Gold(I)-Catalyzed N-Desulfonylative Amination versus N-to-O 1,5-Sulfonyl Migration: A Versatile Approach to 1-Azabicycloalkanes

Article abstract of DOI:10.1002/anie.201604329

Valuable 1-azabicycloalkane derivatives have been synthesized through a novel gold(I)-catalyzed desulfonylative cyclization strategy. An ammoniumation reaction of ynones substituted at the 1-position with an N-sulfonyl azacycle took place in the presence of a gold cation by intramolecular cyclization of the disubstituted sulfonamide moiety onto the triple bond. Depending on the size of the heterocyclic ring and substitution of the substrates, two unprecedented forms of nucleophilic attack on the sulfonyl group were exploited, that is, a N-desulfonylation in the presence of an external protic O nucleophile (37–87 %, 10 examples) and a unique N-to-O 1,5-sulfonyl migration (60–98 %, 9 examples).

Full text of DOI:10.1002/anie.201604329

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604329
German Edition: DOI: 10.1002/ange.201604329
Heterocycle Synthesis
Gold(I)-Catalyzed N-Desulfonylative Amination versus N-to-O
1,5-Sulfonyl Migration: AVersatile Approach to 1-Azabicycloalkanes
Solꢀne Miaskiewicz, Boris Gaillard, Nicolas Kern, Jean-Marc Weibel, Patrick Pale,* and
Aurꢁlien Blanc*
Abstract: Valuable 1-azabicycloalkane derivatives have been
synthesized through a novel gold(I)-catalyzed desulfonylative
cyclization strategy. An ammoniumation reaction of ynones
substituted at the 1-position with an N-sulfonyl azacycle took
place in the presence of a gold cation by intramolecular
cyclization of the disubstituted sulfonamide moiety onto the
triple bond. Depending on the size of the heterocyclic ring and
substitution of the substrates, two unprecedented forms of
nucleophilic attack on the sulfonyl group were exploited, that
is, a N-desulfonylation in the presence of an external protic
O nucleophile (37–87%, 10 examples) and a unique N-to-O
1,5-sulfonyl migration (60–98%, 9 examples).
or basic conditions are typically required for N-desulfonyla-
tion,[10] and such conditions are rarely compatible with
polyfunctional complex natural product targets.
The alleviation of these problems would thus offer new
opportunities in total synthesis based on gold catalysis. The
few known examples of gold-catalyzed intramolecular cycli-
zation reactions of secondary sulfonamides suggest an
interesting approach (Scheme 1).[11] In these reactions, sulfo-
nyl migration from nitrogen to the gold-bound carbon atom
occurs via a transient vinylgold ammonium intermediate.
However, this N-desulfonylation pathway leads to com-
pounds of limited synthetic utility owing to the formation of
[12]
À
a C SO2R bond, which is difficult to cleave.
Since the beginning of this century, homogeneous gold
catalysis has emerged as a continuously growing field of
investigation.[1] Indeed, owing to their exceptional p acidity,
cationic gold(I) complexes have been used in a myriad of
synthetic applications, especially in the catalytic activation of
unsaturated carbon–carbon bonds for nucleophilic addition
reactions.[2] Such studies have led to outstanding achieve-
ments in asymmetric catalysis[3] as well as in total synthesis.[4]
In this area, the gold-catalyzed amination of alkynes has
become a very useful and common tool for the construction of
elaborate heterocyclic structures containing at least one
nitrogen atom.[5] The potential of these transformations has
been demonstrated by their application to the synthesis of
nitrogen-containing natural and biologically active prod-
ucts.[6] However, the amination process still demands appro-
priate substrate engineering. Indeed, basic amine groups
often inhibit catalytic activity by strongly interacting with
gold cations,[7] but also by slowing down the protodemetala-
tion step, which is rate-limiting in many catalytic cycles.[8] To
address this problem, electron-withdrawing nitrogen-protect-
ing groups are generally used, such as the popular and robust
Scheme 1. Known N-to-C 1,3-sulfonyl migration catalyzed by gold(I).[11]
We recently demonstrated that bicyclic vinylgold ammo-
nium intermediates, formed by the gold activation of ynones
A substituted at the 1-position with an N-sulfonyl azacycle,
can be opened regioselectively by oxygenated nucleophiles.
