Synthesis of regioisomeric naphtho-furans via naphthyloxyalkanals

Article abstract of DOI:10.1007/s10593-010-0465-6

A new route to the regioisomeric 2-alkylnaphtho[2,1-b]- and 2-alkylnaphtho[1,2-b]furans via acid-catalyzed cyclization of the corresponding 2-naphthyloxyalkanals under mild conditions over Amberlyst 15 resin has been described. The 2-naphthyloxyalkanals w

Full text of DOI:10.1007/s10593-010-0465-6

Chemistry of Heterocyclic Compounds, Vol. 46, No. 1, 2010
SYNTHESIS OF REGIOISOMERIC NAPHTHO-
FURANS VIA NAPHTHYLOXYALKANALS
H. Kwiecień1*, M. Witczak1, M. Kowalewska1, M. Augustyniak1
A new route to the regioisomeric 2-alkylnaphtho[2,1-b]- and 2-alkylnaphtho[1,2-b]furans via acid-
catalyzed cyclization of the corresponding 2-naphthyloxyalkanals under mild conditions over Amberlyst
15 resin has been described. The 2-naphthyloxyalkanals were obtained by palladium-catalyzed
reduction of 2-naphthyloxyalkanoyl chlorides.
Keywords: aldehydes, ethers, naphthofurans, cyclization, reduction.
The regioisomeric naphtho[1,2-b]-, naphtho[2,1-b]-, and naphtho[2,3-b]furans are present in many
biologically important natural products, mainly belonging to the sesquiterpene class [1]. These products have
been isolated from various natural sources such as plants Liguaria przewalskii [2], Trichilia cuneata [3],
Gossypium barbadens [4], or fungus Fusarium oxysporum [5]. Several synthetic compounds bearing a
naphthofuran skeleton are associated with diverse biological activities such as antibacterial [6], antifungal [7],
antifertility [8], and antiprotozoan activity against Trypanosoma cruzi [9]. Some of nitronaphtho[2,1-b]furans
have been extensively studied for their mutagenic activities [6, 10] and other naphtho[2,1-b]furan derivatives
showed a significant anticancer activity against human colon and liver cancer cell lines in the in vitro assay [11].
Besides, naphthofurans have potential applications as fluorescent dyes and probes as well as phothosensitizers
[12, 13].
A major route for the synthesis of naphthofurans is the intramolecular formation of a furan ring starting
with properly substituted α-naphthyloxycarbonyl compounds and their corresponding acetals [14–16].
Polysubstituted naphtho[1,2-b]furans were obtained by cyclization of asymmetrically substituted 1-naphthyloxy
ketones by heating at high temperature in polyphosphoric acid [17]. Similarly, 2-phenylnaphto[1,2-b]furan and
2-phenylnaphto[2,1-b]furan were prepared by cyclization of naphthyloxyacetophenone with a strong acid [18].
The regioisomeric naphtho[1,2-b]- and -[2,1-b]furans were obtained by treating 1- and 2-naphthol and
methylsulfinylmethyl ethyl ketone with p-toluenesulfonic acid and then desulfurization of 2-alkyl-3-(methyl-
thio)naphtho[1,2-b]- and -[2,1-b]furans with Raney nickel in ethanol [19]. Furthermore, the synthesis of
aminonaphtho[1,2-b]furan by cyclodehydratation of naphthyloxyamides with phosphorous oxychloride [20] as
well as the synthesis of 2-ethylnaphtho[2,1-b]furan by cyclization of 2-(1-formyl-2-naphthyloxy)butanoic acid
[21] have been described. The modern Pd2+-catalyzed oxidative cyclization of 1-allyl-2-naphthol using
_______
* To whom correspondence should be addressed, e-mail: halina.kwiecien@zut.edu.pl.
1Department of Organic Synthesis and Drug Technology, West Pomeranian University of Technology, Al.
Piastów 42, 71-065 Szczecin, Poland.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, 25-36, January, 2010. Original article
received June 24, 2009.
20
0009-3122/10/4601-0020©2010 Springer Science+Business Media, Inc.

Cu(OAc)2−LiCl as a reoxidant was applied for the synthesis of naphtho[2,1-b]furan [22]. The synthesis of
naphtho[2,1-b]furan through a novel ring transformation reaction of suitably functionalized 2H-pyran-2-ones
[1], an annelation of 2-dienylcyclobutenones with both (E)- and (Z)-diene configurations to naphtho-
[1,2-b]furans upon heating followed by treating with acid [23], as well as preparation of hydroxynaphtho-
[1,2-b]furans by interacting naphthoquinone with various nitroenamines [24] have been reported. Cyclized
amidino-substituted naphtho[2,1-b]furans were prepared in the photochemical dehydrocyclization reaction in
ethanol and water from amidinofuryl-substituted phenyl acrylates [25]. Ethyl naphtho[2,1-b]furan-2-carboxylate
was obtained from 2-hydroxy-1-naphthaldehyde with ethyl chloroacetate and potassium carbonate in DMF by
microwave irradiation [7].
In the preceding paper we showed that acid-catalyzed cyclization of 2-phenoxyalkanals provided a
convenient method for the synthesis of 2-alkylbenzo[b]furans [26, 27]. In this paper we describe a facile
synthesis of regioisomeric naphthofurans by acid-catalyzed dehydrative cyclization of the appropriate
naphthyloxyalkanals.
