Light-Mediated Reductive Debromination of Unactivated Alkyl and Aryl Bromides

Article abstract of DOI:10.1021/acscatal.6b01914

Cleavage of carbon-halogen bonds via either single-electron reduction or atom transfer is a powerful transformation in the construction of complex molecules. In particular, mild, selective hydrodehalogenations provide an excellent follow-up to the application of halogen atoms as directing groups or the utilization of atom transfer radical addition (ATRA) chemistry for the production of hydrocarbons. Here we combine the mechanistic properties of photoredox catalysis and silane-mediated atom transfer chemistry to accomplish the hydrodebromination of carbon-bromide bonds. The resulting method is performed under visible light irradiation in an open vessel and is capable of the efficient reduction of a variety of unactivated alkyl and aryl substrates.

Full text of DOI:10.1021/acscatal.6b01914

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Article
Light-Mediated Reductive Debromination
of Unactivated Alkyl and Aryl Bromides
James John Devery, III, John Duy Nguyen, Chunhui Dai, and Corey R. J. Stephenson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01914 • Publication Date (Web): 14 Jul 2016
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LightꢀMediated Reductive Debromination of
Unactivated Alkyl and Aryl Bromides.
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a
a
b
a,
James J. Devery, III, John D. Nguyen, Chunhui Dai, Corey R. J. Stephenson. *
a
Department of Chemistry, University of Michigan, 930 N University Drive, Ann Arbor, MI
48109.
b
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215.
ABSTRACT Cleavage of carbonꢀhalogen bonds via either single electron reduction or atom
transfer is a powerful transformation in the construction of complex molecules. In particular,
mild, selective hydrodehalogenations provide an excellent followꢀup to the application of
halogen atoms as directing groups or the utilization of atom transfer radical addition (ATRA)
chemistry for the production of hydrocarbons. Here we combine the mechanistic properties of
photoredox catalysis and silaneꢀmediated atom transfer chemistry to accomplish the
hydrodebromination of carbonꢀbromide bonds. The resulting method is performed under visible
light irradiation in an open vessel and is capable of the efficient reduction of a variety of
unactivated alkyl and aryl substrates.
Keywords: photoredox, hydrodehalogenation, silane, visible light, radical
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INTRODUCTION
Visible lightꢀmediated photoredox catalysis has advanced to productively exploit the latent
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reactivity of carbonꢀhalogen bonds in the development of new, radicalꢀbased synthetic methods.
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To date, transformations that utilize C−X bonds bearing iodine, bromine, chlorine, and fluorine
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through photocatalysis have each been reported. Based on these initial findings, a panoply of
new transformations have come about, applying both organic and transition metal
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photosensitizers in the use of visible light as an energy source. Chemists have utilized activated
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2a
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C−X bonds incorporated in αꢀhalo carbonyls, benzyl halides, polyhalomethanes, electronꢀ
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deficient aryl halides,
and iodonium salts to develop new reactions. In the case of
unactivated halides, a variety of reductive methods have arisen that proceed via reduction of
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unactivated alkyl and aryl iodides.
Formally, these transformations yield discrete
hydrodeiodinated products as well as products resulting from radical cyclization. However, the
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corresponding reduction of unactivated alkyl and aryl bromides remains a greater challenge.
Synthetic chemists utilize bromine as a directing group in many contexts, including
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electrophilic aromatic substitutions, DielsꢀAlder reactions and the Bartoli indole synthesis,
which stand to benefit from a mild, efficient approach for cleaving carbonꢀbromide bonds.
Traditional methods for the reduction of carbonꢀbromide bonds proceed through metalꢀhalogen
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2a
Figure 1. Fragmentation mechanism and standard reduction potentials of halobenzenes.
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exchange, hydride reduction, atom transfer, or single electron reductions. However, these
methods possess their own limitations: extreme basicity; undesired side reactions; functional
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group intolerance; toxic, explosive, or pyrophoric reagents; or stoichiometric loadings of
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metals.
Organocatalytic Photoredox Methods
iPr O
N
O Pr
i
N
N
iPr O
O Pr
i
S
PTH6
PDI5
No alkyl bromide examples.
Activated aryl bromide examples.
