Pericyclic reaction of a zwitterionic salt of an enedione-diazoester. A novel strategy for the synthesis of highly functionalized resorcinols

Article abstract of DOI:10.1021/ol101744h

Figure Presented. Enedione-diazoesters formed from 3-TBSO-2-diazo-3- butenoates undergo base-catalyzed pericyclization that with dinitrogen extrusion and methyl migration provide a novel and efficient route to 2-carboalkoxyresorcinols. Intercepting the intermediate enolate anion with methyl vinyl ketone leads to the corresponding 4-substituted 2-carboalkoxyresorcinol and suggests generalization of this methodology.

Full text of DOI:10.1021/ol101744h

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4304-4307
Pericyclic Reaction of a Zwitterionic Salt
of an Enedione-diazoester. A Novel
Strategy for the Synthesis of Highly
Functionalized Resorcinols
Yu Liu, Kanwarpal Bakshi, Peter Zavalij, and Michael P. Doyle*
Department of Chemistry and Biochemistry, UniVersity of Maryland, College Park,
Maryland 20742
mdoyle3@umd.edu
Received July 26, 2010
ABSTRACT
Enedione-diazoesters formed from 3-TBSO-2-diazo-3-butenoates undergo base-catalyzed pericyclization that with dinitrogen extrusion and
methyl migration provide a novel and efficient route to 2-carboalkoxyresorcinols. Intercepting the intermediate enolate anion with methyl vinyl
ketone leads to the corresponding 4-substituted 2-carboalkoxyresorcinol and suggests generalization of this methodology.
Resorcinol and its derivatives are important ingredients for
the total synthesis of a number of natural products and
phenolic compounds of pharmaceutical interest.1,2 However,
with few exceptions,3,4 general methods for their synthesis
are difficult to achieve except through traditional methodolo-
gies that originate with resorcinol.1 We wish to report a new
methodology for the synthesis of 2-carboalkoxyresorcinols,
based in part on serendipity, that relies on a convenient
procedure that we recently reported for the synthesis of
diverse R-diazo-ꢀ-keto esters.5 This procedure uses the
readily accessible 3-TBSO-substituted vinyldiazoacetate 1
for zinc triflate-catalyzed Mukaiyama-Michael reactions
with R,ꢀ-unsaturated ketones resulting in functionalized
3-keto-2-diazoalkanoates in high yield and selectivity (Scheme
1). The methodology for resorcinol synthesis employs a
functionalized R,ꢀ-unsaturated ketone that undergoes elimi-
nation to an enedione-diazoester which is susceptible to an
unprecedented pericyclic reaction and rearrangement.
In examining the breadth of the Mukaiyama-Michael
transformation of 1 and its applications, we employed trans-
4-methoxy-3-buten-2-one (2) as the substrate with the
(1) (a) Durairaj, R. B. Resorcinol:Chemistry, Technology, and Applica-
tions; Springer: New York, 2005. (b) Dressler, H. Resorcinol: Its Uses and
DeriVatiVes; Plenum Press: New York, 1994
.
(2) (a) Khatib, S.; Nerya, O.; Musa, R.; Tamir, S.; Peter, T.; Vaya, J.
J. Med. Chem. 2007, 50, 2676. (b) Brizzi, A.; Cascio, M. G.; Brizzi, V.;
Bisogno, T.; Dinatolo, M. T.; Martinelli, A.; Tuccinardi, T.; Di Marzo, V.
Biorg. Med. Chem. 2007, 15, 5406. (c) Marsini, M. A.; Huang, Y.; Van De
Water, R.; Pettus, T. R. R. Org. Lett. 2007, 9, 3229
(3) Kim, A.; Powers, J. D.; Toczko, J. F. J. Org. Chem. 2006, 71, 2170
(4) Ceglia, S. S.; Kress, M. H.; Nelson, T. D.; McNamara, J. M.
Tetrahedron Lett. 2005, 46, 1731
.
.
.
(5) Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008, 10, 1605.
10.1021/ol101744h  2010 American Chemical Society
Published on Web 09/01/2010

