Radical addition to 1,4-benzoquinones: Addition at O- versus C-atom

Article abstract of DOI:10.1021/ol0624629

(Diagram presented) Addition of alkyl radicals generated from B-alkylcatecholboranes onto 1,4-benzoquinones leads to substituted hydroquinones in good overall yields. Formation of aryl ethers via a unique radical addition to the oxygen atom of the enone system is the main reaction when bulky secondary and tertiary alkyl radicals are used. Less hindered secondary and primary radicals give the expected 1,4-conjugate addition products.

Full text of DOI:10.1021/ol0624629

ORGANIC
LETTERS
2
006
Vol. 8, No. 25
861-5864
Radical Addition to 1,4-Benzoquinones:
Addition at O- versus C-Atom
5
Eveline Kumli, Florian Montermini, and Philippe Renaud*
UniVersity of Berne, Department of Chemistry and Biochemistry, Freiestrasse 3,
3012 Berne, Switzerland
philippe.renaud@ioc.unibe.ch
Received October 6, 2006
ABSTRACT
Addition of alkyl radicals generated from B-alkylcatecholboranes onto 1,4-benzoquinones leads to substituted hydroquinones in good overall
yields. Formation of aryl ethers via a unique radical addition to the oxygen atom of the enone system is the main reaction when bulky
secondary and tertiary alkyl radicals are used. Less hindered secondary and primary radicals give the expected 1,4-conjugate addition products.
In the last decades, numerous applications of radical chem-
istry were described in organic synthesis taking advantage
of the formation of carbon-carbon bonds under mild reaction
trialkylborane approach only one out of the three alkyl groups
is transferred. Therefore, the method is restricted to trialkyl-
boranes obtained by hydroboration of easily available and
cheap alkenes.
1
conditions. Organoboranes are reactive radical precursors
that can be employed for a wide range of radical reactions
involving primary, secondary, and tertiary alkyl radicals.
Recently, we have demonstrated that 2-alkylbenzo[d]-
[1,3,2]dioxaboroles (B-alkylcatecholboranes), easily available
by hydroboration of alkenes, are excellent radical precursors.6
For instance, we have reported a modified version of the
conjugate addition of organoboranes to enones and enals
2
2-Substituted hydroquinones and benzoquinones are com-
mon subunits in biologically active secondary metabolites.
Incorporation of this framework during the synthesis of
natural products remains a challenging problem. In our
studies toward the total synthesis of frondosin A and B
7
originally developed by Brown and Negishi. This procedure
involves the hydroboration of an alkene with catecholborane
followed by addition to an R,â-unsaturated ketone or
aldehyde in the presence of oxygen to initiate the radical
(Figure 1), we became interested in developing efficient
procedures to introduce such aromatic moieties.
Preparative conjugate addition of radicals onto 1,4-
3
benzoquinone derivatives is described in the literature. From
a synthetic point of view, addition of radicals generated via
4
decarboxylation of 2-pyridinethione derivatives and from
5
trialkylboranes is the most promising. However, in the
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, Germany, 2001; Vols. 1 and 2. (b) Giese, B.
Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergamon Press: Oxford, UK, 1986. (c) Zard, S. AdVances in Free Radical
Chemistry; Oxford University Press: Oxford, UK, 2003.
(
2) Ollivier, C.; Renaud, P. Chem. ReV. 2001, 101, 3415-3434. Darm-
ency, V.; Renaud, P. Top. Curr. Chem. 2006, 263, 71-106.
3) Barton, D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron 1987, 43,
307-5314 and references therein.
(
Figure 1. Sesquiterpene hydroquinones frondosin A and B
5
1
0.1021/ol0624629 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/08/2006

