A Stereoselective Arylative-Cyclopropanation Process

Article abstract of DOI:10.1021/acs.orglett.7b00248

A new stereoselective arylative cyclopropanation process involving treatment of halogenated dienone systems in the presence of a Michael donor containing a nitro-aryl-sulfone has been developed. This transformation enables production of an arylated cyclop

Full text of DOI:10.1021/acs.orglett.7b00248

Letter
pubs.acs.org/OrgLett
A Stereoselective Arylative-Cyclopropanation Process
Siomenan Coulibali, Elsa Deruer, Elizabeth Godin, and Sylvain Canesi*
Laboratoire de Met
́
hodologie et Synthes
̀ ́ ́ ̀ ́
e de Produits Naturels, Universite du Quebec a Montreal, C.P. 8888, Succ. Centre-Ville,
Montreal, H3C 3P8, Queb
́
́
ec, Canada
S
* Supporting Information
ABSTRACT: A new stereoselective arylative cyclopropana-
tion process involving treatment of halogenated dienone
systems in the presence of a Michael donor containing a nitro-
aryl-sulfone has been developed. This transformation enables
production of an arylated cyclopropane under mild conditions
and occurs via a Michael−Smiles ring closure cascade process,
reflecting the concepts of green chemistry and atom economy.
yclopropanation is an important process in organic
process, we observed that the presence of enone 6 resulted in
formation of an interesting cyclopropanated byproduct 11 with
very good diastereoselectivity instead of 3. The yield of this
transformation product was increased in the presence of oxygen
and decreased in the presence of TEMPO, suggesting a free
radical process10 via oxygen-mediated electron transfer was
responsible. A potential mechanism is described in Scheme 2.
C
synthesis, yielding three-membered ring structures that
are useful as precursors for the elaboration of advanced
intermediates. Cyclopropanes are formed in several processes
such as the Simmons−Smith1 method or its variants mediated
by diazo compounds or iodonium ylides,2 Corey−Chaykovsky3
or Kulinkovich transformations,4 or intramolecular alkylation.5
There is increasing sentiment that transformations should be
atom economical6 and should respect the concept of “green
chemistry.” To this end, we developed a methodology enabling
the formation of functionalized scaffolds 3 mediated by a
Michael−Smiles tandem process.7 In this paper we describe a
new application of this approach on a halogenated enone to
develop an arylative cyclopropanation strategy, Scheme 1.
Scheme 2. Radical-Based-Cyclopropanation Mechanism
Scheme 1. Michael−Smiles Tandem Process Avenues
It should be noted that compound 11 represents a
polyfunctionalized core obtained in a diastereoselective and
environmentally benign manner in one step from simple
starting materials. However, we were unable to extend this
method to other substrates and only one other cyclopropanated
example 13 was obtained from 12 under similar conditions,
Scheme 3.
We therefore investigated alternative methods of generating
this cyclopropane scaffold, beginning with introduction of a
bromine on the enone moiety 14 to replace the uncertain
oxidative cyclopropanation step with an intramolecular
alkylation. We were pleased to observe that cyclopropane 11
was produced in 80% yield by this strategy, Scheme 4.
One advantage of the Smiles rearrangement8 is its capacity
for rapid reconfiguration of a structure into a more elaborated
one under slightly basic and mild thermal conditions. A
judicious combination of this process with a tandem Michael
addition leads to α−β-disubstituted cyclohexanones 3.7 Indeed,
a malonate derivative containing a nitro-aryl sulfonyl moiety9 2
may be used as an activating group, enabling an initial Michael
addition on enone moiety 1 to produce an enolate and
triggering a Smiles rearrangement yielding 3 (Scheme 1) in
which SO2 serves as a leaving group and is released as the sole
byproduct. During our efforts to extend the scope of this
Received: January 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Intramolecular-Radical-Based Cyclopropanation
Scheme 6. Rapid Elaboration of Functionalized Tricycles
Scheme 4. Halide-Mediated Cyclopropanation Alternative
Table 1. Michael−Smiles Cyclopropanation Process
We assume that the mechanism is similar to the mechanism
described in Scheme 2 and the prototypical transformation
involves a Michael−Smiles cyclopropanation cascade process.
We suppose that the aryl migration occurs with retention of
configuration leading to 18 from 17 and enabling an
antiperiplanar attack to produce cyclopropane 19. One
interesting aspect is the potential intramolecular nucleophilic
substitution that would occur on a tertiary alkyl bromide with
inversion of configuration. We suspect that a partial carbocation
leading to a potential enolonium ion11 could be involved due to
the presence of a conjugated system; this species could be
generated in the presence of a cesium ion acting as a Lewis acid.
