A Domino Process toward Functionally Dense Quaternary Carbons through Pd-Catalyzed Decarboxylative C(sp3)-C(sp3) Bond Formation

Article abstract of DOI:10.1021/jacs.7b12608

An efficient protocol was developed to construct functionally dense quaternary carbons with concomitant formation of a new Csp³-Csp³ bond via Pd-catalyzed decarboxylative transformation of vinyl cyclic carbonates. This redox-neutral catalytic system features stereocontrolled formation of multisubstituted allylic scaffolds with an aldehyde functionality generated in situ, and it typically can be performed at room temperature without any additives. DFT calculations provide a rationale toward the selective formation of these compounds and reveal a complex mechanism that with the help of microkinetic models is able to reproduce the nontrivial dependence of the identity of the product on the nature of the substituents in the substrate.

Full text of DOI:10.1021/jacs.7b12608

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Article
A Domino Process towards Functionally Dense Quaternary Carbons
through Pd-Catalyzed Decarboxylative Csp3-Csp3 Bond Formation
Wusheng Guo, Rositha Kuniyil, José Enrique Gómez, Feliu Maseras, and Arjan W. Kleij
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12608 • Publication Date (Web): 16 Jan 2018
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A Domino Process towards Functionally Dense Quaternary Carbons
through Pd-Catalyzed Decarboxylative Csp3-Csp3 Bond Formation
Wusheng Guo,*,† Rositha Kuniyil,† José Enrique Gómez,† Feliu Maseras,*,†,‡ and Arjan W. Kleij*,†,&
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† Institute of Chemical Research of Catalonia (ICIQ), the Barcelona Institute of Science and Technology, Av. Països Cataꢀ
lans 16, 43007 – Tarragona, Spain.
‡
Departament de Química, Universitat Autónoma de Barcelona, 08193 Bellaterra, Catalonia, Spain
& Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 – Barcelona, Spain.
ABSTRACT: An efficient protocol was developed to construct functionally dense quaternary carbons with concomitant formation
of a new Csp3ꢀCsp3 bond via Pdꢀcatalyzed decarboxylative transformation of vinyl cyclic carbonates. This redox neutral catalytic
system features stereocontrolled formation of multiꢀsubstituted allylic scaffolds with an aldehyde functionality generated in situ,
and it typically can be performed at room temperature without any additives. DFT calculations provide a rationale towards the
selective formation of these compounds, and revealed a complex mechanism that is able to reproduce with the help of microkinetic
models the nonꢀtrivial dependence between the identity of the product and the nature of the substituents in the substrate.
ꢀ INTRODUCTION
byproduct in the reaction mixture based on NMR analysis.
Considering the synthetic importance of aldehydes,11 efforts
were made to reveal the molecular identity of this byproduct.
The rather unexpected and multifaceted nature of this product
suggested that the coupling of two molecules of vinyl cyclic
carbonate had occurred upon extrusion of two CO2 molecular
(Scheme 1d). The formation of this aldehyde product features
the construction of an otherwise synthetically challenging
For synthetic chemists, the ultimate goal is to synthesize
highly functionalized building blocks in a single step under
mild reaction conditions generating minimal waste. Transition
metal catalyzed decarboxylative processes have emerged as
attractive and powerful methodologies in synthetic chemistry
generating only CO2 as a byproduct and gained extensive
interest.1 Quaternary (chiral) carbons are ubiquitous in natural
products and pharmaceutically relevant compounds albeit the
construction of highly functionalized quaternary (chiral) carꢀ
bons represents a challenging task.2 Decarboxylative construcꢀ
tion of quaternary carbons has been realized in an intramoꢀ
lecular fashion,3 whereas the intermolecular coupling of reacꢀ
tion partners generating highly functionalized quaternary
carbons with new Csp3ꢀCsp3 bond formation via decarboxylaꢀ
tive methodologies under mild conditions is still in its infanꢀ
cy.1,4
quaternary carbon center and
a stereoꢀdefined, multiꢀ
substituted allylic alcohol fragment. Taking into account the
synthetic application potential of this aldehyde product
(Scheme 1d),11 we set out to examine the generality of this
chemistry and to gain detailed insight for this unusual couꢀ
pling process.12
Scheme 1. Pd-Catalyzed Decarboxylative Transformations
of Vinyl Cyclic Carbonate/Carbamate
Previous work demonstrated that the Pdꢀcatalyzed decarꢀ
boxylative construction of quaternary carbon centers is feasiꢀ
ble via the reaction of an external electrophile with a vinyl
cyclic carbonate/carbamate under mild reaction conditions
(Scheme 1a).5−7 The key to success of these transformations is
the in situ formation of a zwitterionic πꢀallylꢀPd intermediate
upon CO2 extrusion.5ꢀ7 As part of our ongoing research work
on the transformations of cyclic carbonates,8 we developed a
conceptually novel approach involving the use of nucleophiles
toward the synthesis of (Z)ꢀstereoselective allylic manifolds
through a judicious choice of the catalyst source and ligand.9
The mechanistic rationale based on DFT calculations9a sugꢀ
gested that a sixꢀmembered palladacycle intermediate is cruꢀ
cial to control the stereoselectivity of the process (Scheme 1b).
