Br?nsted acid and Pd-PHOX dual-catalysed enantioselective addition of activated C-pronucleophiles to internal dienes

Article abstract of DOI:10.1039/c9sc00633h

We describe the development of Pd-PHOX-catalysed enantioselective couplings of internal dienes with malononitrile and other activated C-pronucleophiles. Reactions are dramatically accelerated by the addition of Et₃N·HBAr^F₄ as a Br?nsted acid co-catalyst, enabling a suite of products bearing a variety of alkyl substituents at the stereogenic carbon to be prepared. A series of mechanism-oriented experiments reveal key aspects of the catalytic cycle and the importance of the non-coordinating BAr^F₄ counterion in not only promoting reactions of internal dienes but also additions of previously unreactive nucleophiles towards terminal dienes.

Full text of DOI:10.1039/c9sc00633h

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DOI: 10.1039/C9SC00633H
Journal Name
ARTICLE
Brønsted Acid and Pd–PHOX Dual-Catalysed Enantioselective
Addition of Activated C-Pronucleophiles to Internal Dienes
Sangjune Park, Nathan J. Adamson and Steven J. Malcolmson*
Received 00th January 20xx,
Accepted 00th January 20xx
We describe the development of Pd–PHOX-catalysed enantioselective couplings of internal dienes with malononitrile and
F
DOI: 10.1039/x0xx00000x
other activated C-pronucleophiles. Reactions are dramatically accelerated by the addition of Et N·HBAr as a Brønsted acid
3
4
co-catalyst, enabling a suite of products bearing a variety of alkyl substituents at the stereogenic carbon to be prepared. A
series of mechanism-oriented experiments reveal key aspects of the catalytic cycle and the importance of the non-
www.rsc.org/
coordinating BArF
counterion in not only promoting reactions of internal dienes but also additions of previously unreactive
4
nucleophiles towards terminal dienes.
1
2–
catalysed addition of activated pro-enolates to these dienes,
1
4
Introduction
and Xiao, Zhou and co-workers demonstrated diene reactions
in Ni–bis(phosphine)-catalysed additions of enolates formed
from simple ketones (Scheme 1). However, the products
obtained from reactions of terminal dienes bear only a methyl
group at the -stereogenic centre.
The addition of carbon-based electrophiles to enolates is a
hallmark strategy in organic synthesis for the enantioselective
formation of C–C bonds. Mannich reactions, aldol and Michael
1
5
1
additions are among the most common approaches for the
construction of small molecules. Enolate alkylations are also  Addition of Enol/Enolate Nucleophiles to Allenes and Terminal Dienes
widespread but often focused towards controlling
O
R1
R1
O
•
2
R2 [Pd] or [Rh]
stereochemistry at a carbonyl’s α-position. An important class
R1 = alkyl, aryl
alkoxy
or
G
G
3
+
of enolate alkylation is allylic substitution, which enables the
R3
R2
R3
R1
Me
assembly of molecules comprised of carbonyls with -
terminal olefins
4
stereogenic centres while often concomitantly setting the
O
Me
O
5
,6
R2 [Pd] or [Ni]
stereochemistry at the α-position. Additionally, the products
contain pendant unsaturation that might be leveraged for
downstream synthesis applications. These enolate alkylations
R1 = alkyl
G
R1
R1
G
+
R2
R3
R3
aryl
Me stereogenic centres
This Work: Addition of Enolates to Internal Dienes
mol %
[Pd(PHOX)]BArF
(allylic and non-allylic electrophiles) utilize preactivated

electrophiles such as alkyl halides or allylic acetates.
R2
7
7
R3
The use of olefins as alkylating agents offers a number of
R2
NC
CN
4
R1
CN
+
R1
distinct advantages, not the least of which is the inherent
stability of an alkene compared to the lability of a leaving group,
facilitating carrying the olefin electrophile through several
transformations in a multistep sequence. A handful of
researchers have explored this approach in enantioselective
R3
7 mol % Et3N•HBArF
00 mol % Et3N
4
CN
3
various R2 groups
internal olefins
Scheme 1 Catalytic enantioselective additions of enols/enolates to
olefins
8
catalysis. For example, enol/enolate addition to allenes has
In comparison, hydrofunctionalisation of internal dienes
delivers molecules with both disubstituted olefins and myriad
groups at the stereogenic -position. Still, enantioselective
additions to acyclic 1,4-disubstituted dienes are challenging:
only indole and amine couplings have been reported. In this
work, we illustrate that malononitrile and related
pronucleophiles undergo highly regio- and enantioselective
additions to internal dienes (Scheme 1). High reaction efficiency
afforded products with a variety of substituents at the -
stereogenic centre (Scheme 1), in some cases with additional
8
a,c
control at the carbonyl’s α-position.
