Reductive alkylation of p-benzoquinone using mixed organoboranes

Article abstract of DOI:10.1016/j.tetlet.2010.03.096

Mixed organoboranes based on diphenyl- or dimethylalkylboranes transfer the alkyl group in the reductive alkylation of p-benzoquinone to form the alkylhydroquinones in very high yields. The auxiliary groups do not transfer or have a low migratory aptitude. Primary and secondary alkyl groups are transferred with retention of regio- and stereochemistry to the hydroquinone. O-Alkylation is the major product with tertiary and secondary groups with steric bulk in proximity to the site of attachment. The presence of metal salts, such as magnesium, results in reduction to the unsubstituted hydroquinone. This reaction makes the first practical route to alkylhydroquinones via organoboranes.

Full text of DOI:10.1016/j.tetlet.2010.03.096

Tetrahedron Letters 51 (2010) 3033–3036
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reductive alkylation of p-benzoquinone using mixed organoboranes
*
David J. Zillman, Gloria C. Hincapié, M. Reza Savari, Farhad G. Mizori, Thomas E. Cole
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Mixed organoboranes based on diphenyl- or dimethylalkylboranes transfer the alkyl group in the reduc-
tive alkylation of p-benzoquinone to form the alkylhydroquinones in very high yields. The auxiliary
groups do not transfer or have a low migratory aptitude. Primary and secondary alkyl groups are trans-
ferred with retention of regio- and stereochemistry to the hydroquinone. O-Alkylation is the major prod-
uct with tertiary and secondary groups with steric bulk in proximity to the site of attachment. The
presence of metal salts, such as magnesium, results in reduction to the unsubstituted hydroquinone. This
reaction makes the first practical route to alkylhydroquinones via organoboranes.
Received 17 December 2009
Revised 19 March 2010
Accepted 23 March 2010
Available online 27 March 2010
Keywords:
p-Benzoquinone
Hydroquinones
Reductive alkylation
Organoboranes
Alkyldimethylboranes
Ó 2010 Elsevier Ltd. All rights reserved.
Substituted hydroquinones and the related quinones are found
extensively in nature and many have important biological activ-
ity.1 Relatively few general methods exist for the formation of
the crucial carbon–carbon bond between the ring and alkyl carbon.
Most techniques depend on the oxidation of substituted phenols to
p-benzoquinone, the majority of which form mixtures or at best re-
sult in moderate yields.2 The Stille and Suzuki reactions give im-
proved carbon–carbon bond formation; they are versatile and
tolerant of a wide variety of functional groups, but are essentially
restricted to aryl and vinyl groups for good to high yields.3,4 Qui-
none or hydroquinone derivatives have been prepared to a limited
extent by these metal-catalyzed reactions. The limitations of these
reactions include the synthesis of the aryl- and vinyl-boranes, as
well as the tin reagents. In addition, the toxicity of the latter, even
at trace levels, along with the difficulty of removing the palladium
catalysts, is a concern in biological and medicinal applications.
Moreover, the palladium ligands and co-catalysts usually require
reaction condition optimization in order to maximize yields. While
promising, these two reactions are not applicable to secondary al-
kyl groups and give reduced yields for primary alkyl groups.
Hawthorne and Reintjes discovered one of the first organobora-
ne reactions after the discovery of hydroboration, the reductive
alkylation of quinone using symmetrical trialkylboranes.5,6 The al-
kyl hydroquinone products were rapidly formed in essentially
quantitative yield. Kabalka noted the similarities of this reaction
ferring only one alkyl group.7 As in the 1,4-addition, Kabalka found
that the reductive alkylation of p-benzoquinone resulted in the for-
mation of a mixture of isomeric alkyl hydroquinone products.8 This
was attributed to the higher migratory aptitude of the more substi-
tuted alkyl groups. While the regioselectivity in the hydroboration
of 1-alkenes using BH3ÁTHF is approximately 94:6, primary to sec-
ondary, the majority of the secondary alkyl groups were preferen-
tially transferred, giving approximately 16% of the isomeric
hydroquinone product (Scheme 1). This regioselectivity decreases
in proximity of the alkene to many of the functional groups due
to directive effects. Although substituted hydroborating agents,
such as 9-BBN, disiamyl, and dicyclohexylborane, give higher reg-
ioselectivities, these hydroborating reagents are based on second-
to the 1,4-addition of organoboranes to a,b-unsaturated aldehydes
and ketones, in which both reactions had radical character, trans-
* Corresponding author. Tel.: +1 619 594 5579; fax: +1 619 594 4634.
