Rational design of cyclopropane-based chiral PHOX ligands for intermolecular asymmetric Heck reaction

Article abstract of DOI:10.3762/bjoc.10.158

A novel class of chiral phosphanyl-oxazoline (PHOX) ligands with a conformationally rigid cyclopropyl backbone was synthesized and tested in the intermolecular asymmetric Heck reaction. Mechanistic modelling and crystallographic studies were used to predict the optimal ligand structure and helped to design a very efficient and highly selective catalytic system. Employment of the optimized ligands in the asymmetric arylation of cyclic olefins allowed for achieving high enantioselectivities and significantly suppressing product isomerization. Factors affecting the selectivity and the rate of the isomerization were identified. It was shown that the nature of this isomerization is different from that demonstrated previously using chiral diphosphine ligands.

Full text of DOI:10.3762/bjoc.10.158

Rational design of cyclopropane-based chiral PHOX
ligands for intermolecular asymmetric Heck reaction
Marina Rubina1, William M. Sherrill1, Alexey Yu. Barkov2
and Michael Rubin*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1536–1548.
1Department of Chemistry, University of Kansas, 1251 Wescoe Hall
Drive, Lawrence, KS 66045-7582, USA and 2Department of
Chemistry, Ural Federal University, pr. Lenina 51, 620000
Ekaterinburg, Russian Federation
doi:10.3762/bjoc.10.158
Received: 19 February 2014
Accepted: 03 June 2014
Published: 07 July 2014
Email:
Michael Rubin* - mrubin@ku.edu
This article is part of the Thematic Series "Organophosphorus chemistry".
Guest Editor: P. R. Hanson
* Corresponding author
Keywords:
© 2014 Rubina et al; licensee Beilstein-Institut.
License and terms: see end of document.
asymmetric catalysis; chiral phosphine ligands; cyclopropane; Heck
reaction; organophosphorus; transition metal catalysis
Abstract
A novel class of chiral phosphanyl-oxazoline (PHOX) ligands with a conformationally rigid cyclopropyl backbone was synthe-
sized and tested in the intermolecular asymmetric Heck reaction. Mechanistic modelling and crystallographic studies were used to
predict the optimal ligand structure and helped to design a very efficient and highly selective catalytic system. Employment of the
optimized ligands in the asymmetric arylation of cyclic olefins allowed for achieving high enantioselectivities and significantly
suppressing product isomerization. Factors affecting the selectivity and the rate of the isomerization were identified. It was shown
that the nature of this isomerization is different from that demonstrated previously using chiral diphosphine ligands.
Introduction
The asymmetric Heck reaction is one of the most powerful and Considerable achievements have also been made towards the
versatile processes for the enantioselective construction of new application of BINAP-type ligands in the intermolecular asym-
carbon–carbon bonds. Intramolecular versions of this reaction metric Heck reaction [15]. This reaction was pioneered by
catalysed by palladium complexes with BINAP and related Hayashi [16], who demonstrated the arylation of dihydrofuran
diphosphine ligands [1,2] allow for efficient installation of (1) with phenyl triflate (2a) (Scheme 1) in the presence of (R)-
tertiary and quaternary chiral centres leading to a rapid increase BINAP [16-18] produced isomeric dihydrofurans 3a and 4a,
of molecular complexity [3-5]. To date, various modes of this with the latter being the major product, due to substantial
transformation are being successfully employed in the syn- isomerization of the double bond. Depending on the reaction
thesis of complex organic molecules [6-14].
conditions, moderate to good selectivities toward formation of
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Later, a number of research groups pursued the design of alter-
native diphosphine ligands to achieve better regio- and enantio-
selectivity in the intramolecular Heck reaction. Several deriva-
tives of BINAP [19,20] and other chiral diphosphines [21-27]
including TMBTP [28-31], BIPHEP [32-34], BITIANP [30,35]
(Figure 1) were tested, some of which provided improved selec-
tivity. Nevertheless, in all cases predominant or exclusive for-
Scheme 1: Intermolecular asymmetric Heck reaction by Hayashi [16].
4a were observed. Remarkably, the obtained products, “normal” mation of the isomerized product 4 was observed.
