Zinc mediated allylations of chlorosilanes promoted by ultrasound: Synthesis of novel constrained sila amino acids

Article abstract of DOI:10.1039/c4ob00294f

A simple, fast and efficient method for allylation and propargylation of chlorosilanes through zinc mediation and ultrasound promotion is reported. As a direct application of the resulting bis-allylsilanes, three novel, constrained sila amino acids are prepared for the first time. The design and synthesis of the constrained sila analogue of GABA (γ-amino butyric acid) is a highlight of this work. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00294f

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Zinc mediated allylations of chlorosilanes
promoted by ultrasound: Synthesis of novel
constrained sila amino acids†
Cite this: Org. Biomol. Chem., 2014,
12, 4093
Received 8th February 2014,
Accepted 27th March 2014
Remya Ramesh and D. Srinivasa Reddy*
DOI: 10.1039/c4ob00294f
www.rsc.org/obc
A simple, fast and efficient method for allylation and propargyla-
tion of chlorosilanes through zinc mediation and ultrasound pro-
motion is reported. As a direct application of the resulting bis-
allylsilanes, three novel, constrained sila amino acids are prepared
for the first time. The design and synthesis of the constrained sila
analogue of GABA (γ-amino butyric acid) is a highlight of this
work.
Organosilanes have wide applications in organic chemistry,
from commonly used protecting groups to synthetic intermedi-
ates.1 Compared to other organometallic reagents, they are
stable in air and hence are easy to handle and store. Apart
from their conventional use in organic synthesis and polymer
chemistry,2 organosilanes have uses in medicinal chemistry3
as well. Since both carbon and silicon belong to the same
group in the periodic table, medicinal chemists have used
silicon as a bioisostere of carbon to improve the drug-like pro-
perties of molecules, hence the use of organosilanes is becom-
ing popular in recent times.4 As part of an ongoing program
(silicon switch approach) in this group, we are interested in
making novel silicon analogues of selected drug molecules to
improve their desired properties. Some of the silicon ana-
logues synthesized in this group have shown promising results
(Fig. 1).5 Biological profiling and lead optimization is currently
in progress with respect to Silinezolid. Along these lines, there
is a need to explore simple and practical methods to access
organosilicon building blocks which will be useful for
the drug discovery programs based on the silicon switch
approach.3
Fig. 1 Silicon analogues of known drugs from the present group.
widely used method for their preparation.7 Reactions mediated
by other organometallic reagents using indium,8 samarium9
and zinc10 are also known. However, there was no report in the
literature for using sonication in preparing allylsilanes. The
ultrasound waves disperse the metal and clean its surface,
which makes it more reactive.11 The experimental safety,
simplicity, low-cost and the rapid reaction rate are the added
advantages of this technique. Herein, organozinc mediated
allylations and propargylations on a variety of chlorosilanes
promoted by ultrasound waves are reported.
The initial attempts started with diphenyldichlorosilane
and allyl bromide using THF as the solvent. The chlorosilane,
allyl bromide and zinc dust in THF solvent were sonicated by
placing them in an ultrasound cleaning bath (37 kHz, 320 W).
The reaction was complete within 10 minutes and the desired
product diallyldiphenylsilane 1 was isolated in 88% yield. For
the comparison purpose, the reaction was conducted without
using ultrasonication and it was found that the present
method is superior. After having this result in hand, the same
conditions (2 eq. of allylbromide and 2 eq. of Zn per chloro)
were applied to a variety of chlorosilanes, which include mono-
chloro, dichloro as well as trichlorosilanes (Scheme 1). All the
results are compiled in Chart 1. In most cases the product was
obtained in good to excellent yields.
