Acid-catalyzed chemoselective C- and O- prenylation of cyclic 1,3-diketones

Article abstract of DOI:10.1016/S1872-2067(20)63575-6

The chemoselective C- and O-prenylation of cyclic 1,3-diketones was achieved by tuning the prenyl source and catalyst. In the presence of the solid acid Nafion, the coupling of 1,3-cyclohexanediones with isoprene gave C-prenylated 5-chromenones. Alternati

Full text of DOI:10.1016/S1872-2067(20)63575-6

Chinese Journal of Catalysis 41 (2020) 1401–1409
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
Acid-catalyzed chemoselective C- and O-prenylation of cyclic
1,3-diketones
Ying Li a,b,†, Yan-Cheng Hu a,†, Ding-Wei Ji a, Wei-Song Zhang a, Gu-Cheng He a, Yu-Feng Cong b,#
Qing-An Chen a,*
,
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
b College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Fushun 113001, Liaoning, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The chemoselective C- and O-prenylation of cyclic 1,3-diketones was achieved by tuning the prenyl
source and catalyst. In the presence of the solid acid Nafion, the coupling of 1,3-cyclohexanediones
with isoprene gave C-prenylated 5-chromenones. Alternatively, using prenol as the substrate with
the Lewis acid AlCl3 as the catalyst resulted in the exclusive O-prenylation of 1,3-cyclohexanediones.
Notably, the resulting products could easily undergo aromatization to deliver prenylated resor-
cinols that are otherwise difficult to prepare. Our methodology is highly selective, atom-economical,
operationally simple, easily scalable, and has potential applications throughout organic synthesis.
© 2020, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Received 19 January 2020
Accepted 27 February 2020
Published 5 September 2020
Keywords:
5-Chromenones
1,3-Cyclohexanediones
O-Prenylation
[3+3] Annulation
Isoprene
Published by Elsevier B.V. All rights reserved.
Prenol
1. Introduction
The synthesis of 5-chromenone derivatives is generally
achieved using the cost-effective and commercially available
Derivatives of 5-chromenone are common among natural
products, particularly in medicinal plants [1–4]. For example,
1,3-cyclohexanedione as the starting material (Scheme 2). Only
a two-step procedure is required to prepare 5-chromenone
derivatives from 1,3-cyclohexanedione and either prenyl bro-
mide [7–9] or bromo-substituted benzyl bromide [10]. Owing
to its atom- and step-economy, the [3+3] annulation of
1,3-cyclohexanedione with unsaturated precursors represents
a more convenient and straightforward strategy. In the pres-
ence of acids or water, α,β-unsaturated aldehydes [11–15] and
propargylic alcohols [16–21] are suitable coupling partners in
this process. Despite these advances, exploiting new [3+3] an-
nulation reactions to access 5-chromenone frameworks from
tomentodiones
H and J, which are two syncarpic ac-
id-conjugated terpenoids (SACTs) isolated from the traditional
Chinese medicinal plant Rhodomyrtus tomentosa, contain mul-
ti-substituted 5-chromenone scaffolds (Scheme 1) [5]. Perhy-
dro-tetrahydrocannabinol (THC) and -cannabichromene (CBC),
constituents of marijuana (Cannabis sativa), also possess such
important cores [6]. Owing to their occurrence in medicinal
compounds, intense efforts have focused on the synthesis of
5-chromenone derivatives.
* Corresponding author. E-mail: yufengcong02@163.com
# Corresponding author. E-mail: qachen@dicp.ac.cn
§ Ying Li and Yan-Cheng Hu contributed equally to this work.
This work was supported by the National Natural Science Foundation of China (21702204, 21801239).
DOI: 10.1016/S1872-2067(20)63575-6 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 41, No. 9, September 2020

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Ying Li et al. / Chinese Journal of Catalysis 41 (2020) 1401–1409
Scheme 1. Representative natural products containing 5-chromenone derivatives.
other easily accessible and low-cost chemicals is still in high
demand.
mesh) using a forced flow of eluent at 0.3–0.5 bar pressure.
Silica gel GF254 was used for TLC analysis and products were
visualized by fluorescence quenching under UV light. H NMR
and 13C NMR spectra were recorded on a 400 MHz instrument
at room temperature in CDCl3 using tetramethylsilane (TMS) as
an internal standard. HRMS data were obtained with a Micro-
mass HPLC-Q-TOF mass spectrometer (ESI) or Agilent 6540
Accurate-MS spectrometer (Q-TOF).
1
Isoprene is an important bulk chemical in industry with an
annual capacity of up to 800,000 metric tons. Expanding on our
continuing interest in exploring the diverse reactivity of iso-
prene [22–25], we have developed an efficient alternative for
the synthesis of 5-chromenone derivatives 3 via [3+3] annula-
tion of isoprene 2a and 1,3-cyclohexanediones 1 using the solid
acid Nafion as a catalyst (Scheme 2, this work). The pathway
for this process involves a domino C-prenylation and intramo-
lecular cyclization. Using prenol 4a as the coupling partner in
the presence of AlCl3 catalyst resulted in the chemoselectivity
of the reaction switching exclusively to O-prenylation [26–33].
Notably, both products 3 and 5 could be aromatized to the cor-
responding prenylated resorcinols that are otherwise difficult
to synthesize [34–39].
