100
10 90
Bn [Pd(hfacac)2] (7.5) 2.5
4
100
[a] Reaction conditions: lactam 3 (0.10 mmol), catalyst (0.05 or
0.075 equiv; see table), Oxone (1.5 or 2.5 equiv, see table), MeCN
(714 mL), and AcOH (286 mL) at 608C for 96 h or until full conversion by
TLC. [b] Conversion was determined from the yield of the isolated
recovered starting material. [c] Yield is that of isolated combined
products 4 and 6. [d] Ratio determined by 1H NMR analysis of the crude
reaction mixture. [e] A solvent mixture of 5:1:1 MeCN/AcOH/Ac2O was
used, and 4Š M.S. (80 mg) were added. acac=acetylacetonate,
Bz=benzoyl, hfacac=1,1,1,5,5,5-hexafluoroacetylacetonate,
M.S.=molecular sieves, TFA=trifluoroacetate.
acetonitrile and acetic acid produced trace amounts of allylic
acetate (4) and enal (6) products. We were pleased to find that
Oxone was superior to other oxidants examined, as it is
readily available, inexpensive, stable, relatively nontoxic, and
environmentally safe.[12] To our knowledge, this is the first
Figure 1. Substrate scope of the allylic acetoxylation. Combined yield
of the isolated separable products 8 and 9. Reaction conditions:
lactam 7 (0.2 mmol), [Pd(hfacac)2] (0.075 equiv), Oxone (2.5 equiv),
MeCN (1.43 mL), AcOH/Ac2O (1:1, 570 mL) and 4Š M.S. (160 mg) at
608C for 3–6 h. [a] Reaction time=24 h. [b] Reaction time=11 h.
PMP=para-methoxyphenyl.
À
report of Oxone as an oxidant for an allylic C H function-
alization reaction.
Although the benzoyl-protected lactam gave only low
À
conversion under these conditions, the free N H lactam
performed better, giving moderate conversion to a separable
mixture of 4 and 6 (entry 2). Further optimization revealed
the N-benzyl lactams to be superior to the free lactams,
resulting in full conversion within a matter of hours
(entries 3–6). Subsequent experiments showed that the addi-
tion of acetic anhydride and molecular sieves was necessary to
obtain the allylic acetate product in good yield. An exami-
nation of other palladium(II) precursors (entries 4–6) led us
to select palladium(II) hexafluoroacetylacetonate, as it
resulted in the shortest reaction time while maintaining
a good ratio of the desired allylic acetate 4 to the undesired
enal 6 (entry 6). With all substrates, we found that acetonitrile
was necessary as a solvent, as its omission led to a significant
decrease in reactivity. In all cases, we observed little or no
formation of the methyl ketone or aldehyde products
expected from Wacker–Tsuji reactivity.
found that the lactam nature of the substrate was critical to
achieving good reactivity. Interestingly, cyclic compounds
lacking an amide functional group gave only low conversion
under our conditions, as did a wide variety of linear amides
investigated. The scope of allylic acetoxylation of lactam
substrates is shown in Figure 1. Substrates incorporating alkyl
groups at the a-position were well tolerated, furnishing the
corresponding allylic acetates (8a,b,d,e) in good yields and
selectivities. Substrates with benzyl (8c) or aryl (8 f) groups at
the a-position were also competent.[13] The benzyl group on
the lactam nitrogen was not necessary, and could be replaced
by other electron-rich groups, such as methyl (8g) and para-
methoxyphenyl (8j), or even olefinic groups like methallyl
(8k), and trans-cinnamyl (8l).[13] The free N H lactam was
À
also a successful substrate (8h). A quaternary stereocenter
was not found to be necessary, with an a-tertiary lactam
undergoing acetoxylation in good yield and exclusive selec-
tivity over enal formation (8i). Finally, substrates derived
With the optimized reaction conditions in hand, we
investigated the substrate scope of the reaction. We quickly
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from caprolactam (8m,n) and butyrolactam (8o–r), readily
accessed by our decarboxylative allylic alkylation chemistry,
also reacted smoothly.[14]
substituents were also successfully oxidized to enals 9c and
9 f, respectively. As with the allylic acetoxylation reaction, we
found that the benzyl-protected nitrogen was not critical, and
À
After exploring the scope of the acetoxylation reaction,
we were intrigued about the possibility of optimizing for the
enal product seen in small amounts in most acetoxylations.
During our early optimization of the allylic acetoxylation
reaction, we observed that the omission of molecular sieves or
acetic anhydride resulted in a higher degree of enal forma-
tion. Using this as a starting point, we identified optimal
reaction conditions for enal formation, which are shown in
Figure 2. Remarkably, only simple changes to the reaction
that the N-methyl, N-aryl, and N H substrates were also
suitable (9g,j,h).[13] Unfortunately, lactams of other ring sizes
showed low conversion (9q),[14] and a-tertiary substrates gave
predominately the methyl ketone product of a Wacker–Tsuji
oxidation (not shown).[15]
The synthetic utility of allylic acetates is well known in the
literature, and we were able to transform product 8a into
several functionalized building blocks using a variety of
oxidations, reductions, and C C bond-forming reactions
(Scheme 3). Enals are also useful synthetic intermediates,
À
and we were able to derivatize product 9a by similar methods.