More recently, the enantioselective synthesis of branched
allylic amines, alcohols or ethers with tertiary carbons was
also achieved using vinyl cyclic carbonate precursors (Scheme
1c).10 Interestingly, during the course of our studies9a we freꢀ
quently encountered trace amounts (< 3%) of an aldehyde
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functionalized aldehyde products (cf., formation of 2a-r, Figꢀ
ꢀ RESULTS AND DISCUSSION
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ure 1). The
We selected the phenylꢀsubstituted cyclic carbonate 1a as a
model substrate for the optimization of the reaction conditions
(Table 1). To our delight, the utilization of [Pd2(dba)3]⋅CHCl3
and DPEPhos (L1) in DMF under anhydrous conditions at
room temperature gave rise to an appreciable yield (66%) of
the targeted aldehyde product 2a with concomitant formation
of the substituted acrolein byproduct 3a (entry 1).13 In the
presence of L1, the use of the White catalyst precursor affordꢀ
ed the highest yield (85%) of product 2a (Table 1, entry 1−5)
although the use of Pd(dba)2 led to a higher ratio of 2a:3a
(Table 1, entries 2 vs 5). The use of other solvents such as
THF, DCM and acetonitrile (ACN) under anhydrous condiꢀ
tions resulted in less efficient catalysis (Table 1, entries 6−8).
Importantly, poor reactivity was observed in the presence of
other ligands (L2−L7) or under ligandꢀfree conditions indicatꢀ
ing the crucial role of ligand L1 towards the success of this
transformation (entries 9−15).
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Table 1. Optimization of the Reaction Conditions towards
the Formation of Aldehyde Product 2a.a
Solvent Yield
Entry
Catalyst
L
2a:3a
[1 M]
2a[%]
70:30
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15
DMF
DMF
DMF
DMF
DMF
THF
ACN
DCM
DMF
DMF
DMF
DMF
DMF
DMF
DMF
66
77
77
<10
85
61
26
81
0
<5
0
0
0
0
[Pd2(dba)3]⋅CHCl3 L1
Pd(dba)2
93:7
80:20
90:10
90:10
84:16
80:20
86:14
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
-
Pd(OAc)2
(PPh3)2PdCl2
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Pd/bisꢀsulfoxide
Figure 1. Scope of carbonates toward the formation of aldehyde
products 2a-r. Reaction conditions unless stated otherwise: 0.2
mmol carbonate, White catalyst (2.0 mol%) and L1 (5.0 mol%) in
anhydrous DMF (0.20 mL), rt, under N2, 12 h. a 80 C, 10 mol%
o
0
b
of the White catalyst, 20 mol% L1. 18% of 3l was isolated and
fully characterized, see supporting information (SI) for details.
c5.0 mol% of the White catalyst and 10 mol% L1 used. Yield of
d
the corresponding reduced diol product upon treatment with
NaBH4.
