Stereospecific cross-coupling of secondary alkyl β- trifluoroboratoamides

Article abstract of DOI:10.1021/ja108949w

The stereospecific cross-coupling of enantioenriched 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.

Full text of DOI:10.1021/ja108949w

Published on Web 11/15/2010
Stereospecific Cross-Coupling of Secondary Alkyl ꢀ-Trifluoroboratoamides
Deidre L. Sandrock,†,§ Ludivine Jean-Ge´rard,†,§ 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: gmolandr@sas.upenn.edu
Table 1. Cross-Coupling of ꢀ-Trifluoroboratoamides with Aryl
Halidesa
Abstract: The stereospecific cross-coupling of enantioenriched
nonbenzylic secondary alkyl boron compounds has been achieved.
The high selectivity toward product formation over an undesired
ꢀ-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 ꢀ-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
ꢀ-trifluoroborato carbonyls9 to the preparation and cross-coupling
of acyclic secondary ꢀ-trifluoroboratoamides. Using the borylation
strategy outlined by Yun and co-workers, a variety of these
trifluoroborates were prepared.9a,10 With the desired substrates in
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
a General conditions: Pd(OAc)2 (10 mol %), XPhos8a (20 mol %),
RBF3K (1 equiv), K2CO3 (3 equiv), and 6.7:1 CPME/H2O (0.25 M).
b Reactions perform better with SPhos8b (20 mol %) and Cs2CO3 (3
equiv).
cyclopentyl methyl ether (CPME)/H2O solvent system giving the
highest isolated yield of potassium N-cyclohexyl-3-(trifluoro-
borato)butanamide in the coupling reaction with 2-chloroanisole
(Table 1, entry 1).
† University of Pennsylvania.
‡ Merck Research Laboratories.
§ These authors contributed equally.
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17108 J. AM. CHEM. SOC. 2010, 132, 17108–17110
10.1021/ja108949w  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Preparation and Cross-Coupling of Enantioenriched
ꢀ-Trifluoroboratoamide
Encouraged by this initial result, we proceeded with further
screening, which revealed that the combination of 10 mol % of
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 ꢀ-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,
entries 1-7), again observing little or none of the undesired
byproducts.
step. The absolute configurations of the major enantiomers of the
borylated starting material and cross-coupled products were deter-
mined to be R and S, respectively, by comparison with the authentic
S isomers prepared from derivatization of commercially available
(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 ꢀ-hydride elimination) represents an important exten-
sion to the previously described methods for the cross-coupling of
secondary organometallics.
Table 2. Cross-Coupling of Various Trifluoroborates with Aryl
Halidesa
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 ꢀ-tri-
fluoroboratoketones nor -esters afford the desired coupled products.
Although other factors could conceivably be involved, the unique
reactivity of ꢀ-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,
inhibiting a syn-coplanar arrangement of the palladium and the
acidic hydrogens alpha to the carbonyl required for ꢀ-hydride
elimination.12 (3) More importantly, the carbonyl interaction with
the coordinatively unsaturated palladium could inhibit the metal
from interacting agostically with the ꢀ-hydrogens, a feature required
for ꢀ-H elimination (Scheme 2). These characteristics result in the
formulation of a new paradigm for successful secondary alkyl cross-
coupling with potentially wide implications.
a General conditions: Pd(OAc)2 (10 mol %), ligand (20 mol %),
RBF3K (1 equiv), base (3 equiv), and 6.7:1 CPME/H2O (0.25 M).
