On the use of (TMS)3CH as novel tin-free radical reducing agent

Article abstract of DOI:10.1016/j.tetlet.2006.05.068

(TMS)₃CH is an efficient free radical reducing agent. Debromination, deiodation, dechlorination as well as decarboxylation of Barton and Kim esters can proceed smoothly using this tin-free reducing agent. Rate constants for hydrogen atom abstraction from TMS₃CH by primary radicals were also determined.

Full text of DOI:10.1016/j.tetlet.2006.05.068

Tetrahedron Letters 47 (2006) 5163–5165
On the use of (TMS)3CH as novel tin-free radical reducing agent
V. Tamara Perchyonok*
ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy
Received 20 February 2006; revised 5 May 2006; accepted 10 May 2006
Available online 5 June 2006
Abstract—(TMS)3CH is an efficient free radical reducing agent. Debromination, deiodation, dechlorination as well as decarboxyl-
ation of Barton and Kim esters can proceed smoothly using this tin-free reducing agent. Rate constants for hydrogen atom abstrac-
tion from TMS3CH by primary radicals were also determined.
ꢀ 2006 Published by Elsevier Ltd.
Organotin hydrides such as Bu3SnH, Ph3SnH and
Me3SnH have successfully been used to mediate pre-
parative radical chain processes in chemistry over the
last 40 years.1 However there are several drawbacks
commonly associated with the use of these reagents in
organic synthesis. Since organostannanes are toxic,1 spe-
cial handling during disposal of tin residues is necessary
and often problems associated with product purification
are encountered.2 It is therefore not surprising that the
so called ‘tin problem’ has been addressed by introduc-
ing a variety of alternative hydride sources.3,3b,4–7 As a
part of our continuing interest in the development of
new reagents for use in free radical chemistry we wanted
to evaluate the ability of TMS3CH to act as a free
radical reducing agent. Tris(trimethylsilyl)methane
(TMS3CH) has several practical advantages over tribu-
tyltin hydride, for example, low toxicity, good stability
and much easier work up procedure.
authentic samples or by isolation of reduced product
and characterization by 1H, 13C NMR spectroscopy
and GC analysis. In this study, reductions were carried
out at substrate concentrations approximately 0.1 M,
2 equiv of TMS3CH were added at 80 ꢁC, initiated with
AIBN, VAZOꢂ or under photolysis conditions at room
temperature.8 Reactions were carried out for 3 h and
percentage of conversion determined by integration of
signals corresponding to the authentic materials.8
Table 1 lists data obtained for the reduction of bromo-
adamantane (1a) as a model compound reacting with
(TMS)3CH at 80 ꢁC in benzene (or cyclohexane) in the
presence of radical initiators such as AIBN (entries 1
and 2), VAZOꢂ (i.e., 1,10-azobis(cyclohexanecarbo-
nitrile))10 (entry 3), also under photolytic initiation condi-
tion (entry 6), also in the presence of a radical
inhibitor such as phenol (entry 4) as well as in the
absence of AIBN (entry 5). Reaction in the presence
of a stoichiometric amount of phenol, a well-known free
radical inhibitor gave only very low amount (10%) of
reduced product (adamantane 1b, entry 4), confirming
the free radical nature of the transformation in question.
We chose to investigate the reduction of bromoadaman-
tane to determine if tris(trimethylsilyl)methane
(TMS3CH) is an effective reducing agent under standard
free radical conditions (Scheme 1). The yields were
determined using GC analysis by comparison with
Table 1. Reduction of bromoadamantane (1a) with TMS3CH under
different conditions
TMS3CH
Entry
Additive
Solvent
Product
Yield (%)
Br
1
2
3
4
5
6
AIBN
AIBN
VAZOꢂ
Phenol
None
hm
Benzene
Cyclohexane
Benzene
Benzene
Benzene
Benzene
1b
1b
1b
1b
1b
1b
85a
80
80
10
8
1a
1b
Scheme 1.
78
*
Tel.: +39 340 9291511; fax: +39 051 6398349; e-mail: tamara@
isof.cnr.it
a Isolated yield using procedure similar to that described in Ref. 8.
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.05.068

