One-pot synthesis of 2H-chromene derivatives from ortho-naphthoquinones

Article abstract of DOI:10.1055/s-2007-990925

A general one-pot synthesis for 2H-chromenes is reported from ortho-naphthoquinones and allyltriphenylphosphonium salts, [(RMeC=CHCH ₂)Ph₃P]⁺Br^-, in the presence of aqueous NaOH and chloroform at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990925

LETTER
3123
One-Pot Synthesis of 2H-Chromene Derivatives from ortho-Naphthoquinones
O
ne-PotSynth
e
esisof
2
H
-
r
Chromene Derivative
a
s
fromorth
n
o
-Naphthoq
d
uinones o de C. da Silva,a Alessandra Jorqueira,a R. M. Gouvêa,a Maria C. B. V. de Souza,a R. Alan Howie,b
James L. Wardell,a Solange M. S. V. Wardell,c Vitor F. Ferreira*a
a
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, 24020-150 Niterói, Rio de Janeiro, Brazil
Department of Chemistry, University of Aberdeen, Old Aberdeen, AB24 3EU, Scotland, UK
Complexo Tecnológico, Medicamentos Farmanguinhos, Av. Comandante Guaranys 447, Jacarepaguá, Rio de Janeiro, RJ, Brazil
b
c
E-mail: cegvito@vm.uff.br
Received 14 June 2007
tion with an ortho-naphthoquinone to produce a quinone
Abstract: A general one-pot synthesis for 2H-chromenes is report-
methide intermediate I, which cyclises to a 2H-chromene,
ed from ortho-naphthoquinones and allyltriphenylphosphonium
salts, [(RMeC=CHCH2)Ph3P]+Br–, in the presence of aqueous
NaOH and chloroform at room temperature.
as outlined in Scheme 1. The yields ranging from 47% to
85% were the result of attack of the phosphorus ylide at
the more reactive 1- or a-position carbonyl carbon of the
ortho-naphthoquinone. No products were detected from
attack at the 2- or b-carbonyl.
Key words: chromenes, Wittig reaction, one-pot cyclisation, naph-
thoquinones
i) aq. NaOH (50%)
R
The chromene or benzopyran substructure is frequently
found in naturally occurring heterocyclic compounds,
many of which exhibit biological activity (Figure 1),1 an
example being naphthohydroquinone of the benzo-
chromene type 1 isolated from the root of Pentas bussei2
(Figure 1). The chromenes have been identified as apop-
tosis-inducing agents,3 anti-HIV4 and antibacterials.5
+
PPh3Br –
R
CHCl3, r.t. (2 equiv)
O
O
X
6a, R = Me
6b, R = CH2CH2CH=CMe2
O
X
Y
Y
I
2–5
(see table 1
for X and Y)
R
O
OH
O
X
O
MeO
OH
Y
1
OMe
7–10
Figure 1 Structure of a compound isolated from the root of Pentas
bussei
Scheme 1 Reaction of ortho-naphthoquinones with allyltriphenyl-
phosphonium salts 5a and 5b
The chromenes have motivated a number of different syn-
thetic approaches.6–10 However, one-pot cyclisation
routes to chromenes are not common.
All chromene derivatives were characterized by spectro-
scopic means, e.g., by 1D and 2D 1H and 13C NMR tech-
niques [1H × H-COSY, HETCOR (1H × 13C, JCH)].
Specifically, the regiochemistry assigned to 7a was con-
firmed by a comparison of its 1H NMR spectrum with that
of the isomeric derivative 11, also known as lapachenole,
produced by Snieckus et al.14 using a different synthetic
route. There was a clear difference in the 1H NMR spectra
1
1
Our general methodology involves the reactions of ortho-
naphthoquinones 2–5 with two equivalents of an allyl-
triphenylphosphonium salt, [(RMeC=CHCH2)Ph3P]+Br–
(6a and 6b), in the presence of aqueous NaOH solution
(50%) and chloroform. The ortho-naphthoquinones used
were ortho-naphthoquinones 2a,b,11 b-lapachone
derivatives 3a–c,12 nor-b-lapachone (4)13 and tetra-
chloro[1,2]benzoquinone (5; commercially available)
(Table 1). The reaction proceeds via in situ formation of
an ylide, (Ph3P=CH–CH=CMeR), and its subsequent reac-
O
O
OMe
OMe
11
SYNLETT 2007, No. 20, pp 3123–3126
Advanced online publication: 03.12.2007
x
x
.x
x
.2
0
0
7
7a
DOI: 10.1055/s-2007-990925; Art ID: S04407ST
© Georg Thieme Verlag Stuttgart · New York
Figure 2 Structure of chromene 7a and lapachenole (11)