2.2. General procedure for the annulation of cyclic
1,3-diketones with isoprene
Isoprene (120 μL, 1.20 mmol) was added to a mixture of
cyclic 1,3-diketones 1 (0.40 mmol) and Nafion (10 wt%) in
1,2-dichloroethane (DCE, 1.0 mL) in a sealed tube and stirred at
110 °C for 24 h. The solvent was evaporated under reduced
pressure and the residue was purified by flash column
chromatography on silica gel using petroleum ether and ethyl
acetate to give the desired 5-chromenones 3.
2. Experimental
2.1. General information
2,2-Dimethyl-7-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-
5-one (3a). Light yellow solid, mp 60–61 °C, 84.1 mg, 82% yield,
Rf = 0.60 (petroleum ether/EtOAc 4/1). 1H NMR (400 MHz,
CDCl3) δ 7.35–7.29 (m, 2H), 7.27–7.21 (m, 3H), 3.39–3.27 (m,
1H), 2.74–2.49 (m, 4H), 2.40–2.14 (m, 2H), 1.75–1.62 (m, 2H),
1.34 (s, 3H), 1.25 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 197.2,
169.7, 143.1, 128.7, 126.9, 126.7, 109.8, 77.5, 43.8, 39.1, 36.6,
32.2, 27.7, 25.5, 15.7. HRMS calculated for C17H21O2 [M+H]+
257.1536, found 257.1543.
Reagents were purchased from commercial sources and
used without further purification. Solvents were treated prior
to use following standard procedures. Unless otherwise stated,
all reactions were conducted under inert conditions. All reac-
tions were monitored by TLC, GC-FID, or NMR analysis. Flash
column chromatography was performed on silica gel (200–300
2,2-Dimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one
(3b). Colorless oil, 53.1 mg, 74% yield, Rf = 0.60 (petroleum
1
ether/EtOAc 4/1). H NMR (400 MHz, CDCl3) δ 2.33–2.24 (m,
4H), 2.20–2.16 (m, 2H), 1.92–1.85 (m, 2H), 1.62–1.58 (m, 2H),
1.22 (s, 3H), 1.21 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 198.2,
170.6, 110.0, 77.0, 36.7, 32.3, 29.2, 26.6, 21.0, 15.7. HRMS
calculated for C11H17O2 [M+H]+ 181.1223, found 181.1225.
2,2,7-Trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one
(3c). White solid, mp 68–69 °C, 62.9 mg, 81% yield, Rf = 0.60
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ
2.43–2.33 (m, 1H), 2.36–2.25 (m, 1H), 2.26–2.10 (m, 3H),
2.10–1.96 (m, 2H), 1.69–1.55 (m, 2H), 1.28 (s, 3H), 1.21 (s, 3H),
1.02 (d, J = 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 198.2,
170.0, 109.5, 77.1, 45.1, 37.3, 32.2, 28.6, 27.5, 25.7, 21.1, 15.6.
HRMS calculated for
195.1385.
C
12H19O2 [M+H]+ 195.1380, found
2,2,7,7-Tetramethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-o
ne (3d). White solid, mp 70–71 °C, 69.6 mg, 84% yield, Rf = 0.70
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ
2.23–2.13 (m, 6H), 1.60 (t, J = 6.6 Hz, 2H), 1.22 (s, 6H), 0.99 (s,
Scheme 2. Synthesis of 5-chromenone derivatives from
1,3-cyclohexanedione.

Ying Li et al. / Chinese Journal of Catalysis 41 (2020) 1401–1409
1403
6H). 13C NMR (100 MHz, CDCl3) δ 197.9, 168.9, 108.7, 77.1, 50.7,
for C11H15O3 [M+H]+ 195.1016, found 195.1018.
43.0, 32.3, 32.2, 28.4, 26.6, 15.5. HRMS calculated for C13H21O2
[M+H]+ 209.1536, found 209.1531.
2.3. General procedure for the O-prenylation of cyclic
1,3-diketones with prenol
2,2,6,6-Tetramethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-o
ne (3e). Colorless oil, 25.7 mg, 31% yield, Rf = 0.70 (petroleum
ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ 2.33 (tt, J = 6.4,
1.7 Hz, 2H), 2.20 (tt, J = 6.6, 1.8 Hz, 2H), 1.77 (q, J = 6.4 Hz, 2H),
1.63 (t, J = 6.6 Hz, 2H), 1.25 (s, 6H), 1.09 (s, 6H). 13C NMR (100
MHz, CDCl3) δ 203.1, 168.4, 108.1, 76.7, 39.9, 34.8, 32.4, 26.7,
Prenol (125 μL, 1.20 mmol) was added to a mixture of cyclic
1,3-diketones 1 (0.40 mmol) and AlCl3 (5.4 mg, 10 mol%) in
DCE (1.0 mL) in a sealed tube and stirred at 70 °C for 24 h. The
solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on silica
gel using petroleum ether and ethyl acetate to give the desired
O-prenylated cyclohexenones 5.
26.2, 25.0, 16.2. HRMS calculated for
209.1536, found 209.1538.