Transition Metal-Catalyzed Photoredox Methods
-
t
tBu
PF6
Bu
2Cl-
N
Ir
tBu
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Ph
Ph
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P
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Au Au
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tBu
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Ph
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Pt
C
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CC6F5
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[Pt(C^N^N)X]13
[Ir(ppy) (dtbbpy)]PF , (2)
[Au ( -dppm) ]Cl
2 2 2
2
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Requires large amounts of
electron source/H-atom
donor.
Requires ultra-violet light
and 10 mol% gold loading.
Only alkyl bromide examples.
Silane-based Methods
TMS
Only activated alkyl bromide examples.
Si H
TMS
TMS
TTMSS, (1)
Two activated aryl bromide cyclization
examples.
24-25
This work
[
Ir(ppy) (dtbbpy)]PF (0.5 mol%)
2
6
DIPEA (2 equiv)
Visible light LEDs
TTMSS (2 equiv)
Low catalyst loading
R-Br
R-H
Unactivated alkyl bromides
Unactivated aryl bromides
MeCN, open to air, rt, blue LED
R = aryl/alkyl
Figure 2. Previous examples of lightꢀmediated hydrodebromination methods.
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The reduction of aryl carbonꢀbromide bonds presents a different challenge than aryl carbonꢀ
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iodide bonds. The addition of an electron to an aryl iodide can result in a purely dissociative,
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concerted bond cleavage (Figure 1). However, reduction of aryl bromides and chlorides occurs
via the formation of a radical anion, which then undergoes rateꢀdetermining fragmentation. This
multistep process results in a thermodynamically more difficult initial electron transfer.
Photoredox methods have been developed in an attempt to address this problem with consecutive
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photoelectron transfer processes, long reaction times, large excesses of electron/Hꢀatom
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source, and UVA light for a limited array of substrates (Figure 2). Herein, we describe a new,
general, photoredoxꢀfacilitated method for the hydrodebromination of unactivated alkyl and aryl
bromides.
RESULTS AND DISCUSSION
In approaching the challenge of developing a general method for the hydrodebromination of
alkyl and aryl bromides, we began with examination of the conditions utilized by Lee et al. at 60
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°
C. Indeed, these conditions provided efficient conversions of primary alkyl bromides (Scheme
1
a). However, some aryl bromides proved resistant to these conditions (Scheme 1b). We next
Scheme 1. Lightꢀmediated hydrodebromination at elevated temperature.
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chose to explore photoredoxꢀfacilitated atom transfer as a means of supplementing single
electron transfer. Tris(trimethylsilyl)silane (TTMSS, 1) is both a potent hydrogen atom donor
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and a competent halogenꢀatom transfer agent, representing an alternative to tin hydrides.
However, methods employing this compound often rely upon the use of traditional radical
initiators like AIBN. Alternatively, Jørgensen and coworkers have employed light and oxygen as
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an initiator for this process to reduce electronꢀdeficient aryl bromides. Similarly, Paixão et al.
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have shown that two aryl bromides can participate in radical cyclizations with modest yields.
Recognizing that [Ir(ppy) (dtbbpy)]PF (2) and an amine were capable of hydrodebrominating Cꢀ
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Br bonds of select substrates based on the findings of Lee and Kim for aryl bromides and our
result for alkyl bromides (Scheme 1a), as well as the fact that TTMSS was capable of Br atom
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transfer under lightꢀmediated conditions,
we posited that the efficiency of 2 and a reductive
quencher could be augmented by the presence of TTMSS acting as both a hydrogen atom source
and atom transfer agent.
Optimization of reaction conditions via an initial screen indicated that the combination of
reductive quenching conditions for 2 (0.5 mol%), using two equivalents diisopropylethylamine
(
DIPEA), with two equivalents of TTMSS, at room temperature, and open to air provided the
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best substrate conversion by H NMR. The combination of the DIPEAꢀfacilitated quenching
cycle of 2 with the atom transfer capability of TTMSS were required for complete consumption
of the substrate. Importantly, rigorous degassing via sparging or freezeꢀpumpꢀthaw, the absence
of 2, and the absence of light resulted in incomplete conversion. Taken together, these results
provide important mechanistic details about this process. Complex 2 is capable of forming
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product in the absence of TTMSS with a large excess of DIPEA. Silane TTMSS facilitates the
formation of product in the absence of photocatalyst. Exhaustive degassing inhibits reactivity,
suggesting that oxygen is important for the success of this transformation. Both findings are
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consistent with Jørgensen and coworkers’ results. It is important to note that only partial
conversion is observed under an oxygen atmosphere.
a
Table 1. Hydrodebromination of Aryl Bromides.
