Site-selective aliphatic C-H bromination using N -bromoamides and visible light

Article abstract of DOI:10.1021/ja508469u

Transformations that selectively functionalize aliphatic C-H bonds hold significant promise to streamline complex molecule synthesis. Despite the potential for site-selective C-H functionalization, few intermolecular processes of preparative value exist. Herein, we report an approach to unactivated, aliphatic C-H bromination using readily available N-bromoamide reagents and visible light. These halogenations proceed in useful chemical yields, with substrate as the limiting reagent. The site selectivities of these radical-mediated C-H functionalizations are comparable (or superior) to the most selective intermolecular C-H functionalizations known. With the broad utility of alkyl bromides as synthetic intermediates, this convenient approach will find general use in chemical synthesis.

Full text of DOI:10.1021/ja508469u

Communication
pubs.acs.org/JACS
Site-Selective Aliphatic C−H Bromination Using N‑Bromoamides and
Visible Light
Valerie A. Schmidt,† Ryan K. Quinn,† Andrew T. Brusoe, and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
bromides are among the most widely used building blocks in
ABSTRACT: Transformations that selectively function-
alize aliphatic C−H bonds hold significant promise to
streamline complex molecule synthesis. Despite the
potential for site-selective C−H functionalization, few
intermolecular processes of preparative value exist. Herein,
we report an approach to unactivated, aliphatic C−H
bromination using readily available N-bromoamide
reagents and visible light. These halogenations proceed
in useful chemical yields, with substrate as the limiting
reagent. The site selectivities of these radical-mediated C−
H functionalizations are comparable (or superior) to the
most selective intermolecular C−H functionalizations
known. With the broad utility of alkyl bromides as
synthetic intermediates, this convenient approach will find
general use in chemical synthesis.
synthetic chemistry and are readily converted to a diverse array of
compounds via general methods such as heteroatom alkylation
or organometallic cross-coupling.9
Hofmann-Loffler-Freytag processes use nitrogen-centered
̈
radicals to perform site-selective, intramolecular C−H function-
alizations, including C−H halogenations.10 These processes
capitalize on the marked preference for 1,5-H-atom abstraction
by heteroatom-centered radicals to achieve high site selectivities.
Intermolecular, heteroatom-centered radical-mediated function-
alizations of unactivated aliphatic C−H bonds, however, are
rarely used in synthesis. Interestingly, there are preliminary
reports indicating that site-selective, intermolecular C−H
functionalizations using N-centered radicals may be possible,11
however the use of strong acid as solvent (e.g., H2SO4) limits
potential synthetic applications of these systems.11a,b We
hypothesized that the development of a set of simple, stable
reagents that deliver an array of unique N-centered radicals could
enable a new approach to site-selective, intermolecular C−H
halogenation. Tuning the steric and electronic parameters of the
reacting species enables reagent-controlled C−H halogenations
that override inherent substrate-controlled selectivities. We
report herein an intermolecular, aliphatic C−H bromination
that uses readily available N-bromoamides and visible light to
achieve this goal (Figure 1).
n important goal of modern chemical synthesis is to develop
Atransformations that achieve the site-selective, intermolec-
ular functionalization of isolated, unactivated aliphatic C−H
bonds.1 The low reactivity and relative ubiquity of these bonds in
small organic molecules renders this task a formidable challenge.2
The transformation of aliphatic C−H bonds to functional groups
such as alcohols and alkyl halides is routinely performed in
Nature by highly selective enzymes featuring tailored reaction
sites and metal−oxo intermediates.3 Accessing chemical
reactions capable of achieving comparable levels of reactivity
and selectivity has proven challenging; few examples of the
functionalization of unactivated, isolated aliphatic C−H bonds
exist that are both efficient and site-selective. While promising
transformations involving aliphatic C−H alkylation, amination,
or oxidation have been reported, the majority use large excesses
of hydrocarbon substrate.4 This requirement limits the utility of
these transformations in contexts involving precious substrates
(i.e., late-stage functionalization of complex molecules or
pharmaceutical agents). Recently, intermolecular, site-selective
oxidations of aliphatic C−H bonds with substrate as limiting
reagent have begun to emerge. Foremost among these methods
are the reactions of strained electrophilic heterocycles5 and
biomimetic Fe-catalyzed oxidation systems.6
Few site-selective methods exist for the intermolecular
halogenation of aliphatic C−H bonds.7 Moreover, existing C−
H halogenations of alkanes commonly require an excess of
substrate. A number of recent reports have disclosed promising
catalytic C−H fluorination systems using substrate as the limiting
reagent.8 However, other practical, intermolecular C−H
halogenations (i.e., bromination) are yet to be developed. Alkyl
Figure 1. Radical-mediated aliphatic C−H brominations using N-
bromoamides offer both high steric and electronic selectivities, enabling
C−H brominations inaccessible using standard protocols.
