Tributylgermanium hydride as a replacement for tributyltin hydride in radical reactions

Article abstract of DOI:10.1039/b310520b

Tributylgermanium hydride (Bu₃GeH) can be used as an alternative to tributyltin hydride (Bu₃SnH) as a radical generating reagent with a wide range of radical substrates. Tributylgermanium hydride has several practical advantages over tributyltin hydride, e.g. low toxicity, good stability and much easier work-up of reactions. The reagent can be easily prepared in good yield and stored indefinitely. Suitable substrates include iodides, bromides, activated chlorides, phenyl selenides, tert-nitroalkanes, thiocarbonylimidazolides and Barton esters. Alkyl, vinyl and aryl radicals can be generated in radical reactions including reduction and cyclisation processes. Common radical initiators such as ACCN and triethylborane can be used. The slower rate of hydrogen abstraction by carbon-centred radicals from Bu ₃GeH as compared to Bu₃SnH facilitates improved cyclisation yields. Polarity reversal catalysis (PRC) with phenylthiol can be used in reactions which generate stable radical intermediates which will not abstract hydrogen from Bu₃GeH.

Full text of DOI:10.1039/b310520b

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Tributylgermanium hydride as a replacement for tributyltin
hydride in radical reactions†
W. Russell Bowman,*a Sussie L. Krintela and Mark B. Schillingb
a Department of Chemistry, Loughborough University, Loughborough, Leicestershire,
UK LE1 3TU. E-mail: w.r.bowman@lboro.ac.uk; Fax: 44 1509 223925; Tel: 44 1509 222569
b Chemical Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts,
UK SG1 2NY. E-mail: mark.b.schilling@gsk.com
Received 29th August 2003, Accepted 24th November 2003
First published as an Advance Article on the web 22nd January 2004
Tributylgermanium hydride (Bu3GeH) can be used as an alternative to tributyltin hydride (Bu3SnH) as a radical
generating reagent with a wide range of radical substrates. Tributylgermanium hydride has several practical
advantages over tributyltin hydride, e.g. low toxicity, good stability and much easier work-up of reactions. The
reagent can be easily prepared in good yield and stored indefinitely. Suitable substrates include iodides, bromides,
activated chlorides, phenyl selenides, tert-nitroalkanes, thiocarbonylimidazolides and Barton esters. Alkyl, vinyl and
aryl radicals can be generated in radical reactions including reduction and cyclisation processes. Common radical
initiators such as ACCN and triethylborane can be used. The slower rate of hydrogen abstraction by carbon-centred
radicals from Bu3GeH as compared to Bu3SnH facilitates improved cyclisation yields. Polarity reversal catalysis
(PRC) with phenylthiol can be used in reactions which generate stable radical intermediates which will not abstract
hydrogen from Bu3GeH.
groups are not present. Similarly, a number of extractable
Introduction
triorganotin hydrides have been developed.1–4 Triorganotin
Tributyltin hydride has proved to be an excellent radical
hydrides have also been attached to solid phase resins3,5 or in
generating reagent and has been central to the development of
reverse, the reagents have been attached to solid phase resins
modern synthetic radical chemistry. However, there are three
and the tin residues washed away.5 Another development is the
major problems with the use of Bu3SnH and other triorganotin
hydrides. Firstly, the toxicity of these compounds rules out their
application of fluorous triorganotin hydrides using fluorous
phase separation techniques.3,6
extensive use in pharmaceutical synthesis. Secondly, removal
2. Use of other group XIV hydrides. Silanes,1–3 in particular,
of tributyltin residues from reaction mixtures is fraught with
tris(trimethylsilyl)silane [(TMS)3SiH or TTMSS] and poly-
problems. Thirdly, Bu3SnH is not very stable and decomposes
methylhydrosiloxanes7 have been extensively developed.
steadily even if carefully stored. The reagent is best bought
in fresh or distilled prior to use. With these problems, great
difficulty has been encountered in removing organotin residues
Polarity reversal catalysis (PRC) developed by Roberts has
allowed triorganosilanes with strong Si–H bonds, e.g. Et3SiH,
to be used in conjunction with thiols.8
in pharmaceutical preparations to below the 100 ppm level
3. New radical generating reagents. An increasing number of
which is required to avoid toxicity in human consumption. This
toxicity problem has almost completely precluded its use by the
pharmaceutical industry and hence precluded a wide range of
very useful radical reactions in pharmaceutical synthesis.
new reagents are being reported, e.g. silylated cyclohexadienes,9
gallium hydride (HGaCl2),10 indium() chloride and sodium
borohydride11 and hypophosphorous acid (H3PO2) and 1-ethyl-
piperidine hypophosphite (EPHP).12 Samarium diiodide has
The search for superior alternatives to Bu3SnH has been
gained popularity as a reductive route to generating radicals
a central goal for free-radical chemists in recent years. A
but is weakly radioactive which precludes its use as a non-
replacement reagent needs to overcome all three problems while
toxic alternative to Bu3SnH.13 Manganese triacetate provides
at the same time exhibiting a similar range of reactivity and
a useful oxidative route to generating radicals but is limited to
ease of use. In addition, the cost of purchase or synthesis of the
new reagent needs to be comparable. In this paper we report
our investigation of the use of Bu3GeH to replace Bu3SnH
β-dicarbonyl compounds.14
4. Precursors which regenerate radicals, e.g. xanthates15 and
Barton esters,16 and the use of atom transfer reactions.17
as a reagent of standard use. Although use of Bu3GeH as a
In our studies, we chose Bu3GeH, a group XIV analogue of
radical generating reagent is not novel, wide ranging studies to
Bu3SnH which is chemically most similar. Potentially, this
demonstrate its potential and applicability have been generally
allows for a similar range of radical reactions and appeared to
lacking.