This reaction allowed the exclusive formation of pyrrolin-4-
ones in high yields (Scheme 2, top).[13] On this basis, an
À
sulfonyl groups ( SO2R), thus inferring the need for a sub-
sequent deprotection step. However, N-desulfonylation reac-
tions are far from trivial and still represent a significant
challenge,[9] which can hamper the transfer of interesting
methodologies to real total synthesis. Indeed, strong reductive
[*] S. Miaskiewicz, B. Gaillard, Dr. N. Kern, Prof. Dr. P. Pale, Dr. A. Blanc
Laboratoire de Synthꢀse, Rꢁactivitꢁ Organiques et Catalyse
UMR 7177 associꢁ au CNRS, Institut de Chimie
Universitꢁ de Strasbourg
4 rue Blaise Pascal, 67070 Strasbourg (France)
E-mail: ppale@unistra.fr
ablanc@unistra.fr
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604329.
Scheme 2. Gold(I)-catalyzed regioselective ammonium substitution or
migration with an external or internal protic nucleophile.
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Table 1: Screening of gold catalysts in the N-detosylative amination of
1a.
alternative pathway could be envisaged through nucleophilic
attack, either inter- or intramolecularly, on the sulfonyl group
on the ammonium intermediate B. Such a cascade would lead
to the synthetically useful 1-azabicycloalkane derivatives C
and D (Scheme 2, bottom).
Thus, after an initial gold-triggered ammoniumation,[14] an
appropriate soft, protic, and sulfur-selective nucleophile
Entry
Catalyst
Time [h]
Yield [%][b,c]
À
would cleave the N S bond and also deliver the requisite
1
2
3
4
5
6
7
8
9
[Ph3PAu]NTf2
5
5
6
24
3
1
2.5
1.5
1.5
0.5
24
5
50
34
5[e]
12[e]
48
49
32
49
66
87
proton for demetalation, thus affording deprotected products
C in a single operation (Scheme 2, bottom left). Besides this
formal hydroamination reaction, another option could be
considered in the absence of an external nucleophile. Indeed,
the in situ generation of an internal O nucleophile, through
a favorable keto–enol equilibrium, could lead to an N-to-O
transfer of the sulfonyl group to afford vinyl sulfonate
derivatives D (Scheme 2, bottom right).[15] Such a gold-
catalyzed 1,5-sulfonyl migration would furnish powerful
partners for palladium- and nickel-catalyzed cross-coupling
reactions,[16] through the conversion of a weakly nucleophilic
sulfonamide into an electrophilic sulfonate.
[(C6F5)3PAu]NTf2
[d]
[LAu]NTf2
[IPrAuCl]/AgNTf2
[JohnPhosAu]NTf2
[Cy3PAu]NTf2
[Ph3PAuCl]/AgSbF6
[Ph3PAuCl]/AgPF6
[Ph3PAuCl]/AgBF4
[Cy3PAuCl]/AgBF4
–
10
11
12
[f]
–
[g]
AgBF4
–
[a] DCE=1,2-dichloroethane; c=0.1 molLÀ1. [b] Yield calculated by
integration of the 1H NMR spectrum of the crude product relative to an
internal standard (dimethyl terephthalate). [c] C6H5OTs was observed in
each reaction affording 2a. [d] L=tris(2,4-di-tert-butylphenyl)phosphite.
[e] Degradation products were observed. [f] No conversion was
observed. [g] The pyrrolin-4-one 3a was obtained in 10% yield (see the
Supporting Information).[13] Cy =cyclohexyl, JohnPhos=2-(di-tert-butyl-
phosphanyl)biphenyl, Tf=trifluoromethanesulfonyl, Ts=para-toluene-
sulfonyl.
Herein, we report the successful implementation of these
hypotheses in a novel step-economic gold-catalyzed strategy
for the synthesis of various 1-azabicyclo[m.n.0]alkanes. These
motifs are very important, as they are present in numerous
natural products, such as carbapenem ([3.2.0]),[17] pyrrolizi-
dine ([3.3.0]), and indolizidine ([4.3.0]) alkaloids,[18] which
exhibit potent and useful biological activity (Scheme 3).
top) along with degradation products (Table 1, entries 11 and
12). Phenyl 4-methylbenzenesulfonate was always produced
concomitantly in these reactions, thus supporting our mech-
anistic hypothesis (Scheme 2).
