Practical synthesis of lespedezol A1

Article abstract of DOI:10.1021/np070493m

A practical formal synthesis of lespedezol A₁ (1) was accomplished in 33% yield for four steps starting from formation of the substituted chalcone. Of particular note is a useful protocol for reduction of the 2-ene bond in the isoflavone intermediate. A significant improvement in the final ring closure when water was scavenged from the reaction is also noteworthy. The ready availability of lespedezol A₁ will provide material for further pharmacological evaluation and for exploration of the pterocarpene nucleus as a potential entry into various 6a-hydroxypterocarpans.

Full text of DOI:10.1021/np070493m

J. Nat. Prod. 2008, 71, 275–277
275
Practical Synthesis of Lespedezol A1
Rahul S. Khupse† and Paul W. Erhardt*
Center for Drug Design and DeVelopment, Department of Medicinal and Biological Chemistry, The UniVersity of Toledo College of Pharmacy,
Toledo, Ohio 43606-3390
ReceiVed September 13, 2007
A practical formal synthesis of lespedezol A1 (1) was accomplished in 33% yield for four steps starting from formation
of the substituted chalcone. Of particular note is a useful protocol for reduction of the 2-ene bond in the isoflavone
intermediate. A significant improvement in the final ring closure when water was scavenged from the reaction is also
noteworthy. The ready availability of lespedezol A1 will provide material for further pharmacological evaluation and
for exploration of the pterocarpene nucleus as a potential entry into various 6a-hydroxypterocarpans.
The 6a-hydroxypterocarpans are isoflavonoid phytoalexins that
display selective estrogen receptor modulating (SERM) properties
and marked antioxidant and anticancer activity.1–3 The glyceollins,
represented by glyceollin I (2 in Figure 1), are particularly
interesting members of this class of compounds. Although 2 can
be elicited from the common soybean Glycine max by various
insults, it is typically obtained as a complex mixture in only very
small quantities.4–6 This situation has prompted explorations
directed toward the production of 2 by chemical synthesis.7,8 Like
others,9 we regard the stereospecific introduction of the 6a-hydroxy
group to be the most challenging step in these types of synthetic
strategies. Noting that certain pterocarpanoids like lespedezol A1
(1 in Figure 1) possess a 6a,11a-double bond that might be amenable
to the addition of a water molecule, we decided to prepare 1 as a
model to investigate such an approach toward producing various
6a-hydroxypterocarpan systems.
Figure 1. Structure 1 is lespedezol A1, a representative member of
the anhydropterocarpanoids also shown with its numbering system.
Structure 2 is glyceollin I, a representative member of the
6a-hydroxypterocarpans. Structure 3 is a prenylated relative of 1
Lespedezol A1 and several related family members were first
isolated by Miyase et al. from a methanolic extract of Lespedeza
homoloba stems.10 Some of these compounds demonstrate signifi-
cant antioxidant and antiallergic activity, while other members from
that has previously undergone total synthesis.
the broader family show promise as SERMs, anticancer agents, and
antifungals.11–13 Although a formal synthesis of 1 has not been
reported, its synthesis was traversed by Prasad et al. during their
unambiguous structural proof of the prenylated relative shown in
Figure 1 as compound 3.14,15
in EtOH to effect this reaction.14 The next step involved oxidative
rearrangement of chalcone 4 to the acetal intermediate 5 followed
by closure to the isoflavone 6. Use of thallium(III) nitrate for the
rearrangement followed by treatment with acid for the ring closure
constitutes a well-trodden path to a variety of isoflavones.21 We
also attempted this sequence by using newer methodology that
deployed Koser’s hypervalent iodine reagent to form the acetal
under conditions that we felt might eventually be developed into
much greener chemistry overall.22,23 In this case, model chemistry
with commercially available 2′-hydroxychalcone, protected as its
benzyl ether, proceeded quite favorably. When attempted on 4,
however, a complex mixture of products was obtained that appeared
to reflect other rearrangement possibilities in addition to the one
that did lead to at least small amounts of desired material. The
more traditional path, “b(i)” and “b(ii)” in Scheme 1, proceeded in
