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AbstractSix 4H-chromenes were synthesized from substituted phenols using vinylstannylation and ring-closing metathesis (RCM) as
key steps. In addition, a different approach involving amongst other steps, an aryl allyl isomerization and RCM afforded a set of seven
2H-chromenes from phenolic precursors.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Compounds in which a benzene and pyran ring are fused
together with various levels of saturation and oxidation are
very common in Nature.1 The 1-benzopyrans include
structural skeletons such as chromane 1, 4H-chromene 2
and 2H-chromene 3 as depicted in Figure 1.
Figure 2.
Figure 1.
00404020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.020
9997
Figure 3.
Figure 4.
Figure 5.
2. Discussion: 4H-chromenes
Variably substituted phenols 12 were initially converted
into their corresponding aryl allyl ethers. Subsequent
thermal Claisen rearrangements then gave the substituted
phenols 13 in acceptable yields over two steps (Scheme 1
and Table 1). The compounds were then converted into the
respective aryl vinyl ethers 14, also in excellent yield, using
Scheme 1. (a) K2CO3, allyl bromide, acetone, 60 8C; (b) 6 (180240 8C),
neat; (c) Cu(OAc)2, Sn(vinyl)4, acetonitrile, O2, rt; (d) 5% catalyst 11,
toluene, 60 8C (for yields see Table 1 below).
3. Discussion: 2H-chromenes
The synthesis of a small set of substituted 2H-chromenes
required us to adopt a different approach. The 2-allylphenols 17 were synthesised as before, making use of the
initial allylation of the substituted phenols 16 followed by a
Claisen rearrangement (Scheme 2 and Table 2). The next
step required the isomerization of the terminal alkene
groups of 17 to the thermodynamically more favoured
internal alkenes of the 2-(prop-1-enyl)phenols 18. This was
accomplished using the ruthenium-based catalyst,
[RuClH(CO)(PPh3)3], utilised by the group of Krompiec,
and co-workers for a variety of isomerization applications.20
For the most part, products 18 were obtained as a mixture of
E- and Z-isomers with the E-isomers predominating. The
only exception to this was that the isomerization of 1-allylnaphthalen-2-ol 17f predominantly afforded the Z-isomer
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a R ,R ,R ZH; R ,R ZOMe
b R1,R4ZH; R2,R3ZOMe; R5ZMe
c R1,R3ZOMe; R2,R4,R5ZH
d R1,R3ZOMe; R2,R4ZH; R5ZMe
e R1,R4ZOMe; R2,R3,R5ZH
f R1,R2ZH; R3,R4Zbenzo
13a
13/14
14/15
45%b
65%b
91%c
42%c
63%d
90%e
98%
98%
99%
98%
99%
74%
90%
98%
80%
82%
85%
63%
Scheme 2. (a) K2CO3, allyl bromide, acetone, 60 8C; (b) D (180240 8C) or
microwave (150200 8C), neat; (c) [RuCl(CO)(PPh3)3] (cat 14 mol%),
toluene, 80 8C; (d) 5% catalyst 11, toluene, rt K60 8C (for yields see
Table 2 below).
4. Conclusion
We have thus demonstrated a simple, versatile method of
synthesizing the 4H-chromene skeleton using as key steps a
copper-mediated aryl vinyl ether formation followed by a
ruthenium-mediated RCM reaction. In addition this paper
discloses our novel approach to the 2H-chromenes
involving an aryl allyl isomerization and a RCM reaction.
An advantage of both approaches is that they require
substituted phenols as precursors. Since a wide variety of
these compounds are commercially available or readily
synthesized, it allows for a versatile approach to both classes
of 1-benzopyrans.