be the most obvious candidate for development. For the same
Several very useful reviews have fully detailed the search for
reasons of similarity to Bu3SnH, TTMSS has been developed
alternatives to Bu3SnH.1,2 Alternatives can be generally grouped
into several main categories which include:
1. Use of triorganotin hydrides with procedures to minimise
and has proved popular although costly.3 Surprisingly, although
the potential of Bu3GeH has been known for a considerable
time,18 there are few reports of its use in synthetic studies.19
the amount of tin residues. The use of catalytic amounts of the
The most useful synthetic protocol has been the triphenyl-
stable Bu3SnCl with another hydride, e.g. sodium borohydride,
to generate and regenerate Bu3SnH in situ has proved useful
and should always be considered if borohydride sensitive
germanium hydride mediated radical carbonylation/cyclisation
reactions.20 Most importantly, reports in the literature21
indicate that organogermanium compounds are not toxic.
However, full toxicology studies on Bu3GeH or Bu3GeX
compounds are required to fully elucidate this factor. There-
fore, the germanium compounds are excellent replacements for
toxic triorganotin hydrides.
† Electronic supplementary information (ESI) available: full experi-
mental details and data. See http://www.rsc.org/suppdata/ob/b3/
b310520b/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Prior to our study, tris(trimethylsilyl)germanium hydride
(TMS)3GeH, an analogue of TTMSS, was developed to over-
come the slow rate of hydrogen abstraction from Bu3GeH.22
This reagent behaves similarly to Bu3SnH with a slightly faster
rate of hydrogen abstraction, i.e. the rate of abstraction of
hydrogen by primary radicals = 3.1 × 106 MϪ1 sϪ1 at 25 ЊC. The
difficulty of synthesis of the reagent has probably precluded
its application more widely. Shortly after our studies were
initiated, several key papers were published by Oshima and
co-workers showing the utility of triorganogermanium
compounds in radical reactions.23–25 Most of these studies
report the use of tri-(2-furyl)germanium hydride. These studies
also include the triethylborane (Et3B)-induced radical hydro-
germylation of alkynes, alkenes and silyl enol ethers using tri-
(2-furyl)germanium hydride25 and the tri-(2-furyl)germanium
hydride mediated hydrogermylation of alkynes and dienes in
water using Pd() catalysis.26
tributylgermanium chloride to the hydride. The mechanism
proposed32 is as follows: Cp2TiCl2 is reduced to Cp2Ti()Cl
followed by substitution of the chloride atom giving Cp2Ti()-
Bu which eliminates butene to afford Cp2Ti()H, which is
responsible for the reduction of the initially formed Bu3GeCl.
The yields were variable but commonly at ca. 50%. The main
difficulty was the requirement for careful distillation using
a ‘Kugelrohr’ apparatus because Bu3GeH and tetrabutyl-
germanium have similar boiling points (123 ЊC/20 mmHg and
170 ЊC/20 mmHg respectively). The distillation normally had
to be repeated.
We were most pleased to discover the excellent stability of
Bu3GeH. Bu3GeH was indefinitely stable when stored in
a freezer under a nitrogen atmosphere. As a test of solvent
stability we followed the decomposition of Bu3GeH and
1
Bu3SnH in CDCl3 solutions (in NMR tubes) using H NMR
spectroscopy. The Bu3SnH was shown to largely decompose
within 24 h whereas the Bu3GeH remained stable over several
weeks with the spectrum unaltered. Bu3GeH can be prepared
on a large scale by this route and stored indefinitely for later use.
Thus, the prohibitive cost of purchasing Bu3GeH at present
is not justified and can be easily synthesised in the laboratory
for ca. 5–7 times the price of the purchase of Bu3SnH. Part of
this excess cost is offset by the superior stability and lack
of wastage, whereas poor stability, considerable wastage and
general frustration are common with the use of Bu3SnH.
We tested the use of Bu3GeH as a radical mediator on a
representative range of radical precursors which included the
generation of aliphatic, vinyl and aryl radicals, cyclisation
and reduction reactions and reactions with a range of radical-
abstractable groups.
As for much of radical chemistry, excellent kinetic studies
have predated the synthetic application, and this is the also the
case for Bu3GeH. Considerable kinetic information has been
reported for Bu3GeH.2,27,28 The rates of bromine abstraction in
SH2 reactions is similar for both Bu3SnH and Bu3GeH, e.g.
