Radical chain reduction of alkylboron compounds with catechols

Article abstract of DOI:10.1021/ja110224d

The conversion of alkylboranes to the corresponding alkanes is classically per-formed via protonolysis of alkylboranes. This simple reaction requires the use of severe reaction conditions, that is, treatment with a carboxylic acid at high temperature (>150 °C). We report here a mild radical procedure for the transformation of organoboranes to alkanes. 4-tert-Butylcatechol, a well-established radical inhibitor and antioxidant, is acting as a source of hydrogen atoms. An efficient chain reaction is observed due to the exceptional reactivity of phenoxyl radicals toward alkylboranes. The reaction has been applied to a wide range of organoboron derivatives such as B- alkylcatecholboranes, trialkylboranes, pinacolboronates, and alkylboronic acids. Furthermore, the so far elusive rate constants for the hydrogen transfer between secondary alkyl radical and catechol derivatives have been experimentally determined. Interestingly, they are less than 1 order of magnitude slower than that of tin hydride at 80 °C, making catechols particularly attractive for a wide range of transformations involving C-C bond formation.

Full text of DOI:10.1021/ja110224d

ARTICLE
pubs.acs.org/JACS
Radical Chain Reduction of Alkylboron Compounds with Catechols
Giorgio Villa, Guillaume Povie, and Philippe Renaud*
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
S Supporting Information
b
ABSTRACT: The conversion of alkylboranes to the corresponding alkanes is classically per-
formed via protonolysis of alkylboranes. This simple reaction requires the use of severe reaction
conditions, that is, treatment with a carboxylic acid at high temperature (>150 °C). We report
here a mild radical procedure for the transformation of organoboranes to alkanes. 4-tert-
Butylcatechol, a well-established radical inhibitor and antioxidant, is acting as a source of
hydrogen atoms. An efficient chain reaction is observed due to the exceptional reactivity of
phenoxyl radicals toward alkylboranes. The reaction has been applied to a wide range of
organoboron derivatives such as B-alkylcatecholboranes, trialkylboranes, pinacolboronates, and alkylboronic acids. Furthermore, the so far
elusive rate constants for the hydrogen transfer between secondary alkyl radical and catechol derivatives have been experimentally
determined. Interestingly, they are less than 1 order of magnitude slower than that of tin hydride at 80 °C, making catechols particularly
attractive for a wide range of transformations involving C-C bond formation.
’ INTRODUCTION
on a fast homolytic substitution (SH2) of an alkyl group of
the trialkylborane by the thiyl radical.10 However, this process is
limited to the reduction of one out of the three alkyl groups of
trialkylboranes. Herein, we report an extensive study of the radi-
cal reaction of organoboranes with 4-tert-butylcatechol (TBC).
The reduction of different classes of organoboron compounds
has been investigated. The unexpected reactivity of aryloxyl radi-
cal toward organoboranes is the key factor for the large scope of
this reaction.
Trialkylboranes are known to undergo bimolecular homolytic
substitutions (SH2) where the attack of a heteroatom centered
radical onto the boron liberates an alkyl radical. This behavior has
led to many applications, and organoboranes are commonly
found as initiators, chain transfer reagents, or substrates.11 Due to
the delocalization of the lone pair of the heteroatom into the
empty orbital of boron, the lower Lewis acidity of borinic and
boronic esters drastically lowers their tendency to undergo SH2;
thus, generally only one out of the three alkyl groups of a trialkyl-
borane can be used for synthetic purposes. Recently, we have shown
that reactive B-alkylcatecholboranes are very efficient for a wide
range of radical reactions.12 Since these organoboron derivatives are
sensitive to oxygen and moisture, they are best prepared in situ by
hydroboration with an excess of catecholborane. Intriguingly, we
observed that when this excess was solvolyzed with methanol,
reduction of the radical intermediate was observed as a side-reaction
in allylation processes.13,14 Taking advantage of this observation, we
reported a protocol for the reduction of alkenes to alkanes via
hydroboration with catecholborane followed by treatment of the
intermediate alkylboronate with methanol in the presence of a
radical initiator.15 Based on preliminary mechanistic observations,
the Lewis acid/base complex A (Scheme 1) formed between
The reduction of alkenes to alkanes has attracted the interest
of synthetic chemists for decades, and many efficient methods
have been developed. However, in the field of natural product
synthesis, the issue of functional group tolerance, stereochemical
control, and chemoselectivity may render this simple process
problematic. In some cases, double bonds have to be reduced via
a hydroboration-reduction process. The usual sequence to
achieve this transformation is the conversion of the intermediate
organoboron species to an alcohol followed by a multistep
deoxygenation process.1 Despite the rich panel of transforma-
