An unexpected acid mediated rearrangement of monoethylene ketal of 2-methyl-2-(3-methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to chromane

Article abstract of DOI:10.1016/j.tetlet.2018.02.045

We herein report a serendipitously observed acid mediated rearrangement of monoethylene ketal of 2-methyl-2-(3-methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to Dihydrobenzopyran and demonstrated the application of this methodology in the construction of core carbon scaffolds of dimethoxyajacareubin, cariphenone-A and crotamadine.

Full text of DOI:10.1016/j.tetlet.2018.02.045

Accepted Manuscript
An unexpected acid mediated rearrangement of monoethylene ketal of 2-meth-
yl-2-(3-methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to chromane
Kukkamudi Sreenivas, Faiz Ahmed Khan
PII:
S0040-4039(18)30234-X
https://doi.org/10.1016/j.tetlet.2018.02.045
TETL 49730
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
29 January 2018
15 February 2018
16 February 2018
Please cite this article as: Sreenivas, K., Khan, F.A., An unexpected acid mediated rearrangement of monoethylene
ketal of 2-methyl-2-(3-methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to chromane, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.02.045
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An unexpected acid mediated rearrangement
of monoethylene ketal of 2-methyl-2-(3-
methylbut-2-en-1-yl)cyclohex-4-ene-1,3-
diones to chromanes.
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Kukkamudi Sreenivas, Faiz Ahmed Khan*

1
Tetrahedron Letters
An unexpected acid mediated rearrangement of monoethylene ketal of 2-methyl-2-(3-
methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to chromane
Kukkamudi Sreenivas, Faiz Ahmed Khan*
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy 502285, Telangana, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We herein report a serendipitously observed acid mediated rearrangement of monoethylene ketal
of 2-methyl-2-(3-methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to Dihydrobenzopyran and
demonstrated the application of this methodology in the construction of core carbon scaffolds of
dimethoxyajacareubin, cariphenone-A and crotamadine.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
[3,3]-sigmatropic rearrangement
Prenyl cation
Dimethoxyajacareubin
Cariphenone-A
Crotamadine
1. Introduction
Dihydrobenzopyran and monoterpene substituted resorcinol
derivatives are ubiquitous in both natural products and
pharmaceutically important substances.1 These compounds are
well known to show a variety of biological activities such as anti-
HIV,2 anti-inflammatory, antimicrobial, cytotoxic,3 tyrosinase
inhibitors,4 antioxidative,5 plant growth inhibitory and known to
control the anticholesteremic level in blood and liver.6 Some of
the biologically important natural products are shown in Figure
1.7-12 Because of this importance, various notable approaches
have been reported in the literature for their synthesis.
The dihydrobenzopyran framework has been traditionally
synthesized from Claisen rearrangement of O-allylated phenol
derivatives followed by acid-catalyzed cyclization.13 Another
convenient procedure is condensation of phenols with 1,3-dienes
or allylic alcohols.14 A tandem C-C and C-O bond forming
reaction between various phenols and allylic alcohols mediated
Figure 1. Naturally occurring biologically important compounds
In connection with an ongoing project, we prepared 2-prenyl
substituted monoethylene ketal of 2,4-dimethylcyclohex-4-ene-
1,3-dione. In our efforts to hydrolyze the monoethylene ketal
moiety in 10a under the usual hydrolytic conditions (Table 1,
entry 1), we observed the formation of three chromatographically
separable products. Isolation and detailed NMR spectroscopic
analysis confirmed the formation of 11, 12, and 13 in 8%, 41%
and 24% yield, respectively (73% overall). Prompted by this
interesting observation, we investigated the reaction in order to
optimize to get dihydrobenzopyrans as the main product. Table 1
depicts the results.
by
recyclable
mesoporous
catalyst
furnished
dihydrobenzopyrans.15 Several catalytic methods have been
developed from phenols and allylic derivatives leading to
dihydrobenzopyrans.16 Herein, we report an unexpected acid
induced tandem method for the synthesis of dihydrobenzopyrans
from monoethylene ketal of 2-methyl-2-(3-methylbut-2-en-1-
yl)cyclohex-4-ene-1,3-dione derivatives.
.
———
* Corresponding author. Tel.: +91 (040)23016084; e-mail: faiz@iith.ac.in (F.A. Khan).

2
Tetrahedron Letters
compound 11 was further confirmed by single crystal x-ray
diffraction analysis (Figure 2).
Table 1. Optimization table for acid mediated tandem
reaction for synthesis of 11a,b,c
Table 2. Lewis acid promoted rearrangement reaction on 10a
Entry Compound Time
Products
Entry
Reagent
Temp.
Solvent
11 d
(%)
12
(%)
13
(%)
1
2
6N HCl
3% HCl
RT
Acetone:H2O
Acetone:H2O
8
41
24
1b
2a
3b
10b
15 h
0 oC to RT
Trace
24
12
3
4
6% HCl
RT
RT
Acetonitrile
THF
8
-
28
-
-
10%
H2SO4
1 6
10c
10d
6 h
5
6
TFA
RT
Acetone:H2O
THF:H2O
Trace
8
24
32
-
PTSA
60 oC
12
7
8
PPTS
AlCl3
60 oC
RT
THF:H2O
Trace
-
24
21
15
41
-
-
15 h
Acetone:H2O
CH3CN:H2O
Acetone:H2O
Acetone:H2O
Acetone:H2O
Acetone:H2O
Acetone:H2O
Acetone:H2O
Acetone:H2O
Acetone:H2O
1,4-dioxane
-
9
CAN
RT
Trace
41
79
12
61
76
30
15
18
5
Trace
10
11
12
13
14
15
16
17
18
19b
20c
Amberlyst
Bi(OTf)3
Zn(OTf)2
La(OTf)3
In(OTf)3
InCl3
72 oC
-
-
72 oC
4b
10e
15 h
72 oC
41
-
16
-
72 oC
72 oC
-
-
aReaction conditions: a) compound 10 (1 mmol), Bi(OTf)3 (1.3 mmol),
72 oC
24
25
-
-
o
solvent acetone:H2O 1 mL per 1 mmol, 72 C, 6 h; b) compound (1 mmol),
reagent (1.3 mmol), solvent acetone:H2O 1 mL per 1 mmol, 50 oC, 15 h.
RuCl3
72 oC
-
Having optimized reaction condition in hand, the scope of
reaction with respect to the cyclohexenone derivatives 10a-e was
examined (Table 2). These cyclohexenone derivatives were
prepared from cyclohexane-1,3-dione as shown in Scheme 1.
Cyclohexane-1,3-diones 7a-c were prenylated or geranylated
according to literature procedure by using diisopropylethyl
PdCl2
72 oC
-
BF3-OEt2
BF3-OEt2
BF3-OEt2
rt to 70 0C
rt to 70 0C
rt to 70 0C
-
-
Acetone:H2O
Acetone:H2O
-
30
8
40
10
amine, at 0 C to room temperature17 and the resulting products
o
60
(8a-e) were further functionalized as a monoethylene ketals 9a-e
in the presence of p-toluenesulfonic acid. Conversion of 9a-e to
the enones 10a-e was accomplished via silyl enol ethers using
trimethylsilyl trifluoromethanesulfonate (TMSOTf) in the
presence of triethyl amine18 followed by Wacker-Tsuji oxidation
of the crude silyl enol ethers, filtered through a short silica gel
pad, in good yield (Scheme 1).19
aReaction conditions: compound 10a (1 mmol), reagent (1.3 mmol), in
solvent (1mL) at mentioned temperature. bBF3-OEt2 (1.2 eq). cBF3-OEt2 (5
eq). dYields are after column chromatography.
Furthermore, various Bronsted acids such as sulfuric acid,
trifluoroacetic acid, and p-toluenesulfonic acid (PTSA) promoted
the reaction to give mainly 12, albeit in low yield (Table 1,
entries 4-9). Subsequently, we investigated Lewis acidic InCl3,
RuCl3, and PdCl2, which though yielded the desired
dihydrobenzopyran along with 12 but with low efficiency (Table
1, entries 15-17). Amberlyst-15 in acetone and water at 72 oC
furnished 1:1 ratio of 11 and 12 with overall 82% yield (Table 1,
entry 10). Use of BF3-OEt2 (Table 1, entries 18-20) did not
improve the reaction outcome significantly.
Reaction of these differently substituted cyclohexenone
derivatives (10b-e) were examined under conditions optimized
for 10a (Table 1). The geranyl substituted cyclohexenone
derivatives 10b and 10d gave a complex mixture under these
conditions. However, when 10b, was treated with Bi(OTf)3, in
acetone and water at 50 oC for 15 h, it furnished interesting
structural motifs 14a, 14b in 32%, 52% yield respectively (84%
overall, Table 2, entry 1). Similarly, 10d gave 16a, 16b in 23%,
60% yield respectively (83% overall, Table 2, entry 3).
Moreover, diprenyl substituted cyclohexenone derivative 10e
provided the diprenyl substituted resorcinol derivative 17 in
moderate (48%) yield (Table 2, entry 4). As expected, 10c which
is similar to 10a sans an -methyl group, afforded corresponding
chromane derivative 15a in 79% yield (Table 2, entry 2).
We then turned our attention to metal triflates due to their well
known reactivity and selectivity as Lewis acids. Among the
triflates that we explored, Zn(OTf)2 was not selective and
La(OTf)3 gave a single, desired product in moderate yield (Table
1, entries 12 and 13). While Bi(OTf)3 and In(OTf)3 (Table 1,
entries 11 and 14) afforded selectively single product with very
good yield. The results depicted in Table 1 shows that Bi(OTf)3
o
and In(OTf)3 in acetone and water at 72 C furnished with good
yield (79%) and selectively single cyclized product 11. The

3
Scheme 1. Synthesis of the cyclohexenone derivatives (10a-e).
chloride in-situ using ZnCl2/POCl3 at 68 C for 1.5 h20 to obtain
the desired core structures 19a-c selectively in moderate to good
yield (Scheme 2).
o
Scheme 2. Synthesis of natural product core structures 19a
Scheme 3. A plausible mechanism for the formation of 2,2-
dimethyl-3,4-dihydrobenzopyran (11).
Entry
Compound
15a
18
Yieldb
Products
83%
1
Vanillic acid
(18a)
15a
15b
65%
41%
2
3
Benzoic acid
Based on isolated intermediates 12 and 13 enroute to 11, a
plausible mechanism as depicted in Scheme 3 is proposed.
Hydrolysis followed by dienone-dienol tautomerization provides
the driving force for the C-C bond cleavage through formation of
aromatic species along with a relatively stable prenyl cation.21
This proposal is corroborated by the isolation and
characterization (1H and 13C NMR) of trace amount of 2,4-
(18b)
4-
Hydroxycinna
mic acid (18c)
dimethylbenzene-1,3-diol.
Recombination
of
2,4-
aReaction condition: Compound 15 (0.1 mmol), 18 (0.1 mmol), ZnCl2 (0.3
mmol), POCl3 (0.8 mL), at 68 0C. bYields are after column chromatography.
dimethylbenzene-1,3-diol and prenyl cation leads to 12 and 13.
Only 13 got converted to 11 under the reaction conditions,
leaving behind unreacted 12.
To demonstrate a synthetic application of this tandem
cyclization reaction, construction of core carbon scaffolds of
some related biologically active natural products such as
dimethoxyajacareubin 4, cariphenone-A 5, crotamadine 6, from
Scheme 4. Cyclization of 20 via [3,3]-sigmatropic
rearrangement.
chromane
derivatives
15a-b
was
achieved.
Dimethoxyajacareubin 4 and cariphenone-A 5 exhibited strong
antioxidative property.10,11 Crotamadine 6 showed antifungal
activity against trichophyton mentagrophytes.12 We envisaged
that a straightforward Friedel-Crafts acylation of 15a or its
methyl ether derivative 15b using appropriately substituted
benzoic or cinnamic acids 18a-c would lead to the core skeletons.
Accordingly, acylation was carried out by generating the acid

4
Tetrahedron
When the compound 12 was separately subjected to Lewis
substituted benzoic or cinnamic acids. Moreover, we have
detailed a mechanistic proposal supported by isolation of key
resorcinol intermediate.
acid mediated cyclization, the cyclized product was not observed.
Interestingly, when the para-position to the cyclizing OH group
(shown in blue color) is unsubstituted (R = H, 20) efficient
cyclization occurred to give unexpected 15a in 87% yield. This
was possible through a sequence of transformations involving
keto-enol tautomerization, [3,3]-sigmatropic shift and cyclization
with other OH (shown in red color), leading to 15a as outlined in
Scheme 4. Having isolated 13, it was separately subjected to
cyclization using different Lewis acids (Table 3). Among them
Bi(OTf)3, In(OTf)3, and Cu(OTf)2 afforded excellent yields
(Table 3, entries 3, 4, 5). Similarly, 17 was subjected to Cu(OTf)2
and BF3-OEt2 mediated bis-cyclization to obtain 21 (Scheme 5).
Acknowledgments
Supplementary material
The detailed experimental procedures and spectroscopic data are
available in supporting information at.
References and notes
Table 3. Lewis acids catalyzed cyclization reaction of 13a.
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Catalystb
Time (h)
Yield (%)
Zn(OTf)2
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4
53
La(OTf)3
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87
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Scheme 5. BF3-OEt2 mediated cyclization of 17
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In conclusion, we have reported an unprecedented acid induced
tandem method for the synthesis of dihydrobenzopyrans from
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5
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6
Tetrahedron
serendipitous
Highlights:
 An
acid
mediated
rearrangement to dihydrobenzopyran is
reported.
 A crucial C-C bond cleavage is responsible
for the formation dihydrobenzopyran.
 Core scaffolds of dimethoxyajacareubin,
cariphenone-A, crotamadine synthesized.