General allylic C-H alkylation with tertiary nucleophiles

Article abstract of DOI:10.1021/ja500726e

A general method for intermolecular allylic C-H alkylation of terminal olefins with tertiary nucleophiles has been accomplished employing palladium(II)/bis(sulfoxide) catalysis. Allylic C-H alkylation furnishes products in good yields (avg. 64%) with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z). For the first time, the olefin scope encompasses unactivated aliphatic olefins as well as activated aromatic/heteroaromatic olefins and 1,4-dienes. The ease of appending allyl moieties onto complex scaffolds is leveraged to enable this mild and selective allylic C-H alkylation to rapidly diversify phenolic natural products. The tertiary nucleophile scope is broad and includes latent functionality for further elaboration (e.g., aliphatic alcohols, α,β-unsaturated esters). The opportunities to effect synthetic streamlining with such general C-H reactivity are illustrated in an allylic C-H alkylation/Diels-Alder reaction cascade: a reactive diene is generated via intermolecular allylic C-H alkylation and approximated to a dienophile contained within the tertiary nucleophile to furnish a common tricyclic core found in the class I galbulimima alkaloids.

Full text of DOI:10.1021/ja500726e

Article
pubs.acs.org/JACS
General Allylic C−H Alkylation with Tertiary Nucleophiles
Jennifer M. Howell, Wei Liu, Andrew J. Young,† 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: A general method for intermolecular allylic C−
H alkylation of terminal olefins with tertiary nucleophiles has
been accomplished employing palladium(II)/bis(sulfoxide)
catalysis. Allylic C−H alkylation furnishes products in good
yields (avg. 64%) with excellent regio- and stereoselectivity
(>20:1 linear:branched, >20:1 E:Z). For the first time, the
olefin scope encompasses unactivated aliphatic olefins as well
as activated aromatic/heteroaromatic olefins and 1,4-dienes.
The ease of appending allyl moieties onto complex scaffolds is
leveraged to enable this mild and selective allylic C−H alkylation to rapidly diversify phenolic natural products. The tertiary
nucleophile scope is broad and includes latent functionality for further elaboration (e.g., aliphatic alcohols, α,β-unsaturated
esters). The opportunities to effect synthetic streamlining with such general C−H reactivity are illustrated in an allylic C−H
alkylation/Diels−Alder reaction cascade: a reactive diene is generated via intermolecular allylic C−H alkylation and
approximated to a dienophile contained within the tertiary nucleophile to furnish a common tricyclic core found in the class I
galbulimima alkaloids.
Scheme 1. Allylic C−H Alkylation of 3° Nucleophiles
INTRODUCTION
■
The development of general C−H to C−C bond trans-
formations that enable novel disconnections in the retrosynthesis
of carbon skeletons stands to profoundly impact organic
synthesis.1 While substantial progress has been achieved in the
alkylation of sp2 C−H bonds, methods for sp3 C−H bond
alkylation are scarce.2
We and others have shown palladium(II)/bis(sulfoxide)
catalysis to be a powerful platform for allylic C−H oxidations,
aminations, dehydrogenations, halogenations and alkylations of
α-olefin substrates.3,4 Unfortunately, C−H alkylation methods
have been limited in scope to disubstituted methylene
nucleophiles bearing two electron-withdrawing groups (Scheme
1A). Previous reports employing tertiary nucleophiles in allylic
C−H alkylation reactions have been limited with respect to
either olefin scope (i.e., only 1,4-dienes) or nucleophile scope
(i.e., tetralones) (Scheme 1B).5,6 We recognized that a general
method for intermolecular allylic C−H alkylation using tertiary
nucleophiles6 with high levels of flexibility in the R4 group would
be very powerful (Scheme 1C). Incorporation of functionality in
the nucleophile that can be further elaborated, for example in the
context of complexity generating reactions, would enable the
rapid construction of topologically varied carbon frameworks
from simple building blocks. Herein, we disclose the first general
allylic C−H alkylation reaction with tertiary nucleophiles. In
contrast to previous allylic C−H alkylations, the method
described herein enables coupling of two complex and valuable
fragments to directly afford a target molecule. For example,
Pd(II)/bis(sulfoxide)-catalyzed allylic C−H alkylation is used to
generate reactive intermediates which concomitantly engage in
intramolecular Diels−Alder cycloadditions in situ, leading to the
rapid assembly of highly functionalized decalin core structures
found in the galbulimima alkaloids.