Received: August 18, 2014
© XXXX American Chemical Society
A
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Table 1. Bromination of Cycloalkanes with N-Bromoamide
Reagents Using Substrate as Limiting Reagent
Table 2. Sterically Dictated Site Selectivities in the
a
a
Bromination of Methylcyclohexane
a
Reactions were performed in PhH at rt under Ar using visible light
irradiation with 1 equiv of substrate and N-bromoamide. Yields were
b
determined by GC analysis. Reaction performed under air
atmosphere using commercial, unpurified reagents.
a
See Table 1 for conditions. Reaction yields and selectivities were
determined by GC analysis.
Initially, we pursued the C−H bromination of simple
cycloalkanes with substrate as limiting reagent. While there are
reports of aliphatic C−H bromination using excess alkane
substrate,7 the only studies with substrate as limiting reagent that
proceed with practical yields (i.e., >50%) require highly reactive
superacids and are not suitable for general applications in
synthesis.12 We began with the bromination of cyclohexane (1
equiv) using a number of N-bromoamide reagents (1−6) (Table
1). These N-bromoamides are stable solids that are easily
accessed from their parent amides.13 The hindered, electrophilic
N-bromoamide 6 provided cyclohexyl bromide in the highest
yield of the reagents studied (70%, entry 6). Notably, these
experiments were performed on the benchtop with common 100
W household bulbs (23 W fluorescent bulbs provided equivalent
yields) and are complete in <30 min. While we typically perform
these reactions under Ar using purified reagents and solvents;
there is only a minor decrease in yield when the reaction is run in
air with undistilled reagent-grade chemicals (68% vs 70%, entry
7). Stoichiometric reactions with other cyclic hydrocarbons
proceeded with similar efficiencies. Dihalogenation was not
observed in any appreciable amounts in these reactions. We
attribute this to the electronic deactivation of the bromoalkane
products.
In order to gain insight regarding the mechanism of the C−H
halogenation, we determined the deuterium kinetic isotope effect
by the competition reaction between cyclohexane and d12-
cyclohexane using reagent 6. The observed primary kinetic
isotope effect of kH/kD = 5.8 is consistent with irreversible
hydrogen atom abstraction. Under identical conditions, neither
Br2 nor N-bromosuccinimide delivered more than a trace
amount of product. This is consistent with an amidyl radical
C−H abstraction step in our approach, as further demonstrated
by the site selectivity studies below.
involved in our system could offer the potential to overcome this
inherent reactivity profile.
We began with the selective functionalization of methyl-
cyclohexane (8) to survey the selectivity of secondary (desired)
versus tertiary (undesired) C−H functionalization (Table 2).
The bromination of methylcyclohexane using common reagent
NBS (N-bromosuccinimide, entry 1) requires a large excess of
substrate to deliver greater than a trace amount of product, and
therefore was performed neat in methylcyclohexane. As
expected, this reaction greatly favored halogenation at the
tertiary C−H site after correcting for the number of tertiary (1)
and secondary (10) sites available (ksecondary/ktertiary, ks/kt, = 0.06).
Bromination using a biomimetic Mn-porphyrin system7a (entry
2) also favored tertiary halogenation (ks/kt, = 0.40). The
photochemical C−H bromination using bromoamide 1
proceeded with a ks/kt selectivity comparable to NBS (0.07,
entry 3), while the reactions of N-bromoamides 3 and 4 were
comparable to the Mn-porphyrin system (entries 5 and 6).
However, the use of bulky N-tBu reagents 2, 5, and 6 led to a
marked increase for methylene functionalization, with bromoa-
mide 6 providing >98% selectivity and ks/kt = 6.6 (entry 6). This
level of methylene selectivity in the functionalization of a simple
cyclic hydrocarbon is unmatched by any known system for
aliphatic C−H halogenation.
A particularly intriguing aspect of these results is the ability to
alter the site selectivity through changing the N-substituent of
the reagent used. While N−H and N-trifluoroethyl N-
bromoamides 1, 3, and 4 favor functionalization of the weakest
C−H bond (tertiary), N-tBu reagents 2, 5 and 6 strongly favor
functionalization at the less sterically hindered secondary sites.
The ability to overcome inherent substrate dictated selectivity in
intermolecular, aliphatic C−H functionalization is a notable
goal,6b and the use of easily tuned radicals such as those
presented herein offers an attractive solution to this problem.
Examination of the steric-based selectivity of our approach
continued with a number of hydrocarbon substrates used as
benchmarks for site-selective aliphatic C−H functionalization
(Table 3). In each case, the C−H bromination proceeded with
excellent levels of steric selectivity. The bromination of
norbornane occurs exclusively on the exo face of the
bicyclo[2.2.1]heptane framework (entry 1). The functionaliza-
tion of trans-1,2-dimethylcyclohexane proceeds only at the
We next explored the potential for site-selective C−H
functionalization. The ability to differentiate sites of functional-
ization on both steric and electronic bases (multidimensional
selectivity) is paramount. Classical radical-mediated C−H
brominations are often selective for tertiary C−H sites.14 In
addition, the preference for tertiary C−H functionalization is also
characteristic of the majority of known polar or metal-catalyzed
C−H functionalizations.4e,15 We hypothesized that tuning the
steric and electronic parameters of the putative amidyl radical
B
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Table 3. Sterically Selective Aliphatic C−H Bromination of
Table 4. Studies of the Electronic Site Selectivity of the
a
a
Diverse Hydrocarbons with Bulky N-Bromoamide 6
Aliphatic C−H Bromination with N-Bromoamide 6
a
See Table 1 for conditions. Yields and selectivities were determined
by GC analysis. For details regarding product distributions, see the
b
Supporting Information. Reaction performed using 1.5 equiv of 6.