3124
F. de C. da Silva et al.
LETTER
Table 1 Reactants, Products and Yields of the Reactions
Reactant
Product
Yield (%)
2
O
1
6
7a: R = Me, R1 = OMe
60
57
65
47
R
O
10
9
2a: R1 = OMe
2b: R1 = OEt
7b: R = CH2CH2CH=CMe2, R1 = OMe
7c: R = Me, R1 = OEt
O
4a
8
7d: R = CH2CH2CH=CMe2, R1 = OEt
5
R1
7
R1
7
O
6
8
8a: R = Me, R1 = H
85
60
65
50
70
65
R
O
9
8b
8b: R = CH2CH2CH=CMe2, R1 = H
8c: R = Me, R1 = OH
O
4b
3a: R1 = H
3b: R1 = OH
3c: R1 = Br
10
11
8d: R = CH2CH2CH=CMe2, R1 = OH
8e: R = Me, R1 = Br
4
O
O
12
R1
O
8f: R = CH2CH2CH=CMe2, R1 = Br
R1
3
R
O
O
9a: R = Me
9b: R = CH2CH2CH=CMe2
79
65
4
5
O
O
Cl
Cl
Cl
1
Cl
Cl
O
O
Cl
Cl
7
2
10
40
4a
O
Cl
of the two compounds, 7a and 11 (Figure 2). Con- The chromene derivatives from b-lapachone (3a) and nor-
firmation of the structure of lapachenole (11) had been b-lapachone (4) are of particular interest. b-Lapachones
further achieved by X-ray crystallography.15 The products have significant biological activities. For example, 3a,
8d and 8f were obtained as diastereoisomers but were not which is found in the heartwood of Tabebuia sp., is effec-
separated.
tive in micromolar concentrations against a variety of can-
cer cells.19 In addition, 3a produces a diversity of
pharmacological effects,20 including antibacterial, anti-
fungal, and trypanocidal activities. Many of their deriva-
tives also have been found to have pharmacological
properties.21
The structure of 8a was confirmed by X-ray crystallogra-
phy.16–18 Figure 3 shows the atomic arrangements and
selected geometric parameters for 8a. Despite the low re-
finement, the bond lengths and hydrogen positions in the
newly formed pyran ring, led to an unambiguous conclu-
sion that the ylide had attacked the C1-carbonyl carbon.
In summary, we have discovered a facile and general one-
pot synthesis of 2H-chromenes22 from ortho-naphtho-
quinones and allyltriphenylphosphonium salts, in the
presence of aqueous NaOH and chloroform at room tem-
perature.
References and Notes
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Figure 3 Atom arrangement and selected bond angles (°) and
lengths (Å) for 8a
Synlett 2007, No. 20, 3123–3126 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 2H-Chromene Derivatives from ortho-Naphthoquinones
3125
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(22) General Procedure for 2H-Chromenes 7–10: A mixture of
the naphthoquinone (0.02 mol), allyltriphenylphosphonium
salt (0.04 mol), CHCl3 (15 mL) and aq 50% NaOH (15 mL,
0.19 mol) was vigorously stirred for 48 h at r.t. The organic
phase was collected, washed with H2O (3 × 10 mL), dried
over MgSO4 and the solvent was evaporated. Purification of
the crude product was achieved by flash column
(15) Reibenspies, J. H.; Willams, H. J.; Ortiz, C.; Scout, A. I.;
Suarez, M.; Domínguez, X. A. J. Crystallogr. Spectrosc.
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(16) Data was obtained at 120 K with Mo KGk–a radiation by
means of the Enraf Nonius KappaCCD area detector
diffractometer of the EPSRC crystallographic service, based
at the University of Southampton. Data collection was
carried out under the control of the program COLLECT17a
and data reduction and unit cell refinement were achieved
with the COLLECT17a and DENZO programs.17b Correction
for absorption, by comparison of the intensities of equivalent
reflections, was applied using the program SADABS.17c The
program ORTEP-3 for Windows17d was used in the
preparation of Figure 3 and SHELXL-9717e and PLATON17f
in the calculation of molecular geometry. The structure was
solved by direct methods using SHELXS-9717g and fully
refined by means of the program SHELXL-97.17e In the final
stages of refinement, hydrogen atoms were introduced in
calculated positions and refined with a riding model.
(17) (a) Hooft, R. W. W. COLLECT; Nonius BV: Delft / The
Netherlands, 1998. (b) Otwinowski, Z.; Minor, W. Methods
in Enzymology, Macromolecular Crystallography, Part A,
Vol. 276; Carter, C. W. Jr.; Sweet, R. M., Eds.; Academic
Press: New York, 1997, 307. (c) Sheldrick, G. M. SADABS,
Version 2.10.; Bruker AXS Inc.: Madison / Wisconsin /
chromatography using hexane–CH2Cl2 as eluent.
6-Methoxy-3,3-dimethyl-3H-benzo[f]chromene (7a): IR
(KBr): 2971, 2938, 1634, 1588, 1574, 1515, 1464, 1450,
1443, 1411, 1379, 1351, 1283, 1247, 1220, 1207, 1199,
1160, 1130, 1119, 1092, 996, 981, 885, 841, 755, 727, 694,
626 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.50 (s, 6 H, Me),
3.98 (s, 3 H, OMe), 5.58 (d, J = 9.8 Hz, 1 H, H-2), 6.48 (s, 1
H, H-5), 6.95 (d, J = 9.8 Hz, 1 H, H-1), 7.30 (ddd, J = 1.2,
6.8, 8.5 Hz, 1 H, H-8), 7.49 (ddd, J = 1.2, 6.8, 8.3 Hz, 1 H,
H-9), 7.89 (ddd, J = 0.7, 1.2, 8.3 Hz, 1 H, H-7), 8.17 (ddd,
J = 0.7, 1.2, 8.5 Hz, 1 H, H-10). 13C NMR (75.0 MHz,
CDCl3): d = 27.4 (Me), 27.4 (Me), 55.5 (OMe), 76.2 (C-3),
97.4 (C-5), 106.8 (C-10b), 118.1 (C-1), 120.9 (C-10), 121.3
(C-6a), 122.3 (C-7), 122.5 (C-8), 126.0 (C-2), 127.1 (C-9),
130.4 (C-10a), 151.6 (C-4a), 156.4 (C-6). EIMS: m/z (%) =
240 (22) [M+], 225 (100), 210 (15). HRMS: m/z calcd for
C16H16O2: 240.1150; found: 240.1139.
2,2,6,6-Tetramethyl-3,4-dihydro-2H,6H-1,5-dioxatri-
phenylene (8a): mp 89–90 °C. IR (KBr): 2975, 2934, 1637,
1578, 1510, 1465, 1453, 1428, 1418, 1396, 1383, 1369,
Synlett 2007, No. 20, 3123–3126 © Thieme Stuttgart · New York