5164
V. T. Perchyonok / Tetrahedron Letters 47 (2006) 5163–5165
performed efficiently with (TMS)3CH on the 1.6 g scale.9
Reactions of Barton and Kim esters (1d (entry 3) and 1c
(entry 2), respectively), derived from 1-adamantanecarb-
oxylic acid also proceeded smoothly in high conversions
on both GC and preparative scale9 (Fig. 1).
Table 2. Radical reduction of various substrates with TMS3CH
(2 equiv) and AIBN (0.5 equiv) in benzene
Entry
Substrate
Product
Yield (%)
1
2
3
4
5
6
7
8
1a
1c
1d
2a
2c
3a
3c
3d
4a
4e
4d
4f
1b
1b
1b
2b
2b
3b
3b
3b
4b
4b
4c
4c
5b
7
85a
98
89
97
Another common synthetic reaction that utilizes tri-
alkyltin hydride is the radical cyclization reaction. Cycli-
zation of o-iodophenyl allyl ether (6) (entry 13) could be
conducted using TMS3CH as a radical reducing agent to
obtain the desired cyclized product (7) in good isolated
yield.9 Importantly, the syringe pump technique, com-
monly used in free radical synthesis in order to have a
control on the rate of addition and the concentration
of the ‘hydrogen source’ present in the reaction is not
necessary to conduct these transformations, which sug-
gests that this reagent can effectively extend the ‘kinetic
range’ available to free-radical chain systems.
89
72a
80a
100a
100
100
70a
72a
86a
72a
9
10
11
12
13
14
5a
6
a Isolated yield, reactions performed following procedure described in
the Ref. 8 under the atmosphere of dry N2.
In order to verify the radical nature of the transforma-
tion we determined rates of the hydrogen transfer
reaction from TMS3CH to a primary radical using
5-exo-cyclization of the 5-hexenyl radical (8) as a radical
clock (Scheme 2).3
Reaction in the absence of AIBN gave only very low
amount (8%) of reduced product (adamantane 1b, entry
5), highlighting once again the free radical nature of the
transformation in question. Reaction under the photo-
lytic conditions conducted at room temperature gave a
high percentage of conversion (78%) to the reduced
product (adamantane 1b, entry 6) suggesting the high
efficiency of the free radical transformation.
Reaction of 6-bromo-1-hexene, carried out at 70 ꢁC with
AIBN (0.5 equiv) as a radical initiator, gave methylcyclo-
pentane (10) and 1-hexene (9) as the exclusive reaction
products, as determined by GC analysis. From the (9)/
(10) = 0.02 ratio we could estimate the rate constant
(kH) for the hydrogen abstraction by the 5-hexen-1-yl
radical (8).
To test the scope and limitations of our new ‘tin hydride’
substitute, that is, (TMS)3CH as an efficient reducing
agent, a series of typical radical chain defunctionaliza-
tion reactions was performed using TMS3CH under
conditions specified in Table 1 and results are summa-
rized in Table 2. Primary (3a,c and d) (entries 6–8), sec-
ondary (2a) (entry 4), tertiary (1a) (entry 1), aromatic
(4a,e) (entries 9 and 10) and benzylic (4d,f) (entries 11
and 12) halides such as chlorides, bromides or iodides
were efficiently reduced in good to excellent yield under
previously described conditions. Moreover, Barton–
McCombie type deoxygenation reaction using xanthates
(2c) and (5a) (entries 5 and 13, respectively) could be
Analysis of the data in Table 3 suggests that (TMS)3CH
transfers a hydrogen atom at least 4 times slower than
(TMS)3SiH (entries 1 and 3). In comparison to the
Bu3SnH (entries 4) (TMS)3CH transfers a hydrogen
atom at least 10 times slower.11 However the kH value
is significantly greater than the corresponding value
for Et3SiH (entry 2) and this explains why TMS3CH
can sustain the radical reaction unlike Et3SiH which
cannot.
X
X
X
3. a. X = Br
b. X = H
c. X = I
1. a. X = Br
2. a. X = Br
b. X = H
b. X = H
c. X = C(O)ONMeC(S)SMe
d. X = N-hydroxypyridine-2-thione
c. X = OC(S)SMe
d. X = Cl
O
I
X
H
6
4. a. X = Br
b. X = H
H
H
O
X
c. X = CH3
d. X= CH2Cl
e. X= I
5. a. X = OC(S)SMe
b. X = H
f. X= CH2Br
7
Figure 1.

