Published on Web 11/15/2010

Stereospecific Cross-Coupling of Secondary Alkyl β-Trifluoroboratoamides

Deidre L. Sandrock,†,§ Ludivine Jean-Gérard,†,§ Cheng-yi Chen,‡ Spencer D. Dreher,‡ and
Gary A. Molander*,†
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of
Chemistry, UniVersity of PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323, United States,
and Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway,
New Jersey 07065, United States
Received October 4, 2010; E-mail: [email protected]

Table 1. Cross-Coupling of β-Trifluoroboratoamides with Aryl

Abstract: The stereospecific cross-coupling of enantioenriched Halidesa
nonbenzylic secondary alkyl boron compounds has been achieved.
The high selectivity toward product formation over an undesired
β-H elimination pathway is achieved via an intramolecular
coordination of an ancillary carbonyl to the metal center in the
diorganopalladium intermediate.

The Suzuki-Miyaura cross-coupling reaction has emerged as

one of the most versatile transformations available for the generation
of C-C bonds.1 Although there are many strategies that exist for
the cross-coupling of sp2-hybridized organometallics,2 the protocols
for the cross-coupling of secondary and potentially enantiomerically
enriched sp3-hybridized organometallics have limited precedent.3
In a previous communication, we described a development toward
this goal by identifying catalytic reaction conditions for the cross-
coupling of cyclic, symmetrical secondary alkyltrifluoroborates with
aryl electrophiles.4 However, when applied to symmetrical acyclic
substrates, it became evident that the use of our optimized conditions
still led to a β-H elimination/isomerization pathway that resulted
in mixtures of the desired cross-coupled products as well as the
undesired isomerized primary alkylated products.
More recently, other attempts at secondary cross-coupling using
various organoboron derivatives have appeared.5 Crudden and co-
workers developed a protocol for the preparation of enantioenriched
styrene-derived secondary boronate esters and demonstrated their
cross-coupling with a variety of aryl iodides.5 Although the reactions
proceed in good yields with retention of configuration,6 this method
was limited to the cross-coupling of benzylic boron derivatives.
During the course of this investigation, Suginome reported the
cross-coupling of R-(acylamino)benzylboronates with aryl bromides
and chlorides, which somewhat surprisingly occurred with overall
inVersion of configuration.7
Herein we report our most recent efforts toward the ultimate
goal of cross-coupling nonbenzylic, enantioenriched secondary alkyl
organoboron reagents with stereochemical fidelity during the cross-
coupling event. Subsequent to our studies on secondary alkyltri-
fluoroborates, efforts were conducted to extend the study of
β-trifluoroborato carbonyls9 to the preparation and cross-coupling
of acyclic secondary β-trifluoroboratoamides. Using the borylation a
General conditions: Pd(OAc)2 (10 mol %), XPhos8a (20 mol %),
strategy outlined by Yun and co-workers, a variety of these RBF3K (1 equiv), K2CO3 (3 equiv), and 6.7:1 CPME/H2O (0.25 M).
b
trifluoroborates were prepared.9a,10 With the desired substrates in Reactions perform better with SPhos8b (20 mol %) and Cs2CO3 (3
equiv).
hand, an initial screen of catalytic conditions led to the combination
of 10 mol % of Pd(OAc)2 and 20 mol % of XPhos, K2CO3 in a
cyclopentyl methyl ether (CPME)/H2O solvent system giving the
highest isolated yield of potassium N-cyclohexyl-3-(trifluoro-
†
University of Pennsylvania. borato)butanamide in the coupling reaction with 2-chloroanisole
‡
Merck Research Laboratories.
§
These authors contributed equally. (Table 1, entry 1).
17108 9 J. AM. CHEM. SOC. 2010, 132, 17108–17110 10.1021/ja108949w  2010 American Chemical Society
 COMMUNICATIONS
Encouraged by this initial result, we proceeded with further Scheme 1. Preparation and Cross-Coupling of Enantioenriched
screening, which revealed that the combination of 10 mol % of β-Trifluoroboratoamide
XPhos or SPhos with Cs2CO3 (3 equiv) also provided good to
excellent yields of the cross-coupled products with both aryl
chlorides and bromides.
Using 10 mol % of Pd(OAc)2 and 20 mol % of XPhos, a variety
of electrophilic partners (including those containing ketone, alde-
hyde, ester, nitrile, and nitro groups) cross-coupled with the model
trifluoroborate in good yields. In a number of cases, the use of
SPhos as the ligand actually provided higher yields of the cross-
coupled product (Table 1, entries 6, 7, 11-13). In all of these
examples, <2% of products resulting from β-H elimination or
isomerization were isolated.
To investigate the scope of this reaction with respect to the
nucleophilic partner, all three sets of suitable catalytic conditions
were applied to a variety of amide substrates, in each case
generating the cross-coupled products in good yields (Table 2, step. The absolute configurations of the major enantiomers of the
entries 1-7), again observing little or none of the undesired borylated starting material and cross-coupled products were deter-
byproducts. mined to be R and S, respectively, by comparison with the authentic
S isomers prepared from derivatization of commercially available
Table 2. Cross-Coupling of Various Trifluoroborates with Aryl
Halidesa
(S)-3-hydroxybutyric acid and (S)-3-phenylbutyric acid. This com-
plete inVersion in stereochemistry during transmetalation for
secondary alkyl boron compounds (in substrates that have the
potential for β-hydride elimination) represents an important exten-
sion to the previously described methods for the cross-coupling of
secondary organometallics.
Subsequent cross-couplings with the enantioenriched cyclohexyl
amide derivative with aryl chlorides also revealed the same
inversion of configuration with no discernible stereochemical
erosion detected (eq 1). Interestingly, neither the analogous β-tri-
fluoroboratoketones nor -esters afford the desired coupled products.

