Safe, facile radical-based reduction and hydrosilylation reactions in a microreactor using tris(trimethylsilyl)silane

Article abstract of DOI:10.1039/b803715a

A highly efficient system for tris(trimethylsilyl)silane (TTMSS) mediated deoxygenation, dehalogenation and hydrosilylation reactions is described in a microstructured device; this convenient platform enables the scale up of radical-based processes. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803715a

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Safe, facile radical-based reduction and hydrosilylation reactions in a
microreactor using tris(trimethylsilyl)silane
Arjan Odedra, Karolin Geyer, Tomas Gustafsson, Ryan Gilmour and Peter H. Seeberger*
Received (in Cambridge, UK) 4th March 2008, Accepted 27th March 2008
First published as an Advance Article on the web 29th April 2008
DOI: 10.1039/b803715a
A highly efficient system for tris(trimethylsilyl)silane (TTMSS)
mediated deoxygenation, dehalogenation and hydrosilylation
reactions is described in a microstructured device; this conveni-
ent platform enables the scale up of radical-based processes.
possible using a simple backpressure valve thereby avoiding
the use of conventional toxic or chlorinated solvents (e.g. CCl4
or benzene).
Initial reductions were performed on the xanthate and
imidazolylthiocarbamate derivatives of dodecanol (entries 1
and 2, respectively, Table 1) to furnish the parent alkane in
excellent yield. Furthermore, the related chloro-substituted
xanthate was chemoselectively reduced to 1-chlorodecane in
70% yield (entry 3).
Microstructured continuous-flow reactors and chip based
microreactors are becoming increasingly popular to overcome
hurdles associated with the use of batch reactors in synthetic
chemistry.1 Traditional batch methods have inherent limita-
tions regarding the optimisation of reaction conditions and
scale-up. The small internal dimensions of microreactors
require minimal amounts of reagent that are processed under
precisely controlled conditions. Subsequently, rapid reaction
screening is possible while overall process safety is improved.
In addition, reactions can be conducted at elevated tempera-
tures and under pressures which are not accessible using
conventional flasks.2 Subsequently, reactions that have pre-
viously been considered to be unattractive on large scale for
practical and/or safety reasons are now within the reach of
process chemists.3
To investigate the scope and applicability of this method to
the synthesis of biologically and industrially relevant small
molecules, the preparation of deoxy sugars was examined. The
deoxygenation of the diacetone-D-glucose derivative to the
corresponding ribohexofuranose (entry 4) proceeded in excel-
lent yield; a process that offers considerable advantages in
operational simplicity compared to the literature procedure.9
The preparation of protected 6-deoxy-D-galactose from the
corresponding primary dithiocarbonate also proceeded in
490% yield (entry 5). More sterically demanding systems
such as the secondary C3 dithiocarbonate of dihydrocholes-
terol were also readily tolerated to furnish the reduced product
in 80% yield, and the tertiary carbinol derivative of adaman-
tane was processed to the parent hydrocarbon in
excellent yield.
Radical reduction reactions such as deoxygenations and
dehalogenations are important synthetic transformations.4 In
particular, free radical based reactions such as Barton–
McCombie deoxygenations5 and dehalogenations have re-
ceived considerable attention due to their versatility and
functional group tolerance.6 Furthermore, development of
tris(trimethylsilyl)silane (TTMSS) as an efficient, non-toxic
alternative to tin hydrides as the reducing agent in radical-
based reductions has overcome many of the drawbacks asso-
ciated with these processes.7 Herein, we report the use of
TTMSS as the reducing reagent in continuous-flow micro-
reactors for radical-based transformations.
Encouraged by these results, we embarked on a comparative
study to explore the radical-based reduction of a variety of
structurally related halides.10 Iodo-, bromo- and chloro-do-
decanol proved to be excellent substrates for this reaction
system yielding dodecanol in excellent yields (85, 83 and 67%
yields, respectively, entries 8, 9 and 10). Similarly, bromoada-
mantane was cleanly dehalogenated in 86% yield (entry 11).
Interestingly, the conversion of the iodo-derivatives of galac-
tose and glucose to the corresponding deoxy-sugars (entries 12
and 13) proceeded in 490% yield; results that compare
favourably with the deoxygenation reactions of the corre-
sponding thiocarbonate derivatives (entries 4 and 5). Finally,
the scope of this dehalogenation process was extended to
include aromatic bromides such as 9-bromophenanthrene
(entry 14). The efficiency of the reduction of this substrate
showed slight concentration dependence. However, after a
Microreactors enable rapid and efficient heat control,
solvent superheating, and high pressures, features that are
advantageous in conducting free radical deoxygenations and
dehalogenations. For this study a glass-chip microreactor with
an internal volume of 1.0 mL was employed (Fig. 1).8 Re-
agents were introduced separately via two inlets using a syringe
pump (Harvard, PHD 22/2000 with multi-syringe rack).