c
1H NMR yield.
methylene sites (entry 2). The more challenging cis-1,2-
dimethylcyclohexane contains a relatively unhindered tertiary
equatorial C−H bond that is prone to react owing to the release
of 1,3-diaxial strain.16 Using 6, the bromination remains selective
for the methylene positions of the carbocycle (ks/kt = 3.0, entry
3). This remarkable level of methylene selectivity of aliphatic C−
H halogenation with this substrate is higher than any other C−H
functionalization method previously reported.6,17
a
Reactions were performed in PhH at rt using visible light with 1 equiv
of substrate and 2 equiv 6. Yields and selectivities were determined by
b
GC analysis. Reaction yield using 5 equiv of substrate and 1 equiv 6.
c
1
The dr was determined by H NMR analysis.
The halogenation of adamantane proceeds with modest site
selectivity with common radical halogenating agents (e.g., Br2
and NBS), yet favors the less encumbered tertiary sites with
sterically selective reagents.18 The reaction of adamantane with
N-bromoamide 6 was highly selective for the tertiary site (kt/ks
>100), consistent with previous studies of amidyl radical
selectivity (entry 4).11c The bromination of trans-decalin
proceeds with excellent methylene site selectivity using 6
(>99%, entry 5). Cis-Decalin is a more challenging substrate
for methylene-selective functionalization, and only modest 2°/3°
selectivity has been achieved to date, owing to the presence of a
reactive equatorial 3° C−H bond.4d,19 With reagent 6, the
bromination of cis-decalin is also highly selective for methylene
functionalization (>99%, entry 6), further demonstrating the
unique levels of steric selectivities obtained using our system.
Next we surveyed the potential for electronic site selectivity in
the C−H halogenation using methyl hexanoate as a test substrate
(Table 4). The Mn-porphyrin-catalyzed bromination7a of this
substrate is highly selective for the δ and γ sites, although there is
little discrimination between these two positions (entry 1).
Functionalization using N-haloamide 6 (2 equiv) leads to a δ-
selective process, favoring functionalization of the methylene
position furthest removed from the electron-withdrawing ester
group (entry 2). We also observe γ-functionalization, but
bromination with reagent 6 provides good selectivity between
the δ and γ sites (δ:γ = 3.2:1).
amine using reagent 6 proceeded with even greater site selectivity
than methyl hexanoate, with a remarkable 81.8% selectivity for
the δ site (entry 3). No α or β functionalization was observed,
clearly indicating the excellent potential for electronically
dictated site selectivity using protected primary amines. The
functionalizations of both hexanenitrile and heptan-2-one also
proceeded with good δ selectivities (68.3% and 53.8%,
respectively, entries 4 and 5). The promising level of δ selectivity
with heptan-2-one is intriguing given the known protocols for the
α-halogenation of ketones using simple brominating agents (e.g.,
NBS) and visible light.20 The reaction of pentyl trifluoroacetate
also displayed good δ selectivity (66.6%, entry 6). Bromination of
n-hexane was 58.7% δ selective, indicating the possibility of a
minor steric component in reactions of linear substrates (entry
7). A minor amount of dihalogenation of n-hexane was observed;
therefore, a reaction using an excess of substrate was performed
to determine the site selectivity. While further studies will seek
reagents with improved selectivities, the efficiency of these
reactions already positions this method as a practical (>50%
yield) approach to C−H bromination.
We also examined the site selectivity using a functionalized
cycloalkane substrate, phthalimide-protected cyclohexylamine
(entry 8). The C−H bromination favored reaction at the C3 and
C4 positions (91.5%), with only a minor amount (8.5%) of the
C2 product detected. The C3 bromination delivered the 1,3-cis
product as a single diastereomer, and the C4 bromination
proceeded diastereoselectively to yield two products with a 80:20
dr favoring functionalization trans to the phthalimide group. The
potential for diastereoselective methylene C−H halogenation is
Our studies of electronic selectivity continued with a set of
linear functionalized hydrocarbons as substrates (Table 4, entries
3−6). The functionalization of phthalimide-protected pentyl-
C
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Journal of the American Chemical Society
Communication
intriguing and is a useful complement to C−H oxidation
approaches which typically deliver sp2-hybridized ketone
products at methylene sites.
We have also begun an initial survey of more complex
substrates (eqs 1 and 2). Amino-adamantanes are found in a large
AUTHOR INFORMATION
Corresponding Author
eja@email.unc.edu
■
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by UNC Chapel Hill, a Venable
Fellowship (V.A.S.) and an NSF graduate fellowship (R.K.Q).
■
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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