CHAPTER 5: SYNTHESIS OF COMPOUND 3a-3m
5.1 Introduction
In 1984, panduratin A (Figure 1) was isolated as a racemate from Boesenbergia rotunda
and it was also known as a cyclohexenyl chalcone.(Tuntiwachwuttikul et al., 1984). In 2008,
another two enantiomers were isolated from the same plant.(Yoshikawa et al ., 2008).A wide
range of promising biological properties were identified for panduratin A such as
anticancer(Yun et al.,2006),anti-inflammatory(Yun et al.,2003),antibacterial(Rukayadi et al.,
2010),antiangiogenic(Lai
et
al.,
2012),
antioxidant(Salama
et
al.,
2013),
anti-
HIV(Cheenpracha et al.,2006), and competitive dengue-2 virus NS3 protease inhibitory
activity(Chee et al., 2010) . Despite having a simple structure. The synthesis of Panduratin A
is not straightforward. There are some factors that makes the synthesis complex such as the
electron rich nature of the diene which requires electron poor dienophile, the dienophile resist
conventional Lewis-acid-promoted cycloaddition and tend to form flavonone and the ocimene
is prone to polymerization in the presence of Lewis acid.(Chee et al., 2010)
Figure 5.1: Panduratin A
In this project, we described an efficient Diels–Alder reaction of trans-chalcones with
alloocimene catalyzed by commercially available BF3.Et2O as a Lewis-acid catalyst. By
employing this readily available catalyst, we prepared variety of 3a derivatives (Figure 5.1) in
moderate to good yields. The scope and limitations of this method were also studied.
Figure 5.2: Derivatives of compound 3a
5.3 Methodology and materials
5.3.1 General
The chalcone derivatives 1-(2-hydroxylphenyl)-3-(2-bromophenyl)-2-propene-1one,3-(4-methoxyphenyl)-1-(4-methylphenyl)-2-propen-1-one,
dimethoxyphenyl)-1-(4-methylphenyl),
2-Propen-1-one,
2-Propen-1-one,
3-(3,5-
3-(4-nitrophenyl)-1-(4-
methylphenyl),1-(4-iodophenyl)-3-phenylpropene-2-one,1-(4-methylphenyl)-3-(4cyanophenyl)-propene-2-one,(E)-1-(4-nitrophenyl)-3-phenylprop-2-en-1-one and (E)-3-(2bromophenyl)-1-(4-nitrophenyl)prop-2-en-1-one were given by industrial students whereas
(E)-1-(3-chlorophenyl)-3-phenylprop-2-en-1-one, (E)-1-(4-chlorophenyl)-3-phenylprop-2-en1-one and (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one were given by Thy Chun Keng.
Ethyl acetate, hexane, toluene, deuterated chloroform (CDCl3-d1) were purchased from Merck
(Darmstadt, Germany) and were of analytical grade.
2,6-Dimethyl-2,4,6-octatriene was
purchased from Sigma-Aldrich (St. Louis, MO, USA). Analytical thin-layer chromatography
(TLC) was carried out on Merck precoated aluminum silica gel sheets (Kieselgel 60 F254).
Column chromatography was performed with silica gel 60 (0.04-0.063 mesh) from
MACHEREY-NAGEL GmbH & Co. KG. NMR spectra were obtained using Jeol ECA 400
(400 MHz) (Jeol Ltd., Akishima, Tokyo, Japan) and Bruker Advance III HD (400 MHz)
(Bruker Biospin Corp., Billerica, USA) NMR spectrometers with tetramethylsilane as the
internal standard. All chemical shifts are reported in ppm. MS analysis was performed on an
Agilent 6500 series accurate mass Q-TOF (Agilent Technologies, Santa Clara, CA, USA).
5.3.2 Synthesis
To a solution of the corresponding chalcone (1 equiv) in dry toluene (2 mL/mmol) at
28 C under nitrogen atmosphere was added BF3.Et2O solution. Next, to the reaction mixture
was added 2,6-Dimethyl-2,4,6-octatriene (5 equiv) and stirred at 28 C until all chalcone was
consumed. The reaction mixture acidified with 1N HCl. The mixture was extracted with ethyl
acetate and the organic phase was dried using anhydrous sodium sulphate. The solvent was
evaporated under reduced pressure and the product was purified using column
chromatography.