tions available from organoboron compounds, their simple
reduction remains challenging. Except for two reports where
two alkyl-boron bonds of a trialkylborane are protonolyzed in
refluxing water,2,3 the transformation of a C(sp3)-B bond into a
C-H bond generally requires assistance. The best-studied
protonolysis of trialkylboranes by carboxylic acids2 is efficient
at room temperature for the first alkyl group, but, due to the
lower acidity of the newly formed borinic ester, further reactivity
requires prolonged stirring or heating. The protonolysis of the
third group occurs only with propionic acid in refluxing diglyme.4
Mineral acids can also form a complex with a trialkylborane and
subsequently transfer a proton to the carbon atom. Nevertheless,
except with anhydrous HF (in a bomb), the reaction stops after
the first alkyl displacement.5 Basic protonolysis is even less
efficient, and forcing conditions or stabilization of the negative
charge are required.6 The hydrogenation of a B-C bond takes
place at high temperatures (g150 °C) and high pressures of
hydrogen (g200 bar) and delivers mixtures of products.7 First
reported by Gilman and Nelson in 1937, the reduction of
trialkylboranes by thiols involves radicals and occurs under
particularly mild conditions.8 Extensive studies by Mikhailov
and Bubnov have demonstrated that a long chain radical process
initiated by traces of oxygen takes place.9 The mechanism relies
Received: November 14, 2010
Published: February 22, 2011
r
2011 American Chemical Society
5913
dx.doi.org/10.1021/ja110224d J. Am. Chem. Soc. 2011, 133, 5913–5920
|

Journal of the American Chemical Society
ARTICLE
Scheme 1. Methanol Mediated Reduction of R-Pinene,15
Postulated Complexes
Scheme 2. Mechanism for the Reduction of B-Isopinocam-
pheylcatecholborane 2a17
2-methoxybenzo[d][1,3,2]dioxaborole (MeOBCat, generated in
situ from methanol and the excess of catecholborane) and methanol
was proposed as the reducing species. This hypothesis was also sup-
ported by the work of Wood et al. showing that a related trimethyl-
borane/water complex (Scheme 1, complex B) was acting as a
reducing species in a Barton-McCombie deoxygenation process.16
Since the oxygen lone pair donating effect makes boric ester
derivatives less Lewis acidic than their boronic ester counterparts,
the methanol complex of MeOBCat (Scheme 1, complex A) is
expected to be weaker than that of B-2-alkylbenzo[d][1,3,2]dio-
xaborole (RBCat, Scheme 1, complex C), thus forecasting for the
latter a better hydrogen atom donor ability. Although the reduction
of a series of olefins was successful (e.g., R-pinene in Scheme 1, eq 1),
almost no reduced product was formed when treating distilled
B-isopinocampheylcatecholborane with methanol (Scheme 1, eq 2).
This and unexpected kinetic results, where PrBCat/MeOH was
shown to be a slower reducing environment than MeOBCat/
MeOH, urged us to study the degree of complexation by methanol.
11B NMR studies failed to bring any evidence for the formation of a
complex for both PrBCat and MeOBCat. Instead, transesterification
was shown to take place to a large extent for MeOBCat, leading to a
significant amount of free catechol in solution, when PrBCat was
relatively stable to methanolysis.17 Moreover, when a solution of pure
B-isopinocampheylcatecholborane was exposed to catechol and air,
cis-pinane was now obtained in good yield (eq 3).
the SH2 of the alkyl radical by the resulting aryloxyl/semiquinone
radical was proposed to propagate the radical chain (Scheme 2, eq
b). The efficiency of that reaction minimizes recombination and
disproportionation reactions and allows a good chain process
(Scheme 2, eq c). Meulenhoff’s free acid (4) is also a potential
reducing agent (vide infra). Due to its low solubility and tendency to
equilibrate with catechol and boric ester derivatives (Scheme 2, eq
d), its exact role was found difficult to study.
’ RESULTS AND DISCUSSION
Reduction of Organoboron Species. The reaction of
B-isopinocampheylcatecholborane 2a with catechol (eq 3) was run
for mechanistic purpose.17 This new protocol shows some very
promising features that could lead to the development of a useful
preparative process. The reaction involving the B-alkylcatechol-
borane 2b obtained by hydroboration of 4-phenylmethylenecy-
clohexane 1b was used for the optimization process (eq , Table 1).
4-tert-Butylcatechol (TBC) was preferred to catechol due to its
better solubility, lower toxicity, and better reactivity (compare also
entries 3 and 6).21 The effects of the solvent and of the initiator
wereexamined first. Dichloromethane, tert-butyl methyl ether, 1,2-
dichloroethane, toluene, and benzene (entries 1-5) were tested.
Best results were obtained with 1,2-dichloroethane (entry 3) and
benzene (entry 5). Concerning the initiator, both di-tert-butyl
hyponitrite (entry 3),22 that thermally decomposed to tert-
butoxyl radicals, and air (entry 7) gave nearly quantitative yields.
Dibenzoyl peroxide was less efficient (entry 8). Reactions with
di-tert-butyl hyponitrite allow a better control of the reaction
parameters, and it was therefore used for the optimization process.
