Solvent-free, metal-free, aza-prins cyclization: Unprecedented access to δ-sultams

Article abstract of DOI:10.1002/chem.201203415

Aza-Prins and the pauper: Aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes was successfully performed under solvent-free and metal-free conditions. When applied to β,γ-unsaturated sulfonamides, the corresponding δ-sultams were isolated in good yields (see scheme). This approach constitutes a new route to cyclic sulfonamides. Copyright

Full text of DOI:10.1002/chem.201203415

COMMUNICATION
DOI: 10.1002/chem.201203415
Solvent-Free, Metal-Free, Aza-Prins Cyclization: Unprecedented Access to
d-Sultams
Damien Clarisse, Bꢀatrice Pelotier, and Fabienne Fache*[a]
Table 1. Substrate scope of the solvent-free and metal-free aza-Prins cyc-
lization reaction.[a]
The aza-Prins cyclization reaction is a straightforward
method that provides access to five- or six-membered aza-
cycles.[1,2] Several Lewis acids, such as GaIII[3] and
BF3·Et2O,[4] have been used as promoters for this reaction.
Among them, FeIII, in stoichiometric[5] or sub-stoichiometric
conditions[6] or in an ionic liquid,[7] and InIII[8] have received
particular attention.[9] Moreover, the syntheses of an increas-
ing number of biologically active alkaloids have been per-
formed by using the intramolecular aza-Prins reaction as a
key step.[10] During the course of our study on the use of the
Prins approach in the synthesis of tetrahydropyran-contain-
ing natural products,[11] we proposed a solvent-free and
metal-free method for performing the Prins cyclization reac-
tion.[12] Herein, we explore the aza version of this method
on homoallylamines and we expand the scope of this reac-
tion to include allylsulfonamides. First, we tested the reactiv-
ity of N-protected homoallyl amines with different alde-
hydes under solvent-free and metal-free conditions
(Table 1).
Entry
R1
R2
X
t
Yield [%] (trans/cis/DHP)[b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
iBu
iBu
iBu
Ph
Ts
Ts
Ts
Ts
Ts
Ns
Ns
CHO
Cl
Br
I
Cl
Br
Br
Br
Br
5 h
10 min
30 min
4.5 h
10 min
4 h
0[c]
65 (77:23:0)[d]
52 (67:25:8)
78 (55:23:22)
85 (70:20:10)
86 (79:16:5)
trace[c]
21 h
19 h
iBu
mixture[e]
[a] Reaction conditions: Compound
1
(1.0 equiv), compound
2
(1.0 equiv), TMSX (1.6 equiv), room temperature. [b] Yield of isolated
product. DHP: dihydropiperidine. [c] Starting material was recovered.
[d] The isomers were separable. [e] Conversion: 40%. Ts=para-methyl-
phenylsulfonyl.
The aza-Prins cyclization reaction between N-tosyl homo-
allylamine and benzaldehyde in the presence of TMSCl was
unsuccessful (Table 1, entry 1). Presumably, TMSCl was not
reactive enough to allow the formation of the key inter-
mediate iminium ion. By using the more-reactive TMSBr,
the reaction went to completion within 10 minutes (Table 1,
entry 2), thereby leading to a separable mixture of cis- and
trans-piperidines, with the trans cycloadduct being predomi-
nant. With TMSI (Table 1, entry 3), it was also possible to
perform the aza-Prins cyclization, whereas Yadav and co-
workers[13] reported no reaction with the same substrates in
a solvent (CH2Cl2). Notably, the yield of the isolated aza-
Prins-cyclization products was only 52%. In this case, TMSI
also reacted with the TMSOH by-product to form the corre-
sponding siloxane[14] and HI, which added onto the olefin of
the starting homoallylamine, thus lowering the yield of the
cycloadduct. With isovaleraldehyde, both TMSCl (Table 1,
entry 4) and TMSBr (Table 1, entry 5) reacted efficiently,
with TMSBr being much more active of the two. Dihydropi-
peridines, which resulted from the dehalogenation of the 4-
halopiperidines, were also formed (Table 1, entries 3–6).
