Catalytic stereospecific allyl-allyl cross-coupling of internal allyl electrophiles with allylB(pin)

Article abstract of DOI:10.1021/ol500456s

Application of internal electrophiles in catalytic stereospecific allyl-allyl cross-coupling enable the rapid construction of multisubstituted 1,5-dienes, including those with all carbon quaternary centers. Compounds with minimal steric differentiation ca

Full text of DOI:10.1021/ol500456s

Letter
pubs.acs.org/OrgLett
Catalytic Stereospecific Allyl−Allyl Cross-Coupling of Internal Allyl
Electrophiles with AllylB(pin)
Hai Le, Amanda Batten, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Application of internal electrophiles in catalytic stereospecific
allyl−allyl cross-coupling enable the rapid construction of multisubstituted 1,5-
dienes, including those with all carbon quaternary centers. Compounds with
minimal steric differentiation can be synthesized with high enantiomeric
excess.
ompounds bearing vicinal 1,5-diene frameworks are
Cversatile building blocks in chemical synthesis. While
one strategy for their direct synthesis is the metal catalyzed
cross-coupling of allyl electrophiles and allyl nucleophiles,1 an
inherent challenge is the difficulty in controlling regioselectivity
of the reaction. Linear-selective allyl−allyl cross-couplings have
been well developed.2 Recently, our laboratory has developed
several palladium-catalyzed methods to synthesize 1,5-dienes in
a branch-selective and highly enantioselective fashion.3 The
excellent selectivity observed in these reactions is reliant on
π−σ−π isomerization4 and 3,3′-reductive elimination proc-
cesses, both of which are influenced by the choice of chiral
bidentate phosphine ligands on the catalyst.5,6 As depicted in
Figure 1, our previous studies employed terminal allyl
electrophiles and capitalized on the ability of Pd to migrate
from one prochiral allyl face to the other (A ↔ B). To broaden
the scope of selective allyl−allyl cross-coupling reactions
further, we have explored the use of internal allyl electrophiles.
Effective use of this class of electrophiles is desirable as it would
not only facilitate rapid construction of 1,5-dienes with high
levels of complexity but also provide products with differ-
entiated olefins. A distinctive feature of reactions involving
internal allylic electrophiles is that Pd is generally not able to
migrate from one π-face to the other (C → D is not possible;
Figure 1). This feature eliminates the need for chiral ligands:
the enantiopurity of the product 1,5-dienes should only be
dependent on that of the starting electrophiles.7 In this paper,
we describe regiocontrol elements in such allyl−allyl coupling
reactions and also document a racemization mechanism that
operates in isolated cases.
Several difficulties may arise when utilizing internal allyl
electrophiles in allyl−allyl cross-coupling. These include (a)
competing formation of byproduct 1,3-dienes, ostensibly arising
from β-hydride elimination;8 (b) regioselectivity of product
formation; and (c) the degree of chirality transfer from the
starting electrophiles. We surmised that if 3,3′ reductive
elimination is operative, the regioselectivity of the reaction
may be controlled by the relative size difference between the
substituents at the two termini of the allyl electrophile (E
versus F, Figure 1). To initiate this study, reaction conditions
were examined using allyl acetate 1a as a probe substrate (Table
1). After some initial optimizations, 1a was found to couple
effectively with allylB(pin) to afford a mixture of 1,5-diene
products 2a and 3a in a 3:1 ratio and 88% combined yield
(Table 1, entry 1). The remainder of the mass was accounted
for by formation of 1,3-dienes as byproducts. To understand
the regioselectivity with this class of electrophiles further, we
investigated substrates with alternate substitution. The
electronic properties of the substrate had a measurable effect
on the regioselectivity of the reaction: electron rich substrate 1b
yielded 1:1 mixture of regioisomers (entry 2), while electron-
poor substrates favored formation of 2 (for example, p-CF3
substrate 1d affording 10:1 selectivity for 2, entry 4). To
Received: February 12, 2014
Published: April 4, 2014
Figure 1. Allyl−allyl coupling with non-interconvertable allyl groups.