Interestingly, when air was used to initiate the reaction, no
autoxidation of the B-alkylcatecholboranes was observed and
this mode of initiation was employed for the scope and limitation
study (vide infra).23
This result is particularly interesting, since it invalidates the
initially proposed mechanism involving complex A, and it demon-
strates that the chain process was propagated by what is generally
seen as an antioxidant. Indeed, phenols have a low O-H bond
dissociation energy (75-90 kcal/mol depending on the substitu-
tion of the ring) allowing facile hydrogen atom abstraction.18 The
stabilized aryloxyl radical generally disrupts the chain via recombina-
tion and disproportionation reactions.19 As B-alkylcatecholboranes
2are known to react even with persistent radicals such as TEMPO,20
The effect of concentration of the reaction mixture was
examined next. Due to the competition between the SH2 at
boron and the recombination/disproportionation process, an
optimum concentration was expected. The best concentration
was found to be 0.3 M (Table 2, entries 1-4). The reaction with
substoichiometric amounts of 4-tert-butylcatechol (entries 5-6)
5914
dx.doi.org/10.1021/ja110224d |J. Am. Chem. Soc. 2011, 133, 5913–5920

Journal of the American Chemical Society
ARTICLE
Table 1. Optimization of the Reaction Conditions for the
Reduction of 2b with 4-tert-Butylcatechol According to
Equationa
Scheme 3. Reductive Radical Rearrangements of
B-Alkylcatecholboranes
entry
solvent
CH2Cl2
temperature
initiator
yield (GC)
1
40 °C
55 °C
83 °C
80 °C
80 °C
83 °C
83 °C
83 °C
t-BuONdNOt-Bu
t-BuONdNOt-Bu
t-BuONdNOt-Bu
t-BuONdNOt-Bu
t-BuONdNOt-Bu
t-BuONdNOt-Bu
air
74
2
3c
t-BuOMe
69
99 (87)d
ClCH2CH2Cl
toluene
4
93
5
6b
benzene
89d
93
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
reaction conditions, a 78:22 mixture of cyclooctene 3d and
bicyclo[3.3.0]octane 5d was formed in 70% yield (vide infra).
Based on the results obtained with the B-alkylcatecholborane
2b, a one-pot sequence starting from alkenes involving hydro-
boration and reduction has been developed (Scheme 4). The
reaction of cholesteryl benzoate 1e was attempted first (eq 7).
Hydroboration at room temperature using two equivalents of
catecholborane and N,N-dimethylacetamide as a catalyst24 af-
forded an intermediate organoborane that was directly treated
with 4-tert-butylcatechol in the presence of air. This reaction
afforded the reduced product 3e in 93% isolated yield as a 5R/5β
(9:1) mixture of diastereomers. The nonprotected cholesterol 1f
could also be reduced under similar conditions (eq 8). In this
case, however, the hydroboration was performed with 3 equiv of
catecholborane under neat conditions at 100 °C. The reaction
afforded the alcohol trans-3f in 72% yield as a single diastereo-
mer. Several attempts to perform a transition metal catalyzed
hydroboration with Wilkinson’s catalyst25 led to poor recovery
after filtration over aluminum oxide.26 Indeed, Wilkinson cata-
lyst/quinone complex have been reported to activate molecular
oxygen.27 The rapid change of color from clear to dark red after
addition of 4-tert-butylcatechol may be a sign for the oxidation of
the catechol derivative to the corresponding o-quinone. The
latter would then act as an excellent radical trap leading to new
catechol derivatives.28 Screening some additives to poison the
catalyst, 1,4-dithiane proved to efficiently prevent this side
reaction. Nevertheless, on our model alkene 1b, the new
rhodium species drastically slows down the reaction and 46 h
was required to obtain the reduced product 2b in 73% GC-yield
(eq 9). The reduction of alkene 1g (eq 10) and 1h (eq 11)
demonstrates that the method is suitable for the reduction of
double bonds in the presence of an aryl iodide and a nitroarene,
respectively, two groups that are reduced with most methods
used to hydrogenate double bonds.
7
99
8
dibenzoyl peroxide
79
a General procedures: 1 equiv of B-alkylcatecholborane, 0.3 M, 1 equiv of
4-tert-butylcatechol. b 4-tert-butylcatechol replaced by 1 equiv of cate-
chol. c 3 mol % initiator gave 70% GC-yield after 1 h, additional 3 mol %
95% after 2 h, and further 3 mol % quantitative GC-yield after 3 h.
d Isolated yield.
Table 2. Optimization of the Concentration for the Reduc-
tion of 2b to 3b According to equation in 1,2-Dichloroethane
and Di-tert-butyl Hyponitrite as an Initiator
entry
TBC [equiv]
[2b]
temperature
GC-yield
1
1
0.1 M
0.3 M
0.5 M
1 M
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
23 °C
71
2
1
>99
3
1
90
4
1
90
5
0.5
0.8
1
0.3 M
0.3 M
0.3 M
80
6
7a
84
traces (3 h)
a Initiation with 50 mL of air for 1 mmol 2b.
afforded good yields, indicating either that Meulenhoff’s free acid
is a source of hydrogen atoms in a chain process or that two
molecules of Meulenhoff’s free acid can equilibrate to give 4-tert-
butylcatechol according to Scheme 2 (eq c). Finally, an attempt
to run the reaction at room temperature (initiation with air) gave
only 20% of the alkane 3b after 48 h. Concerning the purification,
a filtration through a short pad of neutral alumina was found to be
enough to remove impurities derived from 4-tert-butylcatechol
and boron derivatives yielding in most cases analytically pure
products. For instance, under the optimized reaction conditions
of entry 3, the reduced product 3b was isolated in 87% yield.
