Sulfinate-Engaged Nucleophilic Addition Induced Allylic Alkylation of Allenoates

Article abstract of DOI:10.1021/acs.orglett.9b02728

A strategically novel Pd-catalyzed nucleophilic addition induced allylic alkylation reaction (NAAA) of allenoates has been successfully accomplished. By judiciously integrating ZnCl₂-promoted Michael addition with Pd-catalyzed allylic alkylation, allenoates readily undergo allyl-sunfonylation at the internal double bond, thus providing a straightforward avenue for the rapid assembly of a host of structurally diversified α-allyl-β-sufonylbut-3-enoate derivatives. The success of this transformation profits from a delicate control of the reaction kinetic of each elementary step, thanks to the synergistic interaction of Pd/Zn bimetallic system, thus suppressing either direct allylic sulfonylation or premature quenching of therein in situ generated ester enolate intermediate. Furthermore, by expanding the scope of workable Michael acceptor beyond those previously required doubly activated ones, such as methylenemalononitrile, the present work substantially enriches the repertoire of NAAA reactions.

Full text of DOI:10.1021/acs.orglett.9b02728

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sulfinate-Engaged Nucleophilic Addition Induced Allylic Alkylation
of Allenoates
Ling-Zhi Lin, Yuan-Yuan Che, Peng-Bo Bai, and Chao Feng*
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, 30 South Puzhu Road,
Nanjing 211816, P.R. China
S
* Supporting Information
ABSTRACT: A strategically novel Pd-catalyzed nucleophilic addition induced allylic alkylation reaction (NAAA) of allenoates
has been successfully accomplished. By judiciously integrating ZnCl2-promoted Michael addition with Pd-catalyzed allylic
alkylation, allenoates readily undergo allyl-sunfonylation at the internal double bond, thus providing a straightforward avenue
for the rapid assembly of a host of structurally diversified α-allyl-β-sufonylbut-3-enoate derivatives. The success of this
transformation profits from a delicate control of the reaction kinetic of each elementary step, thanks to the synergistic
interaction of Pd/Zn bimetallic system, thus suppressing either direct allylic sulfonylation or premature quenching of therein in
situ generated ester enolate intermediate. Furthermore, by expanding the scope of workable Michael acceptor beyond those
previously required doubly activated ones, such as methylenemalononitrile, the present work substantially enriches the
repertoire of NAAA reactions.
Scheme 1. Development of Nucleophilic Addition Induced
Allylic Alkylation Reactions
ransition-metal-catalyzed allylic alkylations (AA) repre-
sent one of the most important techniques for carbon−
T
carbon or carbon−heteroatom bond constructions and have
therefore found wide applications in the synthesis of natural
products and biologically relevant molecules.1 Within this
territory, while the past several decades have witnessed a
tremendous evolvement, the majority of chemists’ endeavors
were focused either on the exploitation of diverse potentially
applicable pro-nucleophiles2 or on identifying more earth-
abundant transition-metal catalysts capable of offering
comparable or complementary reaction outcomes.3,10 Fur-
thermore, the traditional AA reaction in its own right is not
without limitations. For example, while soft nucleophiles
engaged AA reactions have been well explored,2 the hard ones,
however, remain much more recalcitrant,4 and in the case of
handling active nucleophile with comparatively low kinetic
stability, such as a carbanion with a β-substituted leaving
group, the reaction outcome always proves to be elusive. In
this environment, the development of new strategies, which
could ameliorate the existing issues, have been continuingly
attracting considerable attention from the synthetic commun-
ity. In this light, nucleophilic addition induced allylic alkylation
(NAAA, Scheme 1a), which targets the functionalization of the
nascent nucleophile resulting from Michael-type addition,
emerges as an appealing alternative because of the following
advantages: (i) it allows the generation of more than one bond
in every catalytic cycle, which enables a more step-economical
manifold for the rapid assembly of molecular complexity; (ii)
strong base which is frequently employed in depronative
allylation protocols could be omitted, which is deemed to be
highly desirable in consideration of functionality tolerance;
(iii) for kinetic reasons, the labile carbanion intermediate (such
Received: August 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02728
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Letter
a
as α-CF3-substituted benzylic anion), which would degrade via
retro-Michael pathway in conventional deprotonative manner,
could be functionalized through a Michael addition−allylic
alkylation cascade (Scheme 1b).5
Table 1. Optimization of Reaction Conditions
Notwithstanding the above-mentioned merits, the rational
design of novel NAAA protocols is nontrivial because of the
daunting challenge in identifying appropriate reaction
components for the well-organized reaction sequence while
suppressing the competing premature allylation of the pro-
nucleophile as well as protonation of the post-nucleophile. In
this context, elegant contributions from the groups of
Yamamoto,6 Stoltz,7 Aggarwal,8 Hou,9 and Plietker10 nicely
show the potential of NAAA in the expedient construction of
molecular complexity, although doubly activated Michael
acceptors are always required for guaranteeing reaction
selectivity from kinetic and thermodynamic considerations.