A decrease in the number of phenol equivalents as well as
the temperature would make this N-desulfonylation amina-
tion synthetically more attractive. Furthermore, tuning of the
nature of the phenol reagent should enable the best balance
to be found between nucleophilic addition to the sulfonyl
group and protodemetalation. Thus, the screening of con-
ditions with various phenol derivatives led to optimal reaction
conditions, which afforded 2a in 81% yield with only
2 equivalents of meta-nitrophenol at 308C in the presence of
5 mol% of [Cy3PAuCl]/AgBF4 in dichloroethane (see
Table S1 in the Supporting Information).
Under these conditions, we then explored the scope of this
unprecedented transformation (Scheme 4). We first exam-
ined the effect of the sulfonyl group on the reaction. Substrate
1aa, bearing a para-nitrobenzenesulfonyl group (Ns) on the
nitrogen atom, reacted slowly under our reaction conditions.
The reaction mixture had to be heated at 708C for 4 h for full
conversion to be reached, and product 2a was obtained in
71% yield. In contrast, compound 1ab with a para-methoxy-
benzenesulfonyl group (Mbs) reacted well at 308C, but 2a
was isolated in lower yield from this reaction. Taking into
account that the phenol nucleophile was especially chosen for
the desulfonylation of robust tosyl derivatives (see Table S1),
we next evaluated various substrates 1b–e with the tosyl
protecting group. Avariety of substituents on the alkyne were
well tolerated, as attested by the formation of the 1-
Scheme 3. Examples of naturally occurring 1-azabicyclic systems.
With this aim, we chose the readily available 1-(N-
tosylazetidinyl) ynone 1a[13] as a model substrate to evaluate
the first strategy, that is, the N-desulfonylative cyclization
reaction with phenol as a selective nucleophile. N-to-O
sulfonyl migration should be minimized with this model
compound because the strained azetidinium intermediate
formed upon gold activation (B in Scheme 2) should be less
prone to enolization.
Rewardingly, the simple and stable Gagosz catalyst
smoothly provided the expected azabicyclic product[19] 2a in
50% yield with 10 equivalents of phenol (Table 1, entry 1).
Tuning of the ligand properties did not improve this result
(Table 1, entries 2–6), whereas counterion variations had
a strong effect (entries 7–9). Tetrafluoroborate emerged as
the best anion and led to the best combination with
tricyclohexylphosphine as the ligand. [Cy3PAu]BF4 promoted
the formation of 2a in 87% yield in only 0.5 h (Table 1,
entry 10). Control experiments confirmed that the trans-
formation did not occur in the absence of a gold catalyst,
whereas silver tetrafluoroborate alone afforded a minor
amount of pyrrolin-4-one[13] (3a) (product type in Scheme 2,
2
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Scheme 6. Cyclization/N-to-O 1,5-sulfonyl migration of pyrrolidine and
piperidine derivatives 1g–n (X-ray crystal structure of 6l).
TBDPS=tert-butyldiphenylsilyl.
Scheme 4. Gold(I)-catalyzed N-desulfonylative amination of azetidines
1a–e with meta-nitrophenol (X-ray crystal structure of 2e).
from each substrate. Structural modifications in terms of the
heterocyclic ring size (Scheme 6, products 6g,h versus 6k,l)
and the substituent on the alkyne were perfectly well
tolerated (Scheme 6, products 6h,i). Interestingly, other
sulfonyl groups, such as Ns or Mbs, were able to migrate
just as well as the Ts group, as evidenced by the formation of
products 6j,m,n in high yields.
azabicyclo[3.2.0]heptene derivatives 2b–e in good to high
yields (65–87%).
We synthesized spiroazetidine 1 f to assess the influence of
gem-disubstitution on the azacycle (Scheme 5, top). Interest-
To determine the intermolecular or intramolecular nature
of the N-to-O sulfonyl migration, we performed a crossover
experiment by subjecting a 1:1 mixture of compounds 1i and
1j to our reaction conditions (Scheme 7, top). No crossover
products were formed during this reaction (see the Support-
ing Information). This result clearly indicates that the sulfonyl
migration proceeds in an intramolecular manner. To confirm
the role of enolization in the N-to-O sulfonyl migration,
compound 1g and non-enolizable 1o were treated under the
N-desulfonylative amination conditions. In the presence of
meta-nitrophenol, intermolecular N-desulfonylation did not
Scheme 5. Gold(I)-catalyzed rearrangement of substituted azetidine
1 f.