Allylsilanes are versatile reagents with very rich chemistry,6
with a variety of methods known in the literature for their
preparation. The reaction of Grignard reagents, prepared from
allylhalides with chlorosilanes or alkoxysilanes, is the most
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr HomiBhabha
Road, Pune, 411008, India. E-mail: ds.reddy@ncl.res.in; Fax: +91 20 25902629;
Tel: +91 20 25902445
†Electronic supplementary information (ESI) available: Characterization data,
NMR spectra and detailed experimental procedures. See DOI: 10.1039/
c4ob00294f
In the case of monochlorosilanes, the products 2, 3, 4, 5
and 6 were obtained in the range of 71–98% yield. However in
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the case of dimethylallylchlorosilane, the product 7 was iso-
lated in poor yield due to its volatile nature. Addition of two
and three allyl groups was demonstrated using the same proto-
col to obtain products 7, 8, 9, 10, 11 and 12. It is worth men-
tioning here that products like 9, 11 and 12 are important
building blocks in dendrimers and polymers. To expand the
scope of the present method, the reaction of chlorosilanes
with propargylbromide was also explored and the results are
interesting. Propargylbromide reacted with dimethylphenyl-
chlorosilane and dimethylbenzylchlorosilane under the same
conditions to give exclusively the desired propargyl com-
pounds 13 and 14, respectively. In the case of dichlorosilanes,
the propargylallenyl compounds (15b and 16b) were obtained
as minor compounds in addition to the desired dipropargyl
compounds (15a and 16a). It is interesting to note that a
similar reaction mediated by indium metal as reported by Lai
Scheme 1 Allylation of chlorosilane using Zn mediation.
1
et al8 gives the allene derivative exclusively. The H NMR data
of all the known compounds were compared with the literature
values and were found to be exactly matching.
As a direct application of the resulting allylsilanes, we envi-
saged the preparation of novel constrained unnatural silicon-
containing amino acids which are interesting candidates in
drug discovery or as part of the drug candidates. In addition,
the synthetic unnatural amino acids12 can also be used for
probing bioactive conformations in peptides of interest.13 Syn-
thesis and biological studies of silicon-containing amino
acids, as well as the peptides incorporating them, have been
documented in literature.14,3d However, they are still few in
number with limited structural variation despite their attrac-
tive features. There is a need to find new routes to access novel
and diverse silicon-containing amino acids. Along these lines,
the crucial intermediate diiodo compound 17 was prepared
from diallyldimethylsilane (7), by zirconacyclization followed
by addition of iodine according to the literature protocol.15
This intermediate 17 was used as a starting point to access
various planned unnatural amino acids, particularly α-, β- and
γ-amino acids with unusual 5,5-trans fusion.16 Accordingly,
compound 17, on treatment with ethylisocyanoacetate in the
presence of K2CO3 as base and a phase-transfer catalyst
(18-crown-6), produced compound 18 as a sole product.17 The
ease of formation of such a strained system can be attributed
to the larger Si–C bond length (189 pm as compared to 154
pm for an sp3–sp3 C–C bond),18 which makes the reaction feas-
ible under milder conditions. The isocyano group on hydro-
lysis (aq. HCl) gave the desired amino ester 19, an unnatural
α-amino acid in 91% yield. The free amine group was pro-
tected as the t-butyl carbamate to give orthogonally protected
α-amino acid 20. For the synthesis of the β-amino acid, com-
pound 17 was treated with ethylcyanoacetate under the same
conditions adopted for the synthesis of α-amino acid, to give
α-cyanoester 21 in 86% isolated yield. The cyano group present
in 21 was hydrogenated in the presence of RANEY® nickel
under 60 psi pressure, to furnish β-amino ester 22. When the
hydrogenation reaction was carried out in the presence of Boc
anhydride, the Boc protected amino acid 23 was obtained with
improved yield (Scheme 2). Both the α-, and β-amino acid
Chart 1 Scope of the method.
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Scheme 3 Synthesis of silicon containing GABA analogue.
Synthesis of the newly designed GABA analogue began from
the intermediate 21. The compound 21 on selective ester
hydrolysis, followed by thermal decarboxylation of resulting
α-cyano carboxylic acid, gave the nitrile 24. After a few
attempts, alkylation of 24 with 3,3-dimethylallyl bromide gave
the desired product in less yields.24 The impure alkylated
product was subjected to oxidative cleavage by ozonolysis in
methanolic NaOH to furnish the desired compound 25.25
Although the ozonolysis reaction was clean, the alkylation
needs further optimization. The compound 25 on reduction
(RANEY® Ni, 60 psi) in the presence of Boc anhydride
furnished the novel GABA analogue 26 in 78% yield
(Scheme 3).19 The new GABA analogue is structurally close to
that of the marketed drug Gabapentin and a developmental
candidate Atagabalin. Hence, compound 26 can serve as a
starting point which needs more attention to profile in biologi-
cal assays.