Scheme 3. Synthetic utility of the products. Reaction conditions: a) 8a,
K2OsO4·2H2O, NMO, acetone, H2O, 238C, 83% yield; b) 8a, mCPBA,
CH2Cl2, 238C, 93% yield; c) 8a, [{Ru(p-cymene)Cl2}2], Ph3P, LiHMDS,
dimethyl malonate, THF, toluene, 608C, 82% yield; d) 9a, [VO(acac)2],
H2O2, H2O, MeOH, 238C, 93% yield; e) 9a, H2, Pd/C, EtOAc, 238C,
97% yield; f) 9a, p-OMe-C6H4CO2H, tBuNC, CH2Cl2, 408C, 64% yield.
HMDS=hexamethyldisilazide, mCPBA=m-chloroperbenzoic acid,
NMO=N-methyl-morpholine-N-oxide, THF=tetrahydrofuran. For
additional transformations and full experimental details see the
Supporting Information. CCDC 1057691 (10) contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre.
Figure 2. Substrate scope of the enal formation. Combined yield of the
isolated separable products 8 and 9. Reaction conditions: lactam 7
(0.20 mmol), Pd(OAc)2 (0.075 equiv), Oxone (2.5 equiv), AcOH
(16.0 equiv), H2O (8.0 equiv), and MeCN (1.82 mL) at 508C for 1–2 h.
[a] Starting material not fully consumed.
conditions lead to a significant change in the product ratio,
allowing for facile control of the degree of oxidation.
Essentially, either the presence or absence of water leads to
a switch between a two-electron oxidation of the allyl group
into the allylic acetate (i.e. 7!8) and a four-electron
oxidation of the allyl group into the enal (i.e. 7!9). While
palladium(II) hexafluoroacetylacetonate is an effective cata-
lyst for oxidation to the enal, we opted to use the cheaper and
more widely available palladium(II) acetate, as the results
were similar. We found the presence of small amounts of
water to be necessary to achieve high conversion, and the
presence of acetic acid aided in suppressing formation of the
methyl ketone (i.e., standard Wacker–Tsuji oxidation).[15]
The scope of the enal formation is shown in Figure 2. We
found that N-benzyl valerolactams with a variety of alkyl
groups at the a-position were well tolerated, furnishing the
enal products (9a,b,d,e) in good yields and selectivities over
the allylic acetates. Substrates with a-benzyl and a-phenyl
In summary, we have reported a novel protocol for
À
palladium-catalyzed allylic C H oxidation using inexpensive,
nontoxic, and safe Oxone as the terminal oxidant. This
method is far more tolerant of steric bulk than previously
known examples, possibly as a result of substrate-directed
reactivity. Furthermore, we have discovered that a minor
change in reaction conditions allows for access to either the
allylic acetate products of a two-electron oxidation or the enal
products of a four-electron oxidation. This reactivity switch
demonstrates an unusual ability to selectively achieve differ-
ent increases in oxidation state by a single palladium-
catalyzed system. The synthetic utility of the products
À
resulting from these C H functionalization methods has
been demonstrated by conversion of the prototypical prod-
ucts to a range of functionalized heterocycles. Mechanistic
studies and investigations of further synthetic applications of
the products are currently underway.[16]
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Chem. Soc. 2013, 135, 12990 – 12993; Oxidation of allyl groups to
acrylonitriles: k) C. Qin, N. Jiao, J. Am. Chem. Soc. 2010, 132,
15893 – 15895.
Acknowledgements
This work was supported by the NSF under the CCI Center
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for Selective C H Functionalization, CHE-1205646. Addi-
tional support was provided by Caltech and Amgen. Dr.
Scott C. Virgil is thanked for helpful discussions. Dr. David
VanderVelde (NMR), Dr. Michael K. Takase (X-ray crystal-
lography), and Dr. Mona Shahgholi (HRMS) are acknowl-
edged for assistance with structural determination and
characterization. Guillermo A. Guerrero-Vµsquez, Lukas J.
Hilpert, and Dr. Wen-Bo Liu are acknowledged for exper-
imental assistance.
À
Keywords: allylic compounds · C H functionalization ·
heterocycles · oxidation · palladium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11186–11190
Angew. Chem. 2015, 127, 11338–11342
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[15] It is possible that both the allylic acetate and enal products are
formed through a palladium(II)-p-allyl intermediate, although
other pathways, particularly Wacker-type activation of the
olefin, may also be envisioned. The requirement of an elec-
tron-rich lactam moiety in the substrate suggests intramolecular
direction may play a role in the mechanism. Control experiments
show that both the allylic alcohol and the aliphatic aldehyde are
smoothly converted to the enal, indicating that either could serve
as a mechanistic intermediate. See the Supporting Information
for details.
realized. For example, we recently found that exposure of (S)-
carvone (17) to similar reaction conditions resulted in selective
allylic acetoxylation in moderate yield. See the Supporting
Information for details.
[16] Although it is clear that the allylic oxidation chemistry reported
herein has certain scope limitations, the complete applicability of
Received: May 5, 2015
Revised: June 23, 2015
À
these new conditions for C H functionalization is not yet fully
Published online: July 31, 2015
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