RESULTS AND DISCUSSION
Reaction Development. Our investigation began with a
prototypical nucleophile, ((1-nitroethyl)sulfonyl)benzene (4a).
■
Received: January 24, 2014
Published: March 18, 2014
© 2014 American Chemical Society
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We were delighted to find that upon reaction with allylbenzene
(3a) under our reported conditions4c this tertiary nucleophile
Table 2. Tertiary Nucleophiles for C−H Alkylation
Table 1. Reaction Development
a
Reaction conditions: 3 (1 equiv), 4 (2 equiv), 1 or 2 (10 mol %),
2,6,-dimethylbenzoquinone (DMBQ) (1.5 equiv), 0.33 M dioxane/
b
c
DMSO, 45 °C, 24 h. Isolated yield, average of two runs. Ratio
d
determined by 1H NMR analysis of crude reaction mixture. 72 h, 29%
yield after 24 h. 72 h; 52% yield after 24 h. 72 h.
e
f
a
Reaction conditions: allylbenzene 6 (1 equiv), 7 (2 equiv), 1 (10 mol
%), 2,6-dimethylbenzoquinone (DMBQ) (1.5 equiv), DMSO/dioxane
(4:1, 0.33 M), 45 °C, 24 h. Products isolated as one regio- and stereo-
engaged in alkylation to afford the desired alkylated product 5a in
61% yield (Table 1, entry 1). Evaluation of a nonactivated,
aliphatic terminal olefin substrate, allylcyclohexane (3b),
afforded the desired product 5b, albeit in a modest yield (35%
yield, entry 2). Encouragingly, both reactions proceeded with
excellent regio- and stereoselectivity (>20:1 linear:branched,
>20:1 E:Z). We reasoned that functionalization of a π-allylPd
intermediate with a sterically bulky tertiary nucleophile was
sluggish and may be accelerated by increasing the amount of
DMSO, previously shown to be a ligand that promotes
functionalization.4c Consistent with this hypothesis, shifting the
solvent/DMSO ratio from 4:1 to 1:4 improved the yield with an
activated allylbenzene substrate to 83% (entry 3), and that of the
unactivated allylcyclohexane substrate to 58% (entry 4).
Evaluation of the commercially available phenylbis(sulfoxide)
catalyst 2 resulted in diminished yield (entry 5 and entry 6); high
concentrations of DMSO are thought to interfere with
reassociation of the aryl bis(sulfoxide) ligand to form complex
2, which is required for C−H cleavage.4c The yield was
dramatically decreased to 11% when Pd(OAc)2 was utilized
(entry 7), illustrating the important role of the aryl bis(sulfoxide)
ligand for C−H alkylation under mild conditions. A preliminary
evaluation of varying the R2 group from methyl (4a) to benzyl
(4b) suggested that this reaction would be general (78% yield,
entry 8).
Tertiary Nucleophile Scope. Incorporation of various
functional groups into the nucleophile would greatly extend
the synthetic utility of the Pd(II)/bis(sulfoxide)-catalyzed allylic
C−H alkylation reaction. Latent functionality could be brought
in as part of the nucleophile and unmasked at a later stage to
facilitate further elaboration. A variety of functionalities,
including sulfonyl, nitro, ketone, and ester moieties were found
to be suitable electron-withdrawing groups (Table 2). 2-
Nitropropiophenones as well as a tetralone derivative all proved
to be competent nucleophiles (8a−d). Substitution of the
b
olefin isomer. Isolated yield is the average yield of two runs. 7c (3
equiv). 6 (2 equiv), 7f (1 equiv); 52% yield using 6 (1 equiv), 7f (2
c
equiv).
Scheme 2. Sequential Allylic C−H Alkylation Strategy
benzoyl aromatic ring was tolerated, including an aryl chloride,
which provides a handle for further derivatization (8b, 8c). The R
alkyl substituent of the nucleophile was varied to longer chains,
including ones incorporating oxygen functionality suitable for
additional elaboration (8e, 8f). Notably, for reactions in which
the nucleophile-coupling partner is particularly valuable, it may
be used in limiting quantities with good yields (8f). Nucleophile
pKa dependence on reactivity was noted, consistent with the
notion that the nucleophile must undergo facile keto−enol
tautomerization or deprotonation by endogenous base in situ.