In summary, a simple and rapid method for the preparation
of allyl- and propargyl-silanes has been developed, which can
be an addition to the existing toolbox to access these com-
pounds. The unsaturated organosilanes are very good starting
materials in the polymer industry, since they can undergo
addition polymerization. Using allyl-silanes as starting
material, silicon incorporated unnatural α-, β- and γ-amino
acids with unusual 5,5-trans fusion have been prepared for the
first time. The more lipophilic and conformationally rigid
GABA analogue is expected to be an important compound,
which may be useful for the modulation of various CNS dis-
orders. Biological profiling, conformational studies and struc-
ture activity relationships (SARs) are the subject of future
publications from this group.
Scheme 2 Synthesis of constrained sila α-, β-amino acids.
derivatives 20 and 23 were well characterized using spectral
data.19
After succeeding in the preparation of both α- and β-amino
acids with an unprecedented core, the next task was to syn-
thesize a GABA analogue with the same skeleton. GABA
(γ-amino butyric acid) is the chief inhibitory neurotransmitter
present in the mammalian central nervous system.20 The
deficiency of GABA is associated with several neurological dis-
orders. For disease states associated with the deficiency of
GABA, lipophilic GABA analogues have been synthesized.20
The polar and flexible structure of GABA prevents it from cross-
ing the blood brain barrier (BBB). Atagabalin21 and Gabapentin22
are pharmaceutically important, conformationally rigid GABA
analogues. The incorporation of silicon is believed to increase
the lipophilicity of a molecule which can be an attractive
feature in the development of CNS drugs as it is expected to
increase brain exposures. To our knowledge, Tacke’s group,
the pioneer of silicon switch approach, has claimed the sila-
cyclohexyl and sila-cyclopentyl analogues of Gabapentin in a
patent publication.23 Therefore, we became interested in acces-
sing novel, constrained sila analogues of GABA, which can be
good starting points for the medicinal chemistry programs.
CSIR, New Delhi (GenCODE program under XII Five Year
Plan, BSC0123) is acknowledged for financial support. We
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thank B. Seetharamsingh (CSIR-NCL, Pune) for his help in
some of the initial experiments. RR thanks CSIR, New Delhi,
for the award of a research fellowship.
2010, 695, 310–313; ( j) U. Olszewski, R. Zeillinger,
M. D. Kars, A. Zalatnai, J. Molnar and G. Hamilton, Anti-
Cancer Agents Med. Chem., 2012, 12, 663–671.
5 Unpublished results. However, a PCT document covering
Silinezolid and related compounds is available in public
domain. D. S. Reddy, B. Seetharamsingh and R. Ramesh,
WO, 054275, A1, 2013.
Notes and references
6 Selected reviews and publications on allylsilanes:
(a) H. Sakurai, Pure Appl. Chem., 1982, 54, 1–22;
(b) A. Hosomi, Acc. Chem. Res., 1988, 21, 200–206;
(c) J. R. Hwu, B.-L. Chen and S.-S. Shiao, J. Org. Chem.,
1995, 60, 2448–2455; (d) S. BouzBouz, L. Boulard and
J. Cossy, Org. Lett., 2007, 9, 3765–3768; (e) T. H. Chan and
D. Wang, Chem. Rev., 1995, 95, 1279–1292; (f) C. E. Masse
and J. S. Panek, Chem. Rev., 1995, 95, 1293–1316; (g) J. Wu,
Y. Chen and J. S. Panek, Org. Lett., 2010, 12, 2112–2115;
(h) R. E. Grote and E. R. Jarvo, Org. Lett., 2009, 11, 485–488;
(i) J. W. A. Kinnaird, P. Y. Ng, K. Kubota, X. Wang and
J. L. Leighton, J. Am. Chem. Soc., 2002, 124, 7920–7921;
( j) J. S. Panek and M. Yang, J. Am. Chem. Soc., 1991, 113,
9868–9870.
7 (a) S. D. Rosenberg, J. J. Walburn and H. E. Ramsden,
J. Org. Chem., 1957, 22, 1606–1607; (b) R. E. Scott and
K. C. Frisch, J. Am. Chem. Soc., 1951, 73, 2599–
2600.
8 Z. Li, C. Yang, H. Zheng, H. Qiu and G. Lai, J. Organomet.
Chem., 2008, 693, 3771–3779.