rates of Br-abstraction from CH ᎐CH(CH ) Br at 25 ЊC by:
᎐
2
2 4
7
7
Bu3Ge (4.6 × 10 MϪ1 sϪ1); Bu3Sn (5.0 × 10 MϪ1 sϪ1
)
27 and the
ؒ
ؒ
ؒ
rates of Br-abstraction from (CH3)3CBr at 25 ЊC by: Bu3Ge
(8.6 × 107 MϪ1 sϪ1); Bu3Sn (1.4 × 10 M
s
Ϫ1). However, the
8
Ϫ1
ؒ
rate of H-abstraction by primary alkyl radicals from Bu3GeH is
24 times slower than from Bu3SnH, e.g. rate of H-abstraction
5
ؒ
by primary radicals (RCH2 ) at 25 ЊC from: Bu3GeH (1.0 × 10
M
Ϫ1 sϪ1); Bu3SnH (2.4 × 106 MϪ1 sϪ1).27 The rate of H-abstrac-
tion from Bu3GeH by more reactive radicals is faster as
7
expected, e.g. Me C᎐CH (3.5 × 10 MϪ1 sϪ1 at 27 ЊC). Although
Bromo- and iodo-arenes were first studied in a classic radical
cyclisation reaction. The rate of H-abstraction from Bu3GeH
by aryl radicals is fast (2.6 × 108 MϪ1 sϪ1 at 29 ЊC)27 but the rate
ؒ
᎐
2
rates of radical reactions using tri-(2-furyl)germanium hydride
have not been reported,23–25 the rates of H-abstraction are likely
to be slightly faster than for Bu3GeH by comparison with
Bu3SnH and Ph3SnH. This reagent is also relatively easy to
prepare and therefore further study is required to determine
whether tri-(2-furyl)germanium hydride or Bu3GeH is the more
useful radical reagent.
ؒ
of bromine abstraction from bromobenzene by Bu3Ge radicals
33
at ambient temperature is relatively slow (<1.0 × 105 MϪ1 sϪ1
)
which indicated that the reaction may be slow. Therefore,
iodoarenes were first studied (see Scheme 1, Table 1). Cyclis-
ation of 2-iodo-1-(prop-2-enyloxy)benzene 1 gave similar
yields of 3-methyl-2,3-dihydrobenzofuran using Bu3GeH and
Bu3SnH with the former reaction being slightly slower. The
catalytic use of Bu3GeH with sodium borohydride to reduce the
tributylgermanium iodide back to the hydride was less effective
but needs further study. The use of catalytic phenylthiol for
polarity reversal catalysis (PRC) was unnecessary.34 Cyclisation
of the alkyne 3 using Bu3GeH did not result in the expected
cyclic product 4 (or the tautomer, 3-methylbenzofuran) but gave
Results and discussion
There are no reports in the literature on the other two criteria,
i.e. ease of removal from reaction products and stability of
triorganogermanium hydrides. Our studies were aimed at
determining whether Bu3GeH could replace Bu3SnH as the
general radical reagent. To this end we studied the synthesis
and cost, stability, ease of work-up and the range of reactivity
of Bu3GeH.
ؒ
an intractable mixture which suggested that Bu3Ge radicals
ؒ
had added to the double bond. The slow addition of Bu3Ge
Our first target was to determine a facile synthesis of a suit-
able triorganogermanium reagent. We initially investigated the
synthesis of triphenylgermanium hydride on the basis that the
rate of abstraction of hydrogen would be usefully placed in
between that of Bu3GeH and Bu3SnH. Tetraphenylgermane
was synthesised in good yield by the reaction between
germanium() chloride and phenylmagnesium bromide29 or
phenyllithium.30 The tetraphenylgermane was converted to
triphenylgermanium bromide with bromine in 1,2-dibrometh-
ane31 which in turn was converted to triphenylgermanium
hydride by reduction with sodium borohydride. However, we
discovered that the triphenylgermanium bromide and hydride
were largely insoluble in the common solvents used for radical
reactions and we abandoned this route.
We adapted a published synthesis of Bu3GeH involving a
Cp2TiCl2-catalysed (8 mol%) Grignard reaction between ger-
manium tetrachloride and butylmagnesium chloride.32 This
route uses the cheapest source of germanium, germanium
tetrachloride. Only one reaction is required which is time saving
and also cuts costs, whereas other procedures use two reactions,
one to add the butyl groups and another to reduce the resulting
radicals to alkenes is a known disadvantage, especially if stable
radicals result from the addition.35
Scheme 1
The radical cyclisation reactions of 1-iodo-2-[(3-phenylprop-
2-enyl)oxy]benzene 5a and 1-bromo-2-[(3-phenylprop-2-enyl)-
oxy]benzene 5b were also investigated (Scheme 2 and Table 2).
The rate of bromine abstraction from bromobenzene by
ؒ
Bu3Ge radicals at ambient temperature is relatively slow
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Table 1 Cyclisation of 2-iodo-1-(prop-2-enyloxy)benzene 1
Reaction conditions
yields
Bu3SnH (1.2 equiv.)
Bu3GeH (1.2 equiv.)
Bu3GeH (0.1 equiv.)
Bu3GeH (1.2 equiv.)