The reduction of B-alkylcatecholboranes under our optimized
conditions was examined next for two more systems that should
illustrate the radical nature of the process (Scheme 3). In the first
reaction (Scheme 3, eq 5), the boronate 2c obtained by hydro-
boration of 2-carene afforded 3c resulting from cyclopropane
ring-opening, confirming the radical mechanism. When B-cy-
clooct-4-enylcatecholborane 1d (eq 6) was subjected to the
Encouraged by the positive results obtained for the reduction
of B-alkylcatecholboranes, the reduction of trialkylboranes was
investigated next. So far, no mild method allows the conversion
of the three alkyl groups into the corresponding alkane(s).
However, based on mechanistic considerations, the complete
reduction of trialkylboranes by catechol was anticipated. Indeed,
when exposed to oxygen, trialkylboranes 6 generate alkyl radicals
that are readily reduced by catechol (Scheme 5, eq a,b). The
5915
dx.doi.org/10.1021/ja110224d |J. Am. Chem. Soc. 2011, 133, 5913–5920

Journal of the American Chemical Society
ARTICLE
Scheme 4. One-Pot Reduction of Alkenes Using Catecholborane Mediated Hydroboration
Scheme 5. Hypothetic Mechanism for the Complete Con-
version of Trialkylborane 5 to Alkane 3
homolytic substitution at the boron of an alkyl residue by the
aryloxy radical should take place as previously proposed and
afford borinic esters 7 (Scheme 5, eq c). These esters are also
thought to be capable of hydrogen atom transfer to alkyl radicals
or to the semiquinone radical (Scheme 5, eq d).29 The resultant
aryloxyl radicals could undergo intramolecular homolytic sub-
stitution to liberate a second alkyl radical and the B-alkylcate-
cholboranes 2 (Scheme 5, eq e) which are efficiently reduced as
previously demonstrated (vide supra).30 Following this mechan-
ism, the three alkyl groups should be efficiently reduced. The
deactivation due to the formation of less acidic borinic and
boronic acid derivatives that is usually observed when trialk-
ylboranes are used as radical precursors does not take place.
Indeed, the second alkyl group is generated from borinic acid 7
via a favorable intramolecular homolytic substitution, and the
third alkyl group is produced from the reactive B-alkylcatechol-
borane 2.
A first trial with the isolated trialkylborane 6i derived from β-
pinene 1i was run. Treatment of 6i with three equivalents of
4-tert-butylcatechol afforded cis-pinane 3a in 83% GC-yield
(Scheme 6, eq 12). A one-pot process starting directly from
the alkene was examined next. The reaction of 1b with
chain process. Generally, the limitations of this two-step protocol
were found to be similar to those of the classical hydroboration-
oxidation sequence, with the main drawback being the difficulties
to follow the formation and the disappearance of the reactive
BH3 Me2S followed by treatment with 4-tert-butylcatechol gave
3
the reduced product 3b in good isolated yield as a 1:1 mixture of
diastereomers (eq 13). The use of a substoichiometric amount of
initiator (3 ꢀ 3 mol %) demonstrates the effectiveness of the
5916
dx.doi.org/10.1021/ja110224d |J. Am. Chem. Soc. 2011, 133, 5913–5920

Journal of the American Chemical Society
ARTICLE
Scheme 6. Reduction of Trialkylboranes
organoboron species.31 Thus, hydroboration of dihydropyrane 1j
had to be optimized in order to obtain an acceptable yield (eq 14).32
Similarly, hydroboration of allyl ether 3k had to be performed in 30
min (eq 15), and a longer reaction time led to lower yields.33
Cholesterol 1f was reduced to 3f in 69% yield by running the
acid 40. Thus, the olefin 1b was treated first with BH3 Me2S and
3
then with 0.1 equiv of 4-tert-butylcatechol, ethanol (5 equiv), and
air. Under these conditions, the reduced product 3b was formed in
good yield as a 1:1 mixture of diastereomers. In a blank experiment
without 4-tert-butylcatechol, the formation of 16% product was
observed after 12 h of reaction. No increase was obtained upon
prolonging the reaction time (5 days).