When radical processes were excluded by performing the
reaction in the absence of oxygen or in the presence of
TEMPO, the cyclopropane 19 was still obtained in comparable
yields, Scheme 5.
entry
NO2
R1
R2
yield (%)
a
b
c
d
e
f
ortho
para
Me
Me
Et
Me
Me
H
64
68
61
70
74
73
63
70
50
71
ortho
para
Me
t-Bu
t-Bu
Me
allyl
Br
H
ortho
para
H
H
g
h
i
ortho
para
H
H
para
H
j
para
Et
H
In order to produce a highly substituted cyclopropane
subunit, the process was extended to compound 23, a methyl
derivative of 20. We were pleased to observe that, once again,
only one diastereomer was observed by NMR13 in the
substituted cyclopropane 25.14 The diastereoselectivity was
further verified using NMR NOE. Some examples are described
in Table 2.
Scheme 5. Michael−Smiles Cyclopropanation Mechanism
Table 2. Formation of Highly Substituted Cyclopropanes
entry
R1
yield (%)
a
t-Bu
allyl
Et
67
61
60
49
b
c
Encouraged by this result, we investigated different halides as
nucleofuges. These attempts have been performed on dienone
16, which represents a good Michael acceptor obtained by
direct oxidation of halogenated phenols 15 in the presence of
methanol and a hypervalent iodine reagent.12 Iodine and
bromine provided slightly improved results, Scheme 6.
Unfortunately, this process was not efficient with a simple
halogenated enone.
The transformation was subsequently performed on several
bromo-dienones 21, derivatives of 16. Bromine was selected as
the halogen atom because it was easily introduced on the
phenol precursor. The ortho- and para-nosyl derivatives 20 have
both been tested. An interesting aspect of this process is the
good stereoselectivity observed, with only one diastereomer
observed in NMR spectra.13 The corresponding systems 22
that were obtained are described in Table 1.
d
Me
Interestingly, in the presence of a methyl-substituted
malonate derivative 23, the ester functionality was anti to the
nitro-aryl segment. The difference of diastereoselectivity
observed between the formation of cyclopropane 22 and its
more substituted analogous 25 could be explained by their
enolate precursors 26. Indeed, if R1 is a hydrogen, we supposed
that conformer 26a was favored and led to compound 22.
However, in the presence of a methyl group (R1 = Me) a
potential steric interaction between the aryl and methyl groups
would favor conformer 26b yielding cyclopropane 25, Scheme
7.
B
DOI: 10.1021/acs.orglett.7b00248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Quebec (FQRNT and CCVC) for their precious financial
support in this research. S.C. thanks the “Programme Canadien
de Bourses de la Francophonie” for a scholarship.
Scheme 7. Diastereoselectivity Issues
REFERENCES
■
(1) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80,
5323. (b) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81,
4256. (c) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1.
(d) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(e) Pellissier, H. Tetrahedron 2008, 64, 7041. (f) Lebel, H.; Marcoux, J.
F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
(g) Furukawa, J.; Kawabata, N. Adv. Organomet. Chem. 1974, 12, 83.
(2) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From Cyclo-
propanes to Ylides; Wiley: New York, 1998. (b) Moreau, B.; Charette,
A. B. J. Am. Chem. Soc. 2005, 127, 18014. (c) Marcoux, D.; Goudreau,
S. R.; Charette, A. B. J. Org. Chem. 2009, 74, 8939. (d) Nani, R. R.;
Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 7304. (e) Deng, C.; Wang,
L.; Zhu, J.; Tang, Y. Angew. Chem., Int. Ed. 2012, 51, 11620.
(f) Lindsay, V. N. G.; Fiset, D.; Gritsch, P. J.; Azzi, S.; Charette, A. B. J.
Am. Chem. Soc. 2013, 135, 1463. (g) Lindsay, V. N. G.; Fiset, D.;
Gritsch, P. J.; Azzi, S.; Charette, A. B. J. Am. Chem. Soc. 2013, 135,
1463. (h) Duan, Y. N.; Zhang, Z.; Zhang, C. Org. Lett. 2016, 18, 6176.
(3) (a) Johnson, A. W.; LaCount, R. B. J. Am. Chem. Soc. 1961, 83,
417. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1353. (c) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997, 97,
2341.
An asymmetric variant containing an Evans auxiliary15 was
developed, and the corresponding cyclopropanes 29 were
obtained in 41% and 44% yields with an excellent stereo-
selectivity of 95% based on NMR.13 A potential approach
suggesting an opened transition state to explain the observed
stereoselectivity is depicted in Scheme 8.
Scheme 8. Asymmetric Avenue
(4) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244. (b) Kulinkovich, O.
G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
(5) (a) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2003, 42, 828. (b) Liao, W. W.; Li, K.; Tang, Y. J. Am. Chem.