5. Experimental
1
a R ZNO2; R ,R ,R ZH
b R1,R2,R4ZH; R3ZNO2
c R1ZOMe; R2,R3ZH; R4ZCHO
d R1ZCHO; R2,R3,R4ZH
e R1,R2,R4ZH; R3ZCHO
f R1,R2ZH; R3,R4Zbenzob
g R1,R2,R3,R4ZH
a
16/17a
17/18
18/19
19/20
84%
49%
68%
45%
41%
90%
96%
96%
67%
89%
42%
84%
90%
71%
100%
81%
100%
64%
65%
86%
90%
100%
77%
80%
76%
45%c,d
80%f,g
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(37), 182 (100), 165 (55), 154 (90), 139 (57), 79 (50), 55
(92), 39 (80), 27 (50).
5.2.2. 2-Allyl-4,6-dimethoxyphenol 13c. 1-Allyloxy2,4-dimethoxybenzene (1.1 g, 5.7 mmol) was heated without
solvent at 220236 8C for 45 min under a N2 atmosphere. The
resultant brown residue was then subjected to silica gel column
chromatography (20% EtOAc/hexane) to afford 2-allyl-4,6dimethoxyphenol 13c (0.58 g, 53%) as a light yellow oily
material. (Found: MC, 194.0958, C11H14O3 requires
194.0943); 1H NMR (300 MHz, CDCl3): dZ3.393.41
(2H, m, ArCH2), 3.72 (3H, s, OCH3), 3.77 (3H, s, OCH3),
5.035.11 (2H, m, CH2CH]CH2), 5.50 (1H, s, OH), 5.92
6.06 (1H, m, CH2CH]CH2), 6.35 (1H, d, JZ2.7 Hz, ArH),
6.46 (1H, d, JZ2.7 Hz, ArH); 13C NMR (75 MHz, CDCl3):
dZ33.9 (ArCH2), 55.4 (OCH3), 55.6 (OCH3), 97.1 (CH),
105.4 (CH), 115.3 (CH), 125.7 (C), 136.4 (CH), 137.4 (C),
146.8 (C), 152.7 (C); nmax (CHCl3)/cmK1: 3555 br, 1639,
1617, 1605, 1499, 1467, 1431; MS: m/zZ194 (MC, 100%),
179 (34), 161 (5), 151 (12), 137 (6), 133 (6), 119 (6), 91
(10), 69 (8), 65 (5).
5.3. General procedure for the vinylation of substituted
2-allyl-phenols 13 to 1-allyl-2-vinyloxy-benzenes 14
Anhydrous Cu(OAc)2 (1.2 mol equiv) was added to a
thoroughly degassed solution of substituted 2-allylphenol
13 (ca. 1.0 mmol) in CH3CN (3.0 mL). The reaction vessel
was then fitted with an O2 balloon and tetravinyltin
(1.2 mol equiv) was added through a septum. The mixture
was left to react for 22 h at room temperature after, which
aqueous NH4OAc (0.3 M, 25 mL) was added. The aqueous
layer was then extracted with EtOAc (5!20 mL). The
combined organic extracts were dried with anhydrous
MgSO4, then filtered and the solvent removed in vacuo.
The resultant residue was purified by column chromatography (230% EtOAc/hexane) to afford the product 14. The
following compounds were prepared using this procedure:
5.3.1. 1-Allyl-4,5-dimethoxy-2-(vinyloxy)benzene 14a.
The product 14a (0.23 g, quantitative) was isolated as a
clear oil starting from substrate 13a (0.20 g, 1.0 mmol).
(Found: MC, 220.1100, C13H16O3 requires 220.1099); 1H
NMR (300 MHz, CDCl3): dZ3.303.32 (2H, d m, JZ
6.6 Hz, ArCH2), 3.84 (3H, s, OCH3), 3.85 (3H, s, OCH3),
4.26 [1H, dd, JZ6.2, 1.8 Hz, OCH]C(H)H], 4.47 [1H, dd,
JZ13.9, 1.8 Hz, OCH]C(H)H], 5.025.03 [1H, m, CH2CH]C(H)H], 5.065.08 [1H, m, CH2CH]C(H)H], 5.86
5.97 (1H, m, CH2CH]CH2), 6.56 (1H, dd, JZ13.9, 6.2 Hz,
OCH]CH2), 6.57 (1H, s, ArH), 6.69 (1H, s, ArH); 13C
NMR (75 MHz, CDCl3): dZ33.5 (CH2), 56.0 (OCH3), 56.2
(OCH3), 92.1 (CH), 103.7 (CH), 112.9 (CH), 115.5 (CH),
122.3 (C), 136.9 (CH), 145.5 (C), 147.1 (C), 147.9 (C),
150.4 (CH); IR nmax (CHCl3)/cmK1 1635, 1609, 1510; MS:
m/zZ221 (MCCH, 18%), 220 (MC, 100%), 205 (22), 194
(93), 191 (23), 179 (56), 91 (20), 69 (23).
