Radical aminooxygenation of alkenes with N-fluoro-benzenesulfonimide (NFSI) and TEMPONa

Article abstract of DOI:10.1039/c5cc00591d

Reaction of various alkenes with commercially available N-fluorobenzenesulfonimide (NFSI) and TEMPONa provides the corresponding aminooxygenation products in moderate to good yields. Single electron transfer from readily generated TEMPONa to NFSI allows f

Full text of DOI:10.1039/c5cc00591d

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Radical aminooxygenation of alkenes with
N-fluoro-benzenesulfonimide (NFSI) and
TEMPONa†
Cite this:DOI: 10.1039/c5cc00591d
Received 21st January 2015,
Accepted 16th February 2015
Yi Li,‡ Marcel Hartmann, Constantin Gabriel Daniliuc and Armido Studer*
DOI: 10.1039/c5cc00591d
www.rsc.org/chemcomm
Reaction of various alkenes with commercially available N-fluoro-
benzenesulfonimide (NFSI) and TEMPONa provides the corresponding
aminooxygenation products in moderate to good yields. Single electron
transfer from readily generated TEMPONa to NFSI allows for clean
generation of the corresponding bissulfonylamidyl radical along with
TEMPO. N-radical addition to an alkene and subsequent TEMPO trap-
ping provides the corresponding aminooxygenation product.
Chemistry comprising C-centered radicals is very abundant.1
However, radical transformations occurring via N-centered
radicals have received far less attention in synthesis.2,3 In most
cases, N-centered radicals are generated via cleavage of a
reactive N–X bond.2 Along these lines, the commercially avail-
able N-fluorobenzenesulfonimide (NFSI)4 is an interesting
reagent. In fact, initially introduced for electrophilic fluorina-
tion,4 it has been more recently shown that NFSI also engages
in radical transformations. Fluorination of alkyl radicals by
NFSI was disclosed by Sammis et al.5 Zhang and coworkers
found that NFSI in combination with CuCl allows for radical
amidation of benzylic CH bonds.6 The same group later pre-
sented Cu-catalyzed radical-type vicinal aminocyanation7a and
aminofluorination7b with NFSI as the amine donor. Kanai
et al.8 and we9 further explored Cu-catalyzed radical amination
of alkenes using NFSI as a reagent, and direct radical arene
amidations with NFSI have also been reported.10
Fig. 1 Radical alkene aminooxygenation.
NFSI has a reduction potential of E = ꢀ0.78 versus SCE13 and
therefore it is expected that NFSI is readily reduced by TEMPONa.
Based on these facts, we planned to develop a radical alkene
aminooxygenation14 with NFSI and TEMPONa as reagents. The
novel approach is presented in Fig. 1. TEMPONa first reduces
NFSI to generate NaF, a bissulfonamidyl radical along with
TEMPO. N-radical addition to the alkene followed by trapping
of the adduct radical with TEMPO will afford the targeted
aminooxygenation product. Notably, selective cross-coupling
of the adduct radical with TEMPO is controlled by the Persis-
tent Radical Effect which describes the highly selective cross-
coupling between a persistent and a transient radical.15
We have recently initiated a program towards vicinal radical
difunctionalization of alkenes and already disclosed azidoox-
ygenation,11a oxyarylation,11b trifluoromethylamin-oxylation,11c
hydroxyarylation11d and aminoazidation.9
Initial experiments were conducted with styrene as a radical
acceptor. Styrene (5 equiv.) and NFSI (1 equiv.) were dissolved in
DCM and a freshly prepared THF solution of TEMPONa (1.2 equiv.,
see ESI†) was slowly added over 4 h at room temperature via a
syringe pump. Pleasingly, the targeted aminooxygenation product
2a was isolated in 46% yield (Table 1, entry 1). The reaction in THF
In some of these cases the readily prepared TEMPONa salt11a–c
(TEMPO, 2,2,6,6-tetramethylpiperidine-N-oxyl radical)12 was used
as an organic single electron transfer (SET) reducing reagent.
¨
¨
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat,
16
¨
Corrensstraße 40, 48149 Munster, Germany. E-mail: studer@uni-muenster.de
was less efficient but in PhCF3 a slightly improved yield was
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data for all compounds. CCDC 1043955 (2q). For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c5cc00591d
‡ The manuscript was written by A.S.; Y.L. and M.H. ran all experiments.
obtained (entries 2 and 3). We then decided to use TEMPONa and
NFSI in excess (3 equiv. each) and obtained an improved yield
(55%, entry 4). Diluting the TEMPONa solution gave a worse result
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Table 1 Optimization studies
Entry TEMPONaa (equiv.) NFSI (mol%) Solvent Time (h) Yieldb (%)
1c
2c
3c
4
1.2
1.2
1.2
1.0
1.0
1.0
3.0
3.0
3.0
3.0
1.0
2.0
2.0
2.0
DCM
THF
4
4
4
4
4
6
6
6
6
6
46
41
47
55
51
90
65
59
52
55
70
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
3.0
5
6
3.0d
3.0
7e
8f
9f
10
11
3.0
2.0d
2.0d
2.0d
2.0d
PhCF3 15
a
b
TEMPONa solution in THF (1.7 molar) was used. Isolated yield.
c
d
Styrene (5 equiv.) was used. TEMPONa solution in THF (0.85 molar)
e
f
was used. TEMPO (0.05 equiv.) was added. Styrene (2 equiv.) was used.
(entry 5) and the best yield was achieved upon extending the
reaction time to 6 h (90%, entry 6). We assumed that due to a low
TEMPO concentration during reaction telomerization might occur to
some extent. Therefore, a small amount of TEMPO (0.05 equiv.) was