Scheme 5.1: Synthesis of compound 3a and 4
5.3.2.1 3a ((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6-tetrahydro[1,1'-biphenyl]-2-yl)(phenyl)methanone/3a
1H-NMR (600 MHz, CHLOROFORM-D) δ 7.80 (d, J = 7.7 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.35 (t,
J = 7.7 Hz, 2H), 6.99-7.06 (m, 5H), 5.18 (s, 1H), 4.99 (d, J = 10.3 Hz, 1H), 3.97 (dd, J = 11.7, 9.5 Hz,
1H), 3.62 (dd, J = 11.9, 5.0 Hz, 1H), 3.41 (td, J = 9.8, 1.5 Hz, 1H), 2.17-2.21 (m, 1H), 1.77 (s, 3H),
1.41 (s, 3H), 1.28 (s, 3H), 0.85 (d, J = 7.0 Hz, 3H)
13C-NMR (100 MHz, CHLOROFORM-D) δ 205.44, 142.24, 139.40, 138.83, 133.18, 132.42, 128.60,
128.23, 128.17, 127.96, 127.17, 126.04, 124.02, 47.82, 44.53, 42.30, 40.24, 25.51, 22.29, 17.82, 15.20
M.P: 106-108º C
HRMS (ESI) [M+H] + calculated for C25H29O+: 345.2213, found: 345.2211.
5.3.2.2 ((1S,2S,3R,6R)-4'-chloro-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6tetrahydro-[1,1'-biphenyl]-2-yl)(phenyl)methanone/3b
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.78 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.37 (t,
J = 7.6 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 5.16 (s, 1H), 4.96 (d, J = 10.3 Hz,
1H), 3.90 (dd, J = 11.5, 9.8 Hz, 1H), 3.58 (dd, J = 11.7, 4.9 Hz, 1H), 3.36 (t, J = 9.8 Hz, 1H), 2.112.17 (m, 1H), 1.75 (s, 2H), 1.55 (s, 3H), 1.40 (s, 3H), 0.82 (d, J = 7.1 Hz, 3H)
13C-NMR (101 MHz, CHLOROFORM-D) δ 205.09, 140.87, 139.05, 138.49, 133.36, 132.61, 131.71,
129.67, 128.16, 128.12, 128.03, 126.78, 123.94, 47.24, 44.50, 42.24, 40.02, 25.49, 22.21, 17.66, 14.91
M.P : 122-124º C
HRMS (ESI) [M+H] + calculated for C25H28ClO+: 379.1824 found: 379.1818.
5.3.2.3 (2-chlorophenyl)((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6tetrahydro-[1,1'-biphenyl]-2-yl)methanone/3c
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.48 (d, J = 7.8 Hz, 1H), 7.10-7.13 (m, 2H), 7.05
(d, J = 3.9 Hz, 3H), 6.98 (d, J = 3.7 Hz, 2H), 5.14 (s, 1H), 4.99 (d, J = 11.0 Hz, 1H), 3.86 (dd,
J = 11.6, 9.7 Hz, 1H), 3.53-3.58 (m, 1H), 3.41 (dd, J = 11.9, 4.8 Hz, 1H), 2.07-2.12 (m, 1H),
1.73 (s, 4H), 1.47-1.44 (2H), 1.23 (s, 3H), 0.85 (d, J = 7.3 Hz, 3H)
13C-NMR (101 MHz, CHLOROFORM-D) δ 206.73, 141.48, 138.49, 133.38, 131.28, 130.71,
129.27, 128.98, 127.80, 126.17, 126.13, 123.57, 48.96, 41.01, 40.27, 29.70, 25.62, 22.12,
17.90, 14.93
M.P : 176-178 º C
HRMS (ESI) [M+H] + calculated for C25H28ClO+:379.1824, found: 379.1889.
5.3.2.4 (3-chlorophenyl)((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6tetrahydro-[1,1'-biphenyl]-2-yl)methanon/ 3d
1H-NMR (600 MHz, CHLOROFORM-D) δ 7.72 (t, J = 1.8 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.44
(dd, J = 8.1, 1.1 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.05 (q, J = 7.2 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H),
5.15 (s, 1H), 4.98 (dt, J = 10.3, 1.3 Hz, 1H), 3.87 (dd, J = 11.7, 9.5 Hz, 1H), 3.58 (dd, J = 11.7, 5.1 Hz,
1H), 3.36 (td, J = 9.9, 1.7 Hz, 1H), 2.17-2.20 (m, 1H), 1.75 (s, 3H), 1.44 (s, 3H), 1.26 (s, 3H), 0.83 (d,
J = 7.0 Hz, 3H)
13C-NMR (151 MHz, CHLOROFORM-D) δ 204.17, 141.94, 140.82, 138.82, 134.28, 133.54, 132.28,