3a and “isomerized” 4a, had the opposite absolute configura-
tions of the stereogenic center at C2. Moreover, it was found
that the enantioselectivity improved during the reaction course.
The mechanistic rationale proposed by Hayashi [16] fully
accounts for the observed stereoselectivity change (Scheme 2).
The catalytic cycle begins with the oxidative addition of Pd(0)
species 5 into the aryl triflate 2 resulting in the formation of
cationic complex 6. The latter can coordinate to either of the
prochiral faces of dihydrofuran (1) affording diastereomeric
η2-complexes 7 and 10. Subsequent carbopalladation, followed
by β-hydride elimination, produces species 9 and 12, respective-
Figure 1: Chiral diphosphine ligands used for intermolecular asym-
metric Heck reaction.
ly. It was proposed that the diastereomeric complex 12 has a
higher propensity toward further hydropalladation than 9.
Accordingly, the latter species releases the (S)-enantiomer of
2,5-dihydrofuran 3 (path I), while the former undergoes a series At the same time, several mixed hetereoatom ligands of the P–S
of reversible hydropalladations and β-hydride eliminations, [36,37], P–O [38], and N–N [39,40] type have also been
resulting in the formation of a thermodynamically more explored in the intermolecular Heck arylation; however, they
favoured η2-complex 14, which ultimately produces the (R)- demonstrated in most cases only marginal regio- and enantio-
enantiomer of the isomeric product 4.
selectivities. On the other hand, superior results were obtained
Scheme 2: Mechanistic rationale of asymmetric Heck reaction.
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using chiral ligands of the P,N-type [15,41-44]. Particularly, PHOX ligands are very appealing due to their high catalytic
excellent enantioselectivities were achieved using different vari- potential and modular design, which permits easy preparation of
ations of phosphanyl-oxazoline (PHOX) ligands [45-52], origi- a series of analogues via the same synthetic route. To date,
nally introduced by Pfaltz (Figure 2) [53,54]. The remarkable, however, general approach to the ligand design has been largely
yet not fully understood feature of PHOX ligands is their low empirical due to a poor understanding of the factors affecting
tendency to promote C=C-bond isomerization [45-52]. Thus, in the activity of the corresponding catalytic systems and the oper-
contrast to the diphosphines, PHOX ligands produced dihydro- ating modes of asymmetric induction imparted by the employed
furan 3 with very high selectivity. Structural modification of the chiral ligands. In our investigation, we decided to benefit from a
flat ortho-phenylene tether in the Pfaltz ligand through the well-established strategy commonly used in medicinal chem-
incorporation of additional chirality elements into the ligand istry. According to this approach conformationally constrained
backbone allowed for significant improvement of the enantio- cyclic analogues of biologically active molecules are employed
selectivity. Thus, ferrocene-based ligands introduced by Dai for elucidation of important mechanisms and identifying crit-
and Hou [55,56], and Guiry [57,58] (Figure 2) were employed ical enzyme binding sites. Analogously, we anticipated that
in the asymmetric Heck reaction of different cyclic olefins. incorporation of a three-membered cycle in the ligand structure
Furthermore, Gilbertson demonstrated PHOX ligands featuring [60-63] would impart rigidity to the ligand backbone and
apobornene backbone (Figure 2) exhibit outstanding activities provide conformationally constrained systems with amplified
and selectivities in the arylation and alkenylation of different steric effects, which can be easily modelled and predicted. This,
cyclic substrates [59]. A highly efficient asymmetric arylation in turn, could be used to rationally design the ligand structure en
in the presence of sugar-derived phosphite-oxazoline ligands route to more efficient catalytic systems. In 2008 we communi-
was reported by Diéguez and Pàmies [47,48].
cated the design and synthesis of a novel series of PHOX
ligands featuring a chiral cyclopropyl backbone, as well as their
employment in the enantioselective intermolecular Heck aryl-
ation reaction [64]. Herein we describe the full account on this
investigation, including the results of the structure–activity
studies and provide our insight into the origins of the enantio-
selectivity of this transformation and factors controlling the rate
of isomerization reaction.
