Chemoselective reactions of 3-Benzyloxy-1,2-o-Quinone with organometallic reagents

Article abstract of DOI:10.1021/ol9004068

Chemoselective additions of organometallic reagents to 3-benzyloxy-1,2-o- quinone are described. Various nucleophiles are shown to undergo selective 1,2-addition, 1,4-addition, and etherification. Selective 1,2-additions provide stable, nondimerizing o-quinols as a novel alternative to oxidative dearomatization.

Full text of DOI:10.1021/ol9004068

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1955-1958
Chemoselective Reactions of
3-Benzyloxy-1,2-o-Quinone with
Organometallic Reagents
Luke A. Miller, Maurice A. Marsini, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510
pettus@chem.ucsb.edu
Received February 26, 2009
ABSTRACT
Chemoselective additions of organometallic reagents to 3-benzyloxy-1,2-o-quinone are described. Various nucleophiles are shown to undergo
selective 1,2-addition, 1,4-addition, and etherification. Selective 1,2-additions provide stable, nondimerizing o-quinols as a novel alternative to
oxidative dearomatization.
o-Quinones are useful synthetic building blocks. They are
easily reduced to the corresponding catechol,1 and they
undergo oxidative ring-opening to the corresponding hexa-
dienedioate skeleton.2 Furthermore, their alkene and carbonyl
components can be distinguished by [4 + 2]3 and [3 + 2]4
cycloadditions, as well as by oxidation with peracid5 or
bromine.6 In addition, they react sparingly with organophos-
phorus7 and organobismuth reagents,8 nitroalkane anions,9
and transition metals.10 Sporadic reactions with alkyl,11
alkynyl,12 vinyl,13 and allyl14 organometallic reagents, as well
(1) (a) Booth, J.; Boyland, E.; Turner, E. E. J. Chem. Soc. 1950, 1188.
Cooksey, C. J.; Land, E. J.; Riley, P. A. Org. Prep. Proced. Int. 1996, 28,
463. (c) Dutta, D. K.; Boruah, R. C.; Sandhu, J. S. Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 1992, 31B, 780.
(5) Viallon, L.; Reinaud, O.; Capdevielle, P.; Maumy, M. Tetrahedron
Lett. 1995, 36, 6669.
(6) Kundu, N. G. J. Chem. Soc., Chem. Commun. 1979, 564.
(7) Osman, F. H.; El-Samahy, F. A. Chem. ReV. 2002, 102, 629.
(8) Matano, Y.; Suzuki, H. J. Chem. Soc., Chem. Commun. 1996, 2697.
(9) Itoh, S.; Nii, K.; Mure, M.; Ohshiro, Y. Tetrahedron Lett. 1972, 34,
3975.
(2) Pieken, W. A.; Kozarich, J. W. J. Org. Chem. 1989, 54, 510.
(3) (a) Danishefsky, S. J.; Mazza, S. J. Org. Chem. 1974, 39, 3610. (b)
Paquet, J.; Brassard, P. Can. J. Chem. 1989, 67, 1354. (c) Lee, J.; Snyder,
J. K. J. Org. Chem. 1990, 55, 4995. (d) Lee, J.; Li, J.-H.; Oya, S.; Snyder,
J. K. J. Org. Chem. 1992, 57, 5301. (e) Nair, V.; Maliakal, D.; Treesa,
P. M.; Rath, N. P.; Eigendorf, G. K. Synthesis 2000, 850. (f) Paull, D. H.;
Wolfer, J.; Grebinski, J. W.; Weatherwax, A.; Lectka, T. Chimia 2007, 61,
240. (g) Abraham, C. J.; Paull, D. H.; Bekele, T.; Scerba, M. T.; Dudding,
T.; Lectka, T. J. Am. Chem. Soc. 2008, 130, 17085.
(10) Balch, A. L.; Sohn, Y. S. J. Organomet. Chem. 1971, C31.
(11) Razuvaev, G. A.; Abakumov, G. A.; Klimov, E. S.; Gladyshev,
E. N.; Bayushkin, P. Y. IzV. Akad. Nauk 1977, 1128.
(12) Moore, H. W.; West, K. F.; Wriede, U.; Chow, K.; Fernandez, M.;
Nguyen, N. G. J. Org. Chem. 1987, 52, 2537.
(4) (a) Takuwa, A.; Kai, R.; Kawasaki, K.-I.; Nishigaichi, Y.; Iwamoto,
H. J. Chem. Soc., Chem. Commun. 1996, 703. (b) Nair, V.; Nair, J. S.;
Vinod, A. U.; Rath, N. P. J. Chem. Soc., Perkin Trans. 1 1997, 21, 3129.
(c) Carlini, R.; Fang, C.-L.; Herrington, D.; Higgs, K.; Rodrigo, R.; Taylor,
N. Aust. J. Chem. 1997, 50, 271. (d) Nair, V.; Sheela, K. C.; Radhakrishnan,
K. V.; Rath, N. P. Tetrahedron Lett. 1998, 39, 5627. (e) Nebois, P.; Fillion,
H. Heterocycles 1999, 50, 1137.
(13) Wege, D. Aust. J. Chem. 1971, 24, 1531.
(14) Tersarki, G. S.; Nikolaev, N. A.; Kiseleve, V. G.; Mikhailo, B. M.
Zh. Obshch. Khim. 1971, 41, 152. (b) Maruyama, K.; Takuwa, A.; Naruta,
Y.; Satao, K.; Soga, O. Chem. Lett. 1981, 47. (c) Takuwa, A.; Soga, O.;
Mishima, T.; Maruyama, K. J. Org. Chem. 1987, 52, 1261.
(15) Sagawa, Y.; Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1988, 1105.
(16) Peter, M. G.; Speckenbach, F. HelV. Chim. Acta 1982, 65, 1279.
10.1021/ol9004068 CCC: $40.75
Published on Web 03/30/2009
 2009 American Chemical Society

