Organic Br?nsted acid-catalyzed cycloadditions of o-quinone methides with 1, 3-dicarbonlys: Facile access to xanthenones and chromanones

Article abstract of DOI:10.1002/jhet.4323

The in-situ generation of o-quinone methides and their inverse-electron-demand Diels–Alder reaction in the presence of pentacarboxycyclopentadiene—an organic Br?nsted acid—has been reported. The synthesis of xanthenones and chromanones in good to excellen

Full text of DOI:10.1002/jhet.4323

Organic Brønsted Acid Catalysed Cycloadditions of o-
Quinone Methides with 1, 3-Dicarbonlys: Facile Access to
Xanthenones and Chromanones
Thoppe Sivakumar Priyadarshinia,b,#, Puthiyaparambath Sharathnaa,b,#, Suresh V Sanjaya, Parameswaran Sasikumara,
Kokkuvayil Vasu Radhakrishnana*
a
Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and
Technology (CSIR-NIIST), Thiruvananthapuram 695019, India
b
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
* radhu2005@gmail.com
# The authors have contributed equally
Received: ((will be filled in by the editorial staff))
((Additional Supporting Information may be found in the online version of this article.)).((Please delete if not
appropriate))
Abstract.
The in-situ generation of o-quinone methides and their
inverse electron demand Diels-Alder reaction in the presence
of pentacarboxycyclopentadiene – an organic Brønsted Acid
has been reported. The synthesis of xanthenones and
chromanones in good to excellent yields from the [4+2]
cycloaddition of quinone methides with 1, 3- dicarbonyls
and Meldrum’s acid has been accomplished. The
development of this method helps in generating a number of
biologically potent heterocycles with medicinal applications.
Keywords: Organic Brønsted Acid;
Pentacarboxycyclopentadiene; o-Quinone methide; Inverse
Electron Demand Diels Alder reaction; Xanthenones;
Chromanones
Introduction
Quinones are important structural motifs in synthetic organic chemistry with fascinating chemistry
and wide distribution in nature [1].Benzoquinones are the simplest form of quinones in which a six-
membered ring containing two double bonds in conjugation with one another along with two carbonyl
groups either in the 1,2 (ortho) or 1,4 (para) positions. The immense potential of benzoquinones for
the synthesis of biologically relevant heterocycles attained the attention of scientific community for
the last few decades. Our group was also interested in this area and reported [2] the cycloaddition of
benzoquinones with various partners which delivered various novel heterocyclic compounds like
spirodioxazoles [3], spirodioxazolines [4], benzodioxinones [5] and azapolyclyes [6]. Our research
team has also conducted investigations on the analogues of benzoquinones where one oxygen atom is
replaced by a sulphur atom (o-thioquinones) [7] or a carbon atom (quinone methides) [8] which
drastically expands the horizons of heterocyclic chemistry.
o-Quinone methides, analogues of benzoquinones with relative positions of the carbonyl group and
the exocyclic double bond – 1, 2 (o-quinone methide) are short lived reactive intermediates. These
synthons have occupied pivotal role in the field of organic synthesis due to their contribution in the
synthesis of varied heterocycles. They usually react in one of the three pathways [9] – (a) as an
electron poor diene in an inverse- electron demand Diels-Alder reaction, (b) as a Michael acceptor in
conjugate addition or (c) as a part of oxa-6π electrocylisation reaction. There have also been many
reports of [4+2], [4+3], [4+4] reactions where o-quinone methide is the 4π component that undergoes
cyclization with various partners resulting in the formation of expanded heterocycles [10]. There is an
extensive amount of literature regarding both the generation as well as the numerous reactions of
quinone methides towards the formation of a rich reserve of heterocycles [11].
The generation of quinone methides is a well-explored area involving the use of an impetus to break
their aromaticity. Transition metals [12], chemical oxidants [13], fluoride based reagents [14], thermal
activation [15], photochemical activation [16] and ionic liquids [17] have been used extensively for
generating quinone methides. There are many other methods available in the literature [18], although
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the simplest method available to date is the use of acids/bases to generate o-quinone methides. There
are innumerable reports of using Lewis acids [17], Brønsted acids [18] and bases [19] to facilitate the
formation of o-quinone methides and their subsequent reactions. Among the colossal number of
publications, a particular report by Gheewala and Lambert [20] attracted our attention, wherein they
have used an organic Brønsted acid for making o-quinone methide from salicylaldehyde diethyl acetal
to effect its cycloaddition with vinyl ethers. The synthesis of pentacarboxycyclopentadiene (PCCP),
with a pKa value of 8.85 making use of a potent combination of three factors– induction, resonance
and aromaticity was initially reported by Gheewala et al in 2016 [21].
Since our research group has a long standing interest in the chemistry of benzoquinones and an avid
interest towards natural products, we were naturally drawn towards the generation of quinone
methides and their application to the synthesis of various heterocyclic scaffolds having potential
biological applications. In this paper, we have successfully studied the generation of quinone methides
and their inverse electron Diels-Alder reaction catalysed by PCCP, an organic Brønsted acid.