© 2014 American Chemical Society
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Table 1. Allyl−Allyl Cross-Coupling of Secondary Allyl
Table 2. Allyl−Allyl Cross-Coupling of Trisubstituted Allyl
a
a
Acetates
Acetates
a
Conditions: 3 equiv of allylB(pin), 10 equiv of CsF, 15 equiv of H2O,
b
c
1
0.2 M THF. Ratios were determined by H NMR of crudes. Yields
are average of two or more experiments, and the mass balance is >95%
in all cases. Yields are corrected to account unseparable 1,3-diene
d
elimination products. Yield determined by 1H NMR using
e
trimethoxybenzene as internal standard. Starting material is a mixture
of regioisomers.
a
Conditions: 3 equiv of allylB(pin), 10 equiv of CsF, 15 equiv of H2O,
b
0.2 M THF. Yields are average of two or more experiments and are
corrected to account for inseparable elimination product 1,3-diene. Z-
understand further the significance of electronic and steric
factors in isolation in this reaction, substrates 1e and 1f, with
substituents differentiated only by electronic or steric properties
(entry 5 and 6), were examined. Surprisingly, the coupling of
both substrates proceeded with poor regioselectivity, indicating
only subtle dependence on both effects. However, when
substrates with significant steric bias were employed, such as
those containing an ortho-substituted aromatic ring, high levels
of regioselectivity were achieved. o-Me-substituted substrate 1g
and o-OMe-substituted substrate 1h both yielded 1,5 dienes
with 7:1 regioselectivity favoring isomer 2. Lastly, when 1i, a
substrate bearing an encumbered o-isopropyl group was
employed, the selectivity was improved to 10:1.
The observations in Table 1 suggest that the 3,3′-elimination
reaction depicted in Figure 1 is influenced by the size and the
nature of the allyl substituents with large substituents and
electron-withdrawing groups being disfavored at the R3 site in
structure E. To employ this information to construct
quaternary centers, we investigated trisubstituted allyl electro-
philes (Table 2). In accordance with the previous observations,
significant steric differences dictated regioselectivity across all
tested substrates, and only 1,5-diene products bearing all
carbon quaternary centers were observed. Acylic, aliphatic
substrates were tolerated well, affording good to excellent yields
of the product, including those with sterically demanding
substitution patterns (entries 1−5). Cyclic substrates with 6
and 7 membered ring also worked effectively in the cross-
coupling (entry 7 and 8). Lastly, trisubstituted substrates with
c
allylic acetate was employed.
an aromatic substituent are also suitable for the reaction
regardless of the substituent’s relative position (entries 6, 9, and
10).
To study the efficiency of chirality transfer, we investigated
the use of enantiomerically enriched secondary allylic acetate
(S)-14 (Table 3), prepared by Sharpless epoxidation-based
kinetic resolution of the precursor alcohol.9 Applying previously
optimized conditions, a >20:1 mixture of 1,5-diene isomers was
formed, favoring product (R)-13, with 79% yield (entry 1). The
er of (R)-13 was determined to be 79:21, which corresponded
to only 65% conservation of enantiomeric excess (cee) from
starting material (S)-14. When the amount of allylB(pin) and
CsF was increased to 10 and 30 equiv, respectively, the reaction
afforded a 3:1 mixture of 1,5-dienes in 60% yield with 80% cee
for (R)-13 (entry 2). Further investigation revealed a
correlation between the cee value and catalyst concentration;
as the catalyst concentration increased, the chirality transfer
decreased. At 1 mol % catalyst loading, almost complete
chirality transfer was observed, though at the cost of
diminishing yield and regioselectivity (entry 3). At 2.5 mol %
catalyst, product (R)-13 was obtained with 70% yield and 92:8
er, corresponding to 90% cee (entry 4). Increasing catalyst
concentration to 10 and 15 mol % provided reduced cee at 47%
and 26% cee, respectively (entries 5 and 6).
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Letter
a
Table 3. Optimizations for Stereospecific Allyl−Allyl Cross-
Scheme 1. Chirality Transfer in Allyl−Allyl Cross-Coupling
a
Coupling
b
c
d
e
entry
1
% cat.