Hitherto, there are two reports in the literature on the synthesis of naphthyloxyalkanals. The first
describes preparation of 2-naphthyloxyethanal by condensation of 2-chloro-1,1-diethoxyethane with 2-naphthol
in the presence of sodium methylate at 170°C followed by hydrolysis of the acetal with sulfuric acid [28]. The
second concerns 2-(1-naphthyloxy)propanals prepared by hydrocarbonylation of naphthyl vinyl ethers over a
rhodium catalyst [29].
To obtain isomeric 2-(1-naphthyloxy)- and 2-(2-naphthyloxy)alkanals we decided to use the Rosenmund
catalytic reduction of the corresponding naphthyloxyalkanoic acid chlorides, e.g., the method applied previously
in the synthesis of 2-phenoxyalkanals [26, 27].
The desired 2-(2-naphthyloxy)- (4a-d) and 2-(1-naphthyloxy)alkanoic acids (4e-f) were prepared as
shown in Scheme 1. Williamson ether syntheses were carried out via the reaction of the appropriate naphthoxide
anion with methyl α-bromoalkanoate in the presence of potassium carbonate in DMF. All ethers 3a-f were
obtained in good yields (68-98%). The basic hydrolysis of 3a-f gave the desired acids 4a-f in 73-98% yields.
Scheme 1
O
O
OH
R1
R
R
OMe
OH
O
O
2a,b
R1
R1
3a–d
68–98%
O
4a–d
78–98%
R
OMe
O
O
OMe
R
Br
1a,b
O
OH
R
OH
K2CO3, DMF
O
2c
3e–f
84–91%
4e–f
73–75%
1 a R = Et, b R = Bu; 2 a R1 = H, b R1 = CONHPh; 3, 4 a R = Et, R1 = H; b R = Bu, R1 = H;
c R = Et, R1 = CONHPh; d R = Bu, R1 = CONHPh; e R= Et; f R = Bu
21

2-Naphthyloxyalkanoyl chlorides 5a-f were obtained by the reaction of the appropriate acids with
thionyl chloride in dry benzene. The solvent and the rest of the thionyl chloride were twice evaporated under
vacuum from the crude chlorides, which were directly used for reduction. The reduction was carried out by
refluxing acid chlorides in xylene under a hydrogen stream with 5% palladium on barium sulfate as a catalyst
and quinoline S as a catalyst deactivator. In the reaction conditions acid chlorides 5a,b and 5e,f led to the
formation of the corresponding 2-naphthyloxyalkanals (6a,b and 6e,f) as the main products and to a mixture of
(Z)- and (E)-diastereoisomers of naphthyl alkenyl ethers (7a,b and 7e,f) as well as naphthyl alkyl ethers (8a,b
and 8e,f) as by-products (Schemes 2 and 3). GC/MS analyses showed that only 2-ethylnaphtho[2,1-b]furan (9a)
was also present in the mixture of the reduction products but in small amounts.
Scheme 2
O
O
Cl
R
5a,b
H2, Pd/BaSO4
xylene, 128–130°C
R
R
O
O
O
O
O
+
+
+
R1
7a,b (Z) + (E)
11–14%
R1
6a,b
8a,b
9a
70–75%
11–16%
3%
5−9 a R = Et, R1 = Me; b R = Bu, R1 = Pr
Scheme 3
R
R
O
Cl
O
O
O
R1
O
R1
O
H2, Pd/BaSO4
+
+
xylene, 128–130°C
5e,f
6e,f
69–72%
8e,f
13–17%
(Z) + (E)
7e,f
14–15%
5−9 e R = Et, R1 = Me; f R = Bu, R1 = Pr
TABLE 1. Reduction of Acid Chlorides 5a,b and 5e,f under optimal
conditions
Yield, %*
Chloride 5
Ether 7
Aldehyde 6
Ether 8
Naphthofuran 9
(Z)
(E)
a
b
e
f
75
70
72
69
3
4
4
5
8
10
11
9
11
16
13
17
3
−
−
−
_______
* Relative percentage based on the GC/MS chromatographic area
22

TABLE 2. Mass Spectra of Compounds 3a-f, 6a,b,e,f, 7a,b,e,f, 8a,b,e,f,
and 9a-e
Com-
pound
m/z (Irel, %)
3a
3b
3c
3d
244 [M]+ (100), 185 (38), 170 (3),157 (10), 144 (99), 128 (29), 115 (57), 101 (5), 77 (3),
59 (7)
272 [M]+ (100), 213 (24), 183 (3), 170 (2), 157 (19), 144 (99), 129 (31), 115 (65), 97 (6),
69 (15), 55 (6)
363 [M]+ (46), 304 (4), 271 (11), 243 (94), 211 (22), 171 (100), 155 (5), 142 (19), 128 (6),
115 (27), 93 (8), 73 (8), 59 (4)