Results and Discussion
Our approach to the PHOX ligands with a chiral cyclopropyl
backbone is presented in Scheme 3. The synthesis began from
optically active 1-methyl-2,2-dibromocyclopropanecarboxylic
acid (15) [65] readily available in both enantiomeric forms. The
S-enantiomer of acid 15 was converted into acyl chloride (S)-
Figure 2: Chiral phosphanyl-oxazoline (PHOX) ligands used for inter-
molecular asymmetric Heck reaction.
Scheme 3: Synthetic scheme for preparation of PHOX ligands with chiral cyclopropyl backbone.
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16. Subsequent acylation of (R)-phenylglycinol with (S)-16 phosphorus moiety in L2 negatively affected the asymmetric
afforded amide 17, which was subjected to cyclization in the induction: the corresponding product 3a was obtained in only
presence of mesyl chloride and a base providing dihydrooxa- 78–79% ee (Table 2, entries 3 and 4). However, in contrast to
zole 18. Diastereoselective partial reduction of the dibromo- L1 (Table 2, entries 1 and 2) the selectivity toward 3a in the
cyclopropane moiety with zinc dust in glacial acetic acid reaction using L2 remained high, regardless of the base used.
produced a 1:4 mixture of trans- and cis-bromocyclopropanes
19, which were separated by column chromatography. Lithium
to halogen exchange followed by trapping of the resulting
cyclopropyllithium species with chlorophosphine produced
ligand L1 (Scheme 3).
Ligand L1 once obtained, was tested in the asymmetric aryl-
ation reaction of 2,3-dihydrofuran under various reaction condi-
tions (Table 1). It was found that the reaction proceeded effi-
ciently, yet with only moderate enantioselectivity, in the pres-
ence of palladium acetate and Hünig’s base (Table 1, entry 3).
Interestingly, the employment of proton sponge as a base
resulted in significant isomerization of product 3a into the more
thermodynamically stable dihydrofurans 4a and 20a. Close
monitoring of the reaction by chiral GC revealed, that the
initially formation of “normal” product 3a is observed (Table 1,
entry 4); however, by the time when starting material 1 was
completely consumed, the entire amount of 3a produced was
transformed into 4a (Table 1, entry 5). Remarkably, the
absolute configuration at C2 did not change at all through the
Figure 3: PHOX ligands with chiral cyclopropyl backbone employed in
this study.
reaction course; moreover, the optical purity of both products
3a and 4a remained constant (Table 1, entries 4 and 5). This
feature makes this isomerization mechanistically distinct from
the one reported by Hayashi (vide supra).
Modification of the dihydrooxazole moiety by installation of a
bulky tert-butyl group was pursued in attempt to improve the
To better understand the factors affecting the selectivity and enantioinduction of our catalytic system. Indeed, a number of
efficiency of the asymmetric arylation, we have prepared two previously reported PHOX ligands derived from tert-leucinol
more analogues of L1: ligand L2, possessing a diphenylphos- were shown to provide superior enantioselectivities compared
phanyl group and ligand L3 derived from tert-leucinol to their analogues obtained from less bulky amino alcohols
(Figure 3). Not surprisingly, installation of the less hindered [54,57,59]. However, the arylation carried out in the presence of
Table 1: Selected results on optimization of the reaction conditions for asymmetric Heck arylation using L1.
Entry Pd cat.
Base
Solvent
Time/Temp
3a:4a
ee, %a
conv, %b
1
2
3
4
5
6
Pd2dba3·CHCl3
EtN(iPr)2
benzene
THF
3 d/70 °C
19:1
90
85
83
88
85
82
15
60
99
45
99
99
Pd2dba3·CHCl3
Pd(OAc)2
EtN(iPr)2
20 h/85 °C
20 h/85 °C
20 h/60 °C
70 h/60 °C
20 h/90 °C
10:1
EtN(iPr)2
THF
11:1
Pd(OAc)2
proton sponge
proton sponge
proton sponge
THF
10:1
Pd(OAc)2
THF
>1:50c
>1:50c
Pd(OAc)2
THF
aEe's of major regioisomers are listed. bConversion by GC. cFormation of small amounts of dihydrofuran 20a was observed.
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Table 2: Screening of L1–L3 in the asymmetric Heck arylation of dihydrofuran 1.
