Access to Highly Functionalized Sulfonated Cyclopentanes by Acid-Promoted Rauhut-Currier Reaction with Sulfinamides

Article abstract of DOI:10.1002/chem.201502816

An unexpected acid-mediated cascade reaction induced by conjugate addition of sulfinamides to dienediones has been developed. This highly efficient Rauhut-Currier reaction enables the rapid, high-yielding construction of sulfonated cyclopentanes with three contiguous stereogenic centers in a single operation starting from simple sulfinamides. This process constitutes the first example of sulfinamide-promoted cycloisomerization. Currier opportunities: Sulfinamide-promoted Rauhut-Currier cycloisomerization under acidic conditions afforded

Full text of DOI:10.1002/chem.201502816

DOI: 10.1002/chem.201502816
Communication
&
Cycloisomerization
Access to Highly Functionalized Sulfonated Cyclopentanes by
Acid-Promoted Rauhut–Currier Reaction with Sulfinamides
[
a]
[a]
[b]
[a]
Nicolas Gigant, Emmanuelle Dr›ge, Pascal Retailleau, and Delphine Joseph*
Abstract: An unexpected acid-mediated cascade reaction
induced by conjugate addition of sulfinamides to diene-
diones has been developed. This highly efficient Rauhut–
Currier reaction enables the rapid, high-yielding construc-
tion of sulfonated cyclopentanes with three contiguous
stereogenic centers in a single operation starting from
simple sulfinamides. This process constitutes the first ex-
ample of sulfinamide-promoted cycloisomerization.
In recent years, much effort has been devoted toward design-
ing highly selective strategies giving straightforward access to
new and original frameworks starting from simple and easy
Scheme 1. Design of acid-mediated cascade reactions.
[
1]
available reagents. Based on this strategy, the concept of di-
versity-oriented synthesis (DOS) was introduced by Schreiber
in 2000 with the aim to rapidly generate new collections of
drug-like small molecules and to find potential new therapeu-
Initially, the objective of the present study was to extend
the synthetic potential of our previous methodology in the
Rauhut–Currier (RC) reaction by using deactivated N-nucleo-
philes bearing easily removable amine-protecting group such
[2]
[7]
tic agents for incurable diseases. Cascade reactions are thus
an attractive method by which to prepare these new com-
as the tert-butanesulfinyl moiety (Scheme 1). Indeed, due to
their useful synthetic applications, sulfinamide reagents are
often involved in a wide array of reactions. However, to our
[
3]
pound libraries. Multiple stereocenters can be then created in
a single-pot operation via both diversified and step-economical
approaches.
[
8]
knowledge, they have never been used as RC promoters. Sur-
prisingly, we found that the addition of sulfinamides to octa-
2,6-diene-1,8-diones under acidic conditions serendipitously
led to cyclopentylsulfones.
In our continuing interest in the development of Lobelia al-
kaloid analogues for studying nicotinic acetylcholine receptor
[4]
(
nAChR) allosteric rearrangements, we very recently reported
As the sulfone moiety (ÀSO À) is often encountered in phar-
2
[
9]
[10]
[11]
an original example of a switchable aza-Michael-induced ring
closure (aza-MIRC) by an “on/off” catalyst effect allowing the
maceuticals, agrochemicals, and, materials, this step-eco-
nomical metal-free process constitutes an interesting alterna-
tive strategy to access valuable sulfonated scaffolds. In addi-
tion, sulfones are also involved in a number of useful chemical
transformations for the preparation of olefins, such as the
[5]
selective synthesis of cyclopentanes or pyrrolidines. A range
of polyfunctionalized aminocyclopentanes were selectively pre-
pared through the acid-mediated conjugate addition of deacti-
vated primary amines (Scheme 1). Similarly, Seo and co-workers
recently depicted an elegant synthesis of 1,2,3-trisubstituted
aminocyclohexanes based on an indium triflate-catalyzed aza-
[
12]
[13]
Julia and Ramberg–Bäcklund reactions, making them key
building blocks in organic synthesis. For this reason, several
methods for their preparation have been successfully devel-
oped, but they mainly suffer from limitations due to the harsh
[6]
MIRC, this time using secondary amines.