129.40, 128.42, 127.96, 126.94, 126.21, 126.09, 123.72, 47.71, 44.99, 42.17, 40.04, 25.38, 22.15,
17.74, 15.00
M.P :142-145 º C
HRMS (ESI) [M+H] + calculated for C25H28ClO+ : 379.1824, found: 379.1815
5.3.2.5 (4-chlorophenyl)((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6tetrahydro-[1,1'-biphenyl]-2-yl)methanone/3e
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.73 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7.027.06 (m, 2H), 6.95 (d, J = 6.1 Hz, 2H), 5.16 (s, 1H), 4.97 (d, J = 10.3 Hz, 1H), 3.89 (dd, J = 11.7, 9.5
Hz, 1H), 3.58 (dd, J = 11.9, 5.0 Hz, 1H), 3.35-3.40 (m, 1H), 2.14-2.21 (m, 1H), 1.76 (s, 3H), 1.54 (s,
3H), 1.44 (s, 2H), 0.95 (d, J = 6.6 Hz, 4H)
13C-NMR (101 MHz, CHLOROFORM-D) δ 204.05, 141.98, 138.73, 133.16, 129.53, 128.42, 128.39,
127.93, 126.94, 125.92, 123.64, 47.71, 44.49, 41.98, 39.91, 25.35, 21.90, 17.93, 15.05
M.P :122-124 º C
HRMS (ESI) [M+H] + calculated for C25H28ClO+ : 379.1824, found: 379.1836
5.3.2.6 ((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6-tetrahydro-[1,1'biphenyl]-2-yl)(4-iodophenyl)methanone/3f
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.74-7.78 (m, 3H), 7.53 (d, J = 8.6 Hz, 1H), 7.38 (t, J =
2.0 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 6.1 Hz, 2H), 5.19 (s, 1H), 5.00 (d, J = 10.3 Hz, 1H),
3.91 (dd, J = 11.7, 9.8 Hz, 1H), 3.62 (dd, J = 12.0, 4.9 Hz, 1H), 3.41 (t, J = 9.9 Hz, 1H), 2.02-2.09 (m,
2H), 1.80 (s, 3H), 1.48 (s, 3H), 1.31 (s, 3H), 0.86 (d, J = 6.8 Hz, 3H)
HRMS (ESI) [M+H] + calculated for C25H28IO+ : 471.1179, found:471.1179
5.3.2.7 ((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6-tetrahydro-[1,1'biphenyl]-2-yl)(4-methoxyphenyl)methanone/3g
1H-NMR (600 MHz, CHLOROFORM-D) δ 7.81 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 7.3 Hz, 2H), 6.99
(dd, J = 8.6, 7.2 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.15 (s, 1H), 4.97 (d, J = 10.3 Hz, 1H), 3.90 (dd, J
= 11.7, 9.9 Hz, 1H), 3.84 (s, 3H), 3.59 (dd, J = 11.7, 4.8 Hz, 1H), 3.35 (td, J = 9.8, 1.6 Hz, 1H), 2.142.18 (m, 1H), 1.75 (s, 3H), 1.42 (s, 3H), 1.26 (s, 3H), 0.82 (d, J = 7.0 Hz, 3H)
13C-NMR (151 MHz, CHLOROFORM-D) δ 203.44, 162.91, 142.20, 138.55, 133.01, 132.35, 130.62,
128.44, 127.94, 127.17, 125.76, 123.89, 113.14, 55.41, 47.54, 42.14, 40.16, 25.47, 22.12, 17.74, 14.94
M.P :136-138 º C
HRMS (ESI) [M+H] + calculated for C26H31O2+ : 375.2319, found :375.2313
5.3.2.8 ((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6-tetrahydro-[1,1'biphenyl]-2-yl)(4-nitrophenyl)methanone/3h
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.04
(d, J = 1.7 Hz, 1H), 6.93 (d, J = 2.9 Hz, 1H), 5.16 (s, 1H), 5.00 (d, J = 10.3 Hz, 1H), 3.92 (dd, J =
11.7, 9.8 Hz, 1H), 3.57 (dd, J = 11.9, 5.0 Hz, 1H), 3.40-3.45 (m, 1H), 2.17-2.22 (m, 1H), 1.76 (s, 3H),
1.44 (s, 3H), 1.28 (s, 3H), 0.84 (d, J = 7.1 Hz, 3H)
13C-NMR (151 MHz, CHLOROFORM-D) δ 204.82, 141.95, 138.79, 137.69, 137.46, 129.55, 128.52,
128.00, 126.93, 126.02, 123.74, 100.36, 47.73, 44.60, 42.17, 40.05, 25.53, 22.26, 17.75, 14.93
M.P :153-155 º C
HRMS (ESI) [M+H] + calculated for C25H28NO3+ : 390.2064, found: 390.2051