Entry
Ligand
Base
3a:4a
ee, %a
conv, %b
1
2
3
4
5
6
L1c
L1c
L2
EtN(iPr)2
11:1
>1:50
20:1
15:1
7:1
83
82
79
78
87
84d
99
99
99
99
35
80
proton sponge
EtN(iPr)2
L2
proton sponge
EtN(iPr)2
L3
L3
proton sponge
1.4:1
aEnantioselectivity of a major product. bConversions by GC. cResults from Table 1. dEnantioselectivity of product (R)-4a was 80%.
L3 proceeded much more sluggishly (Table 2, entries 5 and 6), pseudo-axial; and I2, where this relationship is reversed
and allowed for only insignificant improvement in enantio- (Scheme 4). Analysis of these two conformations suggests that
selectivity (84–87% ee). Most remarkably, the same (R)-enan- steric repulsions between the axial syn-substituent and the meth-
tiomer of product 3 was obtained, despite the opposite absolute ylene group in cyclopropane makes conformation I2 thermody-
configuration of L3 with respect to L1 (Figure 3). In other namically disfavored compared to I1. This hypothesis was also
words, switching from Ph to t-Bu substituent in the dihydrooxa- supported by a single crystal X-ray analysis of (L1)PdCl2 com-
zole ring of the ligand resulted in a reversal of enantio- plex (Figure 4). The resolved crystal structure clearly shows
selectivity.
that the syn-(C14) and anti-substituent (C18) at phosphorus
Such an unexpected change in the catalyst selectivity motivated
us to perform structural analysis of the key intermediate
complexes invoked in the catalytic cycle of the Heck arylation.
First, we assessed the possibility of conformational equilibrium
for the six-membered arylpalladium species bearing L1
(Scheme 4). The non-planar six-membered palladacycle [66-69]
can potentially adopt one of two conformations: I1, in which
the syn-tert-butyl substituent at phosphorus assumes a pseudo-
equatorial position, whereas the anti-tert-butyl substituent is
Scheme 4: Conformational equilibrium in cationic arylpalladium(II)
complexes with chiral ligand L1.
Figure 4: X-ray structures of complexes (L1)PdCl2 (left) and (L4)PdCl2 (right). These structures were originally communicated in [64].
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adopt a pseudo-equatorial and a pseudo-axial position, respect- the (R)-enantiomer of the product was predominantly formed,
ively. It would be reasonable to assume that the strained and albeit with moderate enantioselectivity. Analogously, in the
rigid cyclopropyl backbone renders the six-membered pallada- intermediate I5 derived from chiral ligand L2, the less bulky
cycle particularly inflexible, thus significantly suppressing con- pseudo-axial phenyl substituent at phosphorus blocks the
formational fluctuations throughout the catalytic cycle. Further- re-face approach even less efficiently, which ultimately results
more, coordination of the soft π-ligand dihydrofuran should in a further decrease of enantioselectivity (Scheme 5).
take place predominantly trans to a soft phosphorus atom [70-
72] (Scheme 5). In this case, the re-face approach (I4) is The reversal of enantioselectivity observed in the reaction
encumbered by a large pseudo-axial tert-butyl group, while the carried out in the presence of L3 was explained in a similar
si-face approach (I3) is also somewhat hindered by a pseudo- fashion (Table 2, entries 5 and 6, Scheme 6). Thus, a bulky tert-
axial syn-phenyl substituent in dihydrooxazole ring. As a result, butyl group in the dihydrooxazole ring creates the increased
Scheme 5: For discussion on asymmetric induction imparted by chiral ligands L1 and L2 (originally published in [64]).
Scheme 6: For discussion on asymmetric induction imparted by chiral ligands L3 (originally published in [64]).
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steric hindrance, which does not allow for the si-face approach structure was achieved by varying the chlorophosphine source.
resulting in the reaction proceeding predominantly from the Thus, employment of di-tert-butylchlorophosphine, chlorodicy-
re-face, providing the (S)-enantiomer of 3 (Scheme 6). The fact clohexylphosphine, and chlorodiphenylphosphine at the last
that in both intermediates I7 and I8 dihydrofuran experiences step of the sequence provided ligands L4, L5, and L6, respect-
certain impediment on approach to palladium may also be re- ively (Figure 3). Crystallographic data obtained for the
sponsible for the observed decrease in the reaction rate.