a favorable manner to produce the protected isoflavone 6 in
approximately 75% yield, which was comparable to the previous
literature.14,21
The next step of the synthesis involved simultaneous removal
of the two benzyl-protecting groups and reduction of the isoflavone
nucleus to the isoflavanone 7. Not unexpectedly, when this
conversion was undertaken at 15 psi hydrogen over 10% Pd-C, a
mixture was obtained that consisted of debenzylated isoflavone, a
small amount of desired product, and some cyclized product in the
form of a pterocarpan, which was not useful because it lacked the
6a,11a-double bond.14 Alternatively, using ammonium formate as
a source of hydrogen atoms24–26 resulted in a much cleaner reaction
wherein the degree of reduction could be controlled by the choice
Our synthesis of 1 paralleled the biosynthetic pathway for these
types of compounds by going through an isoflavone followed by
conversion to an isoflavonone prior to final cyclization.16 There
are several methods reported for the preparation of isoflavones.17–20
We decided to first examine a Suzuki coupling approach. Using
commercially available 3-bromochromone as a model, coupling
reactions with the appropriate boronic acid partner were attempted
under various conditions.17,18 In all cases, however, only vey low
yields of the desired isoflavone were obtained. Alternatively, we
observed immediate success with the chalcone route depicted in
Scheme 1 wherein the requisite intermediate 4 was first obtained
via a well-behaved Claisen-Schmidt condensation.19 The latter was
performed in anhydrous MeOH using piperidine as base,20
a
combination that afforded crystalline chalcone 4 directly from the
reaction medium upon standing at room temperature after refluxing
for 4 h. After filtration, concentration of the anhydrous MeOH and
refluxing for another 4 h, a second crop was obtained for which
the combined yield became 80%. The latter was nearly double that
previously reported by Prasad et al., who deployed aqueous NaOH
* Corresponding author. Tel: (419) 530-2167. Fax: (419) 530-1994.
E-mail: paul.erhardt@utoledo.edu.
† Present address: Lexington Pharmaceutical Labs, LLC, Lexington, KY
40511.
10.1021/np070493m CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 01/31/2008

276 Journal of Natural Products, 2008, Vol. 71, No. 2
Scheme 1. Synthesis of Lespedezol A1 (1)a
Notes
is very practical and should be amenable to further scale-up. Of
particular note is a useful protocol for reduction of the 2-ene bond
in the isoflavone to produce the penultimate intermediate required
for cyclization to the pterocarpene nucleus. Likewise, a significant
improvement was observed for the final ring closure when water
was scavenged from the reaction. The pterocarpenes and ho-
mopterocarpans are of interest for their potential therapeutic
properties. The availability of lespedezol A1 via the practical
synthesis described herein will allow for further synthetic explora-
tions directed toward producing 6a-hydroxypterocarpans, as well
as allowing for a more thorough characterization of its distinct
pharmacologic profile.
Experimental Section
General Experimental Procedures. Chemical reactions were
conducted under nitrogen in anhydrous solvents unless stated otherwise.
Reagents obtained from commercial suppliers were used without further
purification. Acetone was dried over 4 Å molecular sieves. Tetrahy-
drofuran (THF) was distilled under nitrogen over sodium-benzophenone.
Thin-layer chromatography (TLC) was done on 250 µm fluorescent
plates and visualized by using UV light or iodine vapor. Normal-phase
flash column chromatography was performed using silica gel (200–425
mesh 60 Å pore size) and ACS grade solvents. Melting points (mps)
are uncorrected. NMR spectra were recorded on either a 600 MHz or
a 400 MHz instrument. Peak locations were referenced using either
tetramethylsilane (TMS) or residual nondeuterated solvent as an internal
standard. Proton coupling constants are expressed in hertz. In some
cases, overlapping signals occurred in the 13C NMR spectra. Spectro-
scopic data are in agreement with all known compounds.
a (a) MeOH, piperidine (2 equiv), reflux (80%); (b-i) Tl(NO3) · 3H2O (1.5
equiv), CH2Cl2/MeOH (1:12), rt; (b-ii) 1 N HCl, MeOH, reflux (75%); (c) 10%
Pd-C, ammonium formate (8 equiv), acetone/MeOH (10:1), rt (78%); (d) cat.