With the ultimate goal of developing conditions to generate
optically active materials through the use of an appropriate
organoboron reagent, we prepared an enantioenriched ꢀ-trifluoro-
boratoamide via an asymmetric ꢀ-borylation reaction of the
corresponding R,ꢀ-unsaturated amide using bis(pinacolato)diboron
and (R)-(S)-Josiphos as the chiral ligand (Scheme 1).11
With the enantioenriched secondary organotrifluoroborate in
hand, we subjected it to the optimized reaction conditions for the
cross-coupling of this family of substrates. Using 10 mol % of
Pd(OAc)2, 20 mol % of XPhos, and 3 equiv of K2CO3 in a CPME/
H2O solvent system, the cross-coupled product was obtained in an
enantiomeric ratio of 95:5 (S:R) in 82% yield for the cross-coupling
As in the Suginome study, the inversion of configuration
observed during the cross-coupling reaction with the ꢀ-trifluoro-
boratoamides is attributed to intramolecular coordination of the
carbonyl group to the boron. Chiral benzylstannanes,13 silanes,14
and R-(acylamino)benzylboronic esters7 have been shown to
undergo transmetalation with inversion of configuration, presumably
through an SE2 mechanism via an open transition state, a process
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C O M M U N I C A T I O N S
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. (c) Nagano, T.; Hayashi,
T. Org. Lett. 2004, 6, 1297. (d) Bedford, R. B.; Bruce, D. W.; Frost, R. M.;
Goodby, J. W.; Hird, M. Chem. Commun. 2004, 2822. (e) Bedford, R. B.;
Bruce, D. W.; Frost, R. M.; Hird, M. Chem. Commun. 2005, 4161. (f)
Bedford, R. B.; Betham, M.; Bruce, D. W.; Danopoulos, A. A.; Frost, R. M.;
Hird, M. J. Org. Chem. 2006, 71, 1104. (g) Ohmiya, H.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886. (h) Bica, K.; Gaertner, P.
Org. Lett. 2006, 8, 733. (i) Bedford, R. B.; Betham, M.; Bruce, D. W.;
Davis, S. A.; Frost, R. M.; Hird, M. Chem. Commun. 2006, 1398. (j)
Chowdhury, R. R.; Crane, A. K.; Fowler, C.; Kwong, P.; Kozak, C. M.
Chem. Commun. 2008, 94. Suzuki coupling: (k) Brenstrum, T.; Gerristma,
D. A.; Adjabeng, G. M.; Frampton, C. S.; Britten, J.; Robertson, A. J.;
McNulty, J.; Capretta, A. J. Org. Chem. 2004, 69–7635. (l) Gonzalez-
Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360. Stille coupling: (m)
Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510.
Negishi coupling: (n) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E.
Synlett 2005, 1794. Hiyama coupling: (o) Strotman, N. A.; Sommer, S.;
Fu, G. C. Angew. Chem., Int. Ed. 2007, 46, 3556.
that is favored in polar solvents. More closely related to the current
studies, examples of SE2-type reactions that proceed with inversion
of configuration in borate substrates have been reported previously
as well.15
Scheme 2. Proposed Mechanism for Complete Stereochemical
Inversion
(3) (a) Boudier, A.; Knochel, P. Tetrahedron Lett. 1999, 40, 687. (b) Vyvyan,
J. R.; Loitz, C.; Looper, R. E.; Mattingly, C. S.; Peterson, E. A.; Staben,
S. T. J. Org. Chem. 2004, 69, 2461. (c) Luo, X.; Zhang, H.; Duan, H.;
Liu, Q.; Shu, L.; Zhang, T.; Lei, A. Org. Lett. 2007, 9, 4571. (d) Miyaura,
N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am.
Chem. Soc. 1989, 111, 314. (e) Littke, A. F.; Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2000, 122, 4020. (f) Kataoka, N.; Shelby, Q.; Stambuli, J. P.;
Hartwig, J. F. J. Org. Chem. 2002, 67, 5553. (g) Hayashi, T. J. Organomet.
Chem. 2002, 653, 41. (h) Cahiez, G.; Marquais, S. Tetrahedron Lett. 1996,
37, 1773. (i) Nakao, Y.; Takeda, M.; Matsumoto, T.; Hiyama, T. Angew.
Chem., Int. Ed. 2010, 49, 4447.
In conclusion, the concept of using pendant ligands to serve as
hemilabile ligands16 to enhance transmetalation and inhibit the
ꢀ-hydride elimination pathway in the cross-coupling of secondary
organometallic species is highlighted. Additionally, the first cross-
coupling of a nonbenzylic, enantioenriched secondary alkyl organo-
metallic containing ꢀ-hydrogens that proceeds with complete
inversion of configuration without any loss of enantioselectivity
during the cross-coupling event has been reported.