hydroboration with 1.5 equiv of BH3 Me2S (eq 16). The reaction of
3
limonene 1l with BH3 Me2S followed by treatment with 4-tert-
3
Whereas B-alkylcatecholboranes and trialkylboranes both
readily react with oxygen, pinacolboranes and boronic acids are
bench-stable. In the literature, no report can be found of either of
them being used as a radical precursor in a chain process. Further-
more, no mild protocol for their protonolysis is reported. However,
in situ generation of B-alkylcatecholboranes by esterification of the
corresponding boronic acids should allow their reduction via a
radical process. In the presence of alcohols such as methanol and
catechol, their boronic ester counterparts equilibrate in transester-
ification reactions.17 The cleavage of the B-C bond would displace
the equilibrium and may allow the complete reduction of an organo-
boron species. Indeed, when dodecyl boronic acid 9 was heated in
the presence of 4-tert-butylcatechol, dodecane 10 was obtained in
good yield (Scheme 9, eq 23). Pinacolboranes, unlike unhindered
boronic esters, do not transesterify under mild conditions. However,
when a substoichiometric amount of sulfuric acid is added to induce
pinacol rearrangement, transesterification and reduction could take
place. For instance, the pinacolboronate 11 was converted to
dodecane 10 in 61% yield (eq 24).
butylcatechol produced 4-methyl-1-isopropyl cyclohexane 3l as a 3:1
mixture of diastereomers in 65% isolated yield (eq 17). This
reduction was performed on 40 mmol of limonene, showing the
scalability of the reaction. Interestingly, by decreasing the amount of
hydroborating agent, it was not possible to isolate a monohydroge-
nated product. This result can be explained by the fact that the
hydroboration with BH3 of the terminal double bond isfollowed bya
rapid intramolecular hydroboration of the internal double bond.34
The use of nonsymmetrical trialkylborane was also examined
(Scheme 7). For instance, hydroboration of 1b with 9-BBN
followed by treatment with 4-tert-butylcatechol afforded 3b in 82%
yield as a 3:7 mixture of diastereomers (eq 18). The use of diethyl-
borane, easily produced by mixing Et3B (2 equivalents) and
BH3 Me2S, provided 3b in 76% yield (eq 19).35 The hydroboration
3
is generally highly selective for the less hindered olefin. A competitive
experiment with a 1:1 mixture of 1b and 1e afford the reduced
product 3b in 76% yield and let the more substituted olefin 1e
unchanged (98% recovery, eq 20). Similarly, the single reduction of
the methylene group of limonene 1l was selectively achieved in 65%
yield, using 9-BBN as hydroborating agent (Scheme 7, eq 21).
Finally, an ethanol-mediated reduction using a substoichio-
metric amount of 4-tert-butylcatechol was tested (Scheme 8, eq 22).
Ethanol can regenerate 4-tert-butylcatechol from Meulenhoff’s free
Kinetics of the Reduction with Catechol Derivatives.
Among the comprehensive literature concerning the kinetics of
hydrogen atom transfer from phenol derivatives, some values
toward alkyl radicals are available. Scaiano and Ingold first
5917
dx.doi.org/10.1021/ja110224d |J. Am. Chem. Soc. 2011, 133, 5913–5920

Journal of the American Chemical Society
ARTICLE
Scheme 7. Reduction of Mixed Trialkylboranes
Scheme 8. Reduction with a Catalytic Amount of 4-tert-
Scheme 10. Radical Clock Experiment
Butylcatechol
aryloxyl radical, EDG destabilize the parent phenol resulting in a
reduced BDE.37 For catechols, in addition to the electronic effect
of the second hydroxyl group, an intramolecular hydrogen bond
activates the free hydrogen toward hydrogen atom transfer.38,39
Many experimental and theoretical studies have treated this
reactivity enhancement; nevertheless, no values for the reduction
of alkyl radicals by catechol can be found most probably due to
experimental difficulties associated with the radical chain inhibi-
tion properties of catechol derivatives.40-42
Scheme 9. Reduction of n-Dodecyl Boronic Acid and
n-Dodecyl Boronic Pinacol Ester
Competing unimolecular radical rearrangements (radical
clocks) have been widely used to determine the rate of bimole-
cular reaction of radicals with radical traps such as hydrogen
donors.43,44 Ideally, the reaction of the unrearranged radical U•
with the trap XH leading to the reduced product UH (second-
order rate constant kH) is considered to compete only with the
irreversible unimolecular reaction leading to the rearranged
radical R• (first-order rate constant kR) (Scheme 10).