5.3.2. 1-(But-3-en-2-yl)-4,5-dimethoxy-2-(vinyloxy)benzene 14b. The product 14b (0.22 g, quantitative) was
10000
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10002
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10.05 (1H, s, CHO): Z isomer dZ1.55 (3H, dd, JZ6.8, 1.7 Hz,
CH3), 3.94 (3H, s, OCH3), 4.414.46 (2H, m under E-isomer,
OCH2), 5.185.24 [1H, m under E-isomer, CH]C(H)H],
5.31 [1H, dd, JZ17.2, 1.5 Hz, CH]C(H)H], 6.006.14
(2H, m under E-isomer, CH2CH]CH3 and CH]CHCH3),
6.57 (1H, br d, JZ11.4 Hz, CH]CHCH3), 6.95 (1H, d, JZ
8.8 Hz, 5-H), 7.75 (1H, d, JZ8.7 Hz, 6-H), 9.99 (1H, s,
CHO);13C NMR (75 MHz, CDCl3, only E isomer characterized): dZ19.1 (CH3), 55.8 (OCH3), 73.8 (OCH2), 110.4
(CH), 117.7 (CH), 117.8 (CH), 122.2 (CH), 125.9 (CH),
128.3 (C), 133.9 (C), 136.5 (CH), 145.0 (C), 157.0 (C),
191.4 (CHO); IR nmax (CHCl3)/cmK1: 1676, 1585, 1565,
1511, 1483, 1464, 1440, 1420; MS: m/zZ232 (MC, 37%),
191 (100), 175 (11), 164 (12), 163 (16), 148 (18), 135 (48),
119 (9), 103 (23), 91 (25), 77 (17), 65 (14), 41 (20).
5.7.4. 2-Allyloxy-3-(prop-1-enyl)benzaldehyde 19d. The
product 19d (0.53 g, quantitative, E:Z ratio 85:15) was
isolated as a yellow oil from 18d (0.43 g, 2.7 mmol). Found:
MC, 202.0997, C13H14O2 requires 202.0994); 1H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ1.94
(3H, dd, JZ6.6, 1.7 Hz, CH3), 4.444.47 (2H, m, OCH2),
5.295.37 [1H, m, CH]C(H)H], 5.385.44 [1H, m,
CH]C(H)H], 6.076.15 (1H, m, OCH2CHCH2), 6.29
6.36 (1H, m, ArCH]CH), 6.67 (1H, dd, JZ15.9, 1.5 Hz,
ArCH]CH), 7.157.20 (1H, m, ArH), 7.677.72 (2H, m,
2!ArH), 10.39 (1H, s, CHO); 13C NMR (75 MHz, CDCl3,
only E isomer characterized): dZ18.9 (CH3), 77.0 (OCH2),
118.7 (CH), 124.4 (CH), 124.5 (CH), 126.7 (CH), 128.6
(CH), 129.8 (C), 132.6 (CH), 132.7 (CH), 136.7 (C), 158.8
(C), 190.3 (CHO); IR nmax (CHCl3)/cmK1: 1684, 1590,
1445; MS: m/zZ202 (MC, 16%), 178 (16), 177 (84), 176
(15), 161 (39), 159 (21), 149 (100), 145 (18), 133 (27), 132
(24), 120 (37), 115 (17), 105 (38), 103 (16), 77 (35), 65 (21),
63 (15), 51 (27), 41 (54), 38 (34).
