Rhodium-catalyzed, efficient deutero- and tritiosilylation of carbonyl compounds from hydrosilanes and deuterium or tritium

Article abstract of DOI:10.1021/ol202117t

A cationic rhodium compound which is an active catalyst for both the hydrogen isotope exchange in hydrosilanes and the hydrosilylation of carbonyl compounds permits, in a one-flask, two-step procedure, efficient deutero- and tritiosilylations using SiEt₃H under D₂ (0.5 bar) or T₂, at low catalyst loadings (0.1-0.5 mol %).

Full text of DOI:10.1021/ol202117t

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5236–5239
Rhodium-Catalyzed, Efficient
Deutero- and Tritiosilylation of Carbonyl
Compounds from Hydrosilanes
and Deuterium or Tritium
ꢀ
Miguel Rubio, Jesus Campos, and Ernesto Carmona*
´
ꢀ
´
Departamento de Quımica Inorganica-Instituto de Investigaciones Quımicas,
Universidad de Sevilla-Consejo Superior de Investigaciones Cientıficas, Avda. Americo
´
ꢀ
Vespucio 49, 41092 Sevilla, Spain
guzman@us.es
Received August 4, 2011
ABSTRACT
A cationic rhodium compound which is an active catalyst for both the hydrogen isotope exchange in hydrosilanes and the hydrosilylation of
carbonyl compounds permits, in a one-flask, two-step procedure, efficient deutero- and tritiosilylations using SiEt3H under D2 (0.5 bar) or T2, at low
catalyst loadings (0.1ꢀ0.5 mol %).
There is great demand for molecules labeled with the
hydrogen isotopes deuterium (D) and tritium (T) for a
variety of research and technical purposes, but most im-
portantly in pharmaceutical investigations that lead to
drug discovery and in many clinical studies.1 Tritium is
the most versatile radionucleide in chemical and biochem-
ical research, in which development of tritiated radioli-
gands is a crucial issue.2
labeled hydrosilanes.3,4 Hydrosilanes constitute one of the
most powerful tools in synthetic organic chemistry.5 For
example, the catalytic hydrosilylation of carbonyl func-
tionalities is an extremely useful industrial and laboratory
method for the synthesis of a wide range of organosilicon
compounds.6ꢀ13 Theprocesscombinesinone stepselective
regiocontrol by formation of a CꢀH bond with protection
Asalready noted,3,4 ofthe basic methodsfor introducing
tritium (or deuterium) into organic molecules, synthetic
procedures such as, for example, reductions with a hydride
source (e.g., labeled borohydrides, organotinhydrides, etc.)
are convenient as they provide high T- or D-incorpora-
tion, although they find important limitations by the
chemistry required. This has restricted so far the use of
(5) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102, 4009–
4092.
(6) (a) Marciniec, B. Hydrosilylation: a comprenhensive review on
recent advances; Springer: 2009. (b) Roy, A. K. Adv. Organomet. Chem.
2007, 55, 1–59. (c) Malacea, E.; Poli, R.; Manoury, E. Coord. Chem. Rev.
2010, 254, 729–752. (d) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282–
2291.
(7) (a) Park, S.; Brookhart, M. Organometallics 2010, 29, 6057–6064.
(b) Yang, J.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 2008, 130,
17509–17518.
(8) Tondreau, A. M.; Lobkovsky, E.; Chirik, P. J. Org. Lett. 2008, 10,
2789–2792.
(9) Yang, J.; Tilley, T. D. Angew. Chem., Int. Ed. 2010, 49, 10186–
10188.
(10) Blackwell, J. M.; Morrison, D. J.; Piers, W. E. Tetrahedron 2002,
58, 8247–8254.
(11) Buchan, Z. A.; Bader, S. J.; Montgomery, J. Angew. Chem., Int.
Ed. 2009, 48, 4840–4844.
(1) (a) Elmore, C. S.; John, E. M. Annu. Rep. Med. Chem.; Academic
Press: 2009; Vol. 44, pp 515ꢀ534. (b) Atzrodt, J.; Derdau, V.; Fey, T.;
Zimmermann, J. Angew. Chem., Int. Ed. 2007, 46, 7744–7765.
(2) (a) Skaddan, M. B.; Yung, C. M.; Bergman, R. G. Org. Lett. 2004,
6, 11–13. (b) Skaddan, M. B.; Bergman, R. G. J. Label. Compd. Radio-
pharm. 2006, 49, 623–634.
(3) (a) Heys, J. R. J. Label. Compd. Radiopharm. 2007, 50, 770–778.
(b) Lockley, W. J. S. J. Label. Compd. Radiopharm. 2007, 50, 256–259.
(4) (a) Elander, N.; Jones, J. R.; Lu, S.-Y.; Stone-Elander, S. Chem.
Soc. Rev. 2000, 29, 239–249. (b) Saljoughian, M. Synthesis 2002, 1781–
1801.
(12) Tran, B. L.; Pink, M.; Mindiola, D. J. Organometallics 2009, 28,
2234–2243.
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10.1021/ol202117t
Published on Web 08/30/2011
2011 American Chemical Society