1 Selected reviews and publications: (a) R. West and
T. J. Barton, J. Chem. Educ., 1980, 57, 165–169;
(b) I. Fleming, Chem. Soc. Rev., 1981, 10, 83–111;
(c) G. L. Larson, Recent Synthetic Applications of Organo-
silanes, in Organic Silicon Compounds, 2004, vol. 1 and 2;
(d) S. E. Denmark and R. F. Sweis, Chem. Pharm. Bull.,
2002, 50, 1531–1541; (e) S. E. Denmark and C. S. Regens,
Acc. Chem. Res., 2008, 41, 1486–1499; (f) M. A. Brook,
Silicon in Organic, Organometallic and Polymer Chemistry,
Wiley Interscience, New York, 2000; (g) I. Fleming, in Com-
prehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon Press, Oxford, 1991, vol. 2, pp. 563–593;
(h) H.-J. Zhang, D. L. Priebbenow and C. Bolm, Chem. Soc.
Rev., 2013, 42, 8540–8571.
2 Selected references related to silicon based polymers:
(a) D. Y. Son, Chem. Commun., 2013, 49, 10209–10210;
(b) S. Thames and K. Panjnani, J. Inorg. Organomet. Polym.,
1996, 6, 59–94; (c) R. Richter, G. Roewer, U. Böhme,
K. Busch, F. Babonneau, H. P. Martin and E. Müller, Appl.
Organomet. Chem., 1997, 11, 71–106 and references cited
therein.
9 Z. Li, X. Cao, G. Lai, J. Liu, Y. Ni, J. Wu and H. Qiu,
J. Organomet. Chem., 2006, 691, 4740–4746.
3 See selected recent reviews and publications for the use of 10 Only once Zn was utilized in the literature for the allylation
silicon in medicinal chemistry: (a) J. S. Mills and
G. A. Showell, Drug Discovery Today, 2003, 8, 551–556;
(b) J. S. Mills and G. A. Showell, Expert Opin. Invest. Drugs,
of chlorosilanes, but it was not generalized. See: T. Sanji,
M. Iwata, M. Watanabe, T. Hoshi and H. Sakurai, Organo-
metallics, 1998, 17, 5068–5071.
2004, 13, 1149–1157; (c) S. Gately and R. West, Drug Dev. 11 (a) G. Cravotto, E. C. Gaudino and P. Cintas, Chem. Soc.
Res., 2007, 68, 156–163; (d) A. K. Franz and S. O. Wilson,
J. Med. Chem., 2013, 56, 388–405; (e) R. Tacke, Angew.
Rev., 2013, 42, 7521–7534; (b) C. Einhorn, J. Einhorn and
J.-L. Luche, Synthesis, 1989, 787–813.
Chem., 1999, 111, 3197–3200, (Angew. Chem., Int. Ed., 1999, 12 N. Voloshchuk and J. K. Montclare, Mol. BioSyst., 2010, 6,
38, 3015–3018). 65.
4 Selected recent reports on silicon switch approach: 13 (a) D. A. Dougherty, Curr. Opin. Chem. Biol., 2000, 4, 645–
(a) M. Chang, S.-R. Park, J. Kim, M. Jang, J. H. Park,
J. E. Park, H.-G. Park, Y.-G. Suh, Y. S. Jeong, Y.-H. Park and
H.-D. Kim, Bioorg. Med. Chem., 2010, 18, 111–116;
652; (b) M. Tanaka, K. Anan, Y. Demizu, M. Kurihara,
M. Doi and H. Suemune, J. Am. Chem. Soc., 2005, 127,
11570–11571.
(b) K. Maruyama, M. Nakamura, S. Tomoshige, K. Sugita, 14 (a) M. Mortensen, R. Husmann, E. Veri and C. Bolm, Chem.