Leveraging upon the NAAA strategy, our group has recently
reported a novel synthetic method for the rapid access of α-
aryl-α-allyltrifluoroethane derivatives.5 It is worth pointing out
that the conventional deprotonative allylation protocol turned
out to be fruitless in this regard because of the number of
overwhelming retro-Michael side reactions (Scheme 1b).
While notable advances regarding NAAA have been obtained
during the past two decades, there still remain massive
shortcomings because of its heavy reliance on the use of
doubly activated Michael acceptors or specific starting
materials, which would more or less detract from its more
broad applications in organic synthesis. Therefore, the
development of novel protocols that allows the engagement
of more readily available reaction components is still in high
demand, practicably and theoretically.
Taking into account the reaction mechanism, the feasibility
of a three-component NAAA reaction is envisioned to be
founded on either of the following premises: (i) for the pro-
nucleophile, the initiating Michael addition should be
kinetically favored compared to the background allylation;
(ii) the allylmetallic complex would undergo a reversible
reaction with the pro-nucleophile while irreversibly interacting
with the post-nucleophile. As part of our continuing interest in
the development of new NAAA reactions, sulfinates draw our
attention, assuming that they constitute a class of competent
nucleophiles for Michael type addition11 or substitution
reactions as well as display medicinal importance of sulfone-
derived architectures.12 Furthermore, transition-metal-cata-
lyzed C−S bond functionalization of sulfone was also actively
pursued, with representative works from the groups of
Trost,13b Li,13c Carretero,13d Crudden,13e Yoshikawa,13f
Willis,13g,h and Baran13i underlying the potential applicability
of sulfone as a new type of electrophile in cross-coupling
reactions. Herein, we report a conceptually novel palladium-
catalyzed allyl-sulfonylation of allenoate through a sulfinate-
engaged NAAA reaction (Scheme 1c).
b
entry
deviation from standard conditions
yield (%)
c
1
2
3
4
5
6
7
8
9
none
84
22
0
18
trace
73
Mg(ClO4)2 instead of ZnCl2
without ZnCl2
DPPF instead of XantPhos
MePhos instead of XantPhos
DMA as solvent
DMSO as solvent
NMP as solvent
no Pd(acac)2 or no XantPhos
30
65
0
a
Standard conditions: 1a (0.2 mmol), 2a (0.1 mmol), PhSO2Na (0.2
mmol), ZnCl2 (0.12 mmol), Pd(acac)2 (0.005 mmol), XantPhos
(0.005 mmol) in DMF (1.0 mL) at 40 °C for 12 h. NMR yield
determined with 3,4,5-trimethoxybenzaldehyde as the internal
b
c
standard. Isolated yield.
played a crucial role in this transformation, with ZnCl2 being
the optimal choice. Whereas replacement of ZnCl2 by
Mg(ClO4)2 resulted in a significant decline in the yield of 4a
(entry 2), the omission of Lewis acid additive led to essentially
no desired product formation (entry 3). It is therefore
reasonable to assume that ZnCl2 activates allenoate 1a and
in turn facilitates the assembly of post-nucleophile inter-
mediate, probably as a seven-membered-ring structure.2e,m,n In
addition, the ancillary ligands were found to be of vital
importance for the success of this reaction, among which
XantPhos showed the best performance (entries 1, 4, and 5).
Other polar nonprotic solvents such as DMA, DMSO, and
NMP all proved to be inferior to DMF in terms of reaction
efficiency (entries 6−8). Further control experiments indicated
the indispensability of both the palladium catalyst and the
phosphine ligand, with no desired product obtained (entry 9).