We were encouraged to find that an α-nitropropionate and β-
ketoester, less acidic pro-nucleophiles, engaged in alkylation (8g,
8h).
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Methyl tetronic acid and methyl Meldrum’s acid, two highly
acidic dicarbonyl compounds, were found to be suitable
nucleophiles (8i, 8j). Tricarbonyls also proved to be competent
tertiary nucleophiles (8k, 8l). It is significant to note that these
nucleophiles allow for the construction of quaternary centers via
the allylic C−H alkylation reaction.7
Scheme 3. Diversification of Natural Products
Table 3. Terminal Olefins for C−H Alkylation
be used as a tertiary nucleophile to produce the fully substituted
compound 10 in 91% yield. The two-step reaction sequence
proceeded in 56% overall yield and incorporated all but four
hydrogen atoms of the substrates in the final product. Notably, all
Pd/bis(sulfoxide)-catalyzed allylic C−H functionalizations,
including C−H alkylation, are highly chemoselective for terminal
olefins with internal olefins being well-tolerated.3,4
Terminal Olefin Scope. Upon investigation of the α-olefin
substrate scope, we were delighted to find that, in contrast to
previously reported methods, our reaction was capable of
alkylating unactivated aliphatic α-olefins with tertiary nucleo-
philes in good yields and excellent selectivities (Table 3). Primary
alcohol and amine functionalities masked as benzoate/acetate
esters and phthalimides were well tolerated (13a, 13b, 13c).
Terminal olefin substrates bearing acetals and amides also proved
to be competent alkylation partners (13d, 13e). Most notably, an
unprotected secondary alcohol substrate participated in the
alkylation reaction in good yield (13f). This example underscores
the remarkable chemoselectivity of this allylic C−H functional-
ization method and its orthogonality to standard base-promoted
alkylation methods (alcohol pKa ≈ 15; allylic C−H bond pKa ≈
42).
Additionally, we found that a variety of allylarene and
heteroarenes were readily alkylated. Para, meta, and ortho
substitution of electronically varied groups were all well tolerated
on allylbenzene substrates (13g, 13h, 13i, 13j). Significantly,
bromine and boron substituents, which may be further
elaborated via traditional Pd(0) cross-coupling methods, could
also be present in the substrate (13k, 13l). Highly reactive
electrophiles, such as aldehydes and terminal epoxides, may also
be incorporated into the olefin substrate, highlighting the high
chemoselectivity of this reaction for functionalization of the
electrophilic π-allylPd intermediate (13i, 13m). Allylic C−H
alkylation is also tolerant of a range of medicinally important
heterocyclic aromatic functionalities such as indole and
chromene (13n, 13o), as well as xanthene, important in
a
Reaction conditions: α-olefin 11 (1 equiv), 12 (2 equiv), 1 (10 mol
%), 2,6-dimethylbenzoquinone (DMBQ) (1.5 equiv), DMSO/dioxane
(4:1, 0.33 M), 45 °C, 24 h. Products isolated as one regio- and stereo-
olefin isomer. Isolated yield, average yield of two runs. 72 h. MIDA =
b
c
methyliminodiacetate.
A general strategy to build tertiary nucleophiles containing
internal olefins is afforded by exploiting the divergent reactivity
of our previously reported conditions4c and those of the present
work. Allylic alkylation of a terminal aliphatic olefin (i.e.,
allylcyclohexane) with a secondary nucleophile (i.e., benzoylni-
tromethane) under conditions using minimal amounts of DMSO
furnished monoalkylated product 9 (Scheme 2). Under
conditions employing higher concentrations of DMSO, 9 may
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a b c d
, , ,
Scheme 4. Tandem Allylic C−H Alkylation/Diels−Alder Reaction Cascade
a
Reaction conditions: (1) α-olefin 20 (1 equiv), 21 (1.8 equiv), 1 (10 mol %), 2,6-dimethylbenzoquinone (DMBQ) (1.5 equiv), DMSO/dioxane
b
(4:1, 0.33 M), 45 °C, 24 h followed by warming to 55 °C, 48 h, (2) 20% TiCl3 in 3% HCl, THF, rt. Endo/exo isomers 23 and 24 result from
addition anti to the methyl group of the butenolide. The endo isomer resulting from syn addition was also observed (6:1 endo-anti/endo-syn). 50%
yield after one recycle. Isolated as a 5:1 mixture of diastereomers, major diastereomer shown. 23b was confirmed by X-ray crystallographic analysis.