of the alcohol as an alkoxysilane. Accordingly, Si-D or Si-
T addition to CdO units would place the label exclusively
at the carbonyl carbon, while at the same time allowing
facile, subsequent introduction of a second label by appro-
piate derivatization of the resulting alkoxysilane (for in-
stance by deutero- or tritiodesilylation, by reduction with a
labeled hydride source, etc., as shown in Scheme 1).
Table 1. Screening of Silanesa
Entry
Silane
SiEt3H
temp (°C)
t (h)
conv (%)
1
2
3
4
5
6
7
25
25
25
25
50
50
50
1
1
99
99
99
99
0
Scheme 1. General, Two-Step Labeling of a Carbonyl
SiEt2MeH
SiMe2PhH
Si(nPr)3H
Si(iPr)3H
Compound by Catalytic Tritiosilylationa
1
1
12
12
12
Si(SiMe3)3H
Si(Si(OMe)3)3H
0
0
a Conditions: acetophenone (0.5 mmol), 0.1 mol % of 1, 2.2 equiv of
silane, CD2Cl2 (0.5 mL).
a For simplicity, only tritiodesilylation and reduction of the alkoxy-
silane product have been considered.
room temperature. However, the bulky tertiary silanes
SiR3H (R = iPr, SiMe3, Si(OMe)3) resulted in no reaction
even at 50 °C overnight (entries 5ꢀ7).
We have recently disclosed a very efficient catalytic
synthesis of deuterated and tritiated silanes, using D2 or
T2 as the hydrogen isotope source, that is applicable to a
wide range of hydrosilanes.14 The catalyst is the cationic
rhodium compound 1 shown in Figure 1 that contains a
cyclometalated PMeXyl2 ligand (Xyl = 2,6-Me2C6H3)
coordinated in a κ4-P,C,C0,C00 fashion. Since this com-
pound is alsovery activefor the catalytic hydrosilylation of
CdO bonds, we have developed a wide-scope, one-flask,
two-step atom-economic process for the deutero- and
tritiosilylation of aldehydes and ketones. As discussed
below, this catalytic synthesis is routinely performed at
room temperature (or at 50 °C), with low catalyst loading
(usually 0.1 mol % for SiꢀH and 0.5 mol % for Si-D and
Si-T), and requiresonlystirringof reagentsand the catalyst
under subatmospheric pressure of D2 (0.5 bar) or T2.
With these results in hand, a broad range of ketones
(Table 2) and aldehydes (Table 3) were hydrosilylated with
SiEt3H. Excellent activities to the expected silyl ethers were
attained at 25 °C, with a reaction time of 1 h and a catalyst
concentration of 0.1 mol %. A competition experiment ran
with equimolar amounts of RC(O)Me (R = Me, iPr, tBu)
against 1 equiv of SiEt3H resulted in the formation of the
expected silyl ethers (Scheme 2) in a ratio of 9(Me):2(iPr):
1(tBu). These results, along with those pertaining to the
addition of SiꢀH to di(iso-propyl)ketone (entry 4) and to
1- and 2-acetonaphtone (entries 8ꢀ10), show that an
increase in the steric properties of the ketone substituents
has adetrimentraleffectinthe hydrosilylation reaction. On
the other hand, comparison of the reactivity of the para-X
acetophenones (X = H, CH3, F) disclosed a moderate
increase in the rate with the basicity of the substrate
(Scheme 2), as products formed in the ratio 3(CH3):1(H)
and 2(H):1(F). Other ketones such as benzophenone and
cyclohexanone were efficiently hydrosilylated by catalyst 1.
Similarly, cyclic 2-cyclohexen-1-one and trans-chalcone
reacted readily with SiEt3H in the presence of 1 (entries
13ꢀ14) to give exclusively (13) or mostly (14) the 1,4-
addition products. To complete this study several alde-
hydes were also tested (Table 3). Once again, reactions
were fast and gave the expected silyl alkyl ethers. Addi-
tional reduction of the latter to produce the alkane and
(Et3Si)2O was not observed.7 The very high efficiency of
catalyst 1 was demonstrated by the room temperature
hydrosilylation of heptaldehyde with a S/C ratio of
10000 (entry 1). Other aliphatic aldehydes hydrosilylated
were propionaldehyde, hydrocinnamaldehyde, and 2-phe-
nylpropionaldehyde (entries 2ꢀ4). Reduction of aromatic
aldehydes (entries 5ꢀ8) was carried out with a catalyst
concentration of 1 mol %, since lower catalyst loadings
gave incomplete conversions. It seems that under the
hydrosilylation conditions catalyst 1 reacts slowly with
these aldehydes becoming partially deactivated.
Figure 1. Structure of catalyst 1.14
As a first step in this development, several hydrosilanes
were tested utilizing acetophenone as the reference sub-
strate, with catalyst loadings of 0.1 mol %. Dry silanes are
needed, for compound1catalyzes alsoH2 production from
the hydrosilane and water. The results collected in Table 1
revealthatinmostcases(entries 1ꢀ4) fullconversion tothe
corresponding silyl alkyl ether was obtained after 1 h at
ꢀ
(14) (a) Campos, J.; Esqueda, A. C.; Lopez-Serrano, J.; Sanchez, L.;
Cossio, F. P.; de Cozar, A.; Alvarez, E.; Maya, C.; Carmona, E. J. Am.
ꢀ
ꢀ
Chem. Soc. 2010, 132, 16765–16767. (b) Campos, J.; Esqueda, A. C.;
Carmona, E. Espan~a 2010, No. P201000507.
Org. Lett., Vol. 13, No. 19, 2011
5237

