Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Dihydroquinolinones

Article abstract of DOI:10.1021/acs.orglett.9b00358

A palladium-catalyzed decarboxylative asymmetric allylic alkylation (Pd-DAAA) of benzo-fused and non-benzo-fused δ-valerolactams is disclosed. This methodology gives access to chiral lactams bearing C3-quaternary stereocenters, which are central to many n

Full text of DOI:10.1021/acs.orglett.9b00358

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation
of Dihydroquinolinones
Barry M. Trost,* Anugula Nagaraju, Feijun Wang, Zhijun Zuo, Jiayi Xu, and Kami L. Hull
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed decarboxylative asym-
metric allylic alkylation (Pd-DAAA) of benzo-fused and non-
benzo-fused δ-valerolactams is disclosed. This methodology
gives access to chiral lactams bearing C3-quaternary stereo-
centers, which are central to many natural products and
biologically active compounds. The reaction proceeds via palladium-catalyzed ionization of an allyl ester, followed by carbon
dioxide extrusion and recombination of the electrophilic Pd-π-allyl complex with the in situ generated lactam enolate. This final
step converts racemic allylic ester starting materials into enantiomerically enriched substituted lactams with high yield and
enantiomeric excess.
Scheme 1. Approaches To Access Chiral 3,3-Substituted
Dihydroquinolinones
itrogen-containing heterocycles are ubiquitous in natural
1,2 anddrugmolecules.3 Among
Nproducts,pharmaceuticals,
such compounds, 4-monosubstituted and 3,4-disubstituted
dihydroquinoline-2(1H)-ones are particularly important struc-
tural motifs and appear in many natural products and biologically
relevant compounds (Figure 1).
approach lies in the ease of accessibility of the racemic allyl ester,
bearing 3-substituted dihydroquinolinone substrates from
commercially available dihydroquinolinones in high yield and
straightforward procedure (Scheme 2). Under asymmetric
palladium catalysis, the racemic allyl esters would give rise to
3,3-disubstituted dihydroquinolinone products with high enan-
tioselectivity.
We began our endeavor by identifying an efficient approach to
accesstheracemicdihydroquinolinonematerials.Asillustratedin
Scheme 2, allyl imidazolates were selected as acylating agents to
synthesize the desired substituted dihydroquinolinones. In the
alkylation step, one might be concerned about an enolate Claisen
rearrangement competing with the desired alkylation event.
Figure 1. Biologically active compounds containing 3,4-dihydroquino-
lin-2-ones.
Theimportanceofthisstructuralmotifhasstimulatedactivities
within the synthetic community to evolve methodologies that
could give access to tetrahydroquinolone compounds.4−8 None-
theless, the synthesisofchiral 3-substituted and 3,3-disubstituted
dihydroquinolin-2(1H)-ones is far less developed,9 despite the
frequent appearance of such motifs in pinolinone,10 scandine,11
and a norepinephrine reuptake inhibitor10b(Figure 1).
Scheme 1 illustrates some of the existing synthetic methods for
accessing3-substituted dihydroquinolinonesasillustratedby Cai
and co-workersshown inScheme 1a9c and Pan and co-workersas
shown in Scheme 1b.9d,e We envisioned a possible alternative
strategy using palladium-catalyzed allylic alkylation to access this
motif with high efficiency (Scheme 1c). The effectiveness of our
Received: January 28, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b00358
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Scheme 2. Synthesis of Dihydroquinolin-2-one DAAA
Substrates
Figure 2. Chiral diamine ligands.
Table 1. Optimization of Reaction Conditions for Pd-DAAA
a
on Benzo-Fused Lactams
b
entry
ligand
solvent
temp (°C)
yield (%)
ee (%)
1
2
3
4
5
6
L1
L2
L3
L4
L4
L4
dioxane
dioxane
dioxane
dioxane
toluene
dioxane
23
23
23
23
23
60
43
10
47
76
68
80
27
3
10
98
97
97
a
The reactions were run by using 0.1 mmol of 1a, 2.5 mol % of
b
Pd2dba3·CHCl3, and 7.5 mol % of L4 in 1 mL solvents. Isolated
yields.
AsillustratedinScheme3,awiderangeofdihydroquinolinones
with various substituents at the 3-position of the dihydroquino-
linone core were subjected to the optimized reaction conditions.
With tert-butyloxycarbonyl (Boc)-protected dihydroquinoli-
nones (1a−1f), alkyl, propargyl, vinyl, nitrile, and ester
substituents were well tolerated, and the desired allylated
products 2a−2f were obtained in high yield and enantioselectiv-
ity. Of note, a vinyl chloride is tolerated under the palladium-
catalyzed allylation conditions, and 2d was isolated in 91% yield
and 91% ee. Similarly, favorable results were obtained when
benzoyl-protected dihydroquinolinones 1j−1k were utilized as
substrates, affording allylated products 2j−2k with high
enantioselectivity. Reaction of racemic 1a on 1.0 mmol scale
under theconditionsdescribed inScheme 3at roomtemperature
led to product 2a in 71% yield and 97% ee.
Extension of the above reaction conditions to simple δ-
valerolactams was also explored (Scheme 4). N-Benzoyl
piperidones with various substituents at the 3-position were
effective, and the allylated products 4a−4e were isolated in good
yield and high enantioselectivity. The results for these δ-
valerolactams are comparable to the results for dihydrobenzo-
quinolinone in Scheme 3. In the case of δ-valerolactams,
utilization of substituted allyl motifs is particularly notable (4c
and 4e).
Fortunately,suchacompetitionwasnotobservedinthiscase,and
a wide range of functionalized allylating agents were successfully