as enol ethers15 and enamines,16 have been reported for
hindered systems.
Table 1. Chemoselective 1,2-Additions to o-Quinone 2
o-Quinols, on the other hand, are highly reactive com-
pounds. They are generally synthesized by the oxidative
dearomatization of o-alkylphenols and resorcinols.17 Lead
(IV) and iodine (V) reagents facilitate this dearomatization
via an ortho-delivery mechanism.18 However, simple o-
quinols which possess a cyclohexa-2,4-dienone skeleton
display a propensity for dimerization. Their synthesis by
oxidation has often proven capricious and substrate depend-
ent.19 These drawbacks, in addition to the troubling lack of
experimental reports in this area, prompted us to examine
an alternative for their construction: a chemoselective 1,2-
addition of an organometallic nucleophile to a dissymmetric
o-quinone.
entry
reagent
conditions
product
yield
1
2
MeMgCl
EtMgBr
THF
THF
R ) Me 3a
R ) Et 3b
60%
53%
DCM BF3·
3
4
5
6
n-HexMgBr
i-ButMgCl
H2CdCHCH2CH2MgBr THF
BnMgCl
HCCMgBr
PhMgBr
Et2O
R ) Hex 3c
R ) i-But 3d
R ) C4H9 3e
R ) Bn 3f
50%
56%
42%
50%
THF
THF
DCM BF3·
7
8
Et2O
R ) ethynyl 3g 66%
DCM BF3·
Et2O
3-Benzyloxy-1,2-o-quinone 2 was chosen as our focus for
this model study (Scheme 1). We felt this compound was
R ) Ph 3h
51%
DCM
Al(OPh)3 3h
THF
THF
THF
9
PhMgBr
MeLi CuI
AlMe3
47%
45%
45%
40%
10
11
12
3a
3a
3a
ZnMe2
Scheme 1. Synthesis of o-Quinone 2
respectively. Addition of phenylmagnesium bromide results
in a mixture of etherification products (Table 4, entry 3).
However, addition of BF3·Et2O to the o-quinone prior to
Grignard addition leads exclusively to the 1,2-adduct (Table
1, entry 8).
The change in reaction selectivity observed in the presence
of a Lewis acid prompted additional investigations. Com-
plexation of the o-quinone 2 with bulky aluminum-derived
Lewis acids followed by addition of phenyl Grignard and
dimethylcuprate surprisingly results in 1,2-addition (Table
1, entries 9-10) instead of 1,4-addition. We speculate that
the o-quinone 2 may be acting as a bidentate ligand, which
may facilitate a directed 1,2-delivery of the nucleophile.
Much to our chagrin however, organolithiums were found
to reduce the o-quinone 2 to the corresponding catechol 1.
Remarkably, addition of trimethylaluminum and dimethyl
zinc to the o-quinone 2 results in the formation of the
corresponding 1,2-adduct (Table 1, entries 11-12). Notably,
all o-quinol products proved stable and do not undergo
cyclodimerization.22
We subsequently found that treatment of these alkoxy
o-quinols with hydrogen gas in the presence of rhodium on
charcoal promotes reductive rearomatization with elimination
of water to produce the corresponding dissymmetric resor-
cinol derivatives (Table 2). Rhodium on charcoal was chosen
to ensure that the benzyl protecting group emerged unscathed
from the reaction. Reduction of phenyl o-quinol 3h to the
biaryl 4h (Table 2, entry 3) is a nice alternative for
synthesizing electron rich biaryl compounds that prove
difficult to obtain by standard metal mediated cross-coupling
procedures.
an attractive starting point because the carbonyls and alkene
residues are electronically differentiated. Additionally, com-
pound 2 was expected to be more stable than the parent 1,2-
benzoquinone given its reduced hydride affinity. 4-Alkoxy-
1,2-o-quinones, on the other hand, exhibit a greater proclivity
toward electron transfer.
We began with the known 3-benzyloxy-catechol 1, which
is available in three steps from commercially available
pyrogallol.20 The catechol 1 readily oxidizes using Carlson’s
procedure to afford dissymmetric o-quinone 2 as a stable
crystalline solid, which proves stable for months at 0 °C.21
With o-quinone 2 in hand, several 1,2-additions of
Grignard reagents were investigated (Table 1). We observe
addition of methylmagnesium chloride to give a very
reproducible 60% yield of the corresponding quinol adduct
3a (Table 1, entry 1). As we expected, other alkyl-Grignard
reagents also chemoselectively participate in 1,2-addition
reactions to afford moderate yields of the corresponding
adducts (Table 1, entries 2, 4-6, 9). However, in the case
of hexylmagnesium bromide and alkynylmagnesium bromide
(Table 1, entries 3 and 7), precomplexation of the o-quinone
2 with BF3·Et2O prior to addition of the Grignard reagent
greatly increases the yields of 3c and 3g to 50 and 66%
(17) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104,
1383.
While attempting other assorted 1,2-additions, we observed
that allylmagnesium bromide by itself reduces the o-quinone
(18) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2002, 4, 285.
(19) Marsini, M. A.; Gowin, K. M.; Pettus, T. R. R. Org. Lett. 2006, 8,
3481.
(22) (a) Dong, S.; Zhu, J,; Porco, J. A., Jr. J. Am. Chem. Soc. 2008,
130, 2738. (b) Gagnepain, J.; Me´reau, R.; Dejugnac, D.; Le´ger, J.-M.; Castet,
F.; Deffieux, D.; Pouyse´gu, L.; Quideau, S. Tetrahedron 2007, 63, 6493.
(c) Boppisetti, J. K.; Birman, V. B. Org. Lett. 2009, 11, 1221.
(20) (a) Dietl, F.; Gierer, G.; Merz, A. Synthesis 1985, 626. (b)
Danishefsky, S. J.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
(21) Carlson, B. W.; Miller, L. L. J. Am. Chem. Soc. 1985, 107, 479.
1956
Org. Lett., Vol. 11, No. 9, 2009

