An unexpected thermal [1,3]-[1,3]-para rearrangement of chromone-3-ylmethyl aryl ethers: Mechanism and application of the intercepted [1,3]-rearranged intermediates to the synthesis of cis-homopterocarpans

Article abstract of DOI:10.1246/cl.141162

Chromone-3-ylmethyl aryl ethers with unsubstituted orthopositions have been found to undergo a novel domino [1,3]-[1,3]-rearrangement to give 4′-hydroxyhomoisoflavones under thermal conditions while the para-substituted ethers lead to 2′-hydroxyhomoisofla

Full text of DOI:10.1246/cl.141162

Received: December 17, 2014 | Accepted: January 14, 2015 | Web Released: January 27, 2015
CL-141162
An Unexpected Thermal [1,3]-[1,3]-para Rearrangement of Chromone-3-ylmethyl Aryl Ethers:
Mechanism and Application of the Intercepted [1,3]-Rearranged Intermediates
to the Synthesis of cis-Homopterocarpans
Krishnan Devarajan,1 Somasundaram Devaraj,1 Kalpattu K Balasubramanian,2 and Shanmugasundaram Bhagavathy*1
1Department of Chemistry, B. S. Abdur Rahman University, Seethakathi Estate, Vandalur, Chennai 600 048, India
2Shasun Pharmaceuticals Ltd., Vandalur Kelambakkam Road, Vandalur, Chennai 600 048, India
(E-mail: bhagavathy@bsauniv.ac.in)
R5
R6
Chromone-3-ylmethyl aryl ethers with unsubstituted ortho-
R7
R4
positions have been found to undergo a novel domino [1,3]-
O
O
O
O
ArO-K+
DMF
PBr3
[1,3]-rearrangement to give 4¤-hydroxyhomoisoflavones under
thermal conditions while the para-substituted ethers lead to 2¤-
hydroxyhomoisoflavones involving an O- to C-[1,3]-migration,
instead of the expected Claisen rearrangement. A few cis-
homopterocarpans have been synthesized using the 2¤-
hydroxyhomoisoflavones obtained from the thermal [1,3]-
rearrangement of chromene-3-ylmethyl aryl ethers.
R3
OH
Br
CH2Cl2
O
R1
R1
R1
R2
O
R2
O
2
R2
1
3a-k
Scheme 1. Synthesis of aryl ethers 3.
Table 1. Synthesis of chromone-3-ylmethyl aryl ethers 3
Entry Ether 3 R1
R2
R3 R4
R5
R6 R7 Yielda/%
1
2
3a
3b
H
H
H
H
H
H
H
H
H
H
H
82
69
Despite the passage of more than ten decades, Claisen
rearrangement1 continues to receive wide attention for its
synthetic applications as well as for its mechanistic aspects.2
The aromatic Claisen rearrangement which involves a [3,3]-
sigmatropic shift provides a convenient entry to ortho-allylphe-
nols, precursors to a variety of heterocycles such as chromans,
coumarins, etc. The intervention of O- to C-[1,3]-migration is
very rarely encountered in an uncatalyzed thermal aromatic
Claisen rearrangement,3 though this is frequently observed under
conditions of acid catalysis and transition-metal catalysis.2a,2c,4
The para-Claisen rearrangement typically follows a domino
pathway viz., ortho-Claisen rearrangement, which involves a
[3,3]-sigmatropic shift followed by a Cope rearrangement that is
also a [3,3]-sigmatropic shift. But, there are hardly any examples
of para-Claisen rearrangements involving a domino [1,3]-[1,3]-
migration.5 During the course of our study on the thermal
Claisen rearrangement of chromone-3-ylmethyl aryl ethers 3, we
encountered an unexpected and rare para-Claisen rearrangement
that we describe in this paper. Thermally, the aryl ether 3 with
unsubstituted para-position and at least one unsubstituted ortho-
positions leads to the formation of 4¤-hydroxyhomoisoflavones
4 via a novel domino [1,3]-[1,3]-rearrangement, while the para-
substituted aryl ether leads to 2¤-hydroxyhomoisoflavones 6
via a direct [1,3]-shift. We also report the synthesis of a few
homopterocarpans using our [1,3]-ortho rearrangement strategy.