If the variation of the concentration in trapping agent is
negligible (i.e., [XH] is considered to be constant), the kinetic
model can be simplified to pseudo first order and then integrated
to give eq 25. The rate constant of interest (kH in our case) can be
easily obtained by conducting a series of experiments by varying
the concentration of the reducing agent XH. A plot of
[UH]/[RH] versus [XH] has a slope of kH/kR. If unknown,
the rate constant of rearrangement can be calibrated using a
radical trap for which the rate constant is already known. The use
measured a value of 1.7 ꢀ 106 M-1 s-1 (343 K) for the reaction
of R-tocopherol with primary alkyl radicals using the 5-hexenyl
radical clock. More recently, Pedulli and Lucarini studied the
reactivity of a wide range of phenols with primary alkyl radical
reporting hydrogen atom transfer rate constants from 2 ꢀ 103 to
7 ꢀ 105 M-1 s-1 (298 K).36 The effect of substituent on the O-
H BDE of phenols is now well established: while both electron
donating (EDG) and withdrawing (EWG) groups stabilize the
5918
dx.doi.org/10.1021/ja110224d |J. Am. Chem. Soc. 2011, 133, 5913–5920

Journal of the American Chemical Society
ARTICLE
Scheme 11. Cyclooct-4-enyl Radical Clock
Table 3. Relative and Absolute Rate Constants for the Re-
duction with Catechol and 4-tert-Butylcatechol at 353 K
reducing agent
concentration (M)
kH/kc
kH (M-1 s-1
)
n-Bu3SnH
0.05-0.2
0.02-0.08
0.02-0.08
185 ( 19 6.02 ꢀ 106 (ref 47)
catechol
27 ( 7
40 ( 9
0.9 ( 0.3 ꢀ 106
1.3 ( 0.4 ꢀ 106
4-tert-butylcatechol
the expected substituent effect. The absolute values for catechol
and 4-tert-butylcatechol (secondary alkyl radicals) are found just
slightly below the one previously mentioned for R-tocopherol
(primary alkyl radical) in similar reaction conditions (1.7 ꢀ 106
M-1 s-1, 70 °C, benzene). These results corroborate recent
conclusions on the importance of the intramolecular hydrogen
bond on the BDE of catechol.39,40 Indeed, the authors deter-
mined the BDE for 3,5-di-tert-butylcatechol and R-tocopherol to
be almost identical using the EPR equilibration method (79.3
and 78.2 kcal/mol, respectively) in contradiction to some
computational studies.41
’ CONCLUSIONS
The present study demonstrates that catechol derivatives, an
important class of natural and non-natural antioxidants, are powerful
and synthetically useful reducing agents in radical chain reactions
involving organoboranes. The reaction described herein constitutes
not only a valid and attractive alternative to the use of toxic and
expensive tin hydride reagents for the reduction of alkyl radicals, but
also represents the first report of a catechol-mediated reduction able
to sustain an efficient radical chain. 4-tert-Butylcatechol, unlike tin
hydride, has low toxicity, is cheap, and is easily removed from reaction
products. Furthermore, the so far elusive rate constants for the
reduction of alkyl radicals by catechol and 4-tert-butylcatechol could
be determined. Interestingly, they are less than 1 order of magnitude
slower than tin hydride at 80 °C, making them particularly attractive
for a wide range of transformations. The rate constants measure-
ments were made possible by an unprecedented radical clock based
on an organoborane precursor. A protocol allowing the reduction of
all three alkyl groups of a trialkylborane has been developed. This
represents a formal one-pot reduction of nonactivated olefins,
showing complementary functional group tolerance to that of the
catalytic hydrogenation. Selective reduction in a system bearing
multiple insaturations is made possible by the selective hydroboration
of the desired double bond. In situ esterification also allows the
reduction of bench-stable boronic acids and esters.
Figure 1. Product ratios from reactions of cyclooct-4-enyl radical in
presence of catechol and 4-tert-butylcatechol.
of Bu3SnH to calibrate radical clocks is a well-established
procedure.44
½UHꢁ
½RHꢁ
kH
kR
¼
½XHꢁ
ð25Þ
Our first attempts to measure the rate of hydrogen atom
transfer from catechol using well established radical clocks45 such
as the 5-hexen-1-yl radical generated from the corresponding
iodide in the presence of different initiators46 only led to a
scattered distribution of points. Indeed, when treated under
these conditions, the semiquinone radical breaks the chain
process, preventing any accurate measurement. As the reaction
already proved to proceed cleanly, we decided to use B-cyclooct-
4-enylcatecholborane 2d as the substrate for the radical clock
(Scheme 3, eq 6). The reduction with 4-tert-butylcatechol is
efficient and affords a measurable mixture of products resulting
from 5-exo-trig cyclization (5d) and of direct reduction (3d). The
experiment was conducted in benzene at 80 °C using a large
excess of hydrogen atom donor (ca. 7-30 equiv) in order to
satisfy the pseudo first order conditions (Scheme 11).
’ ASSOCIATED CONTENT
1
S
Supporting Information. Experimental details; H and
b
13C NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Using the rate constant for the reduction with tributyltin
hydride from the Arrhenius equation for the trapping of the
cyclohexyl radical,47 the cyclization rate was approximated to 3.3
( 0.3 ꢀ 104 s-1 (353 K) using 4-iodocyclooctene as a radical
precursor (see the Supporting Information). The plots of
[3d]/[5d] versus [catechol] or [TBC] are shown in Figure 1.
The error limits are two standard deviations and take in account
the experimental error on the dilutions. Relative and absolute
rates are reported in Table 3. In benzene at 80 °C, the rate
constants for the reduction of cyclooctenyl radicals with catechol
and 4-tert-butylcatechol were found to be about 7 and 4 times
slower than tributyltin hydride, respectively, in accordance with
’ AUTHOR INFORMATION
Corresponding Author
philippe.renaud@ioc.unibe.ch
’ ACKNOWLEDGMENT
We thank Dr. Leigh Ford for helpful discussions, Prof. Peter
Bigler and his team for NMR measurements, BASF Corporation
for the generous donation of catecholborane, and the Swiss
National Science Foundation for financial support.