c
d
synthetic and material science applications (13p). Notably, in all
cases with allyl aromatics, high regioselectivity was observed for
formation of linear alkylation products. The observed
regioselectivity we believe is steric in nature, arising from
nucleophilic attack at the least hindered terminus of the π-allylPd
intermediate. This contrasts with our previous observations of
variable regioselectivity in the functionalization of allylarenes
with disubstituted methylene nucleophiles.4a,c Finally, 1,4-diene
substrates were also alkylated in good yields and high selectivities
to furnish 1,3-diene products that may be further elaborated to
generate skeletal complexity (vida infra) (13q, 13r).
Molecular Complexity via C−H Alkylation: A Tandem
Allylic C−H Alkylation/Diels−Alder Reaction Cascade.
Catalytic allylic C−H alkylation holds tremendous potential for
directly accessing synthetic intermediates, which may sub-
sequently be coupled to secondary complexity-generating
reactions to rapidly forge new carbon frameworks. We recently
demonstrated this in the context of a dehydrogenative Diels−
Alder reaction wherein the reactive diene was generated via an
allylic C−H dehydrogenation reaction.3f Given the generality in
scope of the allylic alkylation reaction, we questioned if we could
effect a tandem allylic C−H alkylation/Diels−Alder reaction
cascade wherein a reactive diene intermediate is generated during
C−H alkylation and approximated to a dienophile contained
within the tertiary nucleophile. We became particularly
interested in applying such a strategy to an efficient synthesis
of the galbulimima alkaloid core whose structures have attracted
much interest from both the synthetic and medicinal
communities.9 Whereas current synthetic routes to these
alkaloids have primarily limited chemical derivatizations to the
appended heterocyclic R/R1 group, an allylic C−H alkylation/
Diels−Alder route could rapidly access ketone 25, which offers
an additional synthetic handle for derivatization of the C ring of
the tricyclic core. Upon exposure of the skipped diene α-olefin 20
and dienophile-containing tertiary nucleophile 21 to the Pd(II)/
bis(sulfoxide)-catalyzed allylic C−H alkylation reaction con-
ditions, we were pleased to observe formation of tricycles 23 and
24 in excellent yield (75% yield, 87% yield per step) and
outstanding endo selectivity (27:1 endo/exo) (Scheme 4).
Shorter reaction time confirmed that the reaction proceeds via
initial allylic C−H alkylation to afford isolated intermediate diene
22 (see Supporting Information [SI]), which subsequently
engages in a highly endoselective intramolecular Diels−Alder
cycloaddition with the appended α,β-unsaturated ester to furnish
the tricycles (23, 24). The tricyclic structure of 23b, a C7 epimer
of the endo series, was confirmed via X-ray crystallographic
analysis. Subsequent treatment of the mixture with a Lewis acid
solution efficiently converted the α-nitro sulfone to the
corresponding ketone 25 (50% yield), providing primarily the
endo diastereomer that appears in the galbulimima alkaloid core.
Late-Stage Allylic C−H Alkylation of Natural Product
Derivatives. Rapidly accessing molecular diversity at a late stage
from bioactive natural product skeletons is a promising strategy
for identifying drug candidates.8 Phenolic natural products are
abundant and generally readily available in large quantities from
commercial sources. We envisaged that by combining powerful
allylation reactions with our mild and selective allylic C−H
alkylation we could provide a general strategy to rapidly diversify
phenolic natural products. A range of carbon nucleophiles may
be used that can also be further elaborated. As proof of principle,
the common steroid hormone (+)-estrone (14) was derivatized
via a short synthetic route (Scheme 3). Triflate formation
followed by Stille cross-coupling rapidly appends the allyl moiety,
furnishing allylarene 15. We were delighted that exposure of 15
and 2-nitropropiophenone to the catalytic Pd(II)/bis(sulfoxide)
reaction conditions afforded alkylated product 16 in high yield
(61% yield, 24% yield over three steps, 63% average yield per
step). Markedly, C−H alkylation takes place in the presence of an
enolizable ketone, again demonstrating the orthogonal nature of
this C−H functionalization reaction to base-mediated alkylation
methods. Similarly, (−)-maculosin (17), a naturally occurring
diketopiperazine phytotoxin, was readily functionalized to
provide 19 in good yield (50% yield, 27% yield over three
steps, 65% average yield per step). Highlighting the high
functional group tolerance of this allylic C−H functionalization
method, alkylation proceeded smoothly in the presence of a
secondary amide capable of coordinating to and deactivating the
palladium catalyst.