Employing allenes as
9
electrophiles has exclusively resulted in products bearing a
terminal alkene. In a similar process, Rh–bis(phosphine)-
catalysed enol additions to internal alkynes delivers analogous
products.1 Terminal dienes have also emerged as alkyl
electrophiles capable of affording products comprised of
1
6
17
0,‡
was achievable by the combination of an electron-deficient Pd–
1
1
F
internal alkenes. Recently, our group described the Pd–PHOX- PHOX catalyst and Et N·HBAr as Brønsted acid co-catalyst.
3
4
Department of Chemistry, Duke University, French Family Science Center
24 Science Drive, Durham, NC, 27708, USA; E-mail: steven.malcolmson@duke.edu
1
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Under the optimal conditions, several 1,4-disubstituted dienes
couple with malononitrile (Table 2). Electronic perturbations of the
diene’s aryl group are tolerated, affording 2b–d in 40–66% yield and
Results and discussion
Method development and product functionalisation
View Article Online
DOI: 10.1039/C9SC00633H
We initiated our investigation by examining the addition of >95:5 er. Moving the aryl group substituent to the meta or ortho
malononitrile to diene 1a with Pd–PHOX catalyst Pd-1, the optimal positions generates tolyl products 2e and 2f in higher yields (87–89%)
1
7
catalyst for internal diene hydroamination, which bears the non- and with excellent enantioselectivity (97.5:2.5 and 96:4 er,
F
coordinating BAr
4
counterion (Table 1). We hypothesized that the respectively). Changing the substituent at the 4-position of the diene
1
8
small size of malononitrile, its low pK
a
,
and the relatively high enables products with a variety of alkyl groups at the stereogenic
1
9
nucleophilicity of its anion would make it exceptionally reactive carbon to be obtained (2g–k); the reaction is tolerant of both
towards alkylation. Indeed, in the addition of malononitrile to 1- ethereal (2i–j) and carbonyl functionality (2h and 2k). All aryl/alkyl-
phenylbutadiene—a terminal diene—we found it difficult to substituted diene substrates deliver malononitrile products 2a–k as
1
2
suppress double alkylation. In the absence of any additive, there is a single regioisomer. Additionally, 1,4-dialkyl-containing dienes also
no observable reaction with diene 1a (entry 1); however, with afford malononitrile addition products as a single regioisomer as long
3
00 mol % Et
3
N, the desired 2a is generated in >99:1 er as the sole as the two alkyl groups are sterically differentiated. Vinylcyclohexane
2l is obtained in 72% yield and 94:6 er. In all cases, enantioselectivity
product of the reaction but in only 24% yield (entry 2).
We discovered that the addition of a substoichiometric quantity is constant throughout the course of the reaction, indicating that the
F
3
of Et N·HBAr
4
as a Brønsted acid greatly improves the product yield process is irreversible.
(
entry 3). Notably, the addition of Brønsted acid has been observed
Table 2 Internal diene scope for malononitrile additionsa–c
as a crucial component in several other transformations involving
nucleophilic additions to olefins, including reactions of enols.
Further raising the catalyst loading of both Pd-1 and Et
N·HBArF
2
0
8a–d,10a
NC
CN
7 mol % Pd-1
R2
7 mol % Et3N•HBArF
3
4
to
N,
4
+
CN
CN
300 mol % Et3N
R1
7
mol %, which proved to be the optimal conditions, allows 2a to be
R2
R1
isolated in 93% yield and >99:1 er (entry 4). In the absence of Et
even with stoichiometric Et
3
Et2O, 22 °C, 1 h
F
1bl
2bl
3
N·HBAr
4
(entry 5), alkylation product 2a
(2.0 equiv)
is not formed. Lesser quantities of the base, from 7 mol % up to
00 mol %, drastically reduce the yield of 2a while also enabling its
conversion to bis-alkylation product 3a (entries 6–8). With 200 mol %
Et N, product 2a is again isolated in 93% yield but is still accompanied
1
Me
2
b
G = OMe:
2c G = Me:
G = Cl:
66% yield, 99:1 er
54% yield, 98:2 er
40% yield, 96:4 er
CN
CN
3
by a small quantity of byproduct 3a (entry 9).