391 [M]+ (38), 332 (2), 299 (10), 271 (100), 255 (5), 239 (12), 211 (10), 197 (7), 184 (14),
171 (89), 155 (4), 142 (20), 128 (5), 115 (27), 93 (15), 69 (11), 55 (5)
3e
3f
244 [M]+ (100), 185 (20), 157 (7), 144 (99), 128 (6), 115 (68), 101 (6), 77 (3), 59 (10)
272 [M]+ (100), 213 (12), 183 (1), 170 (5), 157 (8), 144 (99), 129 (9), 115 (58), 97 (7),
83 (1), 69 (12), 55 (5)
6a
6b
6e
6f
214 [M]+ (93), 186 (17), 185 (100), 169 (10), 157 (41), 144 (96), 143 (15), 128 (17),
127 (49), 116 (15), 115 (81), 89 (7), 77 (5)
242 [M]+ (58), 224 (48), 213 (37), 182 (16), 181 (100), 157 (57), 152 (23), 144 (86),
141 (34), 128 (13), 127 (36), 115 (50), 69 (24)
214 [M]+ (70), 196 (7), 185 (56), 181 (10), 157 (10), 144 (100), 143 (21), 127 (24),
116 (27), 115 (71), 89 (6)
242 [M]+ (50), 225 (10), 213 (24), 181 (29), 157 (16), 145 (16), 144 (100), 143 (11),
127 (16), 116 (17), 115 (45), 69 (6)
7a
(E, Z)
184 [M]+ (100), 169 (16), 155 (28), 144 (49), 142 (6), 141 (26), 128 (29), 127 (15),
116 (12), 115 (54)
7b
(E, Z)
212 [M]+ (100), 184 (12), 183 (88), 165 (23), 156 (8), 155 (62), 154 (12), 153 (23),
146 (53), 144 (54), 141 (22), 128 (21), 127 (54), 126 (17), 116 (6), 115 (35), 101 (6), 77 (8)
7e
(E, Z)
184 [M]+ (100), 183 (13), 170 (6), 169 (48), 155 (27), 144 (45), 143 (7), 141 (12),
129 (14), 128 (15), 127 (9), 116 (28), 115 (61), 89 (6)
7f
(E, Z)
212 [M]+ (100), 184 (7), 183 (53), 169 (18), 165 (23), 156 (5), 155 (40), 154 (7), 153 (14),
145 (6),144 (59), 141 (19), 128 (19), 127 (36), 126 (13), 116 (18), 115 (40), 101 (5), 77 (6)
8a
8b
8e
186 [M]+ (45), 145 (13), 144 (100), 126 (7), 116 (8), 115 (30), 89 (4)
214 [M]+ (23), 145 (10), 144 (100), 127 (6), 116 (5), 115 (18)
186 [M]+ (32), 184 (16), 169 (9), 155 (6), 145 (10), 144 (100), 129 (5), 116 (24),
115 (45), 89 (5)
8f
214 [M]+ (24), 145 (11), 144 (100), 127 (5), 116 (13), 115 (23)
9a
196 [M]+ (99), 195 (11), 182 (36), 181 (100), 153 (18), 152 (71), 151 (21), 139 (11),
98 (6), 76 (8)
9b
9c
224 [M]+ (36), 182 (15), 181 (100), 165 (5), 152 (23), 151 (5)
331 [M]+ (100), 274 (21), 259 (3), 245 (62), 217 (19), 197 (24), 184 (11), 170 (54),
155 (3), 142 (34), 127 (16), 114 (22), 91 (3), 77 (7), 63 (2), 50 (1)
9d
9e
359 [M]+ (100), 331 (2), 316 (6), 303 (2), 274 (23), 259 (3), 245 (71), 230 (2), 217 (24),
197 (25), 184 (49), 170 (59), 155 (4), 142 (41), 127 (11), 114 (25), 93 (4), 77 (8), 55 (3)
196 [M]+ (48), 182 (14), 181 (100), 165 (6), 152 (18), 139 (4), 90 (5), 76 (4)
The results of our studies show that two simultaneous processes occur on the catalyst surface during the
palladium-catalyzed hydrogenation of naphthyloxyalkanoyl chlorides, as was in the case of the reduction of
phenoxyalkanoyl chlorides, i.e. hydrogenolysis of C−Cl linkage leading to 2-naphthyloxyalkanal and a bit
slower dehydro-decarbonylation (β-elimination of hydrogen and COCl group) giving rise to a naphthyl alkenyl
ether. Hydrogenation of this one gives the naphthyl alkyl ether.
The optimization of the reduction parameters, weight ratio of the catalyst and its deactivator to the
starting chlorides allowed us to obtain 2-naphthyloxyalkanals in 69-75% yield (Table 1).
All aldehydes 6a-d were purified by column chromatography (hexane−dichloromethane, 1.5:1) and their
structures were established by elemental analyses and spectroscopic methods. Ethers 7a and 8a were also
isolated, purified, and then analyzed, but the others were analyzed only by GC/MS chromatography.