5.7.5. 4-Allyloxy-3-(prop-1-enyl)benzaldehyde 19e. The
product 19e (0.81 g, 64%, E:Z ratio 93:7) was obtained as an
orange oil from 18e (1.0 g, 6.2 mmol). Found: MC,
202.0993, C13 H14O 2 requires 202.0994); 1H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ1.92
(3H, br d, JZ6.6 Hz, CH3), 4.65 (2H, br d, JZ5.1 Hz,
OCH2), 5.33 [1H, br d, JZ10.6 Hz, CH]C(H)H], 5.44 [1H,
br d, JZ17.3 Hz, CH]C(H)H], 6.016.15 (1H, m, OCH2CHCH2), 6.36 (1H, dq, JZ15.8, 6.6 Hz, ArCH]CH), 6.73
(1H, br d, JZ15.8 Hz, ArCH]CH), 6.94 (1H, d, JZ8.5 Hz,
5-H), 7.69 (1H, dd, JZ8.5, 1.7 Hz, 6-H), 7.93 (1H, d, JZ
1.7 Hz, 2-H), 9.88 (1H, s, CHO); 13C NMR (75 MHz,
CDCl3, only E isomer characterized): dZ18.9 (CH3), 69.2
(OCH2), 111.7 (CH), 118.1 (CH), 124.5 (CH), 127.9 (CH),
128.1 (C), 128.4 (CH), 129.8 (C), 130.3 (CH), 132.4 (CH),
159.9 (C), 191.1 (CHO); IR nmax (CHCl3)/cmK1: 1686,
1595, 1492; MS: m/zZ202 (MC, 58%), 173 (13), 161 (34),
159 (11), 133 (27), 115 (11), 106 (9), 105 (100), 103 (16), 79
(16), 77 (26), 51 (11), 41 (32), 39 (19).
5.7.6. 2-(Allyloxy)-1-(prop-1-enyl)naphthalene 19f.25 The
product 19f (0.37 g, 65%, O95% Z isomer) was obtained as
a clear oil from 18f (0.30 g, 2.6 mmol). (Found: MC,
224.1204, C16H 16O requires 224.1201); 1 H NMR
(300 MHz, CDCl3, only Z isomer characterized): dZ1.52
(3H, dd, JZ6.8, 1.7 Hz, CH3), 4.654.68 (2H, m, OCH2),
5.235.27 (1H, m, CH]C(H)H), 5.385.45 [1H, m,
10004
CH]C(H)H], 6.016.16 (2H, m, CHCH3 and CH2CH]CH2), 6.60 (1H, dd, JZ11.2, 1.1 Hz, CH]CHCH3),
7.26 (1H, d, JZ9.0 Hz, ArH), 7.317.36 (1H, m, ArH),
7.417.47 (1H, m, ArH), 7.747.79 (2H, m, 2!ArH), 7.86
(1H, d, JZ8.5 Hz, ArH); 13C NMR (75 MHz, CDCl3, only
Z isomer characterized): dZ15.4 (CH3), 70.2 (OCH2), 115.2
(CH), 117.1 (CH), 121.1 (C), 123.6 (CH), 125.1 (CH), 126.1
(CH), 128.0 (CH), 128.4 (CH), 129.1 (C), 129.7 (CH), 129.8
(CH), 132.7 (C), 133.9 (CH), 153.0 (C); IR nmax (CHCl3)/
cmK1: 1672, 1623, 1596, 1511, 1465, 1435; MS: m/zZ224
(MC, 85%), 183 (100), 165 (49), 155 (93), 139 (31), 115
(33), 41 (35).