(L4)PdCl2 complex (Figure 4) completely confirmed the prefer-
ence of conformation I9 vs I10 (Scheme 7). It should be
Based on this analysis, we rationalized that the “wrong” rela- pointed out, that the resolved crystal structure of (L4)PdCl2
tive configuration of the stereogenic centers in ligands L1, L2 complex shows four sets of crystallographically independent
and L3 could be responsible for the observed marginal enantio- molecules. However, all of them have nearly identical pallada-
selectivity of the corresponding catalytic systems. We envi- cycle conformations with the molecule shown in Figure 4 [64].
sioned that inverting the absolute configuration of the asym- An overlay of X-ray structures obtained for (L1)PdCl2 and
metric center at C4 in the dihydrooxazole ring might poten- (L4)PdCl2 complexes demonstrated that all atoms of the
tially help to improve the enantioselectivity of the arylation palladacycle, cyclopropyl ring, and both tert-butyl substituents
reaction. Indeed, it is reasonable to propose that the inversion of can be almost perfectly superimposed, which for both ligand
the stereogenic center in the dihydrooxazole ring should not configurations, confirms the strong preference of a con-
significantly affect the thermodynamic equilibrium of the formation in which the syn-tert-Bu substituent (C14) and the
corresponding palladacycle conformations I9 and I10 anti-tert-Bu substituent (C18) at phosphorus assume pseudo-
(Scheme 7), as compared to I1 and I2 (Scheme 4). Thus, the equatorial and pseudo-axial positions, respectively. Remark-
cationic palladacycle with (S,S,S)-ligand L4 would still predom- ably, X-ray analysis has also demonstrated that the phenyl
inantly adopt conformation I9 to avoid the unfavorable steric substituent at C4 of dihydrooxazole ring adopts a pseudo-axial
interaction between the pseudo-axial syn-tert-butyl group and position thereby completely blocking any potential re-face
the methylene group of the cyclopropane (Scheme 7). Accord- attack (Scheme 8).
ingly, a synergistic steric effect of both the axial P–t-Bu group
and a bulky substituent at C4 in dihydrooxazolyl moiety Ligands L4, L5, and L6 once obtained were tested in the asym-
observed in the alternative (S,S,S)-configuration of the ligand metric arylation of dihydrofuran 1 (Table 3). Gratifyingly, right
would now provide efficient blocking of the both bottom quad- along with our expectations, the entire series of (S,S,S)-ligands
rants thereby completely averting the re-face attack (I12, L4–L6 not only provided a significant improvement in enantio-
Scheme 8). On the other hand, the si-face attack should become selectivity, but also helped to suppress the unwanted isomeriza-
more favorable after the removal of a bulky group obstructing tion of 3 into 4, as compared to the diastereomeric ligand series
the top right quadrant (I11, Scheme 8 vs I3, Scheme 5). Ulti- (L1–L3, Table 2). Remarkably, changing the absolute configur-
mately, if the above assumptions are correct, this change should ation of the stereocenter in the dihydrooxazole ring did not
result in enhanced enantioselectivity of the asymmetric aryl- cause the change of the absolute configuration of the product.
ation in the presence of ligand L4 in favor of the (R)-enan- This is in contrast to the reactions performed using most known
tiomer of the product 3.
PHOX ligands, in which configuration of the oxazoline moiety
usually determines the stereochemical outcome of the reaction
(however, in the reactions using PHOX ligands bearing a very
bulky planar or axially chiral backbone, the enantiomeric
outcome is controlled by the absolute configuration of the back-
bone rather than that of the oxazoline ring; for discussion, see
[15]). Thus, employment of L4 and L5 afforded dihydrofuran
(R)-3 with very high enantioselectivity regardless of the base
used (Table 3, entries 1–6); however, the reactions proceeded
more sluggishly in the presence of Hünig’s base (Table 3,
entries 2 and 5). Employment of proton sponge helped boost the
reaction rate in the arylation catalyzed by both L4 and L5
(Table 3, entries 3 and 6). Yet, significant isomerization of 3
Scheme 7: Conformational equilibrium in cationic arylpalladium(II)
complexes with chiral ligand L4.
