Direct oxidative allylic and vinylic amination of alkenes through selenium catalysis

Article abstract of DOI:10.1002/anie.201303662

Bringing "N" into the game: The direct chemoselective nitrogenation of unactivated alkenes can be achieved through oxidative selenium catalysis (see scheme). This method provides a broad variety of allylic imides in yields of up to 89 % using N-fluorobenzenesulfonimide (NFSI) as the terminal oxidant and nitrogen source. Furthermore, an unprecedented selenium-catalyzed vinylic C(sp²)-H nitrogenation was discovered. Copyright

Full text of DOI:10.1002/anie.201303662

Angewandte
Chemie
Communications
Selenium Catalysis
J. Trenner, C. Depken, T. Weber,
A. Breder*
&&&& — &&&&
Bringing “N” into the game: The direct
chemoselective nitrogenation of unacti-
vated alkenes can be achieved through
oxidative selenium catalysis (see
scheme). This protocol provides a broad
variety of allylic imides in yields of up to
89% using N-fluorobenzenesulfonimide
Direct Oxidative Allylic and Vinylic
Amination of Alkenes through Selenium
Catalysis
(NFSI) as the terminal oxidant and
nitrogen source. Furthermore, an unpre-
cedented selenium-catalyzed vinylic C-
(sp2)–H nitrogenation was discovered.
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DOI: 10.1002/anie.201303662
Selenium Catalysis
Direct Oxidative Allylic and Vinylic Amination of Alkenes through
Selenium Catalysis**
Johanna Trenner, Christian Depken, Thomas Weber, and Alexander Breder*
Dedicated to Professor Erick M. Carreira on the occasion of his 50th birthday
À
The fundamental importance of efficient C N bond-forming
reactions is reflected in the plethora of nitrogenated, naturally
occurring and anthropogenic compounds with essential
biological function.[1] Due in part to their relevance in the
realm of medicinal as well as agrochemical applications,[2]
numerous efforts have been dedicated to the development of
novel processes for the construction of carbon–nitrogen
bonds.[3] In this context, palladium-catalyzed oxidative ami-
dations and imidations of arenes and olefins have become the
subject of intensive investigations.[4] Hegedus et al. reported
one of the first examples of a PdII-catalyzed intramolecular
oxidative amination of allylic aniline derivatives using CuCl2
or benzoquinone for the regeneration the PdII catalyst.[5] Stahl
and co-workers later documented the use of molecular
oxygen as the terminal oxidant for a cognate amination
reaction.[6] Recently, White and co-workers disclosed an
intermolecular, oxidative allylic amination of simple olefins
catalyzed by a palladium bis(sulfoxide) complex in the
presence of either a chromium–salen complex[7a] or a Brønsted
base[7b] co-catalyst leading to linear allylic amines.
Despite these remarkable achievements, to date there has
been only a limited number of reports on the direct, oxidative
nitrogenation of alkenes promoted by non-transition-metal
catalysts. Given the increasing demand for more cost-efficient
alternatives to precious metals as catalysts, main-group
elements such as sulfur[13] and selenium[14] turned out to be
appropriate candidates. In the course of our research program
towards the development of new metal-free protocols for the
catalytic and chemoselective nitrogenation of unactivated
olefins we became interested in the use of organodiselanes as
potent redox-active catalysts. From reports first by Sharpless
et al.[15] and later by Tunge et al.[16] it is known that reactions
of simple alkenes with N-halosuccinimides (halogen = Cl, Br)
in the presence of selenium catalysts generally furnish the
corresponding allylic and vinylic halides. However, cognate
intermolecular Se-catalyzed processes leading to allylic or
vinylic imide derivatives have, to the best of our knowledge,
not been reported thus far.[17] A major difficulty associated
with the design of such an imidation reaction using N-
haloimides as the terminal oxidant is the inherent preference
for halogen transfer instead of incorporation of the nitrogen
entity. As a viable solution to this problem we present herein
a selenium catalysis protocol for the efficient synthesis of
a broad variety of allylic and vinylic imides 2 and 4,
respectively, using N-fluorobenzenesulfonimide (NFSI)[18] as
the terminal oxidant and nitrogen source (Scheme 1).