developed catalytic system tolerated a range of electronꢀ
donating (2d-e, 2g and 2j-2o) and ꢀwithdrawing (2f, 2h and
2r) functionalities present in the aryl substituent of the carꢀ
bonate substrate. The introduction of thioether and thiophene
functionalities was also feasible as exemplified by the syntheꢀ
ses of products 2i and 2q though higher reaction temperatures
and/or higher catalyst loading were required.14 The installation
of substituents on the metaꢀposition of the aryl group (R) of
the carbonate substrate did not affect the efficiency of the
catalytic process and products 2j-m and 2o could be isolated
in good yields. The attempted synthesis of product 2p from the
aReaction conditions: 0.20 mmol of carbonate, 0.20 mL of solꢀ
vent, rt, anhydrous conditions, under N2; Pd/bisꢀsulfoxide refers to
White catalyst, ACN = acetonitrile. The yield and ratio of 2a:3a
1
were determined by H NMR (CDCl3) using toluene as internal
standard.
With the optimized reaction conditions in hand (Table 1, enꢀ
try 5), a series of vinyl cyclic carbonates (1a-r) was then inꢀ
vestigated toward the synthesis of a wider array of highly
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oꢀmethylꢀaryl substituted carbonate failed and no reaction was
Unlike the reactivity of MeOꢀnaphthyl substituted cyclic
carbonate 1n to afford aldehyde product 2n (Figure 1), the use
of naphthylꢀsubstituted carbonate 1s afforded as major product
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observed, not even with an increased catalyst loading (10%) at
elevated reaction temperature (80oC). In this latter case, quanꢀ
titative recovery of the starting carbonate was noted, thus
indicating some steric limitations of this protocol. The forꢀ
mation of the aldehyde 2o containing a 1,3ꢀbenzodioxole
fragment is of relevance for pharmaceutical development
programs.15 Considering the generally reactive nature of aldeꢀ
hydes, the synthesis of highly functionalized compounds such
as 2aꢀr would be rather challenging using sensitive metal
reagents.16
1
the aldehyde 3s (2s:3s = 7:93 based on H NMR) in 84% isoꢀ
lated yield (Figure 2) suggesting the significant electronic
effect in this transformation. The utilization of alkylꢀ
substituted carbonate 1t and several more challenging carꢀ
bonates 1uꢀx (having heteroatoms or disubstituted double
bonds) also gave rise to aldehydes 3t-x as major products.
Mostly trace amounts of aldehyde products 2t-x were noted
further illustrating the electronic and steric effects of the carꢀ
bonate substituents in this decarboxylative catalytic system
(Figure 2).
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No reaction was observed in the presence of a phosphoꢀ
ramidite type ligand in an attempt to prepare compound 2a
enantioselectively further confirming the privileged role of
ligand L1 (see also Table 1, entries 9−14).17 It should be noted
that during the synthesis of aldehyde products 2a-r virtually
no (E)ꢀconfigured products were formed. This feature adds
further to the attractiveness of this decarboxylative protocol as
stereoselective synthesis of highly substituted alkenes is a
challenging task.18 It is worth noting that products 2a-r also
represent highly functionalized allylic alcohols which are
important building blocks and intermediates in synthetic
chemistry.19 The (Z)ꢀconfiguration of all the products was
supported by 2D 1Hꢀ1H NOESY NMR spectra analysis (see SI
for details), and was further unambiguously confirmed by the
Xꢀray analysis of aldehyde product 2d (bottom inset in Figure
1).20 With the attempt to achieve the crossꢀcoupling between
two different vinyl cyclic carbonates, carbonates 1a (0.1
mmol) and 1b (0.1 mmol) were mixed under the optimized
conditions. Unfortunately, a complex product mixture was
obtained containing at least four different aldehyde products
1
based on the H NMR analysis of the reaction crude mixture.
Similar observations were done when carbonates 1a and 1i
were reacted under comparable conditions (see SI for deꢀ
tails).21
Figure 3. (a) Gram scale synthesis of aldehyde 2a, and (b)
synthetic transformations of 2a under different reaction condiꢀ
tions: (i) NaH2PO4 (0.25 equiv), H2O2 (1.1 equiv), NaClO2
(1.4 equiv), ACN/H2O = 7:3, rt, 12 h; (ii) pyridinium chloroꢀ
chromate (PCC) (1.5 equiv), silica gel (1.3 equiv), anhydrous
DCM, rt, 12 h; (iii) NaBH4 (1.1 equiv), MeOH, 0oC, 3 h; (iv)
4ꢀFꢀC6H4MgBr (3 equiv), THF, 0ꢀrt, 12 h; (v) HC≡CMgBr (3
equiv), THF, −40oC, 10 h; (vi) Oꢀ(diphenylphosphinyl)ꢀ
hydroxylamine (DPPH) (1.15 equiv), toluene, rt−85oC, 8 h.