[
14]
conditions or multistep strategies required. In this context,
a new straightforward pathway for the synthesis of sulfones is
still highly appealing, especially if environmental considera-
tions are taken into account. Herein, we report a totally new
method of sulfone synthesis through an original metal-free
thia-MIRC cascade involving sulfinamides.
[
a] Dr. N. Gigant, Dr. E. Dr›ge, Prof. D. Joseph
UniversitØ Paris-Sud, UMR CNRS 8076 BioCIS, LabEx Lermit
Equipe de Chimie des Substances Naturelles
5
, rue Jean-Baptiste ClØment, 92296 Châtenay-Malabry (France)
E-mail: delphine.joseph@u-psud.fr
We first selected the octadienedione 1a and the tert-butyl-
sulfinamide 2a as substrates to test the viability of our reaction
[
b] Dr. P. Retailleau
Institut de Chimie des Substances Naturelles, UPR CNRS 2301
Bât. 27, 1, Avenue de la Terrasse, 91198 Gif-sur-Yvette cedex (France)
Orgdiv
(
Table 1). In the absence of catalyst activation, none of the ex-
pected five-membered ring compound was isolated, even
under solvent-free conditions and thermal and/or ultrasonic ac-
tivation: the starting material was recovered unchanged or de-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502816.
Chem. Eur. J. 2015, 21, 15544 – 15547
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Communication
Table 1. Discovery of the sulfonated cyclopentane.
[a]
Entry Additive
equiv)
Solvent
2a
[equiv]
Time
[h]
Yield
[%]
[
b]
(
1
2
3
4
5
6
7
8
9
1
HBF
HBF
4
(0.3)
CH
3
3
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
1.2
1.2
1.2
1.2
1.6
0.8
2
1.6
1.6
1.6
1.6
1.6
1.6
24
24
24
9
9
9
17
42
42
41
61
41
70
60
14
40
18
58
61
4
(1)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
HBF
4
(1.2)
HBF
HBF
HBF
HBF
HBF
4
(1)
(1)
(1)
(1)
(1)
4
4
4
4
9
9
[
c]
TMSOTf (1)
BF ·Et O (1)
TfOH (1)
24
24
24
24
6
0
3
2
1
1
1
1
2
3
HBF
HBF
4
(1)
(1)
CH
CN/CH
4:1)
CN/CH
1:1)
CN/CH
1:4)
2
Cl
2
4
CH
CH
CH
3
3
3
2
2
2
Cl
2
Cl
2
Cl
2
(
1
1
4
5
HBF
4
4
(1)
(1)
1.6
1.6
7
7
63
(
[d]
HBF
85 (80)
(
[
a] Reaction conditions, unless otherwise stated: Diene 1a (0.20 mmol),
À1
c=0.4 molL ; [b] NMR yield using 1,4-dimethoxybenzene as internal
standard; [c] c=0.2 molL ; [d] yields refer to isolated products.
À1
Scheme 2. Substrate scope of the reaction. Unless otherwise noted, reaction
conditions were as follows: 1 (1 equiv), 2 (1.6 equiv), HBF
4
(1 equiv) in
À1
CH
3
CN/CH
2
Cl
2
(1:4, c=0.4 molL ) at RT for 7–24 h. Yields refer to isolated
products. Diastereomeric ratio determined by NMR from the purified prod-
À1
ucts. [a] c=0.2 molL ; [b] 2 (2 equiv), HBF
4
(1.5 equiv).