Table 2. Screening of Ketonesa
Scheme 2. Competition Studies
hydrosilanes.14 Accordingly, deutero- and tritiosilanes, e.g.
SiEt3D and SiEt3T, can be generated in situ and used as
reagents for deutero- and tritiosilylations, under condi-
tions similar to those in Tables 2 and 3 for the analogous
SiꢀH additions. Moreover, as both the latter catalytic
process and the hydrosilylation reaction are fast at room
temperature, a convenient two-step but one-flask method,
whereby the labeled silane is generated first from SiEt3H
and D2 or T2 in the presence of 1 and then reacted with the
organic substrate, can be applied for the efficient, atom-
economic deutero- and tritiosilylation of carbonyl com-
pounds. For deuterium labeling, ifg99% D-incorporation
into the product is needed, full deuteration of the silane can
be achieved by subjecting the SiEt3H-plus-catalyst mixture
to three D2 loadings, each involving cooling at 0 °C/
vacuum (0.1 bar)/0.5 barD2 (see Supporting Information).
Clearly, these D- and T-labeling procedures represent an
important simplification of those presently utilized, that
require previous synthesis and isolation of SiEt3D or
SiEt3T, usually from SiEt3Cl and an isotopically labeled
hydride reagent.15,16 For example, the reported synthesis
of SiEt3T uses LiT, which must be prepared in situ from
LiBun and T2 in the presence of Me2NCH2CH2NMe2
(tmed) and then reacted with SiEt3Cl in boiling triglyme.15
This is followed by controlled distillation of SiEt3T, which
is always contaminated by undesirable amounts of tmed
that are difficult to eliminate. In contrast, our catalytic
synthesis of SiEt3T (or SiEt3D) is clean, rapid, and simple,
and it is performed in one step1,3,4 and permits subsequent
use of the silane reagent in the same flask for the silylation
reaction. Entries 1ꢀ7 in Table 4 summarize deuterosilyla-
tion reactions in which the substrate is added after SiEt3D
has been formed from SiEt3H, D2, and 1. Both ketones and
aldehydes converted quantitatively into deuterated silyl
ethers. For acetophenone a kinetic isotope effect kH/kD
a Conditions: 0.1ꢀ0.5 mmol of substrate, 2.2 equiv of SiEt3H;
CD2Cl2 (0.5 mL). b Exclusively 1,4-addition product. c A mixture of
94% of 1,4-addition products (2:1 ratio of Z/E isomers) and 6% of 1,2-
addition product.
Table 3. Screening of Aldehydesa
(15) Neu, H.; Andres, H. J. Label. Compd. Radiopharm. 1999, 42,
992–993.
a Conditions: 0.1ꢀ0.5 mmol of substrate, 2.2 equiv of SiEt3H,
CD2Cl2 (0.5 mL). b Minor amounts of dialkyl ethers (<10%).
(16) (a) Than, C.; Morimoto, H.; Andres, H.; Williams, P. G. J. Org.
Chem. 1996, 61, 8771–8774. (b) Zippi, E. M.; Andres, H.; Morimoto, H.;
Williams, P. G. Synth. Commun. 1995, 25, 2685–2693. (c) Jaiswal, D. K.;
Andres, H.; Morimoto, H.; Williams, P. G. J. Chem. Soc., Chem.
Commun. 1993, 907–909. (d) Andres, H.; Morimoto, H.; Williams,
P. G. J. Chem. Soc., Chem. Commun. 1990, 627–628.
As already reported, complex 1 is also a very effec-
tive catalyst for the hydrogen isotope exchange of
5238
Org. Lett., Vol. 13, No. 19, 2011