8
process. Primary, secondary, and tertiary alkyl groups are
efficiently added to R,â-unsaturated aldehydes and ketones
that are unsubstituted or monosubstituted at the â-position.
We describe here our effort to extend this chemistry to 1,4-
benzoquinones. An astonishing radical addition to the oxygen
atom of 1,4-benzoquinones is reported.
Table 1. Addition of B-Alkylcatecholborane to
1,4-Benzoquinone According to Eq 1
B-Alkylcatecholboranes are easily obtained by hydrobo-
9
ration of olefins with commercially available catecholborane.
The reaction conditions were optimized by using cyclohexene
2c (Scheme 1). Using 2 equiv of B-alkylcatecholborane
Scheme 1. Hydroboration and Subsequent in Situ Radical
Addition to 1,4-Benzoquinone
a
Isolated yields. b Hydroboration catalyzed by Me2NCOMe. c Hydrobo-
ration catalyzed by (Ph3P)3RhCl.
cyclohexene (entry 3) results in the formation 2-cyclohexyl-
1
,4-hydroquinone 3c in 74% yield (entry 3). The reaction
with R-pinene gives the expected hydroquinone 3d in 36%
accompanied by the aryl ether 4d in 39% yield (entry 4). A
similar result is obtained with styrene when the hydroboration
is catalyzed by the Wilkinson’s catalyst (entry 5). The aryl
ether 4e is the major product (61%) and the conjugate
addition product 3e is only formed in 9% yield. The tertiary
thexyl radical generated from 2,3-dimethylbut-2-ene 2f (entry
generated in situ by N,N-dimethylacetamide catalyzed hy-
droboration and 1 equiv of 1,4-benzoquinone turned out to
be the best conditions for this transformation. Under these
reaction conditions, oxidation of the 2-cyclohexyl-1,4-
hydroquinone 3c to the corresponding substituted 1,4-quinone
derivative could be prevented.10 The desired 2-cyclohexyl-
6
(
) affords the aryl ether 4f (60% yield) together with 3f
16%).
The reaction was also tested with duroquinone () 2,3,5,6-
1,4-hydroquinone 3c was produced in 93% yield (NMR
yield, separation of the product from catechol was not
attempted at this stage, see Table 1 entry 3 for the isolated
yield). The reactions were run under nitrogen and no extra
addition of oxygen was necessary to initiate the reaction
tetramethylbenzoquinone) (Scheme 2). Reaction with B-
cyclohexylcatecholborane does not afford any identified
addition product. Interestingly, B-thexylcatecholborane ()
thexyl ) 2,3-dimethylbut-2-yl ) 1,1,2,2-tetramethylethyl)
gives the O-addition product in 80% yield as the only
identified product.
(Scheme 1).
Reactions with several alkenes according to eq 1 were
A radical mechanism is expected for the formation of the
C-addition product in analogy to the work of Brown on
conjugate addition of trialkylboranes to enones2 as well
,11
(
5) (a) Hawthorne, M. F.; Reintjes, M. J. Am. Chem. Soc. 1964, 86, 951.
b) Hawthorne, M. F.; Reintjes, M. J. Am. Chem. Soc. 1965, 87, 4585-
587. (c) Kabalka, G. W. J. Organomet. Chem. 1971, 33, C25-C28. (d)
Bieber, L. W.; Rolim Neto, P. J.; Generino, R. M. Tetrahedron Lett. 1999,
(
4
4
3
1
0, 4473-4476.
investigated next. The results are summarized in Table 1.
The addition of primary radicals derived from 1-octene 2a
and â-pinene 2b (entries 1 and 2) onto 1,4-benzoquinone
affords the expected 2-alkylated 1,4-hydroquinones 3a and
(6) Schaffner, A.-P.; Renaud, P. Eur. J. Org. Chem. 2004, 2291-2298.
(
7) Brown, H. C.; Negishi, E.-I. J. Am. Chem. Soc. 1971, 93, 3777-
779.
(
8) Ollivier, C.; Renaud, P. Chem. Eur. J. 1999, 5, 1468-1473.
(9) Catalysis by Me2NCOMe: Garrett, C. E.; Fu, G. C. J. Org. Chem.
996, 61, 3224-3225. Catalysis with Wilkinson’s catalyst: Zhang, J.; Lou,
3b in 72% and 95% yield, respectively. Reaction with
B.; Guo, G.; Dai, L. J. Org. Chem. 1991, 56, 1670-1672.
(10) 1,4-Benzoquinone oxidizes substituted 1,4-hydroquinone derivatives.
(
4) See ref 3 and: (a) Barton, D. H. R.; Sas, W. Tetrahedron 1990, 46,
This oxidation occurs due to a lower oxidation potential of the substituted
quinones compared to the one of their nonsubstituted counterparts. For
reviews on this topic see: (a) The Chemistry of the Quinonoid Compounds;
Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1988; Vols. 1 and 2. (b)
Naturally Occurring Quinones IV: Recent AdVances, 4th ed.; Thomson, R.
H., Ed.; Blackie Academic & Professional: London, UK, 1997.
3
419-3430. (b) Ling, T.; Poupon, E.; Rueden, E. J.; Kim, S. H.;
Theodorakis, E. A. J. Am. Chem. Soc. 2002, 124, 12261-12267. (c) Ling,
T.; Xiang, A. X.; Theodorakis, E. A. Angew. Chem., Int. Ed. 1999, 38,
3
2
089-3091. (d) Yamago, S.; Hashidume, M.; Yoshida, J.-i. Tetrahedron
002, 58, 6805-6813.
5862
Org. Lett., Vol. 8, No. 25, 2006