5919
dx.doi.org/10.1021/ja110224d |J. Am. Chem. Soc. 2011, 133, 5913–5920

Journal of the American Chemical Society
ARTICLE
’ REFERENCES
(1) Bradshaw, B.; Etxebarria-Jardi, G.; Bonjoch, J. Org. Biomol. Chem.
2008, 6, 772–778.
(2) Meerwein, H.; S€onke, H. J. Prakt. Chem. 1936, 147, 251–255.
(3) Goubeau, J.; Epple, R.; Ulmschneider, D.; Lehmann, H. In
Angew. Chem. 1955; Vol. 67, p 710-711.
(27) Dutta, S.; Peng, S.-M.; Bhattacharya, S. Inorg. Chem. 2000, 39,
2231–2234.
(28) Kumli, E.; Montermini, F.; Renaud, P. Org. Lett. 2006, 8, 5861–
5864.
(29) Foti, M. C.; Ingold, K. U.; Lusztyk, J. J. Am. Chem. Soc. 1994,
116, 9440–9447.
(30) Upon treatment with catechol, a triethylborane solution
evolved gas that was attributed to ethane and EtBCat was observed by
1H and 11B NMR, along with an unknown major compound (11B NMR:
δ = 56.99 ppm) that was attributed to diethyl catecholborinic ester 7.
(31) Reaction with atmospheric oxygen often prevents clean thin
layer chromatography analysis. Moreover, boron derivatives were found
highly detrimental to our GC columns and samples had to be filtered
over aluminium oxide prior to chromatography. Thus, only the disap-
pearance of the starting alkene and the formation of the reduced product
can be monitored.
(32) Brown, H. C.; Prasad, J.; Zee, S. J. Org. Chem. 1985, 50, 1582–
1589.
(33) Brown, H. C.; Cope, O. J. J. Am. Chem. Soc. 1964, 86, 1801–
1807.
(34) Brown, H. C.; Pfaffenberger, C. D. Tetrahedron 1975, 31, 925–
928.
(35) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.;
Knochel, P. J. Org. Chem. 1996, 61, 8229–8243.
(36) Franz, J. A.; Alnajjar, M. S.; Barrows, R. D.; Kaisaki, D. L.;
Camaioni, D. M.; Suleman, N. K. J. Org. Chem. 1986, 51, 1446–1456.
Franchi, P.; Lucarini, M.; Pedulli, G. F.; Valgimigli, L.; Lunelli, B. J. Am.
Chem. Soc. 1999, 121, 507–514.
(37) Foti, M. C.; Daquino, C.; Mackie, I. D.; Dilabio, G. A.; Ingold,
K. U. J. Org. Chem. 2008, 73, 9270–9282.
(38) Litwinienko, G.; Dilabio, G. A.; Mulder, P.; Korth, H.; Ingold,
K. U. J. Phys. Chem. A 2009, 113, 6275–6288. Curran, B. C. J. Am. Chem.
Soc. 1945, 67, 1835–1837.
(4) Brown, H. C.; Murray, K. J. Am. Chem. Soc. 1959, 81, 4108–4109.
Mikhailov, B. M.; Vaver, V. A. J. Gen. Chem. USSR 1961, 31, 528–530.
(5) Johnson, J. R.; Snyder, H. R.; Van Campen, M. G. J. Am. Chem.
Soc. 1938, 60, 115–121. Olah, G. A.; Westerman, P. W.; Mo, Y. K.;
Klopman, G. J. Am. Chem. Soc. 1972, 94, 7859–7862.
(6) Jones, P. R.; Lim, T. F. O. J. Organomet. Chem. 1976, 120, 27–33.
Weinheimer, A. J.; Marsico, W. E. J. Org. Chem. 1962, 27, 1926. Vasil’ev,
L. S.; Veselovskii, V. V.; Mikhailov, B. M. Bull. Acad. Sci. USSR 1977, 26,
1031–1034.
(7) K€oster, R. Angew. Chem. 1956, 68, 383. Dewitt, E. J.; Ramp, F. L.;
Trapasso, L. E. J. Am. Chem. Soc. 1961, 83, 4672. Ramp, F. L.; Dewitt,
E. J.; Trapasso, L. E. J. Org. Chem. 1962, 27, 4368–4372.
(8) Gilman, H.; Nelson, J. F. J. Am. Chem. Soc. 1937, 59, 935–937.
(9) Mikhailov, B. M.; Bubnov, Y. N. J. Gen. Chem. USSR 1961, 31,
150–155. Mikhailov, B. M.; Bubnov, Y. N. Bull. Acad. Sci. USSR 1964, 12,
2258. Mikhailov, B. M. Prog. Boron Chem. 1970, 3, 313–370.
(10) Davies, A. G.; Roberts, B. P. J. Chem. Soc. B 1971, 1830–1836.
(11) Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415–3434.
Darmency, V.; Renaud, P. Top. Curr. Chem. 2006, 263, 71–106.