23

1
TABLE 3. H NMR Spectra (CDCl3/TMS) of Compounds 3a-f, 4a-f,
6a,b,e,f, 7a (E, Z), 8a, and 9a-f
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
3a
7.74 (2H, d, J = 8.5, Ar); 7.68 (1H, d, J = 8.1, Ar); 7.41 (1H, t, J = 7.7, Ar);
7.32 (1H, t, J = 7.2, Ar); 7.20 (1H, d, J = 8.9, Ar); 7.04 (1H, s, Ar); 4.72 (1H, t, J = 6.0, CH);
3.74 (3H, s, OCH3); 2.07-2.01 (2H, m, CH2); 1.11 (3H, t, J = 7.2, CH3)
3b
7.79 (2H, d, J = 8.5, Ar); 7.73 (1H, d, J = 8.1, Ar); 7.46 (1H, t, J = 7.4, Ar);
7.37 (1H, t, J = 7.3, Ar); 7.24 (1H, d, J = 8.8, Ar); 7.09 (1H, s, Ar); 4.82 (1H, t, J = 6.2, CH);
3.78 (3H, s, OCH3); 2.09-2.02 (2H, m, CH2); 1.61-1.54 (2H, m, CH2);
1.48-1.41 (2H, m, CH2); 0.98 (3H, t, J = 7.2, CH3)
3c
10.24 (1H, s, NH); 8.76 (1H, s, Ar); 7.90 (1H, d, J = 8.2, Ar); 7.86-7.84 (2H, m, Ar);
7.70 (1H, d, J = 8.3, Ar); 7.51 (1H, t, J = 1.2, Ar); 7.42-7.37 (3H, m, Ar); 7.18 (1H, s, Ar);
7.15-7.11 (1H, m, Ar); 5.17 (1H, t, J = 5.6, CH); 3.81 (3H, s, OCH3);
2.21-2.13 (2H, m, CH2); 1.11 (3H, t, J = 7.46, CH3)
3d
10.23 (1H, s, NH); 8.74 (1H, s, Ar); 7.89-7.84 (3H, m, Ar); 7.69 (1H, d, J = 8.1, Ar);
7.49 (1H, t, J = 7.4, Ar); 7.38 (3H, t, J = 7.7, Ar); 7.18 (1H, s, Ar);
7.12 (1H, t, J = 7.3, Ar); 5.19 (1H, t, J = 5.5, CH); 3.80 (3H, s, OCH3);
2.14-2.08 (2H, m, CH2); 1.51 (2H, q, J = 7.5, CH2); 1.36 (2H, q, J = 7.3, CH2);
0.87 (3H, t, J = 7.2, CH3)
3e
3f
8.38-8.35 (1H, m, Ar); 7.77-7.74 (1H, m, Ar); 7.49-7.41 (3H, m, Ar);
7.31-7.27 (1H, m, Ar); 6.64 (1H, d, J = 7.7, Ar); 4.75 (1H, t, J = 4.1, CH);
3.70 (3H, s, OCH3); 2.15-2.07 (2H, m, CH2); 1.15-1.13 (3H, m, CH3)
8.38-8.35 (1H, m, Ar); 7.77-7.73 (1H, m, Ar); 7.51-7.40 (3H, m, Ar);
7.30-7.26 (1H, m, Ar); 6.64 (1H, d, J = 7.6, Ar); 4.80 (1H, t, J = 4.2, CH);
3.69 (3H, s, OCH3); 2.14-2.03 (2H, m, CH2); 1.61-1.54 (2H, m, CH2);
1.43-1.37 (2H, m, CH2); 0.93 (3H, t, J = 7.3, CH3)
4a
4b
9.88 (1H, br. s, COOH); 7.75 (2H, d, J = 8.5, Ar); 7.69 (1H, d, J = 8.1, Ar);
7.42 (1H, t, J = 7.6, Ar); 7.34 (1H, t, J = 7.1, Ar); 7.21 (1H, t, J = 8.9, Ar); 7.08 (1H, s, Ar);
4.75 (1H, t, J = 5.8, CH); 2.07 (2H, t, J = 6.3, CH2); 1.13 (3H, t, J = 7.3, CH3)
9.24 (1H, br. s, COOH); 7.75 (2H, d, J = 8.4, Ar); 7.69 (1H, d, J = 8.1, Ar);
7.42 (1H, t, J = 7.6, Ar); 7.34 (1H, t, J = 7.1, Ar); 7.20 (1H, t, J = 8.7, Ar);
7.07 (1H, s, Ar); 4.78 (1H, t, J = 5.9, CH); 2.04-2.01 (2H, m, CH2);
1.58-1.52 (2H, m, CH2); 1.41-1.36 (2H, m, CH2); 0.92 (3H, t, J = 7.1, CH3)
4c
10.20 (1H, s, NH); 8.64 (1H, s, COOH); 8.57 (1H, s, Ar); 7.72 (3H, t, J = 6.8, Ar);
7.57 (1H, d, J = 8.2, Ar); 7.42 (1H, d, J = 6.0, Ar); 7.29-7.24 (3H, m, Ar);
7.12 (1H, s, Ar); 7.05 (1H, t, J = 7.4, Ar); 5.08 (1H, t, J = 5.5, CH);
2.18-2.03 (2H, m, CH2); 1.09-1.02 (3H, m, CH3)
4d