Scheme 1
.
Mukaiyama-Michael Reactions of
Scheme 3. Reactions of Methyl
2-Diazo-3,7-dioxo-5(E)-octenoate
TBSO-Substituted Vinyldiazoacetate 1
expectation that an enolizable enedione6 would be formed
whose chemistry could lead us to cycloaddition products that
contained the diazoester functionality. As anticipated, the
direct Mukaiyama-Michael product (3) was unstable, un-
dergoing elimination under the reaction conditions to form
R,ꢀ-unsaturated ketone 4 exclusively (Scheme 2),7 but the
occurred (36% conversion to 6). Performing the reaction at
elevated temperature with silica gel or by adding acetic acid to
the system produced the same results. When 2.0 molar equiv
of 4 N aqueous HCl was used, 5 was produced in 21% isolated
yield. However, assuming that enolization of 4 is one of the
key steps for this transformation, we anticipated that the addition
of base would facilitate this reaction. With 5.0 equiv of
triethylamine, 5 was obtained in 45% isolated yield; however,
the yield of 5 was further improved when only a catalytic
amount of aqueous sodium hydroxide (0.10 mol/L NaOH, 10
mol %) was employed, and under these catalytic conditions, 5
was isolated in 83% yield.
Scheme 2. Mukaiyama-Michael Reaction with
4-Methoxy-3(E)-buten-2-one
A plausible mechanistic pathway for resorcinol formation
is presented in Scheme 4. Removal of the most acidic proton
from compound 4 produces the conjugated enolate anions
that are depicted by intermediates 7.
Isomerization of 7a in which the 5,6-positions have the
E-geometry to 7b in which the 5,6-positions have the
Z-geometry is critical to the second isomerization in which
the two ends are wrapped together (7c) through a conjugated
triene that is appropriately arranged for pericyclization.
Similar 6-π electrocyclizations involving enolate derivatives
have been reported,8 although none have involved a diazo
compound.
resulting enedione underwent an unexpected transformation
resulting in the formation of a substituted resorcinol.
Examination of this process showed a diverse chemistry that
we now report.
The diazonium ion intermediate 8 resulting from peri-
cyclization is suitably positioned to undergo loss of
dinitrogen in concert with methyl migration to form
intermediate 9 that is the tautomer of the observed
resorcinol product. The conversion of 8 to 9 is, to our
knowledge, unprecedented; also, instead of undergoing
methyl migration to the carbon bearing the diazonium ion
that would be a semipinacol rearrangement9 or, alterna-
tively, forming an epoxide10 with loss of dinitrogen, the
methyl group migrates in the reverse direction to that of
dinitrogen extrusion. The formation of the phenolate anion
that can continue proton removal from reactant 4 is
consistent with the need for only a substoichiometric
amount of base to complete the reaction; after the reaction
is initiated, the transformation is self-sustained.
Attempted chromatographic purification of 4 on silica gel
resulted in the loss of 4, but the highly substituted resorcinol
5 was isolated in low yield (13%) (Scheme 3).
Various conditions were employed to optimize formation of
this unexpected reaction product by first treating 1 and 2 with
zinc triflate and then, after concentrating the mixture but without
isolating 4, adding a suitable promoter to catalyze the formation
of the resorcinol product. Since compound 4 decomposes upon
contact with silica gel, silica gel was added to the reaction
system; however, only migration of the enone double bond
(6) Schuler, M.; Duvvuru, D.; Retailleau, P.; Betzer, J.-F.; Marinetti,
A. Org. Lett. 2009, 11, 4406.
(7) Compound 3 was produced when the zinc triflate catalyzed reaction
was performed in the presence of molecular sieves 4A. A mixture of cis
and trans isomer in about 2/1 ratio was observed by NMR.
Org. Lett., Vol. 12, No. 19, 2010
4305

This compound, which was not observed from reactions with
4, resisted interpretation until an X-ray crystal structure of
compound 13b revealed the 1,2-diazepine structure (Figure
1).
Scheme 4. Base-Catalyzed Pericyclization-Rearrangement of 4
Figure 1. X-ray structure of 1,2-diazepine 13b.
The formation of 13 can be understood as arising from an
8π-electrocyclization for which we are aware of a few
previous examples.11 The origin of the 1,2-diazepine precur-
sors in prior studies has been cyclobutene-substituted diaz-
oacetates or TMS-diazomethyl compounds that undergo
electrocyclic ring opening to the requisite cis-dienyldiazo
intermediate that is structurally situated to undergo 8π-
electrocyclization. The production of 13, and its absence in the
reactions of 4 that produce 5, may be due to steric resistance to
the coiling of 7a to 7c that preceeds electrocyclization in the
formation of resorcinol derivatives (Scheme 4), and indeed, the
yield of 13 varies with the steric bulk of the ester. Accordingly,
the pathway to 13 can be understood as arising from deproto-
nation of 4 to form enolate 7a that isomerizes to 7d before
undergoing electrocyclization (Scheme 5).
Ester derivatives of 4 were prepared and subjected to the
same conditions as those used for the synthesis of 5. The
coresponding resorcinol products were formed (Table 1), but
Scheme 5. Pathway to 1,2-Diazepines 13
Table 1. Influence of Alkyl Ester on Resorcinol Formation from
Alkyl 2-Diazo-3,7-dioxo-5(E)-octenoate
yielda
ratiob
R
equivalents of NaOH
12 + 13 (%)
(12:13)
a
b
c
i-Pr
i-Pr
t-Bu
t-Bu
Bn
0.1 equiv
0.2 equiv
0.1 equiv
0.2 equiv
0.1 equiv
0.2 equiv
73
67
68
72
66
73
81:19
79:21
79:22
73:27
71:29
67:33
In an effort to examine the generality of this novel
cyclization process, substituted vinyl ketone 15 was em-
Bn
a Yield of isolated products after column chromatography. b Ratio based
on isolated yields of compounds 5 and 14.
(8) (a) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem.
Soc. 2004, 126, 1624. (b) Austin, W. F.; Zhang, Y.; Danheiser, R. L. Org.
Lett. 2005, 7, 3905.
(9) (a) For a recent review of the semipinacol rearrangement, see: Snape,
T. J. Chem. Soc. ReV. 2007, 36, 1823. (b) For a relevant example, see:
Kirmse, W.; Hellwig, G.; Van Chiem, P. Chem. Ber. 1986, 119, 1511.
their isolated yields were only moderate, and an additional
product (13) accompanied the derivative resorcinol (eq 1).
4306
Org. Lett., Vol. 12, No. 19, 2010