E-mail address: tcole@sciences.sdsu.edu (T.E. Cole).
Scheme 1. Isomeric products formed with trihexylborane.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.096

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D. J. Zillman et al. / Tetrahedron Letters 51 (2010) 3033–3036
ary alkyl auxiliary groups. These auxiliary groups transfer compet-
itively or faster than the desired group. Only one alkyl group of a
trialkylborane is transferred in the reductive alkylation of p-benzo-
quinone. This results in the loss of two potentially valuable alkyl
groups in reactions with symmetrical trialkylboranes. Separation
of the formed borinic acids, especially those with larger alkyl
groups, using either steam distillation or oxidation presents addi-
tional problems. The borinic acids generate radicals on exposure
to air, which are trapped by the hydroquinone product, forming a
tarry product. This complicates isolation and lowers the purity
and yields of the alkylated hydroquinone products. It is for these
reasons that this reaction has not found widespread application.
More recently, Renaud and co-workers demonstrated the reduc-
tive alkylation of p-benzoquinone using B-alkylcatecholboranes,
forming the corresponding alkylhydroquinones in moderate to
excellent yields.9 The N,N-dimethylacetamide-catalyzed hydrobo-
rations using catecholborane gave lower regioselectivity than cate-
cholborane, approximating that of BH3.10 This resulted in an
isomeric mixture of alkylhydroquinone products. In addition, a
100 mol % excess of the alkylcatecholborane was used. Renaud
found that increasing amounts of alkyl–aryl ether products were
formed with increasing steric bulk about the boron–carbon bond.
This O-alkylation was the dominant product with tertiary alkyl cate-
cholboranes. Overall, Renaud’s results represented a significant
improvement for the reductive alkylation of p-benzoquinone. We
have been exploring new routes to mixed organoboranes, which
may permit the development of the reductive alkylation of p-benzo-
quinone using organoboranes into a more versatile and valuable
reaction.
cal characteristics suggest that the methyl group may also serve as
a suitable auxiliary group for these reactions. There are several
routes that can be used to prepare alkyldimethylboranes.
In this study, we chose dichloroborane as the hydroborating
agent, since it is one of the most regioselective hydroborating
agents, giving P99% of the 1-alkyl group for terminal alkenes.12
The chlorines can be replaced with methyl groups, yielding the
alkyldimethylborane. Matteson’s procedure for the in situ genera-
tion of dichloroborane gave excellent selectivities in forming the
alkyldichloroborane, P96%.13 This method is superior to the coor-
dinated dichloroborane reagents, HBCl2ÁL, which require an equiv-
alent of boron trichloride to remove the ligand.14 In addition, the
presence of boron trichloride potentially complicates the methyla-
tion of the alkyldichloroborane.
Addition of a triethylsilane and 1-hexene mixture to boron tri-
chloride cleanly yielded the 1-hexyldichloroborane. The boron
NMR analysis of the methanolyzed reaction mixture showed a
greater than 98% selectivity in the formation of the alkyldichlorob-
orane, with approximately equal amounts of dihexylchloroborane
and boron trichloride. The 1-hexyldichloroborane solution was
then added to 2 equiv of methylmagnesium bromide in THF/Et2O.
The ratio of alkylmethylboranes can be readily determined from
the 11B NMR spectrum. Tetrahydrofuran complexes to the methyl-
boranes, shifting their resonance signals upfield proportional to the
number of methyl groups. These ratios of the methylboranes were
essentially identical to the purity of the alkylchloroboranes, show-
ing very little, if any, redistribution. By contrast, the addition of the
methyl Grignard reagent in Et2O to the hexyldichloroborane re-
sulted in significant amount of redistribution, forming ca.