In addition to transition-metal-catalyzed protocols,
a number of iodine(III)-mediated nitrogenations of carbon–
hydrogen bonds have been documented, for example amina-
tions of aromatic C(sp2)–H and benzylic C(sp3)–H systems.[8]
Most recently, MuÇiz and co-workers described the stoichio-
metric use of a mixed hypervalent iodine reagent for the
oxidative, allylic amination of 2-arylated propene deriva-
tives.[9] Furthermore, Sharpless et al. reported a seleniu-
m(IV)-mediated allylic amination of alkenes by means of
a hetero-Alder-ene reaction.[10] Koizumi and co-workers
described the stereoselective synthesis of nonracemic allylic
amines derived from selenimides by means of a [2,3]-sigma-
tropic rearrangement.[11] Very recently, Yeung et al. disclosed
an enantioselective bromoaminocyclization of homoallylic
amines using a mannitol-derived tetrahydroselenophene
catalyst.[12]
Scheme 1. Formation of allylic and vinylic amine derivatives through
the selenium-catalyzed intermolecular oxidative imidation of alkenes.
EWG=electron-withdrawing group.
[*] M. Sc. J. Trenner, B. Sc. C. Depken, B. Sc. T. Weber, Dr. A. Breder
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
In initial experiments benzyl pent-3-enoate (1a) was
reacted with 1 equiv of NFSI in the presence of 5 mol% of
various di(hetero)aryldiselanes in THF (0.2m) at ambient
temperature for 16 h (Table 1). While diphenyl diselane
provides access to target structure 2a in a reasonable yield
of 64% (Table 1, entry 1), dipyridin-2-yl diselane and difer-
rocenyl diselane furnished allylic imide 2a only in moderate
yields of 55% and 48%, respectively (Table 1, entries 2 and
3). During the course of these experiments the formation of
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: abreder@gwdg.de
[**] This work was financially supported by the Fonds der Chemischen
Industrie (Liebig fellowship to A.B.). We thank Prof. Dr. Lutz
Ackermann for generous support of our work. We thank Stefan
Ortgies and Hauke Stꢀrznickel for preparing several substrates.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303662.
2
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Table 1: Optimization of the selenium-catalyzed allylic imidation.[a]
Entry
Cat.
Solv.
Additive
Yield [%]
1
2
3
4
5
6
7
(PhSe)2
(2-PyrSe)2
(FcSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
–
THF
THF
THF
THF
–
–
–
64
55
48
84
64
74
60
0
4 ꢀ MS
4 ꢂ MS
4 ꢂ MS
4 ꢂ MS
4 ꢂ MS
4 ꢂ MS
Et2O
1,4-dioxane
MeCN
THF
8
9[b]
(PhSe)2
THF
82
[a] Conditions: 1a (0.27 mmol), NFSI (0.27 mmol), catalyst (5 mol%),
solvent (1.35 mL), 238C under Ar. NFSI=N-fluorobenzenesulfonimide,
2-Pyr=pyridin-2-yl, Fc=ferrocenyl, MS=molecular sieves. Reaction
time: 16 h. [b] 1.1 equiv of 2,6-di-tert-butylpyridine was added to the
reaction mixture.
(E)-benzyl 4-oxopent-2-enoate was observed as a by-product
in varying amounts. This finding was attributed to the
presence of adventitious water in the reaction medium. In
order to sequester any residual water 4 ꢀ molecular sieves
were added to the reaction medium, which led to an improved
yield of 84% under otherwise identical conditions (Table 1,
entry 4). Subsequently, a variety of different solvents were
screened. In general, other ethereal solvents, such as diethyl
ether (64%, Table 1, entry 5) and 1,4-dioxane (74%, entry 6),
led to inferior yields. When the reaction was carried out in
acetonitrile, allylic imide 2a was isolated in a reasonable yield
of 60% (Table 1, entry 7).
In order to exclude the possibility of background reac-
tivity between NFSI and the substrate, the transformation was
attempted in the absence of selenium catalysts. Under these
conditions no conversion was observed in the course of 16 h
(Table 1, entry 8). To further exclude the possibility of
Brønsted acid catalysis promoted by the coproduct HF, the
reaction was carried out in the presence of 1.1 equiv of 2,6-di-
tert-butylpyridine (Table 1, entry 9). However, even in the
presence of a base, product 2a was isolated in 82% yield.
Altogether, these observations support the postulated role of
the organodiselanes as the only catalytically active species in
these transformations.
