Diversity-Oriented Desulfonylative Functionalization of Alkyl Allyl Sulfones

Article abstract of DOI:10.1002/anie.201903668

The diversity-oriented desulfonylative functionalization of alkyl allyl sulfones with various sulfone-type reagents by radical chemistry has been developed. The readily installed allylsulfonyl moiety acts as a C-radical precursor, which is substituted by various functionalities using sulfur-based radical trapping reagents. The generality of this approach is documented by the successful desulfonylative alkynylation, azidation, trifluoromethylthiolation, sulfenylation, trifluoromethylselenylation, halogenation, and deuteration. The method is compatible with a wide range of functional groups. Considering the deuteration, products are obtained in good yields with a high level of deuterium incorporation.

Full text of DOI:10.1002/anie.201903668

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Accepted Article
Title: Diversity-oriented Desulfonylative Functionalization of Alkyl Allyl
Sulfones
Authors: Yong Xia and Armido Studer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903668
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Diversity-oriented Desulfonylative Functionalization of Alkyl Allyl
Sulfones
Yong Xia and Armido Studer*
Abstract: The diversity-oriented desulfonylative functionalization of
alkyl allyl sulfones with various sulfone-type reagents via radical
chemistry has been developed. The readily installed allylsulfonyl
moiety acts as a C-radical precursor, which is substituted by various
functionalities using sulfur-based radical trapping reagents. The
generality of this approach is documented by the successful
desulfonylative alkynylation, azidation, trifluoromethylthiolation,
Allylsulfones are established trapping reagents that react with
C-radicals via addition-fragmentation to the corresponding
allylated products.[9] For example, the allylation of alkyl iodides
with allylsulfones was described by Zard[9l] and Ryu.[9c]
Decarboxylative and deaminative allylation were reported by Li[9g]
and Liu.[9d] Zard developed a radical allylation using alkyl allyl
sulfones as both C-radical precursors as well as allylation
reagents.[10f] Related chemistry for CC-bond formation was later
described by Kim and Ryu.[10a-e] Surprisingly, the use of
allylsulfones as C-radical precursors for carbon-heteroatom bond
construction has remained unexplored. Along these lines, we
assumed that alkyl allyl sulfones would be ideal and readily
accessed substrates for desulfonylative diversity-oriented C-
functionalization and present herein first results on alkynylation,
sulfenylation,
trifluoromethylselenylation,
halogenation,
and
deuteration. The method is compatible with a wide range of functional
groups. Considering the deuteration, products are obtained in good
yields with a high level of deuterium incorporation.
Radical chemistry is highly valuable for the construction and
late-stage functionalization of complex compounds.[1] C-centered
radicals can be generated from various precursors and different
C-radical trapping reagents are available, offering a large portfolio
of methods for functional group interconversion. For example, the
decarboxylative alkylation, borylation and halogenation of
aliphatic carboxylic acids;[2] deiodinative borylation, deuteration
and trifluoromethylation of iodides,[3] and the direct CH
functionalization[4] among other transformations[1] have been
achieved. However, the current methods generally allow the
transformation of one radical precursor into one product class
(Scheme 1a). In view of diversity-oriented synthesis,[5,6]
development of efficient and practical methods enabling diversity-
oriented functionalization where a single radical precursor allows
accessing various compound classes by using derivatives of a
single reagent-type would be important. Notably, staying with the
same radical trapping reagent-type, the chemistry and
mechanism are unaltered and hence similar protocols can be
used.
azidation,
trifluoromethylthiolation,
phenylsulfenylation,
trifluoromethylselenylation and halogenation of alkyl allyl sulfones
by applying various sulfone-type trapping reagents. Product
diversity is further expanded using a deuterated thiol as the
radical trapping reagent enabling the desulfonylative deuteration
(Scheme 1c).
Our previous efforts led to the development of diversity-oriented
remote site-selective functionalization of unactivated aliphatic
CH bonds in amides with sulfone-type reagents.[7] In these
transformations, the N-allylsulfonamide[8] moiety was used as a
stable N-radical precursor. The C-radical, formed via 1,5-
hydrogen atom transfer to the N-radical, is trapped with various
sulfone-type reagents to enable CN, CX (halo), CS and CC
bond construction (Scheme 1b).[7] Motivated by the reliability of
these S-based reagents, we decided to apply them to diversity-
oriented radical desulfonylative functionalization of allyl sulfones.
Scheme 1. Diversity-oriented transformation via radical reactions.