See SI for details.
Figure 2. Scope of carbonates toward the formation of aldehyde
products 3s-x. Reaction conditions unless stated otherwise: 0.20
mmol carbonate, White catalyst (2.0 mol%) and L1 (5.0 mol%) in
anhydrous DMF (0.20 mL), rt, under N2, 12 h; no or traces of
This catalytic system can be easily scaled up as demonstratꢀ
ed by the successful gram scale synthesis of 2a (Figure 3a).
The synthetic potential of the aldehydes 2a-r was then exꢀ
plored in the synthesis of other highly functionalized scaffolds
featuring a quaternary carbon center and a stereoꢀdefined triꢀ
substituted alkene fragment (Figure 3b). For example, the
a
aldehydes 2sꢀx were observed. 5.0 mol% of White catalyst, 10
mol% of L1 were used, 80oC.
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aldehyde group can be selectively oxidized to carboxylic acid
of the substitution in the carbonate substrate. A series of subꢀ
strates (Figure 1) produce as major product the aldehyde speꢀ
cies 2a-r, where fragments from two molecules of substrate
are integrated into each molecule of product. In contrast, other
substrates (Figure 2), produce at most only traces of species 2,
with the major product being aldehyde 3 resulting from a
single molecule of vinyl carbonate. For our calculations we
used the system comprising of the catalyst derived from the
White precursor and DPEPhos (L1) and cyclic carbonate
substrates 1a (Figure 1; R = Ph) and 1s (Figure 2; R1 = H, R2 =
2ꢀnaphthyl). The reactants differ only in the carbonate substitꢀ
uent yet yield rather different products. The results reported in
what follows correspond to geometry optimizations with the
B97D functional in DMF solvent followed by single point
calculations with a SDD basis set for Pd and 6ꢀ311++G(d,p)
for all other atoms. All reported energies (in kcal/mol) are free
energies in solution.24 The same method was also used in our
previous study concerning the synthesis of allylic amines.9a
4a without affecting the vinyl and alcohol groups.16 Treatment
of 2a with pyridinium chlorochromate (PCC) afforded dialdeꢀ
hyde 4b in 59% yield. Selective reduction of the aldehyde
group with NaBH4 gave access to diol 4c in nearly quantitative
yield (98%). Addition of Grignard reagents to 2a afforded
secondary alcohols 4d and 4e in 86% and 80% yield, respecꢀ
tively. The aldehyde group in 2a was easily transformed to the
corresponding nitrile 4f by treatment with oꢀ
(diphenylphosphinyl)ꢀhydroxylamine (DPPH).22 Selective
dihydroxylation of the internal alkene fragment also proved to
be feasible.23 All these transformations illustrate the synthetic
potential of the highly functional aldehydes obtained through
this decarboxylative methodology.
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Scheme 2. Simplified Catalytic Cycle for Carbonate 1a
Derived from the DFT Calculations. The Blue-Colored
Numbers in Parentheses Highlight the Number of Cyclic
Carbonate Fragments Included in Each Species
We will present first and in more detail the results for the
catalytic system using carbonate 1a producing the aldehyde
product 2a. A simplified view of the computed catalytic cycle
is shown in Scheme 2, in which substrate 1a has been labeled
as R (reactant), and the allylic alcohol product 2a as D (diꢀ
mer). The initial part of the mechanism is shown in Figure 4.
There is an additional aldehyde species different from that
observed experimentally that is labeled as M1. The species
inside the cycle are labeled with the prefix t, for theoretical.
