Novel route to triethylsilyl-substituted cyclopropanes

Article abstract of DOI:10.1021/ol503081b

Radical adducts of S-α-ketonyl dithiocarbonates (xanthates) to triethyl vinylsilane are converted into triethylsilyl-substituted cyclopropanes upon ozonolysis followed by exposure to 1,4-dibromobutane and Cs₂CO₃/18-crown-6 in refluxi

Full text of DOI:10.1021/ol503081b

Letter
pubs.acs.org/OrgLett
Novel Route to Triethylsilyl-Substituted Cyclopropanes
Shi-Guang Li and Samir Z. Zard*
̀
Laboratoire de Synthese Organique, CNRS UMR 7652, Ecole Polytechnique, 91128 Palaiseau Cedex, France
S
* Supporting Information
ABSTRACT: Radical adducts of S-α-ketonyl dithiocarbonates (xan-
thates) to triethyl vinylsilane are converted into triethylsilyl-substituted
cyclopropanes upon ozonolysis followed by exposure to 1,4-
dibromobutane and Cs2CO3/18-crown-6 in refluxing acetonitrile. The
sequence works best with phenacyl type adducts, and the use of the less
bulky trimethysilyl (TMS) derivatives results in extensive desilylation.
yclopropanes, the smallest of the cycloalkanes, display a
a diboron derivative.7 Recently, Charette and co-workers
Cunique reactivity that continues to fascinate organic exposed di-tert-butoxy(alkenyl)silanols to 2 equiv of the
preformed zinc carbenoid bis(iodomethyl)zinc [Zn(CH2I)2]
in a Simmons−Smith cyclopropanation reaction furnishing the
corresponding di-tert-butoxy(cyclopropyl)silanols in excellent
isolated yields.8
chemists. Many cyclopropane-containing natural products
exhibit remarkable biological activity or have particularly
unusual structures. The pyrethrins, for example, have acted as
key lead structures for numerous synthetic insecticides built
around the chrysanthemic acid motif representing a billion-
dollar industry.1a The duocarmycins are potent DNA alkylating
agents that have inspired a vast amount of work in search of
clinically useful antitumor drugs.1b−d FR-900848 and U-106305
are two very unusual natural products isolated from a
streptomyces strain and featuring four and five contiguous
cyclopropane rings, respectively.1e−h The increasing interest in
cyclopropanes has spurred the development of numerous
synthetic routes to these strained structures.2 The majority of
the approaches rely on variants of the following reactions: the
Simmons−Smith cyclopropanation, the transition-metal cata-
lyzed cyclopropanations of alkenes with diazo compounds, and
the Corey−Chaykovsky reaction and variants thereof. In the
present letter, we describe a new convergent route to
cyclopropanes with two geminal electrophilic groups that is
particularly suited to the synthesis of silyl substituted
derivatives, a relatively rare class of compounds the chemistry
of which has hardly been explored.
In previous work, the groups of Maas and France employed
(trimethylsilyl)diazomethane as the silicon source and a
polymeric ruthenium(I) complex and copper(I) bisoxazoline
species as the catalysts, respectively, to obtain diverse silicon-
substituted cyclopropanes from the corresponding alkenes.3
Straub and Marko, in contrast, reacted a number of
diazoalkanes with various alkenylsilanes, under a low loading
of Pd(OAc)2, to generate a series of cyclopropylsilanes.4 Takai’s
team also reported a method to prepare cyclopropylsilanes,
whereby treatment of terminal alkenes with Me3SiCHI2 and
organochromium reagents gave cyclopropylsilanes in good
yield.5 Gevorgyan and co-workers developed the first highly
efficient, diastereo- and regioselective transition-metal-catalyzed
addition of silanes to cyclopropenes.6 Ito and Sawamura
described a protocol for the synthesis of optically active boron−
silicon bifunctional cyclopropane derivatives through enantio-
selective copper(I)-catalyzed reaction of allylic carbonates with
Over the past few years, we have disclosed unconventional
approaches to a variety of highly functionalized scaffolds of
potential synthetic or pharmacological interest, such as dienes,9
pyrroles,10 thiophenes,11 dihydrothiazines,12 1,3-dithieta-
nones,13 ketene monothioacetals,14 and thieno[2,3-b]-
thiopyran-4-ones,15 combining the radical and nonradical
chemistries of xanthates. This alliance offers both flexibility
and convergence and allows the introduction of tremendous
diversity into the structures. We have now considered the
possibility of rapidly constructing the synthetically interesting
but hitherto not readily accessible cyclopropylsilylanes
substituted by two different electron-withdrawing groups. Our
three-step approach, outlined in Scheme 1, involves (1)
intermolecular radical addition of xanthate 1 to terminal alkene
2; (2) conversion of xanthate 3 into thiolcarbonate 4 by
ozonolysis;16 an (3) intramolecular transformation into cyclo-
propane 5.