HCl, 3 A molecular sieves, MeOH/trimethyl orthoformate (1:1), reflux (71%).
of solvent, reaction temperature, and the number of reagent
equivalents so as to produce various products in high yield and
purity. For example, when 6 was refluxed in MeOH with 15 equiv
of ammonium formate over 10% Pd-C for 12 h, not only did
debenzylation and reduction of the 2-ene bond occur, but the keto
group was also reduced to an alcohol. Alternatively, stirring 6 in
acetone at room temperature for 12 h and using only 8 equiv of
ammonium formate provided the desired isoflavanone 7 as a white
solid in nearly 80% yield. This represented a considerable improve-
ment over the previous method, which produced an oil in about
10% yield after a tedious separation.14
The final ring closure to form 1 (step “d”) requires considerable
thermal energy even when catalyzed by acid. The previously
reported yield for this reaction was only about 30%.15 It is likely
that the keto group first forms a hemiacetal with MeOH, which
then collapses to a five-membered cyclic ether upon acid-catalyzed,
intramolecular nucleophilic attack by the neighboring othro-hydroxy
group. Subsequent dehydration then produces the highly conjugated
pterocarpene nucleus. Accordingly, the driver for the overall
pathway is the loss of water, leading to formation of the highly
stabilized, conjugated double bond that embeds a fully aromatic
benzofuran system within the pterocarpene nucleus. On the basis
of this mechanism, we imagined that the addition of molecular
sieves and, in particular, equimolar quantities of trimethyl ortho-
formate27 to scavenge water might serve to both facilitate this
reaction and lead to higher yields. To this end, 7 was gently refluxed
in anhydrous MeOH/trimethyl orthoformate over molecular sieves
with a catalytic amount of concentrated HCl for 4 h. After removing
the sieves and evaporating solvent, the residue was extracted with
water and EtOAc. The organic phase was dried and chromato-
graphed through silica gel to provide the desired product 1 as a
solid in approximately 70% yield. Thus, this modified reaction was
accomplished at lower temperature and in a significantly higher
yield.
2,4-Dibenzyloxy-2′-hydroxy-4′-methoxychalcone (4). 2,4-Dibenz-
yloxybenzaldehyde28 (3.18 g, 10 mmol) and 2-hydroxy-4-methoxyac-
etophenone (1.66 g, 10 mmol) were dissolved in 100 mL of MeOH,
followed by addition of piperidine (2 mL, 20 mmol). The mixture was
refluxed for 4 h and cooled to ambient temperature. A yellowish solid
was produced that was filtered and washed with 100 mL of MeOH.
The filtrate was reduced to ca. 50 mL and refluxed for another 4 h,
after which it provided additional product upon cooling to ambient
temperature. The combined yield of solid 4 was 3.71 g (80%): mp
156–157 °C [lit.,14 157–164 °C]; TLC Rf 0.23 in hexanes/EtOAc (5:
1
1); H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H, J ) 15.6 Hz, CHd),
7.75 (d, 1H, J ) 15.6 Hz, CHd), 7.54–7.36 (m, 11H, 2 × C6H6/Ar-
H6), 7.24 (d, 1H, J ) 9 Hz, Ar-H6′), 6.68 (d, 1H, 3J ) 2.4 Hz, Ar-H3)
6.53 (dd, 1H, 2J ) 8.4 Hz, 3J ) 2.4 Hz, Ar-H5), 6.41 (d, 1H, 3J ) 2.4
2
3
Hz, Ar-H3′), 6.24 (dd, 1H, J ) 9 Hz, J ) 2.4 Hz, Ar-H5′), 5.12 (s,
2H, O-CH2), 5.11 (s, 2H, O-CH2), 3.83 (s, 3H, OCH3); 13C NMR (100
MHz, CDCl3) δ 192.9, 166.8, 165.8, 162.2, 160.2, 141.2, 136.4, 136.2,
134.4, 131.4, 129.1, 128.9, 128.7, 128.6, 128.5, 127.8, 119.8, 117.6,
114.5, 107.7, 106.6, 100.8, 100.6, 70.9, 70.5, 55.7.