20 mol % each of trimethyl- and dihexylmethylborane.15
Hawthorne’s observation that triphenylborane did not react with
p-benzoquinone suggests that the phenyl group may be a suitable
auxiliary group for these reductive alkylations using mixed organo-
boranes, Ph2BR. Earlier attempts to prepare mixed arylalkylboranes
generally gave little of the expected product, mainly forming the dis-
proportionation products, symmetrical triphenyl- and trialkylbor-
anes. Recently, we have developed a successful preparation of
alkyldiphenylboranes using the transmetallation of alkyl groups
from a zirconocene complex to diphenylchloroborane.11 The alkyl-
zirconocene chloride is formed by the hydrozirconation of the corre-
sponding alkene using Schwartz’s reagent. The alkyl group is formed
with high regioselectivity, giving >99.6% in the terminal position for
1-alkenes. The addition of 1 equiv of 1-hexyldiphenylborane to a
quinone solution showed a rapid disappearance of its yellow color.
The diphenylborinic acid was precipitated by complexation with
ethanolamine. The solvent was removed and the crude hexylhydro-
quinone product was recrystallized in a 59% yield (Scheme. 2). The
proton NMR showed only mono-alkylation with no detectable pres-
ence of phenylhydroquinone. While other alkyldiphenylboranes can
also be used for the reductive alkylation of p-benzoquinone, the
types of alkyl groups that can be cleanly formed by hydrozirconation
are limited.
The addition of p-benzoquinone to the above-mentioned
alkyldimethylborane solution, containing magnesium salts, re-
sulted mainly in the reduction of the quinone, forming >80% of
the non-alkylated hydroquinone. Washing of the alkyldimethylbo-
rane solution with water, 4 Â 10 mL, before the addition of p-
benzoquinone, reduced the amount of hydroquinone to less than
5%. The dropwise addition of a ca. 1 M THF solution of p-benzoqui-
none at room temperature showed a fast disappearance of its yel-
low color until about 95 mol % or more had been added. The boron
NMR spectrum showed quantitative formation of the borinic acid
as seen at 52 ppm. The volatile dimethylborinic acid and solvents
were removed under vacuum to give an off-white crude product.
The proton NMR showed 64 mol % hydroquinone (6.72 ppm), trace
amounts of methylhydroquinone (2.12 ppm) and 95 mol % hexyl-
hydroquinone. The hydroquinone was removed in a water wash
and the product 1c was purified by column chromatography and
recrystallized from hexane–ethyl acetate to give a 94% yield 1c,
Table 1. The reaction of trimethylborane and p-benzoquinone un-
der essentially identical conditions was considerably slower, tak-
ing at least 2 h to react with the p-benzoquinone. Analysis of the
products showed little of the expected methylhydroquinone prod-
uct, ca. 615%, and the formation of a complex mixture of uniden-
tified products. Thus, indicating that the methyl group will be a
valuable auxiliary.
The migratory aptitudes shown for this reaction, the related 1,4-
addition to a,b-unsaturated aldehydes and ketones and their radi-
Other primary alkyl groups, such as (4-cyclohexenylethyl)-2c
and (2-phenylpropyl) 3c give 88% and 84% yields of the correspond-
ing alkylated hydroquinone products. Secondary alkyl groups, such
as cyclohexyl, are cleanly transferred in the reductive alkylation
forming cyclohexylhydroquinone 4c in an isolated yield of 93%.
While this reductive alkylation reaction has radical character, it is
important to establish whether this affects the stereochemically de-
fined alkyl groups. The hydroboration of norbornene with dichlo-
roborane forms the exo isomer with a selectivity of 99.5%.16 The
reductive alkylation of quinone with (exo)-norbornyldimethylbora-
ne proceeds smoothly to give an isolated yield of 73% of the (exo)-
norbornylhydroquinone 5c. A proton NMR analysis of the crude
Scheme 2. Reductive alkylation of quinone using hexyldiphenylborane.

D. J. Zillman et al. / Tetrahedron Letters 51 (2010) 3033–3036
3035
Table 1
signals for the trifluoromethyl group gave an 89.9% de. All of these
values are within experimental error indicating little, if any, loss of
chirality on transfer of the isopinocampheyl group.