2d
G
Table 1 Reaction optimization for diene–malononitrile couplinga
Me
Me
Me
Me
CN
CN
CN
7
mol %
O
CN
Me
N
PAr2
R
2e
2f
NC
CN
CN
Pd
Ph
89% yield, 97.5:2.5 er
87% yield, 96:4 er
t-Bu
BArF
4
CN
+
n-Pr
2
EtO C
BnO
Pd-1 Ar = 3,5-(F3C)2C6H3
 Et N•HBArF ,  Et N
( )3
( )3
2a R = H
Me
CN
CN
CN
CN
CN
CN
Ph
3a R =
Me
Ph
Ph
Ph
3
4
3
1a
2
Et O, 22 °C, 1 h
Ph
(2.0 equiv)
2
g
2h
2i
7
8% yield, 95.5:4.5 er
62% yield, 95.5:4.5 er
76% yield, >99:1 er
Et3N•HBArF4 (mol %);
Yield 2a (%)b;
Yield 3a (%)b
Entry
3
Et N (mol %)
Erc
TBSO
PhthN
( )4
Me
(
)4
1d
2d
3d
4
0; 0
<2; <2
24; <2
67; <2
93; <2
<2; <2
52; 4

CN
CN
CN
CN
Ph
Ph
Cy
0; 300
5; 300
7; 300
100; 0
7; 7
>99:1
>99:1
>99:1

CN
CN
jd
2kd
2le
2
8
1% yield, 96:4 er
44% yield, 90.5:9.5 er
72% yield, 94:6 er
5
a–c
See Table 1. Dienes were used as a mixture of stereoisomers (1.1:1 to 4.2:1
E,Z:E,E). See the ESI for details. Reaction for 20 h. Reaction for 3 h.
6
>99:1
98.5:1.5
98.5:1.5
>99:1
d
e
7
7; 50
62; 14
62; 17
93; 3
8
7; 100
7; 200
Substituted malononitrile pronucleophiles undergo Pd-1-
catalysed addition to diene 1a within 1 h with complete regiocontrol
O. 1a used as a (Table 3). The methyl-, benzyl-, and cinnamyl-substituted
9
aReaction under N
with 0.2 mmol malononitrile in 0.2 mL Et
2
2
1
.8:1 E,Z:E,E mixture of stereoisomers. See the ESI for experimental details.
Isolated yield of purified product. Determined by HPLC analysis of purified
pronucleophiles generate products 5a–c in 78–99% yield and
b
c
2
1
>
95:5 er. Acetylacetone, both less acidic and its anion less
d
2
. Reaction with 5 mol % Pd-1.
1
9
nucleophilic than malononitrile, leads to diketone 5d in 51% yield
and 92.5:7.5 er after 20 h, still as a single regioisomer. Ethyl
2
| J. Name., 2012, 00, 1-3
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ARTICLE
cyanoacetate addition to diene 1a, however, results in a 60:40 erosion of enantiopurity. Similarly, oxidation in the presence of
View Article Online
DOI: 10.1039/C9SC006 32 43 H
mixture of product regioisomers 5e and 6e (56% yield). Isomer 6e pyrrolidine leads to α-alkenylamide 7b in 78% yield (94.5:5.5 er).
arises from addition of the nucleophile to the phenyl-substituted
carbon of the -allyl–Pd-1 intermediate derived from diene 1a
Mechanism studies
whereas 5e results from nucleophile addition to the ethyl-
substituted carbon of the same -allyl complex. Dimethyl malonate, to internal dienes is illustrated in Scheme 3.