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Isolated
Yield (%)
Entry Substrate
Product
b
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91
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Reactions performed at 0.5 mmol scale for 10 h. Calculated by
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With optimized conditions in hand, we examined the scope of this transformation. Beginning
with aryl bromides, we found that these conditions were capable of reductive debromination of
unactivated arenes (Table 1). These conditions are generally applicable to electronꢀrich arenes as
well as heteroarenes. These conditions are tolerant of benzyl, tosyl, tetrahydropyranyl, and acetyl
protecting groups. Formation of the aryl radical and subsequent cyclization occur preferentially
over hydrosilylation of the pendant olefin (Entry 3, Table 1), consistent with the observations of
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Paixão et al.
We next turned our attention to alkyl bromides (Table 2). These conditions facilitate the
a
Table 2. Hydrodebromination of alkyl bromides.
Entry Substrate
Product
Isolated
Yield
(%)
Entry
Substrate
Product
Isolated
Yield
(%)
b
1
2
99
4
5
91
85
84
89
3
6
9
92
83
7
8
Br
89
85
Br
Ph
Ph
10
88
a
Reactions performed at 0.5 mmol scale, at room temperature with 2.2 equiv of DIPEA, 2.2
b
equiv TTMSS, and 0.5 mol% 2 for 10 h unless otherwise stated. Calculated by UPLC (PDA).
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reductive debromination of both primary and secondary alkyl bromides. Analogous to the aryl
system, the corresponding alkyl radical cyclization proceeds efficiently, favoring the desired
reactivity over hydrosilylation (Entry 3, Table 2). As with aryl substrates, conditions displayed
tolerance for Ts, Cbz, and Boc protecting groups. Visible lightꢀmediated atom transfer radical
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addition products are reduced (Entries 5 and 6, Table 2), showing that photoredox can be used
to produce alkanes in two steps. Finally, these conditions can remove both bromine atoms of 1,1ꢀ
dibromocyclopropanes (Entries 7ꢀ10, Table 2), providing efficient conversions for arylꢀ, diarylꢀ,
and alkylꢀsubstituted cyclopropanes. Traditionally, methods for hydrodebromination of these
structures remove a single halogen atom; whereas, tinꢀ, metalationꢀ, or electrochemicalꢀbased
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methods are required to remove the second bromine. Indeed, this transformation proceeds to
full conversion in the presence of four equivalents of TTMSS. Monitoring of reaction progress of
the dihydrodebromination provides insight into this process. Using 3 as a model, the
transformation begins by selective conversion of the starting material to a single intermediate in
the first 30 min of the reaction. After complete consumption of the dibromocyclopropane, the
intermediate is then consumed and converted into the alkane. The first step of this process is
identical in the presence and absence of 2 under LED irradiation, forming a discrete intermediate
in the first 30 minutes. Performing a reaction in the absence of catalyst with this time constraint
results in the isolation of monodebrominated cyclopropane 4 in 83% yield (Scheme 2).
Scheme 2. Silaneꢀmediated monodebromination of 3.
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Importantly, 4 does not efficiently convert to the corresponding cyclopropane in the absence of
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Due to the disparate mechanistic possibilities that exist in the literature,
gain insight into the reaction mechanism through examination of the kinetic behavior of this
we attempted to
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transformation by monitoring the hydrodebromination of 4ꢀbromoacetophenone (5) by UPLC.