Yields of 2-alkyl-hydroquinones via reductive alkylation using mixed organoboranesa
The reaction of 1,1,2-trimethylpropyldimethylborane (dim-
ethylthexylborane) gave little thexylhydroquinone, 22%, while
O-alkylation was the dominant product, 78%, as reported by Re-
naud.9 We did not further investigate the reductive alkylations of
tertiary-alkyldimethylboranes since there are a limited number
of tertiary alkylboranes that can be formed and the low yields of
the alkylated hydroquinones. The amount of O-alkylation appears
to be dependent on the steric bulk in proximity to the boron–car-
bon bond. All the primary and the secondary alkyl groups, cyclo-
hexyl- and (exo)-norbornyl 1–5, gave only trace amounts, <1%, of
O-alkylated ether product. These aryl–alkyl ethers are observed
slightly downfield, as a symmetric multiplet, from the hydroqui-
none product. Increasing steric bulk in the proximity of the boron
attachment in the (trans)-2-methylcyclohexyl- and isopinocamp-
heyl- groups gave increasing amounts of O-alkylation, 14% 6o
and 41% 7o, respectively. The methylcyclohexyl group gave both
trans and cis O-alkylation products in a 77:23 ratio. These ratios
are in agreement with calculated energies for both the C- and O-
alkylation products. On the other hand, the stereochemistry of
the isopinocampheyl group was completely retained for both C-
and O-alkylation.
Entry
Alkyl group
%Yieldb
c
%Yieldb
o
1
2
3
4
5
6
1-Hexyl-
1c, 59,c 94
2c, 88
3c, 84
4c, 93
5c, 73
6c, 65d
94:6
1o, Trace
2o, Trace
3o, Trace
4o, Trace
5o, Trace
6o, 14d
2-Ethylcyclohex-3-enyl-
2-Phenylpropyl-
Cyclohexyl-
(exo)-Norbornyl-
2-Methylcyclohexyl-
trans:cis
77:23
7o, 41
7
(+)-Isopinocampheyl-
7c, 42
a
All reactions were carried out under an inert nitrogen atmosphere using the
typical reaction procedure.20
b
Yield of isolated products.
Yield based on diphenyl-1-hexylborane.
c
d
These products were isolated as a mixture and their ratios were determined by
1H NMR spectroscopic data.
In conclusion, high yields of primary and secondary alkyl hydro-
quinones are obtained in the reductive alkylation of p-benzoqui-
none using alkyldimethylboranes. There is little, if any, migration
of the methyl auxiliary group. The corresponding borinic acids
can readily be removed from the reaction mixture resulting in im-
proved product purity and yields. O-alkylation becomes more sig-
nificant with increasing bulk about the boron–carbon bond and can
result in a loss of stereochemistry.
product mixture showed no signals at ca. 3.2 ppm, for the endo iso-
mer. This result is similar to that observed in earlier 1,4-additions
studies.17 The X-ray structure, Figure 1, indicates the (exo)-norbor-
nylhydroquinone product.18 The hydroboration of 1-methylcyclo-
hexene yields, with high stereoselectivity, the trans-2-methyl
cyclohexylborane via the syn addition of dichloroborane. Methyla-
tion of the alkyldichloroborane followed by reaction with quinone
gave two isomeric products in a 94:6 ratio with an overall yield of
65% for trans-6c and cis-6c. These ratios are consistent with those
based on mechanics or semi-empirical calculations. The hydrobora-
Acknowledgments
tion of 88% ee (+) a
-pinene19 with dichloroborane, methylation, and
We thank the San Diego Foundation, Blasker Foundation for
financial support of this project. We also acknowledge Professor
Carl Carrano and Mr. Justin Hoffman for the characterization of
the X-ray structure of the (exo)-norbornylhydroquinone. We also
thank Drs. Ratnasamy Somanathan and LeRoy Lafferty for their
valuable assistance in the NMR and stereochemical determination
of the products. Finally, we dedicate this research to Dr. Clinton
Lane whose contributions and encouragement will be missed by
many.
the reductive alkylation of p-benzoquinone gave the 2-isopino-
campheylhydroquinone 7c in a 42% isolated yield as a single isomer
in this sterically biased group. The optical purity was determined by
converting the purified hydroquinone product to the 4-pivaloyl
mono ester then reacting with the S-(+)-MTPA-Cl. The ratios of the
diastereomeric NMR proton signals for the methoxy, hydroquinone,
and phenyl groups gave an 88.2% de average while the 19F NMR
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.096.
References and notes
1. Thomson, R. H. Naturally Occurring Quinones IV: Recent Advances, 4th ed.;
Chapman and Hall: London, UK, 1997. Chapter 1, pp 1–111.
2. Owton, W. M. J. Chem. Soc., Perkin Trans. 1 1999, 2409–2420.
3. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524.
4. Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168.