A mechanism for Pd–PHOX-catalysed addition of malononitrile
1
7,25
After initiation of Pd-
delivers a similar result (57:43 5f:6f in 49% yield). Despite their lower 1 by nucleophilic attack of the malononitrile anion upon its -allyl
2
1,22
but perhaps partially due to their lower nucleophilicities,19 ligand, coordination of diene 1a to the Pd(0) species leads to
a
pK ’s
F
cyclic pronucleophiles such as Meldrum’s acid and dimedone fail to intermediate i. Oxidative protonation at Pd by Et
3
N·HBAr
4
leads to
undergo addition to diene 1a under the conditions shown in Table 3. hydrido complex ii, which undergoes migratory insertion, ultimately
forming -allyl–Pd species iii. The equilibration is accelerated and
Table 3 Pronucleophile scope for internal diene addition reactionsa–c
F
shifted towards complex iii by the addition of exogenous Et
3
N·HBAr
4
Me
as the co-catalyst. At the same time, deprotonation of malononitrile
by Et N leads to the malononitrile anion iv, an equilibrium that
favours the neutral molecule. The anion may then attack -allyl–Pd
iii through an outer sphere pathway. The C–C bond-forming event to
EWG1
EWG2
R
EWG1
3
R
Ph
7
mol % Pd-1
7 mol % Et3N•HBArF
00 mol % Et3N
EWG2
4
af
4
5af
3
form v appears to be irreversible and simultaneously regenerates
+
+
F
Et
3
N·HBAr
4
. Exchange of the olefin within v for diene 1a releases
Et2O, 22 °C, 1 or 20 h
EWG2
Me
R
product 2a and regenerates complex i.
Ph
EWG1
1
a
Me
Ph
Ph
Et3N
BArF
H
Ph
(
2.0 equiv)
6af
BArF4
Me
4
N
N
1
h reactions:
Pd0
Pd
Et3N
P
P
H
Me
Me
Me
Ph
Me
Me
H
Ph
2
a
a
i
ii
CN
CN
CN
CN
Ph
Ph
Ph
CN
CN
5a
5b
5c
Et3N
H
1
P
Pd
N
Me
BArF
Me
9
9% yield, 96:4 er
90% yield, 95.5:4.5 er
78% yield, 95.5:4.5 er
BArF
4
4
>
98:2 5a:6a
>98:2 5b:6b
>98:2 5c:6c
CN
CN
Ph
Pd0
Ph
2
0 h reactions:
N
v
iii
H
Me
O
Me
Me
P
NC
H
CN
Et3N
CN
CO2Me
Ph
NC
CN
Et3N
Ph
Me
Me
Ph
iv
CO2Et
CO2Me
H
O
5
d
5e
5f
Scheme 3 Proposed mechanism of malononitrile addition to internal dienes
d
49% yieldd
5
1% yield, 92.5:7.5 er
56% yield , 60:40 dr
>
98:2 5d:6d
60:40 5e:6e
57:43 5f:6f
In the context of this mechanistic proposal, we sought to
address several facets of the Pd–PHOX-catalysed diene–enolate
couplings. These investigations might allow us to glean further
information about individual steps of this mechanism and more
broadly understand diene couplings to nucleophiles promoted by
Pd–PHOX catalysts.
We first set out to investigate the impact of diene
stereochemistry upon the reaction. The transformations presented
in Tables 1–3 utilize an E,Z/E,E-mixture of diene diastereomers
favouring the Z-stereoisomer at the alkyl-substituted alkene. As
shown in Scheme 4A, E,Z-1a is significantly more reactive than the
E,E-stereoisomer, delivering malononitrile 2a in 90% yield and
99:1 er. Comparatively, E,E-1a (Scheme 4B) leads to only 35% yield
of 2a (99:1 er). In both experiments, one equivalent of diene was
employed and any left unreacted was completely recovered. From
the reaction of E,Z-1a, the recovered diene had almost completely
isomerised to the E,E-diastereomer (Scheme 4A). In contrast, the
recovered diene from reaction of E,E-1a was still entirely that
stereochemistry (Scheme 4B).
a–b
c
d
See Table 1. Er determined by HPLC analysis of purified 5. Isolated yield
of the isomeric mixture; er not determined.
Et
Et
CN
CN
MMPP, Li2CO3
OMe
Ph
Ph
O
MeOH, 0 °C, 3 h
2a
7a
>
99:1 er
71% yield
8.5:1.5 er
9
HN
Et
O2 (balloon), K2CO3
MeCN, 0 °C, 20 h
N
Ph
O
7b
7
8% yield
4.5:5.5 er
9
Scheme 2 Synthesis of α-alkenyl carbonyls from the malononitrile group
The malononitrile adducts of internal dienes are useful building
blocks for further synthesis. For example, the malononitrile unit
within 2a (Scheme 5) may undergo oxidative methanolysis via the
cyanoketone to deliver α-alkenylester 7a in 71% yield with minimal
These data also help explain why under the optimal conditions,
product 2a does not undergo a second alkylation event despite the
2
3
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A)
stereochemical isomerisation of the alkene occurs by Pd–D migratory
insertion to (E,Z)-1a, bond rotation, and preferential -hydride
Et
View Article Online
DOI: 10.1039/C9SC00633H
NC
CN
CN
CN
Me
Ph
Ph
+
Ph
elimination (compared to -deuteride elimination). As mentioned
with regard to the reactivity difference of the two diene
stereoisomers (vide supra), this process does not occur to
incorporate deuterium into (E,Z)-1a via reaction of (E,E)-1a. Finally,
the distribution of the label in d-(E,E)-1a indicates that palladium–
hydride/deuteride insertion may occur at either olefin of the diene,
yet only insertion at the alkyl-substituted olefin leads to product in
the reactions presented in Tables 1–3. The results further confirm
that E,Z-diene coordination to Pd is reversible.
