A Garratt-Braverman route to aryl naphthalene lignans

Article abstract of DOI:10.1016/j.tetlet.2011.01.011

A series of aryl naphthalene lignans were prepared in good yields starting from substituted bis-propargyl ethers. The method involved a base-mediated Garratt-Braverman cyclization followed by benzylic oxidation to the lactone. The chemoselectivity in the

Full text of DOI:10.1016/j.tetlet.2011.01.011

Tetrahedron Letters 52 (2011) 1183–1186
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Tetrahedron Letters
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A Garratt–Braverman route to aryl naphthalene lignans
⇑
Sayantan Mondal, Manasi Maji, Amit Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of aryl naphthalene lignans were prepared in good yields starting from substituted bis-propargyl
ethers. The method involved a base-mediated Garratt–Braverman cyclization followed by benzylic oxida-
tion to the lactone. The chemoselectivity in the GB cyclization and the regioselectivity in the benzylic oxi-
dation could be achieved by controlling the electronic nature of the aryl-substituents as well as by
changing the substitution pattern of the two aryl rings.
Received 18 November 2010
Revised 22 December 2010
Accepted 6 January 2011
Available online 12 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The past three decades have witnessed the power of radical-
mediated C–C bond forming reactions in synthetic organic chemis-
try.1 The precursor radical in these cases are mostly generated by
the action of an initiator and the reactions proceed via a self-sus-
taining process. On the contrary, the diradicals that are thermally
generated via a host of now well-known processes like Bergman,2
Myers–Saito,3 Schmittel,4 Garratt–Braverman5 and Hopf cycliza-
tions6 have drawn limited attention of synthetic organic chemists.
In principle, these diradicals can be utilised for a variety of pur-
poses as detailed in Scheme 1.
Cascade reaction with internal appendages
c
.
d
a
Organic synthesis
particularly
Interaction with
biomolecules
.
natural products
and their mimics
b
Polymer synthesis
Scheme 1. Possible applications of diradicals.
The usefulness of these diradicals in biology (path a) has been
well-exploited in the development of anticancer agents and con-
tinues to be a topic of interest.7 Various polyphenylene polymers8
have been synthesized via the diradicals (path b). Grissom et al.9 in
the mid 90’s had successfully trapped these diradicals in an intra-
molecular fashion with radicophiles to form various interesting
skeletons (path c). However, to the best of our knowledge synthe-
sis of natural products or their mimics following path d has not
been reported.10 One problem with these diradicals is associated
with the usual low yield of the product when quenched by an
external donor because of the competing polymerization. For inter-
nally quenched or self-quenched reactions the scenario is better in
terms of product yield. Garratt–Braverman (GB) cyclization of
bisallenic sulfones belongs to this self-quenching category. In
course of our study11 on the reactivity of various aryl substituted
bis-propargyl sulfones (the precursor of bis-allenes) we found a
striking similarity of the product of GB, an aryl naphthalene deriv-
ative with those of justicidin type lignans.12 These lignans, because
of their wide variety of biological properties, have attracted consid-
erable attention in recent years. Attempts have been made to ex-
ploit these biological properties to develop a molecule suitable
for human use. Many synthetic methodologies have been
developed13 to have an access to this class of molecules. However,
a majority of these methods involve a large number of steps and
low yields. Also some of these methods suffer from lack of or poor
selectivity. In this communication, we report a new approach that
has culminated in short syntheses of a wide array of justicidin ana-
logues. The key feature of the synthesis is the Garratt–Braverman
cyclization of various substituted bis-propargyl ethers followed
by a benzylic oxidation of the resultant dihydroisofuran14 deriva-
tive to the arylnaphthalene lignans in overall excellent yield. The
synthetic approach is shown in Scheme 2.
GB cyclization is known to be the most facile for propargyl sulf-
ones, occurring at room temperature under mild base treatment,
for example, NEt3. The same rearrangement of bis-propargyl ether
requires refluxing in toluene in the presence of a strong base like
KOBut. The yield is, however, almost quantitative. The examples
known till today, all dealt with unsubstituted ethers resulting in
one product. For substituted aryl propargyl ethers, several possibil-
ities exist. The number of products depends upon the substitution
pattern as well as the aryl groups (same or different). Up to a max-
imum of four products (excluding atropisomerism) are possible as
shown in Scheme 3. Another problem that needs to be dealt with is
the issue of regioselectivity during benzylic oxidation of the isofu-
ran to the lactone. Both these issues have been addressed in the
present work.
⇑
Corresponding author.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.011