With the optimized reaction conditions in hand, the scope of
the reaction was subsequently investigated, and the results are
summarized in Table 2. Initially, a collection of electronically
different benzyl allenoate derivatives was examined, thus
showing a nice tolerance of diverse functionalities in this
transformation. For example, benzyl allenoate derivatives with
electron-donating groups such as methyl and methoxy afforded
the desired products in good yields (4b, 4c). Halogen atoms
such as F and Cl were tolerated (4d, 4e). Electron-withdrawing
substituents such as ester, trifluoromethyl, nitro, and nitrile
groups also turned out to be well compatible with these
reaction conditions (4f−4i). Pleasingly, benzyl allenoate
substrate with an o-vinyl substituent was found to participate
in this reaction smoothly, delivering the desired product 4j in
81% yield. Furthermore, ethyl allenoate could be readily
transformed into the desired product 4k, albeit in somewhat
attenuated reaction efficiency. Unfortunately, allenoates with
an additional substituent at the 1- or 3-position failed to afford
the desired products (see the Supporting Information for
details). Subsequently, the reaction generality with respect to
allyl carbonate was explored. The employment of tert-butyl (1-
phenylallyl) carbonate as the reaction partner led to the
formation of desired product 4a in 65% yield, which
unequivocally implicates the engagement of allylpalladium
intermediate in this transformation. With respect to aromatic
At the outset, the model reaction between benzyl buta-2, 3-
dienoate 1a, tert-butyl cinnamyl carbonate 2a, and sodium
benzenesulfinate 3a was examined, and the representative
results are compiled in Table 1. After systematic examination
of all reaction parameters, the optimized reaction conditions
were finally identified as follows: under the protection of N2
atmosphere, a DMF solution of 1a (2 equiv), 2a (1 equiv), and
3a (2 equiv) with Pd(acac)2 (5 mmol %), XantPhos (5 mol
%), and ZnCl2 (1.2 equiv) as the catalyst, ancillary ligand, and
Lewis acid, respectively, was heated at 40 °C for 12 h (entry 1,
see the Supporting Information for details). Lewis acid additive
B
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Letter
Table 2. Reaction Scope of Sufinate-Engaged NAAA Reaction of Allenoates
a
b
c
Reaction using tert-butyl (1-phenylallyl) carbonate as the substrate. Gram-scale reaction. DtBPF (0.005 mmol) was used as the ligand.
Potassium sulfinate substrate was employed.
d
allyl carbonate examined, the electronic effect of decorating
substituents was revealed to be inconsequential to this
reaction, and the desired products with a diverse range of
substituents such as halogen, alkyl, alkoxyl, ester, trifluor-
omethyl, nitrile, and nitro groups were obtained in good yields
(4m−4u). Expectedly, naphthyl-derived allyl carbonate under-
went this transformation without any difficulty and provided
the desired product 4l in 80% yield. It also needs to be pointed
out that allyl carbonates derived from heteroarenes were also
viable substrates as represented by the cases of 4v and 4w. To
our delight, trisubstituted allyl carbonate derivatives also
reacted uneventfully, as showcased by the example of 4x.
While examining the reaction generality of allyl carbonate, we
were quite surprised to find that the simplest allyl carbonate
was inapplicable to the standard reaction conditions. Further
refinement of the reaction parameter ultimately led to the
formation of the desired product 4y in 80% yield when DtBPF
was substituted for XantPhos as the assisting ligand.
Interestingly, while 2-phenyl-substituted allyl carbonate was
accommodated by the XantPhos-based protocol, substrates
with 2-CO2Me and 2-Cl substituents, on the contrary, only
generated the desired products when DtBPF was used as
ligand (4z, 4aa, 4ab). The exact reason for such a discrepancy
is not clear at the present stage. Because of the medicinal
importance of sulfonylated framworks, the reaction generality
of sulfinate was also interrogated. Aryl sulfinates containing
substituents such as Me, OMe, and F afforded the desired
products in moderate to good yields (4ac−4ae). In the case of
using 2-naphthyl sulfinate, the desired product 4af could be
obtained in 40% yield. Delightfully, the reaction was not
restricted to aryl sulfinates, and alkyl sulfinates, irrespective of
being linear or cyclic, were tolerated (4ah, 4ai). Notably, when
potassium sulfinate derived from etoricoxib was employed, the
reaction occurred smoothly and the desired product 4ag was
C
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Letter
isolated in 48% yield. To further challenge the synthetic
applicability of this reaction, allenoates derived from a
collection of naturally occurring molecules were tested, and
the desired products were all obtained in synthetically useful
yields, thus indicating the generality of this method for the
synthetic elaboration of complex architectures (4aj−4ao). Also
of note, a gram-scale reaction of the model reaction led to the
generation of product 4a in 75% yield (1.46 g), which in turn
underscores the practicality of the present transformation.14,15
To gain more insight into the exact role of Pd/Zn bimetallic
composition in this reaction, control experiments with the
omission either ingredient were initially carried out (Scheme
2). It was found that the model reaction carried out in the
To showcase the utility of the obtained α-allyl-β-sufonylbut-
3-enoate derivatives, the synthetic transformation of 4y was
subsequently launched (Scheme 3). The treatment of 4y with
a
Scheme 3. Synthetic Transformation Conditions
Scheme 2. Control Experiments
a
Key: (a) BnNH2, MeOH, 65 °C, 24 h; (b) m-CPBA, DCM, 0 °C to
rt, 42 h; (c) Ir[(dF)(CF3)(ppy)2 (dttbpy)](PF6), benzyloxyacetic
acid, Cs2CO3, DMF, rt, 96 h,15 W blue LED; (d) Ir(ppy)2(dttbpy)-
(PF6), 2-bromopyridine, HEH, H2O/DMSO, rt, 12 h, 15 W blue
LED; (e) PhCl, 160 °C, 12 h.
