Convenient synthesis of novel 2,2-dialkyl-1,2-dihydronaphtho[2,1-b]furans

Article abstract of DOI:10.1016/j.tetlet.2009.07.087

Reaction of 2,2-dialkylacetaldehydes with electron-rich 2-naphthols in presence of p-TSA under closed-vessel solvent-free microwave irradiation conditions resulted in formation of corresponding dihydronaphtho[2,1-b]furans in good to excellent yields. In s

Full text of DOI:10.1016/j.tetlet.2009.07.087

Tetrahedron Letters 50 (2009) 5709–5712
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Tetrahedron Letters
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Convenient synthesis of novel 2,2-dialkyl-1,2-dihydronaphtho[2,1-b]furans
*
Doug Vaughan, Amitabh Jha
Department of Chemistry, Acadia University, Wolfville, NS, Canada B4P 2R6
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 2,2-dialkylacetaldehydes with electron-rich 2-naphthols in presence of p-TSA under
closed-vessel solvent-free microwave irradiation conditions resulted in formation of corresponding dihy-
dronaphtho[2,1-b]furans in good to excellent yields. In several cases, small amounts of 14-alkyl-14H-
dibenzo[a,j]xanthenes were also formed.
Received 5 July 2009
Revised 15 July 2009
Accepted 16 July 2009
Available online 19 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Naphthol
2,2-Dialkyl-1,2-dihydronaphtho
[2,1-b]furans
14-Alkyl-14H-dibenzo[a,j]xanthenes
Microwave-assisted synthesis
Solvent-free
Cyclocondensation
Benzofuran and naphthofuran frameworks are found abundantly
in a number of biologically relevant natural products1 and therefore
where the phenol is condensed with two molar equivalents of an
allene in presence of a Pd(0) catalyst to produce O-dienyl derivative
which undergoes Claisen rearrangement to ortho-C-dienyl derivative,
which in turn undergoes acid-catalyzed intramolecular cyclization to
produce dihydrobenzopyran (major) and dihydrobenzofuran (minor)
derivatives.9 Similar outcomes were achieved when phenols were
reacted with conjugated dienes using 5 mol % silver triflate.10 The
product distribution between the dihydrobenzopyran and dihydro-
benzofuran depended upon the diene used.10 Another interesting
synthetic conversion employs rearrangement of dihydronaph-
tho[1,2]dioxines (prepared from 1-formyl naphthalene) to
1-(b-keto)-2-naphthols which reacted with methyl(triphenylphos-
phoranylidene)acetate to afford 2,2-disubstituted 1,2-dihydronaph-
tho[2,1-b]furans.11 Articulated dihydrobenzofurans were also
prepared in one operation by reacting a vinyl sulfoxide with
phenols.12 Lithiation of 2,2-dialkyl-4H-benzo[d][1,3]dioxine resulted
in formation of the corresponding homobenzylic alcohol which
cyclized in presence of phosphoric acid to 2,2-dialkyl-2,3-dihydro-
benzofurans.13 PdCl2-catalyzed intramolecular activation of electro-
neutral cyclopropane ring of 1-(2-ethylcyclopropyl)naphthalen-2-ol
resulted in cleavage of the cyclopropane ring followed by formation
of 2-ethyl, 2-methyl-1,2-dihydronaphtho[2,1-b]furan.14 Another
study reports Pd-catalyzed alkane arylationof tertiaryalkyl2-bromo-
phenyl ethers resulting in formation of dihydrobenzofurans and
dihydronaphthofurans.15 Buchwald16 and Hartwig17 have also
reported formation of 2,2-dialkyl-2,3-dihydrobenzofurans from
2-1,1-dialkyl-(2-bromophenyl)ethanols employing their protocol of
Pd-catalyzed C–O coupling on aryl halides.
their chemical syntheses have attracted considerable attention.2
A
plethora of biological activities have also been associated with a
large number of synthetic benzofuran and naphthofuran analogs.3
Since this investigation deals with a new synthetic approach to
prepare 1,2-dihydronaphtho[2,1-b]furans, it is imperative to review
common and important literature procedures employed to construct
this type of compounds. Claisen rearrangement of substituted allyl
phenyl ethers followed by subsequent cyclization is a widely studied
route to prepare dihydrobenzofurans and naphtho[2,1-b]furans.4
2-Allyl phenols formed after the first step in this process are often iso-
lated as a side product.4 Recently, an Ir(III)-catalyzed tandem Claisen
rearrangement-intramolecular hydroaryloxylation to produce dihy-
drobenzofurans was developed.5 Alternatively, direct synthesis of
2-allyl phenols by Lewis acid-catalyzed alkylation of phenols fol-
lowed by acid-catalyzed cyclization also led to dihydrobenzofurans.6
Pochini et al. reported ortho-condensation between magnesium phe-
nolates and carbonyl compounds to produce alkylidene-bisphenols,
2-alkenyl-phenols, and 2,3-dihydrobenzofurans in varying ratios.7 A
simple dihydronaphtho[2,1-b]furan was produced by o-allylation of
6-bromo-2-naphthol followed by ozonolysis and reduction sequence
to produce 6-bromo-1-(2-hydroxyethyl)naphthalen-2-ol and finally
the ring closure was affected under acid-catalyzed conditions.8
A
mechanistically interesting approach involves a three-step protocol
* Corresponding author. Tel./fax: +1 902 585 1515.
E-mail address: ajha@acadiau.ca (A. Jha).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.087