2′,4′-Dibenzyloxy-7-methoxyisoflavone (6). Chalcone 4 (0.467 g,
1 mmol) was dissolved in 2 mL of DCM and 25 mL of MeOH was
added, followed by addition of thallium nitrate trihydrate (0.666 g, 1.5
mmol). Upon stirring this suspension for 2 h at room temperature, it
became a clear solution with white thallium(I) nitrate precipitating. After
stirring for an additional 4 h, the TLC showed complete disappearance
of chalcone. Solvents were evaporated to reduce the volume to ca. one-
third, and then 20 mL of CH2Cl2 was added, followed by the addition
of 0.2 g of sodium bisulfite. After stirring for 1 h, the entire solid was
filtered, solvent evaporated, and the resulting residue passed through a
short column of silica with hexanes/EtOAc (10:1) as eluant. The eluting
solvents were evaporated to provide a yellowish, oily acetal, which
was used directly in the next step without further purification. Crude
acetal (ca. 0.5 g) was dissolved in 10 mL of MeOH and refluxed with
2 mL of 1 N HCl for ca. 12 h. After disappearance of acetal (TLC),
the reaction mixture was poured into ice–water (100 mL). A white
solid precipitated. The precipitate was filtered and recrystallized from
MeOH/DCM (ca. 20:5 mL) to provide 0.348 g (75%) of 6 as a white
solid: mp 138–140 °C [lit.,14 139 °C]; TLC Rf 0.14 in hexanes/THF
The overall yield for the entire synthesis of lespedezol A1, 1,
was 33% starting from formation of the substituted chalcone. This
represents a considerable improvement over the 1% yield that can
be calculated across the analogous steps associated with its prior
synthesis by Prasad et al. while on route to 3.14,15 Requiring only
routine separation and purification methods, the present synthesis
1
(5:1); H NMR (400 MHz, CDCl3) δ 8.21 (d, 1H, J ) 9 Hz, Ar-H5),
7.89 (s, 1H, OCHd), 7.42–7.22 (m, 10 + 2H, 2 × C6H5/Ar-H6′/Ar-
H3′), 6.97 (dd, 1H, 2J ) 9 Hz, 3J ) 2.4 Hz, Ar-H6), 6.82 (d, 1H, J )
1.8 Hz, Ar-H8), 6.64 (dd, 1H, 2J ) 8.4 Hz, 3J ) 1.8 Hz, Ar-H5′), 5.05
(s, 2H, Ph-CH2), 5.03 (s, 2H, Ph-CH2), 3.89 (s, 3H, OCH3); 13C NMR
(100 MHz, CDCl3) δ 176.0, 164.0, 160.4, 158.2, 157.8, 154.0, 137.2,

Notes
Journal of Natural Products, 2008, Vol. 71, No. 2 277
References and Notes
137.1, 132.5, 128.9, 128.7, 128.3, 128.0, 127.9, 127.8, 127.4, 122.4,
118.7, 114.5, 106.2, 101.7, 70.8, 70.4, 56.0.
(1) Collins-Burow, B. M.; Burow, M. E.; Duong, B. N.; McLachlan, J. A.
2′,4′-Dihydroxy-7-methoxyisoflavanone (7). 10% Pd-C (0.3 g)
was added to a solution of isoflavone 6 (0.464 g, 1 mmol) in 20 mL of
acetone and 2 mL of MeOH at 0 °C, followed by addition of ammonium
formate (0.504 g, 8 mmol). The reaction mixture was stirred for ca.
8 h at room temperature. Catalyst was filtered through a pad of Celite,
solvent evaporated, and the residue extracted with EtOAc/water (40
mL; 1:1). The organic layer was dried over sodium sulfate and
evaporated to give a reddish solid. The solid was dissolved in EtOAc
and chromatographed over silica using hexanes/EtOAc (3:1) as eluant.
The organic fractions were evaporated to provide 0.224 g (78%) of 7
as a white solid: mp 168–170 °C [lit.,14 oil]; TLC Rf 0.23 in hexanes/
EtOAc (3:2); 1H NMR (400 MHz, acetone-d6) δ 8.51 (s, 1H, OH), 8.2
(s, 1H, OH), 7.80 (d, 1H, J ) 9 Hz, Ar-H5) 6.91 (d, 1H, J ) 7.8 Hz,
Nutr. Cancer 2000, 38, 229–244.
(2) Burow, M. E.; Boue, S. M.; Collins-Burow, B. M.; Melnik, L. I.;
Duong, B. N.; Carter-Wientjes, C. H.; Li, S.; Wiese, T. E.; Cleveland,
T. E.; McLachlan, J. A. J. Clin. Endocrinol. Metab. 2001, 86, 1750–
1758.
