Single-Electron Transmetalation: Protecting-Group-Independent Synthesis of Secondary Benzylic Alcohol Derivatives via Photoredox/Nickel Dual Catalysis

Article abstract of DOI:10.1021/acs.orglett.6b00911

Protecting-group-independent cross-coupling of α-alkoxyalkyl- and α-acyloxyalkyltrifluoroborates with aryl and heteroaryl bromides is achieved through application of photoredox/nickel dual catalysis. Reactions occur under exceptionally mild conditions, with outstanding functional group compatibility and excellent observed tolerance of heteroarenes. This method offers expedient access to protected secondary benzylic alcohol motifs bearing benzyl, pivaloyl, and N,N-diisopropylcarbamoyl protecting groups.

Full text of DOI:10.1021/acs.orglett.6b00911

Letter
pubs.acs.org/OrgLett
Single-Electron Transmetalation: Protecting-Group-Independent
Synthesis of Secondary Benzylic Alcohol Derivatives via Photoredox/
Nickel Dual Catalysis
Rahman Karimi-Nami,†,‡ John C. Tellis,† and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
‡School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, 14174 Tehran, Iran
S
* Supporting Information
ABSTRACT: Protecting-group-independent cross-coupling
of α-alkoxyalkyl- and α-acyloxyalkyltrifluoroborates with aryl
and heteroaryl bromides is achieved through application of
photoredox/nickel dual catalysis. Reactions occur under
exceptionally mild conditions, with outstanding functional
group compatibility and excellent observed tolerance of
heteroarenes. This method offers expedient access to protected
secondary benzylic alcohol motifs bearing benzyl, pivaloyl, and
N,N-diisopropylcarbamoyl protecting groups.
he prominence of the secondary benzylic alcohol motif is
clearly evident from its presence in biologically active
T
compounds, both naturally and synthetically derived, and its
utility as an intermediate in organic synthesis. Although
accessible through a variety of retrosynthetic disconnections
(most notably nucleophilic addition of organometallic reagents
to aldehydes1 and reduction of aryl−alkyl ketones2), few
methods permit direct synthesis of a protected secondary
benzylic alcohol without the intermediacy of an unprotected
derivative. In cases where protection is required for subsequent
manipulations, installation of the protecting group before
assembly of the benzylic alcohol motif is more convergent than
installation of the protecting group after fragment coupling.
Furthermore, the “protected” (or otherwise alkylated, acylated,
silylated, etc.) form may be desired for purposes of bioactivity
and/or pharmacokinetic/pharmacodynamic properties or utility
in subsequent reactions as a reactive functional group. Finally, the
intermediacy of an unprotected benzylic alcohol can be
problematic in cases wherein this intermediate would be prone
to oxidation or other decomposition pathways.
Transition-metal-catalyzed cross-coupling of an α-alkoxyal-
kylmetallic reagent with an aryl halide represents an attractive
manifold for the direct synthesis of protected secondary benzylic
alcohol derivatives because of the commercial availability of
structurally and electronically diverse aryl halides and the general
modularity of cross-coupling methods. This disconnection has
been realized through the efforts of Falck3 and Molander,4 who
have reported the cross-coupling of α-alkoxyalkyltin and -boron
nucleophiles, respectively, with aryl/alkenyl halides (see Figure
1). However, these methods are limited by moderate
demonstrated functional group tolerance and inflexibility of the
oxygen protecting group, wherein alkyltin reagents must bear a 4-
trifluoromethylbenzoyl group, and a benzyl protecting group is
Figure 1. (A) Previously reported methods for direct synthesis of
protected secondary benzylic alcohol derivatives via Pd catalysis. (B)
Present report: photoredox/nickel dual catalytic cross-coupling of α-
alkoxyalkyl- and α-acyloxyalkyltrifluoroborates with (hetero)aryl
bromides.
required for trifluoroborate cross-coupling due to the strongly
basic, high-temperature reaction conditions. These limitations
restrict the utility of the reported methods because neither offers
Received: March 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00911
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Letter
a general, protecting-group-independent approach to the
synthesis of protected secondary benzylic alcohol derivatives.
In view of the deficiencies of prior art, we sought to realize the
goal of a protecting-group-independent synthesis of secondary
benzylic alcohols through the application of photoredox/nickel
dual catalysis. This paradigm has recently proven advantageous
for the cross-coupling of various alkylboron and alkylsilicon
reagents under extraordinarily mild conditions and with
unprecedented levels of functional group tolerance.5−7 Although
previous studies confirmed the feasibility of cross-coupling α-
benzyloxyalkyltrifluoroborates,5a,8 it was unclear if the more
electronically deactivated α-acyloxyalkyl derivatives would be
reactive in this manifold.