All the species involved are included in the free energy proꢀ
files in Figures 4 and 5 (see also Figures S1ꢀS4 in SI). The
reaction starts in a way analogous to the amination process
reported previously which is outlined in Scheme 1b.9a Subꢀ
strate R first coordinates to the catalyst t1, and oxidatively
cleaves a C‒O bond to reach intermediate t3 and after extruꢀ
sion of CO2 forms the palladacycle intermediate t4 (Scheme 2
and Figure 4). In the reported amination process,9a t4 received
the aniline nucleophilic attack toward the formation of the
allylic amine product. The cyclic carbonate is, however, not
nucleophilic enough to attack t4, and thus other alternative
lowꢀenergy paths have to be considered.
Intermediate t4 can rearrange to intermediate t6, which can
then release aldehyde M1 through a lowꢀenergy barrier recovꢀ
ering the catalyst t1 (Scheme 2). The formation of M1 is exerꢀ
gonic, though not enough to be a final product.25 However,
aldehyde M1 is sufficiently nucleophilic to attack t4, and
Figure 5 shows the continuation of this reaction.
ꢀ MECHANISTIC INSIGHTS
DFT calculations were performed in order to gain insight
into the reaction mechanism. We were in particular interested
in understanding the dependence of the reactivity on the nature
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Figure 4. Free energy profile (in kcal/mol) for the first part of the catalytic cycle leading to the departure of aldehyde M1.
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Figure 5. Free energy profile (kcal/mol) for the second part of the catalytic cycle leading to the departure of aldehyde product D.
A second molecule of R is consumed to generate t4 which
then reacts with M1 to produce intermediate t8 (Scheme 2 and
Figure 5).26 Intermediate t8, which incorporates two molecules
of reactant, can rearrange to intermediate t11, and then release
the aldehyde product D while regenerating the catalyst t1. This
domino process thus consumes two molecules of reactant R,
yields product D and releases two molecules of CO2.
influence in the structure of transition state t(4-5) in the exit
channel leading to product M2 (see Figure S3 in SI). In this
transition state, shown in Figure 6 for the system containing a
2ꢀnaphthyl substituent, there is a hydrogen transfer between
two carbon centers. One of these carbon centers, which changꢀ
es its hybridization, is adjacent to the naphthyl group, and this
should account for a strong electronic influence. There is no
such obvious electronic dependence in the exit channel leading
to product D (see Figure S3 in SI). Thus, electronic effects are
likely the key to the chemoselectivity towards either aldehyde
products 2 or 3. This is indeed consistent with the experiꢀ
mental results, where reactant 1n (with a MeOꢀnaphthyl subꢀ
stituent) was shown to behave similarly to 1a despite the simiꢀ
lar steric impediments of substrates 1n and 1s.
In order to understand better the influence of the substituent
on the vinyl cyclic carbonate, we also explored the case of the
conversion of carbonate 1s (Figure 2; R1 = H, R2 = 2ꢀnaphthyl)
into the aldehyde 3s: we found that an alternative cycle domiꢀ
nates as shown in Scheme 3. The cycle differs from the one
reported above in the evolution of intermediate t8. In this
alternative cycle it releases aldehyde M2 and returns to t4 with
M2 being significantly more stable than M1.25 This cycle
consumes one molecule of reactant R and yields product M2
and one molecule of CO2. The free energy profiles for all
intermediates in this alternative cycle are provided in the SI.
Scheme 3. Simplified Catalytic Cycle for the Conversion of
Carbonate 1s Derived from the DFT Calculations. The
Numbers in Parentheses Highlight the Number of Reac-
tant Fragments Included in Each Species
It is difficult to predict product distribution merely based on
the free energy profiles in such a complicated cycle, and thus
we used microꢀkinetic models.27 The free energy profiles were
utilized to compute rate constants and equilibrium constants
for each step, and calculation from the starting concentrations
used in experiment were performed. The result of this microꢀ
kinetic modeling is a prediction of the ratio of aldehyde prodꢀ
ucts (type 2 vs 3) of 88:12 when using carbonate 1a and 11:89
upon converting carbonate substrate 1s (see Tables S1 and S2
in the SI for details). These ratios are close to the experimental
observations (90:10 in the case of 1a, and 7:93 for 1s) suggestꢀ
ing the validity of our mechanistic proposal. The product ratio
follows the order of the relative energies of the exit channels
from equilibrium as mentioned above.