C
13H21O2 [M+H]+
2,2,8,8-Tetramethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-o
ne (3e'). Colorless oil, 41.8 mg, 50% yield, Rf = 0.60 (petroleum
5-((3-Methylbut-2-en-1-yl)oxy)-1,6-dihydro-[1,1'-biphenyl]
-3(2H)-one (5a). Light yellow oil, 65.2 mg, 64% yield, Rf = 0.50
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ
7.37–7.30 (m, 2H), 7.28–7.21 (m, 3H), 5.47 (s, 1H), 5.44–5.35
(m, 1H), 4.49–4.35 (m, 2H), 3.40–3.32 (m, 1H), 2.76–2.49 (m,
4H), 1.79 (d, J = 1.4 Hz, 3H), 1.71 (d, J = 1.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 198.8, 176.9, 142.8, 139.8, 128.8, 127.0,
126.7, 117.9, 102.8, 65.8, 43.9, 39.4, 36.7, 25.8, 18.3. HRMS
calculated for C17H21O2 [M+H]+ 257.1536, found 257.1541.
3-((3-Methylbut-2-en-1-yl)oxy)cyclohex-2-en-1-one (5b).
Light yellow oil, 55. mg, 77% yield, Rf = 0.40 (petroleum
1
ether/EtOAc 4/1). H NMR (400 MHz, CDCl3) δ 2.40–2.34 (m,
2H), 2.19 (t, J = 6.7 Hz, 2H), 1.78–1.72 (m, 2H), 1.59 (t, J = 6.7
Hz, 2H), 1.22 (s, 6H), 1.12 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
198.0, 175.8, 108.4, 76.4, 35.7, 35.2, 33.6, 32.0, 26.4, 25.6, 16.1.
HRMS calculated for
209.1538.
C
13H21O2 [M+H]+ 209.1536, found
2,2,6,6,8,8-Hexamethyl-2,3,4,8-tetrahydro-5H-chromene-5,7
(6H)-dione (3f). Light yellow solid, mp 58–59 °C, 32.0 mg, 32%
yield, Rf = 0.70 (petroleum ether/EtOAc 4/1). 1H NMR (400
MHz, CDCl3) δ 2.33 (t, J = 6.7 Hz, 2H), 1.69 (t, J = 6.7 Hz, 2H),
1.34 (s, 6H), 1.31 (s, 6H), 1.30 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 213.9, 198.3, 170.9, 106.7, 77.7, 55.1, 47.7, 31.9, 26.5,
1
ether/EtOAc 4/1). H NMR (400 MHz, CDCl3) δ 5.40–5.29 (m,
2H), 4.33 (d, J = 6.9 Hz, 2H), 2.36 (t, J = 6.3 Hz, 2H), 2.32–2.27
(m, 2H), 1.93 (p, J = 6.5 Hz, 2H), 1.74 (s, 3H), 1.66 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 199.9, 177.9, 139.6, 117.9, 103.0, 65.4,
36.7, 29.2, 25.8, 21.3, 18.2. HRMS calculated for C11H17O2
[M+H]+ 181.1223, found 181.1227.
25.1, 24.7, 16.7. HRMS calculated for
251.1642, found 251.1646.
C
15H23O3 [M+H]+
2,2-Dimethyl-3,4,6,7-tetrahydrocyclopenta[b]pyran-5(2H)-
one (3g). Light yellow oil, 30.7 mg, 46% yield, Rf = 0.30
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ
2.53–2.50 (m, 2H), 2.43–2.40 (m, 2H), 2.24–2.18 (tt, J = 6.5, 2.0
Hz, 2H), 1.67 (t, J = 6.5 Hz, 2H), 1.35 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 204.0, 183.8, 113.1, 80.5, 33.2, 31.8, 26.8, 26.4, 14.5.
5-Methyl-3-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-en-1-o
ne (5c). Colorless oil, 53.5 mg, 69% yield, Rf = 0.50 (petroleum
1
ether/EtOAc 4/1). H NMR (400 MHz, CDCl3) δ 5.38–5.30 (m,
2H), 4.33 (d, J = 6.9 Hz, 2H), 2.44–2.32 (m, 2H), 2.25–2.06 (m,
2H), 2.04–1.94 (m, 1H), 1.74 (s, 3H), 1.66 (s, 3H), 1.03 (d, J = 6.4
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 199.8, 177.3, 139.6, 118.0,
102.6, 65.5, 45.1, 37.3, 28.9, 25.8, 20.9, 18.2. HRMS calculated
for C12H19O2 [M+H]+ 195.1380, found 195.1382.
5,5-Dimethyl-3-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-en-
1-one (5d). Colorless oil, 36.5 mg, 44% yield, Rf = 0.50
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ
5.42–5.30 (m, 2H), 4.35 (d, J = 6.8 Hz, 2H), 2.25 (s, 2H), 2.18 (s,
2H), 1.76 (s, 3H), 1.67 (s, 3H), 1.04 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 199.7, 176.2, 139.6, 118.0, 101.8, 65.6, 50.8, 43.0, 32.6,
HRMS calculated for
167.1065.
C
10H15O2 [M+H]+ 167.1067, found
2,2-Dimethyl-3,4,6,7,8,9-hexahydrocyclohepta[b]pyran-5(2
H)-one (3h). Light yellow oil, 10.3 mg, 13% yield, Rf = 0.60
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ
2.63–2.55 (m, 2H), 2.52–2.46 (m, 2H), 2.27 (t, J = 6.8 Hz, 2H),
1.80–1.73 (m, 4H), 1.59 (t, J = 6.8 Hz, 2H), 1.25 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 201.9, 170.6, 112.4, 76.5, 41.4, 33.0, 32.2,
26.5, 23.4, 21.2, 18.4. HRMS calculated for C12H19O2 [M+H]+
195.1380, found 195.1373.