3126
F. de C. da Silva et al.
LETTER
1360, 1325, 1289, 1253, 1237, 1220, 1195, 1159, 1137,
1119, 1003, 974, 881, 762, 732, 710, 691, 665, 646 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.41 (s, 6 H, Me), 1.47 (s, 6 H,
Me), 1.86 (t, J = 6.8 Hz, 2 H, H-3), 2.77 (t, J = 6.8 Hz, 2 H,
H-4), 5.54 (d, J = 10.0 Hz, 1 H, H-7), 6.95 (d, J = 10.0 Hz,
1 H, H-8), 7.27 (ddd, J = 1.2, 6.8, 8.3 Hz, 1 H, H-11), 7.41
(ddd, J = 1.2, 6.8, 8.3 Hz, 1 H, H-10), 7.85 (ddd, J = 0.5, 1.2,
8.3 Hz, 1 H, H-12), 8.14 (ddd, J = 0.5, 1.2, 8.3 Hz, 1 H, H-
9). 13C NMR (75 MHz, CDCl3): d = 19.9 (C-4), 29.3 (Me),
29.3 (Me), 78.6 (C-6), 34.7 (C-3), 77.1 (C-2), 78.6 (C-6),
106.6 (C-8a), 110.3 (C-4a), 121.2 (C-9), 123.3 (C-12), 123.6
(C-12a), 124.6 (C-11), 124.8 (C-8), 128.0 (C-7), 128.7 (C-
10), 131.6 (C-8b), 152.5 (C-4b), 152.6 (C-13). EIMS: m/z
(%) = 294 (44) [M+], 279 (77), 223 (100). HRMS: m/z calcd
for C20H22O2: 294.1620; found: 294.1617.
5,6,7,8-Tetrachloro-2,2-dimethyl-2H-chromene (10):
yellow solid; mp 83–84 °C. IR (KBr): 2924, 2870, 2854,
1681, 1600, 1455, 1428, 1392, 1379, 1327, 1308, 1237,
1225, 1205, 1151, 1051, 1018, 996, 970, 924, 900, 834, 791,
663 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.87 (d, J = 1.5
Hz, 3 H, Me), 1.88 (d, J = 1.5 Hz, 3 H, Me), 5.55 (dsept, J =
1.5, 8.3 Hz, 1 H, H-2), 6.92 (d, J = 8.3 Hz, 1 H, H-1). 13
C
NMR (75 MHz, CDCl3): d = 19.0 (Me), 26.4 (Me), 30.0 (C-
3), 111.0 (C-1), 112.9 (C-5), 118.3 (C-2), 125.1 (C-8a),
126.0 (C-7), 128.0 (C-6), 144.9 (C-8), 146.7 (C-4a).
Synlett 2007, No. 20, 3123–3126 © Thieme Stuttgart · New York

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