A novel carbanion-olefin intramolecular cyclization: synthesis of substituted 2-aroyl-3,4-dihydro-2H-benzopyrans from salicylaldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.07.132

Utilization of a novel carbanion-olefin intramolecular 6-endo-trig cyclization reaction to provide 2-aroyl-3,4-dihydro-2H-benzopyrans is described. Through a sequence of a Wittig reaction, O-alkylation, and carbanion-olefin intramolecular cyclization, sal

Full text of DOI:10.1016/j.tetlet.2009.07.132

Tetrahedron Letters 50 (2009) 5748–5750
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Tetrahedron Letters
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A novel carbanion-olefin intramolecular cyclization: synthesis of substituted
2-aroyl-3,4-dihydro-2H-benzopyrans from salicylaldehydes
Liang-Yeu Chen a,b, Sie-Rong Li a,b, Po-Yuan Chen a, Ian-Lih Tsai b, Chia-Ling Hsu a, Hsin-Ping Lin a,
Tzu-Pin Wang a, Eng-Chi Wang a,
*
a Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan, ROC
b Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung City 807, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Utilization of a novel carbanion-olefin intramolecular 6-endo-trig cyclization reaction to provide 2-aroyl-
3,4-dihydro-2H-benzopyrans is described. Through a sequence of a Wittig reaction, O-alkylation, and
carbanion-olefin intramolecular cyclization, salicylaldehydes were converted into a series of new
2-aroyl-3,4-dihydro-2H-benzopyrans in two steps or in one-pot reaction.
Received 8 June 2009
Revised 27 July 2009
Accepted 28 July 2009
Available online 6 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbanion-olefin intramolecular cyclization
Substituted 2-aroyl-3,4-dihydro-
2H-benzopyrans
The search for new cyclization methods for the construction of
organic ring compounds from simple open chain starting materials
is an attractive task for chemists. Carbon–carbon (C–C) bond for-
mation reactions via intramolecular cyclization have been well
documented and have become one of the most efficient methods
in the synthesis of carbocyclic and heterocyclic compounds. In
the previous reports, most of the intramolecular additions of nucle-
ophiles to double bonds are initiated by the attack on the double
bond by an external electrophile to generate a cationic intermedi-
ate that is subsequently cyclized by an internal nucleophile.1 More
recently, the intramolecular Heck reaction, which is known as a
palladium-catalyzed coupling of haloarenes and haloalkenes with
other double bonds, has become a powerful tool for synthesizing
corresponding cyclic compounds.2 Other cyclization reactions re-
ported include the cyclization of unsaturated organolithium re-
agents for the preparation of benzoheterocyclic compounds,3 the
free radical cyclization for construction of both carbocycles and
heterocycles,4 the carbocyclization of gem-difluoroalkenes for the
construction of naphthalene and indene frameworks,5 the 6-
endo-trig intramolecular cyclization of an enone-aldehyde using
samarium (II) iodide for hydrindanone,6 as well as other reactions.
The lack of the regiochemical control between 6-endo-trig and
5-exo-trig closures as well the requirement for expensive transition
metal catalysts, which may produce environmental hazardous
toxic waste,7 are shortcomings of some of these cyclization
reactions. On the other hand, the preparation of 2-aroyl-3,4-dihy-
dro-2H-benzopyrans is still undeveloped in the literature. Further-
more, its oxidation-dehydrogenation products, 2-aroylbenzopy-
ran-4-ones exhibiting biological activities were reported.8 Herein
we report the results of our studies on the intramolecular carban-
ion-olefin cyclization via a 6-endo-trig cyclization leading to the
synthesis of 2-aroyl-3,4-dihydro-2H-benzopyrans by the reaction
of 1-aryl-2-(2-vinylphenoxy)ethanones (3a–k), which were pre-
pared from salicylaldehydes (1a–h), with potassium tert-butoxide
or by the reaction of 1a–h through a sequence of reactions in
one pot.