1,3,7,7-Tetramethyl-1,5,6,7-tetrahydro-2H-pyrano[2,3-d]py
rimidine-2,4(3H)-dione (3i). Light yellow solid, mp 126–127 °C,
26.0 mg, 29% yield, Rf = 0.30 (petroleum ether/EtOAc 2/1). 1H
NMR (400 MHz, CDCl3) δ 3.33 (d, J = 9.5 Hz, 6H), 2.47 (t, J = 6.6
Hz, 2H), 1.78 (t, J = 6.6 Hz, 2H), 1.40 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 163.2, 155.1, 151.3, 85.5, 81.3, 31.9, 28.4, 27.9, 26.5,
16.0. HRMS calculated for C11H17N2O3 [M+H]+ 225.1234, found
225.1232.
2,2,7-Trimethyl-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-5-o
ne (3j). Light yellow oil, 36.2 mg, 47% yield, Rf = 0.40
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ 5.66
(s, 1H), 2.39 (t, J = 6.6 Hz, 2H), 2.13 (s, 3H), 1.72 (d, J = 13.3 Hz,
2H), 1.29 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 165.2, 164.1,
159.8, 100.8, 96.9, 77.6, 32.0, 26.5, 19.7, 16.6. HRMS calculated
28.4, 25.9, 18.3. HRMS calculated for
209.1536, found 209.1541.
C
13H21O2 [M+H]+
6,6-Dimethyl-3-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-en-
1-one (5e). Colorless oil, 47.9 mg, 58% yield, Rf = 0.70
(petroleum ether/EtOAc 4/1). 1H NMR (400 MHz, CDCl3) δ
5.39–5.34 (m, 1H), 5.24 (s, 1H), 4.32 (d, J = 6.9 Hz, 2H), 2.40 (t, J
= 6.4 Hz, 2H), 1.81–1.73 (m, 5H), 1.67 (s, 3H), 1.08 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ 204.6, 175.8, 139.5, 118.1, 101.3, 65.5,
40.2, 35.1, 26.4, 25.8, 24.6, 18.2. HRMS calculated for C13H21O2
[M+H]+ 209.1536, found 209.1530.
2,2,6,6-Tetramethyl-5-((3-methylbut-2-en-1-yl)oxy)cyclohe
x-4-ene-1,3-dione (5f). Light yellow solid, mp 56–57 °C, 13.2
mg, 25% yield, Rf = 0.70 (petroleum ether/EtOAc 4/1). 1H NMR
(400 MHz, CDCl3) δ 5.49 (s, 1H), 5.43–5.35 (m, 1H), 4.45 (d, J =

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Ying Li et al. / Chinese Journal of Catalysis 41 (2020) 1401–1409
6.7 Hz, 2H), 1.79 (s, 3H), 1.71 (s, 3H), 1.39 (s, 6H), 1.34 (s, 6H).
13C NMR (100 MHz, CDCl3) δ 213.7, 199.5, 177.7, 140.0, 117.8,
99.9, 66.2, 55.3, 48.4, 25.9, 25.2, 24.5, 18.4. HRMS calculated for
8/1). 1H NMR (400 MHz, CDCl3) δ 7.46–7.35 (m, 5H), 6.47 (s,
1H), 5.85 (s, 1H), 2.78 (t, J = 6.8 Hz, 2H), 1.84 (t, J = 6.8 Hz, 2H),
1.36 (s, 6H).
C
15H23O3 [M+H]+ 251.1642, found 251.1644.
13C NMR (100 MHz, CDCl3) δ 153.3, 149.7, 139.3, 138.8,
3-((3-Methylbut-2-en-1-yl)oxy)cyclopent-2-en-1-one (5g).
129.4, 128.1, 127.7, 111.8, 109.0, 108.8, 74.6, 32.1, 26.8, 17.8.
Light yellow oil, 32.7 mg, 49% yield, Rf = 0.30 (petroleum
HRMS calculated for
289.0986.
C
17H18ClO2 [M+H]+ 289.0990, found
1
ether/EtOAc 4/1). H NMR (400 MHz, CDCl3) δ 5.42–5.36 (m,
1H), 5.28 (d, J = 1.2 Hz, 1H), 4.48 (d, J = 7.1 Hz, 2H), 2.62–2.55
(m, 2H), 2.44–2.38 (m, 2H), 1.77 (s, 3H), 1.70 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 206.2, 190.2, 140.6, 117.6, 105.0, 68.7, 34.1,
2-Chloro-5-((3-methylbut-2-en-1-yl)oxy)-[1,1'-biphenyl]-3-
ol (7a). Yellow oil, 111.5 mg, 77% yield, Rf = 0.30 (petroleum
1
ether/EtOAc 30/1). H NMR (400 MHz, CDCl3) δ 7.50–7.34 (m,
28.7, 25.8, 18.3. HRMS calculated for
167.1067, found 167.1070.