Scheme 1. Photoredox/Nickel Dual Catalytic Cross-Coupling
of Various α-Alkoxyalkyl and α-Acyloxyalkyltrifluoroborates
with 3-Bromo-5-cyanopyridine
Consistent with previous studies, a catalytic system of
Ir[dFCF3ppy]2(bpy)PF6 1, Ni(COD)2, and dtbbpy proved
most active in promoting the desired reactivity. Use of Ni(II)
sources, such as NiCl2(dme) or Ni(NO3)2·6H2O, is also
possible, but a slight reduction in yield was typically observed
(∼5−20%) Although previous reactions of secondary α-
benzyloxyalkyltrifluoroborates were performed in acetone or
THF with 2,6-lutidine or 2,2,6,6-tetramethylpiperidine as
additives,5a,8 the use of dioxane as a solvent and 2 equiv of
K2HPO4 as an additive were found to be most broadly effective
for the cross-coupling of secondary α-alkoxyalkyltrifluoroborates
bearing benzyloxy, pivaloyl, and N,N-diisopropylcarbamoyl
protecting groups. Notably, although the synthesis of these
pivaloyl and N,N-diisopropylcarbamoyl-protected derivatives
were reported previously,4 the present report is the first
successful example of their cross-coupling. This success
effectively highlights the unique strengths of the photoredox/
nickel dual catalytic cross-coupling manifold relative to conven-
tional Pd catalysis, wherein the strongly basic conditions required
for cross-coupling resulted in decomposition of these hydrolyti-
cally unstable protecting groups. Contrasting the conditions
previously reported for the cross-coupling of α-benzyloxyalkyl-
trifluoroborates (105 °C, 5 equiv of CsOH·H2O) with the
conditions reported here for protecting-group-independent
cross-coupling (room temperature, 2 equiv of K2HPO4) only
further underscores these advantages.
These conditions were found to be widely effective for the
cross-coupling of sterically and electronically diverse secondary
α-alkoxyalkyl and α-acyloxyalkyltrifluoroborates, as summarized
in Scheme 1. Notably, these starting materials are easily
synthesized from commercially available aldehydes via a two-
step procedure involving borylation to afford the α-hydrox-
yalkyltrifluoroborate followed by straightforward, base-mediated
protection with the corresponding acyl halide or benzyl bromide.
We chose to examine the scope of alkyltrifluoroborate tolerance
with 3-bromo-5-cyanopyridine as a coupling partner in an effort
to highlight the exceptional tolerance of this method for the
cross-coupling of heteroaryl bromides. Substrates displaying
simple alkyl chains were readily cross-coupled in good to very
good yields as their benzyloxy (2), pivaloyl (3), and carbamoyl
(4) derivatives. α-Branched substrates were also well-tolerated
(5−7), including a sterically hindered α-tert-butyl substrate (9).
Trifluoroborates containing stereocenters could be cross-
coupled with moderate diastereoselection (6, 7, 10). Functional
groups including benzyl ethers (8) and tertiary carbamates (10)
were also well-tolerated.
Both electron-poor and electron-rich aryl bromides provided
products in good to excellent yields. Cross-coupling proceeded
smoothly in the presence of ortho substituents (20, 31).
A tremendous variety of potentially reactive functional groups
were also tolerated. Substrates bearing aldehydes (17), ketones
(18), esters (19), ethers (11, 15), nitriles (20), and
trifluoromethyl groups (13) generated products in good to
excellent yields. Secondary amides, including acetanilide (24)
and oxindole (23), were readily tolerated. Additional protic
nitrogen substituents and heterocycles including sulfonamide
(35), indole (31, 38), pyrazole (25), indazole (34), and
imidazole (38) were cross-coupled readily. Other tolerated
heterocycles include pyridine (30), azaindole (33), thiophene
(35), benzofuran (36), and benzothiophene (37) systems.