Based on the two-step strategy (Scheme 1), salicylaldehydes (1a–
h) were reacted with methylene(triphenyl)phosphorane, which was
generated from methyltriphenylphosphonium bromide (MTPPB)
and potassium tert-butoxide (2.3 equiv) in situ at 0 °C, to undergo
the Wittig reaction for 1 h. Without isolation of the intermediate,
the reaction mixture was subsequently treated with 2-bromoace-
tophenones (2a–c) and refluxed for an additional 1 h. Following
standard workup and isolation procedures, 3a–k were afforded in
67–85% yield. The structure of 3a–k can be confirmed by their
spectral data.9 Subsequently, as a model reaction, 2-(6-methoxy-
2-vinylphenoxy)-1-phenylethanone (3b) was treated with various
bases and in different solvents to optimize the reaction. When
n-BuLi was used as a base, no desired cyclization product was
observed resulting to the nucleophilic addition product 1-(2-
methoxy-6-vinylphenoxy)-2-phenylhexan-2-ol,10 instead (entry
1). Other bases either LDA (entries 2 and 3) or NaOEt (entries 4
and 5) gave no desired product or lower yield than that of tert-BuOK
at either room temperature (entry 6) or reflux (entry 7) in THF. In
addition to THF, CH2Cl2 (which is toxic and volatile) can also be used
* Corresponding author. Tel.: +886 7 3121101; fax: +886 7 3125339.
E-mail address: enchwa@kmu.edu.tw (E.-C. Wang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.132

L.-Y. Chen et al. / Tetrahedron Letters 50 (2009) 5748–5750
5749
R1
R2
R4
R1
R2
R4
R1
R2
CHO
OH
i
ii
O
O
33-86%
67-85%
R3
O
R3
O
R3
1
3
4
a. R1 = R2 = R3 = R4 = H; b. R1 = R2 = R4 = H, R3 = OMe;
c. R1 = R2 = H, R3 = R4 = OMe; d. R1 = Br, R2 = R3 = R4 = H;
e. R1 = Cl, R2 = R3 = R4 = H; f. R1 = R3 = Cl, R2 = R4 = H;
g. R1 = R4 = Cl, R2 = R3 = H; h. R1 = Cl, R2 = R3 = H, R4 = OMe;
i. R1 = R3 = H, R2 = R4 = OMe; j. R1 = R3 = R4 = H, R2 = Cl;
k. R1 = R3 = R4 = H, R2 = NO2
a. R1 = R2 = R3 = H;
b. R1 = R2 = H, R3 = OMe;
c. R1 = Br, R2 = R3 = H;
d. R1 = Cl, R2 = R3 = H;
e. R1 = Cl, R2 = H, R3 = Cl;
f. R1 = R3 = H, R2 = OCH3
g. R2 = Cl, R1 = R3 = H;
h. R2 = NO2; R1 = R3 = H
Scheme 1. Reagents and conditions: (i) (a) MTPPB (1.2 equiv), tert-BuOK (2.3 equiv), THF, rt, 1 h; (b) 2-bromoacetophenone (2a) (1.1 equiv), 2-bromo-40-methoxyaceto-
phenone (2b) (1.1 equiv) , 2-bromo-40chloroacetophenone (2c) (1.1 equiv), reflux, 1 h; (ii) tert-BuOK (1.2 equiv), THF, reflux, 30 min.
zation and the correct connectivity were confirmed by the acquired
spectral data.8 In addition, the elemental analytical data which
were measured are consistent with the structure of 4a–k. The
proposed mechanism for the carbanion-olefin intramolecular
cyclization of 3 is shown in Scheme 2. The proton near the carbonyl
group of 3, which is more acidic than others, is abstracted by potas-
sium tert-butoxide to generate a carbanion. The resultant carban-
ion attacks the olefinic carbon to undergo 6-endo-trig reaction to
form a benzylic carbanion. Subsequently, the carbanion abstracts
a proton from tert-butyl alcohol generated in situ to yield the title
compounds.