M. Makishima, Y. Hashimoto and M. Ishikawa, Bioorg.
Med. Chem. Lett., 2013, 23, 4031–4036; (c) M. Nakamura,
M. Makishima and Y. Hashimoto, Bioorg. Med. Chem. Lett.,
2013, 21, 1643–1651; (d) M. Nakamura, D. Kajita,
Y. Matsumoto and Y. Hashimoto, Bioorg. Med. Chem. Lett.,
2013, 21, 7381–7391; (e) M. Fischer and R. Tacke, Organo-
metallics, 2013, 32, 7181–7185; (f) J. Wang, C. Ma, Y. Wu,
R. A. Lamb, L. H. Pinto and W. F. DeGrado, J. Am. Chem.
Soc., 2011, 133, 13844–13847; (g) P. Luger, M. Weber,
C. Hübschle and R. Tacke, Org. Biomol. Chem., 2013, 11,
2348–2354; (h) A. P. Ayscough, G. A. Showell, M. R. Teall,
H. E. Temple and S. Ahmed, WO, 092342, A1, 2010;
(i) D. Troegel, F. Möller and R. Tacke, J. Organomet. Chem.,
Soc. Rev., 2009, 38, 1002–1010; (b) R. J. Smith and S. Bienz,
Helv. Chim. Acta, 2004, 87, 1681–1696; (c) R. Tacke,
M. Merget, R. Bertermann, M. Bernd, T. Beckers and
T. Reissmann, Organometallics, 2000, 19, 3486–3497;
(d) B. Vivet, F. Cavelier and J. Martinez, Eur. J. Org. Chem.,
2000, 807–811; (e) R. D. Walkup, D. C. Cole and
B. R. Whittlesey, J. Org. Chem., 1995, 60, 2630–2634;
(f) S. Falgner, G. Buchner and R. Tacke, J. Organomet.
Chem., 2010, 695, 2614–2617; (g) S. Dörrich, S. Falgner,
S. Schweeberg, C. Burschka, P. Brodin, B. M. Wissing,
B. Basta, P. Schell, U. Bauer and R. Tacke, Organometallics,
2012, 31, 5903–5917; (h) S. Falgner, C. Burschka,
S. Wagner, A. Böhm, J. O. Daiss and R. Tacke, Organo-
4096 | Org. Biomol. Chem., 2014, 12, 4093–4097
This journal is © The Royal Society of Chemistry 2014

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metallics, 2009, 28, 6059–6066; (i) S. Falgner, D. Schmidt, 20 (a) K. Gajcy, S. Lochynski and T. Librowski, Curr. Med.
R. Bertermann, C. Burschka and R. Tacke, Organometallics,
2009, 28, 2927–2930.
Chem., 2010, 17, 2338–2347; (b) J. S. Bryans and
D. J. Wustrow, Med. Res. Rev., 1999, 19, 149–177.
15 (a) M. Mirza-Aghayan, R. Boukherroub, G. Etemad-Mogha- 21 D. C. Blakemore, J. S. Bryans, P. Carnell, C. L. Carr,
dam, G. Manuel and M. Koenig, Tetrahedron Lett., 1996, 37,
3109–3112; (b) A. G. Nair, K. M. Keertikar, S. H. Kim,
J. A. Kozlowski, S. Rosenblum, O. B. Selyutin, M. Wong,
W. Yu and Q. Zeng, WO, 112429, 2011.
N. E. A. Chessum, M. J. Field, N. Kinsella, S. A. Osborne,
A. N. Warren and S. C. Williams, Bioorg. Med. Chem. Lett.,
2010, 20, 461–464.
22 (a) G. J. Sills, Curr. Opin. Pharmacol., 2006, 6, 108–113;
(b) N. S. Gee, J. P. Brown, U. K. Dissanayake, J. Offord,
R. Thurlow and G. N. Woodruff, J. Biol. Chem., 1996, 271,
5768–5776.
16 5,5-cis-Fusion of all carbon scaffold is commonly encoun-
tered in the literature.
17 (a) S. Kotha and E. Brahmachary, J. Org. Chem., 2000, 65,
1359–1365; (b) S. Kotha, D. Goyal and A. S. Chavan, 23 R. Tacke, J. Daiss, G. A. Showell and A. Richards, UK Patent,
J. Org. Chem., 2013, 78, 12288–12313 and refs cited
2397576-A, 2004.
therein.
24 The alkylated product could not be purified despite a few
attempts. The reaction and purification need further
optimization.
18 Handbook of Chemistry and Physics, CRC Press, 81st edn,
2000.
19 All the spectral data (IR, 1H NMR, 13C NMR, HRMS) are 25 J. A. Marshall and A. W. Garofalo, J. Org. Chem., 1993, 58,
provided in ESI.†
3675–3678.
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