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23 and 24 and 25 via supercritical fluid chromatography (SFC).
We thank Dr. Lingyang Zhu for assistance with 2D NMR
spectroscopic data, and Dr. Jeffery Bertke and Dr. Danielle Gray
for crystallographic data. We thank Mr. Stephen E. Ammann and
Dr. Paul Gormisky for checking experimental procedures (Table
3, entries 13a and 13b). We thank Ms. Alexandria Brucks for
initial investigations. We thank Johnson Matthey for a gift of
Pd(OAc)2 and Sigma-Aldrich for a gift of catalyst 2.
CONCLUSION
■
In summary, we have disclosed a palladium(II)/bis(sulfoxide)-
catalyzed allylic C−H alkylation reaction that features
unprecedented generality in scope of both the olefin and the
tertiary nucleophile. Aliphatic terminal olefins containing
reactive functionalities such as unprotected secondary alcohols,
amides, ketals, and internal olefins are viable substrates, as are
allylarenes containing reactive electrophiles such as aldehydes,
and terminal epoxides, as well as heterocyclic moieties such as
indoles and diketopiperazines. Cyclic and acyclic tertiary
nucleophiles with appended α,β-unsaturated esters, masked
aliphatic alcohols, or dense carbonyl functionality readily engage
in functionalization. The ability to synthetically tailor both
intermolecular reaction partners has enabled C−H alkylation to
be used to generate intermediates that can undergo intra-
molecular secondary reactions to rapidly construct complex
molecular architectures from simple linear starting materials.
REFERENCES
■
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EXPERIMENTAL PROCEDURES
■
General Procedure for the Allylic C−H Alkylation (Table 2). An
oven-dried, one dram (4 mL, borosilicate) vial fitted with a Teflon
magnetic stir bar was charged with Pd[1,2-bis(benzylsulfinyl)ethane]-
(OAc)2 1 (0.10 equiv, 0.030 mmol) and 2,6-dimethylbenzoquinone
(DMBQ) (1.5 equiv, 0.45 mmol). The α-olefin (1 equiv, 0.30 mmol),
nucleophile (2.0 equiv, 0.60 mmol), dimethylsulfoxide (DMSO) (0.72
mL), and 1,4-dioxane (0.18 mL) were added sequentially to the reaction
vial. The reaction setup is performed open to the atmosphere. The
reaction vial was capped and stirred at 45 °C for 24 h in an oil bath. The
vial was cooled to room temperature, and the reaction mixture was
diluted with saturated aqueous NH4Cl solution (40 mL) and extracted
with ethyl acetate (3 × 30 mL). The combined organics were dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (SiO2, EtOAc/hexanes mixtures) provided the
pure linear product.
Preparation of ((Nitromethyl)sulfonyl)benzene, Synthetic
Precursor to ((1-Nitroethyl)sulfonyl)benzene (4a). The known
compound was prepared following the improved procedure of Prakash
and co-workers.10 We observed lower reactivity for both benzyl and alkyl
substrates when an older literature procedure was employed.11
Alternatively, ((nitromethyl)sulfonyl)benzene (NSM) purchased from
Sigma-Aldrich and methylated following the standard procedure (see
SI) afforded alkylation products in yield comparable to that of the
corresponding reactions run with nucleophile synthesized via the
procedure of Prakash and co-workers.10
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Donckele, E. J. Angew. Chem., Int. Ed. 2013, 52, 1523.
(6) A tertiary nucleophile is defined herein as any molecule having a
carbon atom with three non-hydrogen substituents.
ASSOCIATED CONTENT
■
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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.illinois.edu
■
Present Address
†Dow Chemical, 2301 N. Brazosport Blvd., Freeport, Texas
77541, United States.
Notes
The authors declare no competing financial interest.
(10) Prakash, G. K. S.; Wang, F.; Zhang, Z.; Ni, C. F.; Haiges, R.; Olah,
G. A. Org. Lett. 2012, 14, 3260.
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ACKNOWLEDGMENTS
■
Financial support was provided by the NIH/NIGMS (2R01 GM
076153B). We thank Dr. Christopher J. Welch and Dr. Erik L.
Regalado at Merck for assistance in purification of cycloadducts
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