5.3.2.9 ((1S,2S,3R,6R)-4'-methoxy-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6tetrahydro-[1,1'-biphenyl]-2-yl)(p-tolyl)methanone/3i
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.70 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.89
(d, J = 8.3 Hz, 2H), 6.59 (d, J = 8.6 Hz, 2H), 5.15 (s, 1H), 4.96 (d, J = 10.3 Hz, 1H), 3.88 (dd, 1H),
3.66 (s, 3H), 3.53 (dd, J = 11.7, 4.9 Hz, 1H), 3.36 (t, J = 9.7 Hz, 1H), 2.36 (s, 3H), 2.09-2.16 (m, 1H),
1.75 (s, 3H), 1.41 (s, 3H), 1.27 (s, 3H), 0.83 (d, J = 7.1 Hz, 3H)
HRMS (ESI) [M+H] + calculated for C27H33O2+: 389.2475, found: 389.2473
5.3.2.10 ((1S,2S,3R,6R)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-4'-nitro-1,2,3,6tetrahydro-[1,1'-biphenyl]-2-yl)(p-tolyl)methanone/3j
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.93 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.147.19 (m, 4H), 5.19 (s, 1H), 4.97 (dt, J = 10.4, 1.3 Hz, 1H), 3.94 (dd, J = 11.7, 9.8 Hz, 1H), 3.73 (dd, J
= 11.7, 4.9 Hz, 1H), 3.33-3.38 (m, 1H), 2.39 (s, 3H), 2.17-2.23 (m, 1H), 1.77 (s, 3H), 1.41 (s, 3H),
1.25 (s, 3H), 0.81 (d, J = 7.1 Hz, 3H)
13C-NMR (101 MHz, CHLOROFORM-D) δ 204.03, 150.57, 146.29, 143.70, 137.98, 136.28, 133.59,
129.10, 129.01, 128.32, 126.53, 124.31, 123.22, 77.00, 47.71, 43.90, 42.06, 39.74, 25.39, 22.05,
21.62, 17.71, 14.78
M.P :138-140 º C
HRMS (ESI) [M+H] + calculated for C26H30NO3+ : 404.2220, found: 404.2213
5.3.2.11 (1'S,2'S,3'R,6'R)-5',6'-dimethyl-2'-(4-methylbenzoyl)-3'-(2-methylprop-1-en-1yl)-1',2',3',6'-tetrahydro-[1,1'-biphenyl]-4-carbonitrile/3k
1H-NMR (396 MHz, CHLOROFORM-D) δ 7.69 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.17
(d, J = 7.7 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 5.17 (s, 1H), 4.96 (d, J = 10.4 Hz, 1H), 3.91 (dd, J =
11.6, 9.7 Hz, 1H), 3.66 (dd, J = 11.8, 5.0 Hz, 1H), 3.35 (td, J = 10.0, 1.7 Hz, 1H), 2.38 (s, 3H), 2.132.20 (m, 1H), 1.75 (s, 3H), 1.40 (s, 3H), 1.24 (s, 2H), 0.79 (d, J = 7.2 Hz, 3H)
13C-NMR (100 MHz, CHLOROFORM-D) δ 204.27, 148.39, 143.59, 138.14, 136.37, 133.63, 131.85,
129.23, 129.07, 128.40, 126.67, 124.34, 119.04, 109.91, 47.97, 43.95, 42.13, 39.83, 25.48, 22.16,
21.72, 17.80, 14.50
M.P :153-155 º C
HRMS (ESI) [M+H] + calculated for C27H30NO+ : 384.2322, found: 384.2113.
5.3.2.12 ((1S,2S,3R,6R)-3',5'-dimethoxy-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)1,2,3,6-tetrahydro-[1,1'-biphenyl]-2-yl)(p-tolyl)methanone/3l
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.74 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.13 (s,
3H), 5.14 (s, 1H), 4.97 (d, J = 10.3 Hz, 1H), 3.88 (dd, J = 11.7, 9.8 Hz, 1H), 3.54 (dd, J = 11.9, 4.8
Hz, 1H), 3.45 (s, 6H), 3.34-3.39 (m, 1H), 2.36 (s, 3H), 2.15-2.22 (m, 1H), 1.75 (s, 3H), 1.42 (s, 3H),
1.28 (s, 3H), 0.82 (d, J = 7.1 Hz, 3H)
13C-NMR (101 MHz, CHLOROFORM-D) δ 204.63, 160.21, 144.68, 143.06, 138.78, 136.82, 133.24,
128.81, 128.38, 127.04, 123.98, 106.31, 98.75, 54.86, 47.99, 44.14, 41.98, 25.48, 22.04, 17.57, 14.93
M.P : 148-150 º C
HRMS (ESI) [M+H] + calculated for C28H35O3+: 419.2581, found: 419.2591.