In an alkaline environment, ketone 4 is in equilibrium with
its enolate 6, and the proximity of the latter to the
thiolcarbonate group should encourage a nucleophilic attack
on the carbonyl group leading to intermediate 7, which should
in turn readily evolve into open form 8. By adding 1,4-
dibromobutane into the mixture, the thiolate anion should be
selectively captured and converted into sulfonium intermediate
9. In this manner, a good leaving group is created which can be
substituted by the enolate in 10 to finally furnish the desired
cyclopropane 5.
To give this complex sequence the best chance of success, we
decided initially to prepare a cyclopropane without the silyl
group. Thus, we treated xanthate 1a and 1-heptene 2a with a
small amount of lauroyl peroxide (DLP) in refluxing ethyl
acetate and obtained the desired xanthate 3a in 83% yield as a
Received: October 22, 2014
© XXXX American Chemical Society
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Letter
Scheme 1. General Strategy and Mechanism for
Cyclopropane Formation
Table 1. Optimization of the Reaction Conditions
a
time
(h)
yield
(%)
b
entry
base
solvent
additive
dr
1
K2CO3
t-BuOH/
CH3CN
24
42
1:1
2
3
4
5
6
7
8
K2CO3
K2CO3
LiOH
CH3CN
CH3CN
CH3CN
18-crown-6
18-crown-6
18-crown-6
18-crown-6
10
24
24
40
24
1.5
5.5
74
1:1
1:1
nd
60
trace
trace
nr
KHCO3 CH3CN
DBU CH3CN
nd
nd
Cs2CO3 CH3CN
18-crown-6
86
1:1
1:1
Cs2CO3 CH3CN
80
a
b
Isolated yield; nr = no reaction. The dr was determined by NMR;
nd = not detected.
very poor yield (Table 1, entries 4 and 5). With the soluble
organic base, DBU, in CH3CN, the reaction did not proceed at
all (Table 1, entry 6). Finally, we tested cesium carbonate,
which has better solubility in acetonitrile and is a stronger base
than potassium carbonate. Under the same conditions, except
that 5 equiv of cesium carbonate were used in place of
potassium carbonate, thiolcarbonate 4a was smoothly trans-
formed into the desired product 5a in 86% yield and in the
same epimeric ratio. Moreover, the reaction time was shortened
to 1.5 h (Table 1, entry 7). We also attempted to run this
reaction without 18-crown-6; however, the yield decreased to
80%, and the reaction time increased to 5.5 h (Table 1, entry
8). Finally, we adopted as the optimized cyclopropanation
conditions 5 equiv of Cs2CO3 as the base, 5 equiv of 1,4-
dibromobutane as the electrophile, and 2 equiv of 18-crown-6
as the phase-transfer catalyst in CH3CN (0.2 M) under reflux in
a nitrogen atmosphere.
With these reaction conditions in hand, we next examined
the applicability of this process to the synthesis of silyl-
substituted cyclopropanes. Under the standard conditions for
the radical addition of xanthates and ozonolysis into
thiolcarbonates, we prepared 3b and 4b in 96% and 80%
yield, respectively (Scheme 3). In the event, we obtained the
desired trimethylsilyl (TMS) substituted cyclopropane 5b but
in only 35% isolated yield and as two epimers (dr = 5:1)
although the thiolcarbonate 4b was totally consumed after 2 h
reflux. We also isolated 22% yield of a side product arising from
desilylation of 5b (H instead of TMS). As an extension of this
exploration, we also prepared aliphatic substituted xanthate 3c
in 91% yield and thiolcarbonate 4c in 78% yield. Under
identical conditions for the cyclopropanation, thiolcarbonate 4c
reacted in a similar way to give cyclopropylsilane 5c. Compared
to 4b, 4c gave an even lower yield of the desired TMS
substituted cyclopropane 5c (yield = 18%, dr = 1.5:1) and
additional side products including 16% yield of desilylated
cyclopropane (5c, H instead of TMS) and 29% yield of the
product derived from the desilylation of the starting material
(4c, H instead of TMS).
pale yellow oil. This xanthate was then converted into
thiolcarbonate 4a by ozonolysis in order to eliminate any
interference by unwanted sulfur nucleophiles arising from the
thiono group. This was accomplished by exposing xanthate 3a
in acetone to a stream of ozone at room temperature for a few
minutes, furnishing the desired thiolcarbonate 4a in 69% yield
(Scheme 2).