10.15 (1H, s, NH); 8.59 (1H, s, COOH); 7.77-7.71 (4H, m, Ar); 7.59 (1H, d, J = 8.1, Ar);
7.43 (1H, t, J = 7.3, Ar); 7.33-7.27 (3H, m, Ar); 7.14 (1H, s, Ar);
7.08 (1H, t, J = 7.1, Ar); 5.08 (1H, broad bond, CH); 2.05 (2H, d, J = 6.4, CH2);
1.49 (2H, t, J = 6.6, CH2); 1.32 (2H, q, J = 7.0, CH2); 0.83 (3H, t, J = 7.0, CH3)
4e
4f
11.68 (1H, s, COOH); 8.35-8.32 (1H, m, Ar); 7.79-7.76 (1H, m, Ar);
7.49–7.43 (3H, m, Ar); 7.31-7.27 (1H, m, Ar); 6.67 (1H, d, J = 7.6, Ar);
4.76 (1H, t, J = 6.0, CH); 2.17-2.10 (2H, m, CH2); 1.16 (3H, t, J = 7.4, CH3)
9.20 (1H, br. s, COOH); 8.34-8.31 (1H, m, Ar); 7.77 (1H, m, Ar);
7.51-7.46 (2H, m, Ar); 7.44 (1H, s, Ar); 7.32 (1H, t, J = 8.0, Ar);
6.68 (1H, d, J = 7.5, Ar); 4.84-4.81 (1H, m, CH); 2.20-2.08 (2H, m, CH2);
1.66-1.56 (2H, m, CH2); 1.46-1.38 (2H, m, CH2); 0.93 (3H, t, J = 7.3, CH3)
6a
6b
9.59 (1H, t, J = 1.2, CHO); 7.64 (2H, d, J = 9.0, Ar); 7.56 (1H, d, J = 8.1, Ar);
7.33-7.29 (1H, m, Ar); 7.25-7.21 (1H, m, Ar); 7.11-7.08 (1H, m, Ar);
6.89 (1H, d, J = 1.8, Ar); 4.45-4.41 (1H, m, CH); 1.87-1.79 (2H, m, CH2);
0.98 (3H, t, J = 7.4, CH3)
9.65 (1H, d, J = 2.4, CHO); 7.71 (2H, d, J = 2.4, Ar); 7.63 (1H, d.d, J = 7.6, 0.6, Ar);
7.40-7.36 (1H, m, Ar); 7.32-7.28 (1H, m, Ar); 7.17 (1H, dd, J = 6.4, 2.6, Ar);
6.97 (1H, d, J = 2.6, Ar); 4.57-4.53 (1H, m, CH); 1.86-1.81 (2H, m, CH2);
1.48-1.46 (2H, m, CH2); 1.36-1.30 (2H, m, CH2); 0.89 (3H, t, J = 7.3, CH3)
6e
6f
9.65 (1H, s, CHO); 8.35 (1H, t, J = 8.0, Ar); 7.75 (1H, s, Ar); 7.47 (2H, s, Ar);
7.41 (1H, d, J = 8.2, Ar); 7.23 (1H, d, J = 8.0, Ar); 6.56 (1H, d, J = 7.6, Ar);
4.53 (1H, t, J = 5.4, CH); 2.01-1.93 (2H, m, CH2); 1.09 (3H, t, J = 7.4, CH3)
9.70 (1H, d, J = 3.5, CHO); 8.36-8.33 (1H, m, Ar); 7.81-7.78 (1H, m, Ar);
9.48-7.52 (2H, m, Ar); 7.45 (1H, d, J = 8.3, Ar); 7.29 (1H, t, J = 6.4, Ar);
6.61 (1H, d, J = 7.6, Ar); 4.67-4.63 (1H, m, CH); 2.04-1.92 (2H, m, CH2);
1.60-1.54 (2H, m, CH2); 1.42-1.37 (2H, m, CH2); 0.92 (3H, t, J = 7.3, CH3)
24

TABLE 3 (continued)
1
2
7a (E)
7a (Z)
8a
8.13-7.35 (7H, m, Ar); 6.68-6.62 (1H, m, CH); 5.11-5.06 (1H, m, CH);
1.92-1.90 (3H, m, CH3)
8.13-7.35 (7H, m, Ar); 6.69-6.64 (1H, m, CH); 5.63-5.58 (1H, m, CH);
1.92-1.90 (3H, m, CH3)
7.69-7.63 (3H, q, J = 15.3, 8.8, Ar); 7.55 (1H, t, J = 7.5, Ar); 7.23 (1H, t, J = 7.3, Ar);
7.07 (2H, d, J = 12.4, Ar); 3.96 (2H, t, J = 6.5, CH2);
1.83-1.78 (2H, q, J = 14.0, 7.0, CH2); 1.00 (3H, t, J = 7.3, CH3)
9a
9b
7.98 (1H, d, J = 8.2, Ar); 7.84 (1H, d, J = 8.1, Ar); 7.55 (2H, s, Ar);
7.47 (1H, t, J = 7.5, Ar); 7.38 (1H, t, J = 7.2, Ar); 6.74 (1H, s, Ar);
2.85-2.80 (2H, m, CH2); 1.31 (3H, t, J = 7.6, CH3)
8.03 (1H, d, J = 8.0, Ar); 7.88 (1H, d.d, J = 6.9, J = 0.5, Ar); 7.59 (2H, s, Ar);
7.53-7.49 (1H, m, Ar); 7.44-7.40 (1H, m, Ar); 6.77 (1H, s, Ar);
2.79 (2H, t, J = 7.9, CH2); 1.78-1.70 (2H, m, CH2); 1.46-1.37 (2H, m, CH2);