Table 1
Treatment of 3b (2.68 g, 10 mmol) with various bases (1.2 equiv) and solvents
(15 mL) to examine the yield of 4b
Entry
Base
Solventa
Temp (°C)
Time (hr)
Yield (%)
Ref. 9
1
2
3
4
5
6
7
8
n-BuLi
LDA
LDA
NaOEt
NaOEt
t-BuOK
t-BuOK
t-BuOK
THF
THF
ꢀ78 °C to rt
2
2
2
3
d
ꢀ78 °C to rt
—
THF-HMPAb
EtOH
THF
0 °C to rt
50e
Trace
47
rt
rt
rt
Reflux
rt
4
THF
THF
CH2Cl2
1.5c
0.5c
1.5c
89
86
86
In order to minimize the synthetic steps, to reduce the reaction
wastes, to shorten workup processes, and to increase the efficiency
of the reaction, the synthesis of 2-aroyl-3,4-dihydro-2H-benzopy-
rans (4a–k) was achieved through a sequence of a Wittig reaction,
O-alkylation, and carbanion-olefin intramolecular cyclization from
salicylaldehydes (1a–h) in a three-step one-pot reaction (Scheme
3).11
a
b
c
Solvents were dried by the standard procedures before use.
15 mL THF and 7.5 mL HMPA were used.
Reaction time was determined by checking the consumption of starting mate-
rial with TLC.
d
Even after prolonged reaction time of 4 h, almost no desired product was
detected by TLC, but starting material mixed with messy products was observed.
e
In the mixed solvents, the percentage yield increases and decreases the high
polar unidentified by-products.
The percentage yields of 2-aroyl-3,4-dihydro-2H-benzopyrans
(4a–k) which were obtained from salicyl-aldehydes (1a–h) in a
three-step one-pot reaction are 47% for 4a, 66% for 4b, 64% for
4c, 64% for 4d, 62% for 4e, 67% for 4f, 58% for 4g, 62% for 4h, 41%
for 4i, 48% for 4j, and 26% for 4k, respectively.
In conclusion, we have established a novel carbanion-olefin
6-endo-trig cyclization from the reaction of 1-aryl-2-(2-vinylphen-
oxy)ethanones (3a–k) with potassium tert-butoxide. Based on this
cyclization, a new series of substituted 2-aroyl-3,4-dihydro-2H-
benzopyrans was efficiently synthesized either from the cycliza-
tion of the intermediates 3a–k in a two-step reaction or from the
starting materials 1a–h through a sequence of a Wittig reaction,
O-alkylation, and cyclization in a one-pot reaction. Although the
in this cyclization reaction (entry 8). Therefore, the use of potassium
tert-butoxide as the base and anhydrous THF as solvent provided the
optimum conditions for this type of carbanion-olefin cyclization.
The results of the optimization are compiled in Table 1.
Based on the above results, compounds 3a–k were subjected to
the carbanion-olefin intramolecular cyclization using potassium
tert-butoxide as base in refluxing THF for 0.5–1 h to afford 4a–k
in 33–86% yields. The selected spectral data of 4a–k are summa-
rized in Table 2.