Scheme 2. Addition of B-Alkylcatecholboranes to
Scheme 3. Reaction of the Radical Probe 2-Carene 8 with
1,4-Benzoquinone 1 and Duroquinone 5
Duroquinone
6
as our related work starting with B-alkylcatechoboranes. In
both reactions, no addition of initiator such as oxygen was
necessary when an efficient radical trap such as a vinyl
ketone was used. Traces of oxygen coming presumably from
the solvent were sufficient to initiate the reaction. Since 1,4-
benzoquinone is a particularly reactive radical trap, we
expected the same phenomenon to occur since no extra
oxygen was added for the reaction described in eq 1 (Table
such an activation should favor the addition at the more
hindered C1 carbonyl group. However, reversible com-
plexation of both carbonyl group cannot be excluded.14
1
3
1). Several attempts to run the reaction starting from R-pinene
2
d under oxygen free conditions with carefully degassed
solvents and reagents in a glove box afforded the reaction
products 3d and 4d in similar yield and ratio as the ones
reported in Table 1 (entry 4). This indicates that either the
reaction does not involve a radical intermediate or that a
minute amount of oxygen is sufficient to initiate a particularly
efficient radical chain process. Another type of radical
initiation involving for example a single electron-transfer
process cannot be excluded at the moment. The radical nature
of the mechanism was further investigated by running a
reaction with (+)-2-carene 8, a well-established radical probe
Scheme 4. Addition of B-Alkylcatecholboranes to
Bischlorinated Quinones
1
2
for reactions involving B-alkylcatecholborane derivatives.
Hydroboration of (+)-2-carene 8 followed by addition to 1,4-
benzoquinone 1 and duroquinone 5 under our standard
reaction conditions affords the aryl ethers 9 and 10 as
exclusive product in 69% and 78% yield, respectively
(Scheme 3). Compounds 9 and 10 result from a ring opening
of the cyclopropyl ring demonstrating the presence of radical
intermediates. The ring-opening process does not occur under
non-radical conditions such as for instance the oxidative
treatment with alkaline hydrogen peroxide.12
The reaction proceeds similarly with substituted 1,4-
benzoquinone derivatives. By adding the cyclohexyl radical
onto 2,6-dichloro-1,4-benzoquinone 11, a clean addition at
the carbon atom could be observed that gives the hydro-
quinone 12 in 72% yield (Scheme 4). Reaction of 11 with
B-thexylcatecholborane affords the O-addition product 13
in 41% yield as the major and only isolated product. The
regioselectivity of this reaction, i.e., addition at the less
substituted C4-carbonyl group, supports a radical mechanism
where no activation of 1,4-benzoquinone by complexation
of the carbonyl group by the organoborane is occurring since
Addition of B-thexylcatecholborane to 2,5-dichloro-1,4-
benzoquinone 14 gives the O-addition product 15 in 46%
yield. The similarity of product distribution between the
reaction of benzoquinone 1 and dichlorobenzoquinones 11
and 14 supports further a radical mechanism for the formation
of O- and C-addition products. Indeed, a plausible electron-
(
11) Brown, H. C.; Midland, M. M. Angew. Chem., Int. Ed. 1972, 11,
92-700.
12) We have established that its hydroboration followed by an oxidative
(13) Reaction of alkylaluminum dichlorides with 1,4-quinones gives aryl
ethers via a radical-radical coupling process. Complexation of the carbonyl
oxygen atom by aluminum is occurring in this particular case: Florjanczyk,
Z.; Szymanska-Zachara, E. J. Organomet. Chem. 1983, 259, 127-137.
(14) Such a complexation during the addition of trialklyboranes to enones
has been proposed: Beraud, V.; Gnanou, Y.; Walton, J. C.; Maillard, B.
Tetrahedron Lett. 2000, 41, 1195-1198.
6
(
treatment with alkaline hydrogen peroxide leads to the corresponding
alcohols without opening of the cyclopropane ring: Cadot, C.; Dalko, P.
I.; Cossy, J.; Ollivier, C.; Chuard, R.; Renaud, P. J. Org. Chem. 2002, 67,
7
193-7202.
Org. Lett., Vol. 8, No. 25, 2006
5863