5.3.2.13 ((1S,2S,3R,6R)-2'-bromo-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6tetrahydro-[1,1'-biphenyl]-2-yl)(4-nitrophenyl)methanone/3m
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.26 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.53
(dd, J = 7.8, 1.2 Hz, 1H), 6.88-6.97 (m, 2H), 6.79 (dd, J = 7.6, 1.7 Hz, 1H), 5.21 (s, 1H), 5.04 (d, J =
9.5 Hz, 1H), 3.97 (dd, J = 11.7, 9.8 Hz, 1H), 3.45-3.51 (m, 1H), 2.43-2.49 (m, 1H), 1.82 (s, 3H), 1.46
(s, 3H), 1.30 (s, 3H), 0.86 (d, J = 7.1 Hz, 3H)
HRMS (ESI) [M+H] + calculated for C25H26BrNO3: 469.3904, found: 469.3900
5.3.2.1 ((1S,2S,3S,6S)-5,6-dimethyl-3-(2-methylprop-1-en-1-yl)-1,2,3,6-tetrahydro-[1,1'biphenyl]-2-yl)(phenyl)methanone/4
1H-NMR (600 MHz, CHLOROFORM-D) δ 7.74 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.34 (t,
J = 7.7 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 7.18 (t, J = 7.5 Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 5.39 (d, J =
5.5 Hz, 1H), 5.04 (d, J = 10.3 Hz, 1H), 4.21-4.24 (m, 1H), 3.36-3.39 (m, 1H), 3.02 (dd, J = 11.4, 10.3
Hz, 1H), 2.22-2.27 (m, 1H), 1.73 (s, 3H), 1.59 (s, 2H), 1.05 (s, 3H), 0.95 (d, J = 7.0 Hz, 3H)
13C-NMR (101 MHz, CHLOROFORM-D) δ200.13,145.18,137.53,137.18,132.27,128.36,128.02,
127.87,125.91,123.71,123.23,51.24,45.60,41.77,37.55,25.90,21.59,17.31,17.17
M.P :95-97 º C
HRMS (ESI) [M+H] + calculated for C25H29O+:345.2213, found:
5.3 Results and discussion
5.3.1 Synthesis
In 2018, Thy and group developed an efficient AlBr3-promoted endo-selective Diels–
Alder reaction of trans-chalcones with (E)-ocimene catalyzed by commercially available AlBr3
as a Lewis-acid catalyst. Interestingly, in their finding an exo-adduct was determined as a minor
product or by product which caught our interest. We then aimed to study the formation of the
exo adduct of trans-chalcone as the skeleton structure is similar to that of panduratin A.
Initially, we reacted the trans-chalcone with (Z)-ocimene and allocimene using the condition
developed by Thy et al 2018. From the reaction, we obtained two products which are compound
3a and 4 in a mixture which yielded in 7 % using (Z)-ocimene and 47 % using allocimene.
5.3.2 Control study for (1s,5s) sigmatropic hydrogen migration
In curiosity, we pondered upon the formation of the exo adduct using (Z)-ocimene.
From our research, Chamorro et al., 2014 reported a new theoretical prescience on the
electronic reorganization of cis-β-ocimene to alloocimene. In their paper, it was noted that the
cis-β-ocimene underwent a thermal (1s,5s) sigmatropic hydrogen migration as shown in Figure
5.3.
Figure 5.3: Experimentally proposed [1s,5s] hydrogen shift mechanism for the thermal
isomerization of ocimene (1) to alloocimene (3) through a six-membered cyclic transition
structure (2).
To test on the above theory, we conducted a control study on (Z)-ocimene by reacting
in hexane/DCM (1:1,v:v) and 30 mol% of AlBr3 at room temperature for a time interval of 1
hour, 3 hour, and 24 hours respectively and monitored the changes via GCMS as shown in
scheme 5.1. Based on the GCMS chromatogram, the retention time for (Z)-ocimene is 14.784
and alloocimene 16.792. There were no changes observed in the concentration of (Z)-ocimene
(85%) and alloocimene (15%) for 1, 3 and 24 hours respectively. Few different Lewis acid
catalyst were used to study the migration such as Ga(OTF)3, BF3.Et2O, Eu(FOD)3 and TiCl4.
Unfortunately, all catalyst showed the same outcome as AlBr3. Thereby, we deduced (1s,5s)
sigmatropic hydrogen migration is not the cause for the formation of the exo product.
Additionally, individual GCMS chromatogram of (Z)-ocimene and alloocimene were obtained.
The results showed that (Z)-ocimene contained the mixture of alloocimene in about 15% and
the reason for the lower yield produced using (Z)-ocimene. From the result we were able to
draw a conclusion that the formation of the exo adduct was mainly due to the allocimene.
Scheme 5.2:Control study reaction
5.3.3 Diene screening
Once we identified the source of the exo product, our study continued on the four
different stereoisomer formed by alloocimene (4Z,6z), (4Z,6e), (4E,6Z) and (4E,6E)-2,6dimethylocta-2,4,6-triene. The alloocimene that we used was commercially available and it
was 80 % technical grade. To identify the stereoisomer of the alloocimene, Raman
spectroscopy was conducted, and the result were compared to literature wavenumbers. Based
on the comparison we were able to identify that the alloocimene mostly comprises of (4E,6E)2,6-dimethylocta-2,4,6-triene. The strongest peak was at around 1630.84 cm-1 which was due
to the double bond vibration as shown in Figure 5.4. The peak at 1307.88 cm -1 was due to the
trans- configuration. Comparatively, the peaks at 1348.31 cm-1
and 1646.91 cm-1 were
attributed the cis configuration of the stereoisomer. The isomers were well distinguished by the
peak which was present in (4E,6E)- 2,6-dimethylocta-2,4,6-triene at 1364.91 cm-1
The
intensity of the peaks was in increasing trend when it was compared with the literature value.