graded by high temperatures. Driven by our experiences in ac-
tivation of aza-Michael reaction with deactivated primary
[
5]
amines, we studied the influence of aqueous tetrafluoroboric
HBF (Table 1, entries 9–11). Finally, we focused on the effect of
4
acid (HBF ; Table 1, entries 1–8). To our delight, although the
the solvent. Although the concentration of the solution did
not affect the efficiency of the reaction (Table 1, entry 8), a mix-
ture of CH CN and CH Cl in a 1:4 ratio dramatically increased
4
reaction rate was sluggish with a catalytic amount of HBF , the
4
reaction sequence proceeded more efficiently by using
3
2
2
1
equivalent of HBF . Two new cycloisomerized compounds
the yield of the cascade reaction to 80% (Table 1, entries 12–
15). Indeed, this weakly polar solvent system provided the best
compromise between the conversion, the reaction time, and
4
were formed and separated by flash column chromatography
on silica gel (Table 1, entries 1–3). Their diastereomeric relative
configuration was easily assigned by nOesy experiments, but
single-crystal X-ray diffraction analysis was required to allow us
to clearly elucidate the exact structures of the two unanticipat-
[
16]
the amount of byproducts.
With the optimized conditions in hand, we next set out to
examine the scope and the limitations of this original reaction
(Scheme 2). Except in the case of 3aa and 3da, the generated
cyclopentanes were rapidly isolated as a diastereomeric mix-
ture without endeavoring to separate the two isomers. The re-
activity of various dienediones was first investigated. Electron-
rich para-substituents on the aromatic core did not affect the
reaction and allowed access to the corresponding cyclopen-
tanes 3ba and 3ca in 65 and 72% yield, respectively, and
good diastereoselectivities up to 81:19 always in favor of the
[
15]
ed sulfones 3aa. To our knowledge, this study represents
the first example of the synthesis of a ÀSO À unit starting from
2
a simple sulfinamide. Encouraged by this result, we demon-
strated that 3aa could be prepared in 70% yield by using two
equivalents of sulfinamide in a shorter reaction time (Table 1,
entries 4–8). A variety of Lewis acids or acid promoters were
then examined. Although Bi(OTf) and In(OTf) proved ineffi-
3
3
cient, BF ·Et O, TMSOTf, or TfOH were not more active than
3
2
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Communication
[17]
1
,2-syn/2,3-anti isomer.
Similar results were obtained for
3
da, 3ea, 3 fa and 3ga starting from dienediones substituted
in variable positions by deactivating groups, demonstrating
the generality of the process. However, neither the diastereose-
lectivity nor the yield of the cascade could be correlated with
the electronic properties of the arenes. When applied to the
methyl ketone 1h, the reaction proceeded smoothly to give
the corresponding cyclopentane derivative 3ha in 64% yield
and similar diastereomeric ratio. In contrast, the ester moiety
was not electrophilic enough to promote the thia-MIRC reac-
tion and the starting alkene 1i was recovered.
Given that a range of sulfinamides are commercially avail-
able and that several simple, efficient, and innovative methods
[18]
have been developed for their preparation, we also surveyed
the reactivity of various arylsulfinamides to synthesize structur-
ally diversified sulfones (Scheme 2). We found that arylsulfina-
mides 2b and 2c were easily accommodated, leading to the
corresponding cyclopentyl arylsulfones in good yields and dia-
stereopreferences (d.r. up to 83:17). Finally, an enantioselectivi-
ty experiment was attempted starting from (R)-tert-butanesulfi-
namide but, as expected in the presence of an acid bearing
a non-nucleophilic counter ion, the chirality of the sulfinyl
[19]
group was not preserved.
After the successful synthesis of cyclopentanes starting from
symmetrical dienediones, diversification was also introduced
by evaluating the reactivity of the unsymmetrical scaffold 1j
(
Scheme 3). Even if a complex mixture of isomers could be
forecasted starting from unsymmetrical substrates, we were
pleased to find that a synthetically useful selectivity was ob-
tained in the formation of 3ja: the regioselectivity of the se-
quence was in favor of the isomer resulting from the initial
thia-Michael addition onto the less electrophilic alkene moiety
of 1j.