With this idea in mind, we prepared a new series of ligands with into 4 was observed with this base when the reaction catalyzed
the (S,S,S)-absolute configuration using the synthetic approach by Pd/L4 complex was allowed to run for an additional 20 h
described above (Scheme 3), starting from acid chloride (S)-16 (Table 3, note c). Employment of the diphenylphosphanyl
and (S)-phenylglycinol. Additional diversification of the ligand ligand L6 provided lower enantioselectivity (Table 3, entries 7
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Scheme 8: For discussion on asymmetric induction imparted by chiral ligands L4 (originally published in [64]).
Table 3: Screening of L4–L6 in the asymmetric Heck arylation reaction.
Entry
Ligand
Base
3a:4a
ee (3a), %
Conv, %a
1
2
3
4
5
6
7
8
L4
L4
L4
L5
L5
L5
L6
L6
EtN(iPr)2
>50:1
16:1
98
98
98
94
94
95
88
86
53
97b
74
71
90b
99
76
83
EtN(iPr)2
proton sponge
EtN(iPr)2
>50:1c
>50:1
40:1
EtN(iPr)2
proton sponge
EtN(iPr)2
29:1
16:1
proton sponge
>50:1
aConversions by GC. bConversion after 2 days at 85 °C. cWhen the reaction was allowed to stir for an additional 20 h, the product ratio changed to
2:1. The enantioselectivities of products (R)-3a and (R)-4a in this case were found to be 98% and 97%, respectively.
and 8), which can be attributed to decreased steric demands in Scheme 10. Thus, it seems impossible to realize the si-face
created by phenyl groups at phosphorus as compared to the tert- approach of palladium hydride species I13 to the double bond
butyl (L4) and cyclohexyl (L5) substituents.
of 3 due to severe steric hindrance between the di(tert-
butyl)phospanyl group of the ligand and the aryl substituent in 3
The different tendencies of Pd/L1 and Pd/L4 catalyst systems to on one side, and between the phenyl substituent in dihydrooxa-
promote isomerization of product 3 into 4 can be rationalized as zole ring and C5-methylene of dihydrofuran 3 on the other (I15,
follows. As discussed above (Scheme 2), the isomerization Scheme 10). However, the absence of any significant steric
process involves reversible hydropalladation of the double bond interference upon alternative re-face approach makes this alter-
of product 3. The migration of the double bond can be realized native mechanistic channel available for isomerization (I14,
only when hydropalladation of 3 occurs with addition of palla- Scheme 10).
dium to C4 (Scheme 9, path A), whereas the opposite regiose-
lectivity of hydropalladation would ultimately lead, after the Two potential pathways for hydropalladation of 3 by the
subsequent β-hydride elimination, back to compound 3 diastereomeric Pd/L4 hydride species I16 are shown in
(Scheme 9, path B). The diastereoselectivity of the hydropalla- Scheme 11. In conjunction with L1-derived complex I15
dation of 3 by Pd/L1 hydride species I13 is controlled as shown (Scheme 10), complex I18 produced via the si-face approach
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Scheme 9: Mechanism of migration of C=C double bond leading to isomerization of product 3 into product 4.
Scheme 10: For discussion on isomerization 3→4 imparted by Pd/L1 complex (originally published in [64]).
should be highly disfavored (Scheme 11). In this case, however, ization of compound 3 into 4 should be suppressed in this case.
an alternative complex I17 resulting from the re-face attack It should be mentioned, however, that electronic density at the
should also experience steric repulsion between the C5-meth- phosphine moiety of the ligand also notably affects the propen-
ylene of dihydrofuran 3 and a pseudo-equatorial phenyl sity of the corresponding catalyst to promote the isomerization.
substituent in dihydrooxazole ring (Scheme 11). Accordingly, Thus, our experiments indicate that in the series of di(tert-
complex I17 should be much more unfavorable compared to butyl)-, dicyclohexyl-, and diphenylphosphanyl-containing
L1-derived complex I14, where such interaction does not occur ligands (L4→L6), the former has the highest tendency to in-
(Scheme 10). As a result, both mechanistic channels for isomer- duce isomerization while the latter has the lowest (Table 3). A
Scheme 11: For discussion on isomerization 3→4 imparted by Pd/L4 complex (originally published in [64]).
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Beilstein J. Org. Chem. 2014, 10, 1536–1548.
similar electronic effect was previously observed in the asym- contrast to the Pd/L4-catalyzed reactions, enantioselectivities in
metric Heck arylation in the presence of diphosphine-oxazoline this case varied slightly depending on the aryl triflate used, with
ferrocenyl ligands [56].
the highest value obtained from 1-naphthyl triflate (96%,
Table 4, entry 9) and the lowest from 2-naphthyl triflate (87%,
Next, the most efficient ligands L4 and L5 were tested in the Table 4, entry 10). Interestingly, the electronic nature of the aryl
asymmetric arylation of dihydrofuran 1 against various aryl triflate had a pronounced effect on the reaction rate, which is
triflates (Table 4). It was found that all reactions catalyzed by best seen in the Pd/L5 series of catalyzed reactions. Thus, elec-
Pd/L4 provided excellent enantioselectivities (98–99%) regard- tron-rich aryl triflates (Table 4, entries 6, 7, and 9) reacted much
less of the nature of the aryl triflate (Table 4, entries 1–5). faster than the electron-poor analog 2d (Table 4, entry 8).
However, the reactions carried out in the presence of L4/ Furthermore, a remarkable difference between the reactivity of
Hünig’s base combination proceeded much more sluggishly; as 1- and 2-naphthyl triflates was also observed, suggesting the
a result, the selectivity toward formation of 3 was slightly lower reaction is also sensitive to sterics (Table 4, entries 9 and 10).
in these cases. Reactions performed in the presence of Pd/L5
catalyst and proton sponge proceeded much faster, albeit We also tested all new ligands L1–L6 in the asymmetric Heck
providing somewhat lower ee's (Table 4, entries 6–10). In arylation of cyclopentene (Table 5). Initial experiments
Table 4: Asymmetric arylation of dihydrofuran with aryl tiflates.
Entry
Aryl
Ligand/Base
Time, h
3:4
ee (3), %
Conv, %a
1
2
3
4
5
6
7
8
9
10
p-Me-C6H4
p-MeO-C6H4
p-CF3-C6H4
1-Nphth
2b
2c
2d
2e
2f
L4/Hünig’s base
L4/Hünig’s base
L4/Hünig’s base
L4/Hünig’s base
L4/Hünig’s base
L5/proton sponge
L5/proton sponge
L5/proton sponge
L5/proton sponge
L5/proton sponge
48
20
48
48
20
6
16:1
17:1
>50:1
18:1
>50:1
39:1
35:1
42:1
31:1
17:1
99
98
98
98
98
95
92
91
96
87
96
98
58
70b
32b
93
2-Nphth
p-Me-C6H4
p-MeO-C6H4
p-CF3-C6H4
1-Nphth
2b
2c
2d
2e
2f
6
99
20
6
95
94b
100c
2-Nphth
20
aConversion by GC. bFormation of ca.10% of naphthalene was observed. cFormation of ca. 20% of naphthalene was observed.
Table 5: Evaluation of Ligands L1–L6 in the intermolecular asymmetric Heck reaction of phenyl triflate (2a) with cyclopentene (19).
Entry
Ligand
22:23
ee (22), %
Conv, %a
Yield, %b
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
12:1
15:1
13:1
27:1
44:1
40:1
81
86
82
92
89
80
99
95
15
32
96
60
85
80
ND
ND
80
ND
aConversion by GC. bIsolated yields, obtained by standard aqueous work-up of the reaction mixture, followed by fractionation.
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Beilstein J. Org. Chem. 2014, 10, 1536–1548.
conducted under the conditions optimized for arylation of dihy- Program, supported by the Ministry of Education and Science
drofuran 1 provided no reaction with cyclopentene 21. Addi- of the Russian Federation and the Ural Federal University. We
tional optimization revealed that reasonable reaction rates can also thank National Science Foundation (grant CHE-0079282)
be achieved only in the presence of Pd(dba)2 catalyst and proton for funds to purchase the X-ray instrument and Dr. V. W. Day
sponge. It should be mentioned that employment of (X-ray Crystallography Laboratory, University of Kansas) for
Pd2(dba)3·CHCl3 catalyst in place of Pd(dba)2 provided no his assistance with X-ray crystallography.
reaction. Generally, the enantioselectivities obtained in this
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Financial support from the University of Kansas and the
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