Scheme 2. Synthesis of Starting Thiolcarbonate 4a
With the thiolcarbonate 4a in hand, we were able to turn our
attention to the intramolecular rearrangement−cyclopropana-
tion process through the formation of cyclic tetrahydrothio-
phenonium salts as the leaving group.17 First, we treated
thiolcarbonate 4a with 10 equiv of K2CO3 as the base and 5
equiv of 1,4-dibromobutane as the electrophile in CH3CN/t-
BuOH (9/1) under reflux in a nitrogen atmosphere for 24 h.
After workup, we obtained the desired cyclopropane 5a in only
42% yield as a mixture of two isomers (1:1, as estimated by
NMR) (Table 1, entry 1). We noticed, however, that K2CO3
did not dissolve well in the CH3CN/t-BuOH solvent
combination. We therefore decided to use 2 equiv of 18-
crown-6 to replace t-BuOH as the additive to promote the
solubility of K2CO3 in CH3CN. The thiolcarbonate 4a was
totally consumed after 10 h of reflux, affording a 74% isolated
yield of cyclopropane 5a (Table 1, entry 2). We nevertheless
felt that the yield could still be improved, even though
thiolcarbonate 4a was totally consumed. We assumed that 4a
was indeed converted into the intermediates displayed in
Scheme 1 but that the evolution into the desired cyclopropane
5a was not complete. Unfortunately, prolonging the reaction
time to 24 h furnished an even lower yield (60%) (Table 1,
entry 3). We also screened LiOH and KHCO3 as the bases, but
after 24 and 40 h reflux respectively in CH3CN and in the
presence of 18-crown-6, both of these conditions resulted in a
From the preliminary results above, we realized that the TMS
group was too easily lost under the alkaline conditions. To
overcome this difficulty, we attempted the reaction on the
corresponding triethylsilyl (TES) substituted thiolcarbonates.
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Letter
the desired cyclopropylsilane product 5d in 65% isolated yield,
again as two epimers (dr = 2.1:1). This result confirmed our
expectation that larger substituents on silicon would increase
resistance to desilylation. We also attempted to reduce the
amount of cesium carbonate to 2 equiv, but unfortunately, this
decreased the yield of compound 5d to 54% (dr = 2.4:1), and
the reaction time was increased to 3 h (Scheme 3).
Scheme 3. Synthesis of Substituted Cyclopropanes
The radical addition step was not much affected by
substitution on the aromatic ring and phenacyl xanthates with
either electron-withdrawing and electron-donating groups 1
reacted efficiently with triethyl vinylsilane 2c to give good to
excellent yield of adducts (Scheme 3, 3d−i). The following
ozonolysis also proceeded in generally good yield (Scheme 3,
4d−i). For the cyclopropanation step, we found that substrates
substituted with electron-withdrawing groups, such as Cl and F,
gave higher yields of products. In addition, the reaction time
was reduced to 30−40 min and the ratio of the two epimers
ranged from 2.1:1 to 2.8:1 (Scheme 3, 5e, 5f, 5i). Substrates
with electron-rich substituents provided somewhat lower yields
of products and needed longer reaction times (Scheme 3, 5g,
5h). We encountered some difficulty with the addition of
naphthyl-substituted xanthate 1h to triethylvinylsilane in the
synthesis of 3j. We obtained the xanthate adduct in only 40%
yield even when we prolonged the reaction time and added
more DLP initiator. It is possible that this is due to a competing
radical closure on the less aromatic naphthalene ring. The
following ozonolysis step did not furnish a good yield of the
thiolcarbonate either, presumably because of competing
oxidation of the electron-rich aromatic ring (Scheme 3, 3j,
4j). However, naphthyl substituted thiolcarbonates 4j gave 70%
yield of the desired cyclopropane 5j, again as two epimers (dr =
2.8:1) after 80 min of reaction time (Scheme 3, 5j). The
xanthate with a thiophene substituent provided a 70% yield of
adduct but needed more radical initiator as well as a longer
reaction time (Scheme 3, 3k). After ozonolysis, we obtained the
desired thiolcarbonate 4k in 60% yield, which underwent
cyclization under the standard conditions to furnish 69% yield
of cyclopropane 5k (dr = 1.9:1). In this case, the reaction time
was shortened (30 min) as compared to 5j (Scheme 3, 5k).