Scheme 4. Experimental investigation of reaction mechanism.
the reaction mixture was detected when the sulfinamide was
subsequently added, clearly demonstrating that the sequence
is initiated by a usual hetero-Michael addition, leading to the
These results immediately raised questions about the exact
mechanism of this transformation (Scheme 4). Even if diene-
diones are known to undergo RC cyclization in the presence of
[
21]
expected five-membered ring. To evaluate a possible prelimi-
nary sulfinamide hydrolysis into sulfinic acid prior to the nucle-
[7,20]
a nucleophilic catalyst,
this reaction has never been report-
[
22]
ed starting from sulfinyl derivatives. Therefore, we postulated
that the reaction might be initiated by the sulfinamide nucleo-
philic attack, leading a transient enol intermediate. To test this
hypothesis, the reaction was first carried out in the absence of
sulfinamide: two cyclic products resulting from the water-in-
duced RC reaction were isolated (Scheme 4a). No evolution of
ophilic attack, the reaction was carried out, under similar re-
action conditions, starting from an equimolar mixture of
sodium p-toluenesulfinate and HBF4 (Scheme 4b). The RC
product 3ab was isolated in a lower yield compared to the
use of the corresponding sulfinamide. Although these experi-
ments indicated that our acid-induced RC procedure can be
[
23]
extended to include the use of sulfinate derivatives,
they
don’t exclude a preliminary sulfinamide hydrolysis step. That
was confirmed when the reaction was performed in the pres-
ence of 3 Š molecular sieves. The reaction rate was dramatical-
ly affected, only affording trace amount of the expected cyclo-
pentane 3aa. However, when the reaction was performed
under similar reaction conditions and reaction time in the pres-
ence of benzaldehyde 4, used as
a hard electrophile
(
Scheme 4c), the corresponding imine 5 was then isolated in
a very clean reaction, calling into question the sulfinamide’s
hydrolytic stability. The aforementioned results reveal the am-
bident nucleophilicity of the sulfinamide moiety that could dis-
play both hard (amide nitrogen) and soft (sulfinyl sulfur) nucle-
ophilic additions in the presence of hard (aldehyde) and soft
Scheme 3. Reactivity of unsymmetrical scaffold 1j.
Chem. Eur. J. 2015, 21, 15544 – 15547
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Communication
electrophiles (enone), respectively. Finally, as the mechanism
might be suspected to proceed via a transient sulfoximine in-
[8] For reviews, see: a) F. Foubelo, M. Yus, Eur. J. Org. Chem. 2014, 485–
4
3
91; b) M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 2010, 110,
600–3740. For selected recent examples, see: c) M. Guerola, M.
[
15]
termediate, we attempted to isolate a hydrolytically more
stable sulfoximine species by condensing the N-ethyl sulfina-
mide 2d with the dienedione 1a. However, the sulfone 3aa
was the sole product delivered (Scheme 4d).
Sµnchez-Roselló, C. Mulet, C. del Pozo, S. Fustero, Org. Lett. 2015, 17,
960–963; d) C. N. Rao, D. Lentz, H.-U. Reissig, Angew. Chem. Int. Ed.
2015, 54, 2750–2753; Angew. Chem. 2015, 127, 2788–2792; e) K. Geba-
uer, A. Fürstner, Angew. Chem. Int. Ed. 2014, 53, 6393–6396; Angew.
Chem. 2014, 126, 6511–6514.
For these reasons, even if the formation of a nucleophilic
sulfoximine intermediate cannot be totally ruled out, all the
previous observations seem to suggest that the transformation
might be initiated by sulfinamide hydrolysis to give the corre-
sponding sulfinic acid before the thia-Michael addition
[
9] For relevant examples, see: a) H. Rueeger, R. Lueoend, O. Rogel, J.-M.
Rondeau, H. Mçbitz, R. Machauer, L. Jacobson, M. Staufenbiel, S. Des-
rayaud, U. Neumann, J. Med. Chem. 2012, 55, 3364–3386; b) D. C.
Meadows, J. Gervay-Hague, Med. Res. Rev. 2006, 26, 793–814; c) S. Dos-
wald, H. Estermann, E. Kupfer, H. Stadler, W. Walther, T. Weisbrod, B.
Wirz, W. Wostl, Bioorg. Med. Chem. 1994, 2, 403–410.
(
Scheme 4e). Moreover, the regioselectivity obtained from the
[10] A. Plµcido, P. Paíga, D. H. Lopes, M. Correira, C. Delerue-Matos, J. Agric.