C
10H15O2 [M+H]+
5H), 6.64 (d, J = 2.8 Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 5.78 (s, 1H),
5.49 (t, J = 7.0 Hz, 1H), 4.50 (d, J = 6.8 Hz, 2H), 1.81 (s, 3H), 1.74
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.3, 152.5, 141.5, 139.3,
138.7, 129.3, 128.2, 127.9, 119.3, 110.5, 110.1, 101.5, 65.2, 25.9,
18.3. HRMS calculated for C17H18ClO2 [M+H]+ 289.0990, found
289.0999.
3-((3-Methylbut-2-en-1-yl)oxy)cyclohept-2-en-1-one (5h).
Colorless oil, 10.7 mg, 28% yield (0.2 mmol scale), Rf = 0.60
(EtOAc). 1H NMR (400 MHz, CDCl3) δ 5.41 (s, 1H), 5.40–5.36 (m,
1H), 4.27 (d, J = 6.8 Hz, 2H), 2.61–2.54 (m, 4H), 1.89–1.79 (m,
4H), 1.78 (s, 3H), 1.68 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
202.6, 176.4, 139.3, 118.3, 106.2, 65.7, 41.8, 33.2, 25.9, 23.7,
21.4, 18.3. HRMS calculated for C12H19O2 [M+H]+ 195.1380,
found 195.1377.
3. Results and discussion
In
previous
works,
the
annulations
of
1,3-cyclohexanediones were often performed in the presence
of various homogeneous acids. In comparison, we began our
investigation by employing solid acids to catalyze the [3+3]
annulation of 5-phenyl-1,3-cyclohexanedione 1a and isoprene
2a (Table 1). To our delight, when Nafion was subjected to the
mixture of 1a, 2a, and dioxane at 110 °C, the anticipated [3+3]
adduct 3a was afforded in 76% yield (entry 1). Other
heterogeneous acids, such as H-MOR (Si/Al = 24) and H-USY
(Si/Al = 3), showed no catalytic activity, while Amberlyst-15
was able to promote the annulation, albeit with decreased yield
(entries 2–4). Temperature-programmed desorption of
ammonia (NH3-TPD) experiments revealed the sequence of
acid amount of the catalysts as Amberlyst-15 (3.397 mmol/g) >
H-USY (1.318 mmol/g) > H-MOR (0.876 mmol/g), which is
2.4. Procedure for the recycling experiment
In a sealed Schlenk tube (25 mL), Nafion (10 wt%, 37.7 mg),
5-phenyl-1,3-cyclohexanedione 1a (2.00 mmol, 376.5 mg), DCE
(5.0 mL), and isoprene (0.60 mL, 6.00 mmol) were added in
sequence. The resulting mixture was stirred at 110 °C for 24 h.
Upon completion, Nafion was filtered, washed with ethyl ace-
tate, and dried by vacuum pump for 1 h prior to use in the next
cycle. The collected solution was analyzed by GC-FID using
1,3,5-trimethoxybenzene as an internal standard.
2.5. General procedure for the aromatization of 3a and 5a
An oven-dried Schlenk flask equipped with a magnetic
stirrer was sealed with a rubber plug and then evacuated and
back-filled with nitrogen. The flask was charged with a solution
of LiHMDS (1.0 mol/L in THF, 1.5 mL, 3.0 equiv), dry THF (1.0
mL), and dry pentane (2.0 mL) and cooled to –78 °C. After
stirring for 10 min, a solution of substrate 3a or 5a (128.1 mg,
0.5 mmol, 1.0 equiv) in THF (1.0 mL) was added dropwise over
3 min and stirred at –78 °C for an additional 30 min. A solution
of tosyl chloride (209.7 mg, 1.1 mmol, 2.1 equiv) in THF (1.5
mL) was then added dropwise over 10 min and further stirred
at –78 °C for 30 min. A solution of LiHMDS (1.0 mol/L in THF,
0.5 mL, 1.0 equiv) was then added dropwise over 1 min. The
mixture was subsequently warmed to room temperature over
20 min and then stirred at room temperature for an additional
30 min. The reaction was quenched by 1.0 mol/L HCl (aq, 5 mL)
and diluted with EtOAc (20 mL). The aqueous phase was then
extracted with EtOAc and the combined organic phases were
washed with brine (1 × 10 mL), dried over anhydrous Na2SO4,
filtered through Celite, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel to
afford the desired aromatized product 6a or 7a.
Table 1
Solid acid-catalyzed [3+3] annulation of 1,3-cyclohexanedione 1a with
isoprene 2a.
Catalyst
(10 wt%)
Temperature Yield of 3aa
Entry
Solvent
(°C)
110
110
110
110
110
110
80
(%)
1
2
3
4
5
6
7
8
9
10
Nafion
H-USY
H-MOR
Dioxane
Dioxane
Dioxane
Dioxane
DCE
Toluene
DCE
DCE
76
Trace
N.R.
44
92
64
Amberlyst-15
Nafion
Nafion
Nafion
Nafion
Nafion
10
90
44
DCE
DCE
100
120
53
88
Nafion
Reaction conditions: 1a (0.20 mmol), 2a (0.60 mmol), catalyst (10 wt%,
based on the quantity of 1a), solvent (0.5 mL), T °C, 24 h. Yield was
a
6-Chloro-2,2-dimethyl-7-phenylchroman-5-ol (6a). Brown
oil, 120.5 mg, 83% yield, Rf = 0.50 (petroleum ether/EtOAc
determined by GC-FID using 1,3,5-trimethoxybenzene as an internal
standard. N.R. = no reaction.