Initial studies were devoted to the radical alkynylation,[7b,11]
since alkynes are versatile building blocks in synthesis and
materials science.[12] The readily prepared sulfone 1a (Table 1, for
preparation of sulfones, see the Supporting Information) was
used as the alkyl radical precursor. Three alkynes (2a-c) were
tested as trapping reagents in combination with dilauroyl peroxide
(DLP) as the radical initiator in chloroform. By using the
alkynyltriflone 2a introduced by Fuchs,[11e] C-alkynylation
[a]
Dr. Y. Xia and Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201903668
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COMMUNICATION
occurred and the targeted 3a was obtained in moderate yield
(50%, entry 1). With sulfone 2b and phenylethynylbenziodoxolone
2c, worse results were noted (entries 2,3) and 2a was selected
for further optimization. Yield was increased to 65% by replacing
BPO with AIBN (entry 5). Switching to other initiators (entries 4-6)
and replacing CHCl3 by other solvents (entries 7-10) led to worse
results. Yield further improved to 73% upon increasing the initiator
loading (entry 11) and increasing reaction temperature to 85°C
led to a similar result (74% yield, entry 12).
alkynylation with concomitant regioselective [3+2] alkyne azide
cycloaddition with reagent 2a. When the reaction was performed
on larger scale (1 mmol), a slight decrease of the yield was noted
(3a, 66%).
The potential of the method was further documented by
alkynylation of more complex bioactive relevant compounds. 8-
Mercaptomenthone, which was used as a blackcurrant flavor,
could be alkynylated to give 3r in 69% yield. Alkyne 3s was
obtained in 37% yield as
a 54:46 mixture of the two
diastereoisomers from the corresponding Boc-protected proline
derivative.
Table 1. Reaction optimization.[a]
Entry
Initiator
DLP
2
Solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
EtOAc
Hexane
Toluene
CHCl3
CHCl3
Yield (3a) (%)[b]
1
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
50
19
trace
49
65
50
58
60
56
10
73
74
2
DLP
3
DLP
4
BPO
AIBN
ACBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
5
6
7
8
9
10
11[c]
12[c,d]
[a] Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol, 2.0 equiv) and initiator (20
mol%) in solvent (0.4 mL) were stirred at 80 °C for 24 h. [b] NMR yield using
CH2Br2 as an internal standard. [c] 30 mol% of AIBN was used. [d] Reaction
temperature was increased to 85°C; Isolated yield at 0.2 mmol scale. DLP =
Scheme 2. Variation of alkyl allyl sulfone (reaction conditions: 1 (0.2 mmol), 2a
(0.4mmol, 2.0 equiv) and AIBN (30 mol%) in CHCl3 (0.4 mL) were stirred at
85 °C for 48 h. Yields given correspond to isolated yields. Yield in parentheses
for 1.0 mmol scale experiment). a) Determined by GC-analysis.
dilauroyl peroxide; BPO
=
dibenzoyl peroxide; AIBN
=
α,α′-
azobisisobutyronitrile; ACBN = α,α′-azobis(cyclohexanecarbonitrile).
Next, the scope of the triflone component was probed with allyl
sulfone 1f as the radical precursor (Scheme 3). Electronic effects
exerted by the aryl moiety in the arylalkynyl triflones are weak and
triflones bearing electron-donating and electron-withdrawing
substituents at the para, meta, and ortho-position of the aryl group
provided similar yields (3t−3aa, 62−76%). The 2-thienylalkynyl
triflone also engaged in the alkynylation (3ab, 45%). We were
pleased to find that less activated alkylalkynyl triflones are eligible
reagents, as documented by the preparation of 3ac and 3ad. A
good yield was obtained for the silylalkynylation of 1f (3ae, 78%).
Reaction of allyl sulfone 1h with a chlorophenyl- and a
biphenylalkynyl triflone occurred smoothly and the corresponding
products were obtained in good yields (3af, 68%; 3ag, 64%).
Under optimized conditions, substrate scope varying the alkyl
allyl sulfone was investigated (Scheme 2). Alkynylation
proceeded smoothly for tertiary as well as secondary alkyl
sulfones, and the alkynylated products 3a−3o were obtained in
good yields (53-78%). As compared to tertiary alkyl sulfones,
secondary alkyl congeners provided slightly lower yields. This is
not surprising since the SO2-fragmentation generating the alkyl
radical is less efficient for the secondary alkyl sulfonyl radicals
(see mechanistic discussion below). Along these lines, the
alkynylation of the primary alkyl sulfone 1y was possible, albeit in
lower yield (3p, 27%). The process shows broad functional group
tolerance and ketone (3a), ester (3b, 3m, 3l), ether (3c), alcohol
(3d, 3o), halo (3e,3f), phthalimide (3g, 3n) moieties are tolerated.
Nonfunctionalized sulfones including acyclic and cyclic systems
also engage in this transformation (3i-3k). In the case of the
azidylalkylsulfone 1q, the triazole 3q was obtained through radical
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10.1002/anie.201903668
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COMMUNICATION
the Cl-source (5m, 61%) and with tetrabromomethane (4f) as the
trapping reagent, the bromide 5n was obtained (60%).