ACCN, toluene, reflux, 2 h
ACCN, toluene, reflux, 3 h
AIBN, t-BuOH–toluene, reflux, NaBH4, 2 h; 6 h
AIBN, toluene, reflux, 2 h, PhSH (0.1 equiv.),
2 (86%)
2 (91%)
1 (83%), 2 (0%); 1 (37%), 2 (44%)
2 (85%)
Table 2 Radical cyclisation of 1-iodo- and 1-bromo2-[(3-phenylprop-2-enyl)oxy]benzene (5a and 5b respectively)
Reaction conditions
Radical precursor
Yield 8 (%)
Bu3SnCl (0.1 equiv.), NaBH4, AIBN, t-BuOH, reflux, 4 h
Bu3SnH (2 equiv.),AMBN,a cyclohexane, reflux, 3 h
5a
5b
5a
5b
5a
5a
5b
5a
5a
5a
5a
59
77
92
52
0
75
7
52
4
64
0
Bu3GeH (1.3 equiv.),AMBN, cyclohexane, reflux, 3 h
Bu3GeH (1.0 equiv.), PhSH (0.1 equiv.) ACCN, cyclohexane, reflux, 9 h
Bu3GeH (1.8 equiv.),AMBN, cyclohexane, reflux, 3 h
Bu3SnH (2.2 equiv.), syringe-pump addition AMBN, MeCN/ toluene, reflux, 3 h
Bu3GeH (1.8 equiv.), syringe-pump addition AMBN, MeCN/ toluene, reflux, 3 h
Bu3SnH (2 equiv.), Et3B, THF, 25 ЊC, 21 h
Bu3GeH (1.3 equiv.), Et3B, cyclohexane, 25 ЊC, 21 h
a AMBN = azobismethylisobutyronitrile or by IUPAC nomenclature, 2-(1-cyano-1-methyl-propylazo)-2-methyl-butyronitrile.
slow rate of H-abstraction from Bu3GeH can be a disadvantage
compared to Bu3SnH. In order to overcome the problem of
reduction of the very stable, hence unreactive, benzylic radical
intermediate 7, we applied the ‘polarity-reversal catalysis’
(PRC) technique developed by Roberts34 with excellent success.
The yield of cyclisation to 8 increased to 75% (Table 2). The
benzyl radical intermediate 7, which we suggest is nucleophilic,
reacts relatively rapidly (k3) with the electrophilic source of
hydrogen (PhSH). The rate of reaction between benzyl radicals
and PhSH is 3.1 × 105 MϪ1 sϪ1 at 25 ЊC.27,28 The rate of
H-abstraction from nucleophilic Bu3GeH by electrophilic
phenylthiyl radicals (k4) is unknown but is predicted to be
similar to the rate of H-abstraction by electrophilic tert-butoxyl
radicals (9.2 × 107 MϪ1 sϪ1 at 27 ЊC).28 Therefore, one very slow
rate (k2) is replaced by two relatively fast rates (k3 and k4) using
the favourable polarity of the radical intermediates. This is the
first example of the use of PRC with triorganogermanium
hydrides and provides a route around the problems of slow
H-abstraction by radical intermediates from Bu3GeH.
Scheme 2 Polarity reversal catalysis (PRC) with Bu3GeH using PhSH.
(<1.0 × 105 MϪ1 sϪ1
)
33 but will be faster at higher temperatures
Since we started our studies, Oshima and co-workers
have reported the abstraction of iodine from iodo arenes using
tri-(2-furyl)-germanium hydride.24
and the rate of abstraction of iodine (k1) will be faster again.
The rate of cyclisation of the intermediate aryl radical from 1
has been measured as 6.3 × 109 sϪ1 at 30 ЊC36 and, therefore, the
rate of cyclisation (kC) of the aryl radical 6 will be considerably
faster. Although the rates of H-abstraction by aryl radicals
from Bu3SnH and Bu3GeH are fast (5.9 × 108 MϪ1 sϪ1 and
2.6 × 108 MϪ1 sϪ1 respectively at 30 ЊC)27,36 the rate of cyclis-
ation should be considerably faster and reduction to uncyclised
[(3-phenylprop-2-enyl)oxy]benzene is unlikely. The rates are
favourable and good cyclisation reactions were expected. We
were initially perplexed when the cyclisations using Bu3SnH
gave good yields of the cyclised product 8 with largely unaltered
starting material 5a or 5b whereas the yields with Bu3GeH were
extremely low (Table 2). Various different reaction conditions
and initiators failed to improve the yields.
We suggest that the poor reactions with Bu3GeH are due to
the slow rate of H-abstraction (k2) by the intermediate benzyl
radical 7 from Bu3GeH. While this rate has not been measured,
the rate of H-abstraction from Bu3SnH by benzyl radicals has
been measured (3.6 × 104 MϪ1 sϪ1 at 25 ЊC). The rate is fast
enough to allow chain propagation. However, the rate of
H-abstraction from Bu3GeH is likely to be some 20–30 times
slower, i.e. too slow to facilitate propagation and hence the
chain reaction is inhibited. This example illustrates that the
We used the amides 9–1137 to study the efficacy of Bu3GeH
with different radical-abstractable groups, i.e. Cl, Br, PhSe
(Table 3). Iodine is predicted to react faster than bromine. The
reactions were carried out with the Bu3GeH or Bu3SnH added
at the beginning of the reaction so that the relative amounts of
cyclised 1-(4-methoxybenzyl)-4-methylpyrrolidin-2-one 12 and
the reduced uncyclised product N-allyl-N-(4-methoxybenzyl)-
acetamide 13 could be measured. Slow addition of Bu3GeH or
Bu3SnH with the use of a syringe pump would give largely
cyclised products. The C–Cl bond in the precursors 9, alpha to
the amide moiety, is weakened and is therefore sufficiently
reactive to act as a radical precursor. The rates of reaction
of the initial step should be similar for Bu3GeH and Bu3SnH.
ؒ
In fact, the rate of abstraction for phenylselanyl with Bu3Ge
(9.2 × 108 MϪ1 sϪ1 at 25 ЊC) is slightly faster than that for Bu3Sn
ؒ
(1.2 × 108 MϪ1 sϪ1 at 25 ЊC).38 The major difference in reactivity
will be the rate of H-abstraction by the intermediate radicals
and hence Bu3GeH should favour cyclisation over reduction to
13. This selectivity was in fact observed (Table 3) for all three
radical leaving groups and was most marked for bromine,
i.e. ca. seven times more selective based on recovered 10. As
expected, the Bu3GeH reactions were slower.