Ying Li et al. / Chinese Journal of Catalysis 41 (2020) 1401–1409
1405
consistent with their catalytic performances [40]. An exception
Table 3
to this sequence was Nafion (2.123 mmol/g), which gave the
highest yield of 3a (entry 1), presumably due to the strong,
electron-deficient polyfluoro-substituted sulfonic group on
Nafion making it more acidic than Amberlyst-15. These results
suggested that both acid amount and strength of the catalyst
Nafion-catalyzed [3+3] annulation of cyclic 1,3-diketones with isoprene.
contribute to its reactivity.
A survey of the solvents
demonstrated that the annulation in DCE furnished the product
3a in 92% yield, while the non-polar solvent toluene gave an
inferior result (entries 5 and 6). The temperature exerted a
remarkable influence on the reaction outcome. The yield of 3a
increased dramatically with increasing temperatures in the
range of 80 to 110 °C, at which temperature the productivity
plateaued (entries 7–10).
It is worthwhile to mention that prenol 4a and
1,3-cyclohexanedione 1a could also undergo the [3+3]
annulation efficiently under the standard conditions (Table 2,
entry 1). Surprisingly, when this reaction was performed at 70
°C, a small amount of 5a was detected along with 3a (entry 2).
Compound 3a was the cyclized C-prenylated product, while 5a
was formed by O-prenylation of 1a. Considering that direct
O-prenylation of 1,3-cyclohexanedione is rare [41], additional
efforts were devoted to increasing the selectivity of 5a. Happily,
O-prenylated product 5a was afforded exclusively using Lewis
acid AlCl3 (entry 4). Other Lewis acids, such as InCl3, GaCl3, and
Zn(OTf)2, furnished 3a as the main product, while in the
presence of YCl3, 5a predominated, but with a lower yield
(entries 5–8). Utilizing dioxane/toluene as the solvent
diminished the yield of 5a (entries 9 and 10). Increasing the
temperature increased the formation of 3a (entry 12).
Conditions: 1 (0.40 mmol), 2a (1.20 mmol), Nafion (10 wt%, based on
1), DCE (1.0 mL), 110 °C, 24 h. a Isolated yields. b 150 °C.
standard conditions (Table 3). Using this procedure,
1,3-cyclohexanedione 1b was readily converted to
5-chromenone 3b in 74% yield. Other suitable substrates for
the reaction were 5-methyl- and 5,5-dimethyl-substituted
1,3-cyclohexanediones, which provided the corresponding
products 3c and 3d in 81% and 84% yield, respectively. In the
case of 4,4-dimethyl-1,3-cyclohexanedione 1e, the reaction
gave a mixture of 5-chromenones 3e and 3e' in 81% yield with
moderate regioselectivity. Gratifyingly, sterically hindered,
Having established the optimal conditions, we next explored
the generality of the [3+3] annulation of cyclic 1,3-diketones
with isoprene. The expected adduct 3a was isolated in 82%
yield after subjecting 5-phenyl-1,3-cyclohexanedione 1a to the
Table 2
Lewis acid-catalyzed O-prenylation of 1,3-cyclohexanedione 1a with prenol 4a.
Entry
Catalyst (10 mol%)
Solvent
Temperature (°C)
Yield of 3a a (%)
Yield of 5a a (%)
1 b
2 b
3
4
5
6
7
8
9
Nafion
Nafion
FeCl3
AlCl3
InCl3
GaCl3
YCl3
Zn(OTf)2
AlCl3
AlCl3
AlCl3
AlCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
110
70
70
70
70
70
70
70
70
70
80
90
62
24
N.D. c
0
12
20
0
25
0
0
0
Trace
N.D. c
60
Trace
0
30
Trace
46
Dioxane
Toluene
DCE
10
11
12
58
50
38
0
4
DCE
Reaction conditions: 1a (0.20 mmol), 4a (0.60 mmol), catalyst (10 mol%, based on the quantity of 1a), solvent (0.5 mL), T °C, 24 h. a Yield was deter-
mined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. b Nafion (10 wt%, based on the amount of 1a). c A complex mixture was
afforded. N.D. = not detected.

1406
Ying Li et al. / Chinese Journal of Catalysis 41 (2020) 1401–1409
Table 4
100
Yield of 3a
AlCl3-catalyzed O-prenylation of cyclic 1,3-diketones with prenol.
1,3-Diketones
Products a
1,3-Diketones
Products a
80
60
40
20
0
O
O
O
O
Ph
O
Ph
O
O
O
1a
5a, 64%
1e
5e, 58%
O
O
O
O
O
O
O
O
O
O
1b
5b, 77%
1f
5f, 25%
O
O
O
O
O
O
O
O
O
1
2
3
4
1c
5c, 69%
1g
5g, 49%
Recycling number
O
O
O
O
Fig. 1. Yield of 3a in recycling experiments. Reaction conditions:
5-phenyl-1,3-cyclohexanedione 1a (2.00 mmol, 376.5 mg), isoprene 2a
(6.00 mmol, 0.60 mL), Nafion (10 wt%, 37.7 mg), DCE (5.0 mL), 110 °C,
24 h.