Spectroscopic analysis showed that 5-exo-trig products were
not observed during this reaction. The stereospecificity of the cycli-
Table 2
The selected physical and spectral data of 4a–k
Compd
Yield* (%)
MP (°C)
IR (cmꢀ1
)
1H and 13C NMR
H-2 (d) (Hz)
C-2
C-3
C-4
4a
4b
4c
4d
4e
4f
4g
4h
4i
67
86
82
76
79
80
72
82
55
61
33
69–70
91–93
112–113
90–92
87–88
1693
1695
1685
1691
1689
1682
1692
1683
1682
1693
1695
5.38 (8.4, 3.2)
5.56 (6.8, 4.0)
5.49 (7.2, 3.6)
5.42 (7.6, 3.6)
5.43 (8.4, 3.2)
5.54 (6.8, 4.0)
5.32 (8.0, 3.6)
5.37 (8.0, 3.6)
5.32 (8.4, 3.2)
5.44 (7.2, 3.6)
5.60 (6.6, 4.4)
77.1
77.1
77.0
76.8
76.9
77.5
77.1
76.9
77.2
77.1
76.8
23.5
22.8
22.9
23.1
23.2
22.9
23.2
23.3
23.0
22.9
23.1
24.4
24.2
24.3
23.9
24.0
23.3
23.8
24.2
24.9
24.1
23.4
85–86
109–110
128–130
107–108
110–111
117–118
4j
4k
*
General procedure: Under the protection of N2, to 3a–k (10 mmol) dissolved in THF (15 mL) was added potassium tert-butoxide (1.35 g, 12 mmol). The reaction mixture
was heated to the reflux for 0.5–1 h until the consumption of starting material. Work-up as general procedure, and purified by column chromatography (EA/n-hexane = 1:10)
to yield 4a–k.

5750
L.-Y. Chen et al. / Tetrahedron Letters 50 (2009) 5748–5750
2. (a) Heck, R. F. Accounts Chem. Res. 1979, 12, 146–151; (b) Link, J. T. Org. React.
tert-BuOK
- tert-BuOH
2002, 60, 157–534; (c) Laschat, S.; Narjes, F.; Overman, L. E. Tetrahedron 1994,
50, 347–358; (d) Grigg, R.; Fretwell, P.; Meerholtz, C.; Sridharan, V. Tetrahedron
1994, 50, 359–370; (e) Hudlicky, T.; Olivo, H. F. J. Amer. Chem. Soc. 1992, 114,
9694–9696; (f) Sundberg, R. J.; Cherney, R. J. J. Org. Chem. 1990, 55, 6028–6037.
3. (a) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59–67; (b) Kamyar,
A. J. Chem. Soc., Perkin Trans. 1 1999, 15, 2025–2046; (c) Coldham, I. J. Chem. Soc.,
Perkin Trans. 1 1998, 7, 1343–1364.
tert-BuOK
H
H
O
O
O
O
3
K
4. (a) Malacria, M. Chem. Rev. 1996, 96, 289–306. and literatures cited therein; (b)
Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron 2004, 60, 6239–
6278; (c) Majumdar, K. C.; Ray, K.; Debnath, P.; Maji, P. K.; Kundu, N.
Tetrahedron Lett. 2008, 49, 5597–5600.
5. Ichikawa, J.; Miyazaki, H.; Sakoda, K.; Wada, Y. J. Fluorine Chem. 2004, 125, 585–
593.
tert-BuOH
O
O
O
O
K
6. (a) Sono, M.; Hashimoto, A.; Nakashima, K.; Tori, M. Tetrahedron Lett. 2000, 41,
5115–5118; (b) Sono, M.; Nakashiba, Y.; Nakashima, K.; Tori, M. J. Org. Chem.
2000, 65, 3099–3106.
7. (a) Wataha, J. C.; Hanks, C. T. J. Oral Rehabil. 1996, 23, 309–320; (b) Liu, T. Z.;
Lee, S. D.; Bhatnagar, R. S. Toxicol. Lett. 1979, 4, 469–473; (c) Moore, W.; Hysell,
D.; Hall, L.; Campbell, K.; Stara, J. Environ. Health Persp. 1975, 10, 63–71; (d)
Nyarko, E.; Hara, T.; Grab, D. J.; Habib, A.; Kim, Y.; Nikolskaia, O.; Fukuma, T.;
Tabata, M. Chem. Biol. Interact. 2004, 148, 19–25.
+
tert-BuOK
O
O
4
Scheme 2. The proposed mechanism of intramolecular carbanion-olefin cyclization
of 3.
