Orthogonal reactivity in boryl-substituted organotrifluoroborates

Article abstract of DOI:10.1021/ja807076d

A method was developed for the hydroboration of alkenyl-containing organotrifluoroborates to generate dibora intermediates. The reactivity differences between organotrifluoroborates and trialkylboranes facilitated the cross-coupling of the borane moiety o

Full text of DOI:10.1021/ja807076d

Published on Web 11/04/2008
Orthogonal Reactivity in Boryl-Substituted Organotrifluoroborates
Gary A. Molander* and Deidre L. Sandrock
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania, 231 South 34th Street,
Philadelphia, PennsylVania 19104-6323
Received September 12, 2008; E-mail: gmolandr@sas.upenn.edu
Table 1. Hydroboration and Suzuki-Miyaura Cross-Coupling of
Several different strategies utilizing two orthogonally reactive
boron species have been used to increase complexity and diversity
in organic substructures. Although assorted dibora-substituted
organic molecules have been described and utilized in this context,1
for the most part this approach suffers from a few significant
limitations. For example, the two boron species are often function-
ally identical and both are chemically processed in the same way.2
In other cases, the ultimate fate of the two organoborons takes
advantage of inherent reactivity differences related to the reactive
substituent on boron.3 Lastly, the two boron species may be
symmetrically reactive, and reaction at one center leaves an
organoboron that is unreactive under similar conditions.4
There are a few examples detailing the cross-coupling of
electrophilic partners containing protected versions of boronic
acids,5 but to date a single example can be found that generates a
dibora compound and sequentially cross-couples the organoborons
with selectivity based solely on the nature of the nonparticipating
boron substituents.6
Alkenyl-Containing Potassium Organotrifluoroboratesa
Herein we report the development of dibora-substituted linch-
pins allowing bidirectional syntheses of diverse organic substruc-
tures. Although cross-couplings of organotrifluoroborates with
aryldiazoniums and diaryliodoniums can be carried out under
anhydrous conditions,7 other electrophilic partners (e.g., halides,
triflates) require aqueous or protic conditions.8 Owing to the
reactivity of trialkylboranes in the absence of water, we explored
their formation and selective cross-coupling in the presence of
organotrifluoroborates.
The hydroboration of alkenyl-containing organotrifluorobo-
rates with 9-BBN generates intermediate dibora species. These
linchpins undergo selective cross-coupling at the trialkylborane,
providing pure, elaborated trifluoroborates. Subsequently, a further
increase in molecular complexity can be achieved by cross-coupling
the organotrifluoroborate.
Using 4-bromobenzonitrile as a model electrophile with potas-
sium 4-(but-3-enyl)phenyltrifluoroborate, a brief screening of the
cross-coupling step was carried out.11 Use of 2 mol % Pd(OAc)2,
3 mol % DavePhos,12 and KF (3 equiv), with stirring overnight at
rt, afforded the highest conversion and isolated yield (79%) of the
corresponding cross-coupled product (Table 1, entry 1).
With conditions in hand, various alkenyl-containing aryl-
trifluoroborate substrates were hydroborated and selectively cross-
coupled (Table 1, entries 1-8 and 14). Aryl bromides, chlorides,
iodides, and triflates were found to cross-couple with complete
selectivity at the borane moiety of the dibora intermediate, in each
case providing the elaborated potassium aryltrifluoroborate product
in good yields. The reaction also proved to be scalable to 5 mmol
(Table 1, entry 8).
a General conditions: RBF3K (1.0 equiv), 9-BBN (1.0 equiv) and
THF (0.25 M) then Pd(OAc)2 (2 mol %), DavePhos (3 mol %), aryl
electrophile (1.0 equiv), and KF (3 equiv), rt, overnight. b Reaction
scaled to 5 mmol.
pattern associated with tricoordinate alkenylborons. The resulting
dibora species represents a 1,2-dianion equivalent that is markedly
distinct from the 1,1-dibora intermediates traditionally formed when
tricoordinate alkenylborons undergo hydroboration.13
Alkenyl-containing alkyltrifluoroborates were found to be suit-
able substrates in the reaction sequence (Table 1, entries 12-13).
The limited solubility of potassium alkoxymethyltrifluoroborates14
in THF (Table 1, entry 13) required more dilute reaction conditions
and a significantly longer reaction time for the hydroboration step
to occur.
With the ultimate goal of bidirectional functionalization, we
turned our attention to a one-pot hydroboration/bidirectional cross-
coupling sequence (Table 2). After subjecting the substrates to the
first hydroboration/cross-coupling sequence, reaction with a second
electrophile under conditions previously optimized for aryltrifluor-
oborates (entries 1-3),15 N,N-dialkylaminomethyltrifluoroborates
(entry 4),16 and alkoxymethyltrifluoroborates (entry 5)14 generated
the desired products.
The reaction of potassium vinyltrifluoroborate also proceeded
smoothly in the sequence, cleanly generating the cross-coupled
product (Table 1, entries 9-11). Of particular note is the regiose-
lectivity of the initial hydroboration step, creating a reversal in the
We then investigated the cross-coupling of trialkylborane reagents
with electrophiles containing the organotrifluoroborate moiety.
9
15792 J. AM. CHEM. SOC. 2008, 130, 15792–15793
10.1021/ja807076d CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. One-Pot Hydroboration and Bidirectional Suzuki-Miyaura
Cross-Coupling of Alkenyl-Containing Organotrifluoroboratesa
Taking into consideration the reactivity differences between
organotrifluoroborates and trialkylboranes, a method was devel-
oped to hydroborate alkenyl-containing organotrifluoroborates.
Conditions were found for reaction of the borane moiety of these
dibora-intermediates in a highly chemoselective fashion, leaving
the trifluoroborate intact for subsequent transformation. The stability
of the trifluoroborate moiety to these metal catalyzed reactions
allows simple and efficient strategies for multicomponent complex
molecule construction.
Acknowledgment. The authors thank the NIH (General Medical
Sciences) and Merck Research Laboratories for their generous
support of our program. We acknowledge Johnson Matthey for their
donation of palladium catalysts and Frontier Scientific for their
donation of boronic acids. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
Supporting Information Available: Experimental procedures,
compound characterization data, and NMR spectral data of all
compounds synthesized. This material is available free of charge via
the Internet at http://pubs.acs.org.
a General conditions: RBF3K (1.0 equiv), 9-BBN (1.0 equiv) and
THF (0.25 M) then Pd(OAc)2 (2 mol %), DavePhos (3 mol %), aryl
electrophile (1.0 equiv), and KF (3 equiv), rt, overnight. b RBF3K
coupling: Pd(OAc)2 (0.5 mol %), electrophile (1.0 equiv), K2CO3 (3
equiv) and MeOH (0.125 M), 65 °C, 2 h. c RBF3K coupling: Pd(OAc)2
(3 mol %), XPhos9 (6 mol %), electrophile (1.0 equiv), Cs2CO3 (3
equiv) and 10:1 THF/H2O (0.25 M), 80 °C, 24 h. d RBF3K coupling:
Pd(OAc)2 (3 mol %), RuPhos10 (6 mol %), electrophile (1.0 equiv),
Cs2CO3 (3 equiv) and 10:1 dioxane/H2O (0.25 M), 100 °C, 24 h.
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a General conditions: 9-BBN (1.1 equiv), allylbenzene (1.1 equiv),
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provided the fully elaborated product in excellent yield (eq 1).
JA807076D
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