O
O
O
1d
5d, 44%
1h
5h, 28%
Conditions: 1 (0.40 mmol), 4a (1.20 mmol), AlCl3 (10 mol%, based on 1)
DCE (1.0 mL), 70 °C, 24 h. a Isolated yields.
derivatizations of the resulting products were performed
(Scheme 3). Both transformations could be easily scaled up to
5.0 mmol, leading to the formation of cyclized C-prenylated
product 3a and O-prenylated cyclohexenone 5a in 70% and
68% yield, respectively. Treatment of 3a with lithium
hexamethyldisilazide (LiHMDS) and tosyl chloride (TsCl) pro-
vided the aromatized chloro-substituted resorcinol 6a product
in 83% yield [46]. Following the same procedure, 5a could be
converted to O-prenylated resorcinol 7a in 77% yield. It should
be noted that prenylated resorcinols are also important scaf-
folds that can be found in diverse natural products [47–52].
However, conventional catalytic prenylation of resorcinols
often displays poor selectivity and does not yield the
O-prenylated product [34–39]. Thus, our approach provides an
expedient alternative to construct C- and O-prenylated
resorcinols with high selectivity.
The reusability of the Nafion catalyst for the [3+3]
annulation of 5-phenyl-1,3-cyclohexanedione 1a and isoprene
2a was examined (Fig. 1). Unfortunately, the yield of 3a
gradually decreased after each cycle. The polymerization of
isoprene could not be avoided in the presence of the strong
acid at high temperatures [53–57]. Thus, after several runs
under the optimized conditions, the accumulated coke on the
surface of Nafion led to its diminished catalytic activity.
tetramethyl-substituted 1,3,5-cyclohexanetrione 1f (syncarpic
acid) [42–44] was also tolerated in this process, providing the
target product 3f in an acceptable yield. The structure of 3f was
unambiguously confirmed by X-ray crystallography [45].
Notably, the transformation could be successfully extended to
1,3-cyclopentanedione 1g and 1,3-cycloheptanedione 1h, albeit
with decreased yields. Moreover, this protocol was also
applicable to heterocyclic 1,3-dicarbonyls, such as N-methyl
barbituric acid 1i and 4-hydroxy-6-methyl-2H-pyran-2-one 1j.
The scope of cyclic 1,3-diketone O-prenylation was further
examined (Table 4). In the presence of AlCl3, the coupling of
5-phenyl-1,3-cyclohexanedione 1a and prenol 4a furnished the
desired product 5a in 64% isolated yield. The simple
1,3-cyclohexanedione 1b underwent the process efficiently to
produce O-prenylated cyclohexenone 5b in 77% yield. The
5-methyl-substituted 1,3-cyclohexanediones 1c and 1d were
compatible with the transformation, producing the target
O-prenylated products 5c and 5d in acceptable yields.
Surprisingly, when 4,4-dimethyl-1,3-cyclohexanedione 1e was
employed as the substrate, the reaction afforded 5e in high
selectivity. O-prenylation of syncarpic acid 1f generated 5f in a
decreased yield, which is likely due to its large steric hindrance.
Five- and seven-membered cyclic 1,3-ketones 1g and 1h could
also be employed in this process.
The coupling of 1,3-cyclohexanedione 1b with
isoprene/prenol was used to illustrate the mechanism for the
To demonstrate the potential applications of this
methodology in organic synthesis, gram-scale experiments and
O
O
O
H
2a
H+
O
- H+
H+
OH
A
O
O
1b
B
C
C-prenylation
O
- H+
O
O
O
O
1b'
OH
OH
- AlCl3
- H2O
4a
OH
AlCl3
AlCl3
O
O
O
H
3b
5b
D
O-prenylation
Scheme 4. Proposed mechanism for C- and O-prenylation of
1,3-cyclohexanedione.
Scheme 3. Gram-scale reactions and synthetic transformations.

Ying Li et al. / Chinese Journal of Catalysis 41 (2020) 1401–1409
1407
Graphical Abstract
Chin. J. Catal., 2020, 41: 1401–1409 doi: 10.1016/S1872-2067(20)63575-6
Acid-catalyzed chemoselective C- and O-prenylation of cyclic 1,3-diketones
Ying Li, Yan-Cheng Hu, Ding-Wei Ji, Wei-Song Zhang, Gu-Cheng He, Yu-Feng Cong *, Qing-An Chen *
Dalian Institute of Chemical Physics, Chinese Academy of Sciences; Liaoning Shihua University
OH
O
aromatization
R
R
O
Nafion (10 wt%)
O
O
R
O
OH
O
OH
aromatization
R
R
AlCl3 (10 mol%)
O
O
The coupling of 1,3-cyclohexanediones with isoprene produced C-prenylated product 5-chromenones in the presence of solid acid Nafion,
while O-prenylation turned out to be exclusive when using prenol as substrate and Lewis acid AlCl3 as catalyst.
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two
catalytic
processes
(Scheme
4).
Initially,
1,3-cyclohexanedione 1b can tautomerize into its enol form 1b'.
In the presence of the solid acid Nafion, isoprene 2a is
protonated to yield the active isopentenyl cation A. The
subsequent nucleophilic attack by the enol moiety of 1b'
furnishes the C-prenylated diketone B, which further
undergoes acid-catalyzed intramolecular cyclization to afford
[3+3] adduct 3b. For Lewis acid catalysis, prenol 4a is activated
by AlCl3 to give intermediate D, followed by the nucleophilic
SN2 substitution of the hydroxyl group of enol isomer 1b to
generate O-prenylated product 5b.