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Table 3 Comparison between Bu3SnH and Bu3GeH for Cl, Br and SePh radical leaving groups
Reaction conditions
Radical precursor
Products (Yields)
Bu3SnH (1.5 equiv.),1 h
Bu3GeH (1.5 equiv.), 4 h
Bu3GeH (1.5 equiv.), 8 h
Bu3GeH (1.5 equiv.),12 h
Bu3SnH (1.4 equiv.), 30 min
Bu3GeH (1.1 equiv.), 5.5 h
Bu3SnH (1.7 equiv.), 3 h
Bu3GeH (1.1 equiv.), 3 h
Bu3GeH (1.1 equiv.), 5 h
9
9
9 (0%), 12 (47%), 13 (23%)
9 (25%), 12 (34%), 13 (13%)
9 (23%), 12 (42%), 13 (17%)
9 (22%), 12 (48%), 13 (23%)
10 (0%), 12 (39%), 13 (33%)
10 (12%), 12 (64%), 13 (8%)
11 (0%), 12 (29%), 13 (38%)
11 (48%), 12 (18%), 13 (8%)
11 (0%), 12 (67%), 13 (19%)
9
9
10
10
11
11
11
Table 4 Reactions of Bu3GeH and Bu3SnH with thiocarbonyl reagents
Reaction conditions
Product(s) (Yields)
15, Bu3SnH (8.0 equiv.), 90 mina
15, Bu3GeH (5.4 equiv.), 90 mina
19, Bu3SnH (2.0 equiv.), 3 ha
19, Bu3GeH (2.4 equiv.), 3 ha
19, Bu3SnH (2.0 equiv.), 3 hb
19, Bu3GeH (2.0 equiv.), 3 hb
17 (29%), 18 (28%)
17 (87%), 18 (0%)
19 (0%), 21 (54%), 22 (0%)
19 (0%), 21 (60%), 22 (0%)
19 (51%), 21 (5%), 22 (11%)
19 (0%), 21 (67%), 22 (0%)
Bu3GeH was tested on widely used synthetic reactions using
thiocarbonyl reagents, i.e. decarboxylation using Barton esters
and deoxygenation using the Barton–McCombie reaction.39
a 15 or 19 was added to Bu3SnH or Bu3GeH. b Bu3SnH or Bu3GeH was
added to 19.
ؒ
The Bu3Ge radical adds successfully to the sulfur of the thio-
carbonyl group and facilitates the breakdown of the resulting
ؒ
radical intermediates as reported for Bu3Sn radicals. The use
of Bu3GeH was tested on the Barton ester of adamantane-1-
carboxylic acid. The ester was prepared in situ from the acid
chloride and reacted directly with Bu3GeH and Bu3SnH
(Scheme 3). The one pot reaction is the normal method but does
not indicate the yield of each step. The reaction with Bu3GeH
gave a 33% yield of adamantane whereas the reaction with
Bu3SnH under the same conditions yielded 81%. Although the
reaction was not repeated it indicates that Bu3GeH reacts
successfully with Barton esters in decarboxylation reactions.
Scheme 3 Reagents and conditions: i. DMAP (1.0 equiv.), N-hydroxy-
2-thiopyridone (1.2 equiv.), toluene, reflux, 15 min; ii. Bu3GeH (3.0
equiv.), toluene, reflux, 1 h, adamantane (33%).
Both primary and secondary alcohols can be easily
deoxygenated using Barton–McCombie reactions of thiocarb-
onylimidazolides.39 Bu3SnH-promoted reduction of these com-
pounds is well known in the literature and the reactions
normally proceed in high yields. In order to investigate whether
Bu3GeH could mimic the excellent reactivity of Bu3SnH, the
thiocarbonylimidazolide esters of 1,2:5,6-di-O-isopropylidene-
α--glucofuranose 15 and cholesterol 20 were synthesised and
reacted with Bu3GeH and Bu3SnH for comparison (Scheme 4,
Table 4). The glucose ester 15 was added to Bu3GeH or Bu3SnH
in the reaction mixture to ensure a high concentration of
the radical mediator. When the concentration of Bu3SnH is
relatively high, thiocarbonylimidazolides can be reduced to the
corresponding methoxy compounds.40 The faster H-abstraction
from Bu3SnH facilitates interception of the initial intermediate
radical 16 by reduction and eventually yields the methoxy
analogue 18 (28%) as well as the expected deoxygenated prod-
uct 17 (29%). The H-abstraction is slower from Bu3GeH to the
intermediate 16, which has time to fragment (β-scission), finally
yielding 17 (87%). None of the methoxy derivative 18 was
formed indicating that no reduction of 16 took place.