(12) Baban, J. A.; Goodchild, N. J.; Roberts, B. P. J. Chem. Soc., Perkin
Trans. 2 1986, 157–161. Renaud, P.; Beauseigneur, A.; Brecht-Forster,
A.; Becattini, B.; Darmency, V.; Kandhasamy, S.; Montermini, F.;
Ollivier, C.; Panchaud, P.; Pozzi, D.; Scanlan, E. M.; Schaffner, A.-P.;
Weber, V. Pure Appl. Chem. 2007, 79, 223–233.
(13) Schaffner, A.-P.; Renaud, P. Angew. Chem., Int. Ed. 2003, 42, 2658.
(14) To avoid the undesired reduction of the B-alkylcatecholbor-
anes, we recommend quenching the excess catecholborane with tert-
butanol instead of methanol.
(15) Pozzi, D.; Scanlan, E. M.; Renaud, P. J. Am. Chem. Soc. 2005,
127, 14204–14205.
(39) Lucarini, M.; Pedulli, G. F.; Guerra, M. Chem.—Eur. J. 2004, 10,
933–939.
(40) Lucarini, M.; Mugnaini, V.; Pedulli, G. F. J. Org. Chem. 2002, 67,
928–931.
(16) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros,
M. R.; Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513–12515.
(17) Povie, G.; Villa, G.; Ford, L.; Pozzi, D.; Schiesser, C. H.;
Renaud, P. Chem. Commun. 2010, 46, 803–805.
(18) Bakalbassis, E. G.; Lithoxoidou, A. T.; Vafiadis, A. P. J. Phys.
Chem. A 2003, 107, 8594–8606. Mulder, P.; Korth, H.-G.; Pratt, D. A;
Dilabio, G. A.; Valgimigli, L.; Pedulli, G. F.; Ingold, K. U. J. Phys. Chem. A
2005, 109, 2647–2655.
(19) Kharasch, M. S.; Kawahara, F.; Nudenberg, W. J. Org. Chem.
1954, 19, 1977–1990. Ye, M.; Schuler, R. H. J. Phys. Chem. 1989, 93,
1898–1902. Jonsson, M.; Lind, J.; Reitberger, T.; Eriksen, T. E.;
Merenyi, G. J. Phys. Chem. 1993, 97, 8229–8233. Valgimigli, L.; Amorati,
R.; Fumo, M. G.; Dilabio, G. A.; Pedulli, G. F.; Ingold, K. U.; Pratt, D. A.
J. Org. Chem. 2008, 73, 1830–1841; Land, E. J. Chem. Soc., Faraday Trans.
1993, 89, 803–810.
(20) Ollivier, C.; Chuard, R.; Renaud, P. Synlett 1999, 9807.
(21) 4-tert-Butylcatechol (Aldrich catalog number 124249, as of
October 2010) costs $73.50 for 500 g and has a LD50 of 2 g/kg.
(22) Kiefer, H.; Traylor, T. Tetrahedron Lett. 1966, 6163.
Boukouvalas, J.; Cren, S.; Renaud, P. e-EROS Encyclopedia of Reagents
for Organic Synthesis; John Wiley & Sons: Chichester, 2007.
(23) The corresponding alcohols never exceeded 2% of the product,
and generally only traces can be observed in GC MS analysis.
(24) Garrett, C. E.; Fu, G. C. J. Org. Chem. 1996, 61, 3224–3225.
(25) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992,
114, 6671–6679.
(41) Zhang, H.; Sun, Y. M.; Wang, X. Chem.—Eur. J. 2003, 9, 502–
508. Zhang, H. New J. Chem. 2003, 27, 453–454. Zhang, H. New J. Chem.
2004, 28, 1284–1285.
(42) Sun, Y. M.; Cheng-Bu, L. Eur. J. Org. Chem. 2004, 120–128.
Lithoxoidou, A. T.; Bakalbassis, E. G. J. Phys. Chem. A 2005, 109, 366–
377. Tejero, I.; Gonzalez-Garcia, N.; Gonzalez-Lafont, A.; Lluch, J. M. J.
Am. Chem. Soc. 2007, 129, 5846–5854.
(43) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317–323.
(44) Newcomb, M. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; WILEY-VCH Verlag GmbH: Weinheim, 2001; Vol. 1, pp
317-336.
(45) Evans, C.; Scaiano, J. C.; Ingold, K. U. J. Am. Chem. Soc. 1992,
114, 4589–4593.
(46) Preliminary experiments using 4-cyclooctenyl iodide and UV
initiation, Bu6Sn2/DTBHN, or DLP always led to irreproducible results.
(47) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc.
1981, 103, 7739–7742.
(26) Other radical processes involving B-alkylcatecholboranes gen-
erated in situ by a rhodium catalyzed hydroboration have been reported,
see: Renaud, P.; Ollivier, C.; Weber, V. J. Org. Chem. 2003, 68, 5769–
5772. Schaffner, A.-P.; Montermini, F.; Pozzi, D.; Darmency, V.;
Scanlan, E. M.; Renaud, P. Adv. Synth. Catal. 2008, 350, 1163–1167.
5920
dx.doi.org/10.1021/ja110224d |J. Am. Chem. Soc. 2011, 133, 5913–5920