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Experimental Section
General Procedure for the preparation of the o-hydroxybenzylalcohols (1a – 1e) [22]:
An oven dried flask equipped with a magnetic stir bar was charged with Mg turnings (0.717 g, 29.9 mmol), and
an iodine crystal. The round bottom was fitted with an oven dried reflux condenser and anhydrous THF (8.2
mL) was added. The mixture stirred for 5 minutes, and was treated dropwise with aryl bromide (24.6 mmol, 3
equiv). The Grignard mixture was allowed to stir at room temperature for 30-45 minutes. A solution of
salicylaldehyde (8.2 mmol, 1 equiv) in 41 mL of dry THF was added to the Grignard mixture slowly at 0 °C.
The reaction was monitored by TLC until completion and was quenched with NH4Cl (aq) (30 mL). The reaction
mixture was extracted with 2 x 30 mL Ether. The combined organic extracts were washed with brine, and dried
over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column
chromatography over silica with hexane: ethyl acetate polarities.
1
2-(hydroxy (phenyl) methyl) phenol (1a). White solid (4.67 g, 95%), m.p.. 72 °C H NMR (500MHz, Acetone,
TMS): δ 8.72 (s, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.27 – 7.22 (m, 2H), 7.10 (t, J = 7.5 Hz,
1H), 6.82 (d, J = 8.0 Hz, 2H), 6.14 (s, 1H), 5.33 (s, 1H) 13C NMR (125 MHz, Acetone, TMS): δ 156.9, 156.3,
129.6, 129.5, 129.2, 128.4, 128.0, 125.6, 121.2, 119.8, 117.1, 110.9 HRMS(ESI): C13H12NaO2 Calcd [M+Na]+
223.0735 Found 223.0736
2-((2,6-dimethylphenyl)(hydroxy)methyl)phenol(1b). Green solid (5.27 g, 94%) m.p.. 82 °C 1H NMR
(500MHz, CDCl3, TMS): δ 8.09 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.5 Hz,
1H), 6.31 (s, 1H), 2.32 (s, 3H), 2.22 (s, 3H) 13C NMR (125 MHz, CDCl3, TMS): δ 156.7, 148.9, 136.7, 135.9,
129.8, 126.8, 125.9, 124.8, 116.8, 69.8, 19.5, 19.2. HRMS(ESI): C15H16NaO2 Calcd [M+Na] + 251.1048 Found
251.1048
2-((2,3-dimethylphenyl)(hydroxy)methyl)phenol(1c). White solid (5.21 g, 93%) m.p.. 74 °C 1H NMR
(500MHz, CDCl3, TMS): δ 8.06 (d, J = 9.6 Hz, 1H), 7.17 (dt, J = 14.9, 7.9 Hz, 4H), 6.93 (d, J = 8.1 Hz, 1H),
6.76 (t, J = 7.5 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.32 (s, 1H), 2.33 (s, 3H), 2.23 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 156.15, 139.32, 137.72, 134.96, 130.23, 129.42, 128.16, 126.19, 126.10, 125.56, 120.04, 117.16,
74.37, 20.75, 15.34. HRMS(ESI): C15H16NaO2 Calcd [M+Na] + 251.1048 Found 251.1048
1
2-(hydroxy(3-methoxyphenyl)methyl)phenol (1d). White solid (5.15g, 91%) m.p.. 104 °C H NMR (500MHz,
CDCl3, TMS): δ 8.30 (s, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.24 – 7.19 (m, 1H), 6.95 (t, J = 8.0 Hz, 3H), 6.92 (s,
1H), 6.81 (s, 2H), 6.20 (d, J = 4.0 Hz, 1H), 3.89 (s, 3H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.93, 156.27,
129.58, 129.53, 129.25, 128.38, 128.03, 125.62, 121.24, 119.81, 117.15, 110.87, 73.25, 55.58 HRMS(ESI):
C14H15O3 Calcd [M+H]+ 230.0942 Found 230.0952
2-(hydroxy(p-tolyl)methyl)phenol (1e). White solid ( 5.07 g, 96%) m.p.. 92 °C 1H NMR (500 MHz, CDCl3): δ
8.11 (d, J = 4.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.25 (dd, J = 10.8, 4.7 Hz, 3H), 7.01 – 6.84 (m, 3H), 6.01 (s,
1H), 2.42 (s, 3H).13C NMR (125 MHz, CDCl3) δ 155.53, 139.07, 138.14, 129.51, 129.29, 128.34, 126.92,
126.86, 120.02, 117.30, 77.41, 21.25. HRMS(ESI): C14H14NaO2 Calcd [M+H]+ 237.0891 Found 237.0892
General Procedure for the inverse-electron demand Diels-Alder reaction
o-hydroxybenzyl alcohols (1.0 equiv) and 1,3-diketones (2.0 equiv) were added in the reaction tube followed by
2 mL of acetonitrile. The optimal PCCP catalyst (0.05 equiv) was then added and the reaction vial was stirred
for 12 hours at 80 °C. Upon completion of the reaction, as monitored by TLC and concentrated in vacuo. The
crude mixture was purified by column chromatography eluting with n-hexane-ethyl acetate.