Scheme 4 Reagents and conditions: i. thiocarbonyldiimidazole (2.0
equiv.), DMAP (0.2 equiv.), CH3CN, reflux, 150 min (15, 100%; 20,
84%); ii. toluene, reflux, ACCN, Bu3MH (see Table 4).
the Bu3SnH results were more confusing; when 20 was added to
Bu3SnH a good yield of the deoxygenated product 21 was
obtained (54%), but when Bu3SnH was added to 20 in the
reaction, a mixture of 19, 21 and 22 were obtained. Both 19 and
22 result from Bu3SnH interception of the intermediate radical
by fast H-abstraction from Bu3SnH. By comparison with
literature studies,40 the cholesterol 19 results from hydrolysis of
the reduced radical intermediate, not hydrolysis of the imid-
azolide 20. In summary, Bu3GeH gives more reliable results
than Bu3SnH under various reaction conditions in the two
Barton–McCombie reactions investigated. Reduction of a
The radical deoxygenation of the cholesterol thiocarbonyl-
imidazolide 20 using Bu3GeH also gave a good yield of choles-
tane 21 when either 20 was added to Bu3GeH (60%) or when
Bu3GeH was added to 20 (67%) in the reaction. Unexpectedly,
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thioxanthate has also been reported using reduction with
tri-(2-furyl)germanium hydride.24
Cyclisation onto azoles was investigated in order to ascertain
whether Bu3GeH would give better cyclisation results than
Bu3SnH (Scheme 5). We chose two examples from our previous
studies, imidazole 2341 and pyrazoles 27.42 The slower rate of
H-abstraction from Bu3GeH (as compared to Bu3SnH) by
the intermediate 24 should favour cyclisation to the π-radical
25 over reduction. The mechanism involves an oxidative step
in rearomatisation which is uncertain but H-abstraction by
radicals resulting from breakdown of the initiator is most
likely.42 The reaction of the imidazole 23 was slower for
Bu3GeH than Bu3SnH as expected and neither gave any
uncyclised reduced products [Bu3SnH (1.2 equiv.), AMBN,
MeCN, reflux, 3 h, unaltered 23 (29%) and 26 (62%); Bu3GeH
(1.5 equiv.), AMBN, MeCN, reflux, 3 h, unaltered 23 (69%) and
26 (21%)]. Higher temperatures using refluxing toluene gave
similar yields with no major improvement whereas use of
cyclohexane as the solvent gave lower yields. The ‘oxidative’
step appears to proceed with both radical reagents which
supports the proposition that this step is independent of the
radical reagent.42
Scheme 6 Reagents and conditions: i. Bu3SnH (1.1 equiv.), AIBN,
toluene, reflux, 2 h, (34, 9%; 35, 48%); Bu3GeH (1.1 equiv.), ACCN,
toluene, reflux, 1 h (34, 0%; 35, 63%).
intermediate acyl radical loses carbon monoxide to yield the
indol-3-ylethyl radical 33 which is reduced. The rate of
decarbonylation is slow (ca. 2 × 102 MϪ1 sϪ1 at 80 ЊC to yield
primary alkyl radicals43) and therefore Bu3SnH is able to
intercept some of the acyl radical 32 prior to decarbonylation.
However, the slower rate of H-abstraction from Bu3GeH by 32
allows full decarbonylation to 33 and a good yield of 3-ethyl-
indole. Acyl selanides can be synthesised in high yield from the
carboxylic acids and the radical reaction is facile and, therefore,
the protocol provides a good alternative route to that of Barton
esters for the decarboxylation of carboxylic acids.
Bu3SnH-mediated radical cyclisation using nitro precursors
ؒ
have been developed by Ono and co-workers. The Bu3Sn
radicals add to the oxygen of the nitro group yielding an inter-
mediate nitroxyl which breaks down to yield an intermediate
alkyl radical 37. The mechanism is fully discussed in the
literature.44 We chose a suitable example, 3-nitro-3-methyl-4-
phenyl-4-(prop-2-ynyloxy)butyl cyanide 36,45 but obtained
poor results with both Bu3SnH and Bu3GeH (Scheme 7). Both
diastereomers of the cyclised product 38 and 39 were obtained.
The Bu3GeH reactions were disappointing with large amounts
of unaltered starting material. Longer reaction times with a
larger excess of Bu3GeH did not enhance the yields. It is inter-
esting to note that the diastereoselectivity in the cyclisation
reaction is dependant on the radical mediator used. The
Bu3SnH-mediated reaction gave ca. a 1 : 1 mixture of dia-
stereomers whereas the Bu3GeH-mediated reactions gave a
majority of the diastereomer with the two large groups in a
syn position.
Scheme 5 Radical cyclisation onto azoles.
Cyclisation of the pyrazole 27 had proved problematic with
Bu3SnH and successful results were only obtained using
tris(trimethylsilyl)silane and triethylborane (Et3B) and low
temperatures.42 At higher temperatures considerable amounts
of the alkenes 30 (n = 1, 2) had been formed by an unknown
mechanism. Reaction of 27 (n = 1) in refluxing toluene gave
only the alkene 30 (n = 1, 30%) [Bu3GeH (1.1 equiv.), ACCN,
6 h] whereas reaction in cyclohexane at room temperature gave
only the uncyclised reduced compound 29 (n = 1, 66%)
[Bu3GeH (2.4 equiv.), Et3B, 26 h]. Even with the slow rate of
H-abstraction from Bu3GeH the intermediate alkyl radical is
reduced faster than cyclisation takes place, thereby providing
no advantage over Bu3SnH.42 The six-membered ring cyclis-
ation is more favourable for both reagents due to less ring strain
during cyclisation onto the azole. Reaction of 27 (n = 2) gave a
reasonable yield of the cyclised pyrazole 28 (44%) [Bu3GeH (2.4
equiv.), Et3B, cyclohexane, room temperature, 34 h] with only
traces of the alkene 30 (n = 2, 4%). When the reaction was
repeated in refluxing toluene only the alkene 30 (n = 2, 16%) was
obtained with unaltered 27 (n = 2, 52%). The results using
Bu3GeH are similar to and give no advantage over Bu3SnH.