Although other factors could conceivably be involved, the unique

reactivity of β-trifluoroboratoamides supports an hypothesis in
which the ancillary carbonyl oxygen plays a role in coordinating
with the intermediate diorganopalladium complex. Three beneficial
features would derive from this interaction: (1) The coordination
could facilitate the transmetalation process, as the conditions
optimized for this transformation were not optimal for the cross-
coupling of unfunctionalized secondary alkyltrifluoroborates de-
scribed in our previous communication.4 (2) The complexation may
also restrict the conformation of the diorganopalladium intermediate,
a
General conditions: Pd(OAc)2 (10 mol %), ligand (20 mol %), inhibiting a syn-coplanar arrangement of the palladium and the
RBF3K (1 equiv), base (3 equiv), and 6.7:1 CPME/H2O (0.25 M). acidic hydrogens alpha to the carbonyl required for β-hydride
elimination.12 (3) More importantly, the carbonyl interaction with
With the ultimate goal of developing conditions to generate the coordinatively unsaturated palladium could inhibit the metal
optically active materials through the use of an appropriate from interacting agostically with the β-hydrogens, a feature required
organoboron reagent, we prepared an enantioenriched β-trifluoro- for β-H elimination (Scheme 2). These characteristics result in the
boratoamide via an asymmetric β-borylation reaction of the formulation of a new paradigm for successful secondary alkyl cross-
corresponding R,β-unsaturated amide using bis(pinacolato)diboron coupling with potentially wide implications.
and (R)-(S)-Josiphos as the chiral ligand (Scheme 1).11 As in the Suginome study, the inversion of configuration
With the enantioenriched secondary organotrifluoroborate in observed during the cross-coupling reaction with the β-trifluoro-
hand, we subjected it to the optimized reaction conditions for the boratoamides is attributed to intramolecular coordination of the
cross-coupling of this family of substrates. Using 10 mol % of carbonyl group to the boron. Chiral benzylstannanes,13 silanes,14
Pd(OAc)2, 20 mol % of XPhos, and 3 equiv of K2CO3 in a CPME/ and R-(acylamino)benzylboronic esters7 have been shown to
H2O solvent system, the cross-coupled product was obtained in an undergo transmetalation with inversion of configuration, presumably
enantiomeric ratio of 95:5 (S:R) in 82% yield for the cross-coupling through an SE2 mechanism via an open transition state, a process
J. AM. CHEM. SOC. 9 VOL. 132, NO. 48, 2010 17109
COMMUNICATIONS

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