Scheme 3. Variation of the triflone reagents (reaction conditions: 1 (0.2 mmol),
2a (0.4 mmol, 2.0 equiv) and AIBN (30 mol%) in CHCl3 (0.4 mL) were stirred at
85 °C for 48 h. Yields given correspond to isolated yields.)
To document the diversity of our approach, related radical
transformations varying the sulfone-type radical trapping reagent
were studied and the azidation[13] was first explored (Scheme 4).
Reaction of 1h with trifluoromethanesulfonylazide (TfN3, 4a)[7a,13e]
under the above optimized conditions afforded the azide 5a in 48%
yield. With DLP as the initiator, the yield could be increased to 76%
and all following azidations were initiated with DLP. Reactions
with reagent 4a proceeded well for tertiary and secondary alkyl
sulfones, delivering the corresponding azides 5a−5c in good to
excellent yields (76-96%). More complex allyl sulfones could also
be converted to the targeted azides (5d, 5e).
Scheme 4. Variation of radical trapping reagents (reaction conditions: 1 (0.2
mmol), 4 (0.4 mmol, 2.0 equiv) and AIBN (30 mol%) in CHCl3 (0.4 mL) were
stirred at 85 °C for 48 h. Yields given correspond to isolated yields. Yields in
parentheses for 1.0 mmol scale experiments. Diastereoselectivity was
determined by NMR (5e, 5k) or GC-analysis (5h)); a) Using DLP (30 mol%) as
the initiator. b) CHBr3 was used as the solvent.
Site-specific incorporation of deuterium is important since
deuterium-labeled compounds are widely applied in synthetic and
medicinal chemistry (kinetic isotope effect measurements,
pharmacokinetic and pharmacodynamics research).[17] Radical
deuteration[3a,18] using D2O as the D-source represents a
promising approach due to the low cost of D2O and the high
functional group tolerance of radical chemistry. Recently,
MacMillan[18e] and Renaud[3a] developed radical deuterations with
D2O as the formal D-donor using phenol or thiol type HAT-
reagents, that readily exchange their protons with D2O. Inspired
by these works, we assumed that alkyl allyl sulfones can be
deuterated with D2O in combination with a suitable HAT reagent.
Pleasingly, high level of deuterium incorporation was achieved
with methyl thioglycolate in D2O/CHCl3. Both tertiary and
secondary alkyl allyl sulfones were deuterated in good yields (6a-
6d, 80-91%) and high deuterium incorporation (94-97%), further
documenting the generality of our approach (Scheme 5).
Because of the high lipophilicity of the SCF3 moiety, which
influences membrane permeability and bioavailability of
compound, efforts have been devoted to the development of
trifluoromethylthiolation methods. The direct
a
trifluoromethylthiolation[14] of stable alkyl allyl sulfones with
commercial available S-(trifluoromethyl) benzenesulfonothioate
(PhSO2SCF3, 4b) would be attractive. Gratifyingly, the
desulfonylative
functionalization
proceeded
well
and
trifluoromethylthiolation of tertiary and secondary alkyl sulfones
was achieved in excellent yields (5f, 91%; 5g, 90%). A derivative
of
the
steroid
hormone
thiocholesterol
was
also
trifluoromethylthiolated to afford 5h in 81% yield.
Although selenylated compounds have found various
applications,[15] trifluoromethylselenylation is still not well
investigated. We selected TsSeCF3 (4c) as the radical trapping
reagent[15b,c] and found that trifluoromethylselenylation occurred
smoothly to give the targeted products in excellent yields (5i-5k,
82-95%). By simply switching to commercial S-phenyl
benzenesulfonothioate (PhSO2SPh, 4d), phenylsulfenylation[16]
was possible (5l, 91%). Moreover, chlorination was achieved by
using the commercial trifluoromethanesulfonyl chloride (4e) as
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10.1002/anie.201903668
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processes feature broad substrate scope and excellent functional
group compatibility. The potential of this approach is further
documented by the functionalization of more complex and
biologically relevant compounds.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG).
Keywords: azidation • desulfonylativealkynylation • deuteration•
diversity-oriented synthesis• radical chemistry
Scheme 5. Deuteration of alkyl allyl sulfones (reaction conditions: 1 (0.2 mmol),
methyl thioglycolate (0.3 mmol, 1.5 equiv) and AIBN (30 mol%) in D2O/CHCl3
(1:1 1.0 mL) were stirred at 85 °C for 24 h. Yields given correspond to isolated
yields. Yield in parentheses for 1.0 mmol scale experiment). a)
Diastereoselectivity could not be determined.
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Diversity-oriented Desulfonylative
Functionalization of Alkyl Allyl
Sulfones
Diversity-oriented radical desulfonylative functionaliztion of alkyl allyl sulfones was
realized with various sulfone-based trapping reagents using practical
conditions.The novel approach was successfully applied to desulfonylative
alkynylation, azidation, trfluoromethylthiolation, trifluoromethylselenolation,
phenylthiolation, chlorination, bromination and deuteration.
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