Next, we tested homoallylamines that contained a p-nitro-
benzenesulfonyl (nosyl) group as a more-labile N-sulfonyl
protecting group.[9] With isovaleraldehyde and TMSBr, the
reaction was slower than with the N-tosyl amine (Table 1,
entries 5 and 6) and only trace amounts of the desired prod-
uct were obtained with benzaldehyde (Table 1, entry 7). By
using a formyl activating group, a mixture of 6-membered
azacycles was detected with only 40% conversion after 19 h
(Table 1, entry 8).
Taking into account these modest results with N-sulfonyl
homoallyl amines, we decided to investigate another type of
sulfonamide. We considered that the sulfonyl functional
group could be an integral part of the product and, thus, we
decided to test our reaction conditions on allyl sulfonamides,
which would lead to d-sultams after aza-Prins cyclization.
Sultams represent a promising class of biologically active
compounds as anticonvulsants[15] and as anticancer, antivi-
ral,[16] and, recently, anti-Alzheimer compounds as BACE-1
inhibitors.[17] Because they are amide isosteres, numerous
[a] D. Clarisse, Dr. B. Pelotier, Dr. F. Fache
Universitꢀ Lyon1, Institut de Chimie et
Biochimie Molꢀculaires et Supramolꢀculaires (ICBMS)
UMR CNRS 5246, 43, Bd du 11 novembre 1918
69622 Villeurbanne cedex (France)
Fax : (+33)472448136
E-mail: fache@univ-lyon1.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203415.
Chem. Eur. J. 2013, 19, 857 – 860
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
857

sultam libraries have been synthesized.[18] So far, several
methods have been published for their synthesis,[19] such as
the cyclization of aminosulfonyl chlorides,[20] the intramolec-
ular copper-catalyzed reaction of unsaturated iminoiodi-
nanes,[21] intramolecular alkylation reactions,[22] intramolecu-
lar Diels–Alder reactions,[23] and ring-closing metathesis.[24]
Our results with primary allyl sulfonamide 4 are summar-
ized in Table 2. In neat conditions and in the presence of
Table 3. Aza-Prins reactions of allyl sulfonamide
ketones.[a]
4 with various
Entry
Ketone
X
t [h]
Yield [%][b]
(conversion [%])
1
2
3
4
5
6
7
8
acetone
cyclohexanone
cyclohexanone
cyclopentanone
2-butanone
2-decanone
3-methyl-2-butanone
pinacolone
I
Br
I
I
I
I
I
I
16
16
16
23
23
23
48
24
50 (60)
0 (30)
Table 2. Aza-Prins reactions of allyl sulfonamide 4 with various alde-
ACHTUNGTRENNUNG
hydes.[a]
48 (60)
58 (62)
59 (75)
63 (75)
0 (50)
0 (25)
[a] Reaction conditions: Compound
(1.0 equiv), TMSX (1.6 equiv), room temperature. [b] Yield of isolated
product.
7
(1.0 equiv), compound
4
Entry
R
X
t
Yield[b] [%]
1
2
3
4
5
6
7
8
9
iBu
iBu
iBu
Cl
Br
I
Br
I
Br
Br
Br
Br
Br
17 h
9 h
40 min
5 h
16 h
3 h
1 h
4 h
4 h
24 h
trace
74
76
Ph
70
lead to the completion of the reaction. Nevertheless, the
starting allyl sulfonamide could be recovered and re-engag-
ed in new reactions. With 2-butanone (Table 3, entry 5), no
diastereoselectivity was observed, probably because of the
minimal difference in steric bulk between the methyl and
ethyl groups. Thus, we tested pinacolone (Table 3, entry 8),
but, this time, the bulky tert-butyl group considerably low-
ered the reactivity of the ketone. However, again, we used
the less-hindered 2-decanone (Table 3, entry 6) or 3-methyl-
2-butanone (Table 3, entry 7), almost no diastereoselectivity
was detected (52:48).
pNO2-Ph
pMeO-Ph
oMeO-Ph
pBr-Ph
Cy
trace[c]
58
72
82
80
10
PhCH=CH
77[d]
[a] Typical procedure: Allylic sulfonamide (0.5 mmol), aldehyde
(0.5 mmol), and trimethylsilylhalide (TMSX, 0.8 mmol) were stirred at
room temperature for the required time. The crude mixture was purified
by column chromatography on silica gel (EtOAc/petroleum ether).