Food Chem. 2013, 61, 325–331.
unsymmetrical dienedione 1j seems to corroborate this pro-
posed mechanism: the S-nucleophile reacts preferentially on
the least positively charged b-carbon of the two electron-defi-
cient olefins, which is the softest electrophilic site.
[
11] a) S. Takamuku, P. Jannasch, Macromolecules 2012, 45, 6538–6546; b) S.-
M. Liu, Y. Yang, Z.-J. Jiang, Y.-H. Zhou, J. Zuo, J.-Q. Zhao, J. Appl. Polym.
Sci. 2012, 124, 4502–4511.
[12] C. A ¨ı ssa, Eur. J. Org. Chem. 2009, 1831–1844.
In summary, we have discovered an elegant metal-free ap-
proach to the construction of a series of structurally novel sul-
fonated cyclopentanes bearing three contiguous stereogenic
centers through an unusual RC cascade reaction. This easy-to-
handle process is an original synthetic strategy for the rapid
access to sulfones starting from simple sulfinyl derivatives
under mild reaction conditions.
[13] R. J. K. Taylor, G. Casy, Org. React. 2003, 62, 357–475.
[
14] For recent examples on the sulfones synthesis, see: a) Y. Xi, B. Dong,
E. J. McClain, Q. Wang, T. L. Gregg, N. G. Akhmedov, J. L. Petersen, X. Shi,
Angew. Chem. Int. Ed. 2014, 53, 4657–4661; Angew. Chem. 2014, 126,
4745–4749; b) M. W. Johnson, S. W. Bagley, N. P. Mankad, R. G. Bergman,
V. Mascitti, F. D. Toste, Angew. Chem. Int. Ed. 2014, 53, 4404–4407;
Angew. Chem. 2014, 126, 4493–4496; c) E. J. Emmett, B. R. Hayter, M. C.
Willis, Angew. Chem. Int. Ed. 2013, 52, 12679–12683; Angew. Chem.
2013, 125, 12911–12915; d) M. Jereb, Green Chem. 2012, 14, 3047–
3
052; e) X. Zhao, E. Dimitrijevi c´ , V. M. Dong, J. Am. Chem. Soc. 2009,
1
31, 3466–3467.
Acknowledgements
[
15] HRMS analysis of the initially isolated RC compounds matched with the
+
2
expected sulfinyl cyclopentane structure (m/z [M+H O+H] 430.2061).
However, new HRMS analyses made on crystals used for the X-ray anal-
yses indicated a different molecular mass matching with the sulfone
structure 3aa (m/z [M+Na] 435.1504). We then hypothesized that
We thank K. Leblanc for performing mass spectrometry analy-
ses. The University of Paris-Sud, the French Ministry of Superior
Education and Research, and the CNRS are gratefully acknowl-
edged for financial support.
+
a highly hydrolyzable sulfoximine might be a transient intermediate.
[16] The exchange of CH CN for MeOH dramatically affected the reaction,
3
providing only the degradation of the starting material. Using water as
solvent allowed the recovery of the unmodified starting materials 1a
and 2a, probably due to the insolubility of the dienedione.
Keywords: carbocycles
·
cascade
reactions
·
cycloisomerization · Michael addition · sulfinamides
[17] The relative configuration of each diastereomeric RC product was es-
1
tablished by analogy with the H NMR data obtained for the isolated
diastereoisomers of 3aa, respectively.
18] C. H. Senanayake, D. Krishnamurthy, Z.-H. Lu, Z. Han, I. Gallou, Aldrichi-
mica Acta 2005, 38, 93–104.
19] For a similar result, see: V. K. Aggarwal, N. Barbero, E. M. McGarrigle, G.
Mickle, R. Navas, J. R. Suµrez, M. G. Unthank, M. Yar, Tetrahedron Lett.