Consistent with previous observations, selective cross-coupling
at the aryl bromide site occurred in the reaction of 4-chloro-1-
bromobenzene. Futhermore, the pinacol ester of 4-bromophe-
nylboronic acid smoothly afforded arylboronate product (29),
thereby permitting potentially powerful sequential cross-
coupling sequences with either nucleophilic or electrophilic
partners.8
Most importantly, tolerance was observed for unprotected
primary alcohols, secondary alcohols, and phenols. In this regard,
an aryl bromide linked to a fully unprotected glycoside was cross-
coupled in 68% yield to afford product 27. In these examples,
introduction of the benzylic alcohol in protected form would
avoid any difficulties associated with selective downstream
protection/deprotection in the context of target-oriented
syntheses. Furthermore, the protecting group flexibility offered
by these unified conditions permits strategic selection of the
desired benzylic alcohol protecting group.
We next turned our attention to examining the reaction scope
with regard to the (hetero)aryl bromide partner (Scheme 2).
Here, functional group tolerance far surpasses previous efforts in
the cross-coupling of secondary α-alkoxyalkylmetallic reagents.
Although the presently reported method proved to be highly
amenable to the coupling of electronically and sterically diverse
substrates and also tolerant of a wide variety of functional groups,
several limitations remain. Most notably, α-alkoxyalkyl and α-
B
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Letter
Scheme 2. Photoredox/Nickel Dual Catalytic Cross-Coupling of Benzyloxyalkyltrifluoroborates with Various (Hetero)aryl
Bromides
acyloxyalkyltrifluoroborates derived from benzaldehyde tended
to cross-couple in unsatisfactory yields. We surmise that this may
be a consequence of the enhanced stability of the resultant
radicals, which are resonance stabilized by both donation of the
oxygen lone pair and delocalization throughout the aryl π-
system. These radicals may be less likely to react with the Ni
catalyst or may dissociate more readily from the Ni(III) species,
potentially resulting in homocoupling and disruption of the
catalytic cycle.5c Furthermore, electron-rich aryl bromides
coupled more effectively with α-benzyloxyalkyltrifluoroborates
than α-acyloxyalkyltrifluoroborates, with the latter requiring
extended reaction times to achieve moderate yields. Consistent
with our previous studies, tertiary amines and nitro groups are
not tolerated, and brominated five-membered N-heterocycles
(pyrrole, pyrazole, imidazole, oxazole, etc.) were unreactive
under the reported conditions.
Scheme 3. Elaboration of Reaction Products via (A)
Lithiation/α-Transfer of Benzylic Carbamates and (B) Ni-
Catalyzed Cross-Coupling of Benzylic Pivalates
An important advantage of the method reported herein is its
ability to access synthetically valuable benzylic carbamates and
pivalates directly in a convergent fashion and with excellent
modularity with regard to the steric, electronic, and functional
group demands of the requisite fragments. Aggarwal has
demonstrated that secondary benzylic carbamates can be
converted to tertiary organoboron compounds through a
lithiation/α-transfer sequence.9 These tertiary alkylboron
compounds can be further functionalized to generate, for
example, tertiary alcohols, tertiary amines, or quaternary carbon
centers.10 Furthermore, Ni catalysts have been observed to
engage secondary benzylic pivalates as electrophiles in cross-
coupling reactions with arylboron reagents.11 In view of this
capability, it is possible to consider α-pivaloyloxyalkyltrifluor-
oborates as formal carbene equivalents because they can be
selectively diarylated by sequential reactions with an electrophilic
partner and a nucleophilic partner (Scheme 3). From a strategic
standpoint, this sequence would represent a conceptually novel
approach to the synthesis of 1,1-diarylalkanes.
and α-acyloxyalkyltrifluoroborates with aryl and heteroaryl
bromides. This method affords protected benzylic alcohol
derivatives through a convergent pathway and typically in good
to excellent yields with exceptional functional group tolerance.
The reported protocol represents a significant advance in the
cross-coupling of α-alkoxyalkyl anion synthons and enables the
rapid synthesis of a ubiquitous class of compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00911.
Experimental procedures, compound characterization
data, and NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
In summary, we have reported a general procedure for the
protecting-group-independent cross-coupling of α-alkoxyalkyl-
*E-mail: gmolandr@sas.upenn.edu.
C
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Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIH (NIGMS RO1 GM113878) for funding this
research. Dr. Javad Amani (University of Pennsylvania) is
acknowledged for assistance in compiling compound character-
ization data. Sigma-Aldrich is gratefully acknowledged for
generous donation of materials for synthesis of Ir catalyst 1.
Dr. Rakesh Kohli (University of Pennsylvania) is acknowledged
for collection of HRMS data.
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■
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