9-phenyl-2,3,4,9-tetrahydro-1H-xanthen-1-one(3aa). Yellow Solid ( 96.6 mg, 70%) m.p. 119 °C
1
Rf = 0.42 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.19 (d, J = 8.0 Hz, 2H), 7.17 – 7.14 (m, 2H),
7.08 (dd, J = 13.5, 8.0 Hz, 3H), 7.01 (t, J = 7.5 Hz, 2H), 5.05 (s, 4H), 2.71 (dt, J = 17.5, 5.0 Hz, 1H), 2.64 – 2.58
(m, 1H), 2.42 – 2.29 (m, 2H), 2.05 – 1.94 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 197.02, 166.33, 149.55,
146.28, 130.14, 128.81, 128.49, 127.99, 127.70, 126.44, 125.50, 125.14, 116.54, 114.86, 37.90, 37.07, 27.97,
20.47. HRMS (ESI) C19H17O2 Calcd [M+H]+ : 277.1228 Found :277.1069
9-(2,6-dimethylphenyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one(3ba). White solid (101 mg, 76%) m.p. 181 °C
1
Rf = 0.55 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.13 (t, J =7.5 Hz, 1H), 7.08 (d, J = 7.5 Hz,
1H), 7.01-6.92 (m, 3H), 6.86(d,J=7.5 Hz,1H), 6.82(d, J=7.0 Hz, 1H),5.54 (s, 1H), 2.79 (s, 3H), 2.71 – 2.60 (m,
2H), 2.38 – 2.27 (m, 2H), 2.01 – 1.99 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 197.10, 166.09, 149.40, 141.15,
137.52, 136.66, 130.37, 129.40, 128.41, 127.69, 126.63, 124.93, 124.23, 115.85, 113.08, 37.26, 32.91, 28.01,
21.97, 20.65, 19.43. HRMS (ESI) Calcd [M+Na]+ 327.1361 Found: 327.1368
9-(2,3-dimethylphenyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one(3ca). Yellow solid (96 mg, 72%) m.p. 128 °C Rf
1
= 0.55 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.13 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8 Hz, 1H),
7.01-6.97 (m,2H), 6.92 (s, 2H), 6.86(t,J=4.0 Hz,1H), 5.38 (s, 1H), 2.75 (dt, J = 17.5, 5.0 Hz, 1H), 2.67 (dd, J =
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6.7, 5.5 Hz, 1H), 2.61 (s, 3H), 2.40 – 2.33 (m, 2H), 2.31 (s, 3H), 2.09 – 1.99 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 197.18, 166.12, 149.08, 145.35, 136.67, 133.69, 129.74, 128.02, 127.47, 126.92, 126.57, 125.79,
125.09, 116.59, 115.72, 37.13, 33.92, 28.03, 21.32, 20.62, 15.56. HRMS(ESI): C21H20NaO2 Calcd [M+Na]+
327.1361 Found: 327.1368
9-(3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one(3da). White solid (104 mg, 78%) m.p. 138 °C Rf =
1
0.32 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.24 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H),
7.11 (t, J = 8.0 Hz, 2H), 7.01 – 6.95 (m, 2H), 6.85-6.81 (m, 2H), 5.44 (s, 1H), 3.85 (s, 3H), 2.75(dt, J=17.5
Hz,5.5Hz, 1H), 2.68 – 2.62(m,1H),2.44 – 2.30 (m, 2H), 2.10 – 2.02 (m, 2H). 13C NMR (125 MHz, CDCl3): δ
196.97, 167.05, 156.79, 149.53, 134.83, 129.78, 129.15, 127.73, 127.33, 125.98, 124.82, 120.97, 116.14,
113.87, 111.87, 56.02, 37.19, 31.99, 28.08, 20.75. HRMS (ESI): C20H18NaO3 Calcd [M+Na]+ 329.1154 Found:
329.1146
9-(p-tolyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one(3ea). Yellow solid (95 mg, 70%), m.p.. 109 °C Rf = 0.50
1
(15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.18 – 7.15 (m,1H), 7.11 (t, J = 8.0 Hz, 3H), 7.07 (d, J =
8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 3H), 5.03 (s, 1H), 2.72 (dt, J = 17.5, 5.0 Hz, 1H), 2.67 – 2.60 (m,1H), 2.43 –
2.35 (m,2H), 2.25 (s, 3H), 2.07 – 1.99 (m,2H) 13C NMR (125 MHz, CDCl3): δ 197.09, 166.24, 149.59, 143.51,
136.00, 130.15, 129.26, 127.91, 127.64, 125.76, 125.19, 116.55, 115.05, 37.53, 37.16, 28.03, 21.13, 20.54.
HRMS (ESI): C20H18NaO2 Calcd [M+Na]+ 313.1204 Found 313.1210
9-phenyl-3,9-dihydrocyclopenta[b]chromen-1(2H)-one(3ab). Yellow solid (92 mg, 70%) m.p.. 147 °C
Rf = 0.25 (15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.23 – 7.13 (m, 7H), 7.08 – 7.06 (m, 2H), 4.93
(s, 1H), 2.83 – 2.72 (m, 2H), 2.47 – 2.45 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 202.53, 178.03, 150.64,
144.45, 131.21, 128.62, 128.43, 128.29, 126.87, 125.63, 124.18, 117.91, 117.26, 38.49, 33.61, 25.69.