employed (Scheme 2, 1a−1l).
With these racemic substrates in hand, we set out to identify
conditionsthatcouldaffectthedecarboxylativeasymmetricallylic
alkylation sequence. Although the Stoltz group12 described the
use of the Pfaltz ligands for the DAAA of cyclic amides, they only
applied this methodology to simple lactams. We planned to use
the 2-diphenylphosphinobenzoate chiral ligands L1−L4 (Figure
2)inourstudiesbecausetheDPPBAligandshavegenerallyshown
broader scope in terms of both the electrophile and nucleophile.
Webegantheoptimizationofthereactionusing1aasthemodel
substrate (Table 1). In dioxane, low to moderate yield and poor
enantioselectivity were observed with ligands L1, L2, and L3.
Fortunately, utilizingligand L4resultedin adrasticimprovement
in the yield and the enantioselectivity of the reaction (Table 1,
entry 4). Switching to a less polar solvent (i.e., toluene) gave a
lower yield and similar enantioselectivity (Table 1, entry 5).
Performing the reaction in 1,4-dioxane at 60 °C instead of room
temperature led to 80% yield of the allylated product with 97% ee
(Table 1, entry 6). Thus, the highlighted conditions in entries 4
and6inTable1wereselectedastheoptimalconditionstoexplore
the generality of this transformation.
We further explored the use of a 2-substituted allyl fragment in
the allylation of dihydroquinolinone 1l, and the allylated product
2l was obtained in moderate yield and with perfect enantiose-
lectivity(eq1).Utilizationof1-substitutedallylgroupsinthecase
ofδ-valerolactams3fand3gwasalsodemonstrated(eqs2and3).
B
DOI: 10.1021/acs.orglett.9b00358
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Scheme 3. Scope of the Decarboxylative Asymmetric Allylic
Alkylation of Benzo-Fused δ-Valerolactams
Scheme 4. Scope of the Decarboxylative Asymmetric Allylic
Alkylation of Simple δ-Valerolactams
a b
,
a
a
Reaction conditions: lactam 3 (0.1 mmol), Pd2dba3·CHCl3 (2.5 mol
%), (R,R)-L4 (5.5 mol %), and 1 mL of dioxane.
a
Reactions were carried out on 0.1 mmol scale using 2.5 mol % of
Pd2dba3·CHCl3 and 7.5 mol % of L4 in dioxane (0.1 M) for 12 h.
b
c
Isolated yields. 0.05 mmol of 1 was treated with 2.5 mol % of
Pd2dba3·CHCl3 and 7.5 mol % of L4 in 0.5 mL of dioxane.
Itshouldbenotedthateffortstoemployallylfragmentslikethose
in eqs 2 and 3 were unsuccessful when Pfaltz-type ligands were
utilized.
Theabsolutestereochemistryoftheproductsobtainedthrough
this methodology was assigned using chemical manipulation of
product 2a to access known compound 6 with established
stereochemistry (Scheme 5).13 Comparison of the optical
rotation of 6 with the reported data was then utilized to establish
the absolute configuration of the stereocenter in this compound.
The absolute stereochemistry of 4a was previously established12
and is consistent with our findings for 2a; therefore, all other
products were assigned by analogy.
This reaction presumably proceeds via a typical DAAA
mechanism, as described previously (Scheme 6).14 The major
alteration is the differential behavior of the anthracene-derived
ligand, which showed an enabling effect on these reactions.
Structurally, ligand L4 has the largest dihedral angle among the
DPPBA ligands, and the larger P−Pd−P bite angle may be
instrumental in allowing this reaction to proceed. The catalytic
cycle is initiated by interaction of the active palladium catalyst
(Pd0Ln) with the racemic substrate 1 to form a palladium π-allyl
complex,alongwiththecarboxylateanion.Decarboxylationofthe
carboxylate anion would then easily occur to generate the
stabilized enolate. Nucleophilic attack of this enolate on the
electrophilic palladium π-allyl complex would result in α-
allylation of the enolate, along with regeneration of the palladium
active catalyst (Pd0Ln) for the following catalytic cycles. The
success of these new classes of prochiral nucleophiles further
demonstrates the effectiveness of the chiral palladium DPPBA
complexes for asymmetric allylic alkylation reactions.
In summary, we have developed a palladium-catalyzed
decarboxylative asymmetric allylic alkylation (Pd-DAAA) of
dihydroquinolinones, wherein quaternary stereocenters can be
accessed with high selectivity. Furthermore, this methodology
C
DOI: 10.1021/acs.orglett.9b00358
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Notes
Scheme 5. Application to the Synthesis of a Norepinephrien
Reuptake Inhibitor and Assignment of Absolute
Stereochemistry
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
WegratefullyacknowledgetheScienceandEngineeringResearch
Board, India and Indo−U.S. Science and Technology Forum,
India for financial support (fellowship Indo-US PDF-78/2017 to
A.N.). We thank Hadi Gholami for help in preparing the final
manuscript.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.9b00358.
Experimental details and NMR, HPLC, and ESI-HRMS
data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bmtrost@stanford.edu.
ORCID
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C.; Stoltz, B. M. Nat. Chem. 2012, 4, 130.
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T.; Kitagawa, O. Tetrahedron 2010, 66, 288.
Barry M. Trost: 0000-0001-7369-9121
Kami L. Hull: 0000-0003-3102-2686
D
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(14) For selected reviews, see: (a) Weaver, J. D.; Recio, A., III;
Grenning,A.J.;Tunge,J.A.Chem.Rev.2011,111,1846.(b)Trost,B.M.;
Schultz, J. E. Synthesis 2019, 51, 1 and references therein .
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