With an efficient set of conditions in hand, we continued
our investigations with the exploration of the substrate scope
(Scheme 2). Therefore, alkenes 1a–l were synthesized and
tested in the title transformation. In general, allylic imides
2a–l were isolated in reasonable to very good yields ranging
from 49–89% and with high levels of regio- and chemo-
selectivity.[19] In addition, the method is very tolerant towards
various functional groups, such as ester, sulfone, amide,
ketone, phosphonate, and nitrile moieties.
It should be pointed out that compounds 2a–f showcase
a novel and step-efficient entry to g4-amino acid deriva-
tives.[20] Related structures are found in a number of
biologically active cyclic peptides such as didemnins,[21]
syringolins,[22] and glidobactins.[23] Due to the high potential
with regard to medical applications, natural and artificial
Scheme 2. Substrate scope for the selenium-catalyzed synthesis of
allylic imides 2a–l. Unless indicated otherwise, all reactions were
performed as follows: 1a–l (0.17–0.59 mmol), NFSI (1 equiv), (PhSe)2
(5 mol%), THF (0.2m), 16–20 h 238C. [a] Yield was determined by
1H NMR spectrosctopy. Imides 2c,d and 2l were derived from Z-
configured alkenes.
peptides containing g4-amino acids have recently become the
subject of intensive investigations.[24] In contrast to our
protocol, however, traditional methods for the construction
of vinylogous amino acid motifs commonly rely on dissipative
homologation reactions using phosphorus ylides.[24d]
In order to test the influence of chiral auxiliaries on the
diastereoselectivity, enantiomerically enriched esters 1e and
1 f were subjected to the standard reaction conditions.
Although the corresponding imides 2e and 2 f were obtained
in high yields of 79% and 81%, respectively, each product
was isolated as an equimolar mixture of diastereomers.
Next, we turned our attention to the catalytic imidation of
cyclic alkenes (Scheme 3). For this purpose cyclohex-3-en-1-
one (3a) was initially reacted with 1 equiv of NFSI under
standard conditions. In contrast to expectations, the prefer-
ential formation of vinylic imide 4a (62% yield)[25] along with
its allylic isomer (27% yield)[26] was detected. An even better
chemoselectivity in favor of the vinyl product 4b was
observed when sulfolene (3b) was used. The resulting imide
4b was isolated in 79% yield together with 9% of its allylic
isomer. Although the yield was low yields (37%), conversion
of cyclopentene (3c) exclusively furnished imide 4c as the
only isolable product.[27] To the best of our knowledge, the
formation of imides 4a–c represents the first case of the
oxidative, intermolecular C(sp2)–H imidation of electron-
neutral alkenes promoted by an organodiselane catalyst.
In addition to the vinylic imidation of (hetero)cycloal-
kenes 4a–c, this protocol proved also very fruitful for the
conversion of styrene-type derivatives, such as b-methylstyr-
ene (3g), indenes (3 f and 3i), and dihydronaphthalenes
(Scheme 3). In order to obtain satisfactory yields for the latter
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diselane or by a preformed, oxidized selenium derivative,
such as PhSeN(SO2Ph)2 or PhSeF.[32] In the first experiments,
alkene 1a was reacted with 1 equiv of NFSI in THF (0.2m) in
the presence of PhSeBr (5 mol%) as the catalyst [Eq. (2)].
Under these conditions, however, no product formation was
detected. According to literature precedence, PhSeBr is
known to undergo addition into electron-neutral alkenes to
transiently form aryl alkylselanes.[33] In combination with our
own results these data suggest that NFSI is not sufficiently
reactive to initiate dehydroselenylation, the key step leading
to allylic imide 2a.
Scheme 3. Substrate scope for the selenium-catalyzed synthesis of
vinyl imides 4a–l: Unless indicated otherwise, all reactions were
performed as follows: 3a–l (0.19–0.43 mmol), NFSI (1 equiv), THF
(3a–c) or 1,4-dioxane (3d–l) (each 0.2m), 16–20 h, 238C. [a] 5 equiv of
3k was used and the yield of 4k is based on NFSI.
To further substantiate the key role of diphenyl diselane
for the oxidative imidation, we analyzed an equimolar
mixture of NFSI and (PhSe)2 in [D8]THF by 1H NMR
spectroscopy at ambient temperature over the course of 9 h.