HRMS(ESI): C18H14NaO2 Calcd [M+Na]+ 285.0891 Found 285.0896
9-(2,6-dimethylphenyl)-3,9-dihydrocyclopenta[b]chromen-1(2H)-one(3bb).Pale yellow solid ( 87 mg, 68%)
m.p.. 147 °C Rf = 0.38 (15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.19 (t, J = 7.5 Hz, 1H), 7.09 (d, J
= 7.5 Hz, 1H), 7.05 (dd, J = 11.5, 7.5 Hz, 2H), 7.01-6.98 (m,1H), 6.84 (t, J = 7.0 Hz, 2H), 5.48 (s, 1H), 2.77 (d,
J = 5.5 Hz, 2H), 2.68 (s, 3H), 2.45 (dd, J = 5.5, 4.5 Hz, 2H), 1.84 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
202.22, 178.05, 150.85, 138.72, 137.55, 137.00, 130.44, 129.78, 128.43, 128.15, 127.14, 125.55, 124.14,
116.66, 116.59, 33.41, 33.27, 25.65, 22.06, 19.81. HRMS (ESI): C20H18NaO2 Calcd [M+Na]+ 313.1204 Found
313.1210
9-(2,3-dimethylphenyl)-3,9 dihydrocyclopenta[b]chromen-1(2H)-one(3cb). Yellow powder (89 mg, 70%) m.p.
137 °C Rf = 0.30 (15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.20 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 8.5
Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.98 – 6.94 (m, 3H), 6.78 (s, 1H), 5.25 (s, 1H), 2.86 – 2.74 (m, 2H), 2.48–
2.43 (m, 5H), 2.32 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 202.33, 177.72, 150.48, 142.93, 136.84, 134.35,
130.78, 128.43, 128.00, 127.78, 125.77, 125.57, 125.40, 118.60, 117.10, 34.93, 33.48, 25.74, 21.18, 15.62.
HRMS (ESI): C20H18NaO2 Calcd [M+Na]+ 313.1205 Found 313.1210
9-(3-methoxyphenyl)-3,9-dihydrocyclopenta[b]chromen-1(2H)-one(3db). Pale brown solid (91 mg, 72%) m.p.
117°C Rf = 0.12 (15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.16 (t, J = 7.5 Hz, 3H), 7.09 – 7.07 (m,
2H), 7.02 – 6.99 (m, 1H), 6.85 (t, J = 8.0 Hz, 2H), 5.32 (s, 1H), 3.80 (s, 3H), 2.84 (dt, J = 17.5, 5.0 Hz, 1H),
2.78 – 2.75 (m,1H), 2.48 (t, J = 5.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 202.48, 178.96, 156.93, 150.47,
132.80, 130.52, 129.67, 128.16, 127.79, 125.33, 125.07, 121.02, 117.24, 116.78, 111.75, 55.91, 33.60, 32.29,
25.71. HRMS(ESI): C19H16NaO3 Calcd [M+Na]+ 315.0997 Found 315.0997
9-(p-tolyl)-3,9-dihydrocyclopenta[b]chromen-1(2H)-one(3eb). Cream solid (98 mg, 76%), m.p. 162 °C Rf =
0.25 (15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.24 – 7.20(m, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.10 –
7.05 (m, 6H), 4.90 (s, 1H), 2.81 – 2.76 (m, 2H), 2.49 – 2.46 (m, 2H), 2.27 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ 202.55, 177.91, 150.66, 141.64, 136.46, 131.21, 129.36, 128.30, 128.22, 125.62, 124.43, 118.07, 117.24,
38.11, 33.65, 25.69, 21.16, 0.13. HRMS(ESI): C19H16NaO2 Calcd [M+Na]+ 299.1048 Found 299.1050
3-methyl-9-phenyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (3ac). White solid (127 mg, 88%) m.p. 119 °C Rf =
1
0.53 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.26 – 7.17 (m, 5H), 7.12 – 7.01 (m, 4H), 5.04 (d, J
= 12.5 Hz, 1H), 2.75 – 2.69 (m, 1H), 2.53 – 2.32 (m, 2H), 2.14 – 2.05 (m, 1H), 1.57(d, J = 7.0 Hz,1H) 1.10 (dd,
J = 9.5, 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 197.02, 165.19, 146.33, 130.22, 128.55, 128.52, 128.05,
128.02, 127.75, 126.50, 125.22, 125.15, 116.64, 45.46, 45.39, 38.16, 37.97, 36.21, 35.85, 28.69, 28.02, 21.00,
20.91. HRMS(ESI): C20H18NaO2 Calcd: [M+Na]+ 313.1204 Found 313.1210
9-(2,6-dimethylphenyl)-3-methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (3bc). White solid (100 mg, 72%) m.p.
1
173 °C Rf = 0.65 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.12 (t, J = 7.5 Hz, 1H), 7.09 – 7.06
(m,1H), 7.00 – 6.91 (m, 3H), 6.87 – 6.84 (m, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.53 (d, J = 9.5 Hz, 1H), 2.77 (d, J =
13.0 Hz, 3H), 2.68 (dd, J = 17.0, 4.0 Hz, 1H), 2.44 – 2.17 (m, 3H), 2.11 – 2.02 (m, 1H), 1.97 (d, J = 10.0 Hz,
3H), 1.11 (d, J = 6.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 197.49, 166.07, 149.47, 129.46, 127.73, 126.69,
125.00, 115.93, 77.41, 77.16, 76.91, 45.50, 36.17, 32.96, 28.15, 20.97, 0.14.
HRMS (ESI): C22H22NaO2 Calcd [M+Na]+ 341.1517 Found 341.1517
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9-(2,3-dimethylphenyl)-3-methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one(3cc). White solid (100 mg, 73%) m.p.