Table 2. Reductive Rearomatization of o-Quinols
entry
quinol
product
yield
1
2
3
3a
3f
3h
R ) Me 4a
R ) Bn 4f
R ) Ph 4h
90%
90%
95%
2 to the catechol 1, whereas precomplexation with BF3·Et2O,
affords the unexpected 1,4-product (Table 3, entry 1). In an
effort to obtain the 1,2-adduct, we also tested allyltributyltin
and the allylboronic acid pinacol ester. Both reagents led to
formation of the 1,4-adduct (Table 3, entry 2-3).
Table 3. Chemoselective 1,4-Allylation of o-Quinone 2
Figure 1. Mechanistic preference for formation of catechol 5b.
bromide provide mixtures of phenols (Table 4, entries 3-4).
Remarkably, addition of phenylmagnesium bromide to
3-methoxy-1,2-o-quinone leads to a single regioisomer (not
Table 4. Etherification of o-Quinone 2
On the basis of these results, two possible mechanisms
for allyl addition seemed plausible (Figure 1). In the first,
the allyl group undergoes initial 1,2-addition via a six
membered transition state (A) to afford the o-quinol (B). This
intermediate then succumbs to a 1,2-sigmatropic shift to
produce another o-quinol (C). Successive [3,3] rearrangement
to (D) and rearomatization results in what would appear to
be a ‘net’ 1,4-addition. The second potential mechanism
involves ‘reverse’ 1,4-allylation of the o-quinone. To dis-
tinguish between these two possibilities, we submitted the
o-quinone 2 to the crotylboronic acid pinacol ester shown.
The reaction affords the 1,4-addition product 5b, which
would seem to corroborate mechanism 1. This supposition
agrees with Soga’s work,23 where an allyl group adds 1,2
when the 1,4-position is blocked, and Castle’s observation
of a similar allyl migration.24
Table 4 shows the reagents and conditions that favor
etherification of o-quinone 2. Unlike dimethyl zinc, which
affords only the 1,2-product, Et2Zn and i-Pr2Zn both produce
mixtures of phenols (Table 4, entries 1-2). Likewise,
phenylmagnesium bromide and p-methoxyphenylmagnesium
(23) Maruyama, K.; Takuwa, A.; Soga, O. Nippon Kagaku Kaishi. 1985,
3, 362.
(24) Nielsen, D. K.; Nielsen, L. L.; Jones, S. B.; Toll, L.; Asplund, M. C.;
Castle, S. L. J. Org. Chem. 2009, 74, 1187.
Org. Lett., Vol. 11, No. 9, 2009
1957

