L-Proline catalyzed efficient and convenient synthesis of substituted 2H-chromenes by three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2013.10.091

A convenient and efficient method is described for the synthesis of alkoxy substituted 2H-chromens by l-proline catalyzed reaction of salicylaldehydes with diketone in alcohol. The method is applicable for various substituted salicylaldehydes and aliphatic as well as benzylic alcohols.

Full text of DOI:10.1016/j.tetlet.2013.10.091

Tetrahedron Letters 55 (2014) 1127–1131
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
L-Proline catalyzed efficient and convenient synthesis of substituted
2H-chromenes by three-component reaction
a
a
b
L. Chandrasekhara Rao a, H. M. Meshram a, , N. Satish Kumar , N. Nageswara Rao , N. Jagadeesh Babu
⇑
a Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
b Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient method is described for the synthesis of alkoxy substituted 2H-chromens by L-
Received 2 August 2013
Revised 17 October 2013
Accepted 20 October 2013
Available online 28 October 2013
proline catalyzed reaction of salicylaldehydes with diketone in alcohol. The method is applicable for var-
ious substituted salicylaldehydes and aliphatic as well as benzylic alcohols.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Salicylaldehyde
Pentane-2
4-Dione
2H-Chromens
L
-Proline
2H-chromenes are key structural units found in a variety of bio-
logically active molecules. Moreover, substituted 2H-chromene
derivatives have been reported as anti-HIV,1 antidiabetic,2 antican-
cer,3 antihypertensive,4 antioxidative,5 and antiviral agents.6
Several syntheses have been reported for 2H-chromene core struc-
ture, which includes catalytic Petasis reaction of salicylaldehydes,7
Pd-catalyzed ring closure of 2-isoprenyl phenols,8 intramolecular
cyclization of Wittig intermediates,9 Baylis–Hillman reaction of
2-hydroxy benzaldehydes with methyl vinyl ketones,10 and elec-
trocyclic ring closure of vinylquinone derivatives.11
O
Me
Me
O
OH
Me
O
O
O
HO
Me
OH
Me
O
(+)-Calanolide A 1
(
)-Daurichromenic Acid
Zonouzi et al.12 have reported base catalyzed approach for the
synthesis of 2H-chromene ring containing tertiary hydroxy group.
George et al.13 have synthesized tertiary methoxy group containing
chromene starting from hydroxy chromene in the presence of Le-
wis acid in methanol. However, these methods encountered some
drawbacks like, low yield of hydroxy product and longer reaction
time. Moreover, the preparation of methoxy chromene required
two steps. To the best of our knowledge, there is no direct method
for the synthesis of tertiary alkoxy chromenes. So because of bio-
logical importance of chromene, it is desirable to develop simple
and one pot protocol for the synthesis of alkoxy chromene. Re-
cently multicomponent14 reactions have gained much attention
in synthetic organic chemistry due to their advantages of the
intrinsic atom-economy, simpler procedures, structural diversity,
energy savings, and reduced waste (Fig. 1).
O
N
O
O
O
HO
N
O
O
O
Precocene 1
Cromakalim
Precocene 2
Fig. 1. Structures of 2H-chromene derivatives.
L
-Proline15 was considered as a promising catalyst in view of its
remarkable ability to catalyze a manifold of organic transforma-
tions such as Mannich, Knoevenagel and Michael type reactions
by the way of carbonyl activation through enamine-iminium ion
intermediate formation. We have envisioned the synthesis of ter-
tiary alkoxy chromens by following three component approach.
⇑
Corresponding author. Tel.: +91 40 27191640; fax: +91 40 27160512.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
Herein we wish to report the L-proline catalyzed three component
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.091

1128
L. Chandrasekhara Rao et al. / Tetrahedron Letters 55 (2014) 1127–1131
O
O
R2
R2
CHO
OH
O
O
L-Proline,
RT, 6-8 h
R-OH
+
R
O
R1
R1
R = methyl, ethyl, n-butyl, n-octyl, propargyl,
p -methoxy benzyl
R1 = H, OCH3, R2 = H, Cl, Br, NO2
Scheme 1. Synthesis of novel substituted 2H-chromenes.
data. Further the structre of 4f was confirmed by the X-ray crystal
structure (Fig. 2).16
On the basis of these encouraging results, we investigated the
reaction in detail under various conditions and results are summa-
rized in Table 1. First we have screened the different ratios of
line by varying the loading amount to 55%, 10%, 20% and 30%. The
optimum conversion was obtained with 30 mol % of -proline. In-
L-pro-
L
creased mole ratio (40%) did not improve the yield. Then the study
was planned to screen different amino acids under optimized con-
ditions. It was observed that basic amino acids did not initiate the
reaction, whereas other amino acids gave different degrees of con-
version (Table 1). This observation suggested that the participation
of secondary nitrogen of L-proline is important. This assumption
was further supported by the reaction of N-substituted proline
which did not provide the expected product. Among the screened
amino acids, L-proline emerged as a suitable catalyst for the high
yield of expected product. This may be due to the presence of cyclic
secondary amino group in proline. Based on these observations, a
possible mechanistic pathway was proposed as given in the
Scheme 2.