Me
E,Z)-1a
1a
2
a
(
9
0% yield, 99:1 er 2a
(
1 equiv)
1
0% recovery, 10:1 E,E:E,Z 1a
B)
Et
NC
CN
Me
CN
CN
Me
Ph
+
Ph
Ph
(
E,E)-1a
1a
2
a
(
1 equiv)
3
5% yield, 99:1 er 2a
6
5% recovery, >99:1 E,E:E,Z 1a
NC
Me
CN
D 18% D
Scheme 4 Comparison of reactivity of diene diastereomers; conditions: Pd-1
7 mol % Pd-1
Me
Me
D
95% D
3
7 mol % Et N•HBArF4
Ph
Ph
F
(
3
7 mol %), Et N·HBAr
4
(7 mol %), Et
3
N (300 mol %), Et
2
O, 22 °C, 1 h
d-4a
+
300 mol % Et3N
presence of excess diene 1a (see Table 1). Of the two equivalents of
diene 1a added to the reaction, only ca. 65% (1.3 equiv) is the more
reactive E,Z-stereoisomer. The data also suggest the catalyst is
capable of reacting with the diene and isomerising the E,Z- to the E,E-
diastereomer without product formation. Therefore, during the
course of the reaction, as mono-alkylated product builds up, there is
concomitant isomerisation of the diene occurring (likely along with
catalyst decomposition), thereby slowing formation of bis-alkylated
+
Me
Et2O, 22 °C, 20 h
Ph
(
15% D
D
1a
<2% 5a/6a
>98% recovered 1a
(1:1.7 E,Z:E:E)
d-
-1a
(E,E)
(2.0 equiv)
<2% D in (E,Z)-1a
1.8:1 E,Z:E:E)
Scheme 5 Deuterium labelling studies with deuterated methylmalononitrile
It is noteworthy that whereas malononitrile and acetylacetone
nucleophiles afford a single detectable product regioisomer (Tables
–3), ethyl cyanoacetate and dimethylmalonate deliver a mixture
3
(
3
a. With fewer Et
Table 1). This might be attributable to the equilibrium (see Scheme
) between malononitrile and its deprotonated form iv being shifted
3
N equivalents, 3a is observed to some degree
1
(
5e/6e and 5f/6f, respectively, Table 3). As mentioned earlier, the
product isomers arise from attack of the nucleophiles upon two
different carbons of the same -allyl. Differing regioselectivities
among nucleophiles is likely due to Curtin–Hammett kinetics in the
reaction (Scheme 6) and is the combination of three properties of the
towards the neutral molecule when less base is available, slowing the
rate of formation of 2a. Mono-alkylated 2a that is formed may then
engage in subsequent reaction with remaining E,Z-1a prior to its
consumption in product formation or its stereoisomerisation.
Additionally, although substituted malononitriles, such as those
shown in Table 3, are competent reaction partners, compound 2a is
significantly more hindered (-branching) which slows a second
alkylation event.
a
nucleophile: 1) the pK of the pronucleophile (affecting its
equilibrium with the active deprotonated nucleophile), 2) the
1
9
nucleophilicity of the carbanion, and 3) the sterics of the
3
a
nucleophile. As documented previously for Pd–PHOX complexes,
the -allyl–Pd species exist as a mixture of the thermodynamically
preferred exo-diastereomer and its isomeric endo-complex (Scheme
We next further sought to assess the reversibility of the
individual elementary steps connecting diene 1a to -allyl–Pd iii
6
). In this transformation, faster attack of the nucleophile upon the
(Scheme 3). To do so, we examined the coupling of a deuterated
exo-isomer at the carbon trans to the phosphine (ethyl-substituted
carbon) leads to the observed major enantiomer and regioisomer (2
pronucleophile, 1) to discover the label’s position in the anticipated
addition product with respect to the site of C–C bond formation and
2
) to determine whether deuterium could be incorporated into the
G
G
Me
Me
Me
Me
Me
Me
diene without product forming. We chose deuterated 2-
methylmalononitrile (d-4a) as the pronucleophile (Scheme 5).