Therefore, we were able to deduce that the exo adduct was mainly due the 80 % presence of
(4E,6E)-2,6-dimethylocta-2,4,6-triene.
Alloocimene
1,2
integration a.u
1
0,8
0,6
0,4
0,2
0
0
500
1000
1500
2000
2500
wavenumber (cm-1)
Figure 5.4: Raman spectrum chromatogram
3000
3500
5.3.4 Catalyst screening
Next, since the source for the exo adduct was identified, the allocimene was reacted
with different Lewis acid catalyst to determine the selectivity of the exo adduct as shown in
Table 5.1. Based on the literature, a bulky boron catalyst can generate an exo adduct as a major
adduct(Vallejos et al., 2014). So, we tried B(C6F5)3 catalyst which was commercially available
in the lab. When 10 mol % catalyst was loaded under -78 ºC for 24 hours (entry 4) the reaction
was unsuccessful as only the starting material was obtained after stirring for 24 hours.
Additionally, an elevated temperature of 48 ºC with 30 mol % catalyst loading stirred for 48
hours was able to generate the mixture of compound 3 and 4 in 45 % yield and a diastereomer
ratio of 50: 50 (%) (entry 5). Besides that, TiCl4, Me3Al and Me3Al/(S)-BINOL did not show
a promising result as only starting material were obtained. Ga (OTf3)3, Eu (FOD)3, FeCl3 and
Et2AlCl (entry 6-9) showed poor yield which were less than 20% and a poor diastereomer ratio.
Apart from these catalysts with poor yield, AlBr3 and BF3.Et2O showed a promising result with
47 % and 50% yield (entry 11 and 12) and a high diastereomer ratio for M4 which is more than
90 %. Hence, since BF3.Et2O showed the highest yield we decided to use it as a catalyst to
optimize the condition to selectively obtain the exo adduct as it is our compound of interest.
Table 5.1: Screening of Lewis acid catalyst
Entry
Catalyst
Catalyst
(mol %)
a
loading
Time
Temp
(h)
(°C)
Yield
(%)
b
Diastereomeric ratio
(%)c
3
4
1
TiCl4
30
3
rt
-
-
-
2
Me3Al
30
3
rt
-
-
-
3
Me3Al/(S)-BINOL
30
3
rt
-
-
-
4
B(C6F5)3
10
24
-78
-
-
-
5
B(C6F5)3
30
48
rt
45
1.2
1
6
Ga(OTf3)3
30
3
rt
12
1
1
7
Eu(FOD)3
30
3
rt
8
1.4
1
8
FeCl3
30
3
rt
13
1.6
1
9
Et2AlCl
30
3
rt
18
2.2
1
10
ZnCl2
30
3
rt
31
3
1
11
AlBr3
30
3
rt
47
>20
1
12
BF3.Et2O
30
3
rt
50
>20
1
Reaction conditions: 1 (0.5 mmol), 2 (2.5 mmol), solvent (1.0 mL). bIsolated yield. cDiastereomeric ratio were
based on 1H NMR analyses.
5.3.6 Optimization
Once we have determined the suitable Lewis acid catalyst, then optimization was
carried out on by using various time, temperature and solvents. Among all, 30 mol % BF3.Et2O
in toluene at room temperature stirred for 24 hours yielded the highest amount of 3a and 4
mixture which is about 75%(entry 3).The diastereomeric ratio was also the highest 97% 3a and
3% 4.In general 30 mol % catalyst produced a good yield compared to 50 and 10 mol %. The
higher the catalyst loading the lower the yield. Besides that, the solubility of chalcone in toluene
was better compared to DCM and THF and afforded higher yield. At an elevated temperature
around 50°C (entry 4) the yield is the lowest and the compound polymerized. Additionally, at
lower temperature -40 °C the yield was not so promising as well. The best stirring time that we
obtained was 24 hours. Though starting material was obtained at the end we were still able to
get a good yield 75% when the chalcone was stirred for 24 hours compared to 3 hours. The
longer it was stirred, the adduct starts to decompose. Hence, the optimized condition is as
shown in entry 3.
Table 5.2: Optimisation of reaction conditions.a
Entry
Catalyst
Solvent
loading (mol
Temp
Time
Yield
Diastereomeric ratio
(°C)
(h)
(%)b
(%)c
%)
3
4
1
10
toluene
rt
3
8
19
1
2
30
toluene
rt
3
52
>20
1
3
30
toluene
rt
24
75
>20
1
4
30
toluene
50
24
12
>20
1
5
30
toluene
-40
24
28
>20
1
6
30
CH2Cl2
rt
3
35
2.1
1
7
30
THF
rt
3
18
1.7
1
8
50
toluene
rt
3
50
a
19
b
1
c
Reaction conditions: 1 (0.5 mmol), 2 (2.5 mmol), solvent (1.0 mL). Isolated yield. Diastereomeric
ratio was based on 1H NMR analyses.