The TTMSS-mediated reduction of various alcohol-derived
thiocarbonyl derivatives was performed in a microstructured
device at 130 1C with 5 min residence time. Following an initial
solvent screen, toluene was identified as the solvent of choice.
Superheating to 130 1C to effect the desired reaction was
Laboratory for Organic Chemistry, Swiss Federal Institute of
Technology (ETH) Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich,
Switzerland. E-mail: seeberger@org.chem.ethz.ch;
Fig. 1 Schematic representation of the reaction setup. BPR: back
Fax: +41 44 633 1235; Tel: +41 44 633 2103
pressure regulator.
ꢀc
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Table 1 TTMSS mediated deoxygenations and dehalogenations of
various substrates in continuous flow
Table 2 Hydrosilylation of selected alkynes in a microreactor
Entry Substratea
Product
Yieldb
(%)
1
2
3
4
n-C12H25OC(S)SMe
n-C12H25OC(S)Im
ClC10H20OC(S)SMe
n-C12H26
n-C12H26
n-C10H21Cl
89
94
70
92
Entry
R
Z : E ratioa
Yieldb (%)
1
2
3
Ph
n-C6H13
98 : 2 (84 : 16)c
77 : 23
11 : 89
96 (88)c
91
94
A mixture of the alkyne in toluene (1.0 mol dmꢁ3), TTMS (1.2
equiv.) and AIBN (10 mol%) were injected trough a single inlet with a
flow rate of 200 mL minꢁ1; Z : E ratio determined by 1H NMR
a
5
6
93
85
b
c
spectroscopy. Isolated yield. Literature values (see ref. 11).
dehalogenation reactions appears to general, and led us to
explore additional transformations using this reagent. The
TTMSS adds in a highly regioselective manner across a range
of alkenes and alkynes by a free-radical chain mechanism to
form silanes and vinyl silanes, respectively.11 It was envisaged
that the improved heat and mass transfer inherent to micro-
reactors might have an effect on the cis/trans selectivities in the
hydrosilylation reaction of alkynes while reducing reaction
times. To explore this concept, a premixed solution of pheny-
lacetylene (1.0 mol dmꢁ3 in toluene), TTMSS (1.2 equiv.) and
AIBN (0.1 equiv.) was passed through the microreactor
system at a flow rate of approximately 200 mL minꢁ1 (resi-
dence time 5 min) at 130 1C. The expected reaction product b-
silylstyrene (Table 2, entry 1) was obtained in 96% yield (Z : E
ratio of 98 : 2). It is interesting to note that the microreactor-
based hydrosilylation of phenylacetylene gives a superior Z : E
ratio when compared with the literature batch reaction.11
Similarly, treatment of 1-octyne with TTMS yielded the
expected anti-Markovnikov product vinylsilane in 91% yield
as a mixture of geometric isomers (Z : E = 77 : 23, entry 2).
Finally, hydrosilylation of 1-ethynylcyclohexanol furnished
the E-vinyl silane as the major reaction product in excellent
yield (94%, E : Z = 89 : 11, vide infra).13
7
77
8
9
10
11
n-C12H25
n-C12H25Br
n-C12H25Cl
I
n-C12H26
n-C12H26
n-C12H26
85
83
67c
86
12
98
13
14
93
ð1Þ
92de
Application of this method to effect the transformation of
terminal olefins such as 1-hexadecene to the saturated silane
(eqn (1)) also proved to be highly successful yielding the
desired compound in 86% yield.14
A solution of the substrate (1.0 mol dmꢁ3 in toluene) and TTMSS
(1.2 equiv.) and 10 mol% of AIBN (10 mol%) in toluene were
simultaneously injected into microreactor preheated at 130 1C for
a
In conclusion, we have developed a facile platform to
conduct radical-based transformations in a microstructured
reaction device. Reduction chemistry, namely Barton–
McCombie deoxygenations and dehalogenations, has been
demonstrated using TTMSS as the radical reducing agent.12
Furthermore, the scope of radical-based microreactor pro-
cesses has been expanded to include hydrosilylation reactions
of alkenes and alkynes.
b
5 min of residence time. Isolated yield unless otherwise stated.
c
Conversion in percentage as measured by 1H NMR spectroscopy.
d
A solution of 9-bromophenanthrene (1.0 mol dmꢁ3 in toluene),
TTMS (1.2 equiv.) and AIBN (10 mol%) were premixed and injected
e
through a single inlet. Based on 93% conversion.
facile optimisation process, phenanthrene was reproducibly
formed in 490% yield.