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D. Vaughan, A. Jha / Tetrahedron Letters 50 (2009) 5709–5712
R1
R
R1
R2
R
R2
R1
R2
H
O
OH
p-TSA, mw
+
+
180ºC, 5 min.
O
R
O
R
1a-14a (major, 44-92%)
1b-14b
(trace)
R = H or Br
Scheme 1. Synthetic scheme followed to produce compounds 1a–14a and 1b–14b. Substituents are reported in Table 1.
Although the preceding discussion portrays several elegant
methyl-1,2-dihydronaphtho[2,1-b]furan.14 Our reactions and the
physical data for compounds 1-14 are summarized in Table 1.
The mechanism of formation of naphthofuran products appears
to be straightforward. The proposed mechanism using isobutyral-
dehyde and 2-naphthol as starting materials is shown in Scheme
2. Nucleophilic C attack of 2-naphthol led to formation of a second-
ary alcohol intermediate which formed a secondary benzylic car-
bocation through corresponding oxonium ion under catalytic
amount of p-TSA. 1,2-Hydride shift leading a tertiary carbocation
followed by nucleophilic attack by the naphthol oxygen led to for-
mation of a stable furan ring.
methodologies, it also makes it abundantly clear that the existing
procedures are inefficient, and involve multiple steps, expensive
reagents and non-commercial starting materials. We herein report
a simple, facile, and cost-effective formation of 2,2-dialkyl-1,2-
dihydronaphtho[2,1-b]furans by reacting 2-naphthol analogs and
2,2-dialkyl acetaldehydes in the presence of catalytic amounts of
p-toluene sulfonic acid (p-TSA) under solvent-free microwave irra-
diation conditions. Certain reactions also yielded 14-alkyl-14H-
dibenzo[a,j]xanthenes in small quantities (Scheme 1).
One of the interests of our research group lies in development of
novel structural frameworks from 2-naphthol analogs.18 Reaction
of 2-naphthol with non-enolizable aromatic aldehydes is a widely
studied reaction that produces 14-aryl-14H-dibenzo[a,j]xanthenes
in near quantitative yields.19 On the contrary, aliphatic aldehydes
with two enolizable protons produce a complex mixture of prod-
ucts in the form of tarry masses when reacted with 2-naphthol,
understandably owing to a number of possible competing reac-
tions such as aldol condensations, C-alkylation of 2-naphthol by
aldehydes and aldol products and dehydrated secondary products.
We were curious as to how aliphatic aldehydes with one enolizable
proton will behave when reacted with 2-naphthol; the availability
of a single enolizable proton should limit any possible competing
reactions. Reaction of equimolar ratio of isobutyraldehyde with
2-naphthol in the presence of a catalytic amount of p-TSA under
solvent-free microwave irradiation conditions resulted in forma-
tion of 2,2-dimethyl-1,2-dihydronaphtho[2,1-b]furan as the major
product. Encouraged by the results we decided to test the general-
ity and scope of the reaction by employing a variety of 2,2-dialky-
lacetaldehydes, 2-naphthol analogs, and other phenols.20 Our
literature search indicated that such a synthetic procedure to dihy-
dronaphthofuran is novel and resulting compounds with general
structure 2,2-dialkyl-1,2-dihydronaphtho[2,1-b]furan have not
been reported in the chemical literature with the exception of
2,2-dimethyl-1,2-dihydronaphtho[2,1-b]furan4d,7,15 and 2-ethyl,2-
This reaction appears to work excellently with 2-naphthol and
analogs, but with simpler phenols it appears to behave differently.
Reaction of 4-tert-butylphenol with isobutyraldehyde led to forma-
tion of three products (based on TLC) under the same reaction condi-
tions (Scheme 3). The reaction mixture was analyzed by GC–MS. The
GC–MS indicated four peaks in the chromatograms one of which cor-
responded to the starting phenol [M+ 150]. The molecular ions of the
remaining three peaks were 204, 408, and 462. These were tenta-
tively identified as 4-tert-butyl-2-(2-methylprop-1-enyl)phenol
(15), 4-tert-butyl-1-(1-(4-tert-butylphenoxy)-2-methylpropoxy)-
2-(2-methylprop-1-enyl)benzene (16), and 4,40-(2-methylpropane-
1,1-diyl)bis(oxy)bis(1-tert-butyl-3-(2-methylprop-1-enyl)benzene)
(17), respectively. The compound with M+ at 204 was identified as
4-tert-butyl-2-(2-methylprop-1-enyl)phenol and not as isomeric
5-tert-butyl-2,2-dimethyl-2,3-dihydrobenzofuran due to the
presence of 4,40-(2-methylpropane-1,1-diyl)bis(oxy)bis(1-tert-bu-
tyl-3-(2-methylprop-1-enyl)benzene) for which 4-tert-butyl-2-(2-
methylprop-1-enyl)phenol serves as the intermediate. Extensive
studies on 4-tert-butylphenol and other phenols will be reported
subsequently.
In conclusion, we have developed a simple, facile, and efficient
microwave-assisted reaction for the synthesis of 2,2-dialkyl-1,2-
dihydronaphtho[2,1-b]furans from 2-naphthol analogs, 2,2-dialky-
lacetaldehydes, and catalytic amount of p-TSA. Our preliminary
Table 1
Physical data for compounds 1–14
Entry
R
R1
R2
Naphtho[2,1-b]furans (a)
Dibenzo[a,j]xanthenes (b)
% Yield
Mp
% Yield
Mp
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
Br
Me
Me
Me
Me
Et
Me
Et
n-Pr
Ph
Et
n-Bu
48
80
46
73
71
44
90
74
73
65
79
83
91
92
Liquida
Liquid
Liquid
76–78
Liquid
Liquid
Liquid
60–64
Liquid
Liquid
Liquid
Liquid
Liquid
80–83
8
2
2
NI
NI
5
5
4
NI
NI
NI
NI
NI
NI
128–136
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
188–180
—
—
—
—
—
Et
–(CH2)5–
Me
Me
Me
Me
Et
Me
Et
n-Pr
Ph
Et
n-Bu
Et
–(CH2)5–
—
NI: not isolated.
a
Lit. mp 42–43 °C.7