(3) Salvo, V. A.; Boue, S. M.; Fonseca, J. P.; Elliott, S.; Corbitt, C.;
Collins-Burow, B. M.; Curiel, T. J.; Srivastav, S. K.; Shih, B. Y.;
Carter-Wientjes, C. H.; Wood, C. E.; Erhardt, P. W.; Beckman, B. S.;
McLachlan, J. A.; Cleveland, T. E.; Burow, M. E. Clin. Cancer Res.
2006, 12, 7159–7164.
(4) Al-Hazimi, H. M. G.; Alkhathlan, H. Z. J. King Saud UniV. Sci. 2000,
12, 93–122.
(5) Boue, S. M.; Carter, C. H.; Ehrlich, K. C.; Cleveland, T. E. J. Agric.
Food Chem. 2000, 48, 2167–2172.
(6) Cleveland, T. E.; Boue, S. M.; Burow, M. E.; McLachlan, J. A. U.S.
Pat. Appl. Pub. 2006, 1–16.
(7) Khupse, R. S.; Erhardt, P. W. Total Synthesis of the Soybean
FlaVonoids Glyceollin I and II (Poster # 30),6th Environmental
Signaling Network Symposium, New Orleans, Oct 2004.
(8) Khupse, R. S.; Erhardt, P. W. Approaches Toward the Biomimetic
Total Synthesis of the Soybean FlaVonoids Glyceollin I and II (Poster
# 87),30th National Medicinal Chemistry Symposium, Seattle, June
2006.
2
3
Ar-H6′), 6.64 (dd, 1H, J ) 8.4 Hz, J ) 2.4 Hz, Ar-H6), 6.5 (d, 1H,
J ) 2.4 Hz, Ar-H7), 6.42 (d, 1H, J ) 1.8 Hz, Ar-H3′), 6.30 (dd, 1H,
2J ) 8.4 Hz, 3J ) 2.4 Hz, Ar-H5′), 4.67 (t, 1H, J ) 11.4 Hz, H3), 4.55
2
3
2
(dd, 1H, J ) 11.4 Hz, J ) 5.4 Hz, H-2ax), 4.14 (dd, 1H, J ) 11.4
3
Hz, J ) 5.4 Hz, H-2eq), 3.87 (s, 3H, OCH3); 13C NMR (100 MHz,
acetone-d6) δ 191.5, 166.5, 164.4, 158.5, 156.7, 131.1, 129.4, 115.9,
114.2, 110.3, 107.5, 103.5, 101.2, 71.5, 55.9, 47.5; anal. calcd for
C16H14O5 ·0.25H2O, C 66.08, H 5.02; found, C 66.29, H 4.83.
Lespedezol (A1) or 3-Methoxy-6H-benzo[4,5]furo[3,2-c]chromen-
9-ol (1). To a solution of 7 (0.141 g, 0.5 mmol) in 50 mL of MeOH/
trimethyl orthoformate (1:1) was added two drops of concentrated HCl
and ca. 5 g of 3 Å molecular sieves, after which the solution was gently
refluxed for 4 h. A solid was filtered and the solvent evaporated at 20
°C. The resulting residue was extracted with EtOAc/water (2 × 100
mL; 1:1). The organic layers were combined, dried over sodium sulfate,
and evaporated. The residue was chromatographed over silica using
hexanes/EtOAc (5:1) as eluant. The organic fractions were evaporated
to provide 0.95 g (71%) of 1 as a white solid with slight yellow tinge:
decomposes at 130–140 °C [lit.,15 134 °C]; TLC Rf 0.52 in hexanes/
(9) van Aardt, T. G.; van Rensburg, H.; Ferreira, D. Tetrahedron 2001,
57, 7113–7126.
(10) Miyase, T.; Sano, M.; Nakai, H.; Muraoka, M.; Nakazawa, M.; Suzuki,
M.; Yoshino, K.; Nishihara, Y.; Tanai, J. Phytochemistry 1999, 52,
303–310.
(11) Arnoldi, A.; Merlini, L. J. Agric. Food Chem. 1990, 38, 834–838.
(12) Miller, C. P.; Collini, M. D.; Harris, H. A.; Keith, J. C. U.S. Pat.
Appl. Pub. 2003, 1–17.