During that period continuous degradation of NFSI down to
9% was observed while 82% of the diselane catalyst
remained intact. In a control experiment NFSI alone was
found to be stable in [D8]THF throughout the same time
period. Next, a 5:1 mixture of NFSI and (PhSe)2 was reacted
under otherwise identical conditions. In the course of 16 h the
diselane was completely degraded while 44% of NFSI
remained intact. Importantly, no further decomposition of
NFSI was detected after the disappearance of (PhSe)2. From
these observations we conclude that the Se–Se bond is crucial
for the catalytic activity. Based on the analytical data as
a whole, we postulate the following tentative catalytic cycle
(Scheme 4). First, NFSI undergoes nucleophilic attack by
diphenyl diselane leading to cationic species I. Subsequent
addition to alkene 1 gives rise to cationic adduct II,[34] which in
turn undergoes elimination to complete the catalytic cycle.[35]
substrates, the standard reaction conditions shown in
Scheme 2 had to be altered. Thus, the use of 1,4-dioxane
(0.2m) as the solvent at room temperature in the presence of
5 mol% of the Se catalyst and 4 ꢀ molecular sieves was
identified as the best set of reaction parameters. Under these
modified conditions vinyl imides 4d–l were obtained in
reasonable to excellent yields ranging from 65–95%. Both
electron-deficient (e.g. 4i, 95%; 4l, 91%) and electon-rich
(4h, 65%) substrates were well tolerated.
Having established a robust protocol for the C(sp2)–H
imidation of cyclic alkenes, we eventually envisioned a one-
pot sequence consisting of reductive desulfonylation/proto-
nation followed by nucleophilic trapping of the transiently
formed imine species to arrive at the corresponding function-
alized sulfonamide. Such a scenario would not only demon-
strate that the nitrogen group can be selectively deprotected
but it would also exemplify the use of vinylimides 4 as masked
enamine precursors. To prove our hypothesis, we initially
screened for a number of reducing agents using compound 4i
as our test substrate. Unfortunately, neither samarium(II)
iodide[28] nor sodium naphthalenide[29] provided access to the
desired desulfonylation product.[30] Treatment of vinyl imide
4i with 1 equiv of LiEt3BH in THF at À158C eventually
furnished an unstable enamide intermediate [Eq. (1)].[31]
Direct addition of methanol (100 vol% based on THF) and
sodium borohydride (1.1 equiv) to the enamide-containing
THF solution finally gave rise to benzylic sulfonamide 5 in
60% yield over two steps.
To elucidate the reaction mechanism of the oxidative
imidation, we initially wanted to determine whether forma-
Scheme 4. Tentative catalytic cycle for the oxidative imidation of
alkenes 1 and 3.
À
tion of the C N bond is actually catalyzed by diphenyl
4
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[9] J. A. Souto, D. Zian, K. MuÇiz, J. Am. Chem. Soc. 2012, 134,
In summary, we have disclosed an organodiselane-cata-
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dation of unactivated alkenes using NFSI as both the terminal
oxidant and the nitrogen source. It was also demonstrated
that vinylimides formed by the title procedure can be used as
masked enamides through chemoselective cleavage of a sul-
fonyl group. Furthermore, the method features a new avenue
toward the synthesis of vinylogous g4-amino acid derivatives,
a molecule class often found in protease inhibitors. Con-
sequently, we anticipate this method to successfully comple-
7242.
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Received: April 29, 2013
Published online: && &&, &&&&
À
Keywords: alkene oxidation · C N coupling ·
.
reaction mechanisms · selenium catalysis · synthetic methods
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[26] 1H NMR spectroscopic data of the minor isomer suggest that the
nitrogen entity is located in the g-position with respect to the
a,b-unsaturated carbonyl group.
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[28] E. Vedejs, S. Lin, J. Org. Chem. 1994, 59, 1602.
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[30] No conversion was observed under these conditions.
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[32] For reactions involving selenium fluorides, see: a) S. A. Ler-
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[35] An alternative reaction pathway may involve the formation of
an aziridinium intermediate instead of adduct II. In the case of
linear substrates the former may undergo elimination, which
would give rise to imides 2. Further mechanistic investigations to
account for the change of regioselectivity in the case of cyclic
substrate are currently in progress.
6
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