Incredibly, although the protic version of 4a delivers 5a in 99% yield
after 1 h, no coupled product is formed after 20 h with d-4a. This is
likely due to the combination of a significant kinetic isotope effect
and catalyst decomposition. Diene 1a could be completely recovered
from the mixture: a portion of the diene had isomerised from the E,Z-
isomer to (E,E)-1a (from 1.8:1 to 1:1.7 E,Z:E,E). A significant
percentage of the deuterium label (ca. 43%) was transferred from d-
O
O
P
P
N
N
Pd
Pd
Ph
G
G
Me
Ph
Me
exo-diastereomer
endo-diastereomer
EWG1 EWG2
EWG1 EWG2
slower
4
1
a to the diene with the label confined solely to the recovered E,E-
a and roughly evenly distributed between C1 and C4.
faster
Just as in hydroamination of 1a with Pd-1 (reaction of N-
Me
EWG1
EWG2
deuterated indoline),17 the kinetic isotope effect observed here is
likely at least partially due to an equilibrium isotope effect that
EWG1
Me
Ph
Ph
2 or 5 EWG2
exchanges deuterium from d-4a to diene 1a as mediated by Et
3
N and
6
the Pd catalyst. The lack of label in recovered (E,Z)-1a is owed to its Scheme 6 Curtin–Hammett kinetics likely operative in internal diene–enolate
conversion exclusively to d-(E,E)-1a when it reacts with Pd–D: couplings and responsible for the observed regio- and enantioselectivity
4
| J. Name., 2012, 00, 1-3
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PleaseC dh oe mn oi ct a al dS cj ui es nt cme argins
Journal Name
ARTICLE
or 5). Conversely, some nucleophiles undergo competitive addition isomerisation indicates that catalyst formed from Pd-1 fails to
View Article Online
DOI: 10.1039/C9SC00633H
to the endo-diastereomer, attacking the phenyl-substituted carbon engage the diene at all in the presence of this pronucleophile.
(
trans to the phosphine), affording 6. Although ethyl cyanoacetate
Me Me
2
6
has a similar pK
a
to acetylacetone, generating a certain quantity of
O
O
5
mol % Pd-1
active nucleophile, its nucleophilicity is considerably greater (similar
Me
O
O
O
O
O
300 mol % Et3N
1
9
to malononitrile ). Likewise, even though dimethyl malonate has an
Ph
O
2
2
19
(1.5 equiv)
+
a
even higher pK , its nucleophilicity is greater still. Therefore, it is
Me
CH2Cl2, 22 °C, 3 h
possible that reactants with greater nucleophilicity lead to similar
Me
rates of attack upon the exo- and endo-diastereomers of the -allyl
with [( -C H )Pd(PHOX)]BArF4: 88% yield, 96.5:3.5 er
3
Ph
3 5
1
8
intermediate. The outlier is malononitrile, whose lower pK
a
and
3
with [( -C3H5)Pd(PHOX)]BF4: (ref. 12) 81% yield, 97.5:2.5 er
1
9
high nucleophilicity should seemingly lead to an isomeric mixture.
The high selectivity for products 2 or 5 with malononitrile (via the
exo-isomer) is likely due to the small size of this pronucleophile.
An interesting dichotomy between reactions of terminal dienes,
such as 1-phenylbutadiene, and those of internal dienes with
activated C-pronucleophiles as catalysed by Pd–PHOX complexes
presented itself in this study. In our previous investigations of C-
Scheme 8 Meldrum’s acid addition to phenylbutadiene with Pd(PHOX)
catalysts bearing different counteranions
As mentioned, we previously developed the addition of
Meldrum’s acid to 1-phenylbutadiene with [(η -C
as the catalyst. Unfortunately, reactions of internal dienes are
completely inhibited by having a BF counterion in the reaction
medium, preventing our examining Meldrum’s acid reaction with
3
3
5
H )Pd(PHOX)]BF
4
1
2
4
1
2
pronucleophile additions to terminal dienes, Meldrum’s acid
proved to be one of the best and most versatile pronucleophiles.