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4. Conclusions
We have developed an efficient strategy for achieving C- and
O-prenylation of cyclic 1,3-diketones. Using the solid acid Nafi-
on as a catalyst, 1,3-cyclohexanediones and isoprene could
undergo [3+3] annulation to yield cyclized C-prenylated
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in the formation of O-prenylated cyclohexenones. Notably, both
products could be easily transformed into the corresponding
prenylated resorcinols that are otherwise difficult to prepare.
The advantages of our methodology include excellent selectivi-
ty, high atom-economy, simple operation, and easy scale-up.
These attributes impart great potential for its use in organic
synthesis.
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酸催化1,3-环二酮的选择性C-, O-异戊烯基化反应
李 莹a,b,§, 呼延成a,§, 季定纬a, 何固城a, 张炜松a, 丛玉凤b,#, 陈庆安a,*
a中国科学院大连化学物理研究所, 辽宁大连116023
b辽宁石油化工大学化学学院, 辽宁抚顺113001
摘要: 5-色烯酮类衍生物广泛分布于自然界中, 特别是各种天然药材中. 例如, 传统药材桃金娘和大麻的活性成分都含有这
类骨架. 因此, 发展高效的策略来合成5-色烯酮一直受到科研工作者的关注. 传统的方法主要是以1,3-环己二酮与异戊烯
基溴或卤代苄溴为原料, 经过取代和分子内环化两步反应合成得到. 最近, 1,3-环己二酮与不饱和分子的形式[3+3]环加成
反应, 由于其独特的原子和步骤经济性, 已被用于构建色烯酮骨架. 但这类不饱和分子仅限于α,β-不饱和醛与炔丙基醇. 因
此, 发展新的、简单易得的合成子仍具有很大的吸引力.
本文采用廉价易得的工业化学品异戊二烯作为简单高效的合成子, 用于构建5-色烯酮骨架. 首先, 以5-苯基-1,3-环己
二酮和异戊二烯为模板底物, 通过对固体酸催化剂、溶剂及反应温度等筛选发现, 在固体酸Nafion (10 wt%)催化下, 以DCE
为溶剂, 110 oC反应24 h, 5-苯基-1,3-环己二酮会经过C-异戊烯基化和分子内环化的串联过程, 一步生成[3+3]产物5-色烯酮,
分离收率达到82%. 该反应具有高的区域和化学选择性, 以及原子经济性. 若以异戊烯基醇为原料, 在最优条件下, 也可以
顺利得到5-色烯酮产物. 令人意外的是, 当温度降低到70 oC时, 除了主产物5-色烯酮, 还可以检测到少量O-异戊烯基化产
物. 由于1,3-环己二酮的直接O-异戊烯基化反应至今未有报道, 我们对该选择性进行了优化. 通过对酸催化剂种类、溶剂和
温度等调控发现, 以Lewis酸AlCl3为催化剂, 在DCE中, 70 oC反应24 h, 5-苯基-1,3-环己二酮可以只发生O-异戊烯基化反应,
具有专一的选择性.
随后, 对两种催化体系分别进行了底物普适性考察. 在固体酸Nafion催化体系下, 未取代和5-取代的1,3-环己二酮都能
很好地参与反应. 4,4-二甲基-1,3-环己二酮由于其非对称的结构, 可以得到两种环化产物. 2,2,4,4-四甲基-1,3,5-环己三酮
(syncarpic acid)是很多天然产物分子的前体, 其也可以和异戊二烯发生环化反应, 所得产物结构得到了单晶衍射的确定. 此
外, 该反应还适用于1,3-环戊二酮、1,3-环庚二酮以及巴比妥酸等底物. 对于AlCl3催化体系, 五元、六元和七元环状二酮都

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能顺利地发生O-异戊烯基化反应. 特别是, 在该体系中, 非对称的4,4-二甲基-1,3-环己二酮也只得到一种O-异戊烯基化产
物, 具有优异的区域选择性.
最后, 在两种催化体系下, 1,3-环己二酮的C-和O-异戊烯基化反应能够很容易放大到克级规模, 并且所得到的两类产物
在LiHMDS/TsCl作用下会发生芳构化过程, 得到异戊烯基化的间苯二酚, 该结构也是很多具有药理活性分子的核心单元.
因此, 通过对催化剂种类和异戊烯基源的调节, 首次实现了1,3-环二酮的选择性C-、O-异戊烯基化反应. 在固体酸
Nafion催化下, 1,3-环己二酮和异戊二烯经过C-异戊烯基化和分子内环化的串联过程, 生成[3+3]产物5-色烯酮. 而以异戊烯
基醇为原料时, 在AlCl3催化下, 1,3-环己二酮可以专一地进行O-异戊烯基化反应. 这种利用廉价易得的原材料合成具有高
附加值的结构骨架在有机合成及工业生产中具有潜在的应用价值.
关键词: 5-色烯酮; 1,3-环己二酮; O-异戊烯基化; [3+3]环化反应; 异戊二烯; 异戊烯基醇
收稿日期: 2020-01-19. 接受日期: 2020-02-27. 出版日期: 2020-09-05.
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§李莹和呼延成为共同第一作者.
基金来源: 国家自然科学基金(21702204, 21801239).
本文的电子版全文由Elsevier出版社在ScienceDirect上出版(http://www.sciencedirect.com/science/journal/18722067).