Our initial attempts to synthesize the chromone-3-ylmethyl
aryl ethers 3 via the Buchwald-Hartwig coupling reaction of the
alcohol6 1 with aryl halides led only to the formation of trimeric
compounds.7 Hence, the aryl ethers 3a-3k were prepared in
very good yields from the respective alcohol 1 by the standard
sequence of reactions as depicted in Scheme 1 (Table 1).
-CH=CH-
CH=CH-
H
H
H
H
3
4
5
3c
3d
3e
H
H
H
Cl
Me
H
H
H
Me
H
H
H
H
H
Me
H
H
H
76
66
69
-CH=CH-
CH=CH-
6
3f
Me
H
H
H
H
73
7
8
9
10
11
3g
3h
3i
3j
3k
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
Cl
Et
OMe
H
H
H
H
H
Me
H
H
H
H
76
80
71
71
68
aIsolated yield after column chromatography.
R5
R6
R7
R7
R4
O
O
O
O
R6
OH
R3
O
O
OCOCH3
PhOPh
Reflux
O
R3
R1
R1
R
5 = H
R2
R2
R4
3a-g
5a
4a-g
Scheme 2. Thermal rearrangement of para-unsubstituted aryl
ethers 3a-3g.
ment (Scheme 2). The structure was also confirmed by charac-
terizing its acetate derivative 5a. A few other para-unsubstituted
ethers 3b-3g also underwent similar rearrangements to afford
the corresponding 4¤-hydroxyhomoisoflavones 4b-4g (Table 2).
But, the para-substituted aryl ether 3h upon refluxing in
Ph2O afforded the 2¤-hydroxyhomoisoflavone 6h,8 a product of
formal [1,3]-shift. It is to be noted here that we did not observe
the product due to [3,3]-shift viz., 7 (Scheme 3 and Table 2), in
any of the cases.
Thermal rearrangement of the ether 3a was investigated in
different solvents like DMF, o-dichlorobenzene, N,N-diethylani-
line, diphenyl ether, etc. Among these, diphenyl ether (Ph2O)
turned out to be the best solvent which led to a relatively faster
reaction (4 to 5 h) with good yields. Refluxing the ether 3a in
Ph2O for 4 h led to the product 4a, product of para-rearrange-
Recently, Hou et al.3 had observed that thermal rearrange-
ment of aryl cinnamyl ethers gave rise to a mixture of products
due to normal [3,3]-shift and formal [1,3]-shift. These authors
have shown that the formal [1,3]-shift product actually stems
from a domino process due to migration of the aryloxy moiety
Chem. Lett. 2015, 44, 551–553 | doi:10.1246/cl.141162
© 2015 The Chemical Society of Japan | 551

Table 2. Thermal rearrangement of chromone-3-ylmethyl aryl
ethers 3 in Ph2O
O
O
O
O
Ph2O / reflux
O
Cs2CO3 (2 equiv)
Yielda
/%
Entry Substrate R1
R2 R3 R4 R5 R6 R7 Pdt
OH
6a 76% yield
3a
1
2
3a
3b
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
84
-CH=CH-
CH=CH-
H
H
H
Scheme 4. Rearrangement of ether 3a in the presence of
Cs2CO3.
73
3
4
5
3c
3d
3e
H
H
H
Cl
Me
H
H
H
Me
H
H
H
H
H
Me
H
H
H
4c
4d
4e
72
71
66
ortho stage by bringing about the rapid enolisation of the ortho-
dienone.11 We found no change in the course of the reaction
upon refluxing the ether 3a in Ph2O in the presence of CaCO3,
and the same para-migration product 4a was isolated. Interest-
ingly, the rearrangement of aryl ether 3a to the phenol 6a, which
is the product of [1,3] migration could be achieved by using
Cs2CO3 (Scheme 4). Further, in a control experiment, it was
observed that the phenolic product of ortho [1,3]-rearrangement
6a was stable under thermal conditions and did not get converted
to the para-rearrangement product 4a. These findings reveal that
the first intermediate in the para-rearrangement arises out of
a direct migration of the chromenylmethyl moiety from O- to
ortho carbon, viz., O to C-[1,3]-shift.