D. Vaughan, A. Jha / Tetrahedron Letters 50 (2009) 5709–5712
5711
H
O
HO
H2O
HO
OH
OH
O
OH
OH
O
O
H
H
OH
H shift
+ 2-Naphthol
H2O
-
O
Scheme 2. Proposed mechanism of formation of 2,2-dimethyl-1,2-dihydronaphtho[2,1-b]furan and 14-isopropyl-14H-dibenzo[a,j]xanthenes from 2-naphthol and
isobutyraldehyde.
O
O
O
O
OH
OH
p
-TSA (cat.), mw
H
O
185ºC, 5 min.
15
16
17
Scheme 3. Reaction between 4-tert-butylphenol and isobutyraldehyde. Products were analyzed based on GC–MS data.
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Acknowledgments
The authors thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) and Acadia University for
financial support for this project.
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20. In a typical procedure 2-naphthol (10 mmol) and cyclohexane carboxaldehyde
(10 mmol) are combined in a microwave vial with a catalytic amount of 4-

5712
D. Vaughan, A. Jha / Tetrahedron Letters 50 (2009) 5709–5712
toluene sulfonic acid (ꢀ50 mg), and are heated at 185 °C for 5 min in a CEM
(d, J = 8.2, 1H, Ar–H), 7.69 (d, J = 8.8, 1H, Ar–H), 7.79 (d, J = 8.2, 1H, Ar–H). 13C
NMR: d 23.15, 25.29, 37.54, 39.96, 89.51, 112.56, 117.96, 122.51, 124.05,
126.51, 128.01, 128.77, 128.86, 131.27, 156.40. UV–vis (kmax): 235 nm. IR
Discover S-Class microwave reactor. Subsequent purification of the compound
via column chromatography yielded 10H-spiro[cyclohexane-1,20-naphtho[2,1-
b]furan] as a light-brown viscous liquid in 90% yield. Spectroscopic data are
presented here.1H NMR: d 1.82–1.90 (m, 10H, CH2), 3.26 (s, 2H, Ar–CH2), 7.11
(d, J = 8.8, 1H, Ar–H), 7.31 (d, J = 7.9, 1H, Ar–H), 7.44 (t, J = 7.2, 1H, Ar–H), 7.59
(NaCl;
mmax): 3057, 2926, 2855, 1600, 1465, 1261, 1205, 808. EIMS (amu): 238
[M+, 100%].