Gratifyingly, the use of tris(trimethylsilyl)silane (TTMSS) in
We thank the Swiss Federal Institute of Technology (ETH)
Zurich and AstraZeneca R&D (Molndal, Sweden) for gener-
¨
ous financial support.
microreactor-based Barton–McCombie deoxygenation and
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Organosilanes in Radical Chemistry, John Wiley & Sons Ltd.,
Chichester, UK, 2004.
Notes and references
1. For recent reviews of microreactor-based synthesis, see: W. Ehrfeld,
V. Hessel, and H. Lowe, Microreactors: New Technology for Modern
7. C. Chatgilialoglu, Acc. Chem. Res., 1992, 25, 188;
C. Chatgilialoglu, Chem. Eur. J., 2008, 14, 2310.
8. A Syrris glass reactor with a 1.0 mL heated retention unit was
used. For more information visit www.syrris.com.
¨
Chemistry, John Wiley & Sons Inc., Weinheim, 2000; K. Jahnisch,
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V. Hessel, H. Lowe and M. Baerns, Angew. Chem., Int. Ed., 2004, 43,
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M. T. Rahman, M. Sato and I. Ryu, Synlett, 2008, 151.
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10. During the preparation of this manuscript, similar results
appeared in the literature. See: T. Fukuyama, M. Kobayashi,
M. T. Rahman, N. Kamata and I. Ryu, Org. Lett., 2008, 10,
533.
11. B. Kopping, C. Chatgilialoglu, M. Zehnder and B. Giese, J. Org.
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2. E. R. Murphy, J. R. Martinelli, N. Zaborenko, S. L. Buchwald
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12. For recent examples of radical-based deoxygenationand dehalo-
genation studies performed in batch, see: H. S. Park, H. Y. Lee
and Y. H. Kim, Org. Lett., 2005, 7, 3187; M. R. Medeiros,
L. N. Schacherer, D. A. Spiegel and J. L. Wood, Org. Lett.,
2007, 9, 4427, and references cited therein.
13. Spectral data for (E)-1-(2-tris(trimethylsilyl)silanylvinyl)cyclohex-
anol (Table 2, entry 3): nmax/cmꢁ1 (thin film) 3375 (br), 2934,
2895, 1447, 1394, 1242 and 986; dH (300 MHz, CDCl3): 6.15
(1H, d, J = 18.6 Hz, CH = CH), 5.79 (1H, d, J = 18.6 Hz,
CH = CH), 1.71–1.60 (2H, m, CH2), 1.59–1.41 (6H, m, 3 ꢂ CH2),
1.39–1.12 (2H, m, CH2) and 0.16 (27H, s, 9 ꢂ Si–CH3); dC
(75 MHz, CDCl3): 155.2, 116.9, 73.0, 37.9, 25.6, 22.3 and
V. Hessel, C. Hofmann, P. Lob, J. Lohndorf, H. Lowe and
¨
¨
¨
A. Ziogas, Org. Process Res. Dev., 2005, 9, 479.
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laboratory, see: T. Gustafsson, F. Ponten and P. H. Seeberger, Chem.
Commun., 2008, 1100; K. Geyer, H. Wippo and P. H. Seeberger,
Chem. Today, 2007, 25, 38; F. R. Carrel, K. Geyer, J. D. C. Code
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Press, Oxford, UK, 1991, vol. 8, pp. 793, 811 and 983.
0.9;
found 299.1678.
14. Spectral data for 1-(tris(trimethysilyl)silanyl)hexadecane (eqn (1)):
max/cmꢁ1 (thin film) 2892, 2854, 1466, 1244 and 834; dH (300
HRMS
calc.
for
C17H40OSi4-TMS,
299.1683:
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1975, 1574; D. H. R. Barton, D. Crich, A. Lobberding and S. Z. Zard,
¨
n
MHz, CDCl3): 1.38–1.22 (28H, m, 14 ꢂ CH2), 0.89 (3H, t, J = 6.4
Hz, CH3), 0.79–0.73 (2H, m, CH2) and 0.17 (27H, s, 9 ꢂ Si–CH3);
dC (75 MHz, CDCl3): 34.4, 32.0, 29.8, 29.7, 29.5, 29.3, 22.8,
14.3, 7.7 and 1.3; HRMS calc. for C25H60Si4, 472.3772: found
472.3767.
J. Chem. Soc., Chem. Commun., 1985, 646; D. H. R Barton, D. Crich,
A. Lobberding and S. Z. Zard, Tetrahedron, 1986, 42, 2329.
¨
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