[b] Yield of isolated product. [c] Conversion: 10%. [d] TMSBr (2 equiv);
a
mixture of diastereoisomers of compound
6
were formed.
Secondary allyl sulfonamides also afforded N-substituted
halosultams in good yields (Table 4). In the case of aliphatic
aldehydes, the trans isomers were also obtained, although as
the minor products (Table 4, entries 2–4, and 8). With aro-
matic aldehydes and TMSBr, no aza-Prins reaction occur-
red, but, instead, compound 11 was observed, which resulted
from an unexpected bromocyclization reaction, together
with unreacted starting material (Table 4, entries 5 and 7).
By using the more-reactive TMSI, aza-Prins cyclization took
place with benzaldehyde and only the cis adduct was ob-
tained in 61% yield (Table 4, entry 6). TMSCl was unreac-
tive under neat conditions (Table 4, entry 1), but, by using a
stoichiometric amount of FeCl3 under solvent conditions, a
chlorine atom at the 5-position could also be introduced by
aza-Prins cyclization. When the ethyl group on the nitrogen
atom was replaced by a cyclohexyl substituent, the reactivity
was considerably diminished, probably owing to steric rea-
sons (Table 4, entry 9). Finally, with a tBu group on the ni-
trogen atom (Table 4, entry 10), we obtained the N-unsubsti-
tuted product of aza-Prins cyclization in a good yield. We
assume that the elimination of the N substituent occurs first,
followed by an aza-Prins reaction on the resulting less-hin-
dered allylsulfonamide; this conclusion was corroborated by
the reaction of N-Boc-protected allylsulfonamide, which af-
forded a mixture of the starting material, the deprotected
starting material, and the deprotected cyclized product, but
TMSBr, the aza-Prins cyclization of sulfonamide 4 with ali-
phatic (Table 2, entries 2, 9, and 10) and aromatic aldehydes
(Table 2, entries 6–8) occurred in good yields to afford the
corresponding 3,5-cis-disubstituted sultams as the sole prod-
uct within a few hours (1–9 h). With TMSBr (Table 2,
entry 2), a reaction time of 9 h was necessary to proceed to
completion, whereas it took only 40 min with the more-reac-
tive TMSI (Table 2, entry 3), but with the same final yield of
the isolated product. By using cinnamaldehyde and two
equivalents of TMSBr (Table 2, entry 10), the cis-disubstitut-
ed sultam was isolated as a mixture of diastereoisomers of
dibrominated compounds 6. The hydrobromination step oc-
curred in the presence of in situ generated HBr, owing to
the excess of TMSBr (see below).[14]
Next, we tested ketones as substrates in this reaction and,
to our delight, good-to-excellent yields of spiro-sultams that
contained quaternary centers were obtained (Table 3). In
this case, the more-reactive TMSI had to be used for the re-
action to occur within a reasonable amount of time. Increas-
ing either the reaction time or the quantity of TMSI did not
858
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Chem. Eur. J. 2013, 19, 857 – 860

Solvent-Free, Metal-Free, Aza-Prins Cyclization Reactions
COMMUNICATION
Table 4. Aza-Prins reactions of N-substituted allyl sulfonamides.[a]
Entry
R1
R2
X
t [h]
Yield [%]
(cis/trans)
1
2
3
4
5
6
7
8
iBu
iBu
iBu
iBu
Ph
Ph
pBr-Ph
Cy
Et
Et
Et
Et
Et
Et
Et
Et
Cl
Cl[b]
Br
I
Br
I
Br
Br
Br
Br
Br
24
17
22
4
40
22
40
40
20
18
20
0
65 (88:12)
77 (78:22)
74 (82:18)
0[c]
61 (100:0)
10[d]
64 (86:14)
trace[e]
9
10
11
iBu
iBu
iBu
Cy
tBu
Boc
0[f]
mixture
[a] Reaction conditions: Compound
1
(1.0 equiv), compound
9
(1.0 equiv), TMSX (1.6 equiv), room temperature. [b] FeCl3 (1.5 equiv)
and compound 1 (1.5 equiv) with no TMSX, 1m in CH2Cl2. [c] Compound
11 (26%) was formed. [d] Compound 11 (53%) was formed. [e] Conver-
sion: 10%. [f] Compound 5 (71%) was formed (Table 2, entry 2).Cy=cy-
clohexyl, Boc=tert-butoxycarbonyl.
