Reductive Chlorination and Bromination of Ketones via Trityl Hydrazones

Article abstract of DOI:10.1002/anie.201510909

A method is presented for the direct transformation of a ketone to the corresponding reduced alkyl chloride or bromide. The process involves the reaction of a ketone trityl hydrazone with tBuOCl to give a diazene which readily collapses to the α-chlorocar

Full text of DOI:10.1002/anie.201510909

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International Edition: DOI: 10.1002/anie.201510909
German Edition: DOI: 10.1002/ange.201510909
Halogenation
Reductive Chlorination and Bromination of Ketones via Trityl
Hydrazones
Julius R. Reyes and Viresh H. Rawal*
Abstract: A method is presented for the direct transformation
of a ketone to the corresponding reduced alkyl chloride or
bromide. The process involves the reaction of a ketone trityl
hydrazone with tBuOCl to give a diazene which readily
collapses to the a-chlorocarbinyl radical, reduction of which by
a hydrogen atom source gives the alkyl chloride product. The
use of N-bromosuccinimide provides the corresponding alkyl
bromide. This unique transformation provides a reductive
halogenation that complements Bartonꢀs redox-neutral vinyl
halide synthesis.
a chlorine atom in high-value compounds. Rather than
introducing the chloride through nucleophilic displacement
of an activated alcohol, with the attendant difficulties and
complications noted above, the idea was to introduce the
chlorine first and then, through the generation of a reactive
intermediate, add a hydrogen atom. This concept was
expected to be realized through the use of hydrazone
[6–8]
chemistry (Figure 2a).
The reaction of a trityl hydrazone
T
he transformation of an alcohol into a chloride, one of the
most basic reactions in organic chemistry, can present
unanticipated difficulties when encountered in a complex
molecule. In the course of our studies toward the synthesis of
N-methylwelwitindolinone B isothiocyanate (1; Figure 1), we
Figure 1. Welwitindolinone B and potential precursors.
attempted to convert the C13 hydroxy group of 2 into the
Figure 2. Synthesis of organochlorides from hydrazone precursors.
[
1]
required, inverted chloride. Unfortunately, the neopentyl
and homoallylic nature of the alcohol conspired to trigger
a skeletal rearrangement, thereby foiling the planned syn-
with a chloronium source was expected to give a chlorodia-
[
2]
[9]
thetic route. Others have also observed difficulties, in
completely different systems, in making alkyl chlorides by
zene (5), which upon thermolysis would extrude N2 to
generate a trityl radical and the sought after reactive
intermediate, the a-chlorocarbinyl radical 6. Provided the
thermolysis was carried out in the presence of a hydrogen
atom donor, then diastereoselective hydrogen abstraction
would give the desired chloroalkane product. Introduction of
chlorine and generation and reduction of the reactive
intermediate were envisioned through a single synthetic
maneuver. Realized, this transformation provides a reductive
chlorination from the C=O oxidation state, a method that
[
3]
Walden inversion of suitably activated precursors. Given the
limitations of this transformation, combined with the preva-
[4]
lence of natural products having a chloride attached to an
3
sp -hybridized carbon atom, we set forth to devise a funda-
mentally different solution for the synthesis of such chlor-
[
5]
ides. We report here the realization of a method for the
overall reductive transformation of ketones to alkyl halides.
The reductive chlorination method was conceived to
provide a conceptually new way for the installation of
complements Barton-type vinyl halide synthesis (Fig-
[10,11]
ure 2b).
The feasibility of the above concept was evaluated using
[
*] J. R. Reyes, Prof. Dr. V. H. Rawal
Department of Chemistry, The University of Chicago
hydrazone 11a (Figure 3a), which is available through con-
[12]
densation of trityl hydrazide and benzylacetone (74%).
Treatment of a solution of 11a in THF with tBuOCl
1.1 equiv) at À208C, followed by addition of an excess of
EtSH and warming to room temperature afforded the desired
5
735 South Ellis Avenue, Chicago, IL 60637 (USA)
E-mail: vrawal@uchicago.edu
(
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510909.
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Table 1: Reductive chlorination of trityl hydrazones.
[a]
Entry
1
Hydrazone
Chloride
Yield [%]
82
[b]
2
85
Figure 3. Optimization of reaction parameters. [a] Reactions performed
in THF. Yield determined by NMR spectroscopy.
3
4
57 (3.4:1)
[13]
product of reductive chlorination in 37% yield (NMR).
69 (2.9:1)
71 (1.3:1)
Modest yields in these early reactions were balanced signifi-
cantly by the product of apparent hydrolysis of the starting
hydrazone, that is, benzylacetone. Mechanistic considerations
suggested that the apparent hydrolysis product likely arises by
way of peroxychloroalkane intermediate 14, the product of O2
capture by the a-chlorocarbinyl radical (Figure 3b). Support
for this hypothesis was obtained by carrying out the thermol-
ysis in the absence of a reducing agent and placing it under an
oxygen balloon prior to warming to room temperature. The
major product of the reaction under these reaction conditions
was benzylacetone (10; 57% yield by NMR), with no
evidence of chloroalkane 13a. In contrast, scrupulous exclu-
sion of air through two freeze-pump-thaw cycles completely
eliminated formation of 10 in the reaction mixture. Variable-