added. However, the yield dropped to 65% (entry 7). Lowering the
concentration and amount of reagents or increasing the reaction
time did not lead to a higher yield (entries 8ꢀ11).
Under optimized conditions (Table 1, entry 6), the scope and
limitation of the radical aminooxygenation were explored by
testing alkenes 1b–t. Reaction of ortho, meta and para-methyl
substituted styrene worked well and the corresponding pro-
ducts 2b–d were isolated in good yields (66ꢀ70%, Fig. 2). As
expected, para-tert-butyl-styrene and para-vinyl-biphenyl were
also good substrates (see products 2e,f). However, a signifi-
cantly lower yield was achieved in the transformation of b-vinyl-
naphthalene to 2g. Aminooxygenation of halogenated styrene
derivatives was efficient and TEMPO-adducts 2h–k were
obtained in 60–73% isolated yields. The CF3-derivative 1l
delivered a lower yield of product 2l.
a
Fig. 2 Aminooxygenation of various alkenes.
Conducted in the
b
c
presence of TEMPO (0.05 equiv.). With trans-b-methyl styrene. With
cis-b-methyl styrene.
We were very pleased to observe that unactivated aliphatic
alkenes also undergo radical aminooxygenation as shown by the
successful preparation of compounds 2m and 2n. The bissulfonyl-
amidyl radical generated from NFSI is an electrophilic amidyl
radical. Therefore, the reaction should be particularly efficient with
electron-rich alkenes. In fact, aminooxygenation of vinyl ether 1o
provided 2o in 77% yield. In this case we added a small amount of
TEMPO (0.05 equiv.) to suppress telomerization. As expected,
reaction with the electron-poor methyl acrylate did not work and
the targeted product 2p was not identified in the reaction mixture.
We also investigated the diastereoselectivity of aminooxy-
genation and found trans-b-methyl-styrene to react in good yield
Fig. 3 Crystal structure of compound 2q (thermal ellipsoids are shown
with 50% probability).
configuration of the major isomer of 2r was assigned in analogy
(73%) and good diastereoselectivity (dr = 15 : 1) to 2q. The to 2q. Excellent stereocontrol was also achieved in the trans-
relative configuration of 2q was unambiguously assigned by formation of indene and 2s was isolated as a single diastereoi-
X-ray crystallography (Fig. 3).17 It is obvious for a radical process somer in 69% yield. Dearomatizing vicinal bisfunctionalization
of benzofuran to give 2t is possible with the new method.
Notably, reaction occurred with complete stereocontrol and
regiocontrol, albeit in moderate yield.
that cis-b-methyl-styrene provided 2q with the same selectivity.
trans-Stilbene was converted to 2r which was obtained in
good yield and very high selectivity (dr = 20 : 1). The relative
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ation products in moderate to good yields. Vicinal radical bisfunc-
tionalization works on electron-rich alkenes whereas electron-poor
radical acceptors, such as methyl acrylate, did not provide the
aminooxygenation compounds. With 1,2-disubstituted alkenes
good to excellent diastereoselectivities can be achieved. Moreover,
we have shown that the aminooxygenation products can be readily
further chemically manipulated. Reductive cleavage of the N–O
bond of the TEMPO moiety provides the corresponding alcohol
in excellent yield. C–O bond cleavage is realized quantitatively by a
radical deoxygenation procedure and the TEMPO alkoxyamine
entity can be oxidatively converted to the ketone functionality. If
2-substituted alkenes are used as radical acceptors, aminooxygena-
tion products are not stable and TEMPOH elimination under the
reaction conditions provides the corresponding products of allylic
or vinylic amidation.
Fig. 4 Allylic and vinylic amidation.
The authors declare no competing financial interest.
This work was financially supported by the Deutsche
Forschungsgemeinschaft.
We next investigated whether tertiary alkoxyamines can be
prepared via this novel route. To this end, 2-substituted alkenes
were reacted under optimized conditions. Surprisingly, in the
transformation of 2-ethyl-butene (3a), the targeted amino-
oxygenation compound was not identified and bissulfonamide
4a was isolated in good yield (75%) and complete E-selectivity
(Fig. 4). This alkene is derived from the tertiary alkoxyamine,
which under the applied reaction conditions undergoes regio- and
stereoselective TEMPOH elimination to give 4a. In analogy, alkenes
4b–d were obtained via aminooxygenation and subsequent
TEMPOH elimination. TEMPOH elimination to 4c occurred
with complete regioselectivity. However, in the case of 4d along
with the allylamide the enamide 4d0 was also formed.18
Finally, to show the synthetic value of our new method, we
investigated follow-up chemistry of aminooxygenation product
2a (Fig. 5). N–O bond cleavage in 2a was readily achieved with
Zn under mild conditions (rt) to give alcohol 5 in a quantitative
yield (99%). meta-Chloroperbenzoic acid (MCPBA) mediated
oxidation of 2a in CH2Cl2 provided ketone 6 in excellent yield
(89%) and b-amidoethylbenzene 7 was obtained by a radical
deoxygenation reaction (96%).11b Treatment of 2a with Mg in
HOAc–NaOAc–DMF according to a literature procedure19 gave
sulfonamide 8 in quantitative yield.
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