Finally, we attempted to synthesize aliphatic cyclopropylsi-
lanes. By analogy with the route to TMS-substituted
thiolcarbonate 4c, we prepared the TES-substituted thiolcar-
bonate 4l in two steps. However, the following cyclo-
propanation reaction was still inefficient and sluggish, giving
5l in only 18% yield as two epimers (dr = 1.5:1), along with
28% yield of prematurely desilylated byproduct after 9 h of
reflux. We also recovered 50% of unreacted starting material 4l
(Scheme 3, 5l). In the case of the aliphatic substrates, it appears
that the slightly lower acidity and therefore slower formation of
the corresponding enolates allows unwanted competing
reactions to occur with a consequent decrease in yield. This
was confirmed by examining thiolcarbonate 4m, which can only
enolize from the desired side, but which nevertheless also gave
a low yield of cyclopropane 5m (Scheme 3, 5m).
Larger substituents on the silicon increase resistance to proto-
desilylation, although the introduction of the silyl group
becomes more difficult. Compared to TMS, TES is more
sterically congested and resists longer against the action of
cesium carbonate. Thus, following the standard xanthate
addition procedure, we obtained the desired TES-substituted
adduct 3d in 92% yield, which was ozonolyzed into 4d in good
yield. We next treated the 4d as the starting material in the
cyclopropanation process. After 70 min of reflux under identical
conditions, the thiolcarbonate 4d was totally consumed, as
monitored by thin-layer chromatography (TLC), and furnished
While we have concentrated our efforts on the synthesis of
the rare silicon-substituted cyclopropanes, this strategy is of a
more general applicability. Thus, following the standard radical
addition procedure, we were able to prepare 3n and 3o in 88%
and 78% yield, respectively. Ozonolysis afforded 4n and 4o in
87% and 88% yield, which were converted into the desired
cyclopropanes 5n in 80% yield and 5o in 68% yield under the
usual conditions. It is worth noting that both of these two
reactions proceeded rapidly since the starting thiolcarbonates
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(c) France, M. B.; Milojevich, A. K.; Stitt, T. A.; Kim, A. J. Tetrahedron
Lett. 2003, 44, 9287.
(4) Berthon-Gelloz, G.; Marchant, M.; Straub, B. F.; Marko, I. E.
were totally consumed in 30 to 40 min. And, in both cases, a
1:1 ratio of epimers was observed (Scheme 3).
In summary, we have developed a convenient, practical, and
convergent sequence to access cyclopropanes substituted with
two electron-withdrawing groups. In particular, we were able to
obtain silicon substituted derivatives. The silicon group can act
in principle as a precursor of the corresponding iodide, which
can then be subjected to various organometallic couplings.18
Furthermore, as abundantly documented, the presence of the
two electron-withdrawing groups activates the cyclopropane
rings toward nucleophilic attack paving the way to numerous
subsequent transformations.19 Compared to more conventional
methods, this approach avoids using expensive metal catalysts
and ligands, as well as the use of potentially explosive and
carcinogenic diazoalkanes. Further work is nevertheless still
needed to expand the scope to aliphatic ketones.
Chem.Eur. J. 2009, 15, 2923.
(5) (a) Hirano, M.; Toshikawa, S. Synlett 2004, 8, 1347. (b) Takai,
K.; Toshikawa, S.; Inoue, A.; Kokumai, R.; Hirano, M. J. Organomet.
Chem. 2007, 692, 520.
(6) Trofimov, A.; Rubina, M.; Rubin, M.; Gevorgyan, V. J. Org. Chem.
2007, 72, 8910.
(7) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M.
Angew. Chem., Int. Ed. 2008, 47, 7424.
(8) Beaulieu, L. P. B.; Delvos, L. B.; Charette, A. B. Org. Lett. 2010,
12, 1348.
(9) (a) Lusinchi, M.; Stanbury, T. V.; Zard, S. Z. Chem. Commun.
2002, 1532. (b) Goh, K. K. K.; Sunggak Kim, S.; Zard, S. Z. J. Org.
Chem. 2013, 78, 12274.
(10) Quiclet-Sire, B.; Wendeborn, F.; Zard, S. Z. Chem. Commun.
2002, 2214.
(11) Jullien, H.; Quiclet-Sire, B.; Tet
2014, 16, 302.
́
art, T.; Zard, S. Z. Org. Lett.
ASSOCIATED CONTENT
■
(12) Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2013, 15, 5886.
(13) Quiclet-Sire, B.; Sanchez-Jimenez, G.; Zard, S. Z. Chem.
Commun. 2003, 1408.
(14) Fabre, S.; Vila, X.; Zard, S. Z. Chem. Commun. 2006, 4964.
