Enantioselective carbocycle formation through intramolecular Pd-catalyzed allyl-aryl cross-coupling

Article abstract of DOI:10.1021/ol5019163

Aryl electrophiles containing tethered allylboronate units undergo efficient intramolecular coupling in the presence of a chiral palladium catalyst to give enantioenriched carbocyclic products. The reaction is found to be quite general, affording 5, 6, an

Full text of DOI:10.1021/ol5019163

Letter
pubs.acs.org/OrgLett
Open Access on 08/08/2015
Enantioselective Carbocycle Formation through Intramolecular Pd-
Catalyzed Allyl−Aryl Cross-Coupling
Christopher H. Schuster, John R. Coombs, Zachary A. Kasun, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Aryl electrophiles containing tethered allylboro-
nate units undergo efficient intramolecular coupling in the
presence of a chiral palladium catalyst to give enantioenriched
carbocyclic products. The reaction is found to be quite general,
affording 5, 6, and 7-membered carbocyclic products as single
regioisomers and with moderate enantioselectivities. Examina-
tion of differential coupling partners points to rapid allyl-
equilibration as a key stereodefining feature.
philes.2n More recently, Crudden reported the regioselective
he development of metal-catalyzed cross-coupling reac-
Ttions has revolutionized the manner in which molecules are coupling of internal allyl boronates with aryl electrophiles.2f The
linear-selective coupling of allyl boronates and aryl electrophiles
was accomplished by Organ utilizing a bulky Pd-PEPPSI
catalyst.2g Notably, Buchwald was able to achieve both branch-
and linear-selective coupling with the proper choice of ligand.2h
While Aggarwal and Crudden recently disclosed the enantio-
specific cross-coupling of enantiomerically enriched allyl
boronates with aryl electrophiles,2i the only example of
enantioselective coupling of allyl boronates and aryl electrophiles
with chiral catalysts remains the work of Miyaura.6 When an
electron-rich Josiphos-based ligand with the use of crotyl
potassium trifluoroboronates was employed, a highly branch-
selective coupling was achieved with good enantioselectivity.
In stark contrast to the aforementioned intermolecular
coupling of allyl boronates, an intramolecular version is
unknown.7 In related coupling reactions,8 allylsilanes,9 allyl-
stannanes,10 and allylindium11 reagents have all been successfully
engaged in intramolecular cross coupling to forge the desired
carbo- or heterocyclic products. With the notable exception of
work by Tietze,9d−f all intramolecular allyl−aryl couplings have
thus far been executed in a racemic manner. Herein, we describe
the use of allyl boronates as nucleophilic partners in an
intramolecular coupling with aryl electrophiles to afford
enantiomerically enriched carbocyclic products in a regioselec-
tive fashion.
assembled, providing reliable, predictable, and versatile entry to a
variety of molecular frameworks.1 Recently, allylmetal reagents
have garnered significant attention as valuable partners in cross-
coupling protocols. Employing nonsymmetric allyl fragments
allows bond formation at one of two sites, presenting the
opportunity for both regioselective and in some cases
enantioselective transformations. In particular, allyl boron
compounds2−4 have proven to be practical nucleophilic partners,
in part due to their ease of handling, high functional group
tolerance, and facile preparation.5
Recently, several reports engaging allyl boronates as partners
in both branch- and linear-selective cross coupling reactions have
been disclosed (Scheme 1). In 2006, Szabo achieved a highly
́
branch-selective coupling of allylboronic acids with aryl electro-
Scheme 1. Recent Examples of Intermolecular Allyl Boronate
Aryl Coupling
Initial attempts to achieve the desired transformation are
outlined in Table 1. The use of a variety of bidentate chiral
phosphine ligands generally resulted in efficient conversion to
the carbocyclic product in a regioselective fashion, albeit with low
levels of enantioselectivity (entries 1−6). In contrast to the good