Scheme 7 Reagents and conditions: i. Bu3SnH (1.3 equiv.), AIBN,
MeCN, reflux, 3 h (38, 21%; 39, 18%); Bu3GeH (1.3 equiv.), AIBN,
reflux: MeCN, 3 h, (38, 8%; 39, 15%; 36, 51%) and toluene, 5 h, (38, 3%;
39, 17%; 36, 53%).
Vinyl radicals were also generated using Bu3GeH from the
vinyl bromide 40 which has been the subject of several studies46
(Scheme 8). The vinyl radical 41 cyclises by both 5-exo and
6-endo modes.46 The 5-exo radical intermediate 42 is also able
to rearrange via 44 to the 6-endo radical 43. We hoped that use
of Bu3GeH would allow more time for the rearrangement to
take place, thereby increasing the amount of 6-endo product
relative to the use of Bu3SnH. The Bu3SnH reaction gave an
88% yield of cyclised products as reported in the literature.
However, Bu3GeH gave a very disappointing yield (15%). The
ؒ
Bu3Ge was shown to abstract the PhSe moiety from acyl
selanides, e.g. 31, to generate acyl radicals (Scheme 6). The
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 5 8 5 – 5 9 2
589

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3.1 mmol) in freshly distilled diethyl ether (200 cm3) at Ϫ78 ЊC
over 45 min. The mixture was allowed to warm to room tem-
perature over 45 min during which period a colour change from
milky red to milky green was observed and thereafter refluxed
for 15 h. The reaction mixture was cooled to 0 ЊC, aqueous
hydrochloric acid (2 M, 100 cm3) was added over 1 h and a
colour change to red was observed. The organic layer was
separated and the aqueous phase was extracted with diethyl
ether. The combined organic layer was dried and evaporated to
dryness to yield a residue which was filtered through Celite
to remove a red solid. Distillation under reduced pressure gave
two products; Bu3GeH (5.25 g, 21.5 mmol, 53%) and tetra-
butylgermanium (4.30 g, 14.3 mmol, 35%) as colourless
liquids.32 Bu3GeH: νmax/cmϪ1 2957, 2927, 2870, 2853, 2006 and
1460; δH 0.82–0.92 (15 H, m, 1, 4-H), 1.34–1.43 (12 H, m, 2,
3-H) and 3.68 (1 H, septet, J 2.8, GeH); δC 11.92 (3-C), 13.80
(4-C), 26.19 (2-C) and 28.75 (1-C); m/z 245 (23%), 217 (21), 189
(23), 161 (100), 133 (47) and 105 (41). Bu4Ge: νmax/cmϪ1 2956,
2922, 2870, 2853 and 1460, δH 0.69–0.72 (8 H, m, 1-H), 0.86–
0.94 (12 H, m, 4-H) and 1.31–1.44 (16 H, m, 2, 3-H); δC 12.52
(3-C), 13.80 (4-C), 26.70 (2-C) and 27.56 (1-C). This data is
identical to published data.32
Scheme 8 Reagents and conditions: i. AMBN, toluene, reflux, 4 h:
Bu3SnH (1.1 equiv.), (45, 57%; 46, 31%) and Bu3GeH (1.1 equiv.),
(45,11%; 46, 4%); Bu3GeH (1.1 equiv.), PhSH (0.1. equiv.), AMBN,
toluene, reflux, 5 h, (45, 33%; 46, 5%).
starting material was largely consumed indicating that the
radicals had been formed. Analysis of the crude reaction
mixture by 1H NMR spectroscopy and GCMS showed that the
ؒ
major products resulted from Bu3Ge radical addition to the
alkene group of the cyclised products 45 and 46. These addition
products were not separable and were not further characterised.
These disappointing results indicate a limitation of the use of
Bu3GeH. We also used the PRC protocol with a catalytic
amount of PhSH. As expected, this procedure speeded up the
reaction and therefore facilitated a higher yield of the 5-exo
product (33%).
General procedure for radical reactions
A solution of Bu3GeH or Bu3SnH was added dropwise to a
mixture of the radical precursor in anhydrous solvent at room
temperature under an atmosphere of nitrogen. The mixture was
heated to reflux and the radical initiator was added, followed by
heating under reflux for the time indicated for each reaction. A
portion of the radical initiator was added every 40 min. The
reaction mixture was cooled to room temperature and evapor-
ated to dryness. The residues were analysed by 1H NMR
spectroscopy and TLC and by GCMS when required. The
crude residues were purified by column chromatography.
Experimental
Commercial dry solvents were used in all reactions except for
light petroleum and ethyl acetate which were distilled from
CaCl2 and dichloromethane (DCM) which was distilled over
phosphorus pentoxide. Light petroleum refers to the bp
40–60 ЊC fraction. Sodium hydride was obtained as a 60%
dispersion in oil and was washed with light petroleum. Mps
were determined on an Electrothermal 9100 melting point
apparatus and are uncorrected. Elemental analyses were
determined on a Perkin Elmer 2400 CHN Elemental Analyser
in conjunction with a Perkin Elmer AD-4 Autobalance. IR
spectra were recorded on a Perkin-Elmer Paragon 1000 FT-IR
spectrophotometer on NaCl plates. 1H (250 MHz) and 13C (62.5
MHz) NMR spectra were recorded on a Bruker AC-250 spec-
trometer as solutions of CDCl3 with tetramethylsilane (TMS)
Polarity reversal catalysis (PRC) with the addition of phenyl-
thiol. Phenylthiol (0.1 equiv.) was added along with Bu3GeH or
Bu3SnH at the beginning of the reaction.