5.3.7 Derivatives screening
Using the optimized condition, we endeavored to synthesize various exo derivatives.
Initially, we examined the reaction with regards to the substituent on the R1. Electron donating
group (EDG) and electron withdrawing group (EWG) on R1 all gave a moderate to good yield.
Halogens such as chloro and iodo which decreases in electronegativity Cl>I from bottom to
top of the periodic table and also the weakest EWG , generated derivatives of 3c,3d, 3e, and 3f
(entry 3-6) in a mixture with a yield that ranges from 7-89 %. Chloro group attached at the
position 4’ yielded the highest mixture 89% (entry 5) followed by chloro at 3rd position
49%(entry 4) and 2nd position 7 % (entry 3). The lower yield for chloro at position 2 could be
due to steric effect. Iodo at the 4th position which has lesser electronegativity than chloro
yielded about 26 % (entry 6). Besides that, electron donating group 4-methoxy (4-OCH3)
yielded about 37% mixture(entry 7) and electron withdrawing 4-nitro (4-NO2) yielded about
52% (entry 8) of mixture. Based on the substituents on R1, EWG gave the highest yield
compared the EDG. Additionally, 4-chloro on R2 afforded a mixture with 67% yield(entry 2)
and higher diastereomer ratio of the exo adduct, 2.4:1.
Entry 9, 12, and 17 shows EDG attached on both R1 and R2 in different position. When
the R1 attached to weaker EDG 4-methyl and R2 attached to stronger 4-methoxy the yield of
adduct was in moderate,26% and 38% respectively (entry 9 and 12). Comparing the position
of methoxy on R2, 3 and 5-methoxy facilitated a higher yield compared to methoxy attached
to position 4. Unfortunately, methoxy group attached in both R1 and R2 did not yield in any
adduct (entry 17). When EWG such as 4-NO2 and CN are attached to R2 and EDG 4’ CH3
attached to R1 the yields were 56% (entry 10) and 36% (entry 11) respectively. No conversion
was observed for 2-hydroxyl group (entry 14). If strong EWG is substituted in the R1 and weak
EWG substituted in R2 the reaction yielded in 26% (entry 13) with an equal diastereomer ratio
of both adduct. No conversion was observed for strong EWG in both rings and also strong EDG
on R1 and strong EWG on R2 (entry 15,16 & 18).
Table 5.3: Synthesis of cyclohexenyl chalcone derivatives (3am)a
Entry
R1
R2
exo
endo
Yield
(%)b
1
H
H
3a
4a
75
3a/4a (49/1)c
2
H
4-Cl
3b
4b
67
3b/4b (2.4/1)c
3
2-Cl
H
3c
4c
7
3c/4c (13/1)c
4
3-Cl
H
3d
4d
49
3d/4d (1.8/1)c
5
4-Cl
H
3e
4e
89
3e/4e (32/1)c
6
4-I
H
3f
4f
26
3f/4f (1.3/1)c
7
4-OCH3
H
3g
4g
37
3g/4g (12/1)c
8
4-NO2
H
3h
4h
52
3h/4h (8/1)c
9
4-CH3
4-OCH3
3i
4i
26
3i/4i (1.1/1)c
10
4-CH3
4-NO2
3j
4j
56
3j/4j (1.1/1)c
11
4-CH3
4-CN
3k
4k
36
3k/4k (1.6/1)c
12
4-CH3
3-OCH3,
3l
4l
3l/4l (1.9/1)c
5-OCH3
13
4-NO2
2-Br
38
3m
4m
26
3m/4m (2.5/1)c
14
2-OH
2-Br
-
-
NR
15
4-NO2
4-NO2
-
-
NR
16
4-NO2
4-CN
-
-
NR
17
2-OCH3,
3-OCH3,
-
-
NR
4-OCH3
5-OCH3
2-OCH3,
4-NO2
-
-
NR
18
6-OCH3
a
Reaction conditions: 1 (0.5 mmol), 2 (2.5 mmol). bIsolated yield of exo and endo isomers. NR=no reaction.
c
Diastereomeric ratios were based on 1H NMR analyses
5.3.8 Dienophile screening
We also conducted the Diels–Alder reaction with different dienophiles such as transcinnamaldehyde,
methyl
trans-cinnamate,
trans-4-phenylbut-3-en-2-one,
and
transβ-
nitrostyrene. However, under the optimized conditions, these dienophiles did not yield the
desired Diels–Alder adduct.
Table 5.4 :Diels-Alder cycloaddition of (4E, 6E)-alloocimene (2) with different dienophilesa
a
Entry
R1
R2
Yield (%)
1
H
Ph
-
2
CH3
Ph
-
3
OCH3
Ph
-
4
OCH3
H
-
Reaction conditions: dienophile (0.5 mmol), 2 (2.5 mmol), anhyd. CH 2Cl2 (1.0 mL), r.t. (28 °C), 24h.