1184
S. Mondal et al. / Tetrahedron Letters 52 (2011) 1183–1186
O
O
R
OH
Br
O
R
R
O
R
R
R
R
R
O
R
O
R
Scheme 2. Synthesis of aryl naphthalene lignans.
a
b
O
MeO
MeO
O
1
O
MeO
O
O
O
O
O
MeO
2
3
OMe
O
O
OMe
O
MeO
O
O
OMe
OMe
4
O
5
O
OMe
Scheme 3. (a) Possible GB products from unsymmetrical bis-propargyl ether and (b) 1H NMR of crude reaction mixture.
As a test case, the unsymmetrical bis-propargyl ether 1 was
subjected to the cyclization condition (tBuOK, toluene, reflux).15
All the four products 2–5 were isolated (Scheme 3) in the ratio
1:1:2.5:1.4 in an overall yield of 98% thus emphasizing the need
to bring selectivity in the GB cyclization. We realized that the
selectivity may be induced if a difference is created in the elec-
tronic nature of the two benzylic radicals. This can be achieved
by using aryl rings of different electronic character, namely, one
possibly during work-up17 and the resulting phenol was methyl-
ated with MeI/K2CO3.
Having been successful in controlling the course of GB cycliza-
tion, we next studied the oxidation of isofuran to lactone. This
was successfully carried out using KMnO4/CuSO4.18 From the isofu-
ran derivatives without any substituent at C-5, two regioisomeric
lactones were obtained with some degree of preference for oxida-
tion at the exo-methylene. On the other hand, GB products with a
C-5 substituent gave only the exo-lactone. No trace of the other
regioisomer could be seen in the 1H NMR of crude reaction mix-
ture. Oxidation of other isofuran derivatives with a substituent at
C-5 also led to the exclusive formation of the exo-lactone.19 The re-
sults are shown in Table 1.
donating and the other withdrawing. The radical
rich aryl ring will be nucleophilic and we expected the major prod-
uct to be formed via an involvement of -electrons of the electron
a to the electron
p
rich aromatic ring. To settle the matter, bis-propargyl ethers were
prepared having aryl groups of different electronic nature. When
these were subjected to the GB condition, products via participa-
tion of electron rich aromatic ring were obtained. No product cor-
The structures of the lactones were elucidated on the basis of 1H
NMR spectra. The oxidation at the exo-methylene leads to a consid-
erable downfield shift of the peri-H at C-1 which is not the case
when oxidation takes place at the endo-methylene. The mechanism
of oxidation as proposed by Noureldin et al.18 (Scheme 5) involves
a benzylic cation intermediate. We ruled out the role of any
electronic effect as the cation at C-40 will be stabilized to the same
extent by a methoxy at 5 or 7 position (shown in X and Y). We
responding to
p-participation of aromatic ring containing the
relatively electron withdrawing benzoate could be isolated thus
proving our assertion (Scheme 4).16 The idea was reinforced by
the isolation of only one product from the trimethoxy benzoyloxy
bis-propargyl ether 8 during GB cyclization in a yield of >95%. It
may be mentioned that the benzoate group underwent hydrolysis,

S. Mondal et al. / Tetrahedron Letters 52 (2011) 1183–1186
1185
R1
O
O
R1
R2
+
R2
R1
R2
O
9,10
OMe
11, 12
i, ii
OMe
OCOPh
O
MeO
6-7, 9-12
For 6, 9, 11 R1 = R2 = -OMe.
R1
For 7, 10, 12 R1-R2 = -OCH2O-.
R2
Not Obtained
MeO
O
MeO
O
MeO
O
i, ii
MeO
OMe
OCOPh
MeO
MeO
OMe
OMe
OMe
Not Obtained
13
8
OMe
Scheme 4. Achieving selectivity in GB cyclization. Reagents and conditions: (i) tBuOK, toluene, reflux, 3 h, 98%; (ii) MeI, K2CO3, acetone, reflux, 2 h, 96%.
Table 1
Results of oxidation of various GB products
R1
R2
O
R1
R1
R2
1
7
1'
O
O
4'
O
R2
6
+
5
R3
4
R3
R3
O
R4
R4
R4
R5
9a-17a
R5
9-17
R5
9b-17b
12 R2-R3 = -OCH2O-, R5 = -OMe, R1 = R4 = -H
9 R1 = R2 = R5 = -OMe, R3 = R4 = -H.
10 R1-R2 = -OCH2O-, R5 = -OMe, R3 = R4 = -H 13 R1 = R2 = R4 = R5 = -OMe, R3 = -H.
11 R2 = R3 = R5 = -OMe, R1 = R4 = -H
15 R1 = R2 = R3 = R5 = -OMe, R4 = -H
16 R1 = R2 = R3 = -OMe, R4-R5 = -OCH2O-
14 R2 = R3 = R4 = R5 = -OMe, R3 = -H.
17 R1-R2 = R4-R5 = -OCH2O-, R3 = H
Substratea
Product
Yield (overall) (%)
Regiomeric excess (%)
9
10
11
13
14
15
16
17
9a + 9b
10a + 10b
11a
13a + 13b
14a
94
94
92
92
90
89
93
92
33
50
>99
43
>99
>99
>99
33
15a
16a
17a + 17bb
a
Substrate 12 was obtained as a mixture with 10; its oxidation products led to an inseparable mixture.
Compounds 17a and 17b are the natural products Justicidin E and Tiwanin C, respectively.
b
believe that the regioselectivity is originating from steric effect of-
fered by the non planar aryl group at C-4 to the active oxidising
agent during the endo oxidation (as shown in A). Oxidation occur-
ring at the exo-methylene has no such problem (as shown in B).
The effect is pronounced in C-5 substituted systems because of
the greater non planarity of the appended aryl group.
electronic character of the two aryl rings. The methodology opens
the door to make a large library of justicidin analogues. The evalu-
ation of the biological properties of the synthesized molecules is
currently under progress.
Acknowledgements
In conclusion, we have developed a short synthesis of justicidin
type lignans via the Garratt–Braverman cyclization followed by
oxidation to the lactone. The selectivity issues in both the reactions
have been judiciously addressed by suitable perturbation of the
A.B. thanks the DST for providing a research grant and also for
the 400 MHz NMR facility under the IRPHA programme. S.M. is
grateful to the CSIR, Government of India for a fellowship.