(13) Wallace, O. B.; Lauwers, K. S.; Dodge, J. A.; May, S. A.; Calvin,
J. R.; Hinklin, R.; Bryant, H. U.; Shetler, P. K.; Adrian, M. D.; Geiser,
A. G.; Sato, M.; Burris, T. P. J. Med. Chem. 2006, 49, 843–846.
(14) Prasad, A. V. K.; Kapil, R. S.; Popli, S. P. J. Chem. Soc., Perkin
Trans. 1 1986, 1561–1563.
(15) Prasad, A. V. K.; Kapil, R. S.; Popli, S. P. Indian J. Chem., Sect. B
1986, 25, 407–408.
(16) Kochs, G.; Grisebach, H. Arch. Biochem. Biophys. 1989, 273, 543–
553.
(17) Chaumeil, H.; Signorella, S.; LeDrian, C. Tetrahedron 2000, 56, 9655–
9662.
1
EtOAc (3:2); H NMR (400 MHz, acetone-d6) δ 8.57 (s, 1H, OH),
7.35 (d, 1H, J ) 8.4 Hz, Ar-H1), 7.31 (d, 1H, J ) 8.4 Hz, Ar-H7),
7.01 (d, 1H, J ) 2.4 Hz, Ar-H10), 6.82 (dd, 1H, 2J ) 8.4 Hz, 3J ) 1.8
Hz, Ar-H8), 6.58 (dd, 1H, 2J ) 8.4 Hz, 3J ) 2.4 Hz, Ar-H2), 6.49 (d,
1H, J ) 2.4 Hz, Ar-H4), 5.57 (s, 2H, H6), 3.8 (s, 3H, OCH3); 13C
NMR (100 MHz, acetone-d6) δ 161.7, 157.1, 156.3, 155.8, 147.0, 121.3,
119.8, 118.9, 112.9, 110.4, 107.7, 106.9, 103.0, 98.9, 65.9, 55.5; anal.
calcd for C16H12 O4. 0.25 H2O, C 70.46, H 4.62; found, C 70.33, H
4.42.
(18) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1988,
61, 3008–3010.
(19) Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, in press.
Acknowledgment. We are grateful to the U.S. Department of
Agriculture and the Southern Regional Research Center (New Orleans)
for their financial support of this research.
(20) Tsukayama, M.; Fujimoto, K.; Horie, T.; Masumura, M.; Nakayama,
M. Bull. Chem. Soc. Jpn. 1985, 58, 136–141.
(21) Farkas, L.; Gottsegen, A.; Nogradi, M.; Antus, S. J. Chem. Soc., Perkin
Trans. 1 1974, 305–312.
(22) Moriarty, R. M.; Khosrowshahi, J. S.; Prakash, O. Tetrahedron Lett.
1985, 26, 2961–2964.
Supporting Information Available: (S1) Model chemistry associ-
ated with an attempted Suzuki coupling route to an isoflavone; (S2)
model chemistry associated with use of Koser’s hypervalent iodine
reagent including preparation of 2′-benzyloxychalcone and its related
isoflavone; (S3) preparation of 2,4-dibenzyloxybenzaldehyde in 90%
yield from commercially available starting material, and additional
reference citations pertaining to S1, S2, and S3; (S4) proposed
mechanism for the cyclization of an isoflavanone to the pterocarpene
nucleus in methanolic HCl; and (S5 to S17) copies of proton and carbon
NMR spectra for lespedezol A1 and synthetic intermediates 4, 6, and
7. This material is available free of charge via the Internet at http://
pubs.acs.org.
(23) Hossain, M. M.; Kawamura, Y.; Yamashita, K.; Tsukayama, M.
Tetrahedron 2006, 62, 8625–8635.
(24) Siya, R.; Spicer, L. D. Synth. Commun. 1987, 17, 415–418.
(25) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G. E. J.
Org. Chem. 1979, 44, 3442–3444.
(26) Wahala, K.; Hase, T. A. Heterocycles 1989, 28, 183–186.
(27) Kesslin, G.; Bradshaw, R. Ind. Eng. Chem. Prod. Res. DeV. 1966, 5,
27–29.
(28) Khan, R. A.; Kapil, R. S. J. Heterocycl. Chem. 2001, 38, 1007–1009.
NP070493M