Fig. 2. ORTEP view of 4f with the atom-numbering.
Initially diketone reacts with L-proline to form enamine (1),
which further reacts with aldehyde followed by dehydration to
give intermediate (3). Further this intermediate (3) on rearrange-
ment to form more stable benzopyrylium cation (5) in acidic con-
ditions, which reacts with methanol to from the methoxy product
4a.
We have studied the electronic effect of the substituent on the
reaction. It was observed that salicylaldehyde bearing electron
donating group (4e) gave high yield of product, whereas, salicylal-
one pot reaction for the synthesis of tertiary alkoxy chromenes
(Scheme 1).
The initial reaction of o-hydroxy benzaldehyde (1 mmol) with
pentane-2,4-dione (1 mmol) in methanol in the presence of L-pro-
line (30 mol %) at room temperature gave 1-(2-methoxy-2-methyl-
2H-chromen-3-yl)ethanone (4a) which was confirmed by spectral
Table 1
Optimization experiments for the synthesis of 4aa
O
CHO
L-Proline, RT, 6-8 h
O
O
CH3-OH
+
OH
O
O
1a
2a
Catalyst (30 mol %)
3a
4a
Entry
Time (h)
Yield of 4ab (%)
1
2
3
4
12
12
12
10
—
L
L
L
L
-Lysine
—
-Histadine
31
42
-Glutamic acid
-Aspartic acid
5
6
N-methyl proline
-Thiaproline
N-benzyl proline methyl ester
12
9
—
55
L
7
8
12
6
—
85
L
L
L
L
L
L
-Proline (30 mol %)
-Proline (10 mol %)
-Proline (20 mol %)
-Proline (40 mol %)
-Glycine
9
10
11
12
13
12
12
12
8
40
60
86
61
58
9
-Phenyl alanine
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3a (2 ml), L-proline (30 mol %), rt, 6 h.
Refers to isolated yields after column chromatography.
b

L. Chandrasekhara Rao et al. / Tetrahedron Letters 55 (2014) 1127–1131
1129
O
O
O
O
R
O
O
R
O
L-proline
12 h, RT
N
H
O
OH
O
N
OH
OH
HO
OH
R = Cl, Br
O
1
R = Cl (4s), R = Br (4t)
O
O
O
MeOH
O
Scheme 3.
HO
O
O
5
4a
O
OH2
O
N
product (4p) in 52% yield. Similarly, 5-nitro salicylaldehyde
underwent smoothly in ethanol under standard conditions and re-
sulted into corresponding product (4i) in high yield. In addition to
this, we have examined alkynyl alcohol, benzylic alcohol and
branched alcohols. In our approach the reaction of 3-methoxy sal-
icylaldehyde with propargyl alcohol as well as p-methoxy benzyl
alcohol proceeded efficiently to furnish the corresponding prod-
ucts 4q and 4r respectively in good yields. The reactivity of alcohol
was in the order of methanol > ethanol > butanol > octanol
(Table 2).
O
N
OH
O
O
4
O
2
HO
O
N
OH
O
3
O
Scheme 2.
Surprisingly, the reaction in branched alcohols did not yield in
the expected alkoxy product. When the reaction of salicylaldehyde
with diketone was carried out in iso-propanol or t-butanol, the
intermediate hydroxy was isolated as a sole product.
dehyde having electronic withdrawing substituent (4d) reacted
relatively slowly and gave low yield.
We planned to screen the different alcohols ranging from C2–C8
carbon chain and it was noticed that the reaction in methanol and
ethanol proceeded effectively to give the corresponding product in
high yield. However, as the length of carbon chain in alcohol in-
creased, the reaction proceeded slowly and resulted into corre-
sponding product in low yield. For example, the reaction of
pentane-2,4-dione with 5-nitro salicylaldehyde in n-butanol re-
quired longer reaction time and gave 60% of product (4n) after
10 h. The efficiency of this protocol was demonstrated by examin-
ing a variety of alcohols. The reaction of diketone with 5-nitro sal-
icylaldehye in n-octanol under optimized conditions gave desired
Furthermore, we have screened heptane-3,5-dione with salicyl-
aldehyde in methanol and ethanol in the presence of the L-proline
which did not give the required alkoxy product, instead the hydro-
xy product was isolated in low yield, which was confirmed by
spectral data of hydroxy compounds.