We examined the associated structures in search of a qualitaꢀ
tive explanation for the product selectivity. There is no obviꢀ
ous steric influence from phenyl/2ꢀnaphthyl replacement in
any of the intermediate structures, as the additional ring in
naphthyl fragment points in all cases away from the rest of the
atoms. In contrast, electronic effects are very likely to exert an
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O
Supporting Information. The Supporting Information is availaꢀ
ble free of charge on the ACS Publications website at DOI:
xxxxx.
O
1
2
3
P
P
O
Pd
(0)
R
R
t1
Experimental/DFT details and characterization data
(PDF), Crystallographic data for 2d (in CIF format)
O
O
4
5
O
R
O
ꢀ AUTHOR INFORMATION
R
6
7
8
9
Pd
H
Pd
P
P
Corresponding Author
P
P
R
(1)
t3
* wguo@iciq.es
* fmaseras@iciq.es
* akleij@iciq.es
(1) t6
R
H
H
O
O
CO2
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Pd
M1
P
P
ORCID
H
M2
(1)
t4
O
Wusheng Guo: 0000ꢀ0001ꢀ5259ꢀ3600
Feliu Maseras: 0000ꢀ0001ꢀ8806ꢀ2019
Arjan W. Kleij: 0000ꢀ0002ꢀ7402ꢀ4764
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Me
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Notes
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The authors declare no competing financial interest. A data set
collection of computational results is available in the ioChemꢀBD
repository.28
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ꢀ ACKNOWLEDGEMENTS
We thank CERCA Programme/Generalitat de Catalunya, ICREA,
and the Spanish MINECO through projects CTQ2014ꢀ57761ꢀR,
CTQꢀ2014–60419ꢀR, Severo Ochoa Excellence Accreditation
2014–2018 through project SEVꢀ2013–0319 and Severo
Ochoa/FPI fellowship to J.E.G. Dr. Eddy Martin and Eduardo C.
EscuderoꢀAdán are acknowledged for the Xꢀray analysis.
ꢀ REFERENCES
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exceptions, for instance: (a) Li, C.; Breit, B, J. Am. Chem. Soc. 2014,
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Figure 6. Optimized structure of transition state t(4-5)s. The
hydrogen atom most involved in the reaction coordinate is highꢀ
lighted with a label. Most other hydrogen atoms are omitted for
clarity.
ꢀ CONCLUSION
In summary, we herein report an interesting Pdꢀcatalyzed
decarboxylative domino process enabling the synthesis of
vinyl scaffolds with highly functionalized quaternary carbon
centers. In most cases, the reaction can be performed at room
temperature without any additives. This protocol also features
the in situ formation of synthetically attractive aldehyde and
(Z)ꢀconfigured polysubstituted allylic alcohol fragments in a
single step from readily available and modular vinyl cyclic
carbonates. These highly functionalized products are useful
building blocks as exemplified by several synthetic transforꢀ
mations. DFT calculations provide a rationale and suggest a
complex mechanism where subtle electronic effects are able to
modify the nature of the major product of the reaction. These
findings shed light on the development of new catalytic domꢀ
ino reactions for challenging Csp3ꢀCsp3 bond formations via
decarboxylative methodologies under mild reaction condiꢀ
tions.
ꢀ ASSOCIATED CONTENT
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trace amounts of water) would result in 1,4ꢀbutꢀ2ꢀene diol formation,
see ref 9c. The starting carbonate should be dried under vacuum (<
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and anhydrous solvents are warranted.
(14) The sulfurꢀcontaining substrates have the potential to deactiꢀ
vate the Pdꢀcatalyst and substrates containing Sꢀatoms generally
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A. G.; Malinowski, J. T.; McAlpine, N. J.; Kuhne, J.; MacMillan, D.
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(17) The use of phosphoramidite ligands is based on our previous
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(20) For further details see the SI.
(21) Cross coupling between vinyl carbonates 1a and 1i also resultꢀ
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(23) Rearrangement of the dihydroxylation product gave rise to the
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see SI for details.
(24) See the SI for full computational details.
(25) The isomerization from M1 to M2 has also been noted by othꢀ
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(26) Based on the mechanism presented in Scheme 2, the cross
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