5. Hawthorne, M. F.; Reintjes, M. J. Am. Chem. Soc. 1964, 86, 951.
6. Hawthorne, M. F.; Reintjes, M. J. Am. Chem. Soc. 1965, 87, 4585–4587.
7. Kabalka, G. W. J. Organomet. Chem. 1971, 33, C25–C28.
8. Kabalka, G. W. Tetrahedron 1973, 29, 1159–1162.
9. Kumli, E.; Montermini, F.; Renaud, P. Org. Lett. 2006, 8, 5861–5864.
10. Garrett, C. E.; Fu, G. C. J. Org. Chem. 1996, 61, 3224–3225.
11. Mizori, Farhad G. Ph.D. Disseration, University of California, San Diego and San
Diego State University, 2004.
12. Brown, H. C.; Racherla, U. S. J. Org. Chem. 1986, 51, 895–897.
13. Soundararajan, R.; Matteson, D. S. Organometallics 1995, 14, 4157–4166.
14. Zaidlewicz, M.; Kanth, J. V. B.; Brown, H. C. J. Org. Chem. 2000, 65, 6697–6709.
15. Manuscript in preparation.
16. Brown, H. C.; Ravindran, N. J. Org. Chem. 1977, 42, 2533–2534.
Figure 1. ORTEP drawing of 5c.

3036
D. J. Zillman et al. / Tetrahedron Letters 51 (2010) 3033–3036
17. Suzuki, A.; Arase, A.; Matsumoto, H.; Itoh, M.; Brown, H. C.; Rogic, M.; Rathke,
M. W. J. Am. Chem. Soc. 1967, 89, 5708–5709.
18. The crystal of 5c has been deposited in CCDC with number 719666. Empirical
formula: C13H16O2; formula weight: 204.26; crystal size: 0.8 Â 0.1 Â 0.1 mm;
crystal color, habit: colorless, prismatic; crystal system: tetragonal;
washing with water (4 Â 10 mL). A solution of 4.75 mmol p-benzoquinone
dissolved in THF was added dropwise by syringe at room temperature and
stirred for 30 min. Solvents and Me2BOH were removed under vacuum. The
crude reaction mixture was dissolved in methylene chloride, washed with
water, saturated sodium chloride, and dried with magnesium sulfate. The
organics were evaporated onto silica gel and eluted with hexanes followed by
hexanes/ethyl acetate (80:20). The hexanes/ethyl acetate fraction was
evaporated under vacuum and the residue recrystallized from hexanes/ethyl
acetate to afford compound 1c in a 94% yield as a white solid, mp 81.5–82.7 °C;
IR (KBr pellet), 3400–3100 (br), 2955, 2929, 2856, 1618, 1518, 1376, 1196, 863,
parameters: a = 18.677(2) Å, b = 18.677(2) Å, c = 13.094(2) Å,
c
a = 90°, b = 90°,
= 90°, V = 4567.4 Å3; space group: P4nc; Z = 18; Dcalcd = 1.188 g/cm3;
F000 = 1760; R1 = 0.0828, wR2 = 0.2334. Diffractometer: Bruker X8 Apex.
19. Brown, H. C.; Joshi, N. J. Org. Chem. 1988, 53, 4059–4063.
20. Typical reaction procedure (Table 1, entry 1): A mixture of 5 mmol each of
triethylsilane and 1-hexene was transferred by double ended needle over
15 min to 5 mmol of BCl3 in hexane, stirred at 0 °C for 4 h, then allowed to
warm to room temperature. The resulting hexyldichloroborane was quickly
transferred by double ended needle to 10 mmol of MeMgBr in ethyl ether
(3.33 mL) and THF (10 mL), cooled to 5 °C, and stirred for an additional 30 min,
then warmed to room temperature. Magnesium salts were removed by
815 cmÀ1 1H NMR (500 MHz, CDCl3): d = 6.63 (d, J = 8.5 Hz, 1H), 6.62 (d,
;
J = 3.0 Hz, 1H), 6.54 (dd, J = 8.5, 3.0 Hz, 1H), 4.57 (s, 1H), 4.46 (s, 1H), 2.53 (t,
J = 7.75 Hz, 2H), 1.58 (quintet, J = 7.6 Hz, 2H), 1.36 (m, 2H), 1.30 (m, 4H), 0.88 (t,
J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d = 149.31, 147.39, 130.11, 116.85,
116.06, 113.30, 31.75, 30.05, 29.65, 29.18, 22.62, 14.09.