In summary, we have developed a one pot protocol for the syn-
thesis of alkoxy-substituted 2H-chromenes. The procedure is appli-
cable for various alcohols and substituted salicylaldehydes. The
present method provides direct access for the synthesis of a large
number of 1-(2-alkoxy-2-methyl-2H-chromene-3-yl)ethanone
which may find applications in drug discovery program. Moreover
Table 2
L-Proline catalyzed three-component reaction at room temperaturea
O
R2
R2
CHO
OH
O
O
L-Proline, RT, 6-8 h
R-OH
R
+
O
O
R1
R1
R = methyl, ethyl, n-Butyl, n-Octyl, propargyl,
p-methoxy benzyl
R
1 = H, OCH3, R2 = H, Cl, Br, NO2
Entry
Alcohol
R1
R2
Product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Methanol
Methanol
Methanol
Methanol
Methanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
n-Butanol
n-Butanol
n-Butanol
n-Butanol
n-Butanol
n-Octanol
3-Butyn-1-ol
H
H
H
H
OMe
H
H
H
H
OMe
H
H
H
H
OMe
H
OMe
H
Cl
Br
NO2
H
H
Cl
br
NO2
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
6
6
6
6
6
6
6
6
6
6
8
8
8
10
8
12
8
85
82
80
75
89
86
83
81
74
90
76
75
72
60
85
52
73
76
H
Cl
Br
NO2
H
NO2
H
p-Methoxy benzylalcohol
OMe
H
7
a
Refers to isolated yields of products after column chromatography.
Refers to isolated yields of products after column chromatography.
b

1130
L. Chandrasekhara Rao et al. / Tetrahedron Letters 55 (2014) 1127–1131
B.; Almendros, P.; Luna, A.; Torres, M. R. J. Org. Chem. 2006, 71, 4818; (d)
Hossein, A. O.; Elham, R.; Majid, M. H. J. Chem. Res. 2006, S, 246; (e) Rasalkar,
M. S.; Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. J. Mol. Catal. A: Chem. 2005,
235, 267; (f) Bogevig, A.; Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790.
these results may serve as guidelines for the predictable incorpora-
tion of alkoxy, benzyloxy group in chromene (Scheme 3).
General procedure
[16]. CCDC 911855 contains the supplementary crystallographic data for this
paper. This data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html.
In a typical experiment the diketone (1mmol), alcohol (2ml)
and L-proline (30%) were placed in a 10ml round-bottomed flask
and stirred for 15 minutes. To this reaction mixture aldehyde
was added and stirred at room temperature (monitored by TLC).
After completion of the reaction, removed methanol under reduced
pressure and purified by silica gel column chromatography using
ethyl acetate/hexanes. All compounds were characterized by
(M.P, NMR, Mass and IR) spectral data.17
[17]. Spectral data for compounds 1-(2-methoxy-2-methyl-2H-chromen-3-yl)
ethanone (Table 1 (4a) : Yellow oil; IR: mmax 2990, 1666, 1626, 1484, 1378,
1267, 1116, 896, 796, 754 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.91 (s, 3H),
;
2.46 (s, 3H), 3.25 (s, 3H), 6.96 (m, 2H), 7.25 (d, J = 7.99 Hz, 1H), 7.33 (t,
J = 7.99 Hz, 1H), 7.52 (s, 1H); 13C NMR (75 MHz, CDCl3): d 195.8, 153.7, 136.1,
132.7, 132.0, 128.5, 121.5, 118.6, 116.1, 101.5, 50.1, 27.0, 25.1; m/z (ESI); 241
[M+Na]+, 188 [MÀOMe]+.
1-(6-chloro-2-methoxy-2-methyl-2H-chromen-3-yl)ethanone (4b): Yellow oil;
IR: mmax 2972, 2894,1672, 1480, 1372, 1268, 1077, 861, 795, 723 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d 1.91 (s, 3H), 2.47 (s, 3H), 3.26 (s, 3H), 6.91 (d,
J = 9.07 Hz, 1H), 7.24–7.30 (m, 2H), 7.43 (s, 1H); 13C NMR (75 MHz, CDCl3): d
195.7, 152.5, 135.1, 134.9, 134.3, 130.8, 120.3, 118.5, 117.8, 101.5, 50.1, 27.0,
24.6; m/z (ESI); 275 [M+Na]+, 221 [MÀOMe]+.