temperature NMR experiments provided an understanding of
the thermal requirements for the different steps of the
5
6
[b]
56
[c]
7
50
8
9
83 (21:1)
70 (2.6:1)
[
14,15]
reaction.
A À788C sample of 11a and tBuOCl was
examined by NMR spectroscopy in a probe precooled to
À308C. After 10 minutes had elapsed, a reaction was
observed, and the starting hydrazone was found to be fully
consumed. The resulting putative chlorodiazene 12 was found
to persist as the temperature was increased from À308C to
À108C. Upon further warming above À108C, diazene 12
decomposed to give a mixture of products. With the sequence
of reagent addition and temperature control guided by the
[d]
1
0
67
[
a] Yield of the isolated product. Diastereomeric ratio (d.r.; given within
parentheses) determined by H NMR analysis of purified chlorides.
b] Yield determined by NMR spectroscopy. [c] Yield for isolated
diastereomer shown (major), 2.8:1 crude d.r. [d] Lithiated hydrazone
treated with dichloramine-T. Cy=cyclohexyl, DCM=dichloromethane,
TBS=tert-butyldimethylsilyl.
1
[
above study, as well as careful O exclusion, the reaction was
2
optimized to furnish 13a in 82% isolated yield (Table 1,
entry 1). A brief screen of chloronium ion sources and
H-atom donors offered no improvement over tBuOCl and
EtSH, with N-chlorosuccinimide yielding none of the desired
chloride. Less odorous, high-molecular weight thiols were
examined briefly as H-atom donors, but found to give less
satisfactory results.
The capability of the reductive chlorination procedure
was examined in a range of substrates, as shown in Table 1.
The hydrazone of phenoxyacetone was converted into the
corresponding chloride in 85% yield (entry 2). Diastereose-
lectivity in the reduction event displayed high substrate
dependence. Substrates in which the hydrazone was part of
a conformationally locked six-membered ring favored axial
hydrogen abstraction to give the equatorial chloride. Reduc-
tive chlorination of 11c and 11d gave a mixture of chlorides,
with a preference for the equatorial chlorides by approx-
imately 3:1 (entries 3 and 4). Diminished selectivity was
observed for the reaction of the hydrazone of trans-1-
decalone, wherein the three 1,3-diaxial interactions may
disfavor axial hydrogen abstraction (entry 5). The neopentyl,
homoallylic hydrazone 11g, comprising the cyclohexane core
of welwitindolinone B, gave a 2.8:1 mixture of chloride
diastereomers, from which the major component 13g was
isolated in 50% yield. Notably, this reductive chlorination
occurs without 1,2-migration of the vinyl group, possibly
[16]
reflecting the radical stabilizing effect of chlorine.
Among cyclopentanone-derived trityl hydrazones, the
facial bias of the [2.2.1]-bridged system in 11h engendered
high selectivity for the endo chloride 13h, which was isolated
3
078
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in 83% yield, with greater than 20:1 diastereoselectivity
with a range of trityl hydrazones, and affords chloride
(
Table 1, entry 8). The hydrazone of (À)-a-thujone (11i) gave
products with stereoselectivities that may complement those
available through ionic processes. The basic transformation
was also successfully demonstrated for the synthesis of alkyl
a mixture of chlorides (13i) in 70% yield, wherein hydrogen
abstraction had taken place predominantly from the face
[17]
[19]
opposite the a-methyl substituent (entry 9). The utility of
this method was further demonstrated by the reductive
chlorination of the sterically encumbered hydrazone 11j,
derived from O-methyl estrone (entry 10). The lower reac-
tivity of 11j to chlorination necessitated deprotonation
followed by chlorination, which was achieved efficiently
with dichloramine-T. The protocol afforded chloride 13j in
bromides. The ability of this method to efficiently construct
neopentyl alkyl chlorides from the carbonyl functional group
provides a distinct tactic for the preparation of such halide-
containing natural products, syntheses of which are of
ongoing interest in our laboratories.
good yield and high selectivity for the b-chloride shown, with Acknowledgments
hydrogen abstraction taking place anti to the adjacent C13
methyl group.
The underlying concept of the reductive chlorination
appeared transferrable to bromination. Thus, upon treatment
of 11a with N-bromosuccinimide (NBS) in place of tBuOCl
followed by addition of EtSH and warming, it was converted
into the expected reductive bromination product 16a
Financial support from the National Cancer Institute of the
NIH (R01 CA101438) is gratefully acknowledged. Addition-
ally, we generously thank Dr. Antoni Jurkiewicz for his NMR
expertise and assistance.
Keywords: diastereoselectivity · halogenation · hydrazones ·
(
Table 2). Three other hydrazones were similarly subjected
radical reactions · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3077–3080
Angew. Chem. 2016, 128, 3129–3132
Table 2: Reductive bromination of trityl hydrazones.
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[
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[19] In preliminary studies, we have found that lithiation of 11a and
subsequent treatment with NFSI generated the corresponding
fluoride in 33% yield (NMR, unoptimized).
1
[
[
(
1
2
(
258C, 30 days) or photolysis (10 h) of the resulting a,a’-
Received: November 24, 2015
dichloroazoalkanes in the presence of thiophenol produces
Published online: January 28, 2016
3
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