Scheme 1. Proposed intermediates in the aza-Prins cyclization reactions
to afford halopiperidines and halosultams.
an alkyl substituent, a minor amount of the trans isomer is
also formed along with the major cis isomer (Table 4, en-
tries 2–4 and 8). It cannot be excluded that the trans isomer
might result from a pseudo-axial attack of the halide ion on
the (E)-iminium intermediate, but this was not observed
under the same neat conditions with R2 =H.
In conclusion, we have described a new application of the
aza-Prins cyclization reaction, which leads to sultam deriva-
tives under solvent-free and metal-free conditions. Owing to
the increasing interest in sultams, in particular as promising
candidates for drug discovery, the full scope and limitations
of this new strategy are currently under investigation.
no N-Boc-protected sultam was observed (Table 4,
entry 11).
It is worth noting that the classical aza-Prins cyclization of
N-sulfonyl homoallylamines predominantly leads to trans-
disubstituted halopiperidines (Table 1), whereas the aza-
Prins cyclization of allyl sulfonamides affords cis-disubstitut-
ed halosultams as the major or sole adducts (Tables 2–4). In
the former case, the stereochemical outcome is in agreement
with the initial results reported by Padrꢂn and co-workers[5]
by using TMSCl/FeCl3 (cat.). The calculated most-stable
(E)-iminium intermediate (Scheme 1) leads the trans
isomer, assuming a pseudo-equatorial attack of the halide
ion. In the case of N-substituted allyl sulfonamides, the re-
sulting disubstituted halosultam is obtained as the major
product with the opposite relative stereochemistry. These re-
sults can be rationalized by the formation of two iminium
intermediates in equilibrium (Scheme 1). When R2 =H
(Table 2), only the corresponding cis isomer is obtained. In
this case, the formation of the (E)-iminium is greatly fa-
vored, both because there are no steric interactions between
the R1 group and the sulfonyl substituent and because it
places the R1 group at a pseudo-equatorial position in the
preformed six-membered transition state. By increasing the
steric hindrance of the R2 group, the equilibrium is slightly
displaced in favor of the (Z)-iminium, depending on the R1
group. When the R1 group is an aromatic ring, the (E)-imini-
um intermediate remains the most stable and only the cis
isomer is obtained (Table 4, entry 6). When the R1 group is
Acknowledgements
D.C. thanks the “Ministꢃre de l’Enseignement Supꢀrieur et de la Recher-
che” for a PhD grant. Support from the CNRS and the Universitꢀ Lyon1
are acknowledged. We warmly thank Prof. O. Piva for his stimulating dis-
cussions and F. Albrieux, C. Duchamp, and N. Henriques from the
Centre Commun de Spectromꢀtrie de Masse (ICBMS UMR-5246) for
their assistance and access to the mass spectrometry facilities.
Keywords: aza-Prins reaction
chemistry · sulfonamides · sultams
·
cyclization
·
green
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Received: September 24, 2012
Published online: December 18, 2012
860
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