8. Payard, M.; Tronche, P.; Bastide, J.; Bastide, P.; Chavernac, G. European J. Med.
Chem. 1981, 16, 453–470.
9. The procedure for the preparation of compounds 3a–k, and 4a–k together with
their physical and spectral data which were obtained are given in
Supplementary data.
R1
R2
CHO
OH
R1
R2
R4
i, ii, iii
O
10. 1-(2-Methoxy-6-vinylphenoxy)-2-phenylhexan-2-ol (2.22 g, 68%) was obtained as
R3
1a-e
R3
O
colorless liquid, Rf = 0.48 (ethyl acetate/n-hexane = 1:7), IR (neat)
3062, 3026, 2955, 2869, 1576, 1473, 1299, 1266, 1212, 1069, 1028, 909, 795, 747,
702 cmꢀ1 1H NMR (CDCl3, 200 MHz) d 0.83 (t, J = 7.0 Hz, 3H, (CH2)2CH2CH3),
mmax: 3497,
4a-i
;
Scheme 3. Synthesis of 2-aroyl-3,4-dihydro-2H-benzopyrans (4ai) from salicyli-
caldehydes (1a–e) in a three-step one pot reaction. Reagents and conditions: (i) (a)
MTPPB (1.2 equiv), tert-BuOK (2.3 equiv), THF, rt, 1 h; (ii) (b) 2-bromoacetophenone
(2a) (1.1 equiv), 2-bromo-40-methoxyacetophenone (2b) (1.1 equiv), 2-bromo-40-
chloro-acetophenone (2c) (1.1 equiv), reflux, 1 h; (iii) tert-BuOK (1.2 equiv), THF,
reflux, 30 min.
1.00–1.45 (m, 4H, CH2(CH2)2CH3), 1.75–2.04 (m, 2H, CH2(CH2)2CH3), 3.79 (s, 3H,
OCH3), 4.05 (d, J = 9.6 Hz, 1H, OCHaHbC), 4.05 (br s, 1H, OH), 4.14 (d, J = 9.4 Hz, 1H,
OCHaHbC), 5.23 (dd, J = 11.2, 1.2 Hz, 1H, ArCH@CHaHb), 5.66 (dd, J = 17.8, 1.2 Hz,
1H, ArCH@CHaHb), 6.74 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 6.82 (dd, J = 17.8, 11.2 Hz,
1H, ArCH@CH2), 6.96 (t, J = 8.0 Hz, 1H, ArH), 7.05 (dd, J = 8.0, 1.6 Hz, 1H, ArH),
7.18–7.26 (m, 1H, ArH), 7.30–7.38 (m, 2H, ArH), 7.49–7.54 (m, 2H, ArH); 13C-
NMR (CDCl3, 50 MHz) d 13.9, 23.0, 25.2, 38.6, 55.7, 76.3, 81.4, 111.3, 115.5, 118.1,
124.1, 125.5, 126.5, 127.9, 131.1, 131.9, 143.8, 145.6, 152.1; EI-MS (70 eV) m/z
(rel intensity, %) 308 (M+ꢀH2O, 3), 251 (19), 164 (100), 150 (98), 135 (28), 121
(29), 107 (23), 91 (29).
one-pot reaction could not improve the total yields compared to
that of the two-step reaction, it provides a unique and concise
route to handle and leads to less workup procedures. Besides, the
reduction of environmental pollutants is also advantage. Thus,
we have provided a concise and green chemistry for the synthesis
of title compounds either in two steps or in a one-pot reaction in
good total yields, respectively. Further applications and the devel-
opment of this type of reaction for other heterocyclic compounds
are currently in progress in our laboratory.