Soc. 2003, 125, 13030. (c) Bremeyer, N. S.; Smith, S. C.; Ley, S. V.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 2681. (d) Kunz, R. K.;
MacMillan, D. W. J. Am. Chem. Soc. 2005, 127, 3240. (e) Ibrahem, I.;
In summary, we have developed a novel stereoselective
arylative cyclopropanation transformation mediated by a
Michael−Smiles ring closure cascade process. These methods
occur under slightly basic conditions at moderate temperatures
with sulfur dioxide as the only byproduct. Very good
diastereoselectivity is observed during this multistep trans-
formation even during the formation of highly substituted
cyclopropane moieties. We are currently looking for novel
applications for these transformations.
́ ́
Zhao, G. L.; Rios, R.; Vesely, J.; Sunden, H.; Dziedzic, P.; Cordova, A.
Chem. - Eur. J. 2008, 14, 7867. (f) Gao, L.; Hwang, G. S.; Ryu, D. H. J.
Am. Chem. Soc. 2011, 133, 20708. (g) Ferrary, T.; David, E.; Milanole,
G.; Besset, T.; Jubault, P.; Pannecoucke, X. Org. Lett. 2013, 15, 5598.
(h) Aitken, L. S.; Hammond, L. E.; Sundaram, R.; Shankland, K.;
Brown, G. D.; Cobb, A. Chem. Commun. 2015, 51, 13558. (i) Shim, S.
Y.; Kim, J. Y.; Nam, M.; Hwang, G. S.; Ryu, D. H. Org. Lett. 2016, 18,
160.
(6) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(b) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404.
(7) Coulibali, S.; Godou, T.; Canesi, S. Org. Lett. 2016, 18, 4348.
(8) (a) Levy, A. A.; Rains, H. C.; Smiles, S. J. Chem. Soc. 1931, 0,
3264. (b) Truce, W. E.; Kreider, E. M.; Brand, W. W. Organic Reactions
1970, 18, 99.
(9) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(10) Boyd, R. J.; Gupta, A.; Langler, R. F.; Lownie, S. P.; Pincock, J.
A. Can. J. Chem. 1980, 58, 331.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00248.
■
S
Experimental procedures and spectral data for key
compounds (PDF)
(11) Arava, S.; Kumar, J. N.; Maksymenko, S.; Iron, M. A.; Parida, K.
N.; Fristrup, P.; Szpilman, A. M. Angew. Chem., Int. Ed. 2017, 129, doi:
10.1002/anie.201610274.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: canesi.sylvain@uqam.ca.
ORCID
(12) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem.
1987, 52, 3927. (b) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.;
Fujita, S.; Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116,
3684. (c) Dohi, T.; Yamaoka, N.; Kita, Y. Tetrahedron 2010, 66, 5775.
(d) Singh, J.; Rehbein, F. V.; Wirth, T. ChemistryOpen 2012, 1, 245.
(e) Farid, U.; Malmedy, F.; Claveau, R.; Albers, L.; Wirth, T. Angew.
Chem., Int. Ed. 2013, 52, 7018. (f) Zhdankin, V. V. Hypervalent Iodine
Chemistry: Preparation, Structure, and Synthetic Applications of
Polyvalent Iodine Compounds; John Wiley & Sons: Chichester, U.K.,
Sylvain Canesi: 0000-0002-0639-7796
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
2013. (g) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010,
We are very grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Canada Founda-
tion for Innovation (CFI), and the provincial government of
66, 2235. (h) Jacquemot, G.; Canesi, S. J. Org. Chem. 2012, 77, 7588.
(i) Jacquemot, G.; Menard, M. A.; L’Homme, C.; Canesi, S. Chem. Sci.
2013, 4, 1287. (j) Beaulieu, M. A.; Ottenwaelder, X.; Canesi, S. Chem. -
C
DOI: 10.1021/acs.orglett.7b00248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Eur. J. 2014, 20, 7581. (k) L’Homme, C.; Menard, M. A.; Canesi, S. J.
Org. Chem. 2014, 79, 8481. (l) Desjardins, S.; Maertens, G.; Canesi, S.
Org. Lett. 2014, 16, 4928. (m) Jacquemot, G.; Maertens, G.; Canesi, S.
Chem. - Eur. J. 2015, 21, 7713. (n) Guer
Guerinot, A.; Bouchard-Aubin, C.; Canesi, S. Chem. - Eur. J. 2015, 21,
18068.
́
ard, K. C.; Hamel, V.;
́
(13) Only one diastereomer was observed by NMR, and the
stereoselectivity was verified by nuclear Overhauser effect (NOE). The
coupling constants for the cyclopropane hydrogens 22 were close to 6
Hz and in agreement with a trans isomer.
(14) Unfortunately, this process was not efficient in the presence of
an alkyl-substituted malonate derivative more sterically hindered.
(15) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
D
DOI: 10.1021/acs.orglett.7b00248
Org. Lett. XXXX, XXX, XXX−XXX