0.96 (3H, t, J = 7.4, CH3)
9c
8.76 (1H, s, Ar); 7.92 (1H, d, J = 8.2, Ar); 7.80 (1H, d, J = 8.3, Ar);
7.59 (2H, t, J = 7.0, Ar); 7.51-7.40 (4H, m, Ar); 7.22 (2H, d, J = 7.9, Ar);
4.58 (1H, t, J = 4.2, CH); 2.20-2.08 (2H, m, CH2); 1.19 (3H, t, J = 7.3, CH3)
9d
9e
8.77 (1H, s, Ar); 7.96-7.23 (10H, m, Ar); 4.67 (1H, broad bond, CH);
2.12-2.01 (2H, m, CH2); 1.71-1.26 (4H, m, CH2); 0.96 (3H, t, J = 7.0, CH3)
8.26 (1H, d, J = 8.3, Ar); 7.88 (1H, d, J = 8.2, Ar); 7.60-7.55 (2H, m, Ar);
7.55-7.51 (1H, m, Ar); 7.43-7.39 (1H, m, Ar); 6.47 (1H, s, Ar); 2.91-2.86 (2H, m, CH2);
1.38 (3H, t, J = 5.0, CH3)
9f
8.26 (1H, d, J = 8.3, Ar); 7.89 (1H, d, J = 8.2, Ar); 7.61-7.52 (3H, m, Ar);
7.44-7.40 (1H, m, Ar); 6.48 (1H, s, Ar); 2.86 (2H, t, J = 7.7, CH2);
1.82-1.74 (2H, m, CH2); 1.48-1.42 (2H, m, CH2); 0.97 (3H, t, J = 7.4, CH3)
In the case of chlorides 5c and 5d, no desired aldehydes were obtained by this method. Under the
reaction conditions the chlorides underwent intramolecular N-acylation giving naphtho-1,4-oxazepine-
3,5-diones 9c and 9d (Scheme 4). The same products were obtained when chlorides 5c and 5d were heated for
several minutes in boiling toluene without palladium.
Scheme 4
O
R
Cl
R
O
O
O
H2, Pd/BaSO4
xylene, reflux
O
NH
N
O
5c,d
9c,d
62–95%
5,9 c R = Et; d R = Bu
Scheme 5
R
R
O
O
Amberlyst 15
DME, 20 min
Amberlyst 15
DME, 20 min
6e,f
6a,b
9e,f
(70–73%)
9a,b
(94–95%)
25

Cyclization of 2-naphthyloxyalkanals was carried out in dimethoxyethane (DME) using Amberlyst 15
resin as a catalyst. The best results and high cyclization yield were achieved when the reaction mixture was
heated in boiling DME for 20 min (Scheme 5).
It was found that cyclization of 2-(2-naphthyloxy)alkanals 6a and 6b over Amberlyst 15 resin provided
only 2-alkylnaphtho[2,1-b]furan regioisomer, while the cyclization of model ethyl acetal of 2-naphthoxybutanal 6a
resulted in formation of 2-ethylnaphtho[2,1-b]furans as main products and small amounts of 2-ethylnaphtho-
[3,2-b]furans. The isomeric product was observed when cyclization of compound 6a was carried out using
homogenous sulfuric acid as a catalyst.
A new synthetic method for regioisomeric naphthofurans by cyclization of naphthyloxyalkanals has
been developed. The optimum reduction conditions of naphthyloxyalkanoic acid chlorides allowing one to
prepare 2-naphthyloxyalkanals with good yields with a minimum of the ethers as by-products were established.
The efficient cyclization of 2-naphthyloxyalkanals to 2-alkylnaphthofurans as a green chemistry process carried
out under mild conditions over the acidic Amberlyst 15 resin has been presented. The cyclization of
naphthyloxyalkanals afforded the desired naphthofurans in excellent yields.