13:15
yield (%)
er
cee (%)
5
5
>20:1
3:1
79
60
50
70
72
73
79:21
85:15
94:6
65
80
98
90
47
26
f
2
3
4
5
6
1
1:1
2.5
10
15
7:1
92:8
>20:1
>20:1
71:29
61:39
a
Conditions: 3 equiv of allylB(pin), 10 equiv of CsF, 15 equiv of H2O,
b
c
1
0.2 M THF. Ratios were determined by H NMR of crudes. Yields
are average of two or more experiments and are combined yields of 13
and 15 corrected to account for inseparable elimination product 1,3-
d
diene. er ratios were determined using chiral GC or HPLC. Absolute
configuration assigned in analogy to known compounds. See the
a
e
Conditions: 3 equiv of allylB(pin), 10 equiv of CsF, 15 equiv of H2O,
Supporting Information. cee is calculated as follow: cee = (product
b
c
f
0.2 M THF. Yields are average of two or more experiments. er ratios
were determined using chiral GC or HPLC analysis. 2:1 mixture of
regioisomers. 10:1 mixture of regioisomers. 5:1 mixture of
regioisomers. Starting material with (S) configuration was employed.
ee/starting material ee) × 100. 10 equiv of allylB(pin) and 30 equiv of
d
CsF were employed.
e
f
g
In accord with findings by Backvall,10d Amatore,10f and
̈
others, we surmised that the incomplete chirality transfer
observed at higher catalyst loading may be a result of a redox-
transmetalation process (Figure 2).10 Upon formation of
using 2.5 mol % of catalyst. Diphenylmethane derivative 18 was
synthesized with excellent yield and regioselectivity and
moderate cee of 67%. In contrast with aromatic-substituted
substrates, aliphatic substrates demonstrated excellent chirality
transfer properties. Allyl−allyl coupling product 19 was
obtained in 49% yield and 94:6 er, corresponding to >99%
cee. Geraniol-derived 1,5-diene 20 was also produced with 96:4
er, corresponding to 99% cee.
In conclusion, we have extended the Pd-catalyzed allyl−allyl
cross-coupling reaction to include internal allyl electrophiles.
This strategy enables rapid construction of multisubstituted 1,5-
dienes with predictable regio- and enantioselectivity while
omitting the requirement for chiral phosphine ligand.
Figure 2. Racemization during allyl−allyl cross-coupling may occur by
redox transmetalation (C → D).
ASSOCIATED CONTENT
* Supporting Information
■
S
Pd−π-allyl intermediate C, available Pd0 complexes in the
reaction media may displace the PdII from C in an anti fashion,
leading to enantiomer D.3a,11 This could then undergo
transmetalation and 3,3′ reductive elimination to afford
enantiomeric 1,5-diene product, thereby diminishing the er of
the reaction product. This mechanism for racemization should
be second order in [Pd], whereas the cross-coupling process
itself should exhibit first-order dependence on [Pd]. Thus,
improved cee is anticipated at lower catalyst concentrations.
The observation that increased concentrations of allylB(pin)
and CsF improve cee (entry 2) suggest that the redox
transmetalation operates on intermediates C and D and does
not operate on subsequent bis(allyl)Pd complexes.
The scope of chirality transfer was studied with a range of
substrates, including those with aromatic and aliphatic
substitution (Scheme 1). p-Methoxy-substituted 16 exhibited
a correlation between cee and catalyst loading level similar to
13.12 At 2.5 mol % catalyst loading, 88% cee was obtained,
while at 5% and 10% catalyst loadings, the cee dropped to 56%
and 48%, respectively. When p-CF3-substituted product 17 was
examined, significant erosion of enantiomeric purity was
observed and the products were acquired with only 34% cee
Complete experimental procedures and characterization data
(1H and 13C NMR, IR, and mass spectrometry). This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: morken@bc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support by the NIGMS (GM-64451) is gratefully acknowl-
edged. We thank AllyChem for a donation of B2(pin)2.
■
REFERENCES
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