V. T. Perchyonok / Tetrahedron Letters 47 (2006) 5163–5165
5165
Han, X.; Hartmann, G. A.; Brazzale, A.; Gaston, R. D.
Tetrahedron Lett. 2001, 42, 5837.
kC
TMS3C
Br
5. (a) Lusztyk, J.; Maillard, B.; Lindsay, D. A.; Ingold, K. U.
J. Am. Chem. Soc. 1983, 105, 3578; For reductive radical
chain reactions using Bu3GeH see: (b) Pike, P.; Hersh-
berger, S.; Hershberger, J. Tetrahedron 1988, 44, 6295;
Bowman, R. W.; Krintel, S. L.; Schilling, M. B. Synlett
2004, 1215; Pedersen, J. M.; Bowman, R. W.; Elsegood,
M. R. J.; Fletcher, A. J.; Lovell, P. J. J. Org. Chem. 2005,
70(25), 10617; For examples of Ph3GeH in preparative
radical chemistry see: (c) Gupta, V.; Kahne, D. Tetra-
hedron Lett. 1993, 34, 591; (d) Bowman, R. W.; Krintel, S.
L.; Schilling, M. B. Org. Biomol. Chem. 2004, 2, 585–592.
6. For examples on uses of 1-ethylpiperidine phosphite (1-
ETHP) see: (a) Martin, C. G.; Murphy, J. A.; Smith, C. R.
Tetrahedron Lett. 2000, 41, 1833; (b) Graham, S. R.;
Murphy, J. A.; Kennedy, A. R. J. Chem. Soc., Perkin.
Trans. 1 1999, 3071; For examples of uses and kinetic data
associated with diethylphosphine oxide see: Chatgilia-
loglu, C.; Timokhin, V. I.; Ballestri, M. J. Org. Chem.
1998, 63, 1327.
8
TMS3CH
kH
TMS3CH
9
10
Scheme 2.
Table 3. Rate constants for the hydrogen transfer from TMS3CH
(0.09 M) to primary radical in comparison with alternative hydrogen
donors at 70 ꢁC
Entry
H-donor
10ꢀ5 kH/Mꢀ1 sꢀ1
Reference
1
2
3
4
(Me3Si)3SiH
Et3SiH
(Me3Si)3CH
Bu3SnH
11
7
7. There are some examples using i-PrOH as the reducing
reagent in radical reaction however these processes are not
chain reactions: (a) Liard, A.; Quiclet-Sire, B.; Zard, S. Z.
Tetrahedron Lett. 1998, 39, 9435; Et2O as a C–H reductant
in non-chain radical reactions: (b) Matsumoto, A.; Ito, Y.
J. Org. Chem. 2000, 65, 5707; (c) Quiclet-Sire, B.; Zard, S.
Z. J. Am. Chem. Soc. 1996, 118, 9190.
0.04
2.5
24
10
twa
11a
a tw, Signifies this work, average of three experiments.
8. Typical reduction procedure is as follows: (TMS)3CH
(2 equiv) and the radical precursor (1 equiv) were dis-
solved in benzene (50 lL). A pyrex tube was charged with
the required solution (300 lL) and AIBN (0.5 equiv)
added. The solution was frozen in liquid nitrogen, sealed
under vacuum and heated in the 80 ꢁC constant temper-
ature oil bath overnight. The reaction mixture was then
analyzed by GC. Chromatography column used in inves-
tigation: trifluoroacetylated c-cyclodextrin (ChiraldexTM
G-TA 30 m · 0.25 mm) capillary column purchased from
Alltech.
In summary (TMS)3CH is a highly-efficient, tin-free,
radical reducing agent, which is compatible with
standard radical precursor systems. Kinetic experiments
as well as some preliminary computational evidence
point towards (TMS)3CH being a versatile and environ-
ment friendly addition to the toolkit of organic chemists.
We are currently investigating further the scope and
limitations in the use of the (TMS3)CH in radical
cascade reactions.
9. The typical procedure for the preparative scale reactions is
as follows: To a solution of freshly recrystallized xantate
derived from dihydrocholestane (0.1 M) in dry benzene
(5 ml), tris(trimethylsilyl)methane (2 equiv) was added. At
that stage reaction mixture was degassed using freeze-
pump-thaw technique. AIBN was added (0.5 equiv) at
room temperature and the degassing cycle repeated again
at room temperature and liquid nitrogen. Reaction mix-
ture was allowed to be heated at the constant temperature
(80 ꢁC) oil bath for 12 h under the atmosphere of dry N2.
Excess of solvent was removed in vacuo and the crude
reaction mixture analyzed by 1H, 13C NMR, revealed
complete conversion of the starting material to the desired
product. Cholestane (72%) was isolated as a white solid
after recrystallization from diethyl ether/ethanol.
References and notes
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