(4) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257.
(5) (a) van den Hoogenband, A.; Lange, J. H. M.; Terpstra, J. W.; Koch, M.;
Visser, G. M.; Visser, M.; Korstanje, T. J.; Jastrzebski, J. T. B. H.
Tetrahedron Lett. 2009, 49, 4122. (b) Ohmura, T.; Awano, T.; Suginome,
M. Chem. Lett. 2009, 38, 664. (c) Endo, K.; Ohkubo, T.; Hirokami, M.;
Shibata, T. J. Am. Chem. Soc. 2010, 132, 11033. (d) Imao, D.; Glasspoole,
B. W.; Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024.
(6) (a) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461. (b) Ridgway,
B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458.
(7) Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191.
(8) (a) XPhos (2-dicyclohexylphosphino-2′,4′,6′-diisopropyl-1,1′-biphenyl). (b)
SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl).
(9) (a) Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795. (b) Molander,
G. A.; Jean-Ge´rard, L. J. Org. Chem. 2009, 74, 1297. (c) Molander, G. A.;
Jean-Ge´rard, L. J. Org. Chem. 2009, 74, 5446.
(10) (a) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887. See also: (b)
Bonet, A.; Gulya´s, H.; Koshevoy, I. O.; Estevan, F.; Sanau´, Ubeda, M. A.;
Ferna´ndez, E. Chem.sEur. J. 2010, 16, 6382. (c) Smith, S. M.; Takacs,
J. M. J. Am. Chem. Soc. 2010, 132, 1740.
(11) Chea, H.; Sim, H.-S.; Yun, J. AdV. Synth. Catal. 2009, 351, 855.
(12) Spessard, G. O.; Miessler, G. L. Organometallic Chemistry; Prentice Hall:
Upper Saddle River, NJ, 1997.
Acknowledgment. G.A.M. thanks the NIH General Medical
Sciences (GM035249) and the NSF GOALI program (CHE-
0848460) for their generous support of this research. Dr. Rakesh
Kohli (University of Pennsylvania) is acknowledged for obtaining
HRMS data. BASF is acknowledged for their generous donation
bis(pinacolato)diboron, and Solvias for the donation of (R)-(S)-
JosiPhos. Petr Valenta, Jason Melvin, and Genette McGrew
(University of Pennsylvania) are acknowledged for their assistance
in HPLC and SFC analysis.
Supporting Information Available: Experimental details and
spectral data of all compounds synthesized. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) (a) Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129. (b)
Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666.
(14) Hatanaka, Y.; Hiyama, T. J. Am. Chem. Soc. 1990, 112, 7793.
(15) (a) Bergbreiter, D. E.; Rainville, D. P. J. Organomet. Chem. 1976, 121,
19. (b) Kabalka, G. W.; Gooch, E. E., III. J. Org. Chem. 1980, 45, 3578.
(16) (a) Giovannini, R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew. Chem.,
Int. Ed. 1998, 37, 2387. (b) Johnson, J. B.; Rovis, T. Angew. Chem., Int.
Ed. 2008, 47, 840. (c) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.;
Zhang, T.; Lei, A. Org. Lett. 2007, 9, 4571.
References
(1) For reviews on potassium organotrifluoroborates, see: (a) Darses, S.; Geneˆt,
J.-P. Eur. J. Org. Chem. 2003, 4313. (b) Molander, G. A.; Figueroa, R.
Aldrichimica Acta 2005, 38, 49. (c) Molander, G. A.; Ellis, N. Acc. Chem.
Res. 2007, 40, 275. (d) Stefani, H. A.; Cella, R.; Adriano, S. Tetrahedron
2007, 63, 3623. (e) Darses, S.; Geneˆt, J.-P. Chem. ReV. 2008, 108, 288. (f)
Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240.
(2) Kumada coupling: (a) Tamao, K.; Kiso, Y.; Sumitani, K.; Kumada, M.
J. Am. Chem. Soc. 1972, 94, 9268. (b) Nakamura, N.; Matsuo, K.; Ito, S.;
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