Those reactions are promoted by the same PHOX ligand for Pd as in
3
internal diene 1a catalysed by [(η -C
Meldrum’s acid addition to 1-phenylbutadiene occurs smoothly with
3 5
H )Pd(PHOX)]BF
4
. However,
F
BAr
4
-containing Pd-1, delivering a nearly identical result to its BF
4
Pd-1 but with a catalyst that bears a tetrafluoroborate counterion in
analogue (Scheme 8). These data highlight that the acidic Meldrum’s
acid is compatible with Pd-1 no matter what its counteranion as long
as a more reactive terminal diene is present. This suggests that as the
internal diene 1a is more difficult to coordinate to the metal centre,
significant catalyst decomposition occurs under the more acidic
conditions imposed with Meldrum’s acid (lower pK ) compared to
a
other pronucleophiles, thereby impeding the desired reaction
pathway.
F
place of BAr
4
. Additionally, terminal diene reactions do not require
Brønsted acid additive. Contrastingly, dimethyl malonate fails to
undergo addition to 1-phenylbutadiene under the previously
established optimal terminal diene conditions with the BF
4
-
containing catalyst.
We wished to determine whether these differences arise from
the BArF
F
additive. As shown
4
3
counterion of Pd-1 or the Et N·HBAr
4
in Scheme 7, dimethyl malonate 4f is able to add to 1-
F
phenylbutadiene in the presence of Pd-1 (BAr
4
counterion).
F
Although the yield is slightly higher with the addition of Et
3
N·HBAr
4
,
Conclusions
both the regioselectivity and enantiopurity of the major product (8)
are the same with or without Brønsted acid. Therefore, higher pK
pronucleophiles may react with terminal dienes with a Pd–PHOX
We have demonstrated that internal dienes act effectively as
alkylating agents for enantioselective intermolecular couplings
with in situ-generated enolates under Pd–PHOX catalysis. The
a
F
4
catalyst comprised of the non-coordinating BAr . It is noteworthy
atom economic olefin hydrofunctionalisations are accelerated
that the regiomeric ratio favouring the 4,3-addition product 9 is
higher for dimethyl malonate coupling to phenylbutadiene than to
internal diene 1a (cf., Table 3, compound 5f).
F
by the addition of Et
3
N·HBAr
4
as a Brønsted acid co-catalyst.
Somewhat counterintuitively, the use of superstoichiometric
Et N is needed to generate sufficient quantities of the active
3
Me
nucleophile in order to form the mono-alkylation product
selectively (i.e., avoid over-alkylation). Several features of the
reaction mechanism have been uncovered through deuterium
labelling the pronucleophile and by selectively employing
different diastereomerically pure diene stereoisomers in
reactions. Notable differences in participating C-
pronucleophiles in Pd–PHOX-catalysed reactions of internal
versus terminal 1,3-dienes have been unveiled. Further
investigation of reaction mechanism and applications to
additional methodology development from lessons learned in
these studies are ongoing.
MeO2C
CO2Me
CO2Me
7
mol % Pd-1
Ph
F
4
f
±7 mol % Et N•HBAr
3
4
CO2Me
8
3
00 mol % Et3N
+
+
Et2O, 22 °C, 4 h
MeO2C
Ph
CO2Me
Me
Ph
2.0 equiv)
(
9
with Et3N•HBArF4: 76% yield, 88.5:11.5 er, 83:17 8:9
without Et3N•HBArF4: 59% yield, 88.5:11.5 er, 83:17 8:9
Scheme 7 Addition of dimethyl malonate to phenylbutadiene with Pd-1
We finally turned to addressing the lack of reactivity of
Meldrum’s acid towards internal diene 1a with Pd-1. In fact, not only
does C–C bond formation fail to occur in this case, based on the diene
recovered from the reaction mixture, the initial 1.8:1 E,Z:E,E ratio of
Acknowledgements
This work was supported by the National Science Foundation
(CHE-1800012), the ACS Petroleum Research Fund (56575-
1
a also remains unchanged. The absence of stereochemical
DNI1), and Duke University. N.J.A. is grateful to the Duke
Chemistry Department for a Burroughs–Wellcome Fellowship.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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8
(a) B. M. Trost, C. Jäkel and B. Plietker, J. AmV.ieCwhAertmicle. OSnolicn.e,
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DOI: 10.1039/C9SC00633H
‡
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