TABLE 4. 13C NMR Spectra Data (CDCl3/TMS) of Compounds
3a,b,d,e,f, 4a-f, 6a,b,e,f, and 9a,b,e,f
Com-
pound
Chemical shifts, δ, ppm
3a
3b
3d
3e
3f
172.2, 155.8, 134.3, 129.7, 129.3, 127.6, 126.9, 126.4, 123.9, 118.9, 107.6, 77.7, 52.3,
26.2, 9.7
172.5, 155.9, 134.4, 129.8, 129.4, 127.7, 126.9, 126.5, 124.1, 118.9, 107.6, 77.5, 52.3,
32.7, 27.5, 22.4, 14.0
172.0, 163.4, 152.1, 138.9, 135.4, 134.3, 129.0, 128.8, 128.5, 126.4, 125.1, 124.4, 124.0,
120.2, 108.3, 77.5, 52.9, 32.1, 27.0, 22.4, 13.8
172.2, 153.7, 134.6, 127.4, 126.5, 125.7, 125.6, 125.3, 122.2, 121.1, 105.2, 77.8, 52.1,
26.3, 9.8
172.4, 153.7, 134.6, 127.4, 126.5, 125.7, 125.6, 125.3, 122.2, 121.0, 105.1, 76.7, 52.2,
32.7, 27.5, 22.4, 13.9
4a
4b
177.4, 155.5, 134.2, 129.8, 129.4, 127.6, 126.9, 126.5, 124.1, 118.7, 107.8, 26.0, 9.6
177.8, 155.6, 134.2, 129.9, 129.5, 127.7, 126.9, 126.6, 124.2, 118.8, 107.7, 76.0, 32.4,
27.4, 22.3, 13.9
4c
174.4, 164.7, 151.9, 138.1, 136.3, 135.4, 133.8, 129.0, 128.6, 126.4, 125.2, 124.6, 123.9,
120.7, 108.7, 77.8, 25.5, 9.3
4d
175.0, 164.4, 152.2, 138.3, 135.4, 133.7, 129.0, 128.6, 128.5, 126.4, 125.1, 124.4, 124.1,
120.5, 108.7, 77.4, 32.2, 27.1, 22.4, 13.8
4e
4f
178.0, 153.4, 134.6, 127.4, 126.6, 125.6, 125.5, 125.4, 122.1, 121.3, 105.3, 26.2, 9.8
178.0, 153.4, 134.6, 127.4, 126.6, 125.6, 125.5, 125.5, 122.1, 121.3, 105.2, 76.0, 32.5,
27.5, 22.3, 13.9
6a
6b
201.8, 154.5, 133.2, 128.9, 128.3, 126.6, 125.8, 125.6, 123.1, 117.8, 106.8, 81.6, 22.6, 8.1
203.0, 155.7, 134.3, 130.0, 129.4, 127.7, 126.9, 126.7, 124.2, 118.9, 107.9, 81.7, 30.0,
26.9, 22.5, 13.9
6e
6f
203.1, 153.4, 134.8, 127.7, 126.8, 125.6, 122.1, 121.5, 105.7, 99.9, 82.8, 23.9, 9.4
203.2, 153.3, 134.7, 127.4, 126.7, 125.6, 125.5, 121.9, 121.3, 105.5, 81.7, 30.1,
26.9, 22.5, 13.9
9a
9b
9e
9f
159.0, 150.6, 129.1, 127.5, 126.3, 124.7, 122.9, 122.8, 122.6, 122.2, 110.9, 98.9,
20.7, 10.9
159.2, 152.0, 130.4, 128.9, 127.7, 126.1, 124.3, 124.2, 123.9, 123.6, 112.3, 101.0, 30.2,
28.5, 22.6, 14.1
160.2, 149.7, 130.8, 128.3, 126.0, 124.4, 124.3, 122.8, 121.2, 119.7, 119.3, 102.1,
21.9, 12.1
159.0, 149.7, 130.8, 130.8, 128.3, 126.0, 124.4, 122.9, 121.2, 119.7, 119.3, 102.8, 30.1,
28.2, 22.3, 13.8
26

TABLE 5. Elemental Analysis Data for Compounds 3a-f, 4a-f, 5a-f,
6a,b,e,f, and 9a-f
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
C
H
Cl
N
3a
3b
3c
3d
3e
3f
C15H16O3
73.64
73.75
74.85
74.97
72.63
72.71
73.49
73.64
73.67
73.75
74.89
74.97
6.68
6.60
7.46
7.40
5.93
5.82
6.53
6.44
6.65
6.60
7.51
7.40
C17H20O3
C22H21NO4
C24H25NO4
C15H16O3
3.73
3.85
3.37
3.58
C17H20O3
4a
4b
4c
4d
4e
4f
C14H14O3
72.97
73.03
74.31
74.39
72.03
72.19
73.13
73.19
72.95
73.03
74.29
74.39
6.19
6.13
7.11
7.02
5.61
5.48
6.31
6.14
6.18
6.13
7.09
7.02
C16H18O3
C21H19NO4
C23H23NO4
C14H14O3
3.92
4.01
3.65
3.71
C16H18O3
5a
5b
5c
5d
5e
5f
C14H13ClO2
C16H17ClO2
C21H18ClNO3
C23H22ClNO3
C14H13ClO2
C16H17ClO2
C14H14O2
67.46
67.61
69.38
69.44
68.33
68.57
69.73
69.78
67.52
67.61
69.23
69.44
78.46
78.48
79.29
79.31
5.34
5.27
6.34
6.19
5.02
4.93
5.71
5.60
5.41
5.27
6.31
6.19
6.61
6.59
7.52
7.49
13.99
14.26
12.52
12.81
9.38
9.64
8.77
8.96
14.02
14.26
12.63
12.81
3.65
3.81
3.43
3.54
6a
6b
6e
6f
C16H18O2
C14H14O2
78.45
78.48
79.27
79.31
6.63
6.59
7.54
7.49
C16H18O2
9a
9b
9c
9d
9e
9f
C14H12O
85.65
85.68
85.66
85.68
76.03
76.12
76.75
76.86
85.66
85.68
85.64
85.68
6.19
6.16
7.22
7.19
5.24
5.17
5.98
5.89
6.19
6.16
7.27
7.19
C16H16O
C21H17NO3
C23H21NO3
C14H12O
4.09
4.23
3.71
3.90
C16H16O
27

EXPERIMENTAL
1H and 13C NMR spectra were recorded on a TM Bruker DPX 400 (400 MHz) instrument, solvent
1
CDCl3. Chemical shifts δ are given from TMS (0 ppm) as an internal standard for H NMR and CDCl3
(77.0 ppm) for 13C NMR (100 MHz). Mass spectra were obtained using an Agilent Technologies 6890 N gas
chromatograph equipped with a mass detector 5973 Network and 30 m × 0.25 mm capillary column filled with a
0.25 µm film of a 5% MePh silicate. All melting points were determined on a Boetius apparatus and are
uncorrected.