benzylamine allows a smooth generation of pyrrolidin-2-one
product 7a in 73% yield,17 and the m-CPBA-mediated
epoxidation selectively occurred on the more electron-rich
double bond to deliver product 8a in 71% yield.18 In addition,
while the present reaction is not applicable to γ-substituted
allenoates, the Giese reaction, to some extent, provides a
pathway by enabling an expedient introduction of either aryl or
alkyl groups to the γ-position (9a, 10a).19,20 Finally, hepta-2,6-
dienoate product 11a could be readily obtained through Cope
rearrangement from 4y.
In summary, by making use of sulfinates, allyl carbonates as
pro-nucleophiles, and allyl donors, respectively, a regioselective
NAAA reaction of a wide spectrum of structurally diversified
allenoates was developed. The employment of the Pd/Zn
bimetallic reaction system is believed to be the key point for
suppressing the competing background side reactions, thus
enabling a well-organized cascade elaborations. Furthermore,
the amenability of allenoate derivatives in this transformation
not only allows the generation of molecular framework in high
complexity but more importantly greatly expands the
compatibility of NAAA type reaction beyond those often
required doubly activated Michael acceptors.
absence of ZnCl2 exclusively afforded the allylic sulfonylation
byproduct 5a, while the omission of Pd catalyst led to the
formation of only Michael addition products 6a/6a′, with
protonation of in situ formed ester enolate on the α- and γ-
position, respectively.16 Collectively, these results could be
interpreted by assuming that (i) zinc salt could selectively
activate allenoate 1a, thus making the sulfinate-based Michael
addition kinetically much more favored compared with the
background allyic sulfonylation reaction, and (ii) the palladium
catalyst on the other hand engages allyl carbonate with ease to
generate allylpalladium intermediate; the regioselectivity for
the enolate allylation is believed to be controlled globally by
electronic and steric effects. Subsequently, to differentiate the
working modes that we assumed as the premise for the success
of this three-component NAAA reaction, further control
experiments with 5a and 6a were examined. When the
reaction of 1a and 5a was subjected to the standard reaction
conditions, essentially no desired product 4a was obtained,
which firmly rules out the reversibility of allylic sulfonylation
process and also the intermediacy of 5a in the whole
transformation. In addition, when we added 6a to the reaction
carried out between 1c and 2a, both allylation products 4a and
4c were obtained. It follows that the success of this reaction is
attributed to the kinetically favored Michael addition
associated with irreversible enolate allylation by virtue of the
integrated effects of Pd/ZnCl2 bimetallic system.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02728.
Experiemental procedures, characterization data, and
NMR spectra (PDF)
D
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Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: iamcfeng@njtech.edu.cn.
ORCID
Chao Feng: 0000-0003-4494-6845
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the
“Thousand Talents Plan” Youth Program, the “Jiangsu
Specially-Appointed Professor Plan”, the National Natural
Science Foundation of China (21871138), and the Natural
Science Foundation of Jiangsu Province (BK20170984).
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(14) While an asymmetric version of this reaction was also
investigated using a series of privileged chiral ligands for allylic
alkylation, only marginal enantiomeric excess was acquired at this
stage. See the Supporting Information for details.
(15) In order to achieve asymmetric allylic alkylation, chiral Zn-
based complexes were examined in the reaction, resulting in either no
desired product formation or no enantioselectivity. See the
Supporting Information for details. For the selected examples of
chiral Zn-complex-engaged asymmetric allylic alkylation reactions,
see: (a) Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am. Chem. Soc.
2016, 138, 11093. (b) He, R.; Liu, P.; Huo, X.; Zhang, W. Org. Lett.
2017, 19, 5513.
(16) The postisomerization of 6a/6a′ after a regioselective
protonation of ester enolate intermediate could not be precluded.
̂
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DOI: 10.1021/acs.orglett.9b02728
Org. Lett. XXXX, XXX, XXX−XXX