1
108 °C Rf= 0.60 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.12 (t, J = 7.5 Hz, 1H), 7.07 – 6.93 (m,
3H), 6.91 – 6.90 (m, 2H), 6.86 – 6.80 (m, 1H), 5.35 (d, J = 7.0 Hz, 1H), 2.77 – 2.68 (m, 1H), 2.60 (s, 3H), 2.53
– 2.34 (m, 3H), 2.30 (s, 3H), 2.11 – 2.03 (m,1H), 1.10 (t, J = 5.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
197.08, 165.81, 149.18, 136.71, 133.70, 129.76, 128.04, 127.49, 126.96, 125.81, 125.13, 116.65, 77.41, 77.16,
76.91, 45.39, 36.18, 35.86, 33.95, 28.08, 21.33, 20.99, 15.57.
HRMS(ESI): C22H22NaO2 Calcd [M+Na]+ 341.1517 Found 341.1517
9-(3-methoxyphenyl)-3-methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one(3dc). White solid (111 mg, 80%) m.p.
1
143 °C Rf = 0.39 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.23 (dd, J = 16.5, 7.5 Hz, 1H), 7.14 –
7.09 (m, 3H), 7.00 – 6.94 (m, 2H), 6.85 – 6.81 (m, 2H), 5.43 (d, J = 9.0 Hz, 1H), 3.84 (d, J = 1.5 Hz, 3H), 2.77 –
2.68 (m, 1H), 2.53 – 2.28 (m, 3H), 2.13 – 2.05 (m, 1H), 1.13 – 1.11 (m, 3H). 13C NMR (125 MHz, CDCl3): δ
196.94, 166.73, 165.88, 156.79, 156.74, 149.59, 149.53, 134.79, 129.81, 129.79, 129.21, 129.15, 127.74,
127.70, 127.35, 127.33, 126.04, 125.76, 124.84, 124.79, 120.97, 120.92, 116.18, 116.14, 113.47, 113.29,
111.88, 111.77, 56.01, 56.00, 45.48, 45.36, 36.23, 35.87, 32.14, 31.99, 28.55, 28.23, 21.06, 20.91. HRMS(ESI):
C21H20NaO3 Calcd [M+Na]+ 343.1310 Found 343.1310
3-methyl-9-(p-tolyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one(3ec). Pale Yellow solid (81 mg, 57%) m.p. 87 °C
1
Rf= 0.58 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.18 – 6.99 (m, 8H), 5.00 (d, J = 12.0 Hz, 1H),
2.75 – 2.67 (m, 1H), 2.52 – 2.42 (m, 2H), 2.37 – 2.30 (m, 1H), 2.25 (s, 3H), 2.13 – 2.05 (m, 1H), 1.10 (t, J = 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 197.10, 165.95, 165.11, 149.64, 149.49, 143.50, 143.40, 136.01,
135.96, 130.17, 129.26, 129.24, 127.87, 127.64, 125.80, 125.57, 125.20, 125.14, 116.59, 116.56, 114.67,
114.33, 45.45, 45.40, 37.72, 37.52, 36.19, 35.84, 28.69, 28.01, 21.12, 21.01, 20.94. HRMS(ESI): C21H20NaO2
Calcd [M+Na]+ 327.1361 Found 327.1358
3,3-dimethyl-9-phenyl-2,3,4,9-tetrahydro-1H-xanthen-1-one(3ad). White solid (121 mg, 80%) m.p. 133 °C Rf
1
= 0.54 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.23 – 7.00 (m, 9H), 5.03 (s, 1H), 2.56 (d, J = 2.5
Hz, 2H), 2.25 (m, 2H), 1.12 (s, 3H), 1.04 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 196.93, 164.65, 149.57,
146.23, 130.24, 128.55, 127.99, 127.74, 126.49, 125.54, 125.18, 116.65, 113.60, 50.97, 41.74, 38.06, 32.29,
29.40, 27.56. HRMS(ESI): C21H20NaO2 Calcd [M+Na]+ 327.1361 Found 327.1367
9-(2,6-dimethylphenyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one(3bd). White solid (106 mg, 73%)
m.p. 192 °C Rf =0.59 (15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.13 (t, J = 7.5 Hz, 1H), 7.08 (d, J =
7.5 Hz, 1H), 7.01 - 6.93 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H),6.82(d, J=7.0 Hz, 1H), 5.55 (s, 1H), 2.79 (s, 3H),
2.58 – 2.45 (m, 2H), 2.23 (d, J = 3.5 Hz, 2H), 1.98 (s, 3H), 1.12 (d, J = 5.5 Hz, 6H). 13C NMR (125 MHz,
CDCl3): δ 197.16, 164.27, 149.60, 141.14, 137.64, 136.61, 130.38, 129.46, 128.41, 127.70, 126.66, 124.94,
124.32, 115.89, 112.00, 51.23, 41.79, 32.87, 32.06, 28.79, 28.53, 22.00, 19.31. HRMS(ESI): C23H24NaO2 Calcd
[M+Na]+ 355.1674 Found 355.1682
9-(2,3-dimethylphenyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one(3cd). Cream solid (99 mg, 68%)
1
m.p. 143 °C Rf = 0.62 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3): δ 7.13 (t, J = 7.0 Hz, 1H), 7.06 (d, J
= 8.0 Hz, 1H), 7.02 (d, J = 6.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.93 – 6.92 (m, 2H), 6.87 (d, J = 3.0Hz, 1H),
5.38 (s, 1H), 2.64 (s, 3H), 2.58 (d, J = 3.5 Hz, 2H), 2.34 (s, 3H), 2.24 (q, J = 16.0 Hz, 2H), 1.14 (s, 3H), 1.08 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 197.05, 164.41, 149.11, 145.22, 136.67, 133.58, 129.74, 127.96, 127.46,
126.79, 126.53, 125.70, 125.08, 116.63, 114.37, 50.92, 41.70, 33.70, 32.26, 29.32, 27.65, 21.32, 15.56.