trans-chalcone (entries 6,7), that provided with high selec-
tivity products labeled at position 4, could add a second
label at position 3 after deuterolysis.
Table 4. Deuterosilylations and Tritiosilylationsa
The same concept of labeling may be used for tritiosily-
lations. However, considering the very small amounts of
the radioisotope needed for the labeling and taking addi-
tionally into account reasons of security and convenience
of handling, the tritiated complex 1(Tn) was employed as a
very efficient tritium transferring reagent in the experiment
in entry 8 of Table 4. Thus, a mixture of 1(Tn) (4 mCi/mg),
SiEt3H, and acetophenone yielded the corresponding silyl
ether 2(Tn) with a nonoptimized reaction time of 8 days to
ensure complete T transfer. The resulting 2(Tn) was sub-
sequently hydrolyzed and isolated by column chromato-
graphy as 1-phenylethanol 3(Tn) with a specific activity of
5.88 mCi/mmol (ca. 97% T-incorporation).
From a practical point of view, the same tritiation was
performed with previously labeled SiEt3H(Tn) (0.19 mCi/
mmol) and provided 99% tritium incorporation into
2(Tn) (entry 9). With the latter procedure, the scope of
tritiosilylation was also extended successfully to aldehydes
and R,β-unsaturated ketones, like hydrocinnamaldehyde
(entry 10) and 2-cyclohexen-1-one (entry 11), with T-in-
corporation of 99% into both 4(Tn) and 5(Tn).
In summary, we have exploited the capacity of the
rhodium compound 1 to catalyze both the hydrosilylation
of carbonyl compounds and the hydrogen isotope ex-
change in hydrosilanes to develop efficient, one-pot, two-
step procedures for the selective labeling of aldehydes and
ketones at the carbonyl atom.
Acknowledgment. Financial support (FEDER support)
ꢀ
from the Spanish Ministerio de Educacion (Project No.
CTQ2010-17476), Consolider-Ingenio 2010 (No. CSD2007-
0006), and the Junta de Andalucia (Grant FQM-119 and
Project No. P09-FQM-4832) is gratefully acknowledged.
M.R. thanks CSIC for a JAE postdoctoral contract (ref.
ꢀ
JAEDoc107), and J.C. thanks the Ministerio de Educacion
for a research grant (ref. AP20080256).
a Conditions: 0.5 bar of D2 (3 D2/vacuum cycles, 30 min), 0.25 mmol
of substrate, 0.5 mol % 1, 2.2 equiv of SiEt3H, CD2Cl2 (0.5 mL), 25 °C.
b Minor amounts of dialkyl ethers R1C(O)R1 (<10%). c 2.2 mmol of
substrate, 0.1 mol % 1(Tn), 0.9 equiv of SiEt3H, CD2Cl2 (0.5 mL), 50 °C.
d 0.44 mmol of substrate, 0.5 mol % 1, 0.9 equiv of SiEt3H(Tn), CD2Cl2
(0.5 mL), 50 °C
Supporting Information Available. Experimental pro-
cedures, characterization data of new compounds, and
determination of kinetic isotope effect. This material
is available free of charge via the Internet at http://
pubs.acs.org.
of ca. 1.9 was measured. It is worth mentioning that
R,β-unsaturated ketones like 2-cyclohexen-1-one and
Org. Lett., Vol. 13, No. 19, 2011
5239