ployed, and the resultant resorcinol 16 was formed in
moderate yield (Scheme 6). Reactant 15 was prepared from
Scheme 7. Michael Addition/Pericyclization/Rearrangement
Scheme 6. Synthesis of Atraric Acid Derivative
case for 4. Subsequent treatment of 18 with triethylamine at
room temperature resulted in the formation of resorcinol 19
in 45% isolated yield, thus further demonstrating the versatil-
ity of the methodology.
In summary, enedione-diazoesters undergo a novel base-
catalyzed pericyclization that, with subsequent dinitrogen
extrusion and alkyl migration, forms 2-carboalkoxy-resor-
cinols in good yield. Interception of the enolate intermediate
on the pathway to pericyclization by a Michael acceptor,
and its subsequent conversion to a 4-substituted-2-car-
boalkoxyresorcinol, suggests the synthetic potential of this
methodology. Efforts are underway to further develop this
novel synthetic process.
methyl 2-diazo-3-ketopenanoate. Compound 17 has been
used as an atraric acid derivative for treatment of benign
prostate hyperplasia, prostate carcinoma, and spinobulbar
muscular atrophy.12
The pathway to substituted resorcinols that is described
in Scheme 4 involves initial formation of enolate 7 that was
expected to be suitable for trapping by Michael acceptors.13
If isomerization from the original E-isomer to the Z-isomer
(7a to 7b in Scheme 4) is the limiting factor, then reaction
of 7 with a Michael acceptor should not only be possible,
yielding product with the same E olefin geometry, but also
make possible further reaction that results in additional
functionalization of the resorcinol core. Accordingly, treat-
ment of 4 with a catalytic amount of sodium hydroxide in
the presence of 4.0 molar equiv of methyl vinyl ketone at 0
°C resulted in the formation of Michael addition product 18
in 65% isolated yield (Scheme 7); 18 was the sole addition
product, and resorcinol 19 was not formed under these
conditions. The Michael addition product 18 was sufficiently
robust to survive silica gel purification, which was not the
Acknowledgment. We are grateful to the National Insti-
tutes of Health for their financial support of this research
(GM46503). We wish to thank Arnold R. Romero Boho´rquez
of the Laboratorio de Qu´ımica Orga´nica y Biomolecular,
Escuela de Qu´ımica, Universidad Industrial de Santander in
Bucaramanga, Colombia, for early efforts in this research.
Supporting Information Available: General experimental
procedures, structure of 13b, and spectroscopic data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Padwa, A.; Cimiluca, P.; Eastman, D. J. Org. Chem. 1972, 37 (6),
805.
OL101744H
(11) (a) Sharp, J. T. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. l.7, pp
595-604. (b) Ohno, M.; Noda, M.; Yamamoto, Y.; Eguchi, S. J. Org. Chem.
1999, 64, 707. (c) Matsuya, Y.; Ohsawa, N.; Nemoto, H. J. Am. Chem.
Soc. 2006, 128, 13072.
(12) Hoffmann, H.; Matusch, R.; Baniahmad, A. PCT Int. Appl. 200608,
1997.
(13) Permutter, P. Conjugate Addition Reactions in Organic Synthesis,
Tetrahedron Organic Chemistry Series; Oxford, NY, 1992; Vol. 9.
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