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S. Mondal et al. / Tetrahedron Letters 52 (2011) 1183–1186
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Mn
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Mn
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KMnO4
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O
O
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O
O
HMnvO3
O
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H2O
+
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OH
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O
H
x
MeO
H
R
O
O
H
O
R
Mn
O
O
A
X
O
H
14. The correct IUPAC name of the isofuran derivative is 1,3-dihydro-naphtho[2,3-
c]furan.
H
O
R
15. General procedure: For Garratt–Braverman cyclization: To a solution of bis-
propargyl ether in toluene, KOBut (1.0 equiv) was added and refluxed at 110 °C
for 3 h. It was then evaporated under reduced pressure and diluted with ethyl
acetate, washed with water, brine and dried over Na2SO4. The ethyl acetate
was then evaporated and products were isolated by column chromatography
(Si-gel, petroleum ether–ethyl acetate as eluent).
H
R
O
:
OMe
O
Mn
O
O
For phenols O-methylation: The phenolic compounds were dissolved in acetone
and MeI (2.0 equiv per phenolic OH group) and K2CO3 (1.2 equiv per phenolic
OH group) were added and the mixture was refluxed at 56 °C for 2 h. Acetone
was then evaporated and diluted with water and extracted with ethyl acetate.
The organic layer was washed with brine and dried over Na2SO4. The ethyl
acetate was then evaporated and product was isolated by column
chromatography (Si-gel, petroleum ether–ethyl acetate mixture as eluent).
For benzylic oxidation: Equal weights of potassium permanganate and copper
sulfate pentahydrate were ground together in a mortar. The resulting fine,
B
Y
Scheme 5. Mechanism of lactone formation.
Supplementary data
highly coloured product was used as
a heterogeneous oxidant (3.2 g for
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.011.
1.4 mmol) in a methylene chloride solution of dihydroisofuran derivative and
stirred vigorously under gentle reflux for 72 h. The resulting mixture was then
filtered through a Celite pad and concentrated. The products were isolated by
column chromatography (Si-gel, petroleum ether–ethyl acetate mixture as
eluent).
References and notes
16. A detailed study on the electronic effect on GB cyclization has been carried out
using other electron withdrawing groups like nitro and cyano: Maji, M.;
Mallick, D.; Mondal, S.; Anoop, A.; Bag, S. S.; Basak, A.; Jemmis, E. D.
Org. Lett., accepted for publication. Manuscript under preparation. In the
present work, benzoate was used as the electron withdrawing group as it could
be readily hydrolysed to the phenol.
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17. The selectivity showed by the reaction indicated that the benzoate was
hydrolysed after the GB process.
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19. Representative spectral data. Compound 15: yellow viscous liquid; Yield 98%; 1
H
NMR (200 MHz, CDCl3) dH 3.17 (3H, s), 3.75 (3H, s), 3.76 (3H, s), 3.86 (3H, s),
4.71 (2H, s), 5.12 (2H, s), 6.82 (2H, d, J = 8.4 Hz), 6.87 (1H, s), 7.08 (2H, d,
J = 8.4 Hz), 7.40 (1H, s). 13C NMR (50 MHz, CDCl3) dC 55.2, 55.7, 60.6, 61.0, 73.4,
73.5, 103.1, 112.9, 117.8, 112.4, 128.9, 130.5, 132.0, 134.2, 136.9, 137.2, 142.2,
150.0, 152.5, 158.1. MS: m/z = 389.14 [MNa+], 367.13 [MH+]; HRMS: calcd for
C
22H22O5+H+ 367.1445; found 367.1461. Compound 15a: yellow viscous liquid;
Yield 89%; 1H NMR (400 MHz, CDCl3) dH 3.30 (3H, s), 3.85 (3H, s), 3.93 (3H, s),
4.02 (3H, s), 5.05 (2H, s), 6.98 (2H, d, J = 8.7 Hz), 7.16 (1H, s), 7.21 (2H, d,
J = 8.7 Hz), 8.30 (1 h, s). MS: m/z = 403.11 [MNa+], 381.12 [MH+]; HRMS: calcd
for C22H20O6+H+ 381.1338; found 381.1347.
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