5.3.9 Structure elucidation
Based on the NMR results, we were able to distinguish the (3a) exo and the (4) endo
adduct through its chemical shift. Four chiral centers have been observed on the new six
membered rings. For 3a two aromatic ring from the trans chalcone were identified at δ 7.80 (d,
J = 7.7 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 6.99-7.06 (m, 5H).Vinyl
hydrogen was identified at 4.99 (d, J = 10.3 Hz, 1H), methine hydrogen was at 5.18 (s, 1H).
Four CH3 groups were identified at 1.77 (s, 3H), 1.41 (s, 3H), 1.28 (s, 3H), 0.85 (d, J = 7.0 Hz,
3H).The hydrogen that was attached to 5’ was identified at 2.17-2.21 (m, 1H) due to shielding
effect from the CH3 . Compound 4 had approximately similar chemical shifts as mentioned
above. The distinguishing factors were the 2 hydrogens that were attached to the new six
membered rings. For compound 3a was identified that the H-1’ and H-2’ were in trans position
at 3.97 (dd, J = 11.7, 9.5 Hz and 3.41 (td, J = 9.8, 1.5 Hz, 1H). In comparison, the H-1’ and H2’ of compound 4 were in cis position at 4.21-4.24 (m, 1H) and 3.02 (dd, J = 11.4, 10.3 Hz,
1H). The structure of 3a and 4 was confirmed unambiguously by single-crystal X-ray
crystallography as shown in Figure 5.
a)
b)
Figure 5.5:a) X-ray crystallography structure of 3a b) X-ray crystallography structure of 4
5.3.10 Proposed mechanism
Based on the experimental results and previous report (Thy et al., 2018), a plausible
mechanism of synthesis of trans chalcone is proposed as in Scheme 5.3. It involves an [4+2]
cycloaddition Diels -Alder reaction where the 4π electron system which is the alloocimene
interacts with the 2π electron system the trans-chalcone that leads to a transition state before
yielding the product. It was notable that endo adduct was the minor due to steric hindrance and
afforded exo as the major product. Relative configuration was determined based on the
mechanism
Scheme 5.3: Proposed mechanism pathway
5.4 Conclusion
Therefore, we can deduce that using BF3.EtO as Lewis acid catalyst exo DA adduct was
successfully synthesized via [4+2] cycloaddition reaction. Various derivatives were
synthesized and characterized. A possible mechanism was also derived based on the literature
studies.
5.5 Appendix
Table 5.5: Raman spectrum comparison between literature and analysis value
Literature value
Analysis value
Wavenumber (Cm-1) Intensity a.u
Form A
Wavenumber (Cm-1) Intensity a.u
Alloocimene
196
2vb
196.136
0.023
258
0.25
257.814
0.012
296
0.25
295.161
0.007
361
0.25
361.486
0.007
440
0.5
440.463
0.011
581
0.125
580.959
0.003
790
0.5
790.313
0.012
844
0.25
843.169
0.014
871
1
870.735
0.025
964
5
965.324
0.070
1026
0.25
1027.02
0.015
1091
0.5
1090.74
0.021
1151
7
1151.59
0.212
1184
5
1183.07
0.128
1236
6
1236.09
0.162
1307
6
1307.88
0.150
1365
3
1364.91
0.101
1383
3
1383.83
0.115
1448
2
1447.41
0.065
1532
0.5
1531.48
0.012
1590
6
1591.69
0.235
1631
10
1630.84
0.978
2878
1
2878.64
0.074
2914
3
2914.19
0.205
2971
0.5
2971.15
0.079
3012
0.25
3012.14
0.062
Figure 5.6: HNMR spectrum for compound 3a
Figure 5.7: CNMR spectrum for compound 3a
Figure 5.8: Cosy nmr of compound 3a
Figure 5.9: HMBC nmr of compound 3a
Figure 5.10: HSQC nmr of compound 3a
Figure 5.11: HNMR of compound 4
Figure 5.12: CNMR of compound 4
Figure 5.13: HNMR of compound 3b
Figure 5.14: CNMR compound 3b
Figure 5.15: HNMR compound 3c
Figure 5.16: CNMR compound 3c
Figure 5.17: HNMR compound 3d
Figure 5.18: CNMR compound 3d
Figure 5.19: HNMR compound 3e
Figure 5.20: CNMR compound 3e
Figure 5.21: HNMR compound 3f
Figure 5.22: HNMR compound 3g
Figure 5.23: CNMR compound 3g
Figure 5.24: HNMR compound 3h
Figure 5.25: CNMR compound 3h
Figure 5.26: HNMR for 3i
Figure 5.27: HNMR for compound 3j
Figure 5.28: CNMR for compound 3j
Figure 5.29: HNMR for compound 3k
Figure 5.30: CNMR for compound 3k
Figure 5.31: HNMR for compound 3l
Figure 5.32:CNMR for compound 3l
Figure 5.33: HNMR for compound 3m