Most of the reagents and solvents were purchased in a commercially available grade purity. 1-Naphthol,
2-naphthol, butanoic and hexanoic acids, 3-hydroxynaphthalene-2-carboxylic acid phenylamide, catalyst
(5 wt.% BaSO4), and Amberlyst 15 resin were used without further purification. Methyl 2-bromobutanoate 1a
and methyl 2-bromohexanoate 1b were prepared according to the literature [30]. Benzene, xylene, and DME
were dried over sodium, and DMF was dried over type 4A molecular sieves before using.
Synthesis of 2-(Naphthyloxy)alkanoic Acid Methyl Esters 3a-f (General Method). A mixture of
naphthol 2a-c (0.05 mol), methyl 2-bromoalkanoate 1a-b (0.05 mol), anhydrous potassium carbonate
(0.05 mol), and dry DMF (70 ml) was heated at 92–94ºC with stirring for 4 h. Then the solution was poured into
ice water and the precipitate was filtered off, washed with water, and dried on air. The crude ester was
crystallized from methanol to give compounds 3a–f (Tables 2-5). Yield: compounds 3a – 98, 3b – 80, 3c – 68,
3d –96, 3e – 84, 3f – 91%. Compounds 3a, mp 55.5-56.5ºC; 3b,d-f, oil products; 3c, mp 100-103ºC.
Synthesis of 2-(Naphthyloxy)alkanoic Acids 4a-f (General Method). A mixture of ester 3a-f
(0.05 mol) and 10% sodium hydroxide (100 ml) was stirred and heated on a boiling water bath for 4 h. The
solution was acidified with 5% hydrochloric acid and the precipitate was isolated. The crude product was
purified by activated carbon to give compounds 4a–f (Tables 3–5). Yield: compounds 4a – 95, 4b – 78, 4c – 98,
4d – 87, 4e – 75, 4f – 73%; mp compounds 4a, 126–127 (Lit. [31] mp 126.5); 4b, 107–109 (Lit. [32] 108–110);
4c, 106–111, 4d, oil product, 4e, 114-116, 4f, 98-100ºC.
Synthesis of 2-(naphthyloxy)alkanoyl chlorides 5a-f (General Method). A solution of an anhydrous
2-(naphthyloxy)alkanoic acid 4a-f (0.02 mol) and thionyl chloride (0.06 mol) in anhydrous benzene (40 ml) was
heated at 45-50ºC for 1.5 h and then at 58-60ºC for 3 h. Benzene and an excess of thionyl chloride were
evaporated. Then a new portion of anhydrous benzene was added and evaporated again. The crude
2-(naphthyloxy)akanoyl chloride was dried under reduced pressure at room temperature to give oil product 5a-f
(Table 5). Yield: compounds 5a – 90, 5b – 98, 5c – 88, 5d – 95, 5e – 78, 5f – 80%. The crude chlorides were
used for reduction without any analyses.
Reduction of 2-(Naphthyloxy)alkanoyl Chlorides 5a,b,e,f (General Method). A magnetically stirred
mixture of palladium catalyst (5% on barium sulfate, 0.45 g), catalyst poison (quinoline S, 0.2 g), and dry xylene
(35 ml) was heated under a hydrogen stream passing at the rate of 2-3 bubbles per second for 20 min. Then it
was warmed up to 100ºC and crude compounds 5a,b,e,f (8 mmol) were added. The mixture was heated at 126-
128ºC afterwards. The reaction was monitored by titrating the HCl liberated using 1 M NaOH and was carried
out until the chloride conversion was completed (1.5-2 h). The mixture was then cooled and left overnight. The
catalyst was filtered off the next day, and the solvent was evaporated. The residual liquid, chromatographically
determined, was purified by column chromatography (hexane–dichloromethane, 1.5:1) to give products such as
aldehydes 6 and ethers 7, 8 (Tables 1-5).
Reduction of 2-(3-Phenylcarbamoyl-2-naphthyloxy)alkanoyl Chlorides 5c,d. Starting with
compounds 5c,d (3 mmol) the same procedure was followed as for compound 5a to obtain the product, which
was crystallized from diethyl ether to give compounds 9c,d (Tables 2, 3, 5). Yield: 9c – 95, 9d – 62%; mp:
compounds 9c, 168-171, 9d, 91-94ºC.
Synthesis of 2-alkylnaphthofurans 9a,b,e,f (General Method). A solution of compound 6 (4 mmol)
and resin Amberlyst 15 (1.36 g) in DME (30 ml) was heated under reflux with stirring for 20 min. The mixture
28

was cooled and the resin was filtered off. The solvent was evaporated and the residue was purified by column
chromatography (hexane–dichloromethane, 1.5:1) to give oil products 9a,b,e,f (Tables 2-5). Yield: compounds
9a – 95, 9b – 94, 9e – 73, 9f – 70%.
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