ingly, pyrrole 5 f was formed as the sole product when 1 f was
subjected to our reaction conditions. This product clearly
arises from the postulated N-to-O sulfonyl migration
(Scheme 2) followed by ring opening of the azetidine
moiety upon elimination. Thus, the sterically demanding
spirocyclic carbon core of 1 f seems to preclude the addition
of meta-nitrophenol to the sulfonyl group. Indeed, the less-
hindered nucleophile methanol[13] was partially able to restore
the N-desulfonylation reactivity, thus affording the desired
product 2 f (37%) along with 6 f (Scheme 5, bottom). The
latter compound was unstable in CDCl3, and rapidly evolved
to 5 f through elimination.
We then explored the N-to-O sulfonyl migration with
more flexible substrates, as they should be more prone to
enolization. To our delight, various pyrrolidine and piperidine
substrates 1g–n were readily converted into the expected
sulfonates 6g–n in the presence of triphenylphosphine gold(I)
triflimidate (5 mol%) in CH2Cl2 at room temperature without
an external nucleophile (Scheme 6). Pyrrolizine[20] or indoli-
zine[21] derivatives were obtained in high yields (62–98%)
Scheme 7. Enolization-controlled intramolecular N-to-O sulfonyl migra-
tion versus desulfonylative cyclization.
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occur with 1g, and the tosylate 6g was the sole product
formed, without any trace of 4a (Scheme 7). Predictably, only
intermolecular N-desulfonylation occurred with 1o, and the
pyrrolizin-1-one 2o was isolated in good yield, despite the
need to heat the reaction mixture at 708C for full conversion
to occur (Scheme 7). These results fully confirmed that
enolization could be used to switch between N-desulfonyla-
tion pathways.
(+)-nor-NP25302. Further investigations to extend these
transformations to unactivated alkyne substrates and to
apply these reactions in the total synthesis of bioactive
alkaloids are ongoing in our laboratory.
Acknowledgements
As mentioned above, the pyrrolyl tosylate products 6 offer
a unique opportunity to reach more complex compounds
through palladium- or nickel-catalyzed cross-coupling reac-
tions. To demonstrate this possibility, we performed a Suzuki–
Miyaura coupling between the dihydropyrrolizine 6g and
phenyl boronic acid. Under conditions reported for some
heteroaryl tosylates,[16d] but without further optimization,
these two compounds could be coupled to produce the
arylated product 7 in good yield (Scheme 8, top). To further
We gratefully acknowledge the French Ministry of Research
and the CNRS for financial support. S.M. and N.K. thank the
French Ministry of Research for PhD fellowships. S.M. and
A.B. thank Arno Lalaut for his contribution to the synthesis
of substrates.
Keywords: desulfonylation · gold · homogeneous catalysis ·
N heterocycles · sulfonyl migration
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catalyst and meta-nitrophenol under the conditions described
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molecules containing 1-azabicycloalkane motif, such as bicy-
clic azetidines, pyrrolizidine and indolizidine alkaloids. The
gold(I)-catalyzed N-desulfonylative amination is a formal
hydroamination of alkynes by sulfonamides at room temper-
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migration of the sulfonyl protecting group from the nitrogen
to the oxygen atom provides products suitable for postfunc-
tionalization through transition metal-catalyzed cross-cou-
pling reactions. The usefulness of both methodologies has
been highlighted by the Suzuki–Miyaura cross-coupling of
a dihydropyrrolizinyl tosylate and by a formal synthesis of
4
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Received: May 4, 2016
Published online: && &&, &&&&
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Communications
Heterocycle Synthesis
S. Miaskiewicz, B. Gaillard, N. Kern,
J.-M. Weibel, P. Pale,*
A. Blanc*
&&&& — &&&&
Gold(I)-Catalyzed N-Desulfonylative
Amination versus N-to-O 1,5-Sulfonyl
Migration: A Versatile Approach to 1-
Azabicycloalkanes
Worth their weight in gold: The great
value of sulfonamides in gold catalysis is
highlighted by two hydroamination reac-
tions that occur by migration or cleavage
of sulfonyl group (see scheme). These
unprecedented gold-promoted sulfonyl-
transfer reactions open the way to
appealing synthetic applications of these
robust nitrogen-protecting groups, as
demonstrated by the formation of versa-
tile azabicycles.
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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