transfer mechanism leading to the aryl ether and involving
formation of a carbenium ion should have been favored with
the bischlorinated quinones since they are better oxidants
than non-chlorinated quinones.
Scheme 5. Proposed Mechanism for the Addition of
B-Alkylcatecholborane to 1,4-Benzoquinone
Since the conversion of 11 to 13 suggests that the reaction
is a simple radical addition to the noncomplexed 1,4-
benzoquinone, we decided to investigate the reaction of the
Barton ester derived from pivalic acid with 1,4-benzoquinone
1
(see the Supporting Information for experimental details).
Under our reaction conditions (excess of the Barton ester
relative to the quinone), no product of C-addition was isolated
and only 4-tert-butoxyphenol resulting from the addition at
the oxygen atom was obtained in low yield (24%). This
observation supports our assumption that complexation of
the quinone by the organoboron compound is not required
for the addition at the oxygen atom of a quinone. The low
yield of the Barton ester reaction results presumably from
the lack of an efficient propagation step. The mechanistic
details of this low-yielding transformation have not been
further examined.
•
boronphenolate and the alkyl radical R . Hydrolysis of the
boronphenolates affords the hydroquinone 3 and the aryl
ether 4.
In conclusion, addition of alkyl radicals generated from
B-alkylcatecholboranes onto 1,4-benzoquinones leads to
substituted hydroquinone derivatives in good overall yield.
Formation of aryl ethers via a unique radical addition to the
oxygen atom of the enone system is the main reaction when
bulky secondary and tertiary alkyl radicals are used. Less
hindered secondary and primary residues give the normal
1,4-conjugate addition products. The unexpected C-O bond-
forming reaction represents an interesting and unique pro-
cedure for the conversion of organoboranes to aryl ethers.
On the basis of these results, a possible reaction mecha-
nism rationalizing the formation of C- and O-addition
products during the addition of B-alkylcatecholboranes to
quinones is depicted in Scheme 5. The quinone reacts with
an alkyl radical via either O-addition (Pathway A, 1,6-
1
5,16
addition) or C-addition (Pathway B, 1,4-addition).
The
radical adducts react rapidly with R-BCat to produce a
(15) Addition of acyl radicals to carbonyl oxygen atom is reported in
the literature: (a) Urry, W. H.; Nishihara, A.; Niu, J. H. Y. J. Org. Chem.
1
1
1
1
967, 32, 347-352. (b) Kuivila, H. G.; Walsh, E. J., Jr. J. Am. Chem. Soc.
966, 88, 571-576. (c) Kuivila, H. G.; Walsh, E. J., Jr. J. Am. Chem. Soc.
966, 88, 576-581. (d) Kaplan, L. J. Am. Chem. Soc. 1966, 88, 1833-
834.
Acknowledgment. We thank the Swiss National Science
Foundation (Project 20-103627) for financial support and
BASF Corporation for the gift of catecholborane.
(16) See ref 13 and: Ferreira, V. F.; Schmitz, F. J. J. Organomet. Chem.
1
998, 571, 1-6. Addition of the 2-cyano-2-propyl radical generated by
Supporting Information Available: Experimental pro-
cedures and product characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
thermal decomposition of AIBN to 1,4-benzoquinone has been described
and formation of aryl ethers via either C-addition followed by a rearrange-
ment or via direct O-addition has been postulated: Giorgini, E.; Tommasi,
G.; Stipa, P.; Tosi, G.; Littarru, G.; Greci, L. Free Radical Res. 2001, 35,
63-72. See also: Buckley, R. P.; Rembaum, A.; Swarc, M. J. Chem. Soc.
1958, 3442. Simandi, T. L.; Rockenbauer, A.; Simandi, L. Eur. Polym. J.
1995, 31, 555-558.
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Org. Lett., Vol. 8, No. 25, 2006