HRMS(ESI): C23H24NaO2 Calcd [M+Na]+ 355.1674 Found 355.1679
9-(3-methoxyphenyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one(3dd). Yellow solid (128 mg, 88%)
m.p. 114 °C Rf = 0.40 (15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.22 (d, J = 8.0 Hz, 1H), 7.18 (d, J
= 8.0 Hz, 1H), 7.12 (t, J = 7.5 Hz, 2H), 7.01 (d, J = 8.0 Hz, 1H),6.97(t, J=7.5 Hz, 1H), 6.84 (d, J = 8.0 Hz, 2H),
5.43 (s, 1H), 3.83 (s, 3H), 2.57 (s, 2H), 2.25 (q, J = 16.0 Hz, 2H), 1.14 (s, 3H), 1.10 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 196.78, 165.28, 156.66, 149.55, 134.57, 129.76, 129.32, 127.69, 127.28, 125.79, 124.74,
120.82, 116.10, 112.46, 111.64, 55.83, 50.91, 41.73, 34.76, 32.20, 32.17, 32.02, 31.66, 29.78, 29.42, 27.48,
25.37, 22.72, 14.28, 14.19. HRMS(ESI): C22H22NaO3 Calcd [M+Na] 357.1466 Found 357.1466
3,3-dimethyl-9-(p-tolyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one(3ed). Colourless liquid ( 97 mg, 65%) Rf= 0.54
(15% EtOAc/Hexane) 1H NMR (500 MHz, CDCl3): δ 7.16 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 8.5 Hz, 3 H), 7.06 (d,
J = 8.0 Hz, 1H), 7.02 (t, J = 8.5 Hz, 3H), 4.99 (s, 1H), 2.55 (d, J = 2.5 Hz, 2H), 2.26 – 2.23 (m, 5H), 1.12 (s,
3H), 1.05 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 196.95, 164.52, 149.52, 143.40, 135.95, 130.18, 129.26,
127.82, 127.62, 125.74, 125.16, 116.60, 113.68, 50.98, 41.73, 37.64, 32.27, 29.83, 29.38, 27.61, 21.12. HRMS
(ESI): C22H22NaO2 Calcd [M+Na]+ 341.1517 Found 341.1524
1-(2-ethyl-2-hydroxy-4-phenylchroman-3-yl) propan-1-one (3ae). White sticky solid (100 mg, 65%), Rf = 0.50
1H NMR (500 MHz, CDCl3) δ 7.27-7.19 (m,3H), 7.09 (d, J = 7.0 Hz, 3H), 6.86 (d, J = 8.5 Hz, 1H), 6.74 (t, J =
7.5 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 4.35 (d, J = 12.5 Hz, 1H), 4.18 (s, 1H), 3.25 (d, J = 12.0 Hz, 1H), 2.20
(dq, J = 17.0, 7.0 Hz, 1H), 1.75 – 1.55 (m, 3H), 1.06 (t, J = 7.5 Hz, 3H), 0.69 (t, J = 7.0 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 216.02, 151.89, 141.60, 130.04, 129.28, 129.09, 128.76, 128.17, 127.64, 127.19,
124.47, 121.31, 117.25, 117.17, 96.86, 58.48, 44.50, 44.35, 40.20, 39.64, 33.70, 24.82, 7.48, 7.15, 6.83, 5.50.
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HRMS (ESI): C20H22NaO3 Calcd [M+Na]+ 333.1466 Found 333.1473
1-(4-(2, 3-dimethylphenyl)-2-ethyl-2-hydroxychroman-3-yl) propan-1-one(3ce).Yellow liquid (66 mg, 44%)
Rf = 0.52 1H NMR (500 MHz, CDCl3) δ 7.11 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 4.5 Hz, 2H), 6.91 (d, J = 8.0 Hz,
2H), 6.77 (t, J = 7.5 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.35 (s, 1H), 3.37 (d, J = 12.0
Hz, 1H), 2.32 (s, 3H), 2.24 (m, 3H), 1.82 – 1.68 (m, 4H), 1.12 (t, J = 7.5 Hz, 3H), 0.73 (t, J = 7.0 Hz, 3H).13C
NMR (125 MHz, CDCl3) δ 216.26, 151.99, 139.83, 137.08, 135.81, 128.92, 128.85, 128.53, 127.84, 126.45,
126.36, 125.38, 121.31, 117.12, 97.11, 77.41, 77.16, 76.91, 57.98, 39.48, 38.48, 36.75, 36.63, 33.67, 27.75,
24.81, 23.46, 21.42, 21.10, 15.16, 14.98, 7.72, 7.53, 6.99. HRMS (ESI): C22H26NaO3 Calcd [M+Na]+ 361.1779
Found 361.1788
1-(2-ethyl-2-hydroxy-4-(p-tolyl)chroman-3-yl)propan-1-one(3ee). Colourless liquid (97 mg, 64%) Rf = 0.50
1H NMR (500 MHz, CDCl3) δ 7.12 (d, J = 8.0 Hz, 3H), 7.03 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.79
(t, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 4.37 (d, J = 12.0 Hz, 1H), 4.26 (s, 1H), 3.30 (d, J = 12.5 Hz, 1H),
2.34 (s, 3H), 2.27 (ddd, J = 18.0, 12.5, 5.0 Hz, 1H), 1.78 – 1.67 (m, 3H), 1.12 (t, J = 7.5 Hz, 3H), 0.77 (t, J = 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 216.06, 151.89, 138.43, 137.23, 130.02, 129.75, 129.43, 129.12,
129.08, 128.06, 128.00, 124.74, 121.38, 121.25, 117.20, 117.12, 96.90, 58.48, 44.10, 43.89, 39.56, 33.73, 21.22,
7.46, 6.87. HRMS (ESI): C21H24NaO3 Calcd [M+Na]+ 277.0840 Found 277.0840
4-phenylchroman-2-one (3af). White sticky solid (56 mg, 50%) Rf = 0.54 (15% EtOAc/Hexane) 1H NMR (500
MHz, CDCl3) δ 7.29 – 7.20 (m, 4H), 7.10 – 7.06 (m, 3H), 7.01 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 4.28
(t,J = 7.0 Hz, 1H), 2.98 (qd, J = 15.0, 6.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 167.80, 151.86, 140.41,
129.29, 128.96, 128.48, 127.82, 127.72, 125.92, 124.81, 117.28, 40.83, 37.16, 29.85. HRMS (ESI): C15H13O2
Calcd [M+H]+ 225.0915 Found 225.0915
4-(2,6-dimethylphenyl)chroman-2-one (3bf).