[
1] a) A. Grossmann, S. Bartlett, M. Janecek, J. T. Hodgkinson, D. R. Spring,
Angew. Chem. Int. Ed. 2014, 53, 13093–13097; Angew. Chem. 2014, 126,
[
[
1
1
3309–13313; b) J. Kim, H. Kim, S. B. Park, J. Am. Chem. Soc. 2014, 136,
4629–14638; c) B. M. Ibbeson, L. Laraia, E. Alza, C. J. O’Connor, Y. S.
Tan, H. M. L. Davies, G. McKenzie, A. R. Venkitaraman, D. R. Spring, Nat.
Commun. 2014, 5, 3155; d) C. Serba, N. Winssinger, Eur. J. Org. Chem.
2009, 50, 3482–3484.
[
20] For selected examples, see: a) X. Dong, L. Liang, E. Li, Y. Huang, Angew.
Chem. Int. Ed. 2015, 54, 1621–1624; Angew. Chem. 2015, 127, 1641–
2013, 4195–4214.
[
[
2] S. L. Schreiber, Science 2000, 287, 1964–1969.
3] For recent reviews, see: a) J. M. Smith, J. Moreno, B. W. Boal, N. K. Garg,
Angew. Chem. Int. Ed. 2015, 54, 400–412; Angew. Chem. 2015, 127,
1
644; b) S. Takizawa, T. M.-N. Nguyen, A. Grossmann, D. Enders, H. Sasai,
Angew. Chem. Int. Ed. 2012, 51, 5423–5426; Angew. Chem. 2012, 124,
519–5522; c) Z. Shi, Q. Tong, W. W. Y. Leong, G. Zhong, Chem. Eur. J.
5
4
1
10–422; b) C. M. R. Volla, I. Atodiresei, M. Rueping, Chem. Rev. 2014,
14, 2390–2431; c) H. Pellissier, Chem. Rev. 2013, 113, 442–524; d) E.
Ricca, B. Brucher, J. H. Schrittwieser, Adv. Synth. Catal. 2011, 353, 2239–
262; e) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993–3009.
2
2
2
012, 18, 9802–9806; d) F. O. Seidel, J. O. Gladysz, Adv. Synth. Catal.
008, 350, 2443–2449; e) C. E. Aroyan, S. J. Miller, J. Am. Chem. Soc.
007, 129, 256–257; f) L.-C. Wang, A. L. Luis, K. Agapiou, H.-Y. Jang, M. J.
2
Krische, J. Am. Chem. Soc. 2002, 124, 2402–2403.
[
[
4] a) Z. Amara, G. Bernadat, P.-E. Venot, P. Retailleau, C. Troufflard, E. Dr›ge,
F. Le Bideau, D. Joseph, Org. Biomol. Chem. 2014, 12, 9797–9810; b) H.
Boufroura, M. Mauduit, E. Dr›ge, D. Joseph, J. Org. Chem. 2013, 78,
[
21] Similarly, no evolution was observed when sodium p-toluenesulfinate
instead of sulfinamide was subsequently added.
[
[
22] A. M. Piggott, P. Karuso, Tetrahedron Lett. 2007, 48, 7452–7455.
23] For the reactivity of sulfinates with acrylic derivatives, see: J. D. Marge-
rum, R. G. Brault, A. M. Lackner, L. J. Miller, J. Phys. Chem. 1973, 77,
2
346–2354; c) Z. Amara, E. Dr›ge, C. Troufflard, P. Retailleau, D. Joseph,
Org. Biomol. Chem. 2012, 10, 7148–7257.
5] Z. Amara, E. Dr›ge, C. Trouffard, P. Retailleau, M.-E. Tran Huu-Dau, D.
Joseph, Chem. Eur. J. 2014, 20, 15840–15848.
2720–2725.
[
[
6] B. Thirupathaiah, S. Seo, Chem. Commun. 2015, 51, 4216–4219.
7] For reviews, see: a) P. Xie, Y. Huang, Eur. J. Org. Chem. 2013, 6213–
6
4
226; b) C. E. Aroyan, A. Dermenci, S. J. Miller, Tetrahedron 2009, 65,
069–4084.
Received: July 17, 2015
Published online on September 10, 2015
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15547
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim