Uniting C1-Ammonium Enolates and Transition Metal Electrophiles via Cooperative Catalysis: The Direct Asymmetric α-Allylation of Aryl Acetic Acid Esters

Article abstract of DOI:10.1021/jacs.6b01694

The direct, catalytic, asymmetric α-functionalization of acyclic esters constitutes a significant challenge in the area of asymmetric catalysis, particularly where the configurational integrity of the products is problematic. Through the unprecedented mer

Full text of DOI:10.1021/jacs.6b01694

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Communication
Uniting C1-Ammonium Enolates and Transition Metal
Electrophiles via Cooperative Catalysis: The Direct,
Asymmetric #-Allylation of Aryl Acetic Acid Esters .
Kevin J. Schwarz, Jessica L. Amos, James Cullen Klein, Dung T. Do, and Thomas N. Snaddon
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01694 • Publication Date (Web): 30 Mar 2016
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Uniting C1ꢀAmmonium Enolates and Transition Metal Electrophiles
via Cooperative Catalysis: The Direct, Asymmetric αꢀAllylation of
Aryl Acetic Acid Esters.
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Kevin J. Schwarz, Jessica L. Amos, J. Cullen Klein, Dung T. Do, Thomas N. Snaddon*
Department of Chemistry, Indiana University, 800 E. Kirkwood Ave., Bloomington, Indiana 47405, United States.
Supporting Information Placeholder
ABSTRACT: The direct, catalytic, asymmetric α-
functionalization of acyclic esters constitutes a significant
challenge in the area of asymmetric catalysis, particularly
where the configurational integrity of the products is prob-
lematic. Through the unprecedented merger of two inde-
pendent, yet complementary, catalysis events it has been
possible to facilitate the direct asymmetric α-allylation of
readily available, inexpensive aryl acetic acid esters. Since
enantioselection is determined by the nucleophile, this con-
ceptual approach to cooperative catalysis constitutes a po-
tentially general solution to the direct catalytic asymmetric
α-functionalization of acyclic esters
.
In cooperative or synergistic catalysis chemical bond
formation occurs via the unification of distinct interme-
diates manufactured by simultaneous yet discrete cataly-
sis events.1 Attracted by this potentially expansive ap-
proach to reaction design, we questioned whether this
notion might be harnessed to develop a general solution
to the direct, catalytic asymmetric α-functionalization of
acyclic esters (Figure 1a). More specifically, we envi-
sioned the union of C1-ammonium enolate nucleophiles
and transition metal electrophiles via two precisely or-
chestrated and complementary catalysis platforms.2
Within this nascent framework we describe the direct,
asymmetric, α-allylation of acyclic aryl acetic acid es-
ters (Figure 1b).
Transition metal catalyzed allylic alkylation reac-
tions are much lauded, versatile and now commonplace
methods for asymmetric carbon–carbon and carbon–
heteroatom bond formation.3 Adorned with a bewilder-
ing array of ligands, numerous low valent transition
metals serve as effective catalysts and direct the trajecto-
ry of a wide range of nucleophiles with high levels of
regio-, diastereo- and enantio-control. However, while
the catalyst governs electrophile facial selectivity with
high fidelity, extending stereoselection to the nucleo-
Figure 1. (a) Conceptual framework for the direct
asymmetric α-functionalization of esters; (b) This work:
the direct α-allylation of aryl acetic acid esters.
philic partner can be more challenging. Prochiral esters
are commonly employed but require the derived enolate
be stereodefined. Electronically and sterically biased
ester pro-nucleophiles4 are effective, as are stereode-
fined ester enolate equivalents,5 but the direct employ-
ment of linear esters is complicated by the strong bases
necessary for their preparation and/or the inevitable pro-
duction of enolate isomers.6 Cognizant of this, we con-
sidered C1-ammonium enolates as non-stabilized, acy-
clic ester enolate equivalents.7 These can be generated
from simple, activated carboxylic acid derivatives, exist
as single isomers, and engage in enantioselective car-
bon–carbon, carbon–heteroatom and carbon–halogen
bond formation with standard electrophiles under the
escort of simple nucleophilic tertiary amine catalysts.
Furthermore, their generation does not require strong
bases, thereby preserving the integrity of enolizable ste-
reogenic centers.8 However, critical to their union with
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Scheme 1. Postulated cooperative catalysis mechanism.
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Table 1. Optimization Studies.
any π-(allyl)metal electrophile is the identification of a
turnover mechanism for the nucleophilic catalyst.
In typical reactions implicating C1-ammonium eno-
lates discrete ion pairs are not formed and catalyst turn-
over occurs by intramolecular attack of a proximal nu-
cleophile on an intermediate acyl ammonium ion.7 In a
cooperative regimen successful turnover would demand
intermolecular attack by an exogenous nucleophile. The
feasibility of this finds support in recent reports. In a
seminal study, Scheidt and co-workers revealed the pro-
pensity of 4-nitrophenolate to act as a rebound nucleo-
phile and effect turnover of N-heterocyclic carbene cata-
lysts via phenolysis of intermediate acyl azolium ions.9
In the only report of an analogous process implicating
acyl ammonium ion intermediates, Smith and co-
workers harnessed Scheidt’s 4-nitrophenolate rebound in
their generation and asymmetric [2,3]-sigmatropic rear-
rangement of C1-ammonium enolates.10,11 In consider-
ing these, we envisioned a plausible mechanistic scenar-
io where C1-ammonium enolates and π-(allyl)palladium
electrophiles unite via cooperative catalysis, and turno-
ver of the nucleophilic catalyst occurs via phenolate re-
bound (Scheme 1). Additionally, the plenitude of availa-
ble chiral nucleophilic tertiary amine catalysts raised the
prospect of developing an enantioselective process.
Our initial efforts focused on the structure of the ar-
yl ester and nature of the allyl nucleofuge (Table 1).
Employing XantphosPd12 and (+)-benzotetramisole13 as
transition metal and nucleophilic catalysts, respectively;
the α-allylation of p-nitrophenyl ester 1 was utilized as
a benchmark transformation14 (entries 1–7). While the
allylation product was obtained regardless of the leaving
group employed, the degree of enantioselectivity varied
markedly. Moving from allylic esters (entries 1 and 2) to
allylic phosphonates and allylic carbonates (entries 3–6)
resulted in higher yields and enhanced levels of (R)-
enantioenrichment. In response to this initial trend we
increased the nucleofugality of the leaving group. While
allyl chloride provided the desired product in modest
aReactions performed on a 0.1 mmol scale. bYields determined
1
by H-NMR comparison with an internal standard (1,2,4,5-
c
d
tetramethylbenzene). Isolated yields in parentheses. Deter-
e
mined by chiral HPLC analysis. 12:1 mixture of aryl:iBu
esters. fNo (+)-BTM. gNo XantphosPd.
yield and enantioselectivity (entry 7), allyl mesylate re-
sulted in 62% yield (42% isolated)15 and 92% ee (entry
8). Unfortunately, material loss during isolation could
not be suppressed, and neither the yield nor reaction
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sive reassessment of the leaving group revealed cinnam-
Table 2. Substrate Scope.
1
yl tert-butylcarbonates to be particularly effective reac-
tion partners (Table 2, X = OCO2tBu).18 In each case the
linear product was obtained as the E-alkene isomer in
excellent isolated yield and enantiomeric excess. More-
over, electronic modulation was again inconsequential
(18–22) and the arene structure could be varied (23 and
24).
The synthetic utility of this process is further en-
hanced by the activated nature of the product esters. De-
spite their configurational sensitivity, their transfor-
mation to standard products could be accomplished in
high yields and with little to no erosion of enantiopurity
(Scheme 2).
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Scheme 2. Transformation of products.
Conditions: (a) LiAlH4, Et2O, r.t., 2 h; (b) HCl/MeOH,
60 °C, 36 h; (c) Me3SnOH, 1,2-DCE, 70 °C, 12 h.
The mechanistic scenario we have posited provides
useful didactic guidelines for further development
(Scheme 1); however, the precise manner in which the
two catalytic events integrate is unknown. Nonetheless,
it is tempting to speculate on the intermediacy of eno-
late-ligated π-(allyl)Pd(II) species19-21 (Scheme 1, right).
In addition to a well-ordered transition state, this offers a
possible explanation for the critical influence of the nu-
cleofuge (X–) where affinity for Pd(II) might well be
determinant. While mechanistic clarification must await
further study, the sense of enantioselectivity observed
can nevertheless be rationalized by a tentative induction
model (Figure 2).10 In a highly pre-organized (Z)-C1-
ammonium enolate incorporating a stabilizing and rigid-
All yields refer to isolated yields following silica gel chroma-
tography. Enantiomeric excess was determined by chiral
HPLC in comparison to the racemate.
time optimized further. We therefore undertook a survey
of aryl esters to assess their capacity as Scheidt-type
rebound nucleophiles (entries 9–12). Of these, fluorinat-
ed phenyl esters 3 and 4 proved to be exceptionally ef-
fective. Furthermore, and in contrast to the 4-nitrophenyl
esters, greatly reduced reaction times were required and
chromatographic isolation of the product esters was triv-
ial and efficient. We selected pentafluorophenyl esters
(such as 4) for further study as they are established and
versatile acyl donors and exhibit useful hydrolytic stabil-
ity.16 Having established effective conditions17 a variety
of aryl acetic acid pentafluorophenyl esters was evaluat-
ed (Table 2, X = OMs). There appears to be little sensi-
tivity to changes in the electronics of the arene; fluoride,
chloride and bromide substituents are tolerated (15, 9
and 11), as is ortho substitution. Of further synthetic
utility is the allylation of indole-containing NSAID-Pfp
ester, 17. Unfortunately, efforts to extend the scope of
the partner mesylate were unsuccessful. A comprehen-
ifying nO→σ*
electrostatic interaction (28),22 facial
addition is governed by the pendant phenyl group. Acco-
C–S
Figure 2. Stereochemical model.
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In conclusion, we have developed a novel coopera-
tive catalysis-based method for the direct asymmetric
α-allylation of acyclic esters. Notably, this protocol
occurs at room temperature, does not require the prior
preparation of a stereodefined ester enolate, nor does it
require strong bases that compromise the optical purity
of the products. Furthermore, and in contrast to common
transition metal catalyzed approaches, stereocontrol is
provided by the nucleophilic catalyst rather than by met-
al-based ligand frameworks. On a fundamental level this
work constitutes the first example of C1-ammonium
enolates being united with catalytically generated transi-
tion metal electrophiles and emulates Nature’s ubiqui-
tous employment of simultaneous yet distinct catalysis
events to effect chemical transformations.
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ASSOCIATED CONTENT
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Rev. 2014, 43, 6214–6226; (b) Paull, D. H.; Weatherwax, A.; Lectka,
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71, 6349–6353; (b) Korch, K. M.; Eidamnshaus, C.; Behenna, D. C.;
Nam, S.; Horne, D.; Stoltz, B. M.; Angew. Chem., Int. Ed. 2015, 54,
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(10) West, T. H.; Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D.
J. Am. Chem. Soc. 2014, 136, 4476–4479.
(11) For other acyl ammonium phenolysis,, see: (a) Lee, S. Y.;
Neufeind, S.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 8899–8902; (b)
Dogo-Isonagie, C.; Bekele, T.; France, S.; Wolfer, J.; Weatherwax,
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Chem. 2007, 1091–1100.
(12) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013,
4, 916–920.
(13) A range of common nucleophilic amine catalysts was sur-
veyed and isothioureas proved uniquely effective (see supporting
information for details). Smith and co-workers have noted similar
observations, see Ref (10).
(14) Andrus, M. B.; Harper, K. C.; Christiansen, M. A.; Binkley,
M. A. Tetrahedron Lett. 2009, 50, 4541–4544; (b) Stivala, C. E.;
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(15) For similar lower than expected isolated yields. See ref 11.
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(17) Both catalysts are required (Table 1, entries 14 and 15).
(18) See supporting information for details.
(19) For Pd(II)-metallated C1-ammonium enolates, see: (a) Erb, J.;
Paull, D. H.; Dudding, T.; Belding, L.; Lectka, T. J. Am. Chem. Soc.
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Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures and characterization data (PDF).
AUTHOR INFORMATION
Corresponding Author
*tsnaddon@indiana.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge generous financial support
from Indiana University. This manuscript is dedicated to
Professors Philip J. Kocienski, Alois Fürstner and Steven V.
Ley.
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(2) For selected examples of merging organocatalysis-derived nu-
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