Yellow Sticky Solid (44mg, 40%) Rf = 0.62 (15% EtOAc/Hexane) H NMR (500 MHz, CDCl3) δ 7.29 – 7.25
1
(m, 1H), 7.17 – 7.11 (m, 3H), 7.06 – 7.00 (m, 2H),6.76 (d, J = 8.0 Hz, 1H), 4.94 (dd, J = 14.5, 5.5 Hz, 1H), 3.20
(dd, J = 16.5, 14.5 Hz, 1H), 2.41 (s, 3H), 2.00 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.05, 152.20, 137.90,
137.74, 134.59, 129.56, 129.40, 128.77, 128.27, 126.36, 126.24, 124.85, 124.80, 120.77, 117.15, 114.02, 55.25,
37.07, 36.30, 21.11, 15.26. HRMS(ESI): C17H16NaO2 Calcd [M+Na]+ 275.1048 Found 275.1048
4-(2,3-dimethylphenyl)chroman-2-one (3cf). Yellow sticky solid (53mg, 48%) Rf = 0.54 (15% EtOAc/Hexane)
1H NMR (500 MHz, CDCl3) δ 7.32 – 7.29 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.06 (q, J
= 7.5 Hz, 2H), 6.87 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.67 (dd, J = 8.5, 6.0 Hz, 1H), 3.00 (qd, J =
15.5, 8.5 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.05, 152.20, 137.90, 137.74,
134.59, 129.56, 129.40, 128.77, 128.27, 126.36, 126.24, 124.85, 124.80, 120.77, 117.15, 114.02, 55.25, 37.07,
36.30, 21.11, 15.26. HRMS (ESI): C17H16NaO2 Calcd [M+Na]+ 275.1048 Found 275.1047
4-(3-methoxyphenyl)chroman-2-one (3df). Yellow crystalline solid (57mg, 52%) m.p. 117 °C Rf = 0.46 (15%
1
EtOAc/Hexane) H NMR (500 MHz, CDCl3) δ 7.30 – 7.22 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.09 – 7.01 (m,
2H), 6.91 – 6.83 (m, 3H), 4.67 (t, J = 6.0 Hz, 1H), 3.82 (s, 3H), 3.10 (dd, J = 16.0, 5.5 Hz, 1H), 2.98 (dd, J = 16.
0, 7.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.16, 156.95, 152.20, 128.93, 128.90, 128.61, 128.57, 128.41,
125.08, 124.61, 120.99, 117.07, 110.89, 55.24, 35.63, 35.28. HRMS (ESI): C16H14NaO3 Calcd [M+Na]+
277.0840 Found 277.0840
4-(p-tolyl)chroman-2-one (3ef). White sticky solid (55mg, 50%) Rf = 0.65 (15% EtOAc/Hexane) 1H NMR (500
MHz, CDCl3) δ 7.29 (t, J = 7.5 Hz, 1H), 7.14 (m, 3H), 7.07 (m, 3H), 6.98 (d, J = 7.5 Hz, 1H), 4.33 – 4.29 (t, J =
7.0 Hz, 1H), 3.08 – 2.98 (m, 2H), 2.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.85, 151.85, 137.50, 137.38,
129.92, 128.83, 128.44, 127.57, 126.20, 124.73, 117.21, 40.45, 37.20, 21.15, 0.12. HRMS (ESI): C16H14NaO2
Calcd [M+Na]+ 261.0891 Found 261.0891
Acknowledgements
The authors thank Department of Science and Technology (DST), Council of Scientific and Industrial Research, India
(CSIR), New Delhi for research fellowships. Financial assistance from the Science and Engineering Research Board
(SERB), New Delhi, (SERB/F/9708/2018-2019) is gratefully acknowledged. The authors also acknowledge Mrs. Saumini
Mathew and Mrs. S. Viji of CSIR-NIIST for recording the NMR and mass spectra
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o-Hydroxybenzyl alcohols have been readily converted into the respective o-quinone methide (o-
QM) intermediates in the presence of organic Brønsted acid and serve as a suitable diene for inverse
electron demand Diels Alder reaction. The reaction proceeds through a similar mechanism as that
proposed by Gheewala [21].The plausible mechanism for the reaction has been proposed in Scheme 6.