Catalytic amounts of the radical mediator. Bu3GeH or
Bu3SnH was added dropwise to the solution of the radical
precursor in t-BuOH at room temperature, followed by
addition of sodium borohydride (2 equiv.). The mixture was
heated to reflux and AIBN was added, followed by heating
under reflux for the time indicated. More AIBN was added
every hour upto a total of 0.2 equivalents. After cooling to
room temperature the mixture was poured into water and
extracted with diethyl ether. The organic layer was washed with
water to remove t-BuOH, dried and evaporated to dryness.
1
as the internal standard for H NMR spectra and deuterio-
chloroform the standard for 13C NMR spectra unless otherwise
specified. Chemical shifts are given in parts per million (ppm)
and J values in hertz (Hz). Mass spectra were recorded on a
JEOL SX102 mass spectrometer or carried out by the EPSRC
Mass Spectrometry Service at the University of Wales,
Swansea. GC-MS was carried out on a Fisons 8000 series
GC-MS apparatus using a 15 m × 0.25 mm DB-5 column and
an electron impact low resolution mass spectrometer. TLC
using silica gel as absorbent was carried out with aluminium
backed plates coated with silica gel (Merck Kieselgel 60 F254).
Silica gel (Merck Kieselgel 60 H silica) was used for column
chromatography unless otherwise specified.
Triethylborane as the radical initiator. Bu3GeH or Bu3SnH
and triethylborane (1.0 M solution in THF) were added drop-
wise to a solution of the radical precursor in anhydrous solvent
at room temperature. If the radical mediator was used in a
catalytic manner, sodium borohydride was also added at this
stage. The mixture was stirred at room temperature for the time
indicated. Air was allowed to infuse into the reaction through
an open syringe needle in a septum covering one of the necks of
the reaction flask.
1,2:5,6-Di-O-isopropylidene-3-O-thiocarbonylimidazole-α-
-glucofuranose 15,47 the thiocarbonylimidazolide of choles-
terol 20,48 1-(3-bromobutyl)-2-methyl-1H-imidazole-4-carb-
aldehyde 23,41 4-phenyl-1-(3-phenylselanylpropyl)-1H-pyrazole
27 (n = 1),42 4-phenyl-1-(4-phenylselanylbutyl)-1H-pyrazole 27
(n = 2)42 and 3-nitro-3-methyl-4-phenyl-4-(prop-2-ynyloxy)-
butyl cyanide 3644 were synthesised using literature procedures.
Syringe-pump addition of the radical mediator. A solution of
Bu3GeH or Bu3SnH in anhydrous solvent was added by syringe
pump to a refluxing mixture of the radical precursor in
anhydrous solvent over the period of time indicated under each
reaction. The radical initiator was added initially and every
40 min.
Tributylgermanium hydride32
Tetrachlorogermanium (8.75 g, 40.8 mmol) and butylmag-
nesium chloride (2 M solution in diethyl ether, 100 cm3) were
successively added dropwise to a solution of Cp2TiCl2 (0.76 g,
Representative procedures are detailed below and the rest of
the procedures are reported in the supplementary data.†
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 5 8 5 – 5 9 2
590

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Cyclisation of 2-iodo-1-(prop-2-enyloxy)benzene 1
5-H); m/z 198 (Mϩ, 42%), 197 (46), 170 (28), 157 (100), 144 (53),
130 (27) 103 (33), 89 (21), 77 (23) and 39 (38).
A solution of Bu3GeH (0.11 g, 0.44 mmol), 2-iodo-1-(prop-2-
enyloxy)benzene 1 (96.0 mg, 0.37 mmol) and AIBN (35.0 mg,
0.2 mmol) in toluene (38 cm3) was heated under reflux for 2 h.
Purification gave 3-methyl-2,3-dihydrobenzofuran 2 (45.1 mg,
0.34 mmol, 91%) as a colourless oil. δH 1.33 (3 H, d, J 6.9, Me),
3.47–3.62 (1 H, m, CHMe), 4.07 (1 H, dd, J 7.8, 8.8, CHAHBO),
4.68 (1 H, dd, J 8.8, 8.8, CHAHBO), 6.77–6.89 (2 H, m, Ar
4,6-H) and 7.08–7.17 (2 H, m, Ar 3,5-H); δC 20.01 (Me), 37.16
(CHMe), 79.10 (OCH2), 110.09 (Ar 6-C), 121.05 (Ar 4-C),
124.41 (Ar 5-C), 128.61 (Ar 3-C), 132.87 (Ar 2-C) and 160.29
(Ar 1-C); m/z 134 (84%), 119 (95) and 91 (100). Spectroscopic
data agreed with those in the literature.49 Other reactions of
2-iodo-1-(prop-2-enyloxy)benzene 1 are reported in Table 1.
Acknowledgements
We thank GlaxoSmithKline and Loughborough University for
a Postgraduate Studentship (S. L. K.), GlaxoSmithKline for
generous financial support and the EPSRC Mass Spectrometry
Unit, Swansea University, Wales for mass spectra.
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