enantioselectivities obtained by Miyaura under similar reaction
conditions for intermolecular allyl−aryl coupling, employment
of a Josiphos-based catalyst results in a nearly racemic reaction
Received: July 2, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5019163 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Survey of Chiral Ligands in Intramolecular Allyl−
Table 2. Survey of Reaction Conditions in Intramolecular
Allyl−Aryl Coupling
a
a
Aryl Coupling
entry
base
solvent
ligand
conv (%)
er
1
KOH
KOH
KOH
KOH
KOH
KOH
CsF
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF
JosiPhos
Binap
>98
>98
>98
>98
>98
>98
63
51:49
51:49
56:44
51:49
56:44
57:43
56:44
59:41
83:17
84:16
71:29
entry
X
base
solvent
additive
conv (%)
er
2
1
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cs2CO3
K3PO4
CsF
THF
>98
>98
>98
24
68:32
56:44
84:16
76:24
46:54
61:39
83:17
82:18
74:26
74:26
90:10
90:10
93:7
3
QuinoxP*
PhBPE
2
THF
4
3
THF
5
iPr-DuPhos
Me-DuPhos
Me-DuPhos
Me-DuPhos
L1
4
KF
THF
6
5
TBAF
CsF
THF
>98
>98
74
7
6
MeCN
EtOAc
dioxane
toluene
hexane
THF
8
CsF
>98
>98
>98
>98
7
CsF
9
CsF
THF
8
CsF
>98
>98
>98
70
10
CsF
THF
L2
9
CsF
11
CsF
THF
L3
10
11
12
13
CsF
a
Percent conversion determined by 1H NMR analysis; er (enantiomer
ratio) determined by GLC analysis with a chiral stationary phase.
CsF
Bu4NCl
Bu4NCl
CsF
THF
>98
CsF
THF
45
a
Percent conversion determined by 1H NMR analysis; er (enantiomer
ratio) determined by GLC analysis with a chiral stationary phase.
Scheme 2. Survey of Reaction Conditions in Intramolecular
a
Allyl−Aryl Coupling
product (entry 1). Utilization of cesium fluoride under
anhydrous conditions resulted in a slight improvement in
selectivity with Me-DuPhos (entry 8); however, significantly
higher enantiomeric selectivity was obtained with the use of
monodentate phosphoramidite ligands utilizing a TADDOL
based backbone (entries 9−11). While increasing the size of the
ligand aryl groups resulted in only marginally elevated
selectivities, the nature of the amino group proved more
influential, with small groups yielding superior results (cf. L2
vs L3); thus, (R,R)-L2 was selected for further study.
In an effort to improve reaction efficiency further, additional
conditions were examined (Table 2). While promoting efficient
ring closure in most cases, bases other than CsF gave inferior
levels of enantioselectivity (entries 1−5). Similarly, both polar
(entries 3, 6−8) and nonpolar (entries 9, 10) solvents proved to
be suitable reaction media, with THF affording the best
selectivity. Because of its ability to promote π−σ−π isomer-
ization, the use of NBu4Cl was examined. In line with
observations by Trost12 and Togni,13 this led to a significant
increase in the levels of enantioselectivity obtained. Employing
aryl chlorides (entry 12) in place of aryl bromides also resulted in
greater selectivity, which can be further augmented with the use
of NBu4Cl (entry 13); however, reactivity generally suffers under
these conditions. Taken together, the use of aryl chlorides
without additive in THF, and with CsF as the base, was found to
yield the best results, achieving full conversion with good levels of
enantioselectivity.
a
Yield refers to isolated yield of purified material and is an average of
two experiments. er was determined chromatographically by either GC
b
or SFC analysis using a chiral stationary phase. Yield in parentheses
c
determined by 1H NMR versus internal standard. Selectivity obtained
with NBu4Cl (1.5 equiv), < 30% conversion in both cases.
substrates exhibited enhanced selectivity (products 4, 7) with
substitution in the ortho position affording lower selectivities
(5). Importantly, the use of NBu4Cl can restore selectivity to
achieve moderate levels of asymmetric induction for this more
challenging substitution pattern, albeit with diminished yield.
Both electron-rich (6) and electron-poor (8) substrates
engage smoothly in intramolecular coupling, with the selectivity
for electron-poor substrates benefiting from the use of NBu4Cl.