(15) (a) Corbet, M.; Zard, S. Z. Org. Lett. 2008, 10, 2861.
(b) Boutillier, P.; Quiclet-Sire, B.; Zafar, S. N.; Zard, S. Z. Tetrahedron:
Asymmetry 2010, 21, 1649. (c) Boivin, J.; Boutillier, P.; Zard, S. Z.
Tetrahedron Lett. 1999, 40, 2529.
(16) (a) Li, S. G.; Zard, S. Z. Org. Lett. 2013, 15, 5898. (b) Quiclet-
Sire, B.; Zard, S. Z. Bull. Korean Chem. Soc. 2010, 31, 543.
(17) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1353. (b) For a review, see: McGarrigle, E. M.; Myers, E. L.; Illa, O.;
Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chem. Rev. 2007, 107, 5841.
(c) Boivin, J.; Pothier, J.; Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1999,
40, 9239.
S
* Supporting Information
Experimental procedures, full spectroscopic data, and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
s.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: samir.zard@polytechnique.edu.
Notes
The authors declare no competing financial interest.
(18) (a) Tamao, K.; Mishima, M.; Yoshida, J. I.; Takahashi, M.;
Ishida, N.; Kumada, M. J. Organomet. Chem. 1982, 225, 151.
(b) Beaulieu, L. P. B.; Zimmer, L. E.; Gagnon, A.; Charette, A. B.
Chem.Eur. J. 2012, 18, 14784. (c) Hohn, E.; Palecek, J.; Pietruszka,
J.; Frey, W. Eur. J. Org. Chem. 2009, 3765.
ACKNOWLEDGMENTS
■
We thank the China Scholarship Council for a grant to S.-G. L.
and Dr Mario Lanteri (Universidad Nacional de Cor
Argentina) for a preliminary experiment.
́
doba,
(19) For recent reviews, see: (a) Schneider, T. F.; Kaschel, J.; Werz,
D. B. Angew. Chem., Int. Ed. 2014, 53, 5504. (b) Cavitt, M. A.; Phun, L.
H.; France, S. Chem. Soc. Rev. 2014, 43, 804. (c) A cluster of
publications on activated cyclopropanes has appeared in a very recent
issue of Synlett: Synlett 2014, 25, 2258−2318. (d) Wang, Z. Synlett
2012, 23, 2311.
DEDICATION
■
This paper is dedicated with respect to the memory of Prof.
Ekkehard Winterfeldt (University of Hanover).
REFERENCES
■
(1) (a) Matsuo, N., Mori, T., Eds. Pyrethroids. In Top. Curr. Chem.
2012, 314, 1−224. (b) Takahashi, I.; Takahashi, K.; Ichinura, M.;
Morimoto, M.; Asano, K.; Kawamoto, I.; Tomita, F.; Nakano, H. J.
Antibiot. 1988, 41, 1915. (c) Yoshida, M.; Ezaki, M.; Hashimoto, M.;
Yamashita, M.; Sigematsu, N.; Okuhara, M.; Kohsaka, M.; Horikoshi,
K. J. Antibiot. 1990, 43, 748. (d) Tse, W. C.; Boger, D. L. Chem. Biol.
2004, 11, 1607. (e) Kao, M. S.; Zielinski, R. J.; Cialdella, J. I.;
Marschke, C. K.; Dupis, M. J.; Li, G. P.; Kloosterman, D. A.; Spilman,
C. H.; Marshall, V. P. J. Am. Chem. Soc. 1995, 117, 10629. (f) Pietruzka,
J. Chem. Rev. 2003, 103, 1051. (g) Wessjohann, L. A.; Brandt, W.
Chem. Rev. 2003, 103, 1625. (h) Thibodeaux, C. J.; Chang, W. C.; Liu,
H. W. Chem. Rev. 2012, 112, 1681.
(2) For selected reviews, see: (a) Chen, D. Y.-K.; Pouwer, R. H.;
Richard, J.-A. Chem. Soc. Rev. 2012, 41, 4631. (b) Rubin, M.; Rubina,
M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c) Reissig, H. U.;
Zimmer, R. Chem. Rev. 2003, 103, 1151. (d) Lebel, H.; Marcoux, J. F.;
Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
(e) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (f) The Chemistry
of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: Chichester, 1987,
1995; 2 volumes.
(3) (a) Maas, G.; Seitz, J. Tetrahedron Lett. 2001, 42, 6137. (b) Maas,
G.; Werlr, T.; Alt, M.; Mayer, D. Tetrahedron 1993, 49, 881.
D
dx.doi.org/10.1021/ol503081b | Org. Lett. XXXX, XXX, XXX−XXX