All the products are stable and can be stored at room tempera-
ture for a long time.
1-(6-bromo-2-methoxy-2-methyl-2H-chromen-3-yl)ethanone (4c): yellow oil;
Acknowledgments
IR m ;
max 2969, 1674, 1371, 1268, 1047, 858, 832, 794 cmÀ1 1H NMR (300 MHz,
CDCl3): d 1.90 (s, 3H), 2.45 (s, 3H), 3.25 (s, 3H), 6.84 (d, J = 8.83 Hz, 1H), 7.38–
7.42 (m, 3H); 13C NMR (75 MHz, CDCl3): d 195.6, 152.6, 135.4, 135.0, 134.2,
130.9, 120.5, 118.7, 117.9, 101.7, 50.2, 27.1, 24.8; m/z (ESI); 320 [M+Na]+, 265
[MÀOMe]+.
L.C.R., N.S.K., and N.N.R. thank CSIR-UGC for the award of a fel-
lowship and Dr. Ahmed Kamal, outstanding scientist and Head of
MCP Division for his support and encouragement.
The authors thank CSIR, New Delhi for financial support as part
of XII five year plan program under the title ORIGIN (CSC-0108).
1-(2-methoxy-2-methyl-6-nitro-2H-chromen-3-yl)ethanone (4d): Yellow solid;
Mp 126–128 °C; IR: m ;
max 2976, 1673, 1519, 1339, 1271, 1044, 866, 821 cmÀ1
1H NMR (300 MHz, CDCl3): d 1.9 4 (s, 3H), 2.49 (s, 3H), 3.28 (s, 3H), 7.04 (d,
J = 7.99, 1H), 7.54 (s, 1H), 8.21–8.22 (m, 2H); 13C NMR (75 MHz, CDCl3): d
195.3, 158.4, 141.9, 133.8, 133.5, 127.7, 124.5, 118.4, 116.8, 103.2, 50.5, 27.1,
25.1; m/z (ESI); 286 [M+Na]+, 232 [MÀOMe]+.
References and notes
1-(2,8-dimethoxy-2-methyl-2H-chromen-3-yl)ethanone (4e): Yellow solid; Mp
82–84 °C; IR: mmax 2943, 1665, 1481, 1375, 1266, 1106, 887, 776, 740 cmÀ1
;
[1]. (a) Zhendong, J.; Ying, K. Total synthesis of daurichromenic acid. PCT Int. Appl.
WO 2004058738, 2004.; (b) Iwata, N.; Wang, N.; Yao, X.; Kitanaka, S. J. Nat.
Prod. 2004, 67, 1106; (c) Hu, H.; Harrison, T. J.; Wilson, P. D. J. Org. Chem. 2004,
69, 3782.
[2]. Korec, R.; Sensch, K. H.; Zoukas, T. Arzneim. Forsch. 2000, 50, 122.
[3]. Cassidy, F.; Evan, M. J.; Hadel, M. S.; Halodij, A. H.; Leach, P. E.; Sternp, G. J.
Med. Chem. 1992, 35, 1623.
[4]. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.;
Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939; (b) Nicolaou, K. C.;
Pfefferkorn, J. A.; Mitchell, H. J.; Roecker, A. J.; Barluenga, S.; Cao, G.-Q.;
Affleck, R. L.; Lillig, J. E. J. Am. Chem. Soc. 2000, 122, 9954; (c) Nicolaou, K. C.;
Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao, G.-Q. J. Am.
Chem. Soc. 2000, 122, 9968; (d) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.;
Yamasisbi, T.; Fujioka, T.; Milashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.
S.; Natschke, L. M.; Lee, K.-H. Tetrahedron 2001, 57, 1559; (e) Zeni, G.; Larock,
R. C. Chem. Rev. 2004, 104, 2285; (f) Mori, J.; Iwashima, M.; Takeuchi, M.;
Saito, H. Chem. Pharm. Bull. 2006, 54, 391.
1H NMR (300 MHz, CDCl3): d 1.8 (s, 3H), 2.47 (s, 3H), 3.28 (s, 3H), 3.91 (s, 3H),
6.87–6.97 (m, 3H), 7.51 (s, 1H); 13C NMR (75 MHz, CDCl3), d 195.9, 147.7,
142.8, 135.9, 132.4, 121.1, 120.4, 119.4, 114.9, 101.5, 56.1, 50.1, 27.0, 24.6;
m/z (ESI); 271 [M+Na]+, 217 [MÀOMe]+.
1-(2-ethoxy-2-methyl-2H-chromen-3-yl)ethanone (4f): White solid; Mp 110–
112 °C; IR: mmax 2981, 1657, 1632, 1475, 1380, 1258, 1112, 891, 769,
745 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.1 (t, J = 6.59 Hz, 3H), 1.9 (s, 3H),
;
2.45 (s, 3H), 3.5 (m, 3H), 6.94 (m, 2H), 7.22 (d, J = 7.69 Hz, 1H), 7.31
(t, J = 7.69 Hz, 1H), 7.49 (s, 1H); 13C NMR (75 MHz, CDCl3): d 195.8, 153.9,
135.8, 132.6, 132.4, 128.9, 121.4, 118.6, 116.0, 101.5, 58.3, 27.1, 25.8, 15.3;
m/z (ESI); 265 [M+Na]+, 188 [MÀOEt]+.
1-(6-chloro-2-ethoxy-2-methyl-2H-chromen-3-yl)ethanone (4g): Yellow solid:
Mp 106–108 °C; IR: mmax 2980, 1675, 1478, 1379, 1265, 1074, 863, 798,
724 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.11 (t, J = 6.79 Hz, 3H), 1.90 (s, 3H),
;
2.46 (s, 3H), 3.45–3.61 (m, 2H), 6.87 (d, J = 8.31 Hz, 1H), 7.22–7.28 (m, 2H),
7.40 (s, 1H); 13C NMR (75 MHz, CDCl3): d 195.6, 152.2, 134.0, 133.5, 132.0,
127.8, 126.0, 119.9, 117.4, 101.6, 58.3, 27.1, 25.4, 15.1; m/z (ESI); 299
[M+Na]+, 221 [MÀOEt]+.
[5]. Kwak, J. H.; Kang, H. E.; Jung, J. K.; Kim, H.; Cho, J.; Lee, H. Arch. Pharmacal Res.
2006, 29, 728.
1-(6-bromo-2-ethoxy-2-methyl-2H-chromen-3-yl)ethanone (4h): Yellow solid;
[6]. (a) Toste, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074; (b) Varma, R. S.;
Dahiya, R. J. Org. Chem. 1998, 63, 8038; (c) Nicolaou, K. C.; Pfefferkorn, J. A.;
Cao, G.-Q. Angew. Chem., Int. Ed. 2000, 39, 734; (d) Nicolaou, K. C.; Cao, G.-Q.;
Pfefferkorn, J. A. Angew. Chem., Int. Ed. 2000, 39, 739; (e) Miao, H.; Yang, Z. Org.
Lett. 2000, 2, 1765; (f) Maggiani, A.; Tubul, A.; Brun, P. Helv. Chem. Acta. 2000,
83, 650.
[7]. (a) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063–4065; (b) Kabalka, G. W.;
Venkataiah, B.; Das Bhaskar, C. Synlett 2004, 2194–2196.
[8]. Iyer, M.; Trivedi, G. R. Synth. Commun. 1990, 20, 1347.
Mp 86–88 °C IR mmax 2971, 1676, 1375, 1267, 1046, 857, 830, 796 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d 1.10 (t, J = 6.79 Hz, 3H), 1.89 (s, 3H), 2.46 (s, 3H),
3.42–3.60 (m, 2H), 6.84 (d, J = 8.31 Hz, 1H), 7.37–7.41 (m, 3H); 13C NMR
(75 MHz, CDCl3): d 195.6, 152.7, 134.8, 133.9, 133.5, 130.9, 120.5, 117.9,
113.1, 101.6, 58.4, 27.2, 25.5, 15.2; m/z (ESI); 334 [M+Na]+, 265 [MÀOEt]+.
1-(2-ethoxy-2-methyl-6-nitro-2H-chromen-3-yl)ethanone (4i): Yellow solid;
Mp 154–156 °C; IR: mmax 2980, 1668, 1522, 1340, 1268, 1045, 867,
819 cmÀ1
; d 1.13 (t, J =6.79 Hz, 3H), 1.94
1H NMR (300 MHz, CDCl3):
(s, 3H), 2.50 (s, 3H), 3.47–3.59 (m, 2H), 7.04 (d, J = 9.82, 1H), 7.52 (s, 1H),
8.21–8.24 (m, 2H); 13C NMR (75 MHz, CDCl3): d 195.4, 158.7, 141.9, 134.4,
133.4, 127.8, 124.6, 118.6, 116.8, 103.2, 59.0, 27.4, 25.9, 15.2; m/z (ESI); 300
[M+Na]+, 232 [MÀOEt]+.
[9]. Hanamoto, T.; Shindo, K.; Matsuoka, M.; Kiguchi, Y.; Kondo, M. J. Chem. Soc.,
Perkin Trans. 2000, 1, 3082.
[10]. Kaye, P. T.; Nocanda, X. W. J. Chem. Soc., Perkin Trans. 2000, 1, 1331.
[11]. Parker, K. A.; Mindt, T. L. Org. Lett. 2001, 3, 3875.
[12]. (a) Zonouzi, A.; Sadeghi Googheri, M.; Miralinaghi, P. S. Org. Prep. Proced. Int.
2008, 40, 471; (b) Zonouzi, A.; Binjaz, M.; Rahmani, H.; Ng, S. W. Acta Cryst.
2009, E65, o752; (c) Zonouzi, A.; Rahmani, H.; Jahangiri, A.; Z. Kristallogr. New
Cryst. Struct. 223, 155.; (d) Zonouzi, A.; Izakain, Z.; Binaiz, M. Org. Prep. Proced.
Int. 2009, 41, 543; (e) Zonouzi, A.; Binaiz, M.; Mirzazadeh, R.; Talebi, M.; Ng, S.
W. Heterocycles 2010, 81, 1271.
1-(2-ethoxy-8-methoxy-2-methyl-2H-chromen-3yl)ethanone (4j): Yellow solid;
Mp 106–108 °C; IR: mmax 2942, 1666, 1483, 1374, 1267, 1104, 879, 775,
741 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.08 (t, J = 6.46 Hz, 3H), 1.96 (s, 3H),
;
2.45 (s, 3H), 3.51–3.59 (m, 2H), 3.89 (s, 3H), 6.87–6.93 (m, 3H), 7.48 (s, 1H);
13C NMR (75 MHz, CDCl3): d 195.9, 147.7, 142.9, 135.7, 132.7, 121.0, 120.6,
119.4, 114.7, 101.5, 58.2, 56.1, 27.1, 25.4, 15.1; m/z (ESI); 285 [M+Na]+, 217
[MÀOEt]+.
[13]. Ramaiah, D.; Scaria, P. M.; Cyr, D. R.; Das, P. K.; George, M. V. J. Org. Chem.
1988, 53(9), 2016–2022.
1-(2-butoxy-2-methyl-2H-chromen-3-yl)ethanone (4k): yellow oil; IR: mmax
2945, 1662, 1632, 1482, 1372, 1248, 1118, 869, 765, 750,745 cmÀ1 1H NMR
;
[14]. (a) Ghandi, Mehdi; Ghomi, Ali-Tabatabaei; Kubicki, Maciej J. Org. Chem. 2013,
78, 2611; (b) Gaden, Joanna V.; Pancholi, Alpa K.; Shilpman, Michael J. Org.
Chem. 2013, 78, 4158; (c) Rodrigo, S. K.; Guan, H. J. Org. Chem. 2012, 77, 8303;
(d) Sharma, R.; Pandey, A. K.; Chauhan, P. M. S. Synlett 2012, 2209; (e)
Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2012, 14, 4274; (f)
Zheng, L.; Ju, J.; Bin, Y.; Hua, R. J. Org. Chem. 2012, 77, 5794; (g) Meyet, C. E.;
Pierce, C. J.; Larsen, C. H. Org. Lett. 2012, 14, 964; (h) Adib, M.; Sheikhi, E.;
Bijanzadeh, H. R. Synlett 2012, 85; (i) Trost, B. M. Compr. Org. Synth. 1991, 2,
34; (j) Gilchrist, T. L. Heterocyclic Chem. 1992, 181; (k) Smith, M. B.; March, J.
Adv. Org. Chem. 2001, 1225.
(300 MHz, CDCl3): d 0.81 (t, J = 7.36 Hz, 3H), 1.21 (m, 2H), 1.47 (m, 2H), 1.91
(s, 3H), 2.46 (s, 3H), 3.47 (m, 2H), 6.94 (m, 2H), 7.23 (d, J = 7.37 Hz, 1H), 7.32
(t, J = 7.37 Hz, 1H), 7.59 (s, 1H); 13C NMR (75 MHz, CDCl3): d 195.8, 153.2,
135.7, 133.1, 132.7, 128.0, 121.1, 118.5, 116.6, 101.5, 62.8, 31.0, 27.1, 25.6,
19.1, 13.7; m/z (ESI); 283 [M+Na]+, 188 [MÀOBut]+.
1-(6-chloro-2-butoxy-2-methyl-2H-chromen-3-yl)ethanone (4l): Yellow oil; IR
mmax 2983, 1676, 1480, 1377, 1266, 1075, 862, 796, 721 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 0.82 (t, J = 7.55 Hz, 3H), 1.24 (m, 2H), 1.45 (m, 2H), 1.90
(s, 3H), 2.46 (s, 3H), 3.36–3.52 (m, 2H), 6.86 (d, J = 9.06 Hz, 1H), 7.22–7.28 (m,
2H), 7.40 (s, 3H); 13C NMR (75 MHz, CDCl3): d 198.1, 151.4, 134.1, 133.5,
132.6, 132.0, 128.0, 118.3, 117.5, 101.5, 62.5, 31.6, 27.2, 25.3, 19.1, 13.7; m/z
[15]. (a) Shi, C. L.; Shi, D. Q.; Kim, S. H.; Huang, Z. B.; Ji, S. J.; Ji, M. Tetrahedron 2008,
64, 2425; (b) Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946; (c) Alcaide,

L. Chandrasekhara Rao et al. / Tetrahedron Letters 55 (2014) 1127–1131
1131
(ESI); 317 [M+Na]+, 221 [MÀOBut]+.
1-(8-methoxy-2-methyl-2-(prop-2-ynyloxy)-2H-chromen-3-yl)ethanone (4q):
Yellow solid; Mp 74–76 °C; IR: mmax 3003, 2945, 2295, 1669, 1485, 1375,
1-(6-bromo-2-butoxy-2-methyl-2H-chromen-3-yl)ethanone (4m): Yellow oil;
IR
m
max 2972, 1674, 1376, 1271, 1045, 855, 828, 795 cmÀ1
;
1H NMR (300 MHz,
1264, 1080, 882, 778 cmÀ1 1H NMR (300 MHz, CDCl3): d 2.03 (s, 3H), 2.30
;
CDCl3): d 0.82 (t, J = 6.79 Hz, 3H), 1.24 (m, 2H), 1.45 (m, 2H), 1.89 (s, 3H), 2.45
(s, 3H), 3.35–3.52 (m, 2H), 6.81 (d, J = 8.31 Hz, 1H), 7.37–7.41 (m, 3H); 13C
NMR (75 MHz, CDCl3): d 195.6, 152.8, 134.8, 133.9, 133.6, 130.8, 120.5, 117.9,
113.1, 101.6, 62.5, 31.6, 27.2, 25.4, 19.1, 13.7; m/z (ESI); 362 [M+Na]+, 265
[MÀOBut]+.
(s, 1H), 2.47 (s, 3H), 3.89 (s, 3H), 4.15–4.30 (m, 2H), 6.88–6.98 (m, 3H), 7.51
(s, 1H); 13C NMR (75 MHz, CDCl3): d 195.2, 147.2, 142.2, 134.9, 132.1, 121.5,
121.4, 120.6, 115.1, 114.7, 73.8, 56.1, 50.6, 27.7, 25.1; m/z (ESI); 295 [M+Na]+,
273 [M+H]+.
1-(8-Methoxy-2-(4-methoxybenzyloxy)-2-methyl-2H-chromen-3-yl)ethanone
1-(2-butoxy-2-methyl-6-nitro-2H-chromen-3-yl)ethanone (4n): Yellow solid;
(4r): Yellow solid; Mp 88–90 °C; IR: mmax 2995, 1672, 1485, 1268, 1110, 873,
Mp 104–106 °C; IR:
m
max 2979, 1665, 1519, 1343, 1259, 1058, 871, 805 cmÀ1
;
765 cmÀ1 1H NMR (300 MHz, CDCl3): d 2.07 (s, 3H) , 2.45 (s, 3H), 3.74 (s, 3H),
;
1H NMR (300 MHz, CDCl3): d 0.82 (t, J = 6.79 Hz, 3H), 1.17–1.29 (m, 2H), 1.42–
1.51 (m, 2H), 1.94 (s, 3H), 2.50 (s, 3H), 3.39–3.53 (m, 2H), 7.03 (d, J = 9.82,
1H), 7.52 (s, 1H), 8.19–8.24 (m, 2H); 13C NMR (75 MHz, CDCl3): d 195.2, 158.8,
141.9, 134.4, 133.2, 127.6, 124.7, 118.6, 116.7, 103.1, 63.9, 31.5, 27.3, 25.6,
19.0, 13.7; m/z (ESI); 328 [M+Na]+, 232 [MÀOBut]+.
3.90 (s, 3H), 4.52 (s, 2H), 6.74 (d, J = 9.06 Hz, 2H), 6.87–6.98 (m, 3H), 7.06 (d, J
= 8.31 Hz, 2H), 7.50 (s, 1H); 13C NMR (75 MHz, CDCl3): d 195.8, 158.9, 147.9,
142.8, 135.7, 132.9, 130.0, 129.2, 128.5, 121.2, 120.6, 119.8, 114.8, 113.9,
113.5, 101.4, 64.4, 56.1, 55.1, 27.1, 25.2; m/z (ESI); 377 [M+Na]+.
1-(6-Chloro-2-ethyl-2-hydroxy-2H-chromen-3-yl)propan-1-ol (4s): Yellow oil;
1-(2-butoxy-8-methoxy-2-methyl-2H-chromen-3-yl)ethanone (4o): Yellow
solid; Mp 78–80 °C; IR: mmax 2943, 1667, 1482, 1266, 1102, 875, 786,
IR: mmax 3371, 2979, 1679, 1336, 1243, 1058, 839, 822, 772 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 0.89 (t, J = 7.55 Hz, 3H), 1.18 (t, J = 6.80 Hz, 3H), 1.88–
2.06 (m, 1H), 2.16–2.31 (m, 1H), 2.73–2.98 (m, 2H), 4.71 (br s, 1H), 6.92
(d, J = 9.06 Hz, 1H), 7.19–7.31 (m, 2H), 7.35 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 201.6, 151.8, 133.0, 132.4, 128.0, 126.3, 119.8, 118.1, 101.5, 33.2, 31.5, 8.5,
8.1. m/z (ESI); 267 [M+H]+, 289 [M+Na]+, 248 [M–OH]+.
735cm-1 1H NMR (300 MHz, CDCl3): d 0.79 (t, J = 7.36 Hz, 3H), 1.13–1.25
;
(m, 2H), 1.39–1.48 (m, 2H), 1.99 (s, 3H), 2.46 (s, 3H), 3.46–3.57 (m, 2H), 3.91
(s, 3H), 6.85–6.96 (m, 3H), 7.50 (s, 1H); 13C NMR (75 MHz, CDCl3): d 195.9,
147.7, 142.9, 135.6, 132.9, 120.9, 120.5, 119.6, 114.6, 101.3, 62.2, 56.0, 31.6,
27.1, 25.1, 19.0, 13.6; m/z (ESI); 313 [M+Na]+, 217 [MÀOBut]+.
1-(6-Bromo-2-ethyl-2-hydroxy-2H-chromen-3-yl)propan-1-ol (4t): Yellow oil;
1-(2-methyl-6-nitro-2-(octyloxy)-2H-chromen-3yl)ethanone (4p): semi solid;
IR: mmax 3381, 2975, 1682, 1356, 1273, 1038, 840, 832, 782 cmÀ1 1H NMR
;
IR: mmax 2975, 1667, 1518, 1345, 1248, 1073, 854, 821 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d 0.88 (t, J = 7.55 Hz, 3H), 1.18 (t, J = 7.36 Hz, 3H), 1.88–
2.02 (m, 1H), 2.16–2.30 (m, 1H), 2.74–2.96 (m, 2H), 4.73 (br s, 1H), 6.86
(d, J = 8.49 Hz, 1H), 7.34–7.37 (m, 2H), 7.38–7.44 (m, 1H). 13C NMR (75 MHz,
CDCl3): d 201.6, 152.3, 135.3, 132.9, 132.4, 131.0, 120.4, 118.5, 113.4, 101.5,
33.3, 31.5, 8.5, 8.1; m/z (ESI); 311 [M+H]+, 334 [M+Na]+, 292 [M–OH]+.
(300 MHz, CDCl3): d 0.85 (t, J = 6.79 Hz, 3H), 1.18–1.28 (m, 10H), 1.47 (m, 2H),
1.95 (s, 3H), 2.50 (s, 3H), 3.41–3.51 (m, 2H), 7.01 (d, J = 9.82, 1H), 7.51 (s, 1H),
8.20–8.24 (m, 2H); 13C NMR (75 MHz, CDCl3): d 195.2, 158.6, 141.8, 134.4,
133.1, 127.5, 124.5, 118.6, 116.7, 103.1, 63.3, 31.7, 29.4, 29.1, 29.1, 27.2, 25.9,
25.6, 22.5, 14.0; m/z (ESI); 384 [M+Na]+, 232 [MÀOOct]+.