Notably, substitution on the allyl boronate moiety is well
tolerated, and 9 is produced in good yield with moderate
With the optimal conditions in hand, the scope of the
intramolecular allyl−aryl coupling was examined (Scheme 2).
Compared to unsubstituted substrate 3, meta-substituted
B
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Organic Letters
Letter
enantioselectivity. Changing the tether length between the aryl
electrophile and the allyl boronate allows efficient formation of
six- and seven-membered rings (10 and 11) in moderate yield
with moderate levels of enantioselectivity.
Seeking a more complete understanding of the origins of
stereoinduction in the reaction, it was reasoned that selectivity
could be imparted during olefin binding (formation of A),
transmetalation (A → D, Scheme 3), or reductive elimination (B,
followed the intermolecular precedent established by Miyaura,6
it was reasoned that changing the geometry of the allyl boronate
moiety would have a significant impact on the stereochemical
outcome of the coupling reaction. However, employing the Z-
allyl boronate under the standard reaction conditions produces
the same enantiomer of product that is observed when the E-allyl
boronate is used and with nearly identical levels of selectivity
(Scheme 4, eq 1 vs 2). Moreover, the use of substrates with
inverse polarity coupling partners also resulted in formation of
the same enantiomer of product (eqs 3 and 4). Since the
likelihood of achieving similar levels of selectivity during
transmetalation of vastly different species is low, it seems
plausible that allyl equilibration14 of the transmetalation adducts
results in stereochemical convergence to a common palladacycle
intermediate, followed by stereochemistry-determining reduc-
tive elimination to give the observed carbocycle.
Scheme 3. Proposed Catalytic Cycle
This mechanistic proposal in Scheme 3 accounts for many of
the observations noted earlier. In order to have the opportunity
to correct for a nonselective transmetalation that gives both B
and C, the rate of this isomerization must be rapid relative to
reductive elimination. Consequently, any features of the reaction
system which either expedite reductive elimination or slow
isomerization, may ultimately result in decreased enantioselec-
tivity. For instance, in line with experiments by Trost,12 the
beneficial influence of NBu4Cl can be attributed to stabilization
of 14 electron η1 allyl intermediates, which are required for
stereoinvertive isomerization. Similarly, the detrimental effects of
bidentate ligands could arise from accelerated reductive
elimination and the suppression of isomerization by disfavoring
η-bound Pd(II) intermediates required for isomerization.15
While these high energy 18-electron intermediates appear to
be accessible in intermolecular systems3b,c,e,f and with the use of
nickel,16 in the current Pd-catalyzed intramolecular case this
could be problematic.17
C, D → product). Miyaura and co-workers found that during the
related enantioselective intermolecular allyl−aryl coupling,
transmetalation was the stereochemistry determining step.6b
Thus, after oxidative addition with an aryl halide, the Josiphos-
based catalyst effectively selected one of the prochiral faces of the
crotyl boronate during SE2′ transmetalation, thereby establishing
a palladium−carbon bond in an enantioselective fashion. For the
Miyaura system, in order to suppress competing allyl isomer-
ization, a subsequent rapid reductive elimination of the product
was found to be essential to achieve high regio- and
enantioselectivity.
To test whether the intramolecular reaction occurs with a
similar mode of selectivity to the intermolecular variant, a series
of substrates were prepared in which the nucleophile and
electrophile components were altered (Scheme 4). If the
stereochemistry-determining step of the intramolecular coupling
In conclusion, we have described a catalytic strategy for the
stereoselective construction of carbocycles by intramolecular
allyl aryl cross-couplings. Further exploration of the scope and
applications of this process is in progress and will be reported in
due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 4. Examination of Alternate Substrate
a
Configurations
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 acknowledged.
We thank AllyChem for a donation of B2(pin)2; C.H.S. and
Z.A.K. are grateful for LaMattina Graduate Fellowship and
Kozarich Fellowships, respectively.
REFERENCES
■
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a
1
Yields determined by H NMR versus internal standard.
C
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Letter
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dx.doi.org/10.1021/ol5019163 | Org. Lett. XXXX, XXX, XXX−XXX