11. General procedure for the preparation of 2-aroyl-3,4-dihydro-2H-benzopyranes
(4a–k) from salicylaldehydes (1a–h) in one pot: under nitrogen, a suspension of
MTPPB (4.29 g, 12 mmol) in anhydrous THF (15 mL) was treated with potassium
tert-butoxide (1.35 g, 12 mmol) in portions. After stirring for 10 min at room
temperature, to the resultant reaction mixture was added a mixture of 2-
hydroxybenzaldehydes (1a–h) (10 mmol) and potassium tert-butoxide (1.23 g,
11 mmol) in THF (15 mL). The given mixture stirred at room temperature for 1 h
was heated to the reflux, and then was added
a solution of 2-
bromoacetophenones (2a–c) (33 mmol) in THF (15 mL) in drops. To the
resultant mixture continually stirred under reflux for 1 h was added another
portion of potassium tert-butoxide (1.35 g, 12 mmol). The reaction mixture was
kept at reflux for 0.5–1 h until the desired 4 did not increase apparently as
denoted by the TLC analysis. Finally, the reaction was quenched with saturated
NH4Clsolution. Most of the THF was removed in vacuo, and the resultant mixture
was extracted with EtOAc (20 mL ꢁ 4). The organic layers were combined,
washed with brine, and dried with anhydrous MgSO4. After filtration, the filtrate
was concentrated in vacuo. The residue was purified by silica gel column
chromatography (ethyl acetate/n-hexane = 1:10) to give pure 4a (1.11 g, 47%),
4b (1.77 g, 66%), 4c (1.92 g, 64%), 4d (2.03 g, 64%), 4e (1.69 g, 62%), 4f (2.05 g,
67%), 4g (1.79 g, 58%), 4h (1.88 g, 62%), 4i (1.21 g, 41%), 4j (1.30 g, 48%), and 4k
(0.74 g, 33%), respectively. Selected physical and spectra data of 4b: it was
Acknowledgment
We are grateful to NSC (NSC 97-2113-M-037-001-MY2),
Taiwan, for financial support.
Supplementary data
obtained as
hexane = 1:4); IR (KBr)
1217, 1091, 991, 903, 694 cmꢀ1
a
colorless crystal, mp 91–93 °C; Rf 0.49 (ethyl acetate/n-
max: 3062, 2931, 2836, 1695 (C@O), 1579, 1478, 1339,
1H NMR (400 MHz, CDCl3) d 2.18–2.27 (m, 1H,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.132.
m
;
Ha-3), 2.29–2.36 (m, 1H, Hb-3), 2.69–2.76 (m, 1H, Ha-4), 2.79–2.87 (m, 1H, Hb-
4), 5.56 (dd, J = 6.8, 4.0 Hz, 1H, H-2), 6.65 (dd, J = 7.6, 1.2 Hz, 1H, ArH), 6.73, (dd,
J = 7.6, 1.2 Hz, 1H, ArH), 6.81(t, J = 7.6 Hz, 1H, ArH), 7.43–7.47 (m, 2H, ArH), 7.56
(tt, J = 7.6, 1.2 Hz, 1H, ArH), 8.01–8.03 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3) d
22.8, 24.2, 55.9, 77.1, 109.7, 120.1, 121.3, 122.1, 128.6, 128.8, 133.4, 134.5, 143.4,
148.3, 196.9; EIMS (70 eV) m/z (rel intensity, %) 268 (M+, 26), 163 (100), 105 (31);
Anal. Calcd for C17H16O3: C, 76.10; H, 6.01. Found: C, 76.11; H, 5.76.
References and notes
1. (a) Harding, K. E.; Tiner, T. H.. In Comprehensive Organic Synthesis; Semmelhack,
M. F., Ed.; Pergamon Press: Oxford, 1991; Vol. 4, p 363; (b) Frederickson, M.;
Grigg, R. Org. Prep. Proced. Int. 1997, 29, 33–62. and 63–116; (c) Ali Dondas, H.;
Grigg, R.; Hadjisoteriou, M.; Markandu, J.; Kennewell, P.; Thornton-Pett, M.
Tetrahedron 2001, 57, 1119–1128.