Initially the organic Brønsted acid reacts on o-hydroxybenzylalcohol 1a, to generate the
corresponding o-quinone methide I-1. Subsequently I-1 reacted with 2a with the assistance of
Brønsted acid to give an adduct I-2 which underwent the cycloaddition reaction to form I-3.
Dehydration of I-3 in presence of Brønsted acid yields the desired product 3aa and regenerates the
Brønsted acid. The utilization of o-hydroxybenzyl alcohols as precursors of dienes and 1, 3-diketones
as dienophiles, as well as the hydrogen-bonding activation mode of the Brønsted acid catalyst to the
substrates delivers the biologically important chroman scaffolds.
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Meldrum’s acid (2, 2-dimethyl-1, 3-dioxane-4, 6-dione) as a 2π partner gave the corresponding
arylchromanones when reacted with 1a (Scheme 5). Under the heating conditions, Meldrum’s acid
was converted to its ketene form which then reacted with the quinone methide giving the
arylchromanones.
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Results and Discussion
We initiated our efforts with one of the well-known electron rich dienophile 1, 3-diketones and o-
quinone
methides
promoted
by
organic
Brønsted
acid
catalyst
based
on
pentacarboxycyclopentadienes (PCCPs), which are strongly acidic and simple to prepare from alcohol
precursors [21].
We commenced the reaction of o-hydroxy benzyl alcohol (1a) with 5, 5-dimethyl-1, 3-
cyclohexadione (2) in the presence of catalytic amount of the prepared organic Brønsted acid (20
mol %) in dichloromethane at room temperature. The inverse electron demand Diels-alder reaction
proceeded smoothly and generated the 4H- chromene product within 12 h in moderate yield (Scheme
1
1). The structure of the product was confirmed by various spectroscopic techniques such as H NMR,
13C NMR and HRMS analyses. (See Supporting Information)
The reaction conditions were optimized by examining various solvents and temperatures. From the
optimization studies, a combination of o-hydroxy benzyl alcohol (1 equiv), 1, 3-cyclohexadione
(2equiv), Brønsted acid (20 mol %), in ACN (2 mL) at 80°C was found to be the best condition under
which the product was delivered in 80 % yield. When the reaction was carried out in dry solvents
there was a drastic decrease in yield indicating that the presence of moisture plays a major role in
maintaining the acidity required for the reaction to produce the quinone methide. The optimization
studies are showed in Table 1.
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With the optimal conditions in hand, we investigated the scope of reaction with substituted o-
hydroxy benzyl alcohols (Scheme 2 - 4). The attempt to prepare o-hydroxy benzyl alcohols with
electron-withdrawing groups on both the aldehyde as well as the aryl halide did not succeed hence
only o-hydroxy benzyl alcohols bearing diverse electron donating groups were taken up for the
substrate scope. These substrates afforded the corresponding products in moderate to good yields.
Initially, the quinone methides were subjected to unsubstituted cyclic 1, 3- diketones which
yielded the corresponding xanthenones in good yields. There was no appreciable difference in the
products of cyclopentadione as well as cyclohexadiones.
To further check the substrate scope of the reaction, substituted cyclic 1, 3- diketones were taken
under consideration, which gave almost the same yields as those of unsubstituted analogues.
We next moved on to the acyclic 1, 3-diketones. 3, 5- heptadione was taken as the representative
for the above mentioned class and allowed to react with the quinone methides which afforded the
cycloaddition product without elimination of a water molecule giving the corresponding
chromanones with a hydroxyl group.
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Conclusion
In conclusion, the hydroxyl benzyl alcohols were converted into their respective ortho quinone
methides in the presence of a novel organic Brønsted acid and their reactivity as a 4π partner in an
inverse electron demand– Diels Alder reaction was explored with a variety of scaffolds giving
biologically useful heterocyclic compounds. The further study of this reaction to give steroselective
products in the presence of chiral Brønsted Acids are currently under progress in our laboratory.
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ARTICLE
Title Text
J. Heterocyclic Chem. Year, Volume, Page – Page
TOC Graphic
Author(s), Corresponding Author(s)*
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Table 1. Optimization of the Bronsted Acid catalysed inverse –electron demand Diels Alder reactiona
Sl No Solvent Temperature
(°C)
Catalyst
(mol %)
Yield
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19b
20
CHCl3
CHCl3
CH2Cl2
CH2Cl2
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
70
120
80
80
80
140
70
70
70
80
80
5
10
5
10
10
10
10
10
10
10
10
10
20
10
10
10
NR
6
20
70
NR
NR
Trace
Trace
60
50
53
80
81
60
54
15
Trace
37
ACN
Ethanol
Benzene
Toluene
Toluene
Toluene
ACN
ACN
DCE
Xylene
EtOAc
THF
Benzene
DCE
10
10
10
NR
NR
ACN
No Catalyst
a Reaction conditions: 1a (1 equiv), 2a (2 equiv), organic Brønsted acid, solvent (2 mL), rt - room temperature,
NR - No reaction
bSc(OTf)3 was used in place of the organic Brønsted acid.
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