shown). We believe these results reflect the greater electro-
philicity of one of the carbonyls and the greater single
electron character of the organometallic species (as compared
to their corresponding dimethyl zinc and alkyl Grignard
counterparts).25 Precoordination with BF3·Et2O and other
Lewis acids was not observed to influence formation of the
corresponding ethers with these reagents.
Attempts to implement a Charette cylcopropanation26 of
compound 2 using copper triflate and diazomethane resulted
in the benzodioxolane 6e in a 90% yield (Table 4, entry 5).
However, in the absence of copper triflate, diazomethane
smoothly provides the o-quinol spiroepoxide 6f (Scheme 2).27
Figure 2. Other nucleophiles investigated with o-quinone 2.
Scheme 2
.
Synthesis of Benzodioxolane 6e via Spiroepoxide 6f
proved unreactive or resulted in either reduction or decom-
position of the starting material. Organolithium, organocad-
mium, and organocerium reagents all led to catechol
formation. Organomercury reagents failed to undergo reac-
tion with 2. Grignard reagents 7-9 and anions 10-11 all
resulted in catechol formation, even when introduced in the
presence of BF3·Et2O. Reagents 12-16 proved unreactive
under forceful conditions. On the other hand, 2 undergoes
reaction with 17 to afford the corresponding 1,4-addition
product. Exposure of 2 to 18 results in 1,6-addition and
provides the corresponding thioetherificated catechol.31
This product is then readily converted into the benzodiox-
olane 6e by subsequent treatment with copper triflate or
BF3·Et2O. Spiroepoxides resembling 6f are most often
produced by the corresponding Becker-Adler oxidation of
hydroxymethyl phenols.28 The utility of these highly func-
tionalized spiroepoxide intermediates in diastereoselective
syntheses is well documented.29
Several other reagents and conditions were also investi-
gated in conjunction with the o-quinone 2 (Figure 2).
Conditions were limited to low temperature because of the
propensity of compound 2 to dimerize.30 Most reagents
To summarize, several new modes of reactivity for 2 have
been identified. 1,2-Addition followed by reductive rearo-
matization provides dissymmetric resorcinol derivatives.
Allyl organometallic reagents undergo net 1,4-addition
reactions. Organometallic reagents displaying single electron
character favor 1,4-addition to an oxygen atom resulting in
net etherification. Further expansion of the 1,2-addition
technology may provide chiral o-quinol scaffolds in an
enantioselective manner.
(25) Blomberg, C.; Grootveld, H. H.; Gerner, T. H.; Bickelhaupt, F. J.
Organomet. Chem. 1970, 24, 549.
(26) Charette, A. B.; Janes, M. K.; Lebel, H. Tetrahedron: Asymmetry
2003, 14, 867.
Acknowledgment. We thank the NSF (CHE-0806356) for
current financial support.
(27) For similar additions of diazomethane to lapachone derivatives, see:
da Silva, M. N.; Ferreira, S. B.; Jorqueira, A.; de Souza, M. C. B. V.; Pinto,
A. V.; Kaiser, C. R.; Ferreira, V. Tetrahedron Lett. 2007, 48, 6171.
(28) Becker, H. D.; Bremholt, T.; Adler, E. Tetrahedron Lett. 1972,
13, 4205.
Supporting Information Available: Full experimental
procedures and data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(29) (a) Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256.
(b) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1994,
116, 12109. (c) Danishefsky, S. J.; Shair, M. D. J. Org. Chem. 1996, 61,
16. (d) Churcher, I.; Hallett, D.; Magnus, P. J. Am. Chem. Soc. 1998, 120,
10350.
OL9004068
(30) Adler, E.; Magnusson, R.; Berggren, B. Acta Chem. Scand. 1960,
14, 539.
(31) Horner, L.; Gowecke, S. Chem. Ber. 1961, 94, 1267.
1958
Org. Lett., Vol. 11, No. 9, 2009