5.7.7. 1-Allyloxy-2-(prop-1-enyl)benzene 19g. The
product 19g (0.45 g, 86%, E:Z ratio 90:10) was obtained
as a clear oil from 18g (0.40 g, 3.0 mmol). Found: MC,
174.1043, C12H 14O requires 174.1045); 1 H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ1.89
(3H, dd, JZ6.7, 1.5 Hz, CH3), 4.544.55 (2H, m, OCH2),
5.27 [1H, dd, JZ10.5, 1.3 Hz, CH]C(H)H], 5.41 [1H, dd,
JZ17.3, 1.3 Hz, CH]C(H)H], 6.016.14 (1H, m,
CH]CH2), 6.166.29 (1H, m, CH]CH), 6.75 (1H, d,
JZ15.9 Hz, ArCH]CH), 6.816.92 (2H, m, 2!ArH),
7.117.16 (1H, m, ArH), 7.39 (1H, d, JZ7.6 Hz, ArH); 13C
NMR (75 MHz, CDCl3, only E isomer characterized): dZ
19.3 (CH3), 69.6 (OCH2), 112.8 (CH), 117.6 (CH), 121.3
(CH), 126.1 (CH), 126.7 (CH), 126.8 (CH), 128.0 (CH),
130.6 (C), 134.0 (CH), 155.6 (C); IR nmax (CHCl3)/cmK1:
1601; MS: m/zZ174 (MC, 51%), 145 (24), 133 (71), 121
(20), 105 (100), 91 (11), 77 (28), 65 (10), 51 (15), 41 (34),
39 (25).
5.8. General RCM procedure for the synthesis of
substituted 2H-chromenes 20 from 1-allyloxy-2-(prop-1enyl)benzenes 19
Typically, Grubbs catalyst 11 (46 mol%) was added to a
degassed solution of the substituted 1-allyl-2-vinyloxybenzene 19 (ca. 0.51.0 mmol) dissolved in degassed,
distilled toluene (ca. 30 mL, ca. 0.020 M). The reaction
mixture was then heated at 60 8C for 1 h under a N2
atmosphere. After removal of the solvent under reduced
pressure the residue was purified by silica gel column
chromatography (520% EtOAc/hexane) to afford the
desired product 20. The following compounds were
obtained using this procedure:
5.8.1. 8-Nitro-2H-chromene 20a.27 The product 20a
(0.14 g, 88%) was obtained as a light yellow oil from 19a
(0.20 g, 0.91 mmol). (Found: MC, 177.0431, C9H7O3N
requires 177.0426); 1H NMR (300 MHz, CDCl3): dZ5.00
(2H, dd, JZ3.4, 1.9 Hz, 2-H), 5.90 (1H, dt, JZ10.0, 3.4 Hz,
3-H), 6.45 (1H, dt, JZ10.0, 1.9 Hz, 4-H), 6.876.93 (1H, m,
ArH), 7.14 (1H, dd, JZ7.4, 1.4 Hz, ArH), 7.67 (1H, dd, JZ
8.3, 1.4 Hz, ArH); 13C NMR (75 MHz, CDCl3, one
quaternary carbon not observed in spectrum): dZ66.5 (2C), 120.4 (CH), 123.3 (CH), 123.4 (CH), 124.5 (C), 124.8
(CH), 130.9 (CH), 148.2 (C); IR nmax (CHCl3)/cmK1: 1609,
1527, 1477, 1343; MS: m/zZ177 (MC, 100%), 176 (81),
130 (41), 103 (24), 102 (20), 77 (14), 51 (6).
5.8.2. 6-Nitro-2H-chromene 20b. The product 20b
(0.12 g, quantitative) was obtained as a fluffy yellow solid
9.
Acknowledgements
This work was supported by the National Research
Foundation (NRF, GUN 2053652), Pretoria, and the
University of the Witwatersrand (University and Science
Faculty Research Councils). Prof. J. P. Michael is thanked
for many helpful discussions and Mr. L. G. Madeley
(Honours) and Ms. N. Thornton (Honours) are acknowledged for preparing a number of synthetic precursors. We
also gratefully acknowledge the Mellon Postgraduate
Mentoring Programme (sponsored by the Andrew W.
Mellon Foundation) for generous funding for Mr. E. L.
Ngidi and Mr. S. S. Moleele. Mr. R. Mampa and Mr. T. van
der Merwe are also thanked for providing the NMR and MS
spectroscopy services, respectively.
10.
11.
12.
13.
14.
15.
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16.
17.
18.
19.
20.