When the progress of the reaction in the case of 3a was
followed by HPLC, no evidence could be seen for the formation
of ortho-dienone intermediate or for the phenol 6a indicating
that para-rearrangement is much faster compared to the initial
ortho-migration and enolisation of the ortho-dienone. Nor was
there any indication for the intermediate 8 (Scheme 5).3
In the case of the rearrangement of para-substituted ether
3h, HPLC and NMR reaction monitoring again did not reveal
the formation of any intermediate. The NMR spectra of the
samples taken in the early stages were devoid of the signals due
to the exomethylene protons and acetal protons, characteristic of
8, which is a crucial intermediate in the mechanistic pathway
based on the work of Hou et al.3 Thus, the HPLC and NMR
reaction monitoring of this rearrangement clearly rules out a
domino C- to C-[1,3] and O- to C-[3,3]-pathway for the ortho-
rearrangement. Based on the above data, we propose that the
ortho-rearrangement proceeds through a concerted O- to C-[1,3]-
shift, while the para-rearrangement proceeds through a domino
O- to C-[1,3]-rearrangement and C- to C-[1,3]-shifts as outlined
in Scheme 5.
Following this, we applied our strategy towards the synthe-
sis of cis-homopterocarpans via a simplified route. Homoptero-
carpans possessing the benzopyrano-[4,3-b]-[1]-benzopyran
system are biologically active compounds homologous to the
second largest group of natural isoflavonoid pterocarpans.12 So
far, only a few syntheses have been reported for cis-homoptero-
carpans.13 We could successfully convert the 2¤-hydroxyhomo-
isoflavones 6 to the respective cis-homopterocarpans 10 as
outlined in Scheme 6. Palladium-catalyzed hydrogenation of 6
in the presence of pyridine yielded cis-chromanol 9 in 69% to
78% yields. Our attempts at the intramolecular Mitsunobu
reaction of 9 did afford the cis-homopterocarpans 10, but in very
low yield. However, heating the chromanol 9 in acetic acid
resulted in a smooth cyclodehydration, furnishing the cis-
homopterocarpans 10 in good yield. The NMR spectral data of
10 were in accordance with those reported in literature.13a
In conclusion, we describe an unusual ortho rearrangement
involving a rare [1,3]-shift and a novel para-rearrangement in-
volving a domino [1,3]-[1,3]-migration of chromone-3-ylmethyl
-CH=CH-
CH=CH-
6
3f
Me
H
H
H
H
4f
76
7
8
9
10
11
3g
3h
3i
3j
3k
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
Cl
Et
OMe
H
H
H
H
H
Me 4g
68
83
73
69
65
H
H
H
H
6h
6i
6j
6k
aIsolated yields after column chromatography.
R5
R5
R3
R6
O
R6
R4
R3
R5
R7
R4
R6
R4
R3
O
O
O
O
O
PhOPh
Reflux
R5 = H
OH
R1
R1
R1
R2
O
R2
R2
OH
I
7
3h-k
6h-k
Scheme 3. Thermal rearrangement of para-substituted aryl
ethers 3h-3k.
from α- to γ-position of the allyl group (C- to C-[1,3]-shift),
designated by them as O[1,3] shift, followed by a [3,3]-shift.
Majumdar et al. observed that thermal rearrangement of cou-
marin-3-ylmethyl aryl ethers led to para-migration products
when the para-position is unsubstituted and ortho [1,3]-products
when the para-position is blocked.9 They speculated that the
para-rearrangement proceeds through a direct migration of the
allyl moiety involving a [1s,5s]-shift (which is geometrically not
feasible) and the ortho-rearrangement via a [1s,3s]-shift. In view
of these reports, we investigated the mechanism of our trans-
formation of the ethers 3 to the aryl chromones 4 and 6 in detail.
We observed that the thermal transformation of the ether 3a
to chromone 4a was inhibited neither when the reaction was
performed in N,N-diethylaniline, which is known to be a good
free radical inhibitor,10 nor in the presence of free radical
inhibitors like Tempo or BHT in Ph2O. The possibility of a
breakage of the ether 3 into its ion pairs and recombination of
the ion pairs within the solvent cage is ruled out, as there was no
change in the course of the reaction on going from nonpolar
Ph2O to a mixture of Ph2O and dipolar aprotic N-methyl-
2-pyrrolidone, as monitored by HPLC. The findings from a
crossover experiment conducted with ethers 3b and 3d ruled out
the possibility of a breakage and recombination mechanism.
When an equimolar mixture of the ethers 3b and 3d was refluxed
in Ph2O and the crude products analyzed by HPLC, we could
detect only the phenols 5b and 5d and no evidence could be
found for the presence of the crossover products 5a and 5f. In
addition, we did not find any evidence for the formation of bis-
alkylated products,4a which rules out the mechanism based on
breakage and ion pair recombination outside the solvent cage. It
is known that CaCO3 can stop the Claisen rearrangement at the
552 | Chem. Lett. 2015, 44, 551–553 | doi:10.1246/cl.141162
© 2015 The Chemical Society of Japan

R
O
R
H
O
O
O
O
O
O
O
O
O
O
OH
[1,3]
[1,3]
H
R = H
R = H
R
O
R
O
3
O
[1,3]
4
8
R5
I
= H
R
O
O
O
H
O
OH
O
6
Scheme 5. Mechanistic pathway for the thermal rearrangement of chromone 3.
O
Cervantes, F. Franco, S. T. Cutler, D. G. Loughhead, D. J.
Morgans, Jr., R. J. Weikert, Tetrahedron Lett. 1997, 38,
4725.
R1
H
R1
O
O
O
Pd/C-H2, pyr.
MeOH/EtOAc
H
AcOH/reflux
O
5
6
There is no well-documented example for para-Claisen
rearrangement involving a domino [1,3]-[1,3]-migration.2a,2f
a) R. Araya-Maturana, J. Heredia-Moya, H. Pessoa-Mahana,
B. Weiss-López, Synth. Commun. 2003, 33, 3225. b) C. K.
Ghosh, S. Bhattacharyya, Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1997, 36, 267.
OH
R1
OH
OH
10a-c
6
9a-c
9a, 10a R1 = H
9b, 10b R1 = Me
9c, 10c R1 = Et
Scheme 6. Synthesis of cis-homopterocarpans 10.
7
8
9
K. Devarajan, K. K. Balasubramanian, S. Bhagavathy, Synth.
Commun. 2013, 43, 2165.
F. M. Dean, M. Malki, L. J. O’Keeffe, J. Chem. Soc., Perkin
Trans. 1 1993, 2675.
K. C. Majumdar, G. H. Jana, S. K. Ghosh, S. Saha, Monatsh.
Chem. 1997, 128, 641.
aryl ethers under thermal conditions. cis-Homopterocarpans
have been synthesized using the 2¤-hydroxyhomoisoflavones.
Our method provides yet another entry to homoisoflavonoids,
which allows variation in both the aromatic rings. The 3-
benzylchromones (homoisoflavones) 4 and 6 are known to
possess anti-inflammatory, antioxidant, antiproliferative, anti-
fungal, antiviral, and antimutagenic activities.14,15 Comparative
biological studies on these homopterocarpans and homoisofla-
vones are in progress.
10 A. W. Burgstahler, L. K. Gibbons, I. C. Nordin, J. Chem.
Soc. 1963, 4986.
11 a) R. Irie, K. Noda, Y. Ito, T. Katsuki, Tetrahedron Lett.
1991, 32, 1055. b) R. Irie, K. Noda, Y. Ito, N. Matsumoto, T.
Katsuki, Tetrahedron: Asymmetry 1991, 2, 481.
The authors thank DST, New Delhi for financial support
(SR/S1/OC11/2010).
12 a) L. Jiménez-González, M. Álvarez-Corral, M. Muñoz-
Dorado, I. Rodríguez-García, Phytochem. Rev. 2008, 7, 125.
b) C. Selvam, S. M. Jachak, R. G. Oli, R. Thilagavathi, A. K.
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Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 551–553 | doi:10.1246/cl.141162
© 2015 The Chemical Society of Japan | 553