We, also, examined the kinetic roles of the other components in this reaction, and probed if the
mechanism varied for alkyl, activated aryl, and unactivated aryl bromides. Indeed, different
mechanistic properties were observed for 5, bromoethylbenzene (6), and 4ꢀbromophenol benzyl
ether (7). Table 3 displays the rate orders observed for the different components present in the
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Table 3. Summary of Rate Orders
0
0
0
.28±0.06
0
-0.9±0.1
DIPEA
2
.1±0.1
0.5±0.1
2.2±0.1
-0.28±0.06
1.92±0.01
TTMSS
reaction mixture. Substrate decay varied between each system. Substrates 5 and 6 decayed
exponentially, while 7 decayed with constant slope, in keeping with zero order kinetics. Despite
low or zero orders, the presence of both DIPEA and 2 are required for full conversion. Finally, 6
and 7 both displayed second order behavior with respect to TTMSS (Figure 3), while the rate of
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conversion of 5 displayed a negligible increase in rate. These collective data imply that a
different dominant mechanism exists for each substrate. The second order in silane for 6 and 7,
in concert with the orders for DIPEA and 2, implies a dominant, silaneꢀmediated process for
these substrates.
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b)
-6.0
-
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-6.5
-7.0
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-1.5
ln[TTMSS]
ln[TTMSS]
Figure 3. ln(k ) vs. ln[TTMSS] for hydrodebromination of 6 with slope of 2.2±0.1 (a) and 7
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with slope of 1.92 ± 0.01 (b).
The success of our optimized system, the results from kinetic analysis, as well as the partial
successes in our initial screen provide significant insight into the complexity that exists in this
process. First, a traditional reductive quenching cycle is capable of, at minimum, partial
hydrodebromination (Figure 4a). Promotion of 2 to its excited state (2*) by visible light,
followed by reductive quenching by DIPEA (8) results in the formation of Ir(II) (9) and amine
radical cation 10. Single electron transfer to the substrate (11) regenerates 2 and forms carbonꢀ
centered radical 12 via generation of a radical anion and unimolecular fragmentation in electronꢀ
accepting systems, and direct formation of 12 in alkyl systems. Radical 12 can then abstract a
9
hydrogen atom from 10, yielding hydrodebrominated product. Alternatively, 12 can abstract a
hydrogen atom from TTMSS, forming 13 and silyl radical 15. The need for oxygen suggests that
2
* can also be directed through an oxidative quenching cycle, resulting in the formation of
superoxide (16) and Ir(IV) (17) (Figure 4b). DIPEA (8) is capable of donating an electron to 17,
yielding amine radical cation 10 and turning over the catalyst. A proton transfer cascade from 10
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Figure 4. Proposed mechanistic pathways.
to 8 to 16 forms peroxyl radical 20, which can accept a hydrogen atom from TTMSS to form
hydrogen peroxide and 15. Finally, 15 is capable of abstracting a bromine atom from 11 to form
12, which can result in product via hydrogen atom abstraction from TTMSS (Figure 4c). The
differences in rate orders observed for 5, 6, and 7 suggest that the resting state and rateꢀ
determining/turnoverꢀlimiting steps vary from substrate to substrate. However, based on the
proposed pathways, it is possible that hydrogen atom transfer to both 12 and 20 accounts for the
observed second order dependence with respect to [TTMSS].
CONCLUSIONS
We have developed a mild hydrodebromination method, combining visible light mediated
photoredox catalysis and silaneꢀmediated atom transfer that is performed open to air. We have
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provided a mechanistic rationale to the design of reaction conditions that are applicable to both
unactivated alkyl and aryl bromides. Product forming hydrogen atom transfer is slower than the
disclosed radical cyclizations, rendering this method amenable to radical cyclization cascades
after initial carbonꢀbromide bond cleavage. We have proposed an intricate mechanism that is
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consistent with our initial synthetic and kinetic observations. Importantly, our observation of 2
order dependency in TTMSS for hydrodebromination is consistent with the silyl radicalꢀ
activated cross coupling reported by MacMillan and coworkers, a method requiring 1 equiv
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TTMSS to yield the crossꢀcoupled product. We are currently investigating this mechanism in
greater detail to validate our proposal for the manner in which oxygen participation occurs.
ASSOCIATED CONTENT
Supporting Information.
Experimental details, kinetic data, and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
crjsteph@umich.edu
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
The authors thank Dr. Joel Beatty, Dr. James Douglas, Prof. Robert Flowers, Dr. Mitchell
Keylor, Dr. Bryan Matsuura, and Dr. Niki Patel for their helpful discussions and suggestions.
Financial support from the NSF (CHEꢀ1440118), the Alfred P. Sloan Foundation, the Camille
and Henry Dreyfus Foundation, and the University of Michigan is gratefully acknowledged.
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