Reactions of O-quinone methides with pyridinium methylides: A diastereoselective synthesis of 1,2-dihydronaphtho[2,1- b ]furans and 2,3-dihydrobenzofurans

Article abstract of DOI:10.1021/jo400621r

A simple, general route to the 1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans substituted at C-2 by an acyl or aryl group, starting from phenolic Mannich bases and pyridinium ylides, has been developed. The mechanism of the reaction is believed to involve the formation of the o-quinone methide intermediate, Michael-type addition of the ylide to the o-quinone methide, followed by intramolecular nucleophilic substitution.

Full text of DOI:10.1021/jo400621r

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Article
Reactions of o-quinone methides with pyridinium
methylides: a diastereoselective synthesis of 1,2-
dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans
Vitaly Aleksandrovich Osyanin, Dmitry Vladimirovich Osipov, and Yuri Nikolaevich Klimochkin
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 13 May 2013
Downloaded from http://pubs.acs.org on May 13, 2013
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Reactions of o-quinone methides with pyridinium methylides: a diastereoselective synthesis
of 1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans
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Vitaly A. Osyanin*, Dmitry V. Osipov, Yuri N. Klimochkin
Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeiskaya
St., 443100 Samara, Russian Federation.
*E-mail: vosyanin@mail.ru
Abstract: A simple, general route to the 1,2-dihydronaphtho[2,1-b]furans and 2,3-
dihydrobenzofurans subsituted at C-2 by an acyl or aryl group, starting from phenolic Mannich
bases and pyridinium ylides has been developed. The mechanism of the reaction is believed to
involve the formation of the o-quinone methide intermediate, Michael-type addition of the ylide
to the o-quinone methide followed by intramolecular nucleophilic substitution.
Keywords: o-Quinone methides, 1,2-dihydronaphtho[2,1-b]furans, 2,3-dihydrobenzofurans,
pyridinium ylides, Mannich base, Michael reaction, cascade reaction.
Introduction
The dihydrobenzo(naphtho)furans belong to an important class of heterocycles, principally
because this ring-system constituents the core skeleton of an increasing number of
pharmaceuticals and biologically active natural products. Remarkable examples of this class are
the antileukemic agent megapodiol,1 neolignan callislignan A, which exhibits antibacterial
activity against Staphylococcus aureus,2 the antitumor neolignan (2R,3S)-3,4′-di-O-
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methylcedrusin,3 as well as isolated from Cordyceps annullata annullatin A, which exhibits
potent agonistic activity toward the cannabinoid receptors CB1 and CB2 (Scheme 1).4
Scheme 1. Selection of natural products containing 2,3-dihydrobenzofuran rings
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In addition, 1,2-dihydronaphtho[2,1-b]furans occupy a prominent place in medicinal chemistry
due to their diverse pharmacological activities (Scheme 2).5–9 Thus, the development of new and
efficient methods for the synthesis of dihydrobenzo(naphtho)furans remains an area of current
interest.
Scheme 2. Biologically relevant 1,2-dihydronaphtho[2,1-b]furans
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Although various methods for the preparation of 2,3-dihydrobenzofurans have been
reported,10 there are few reports about the synthesis of 1,2-dihydronaphtho[2,1-b]furans. Claisen
rearrangement of allyl 2-naphthyl ethers in 1-allyl-2-naphthols followed by cyclization is the
most frequently used to prepare 1,2-dihydro[2,1-b]naphthofurans.11–15 Another synthetic path
includes rearrangement of dihydronaphtho[1,2]dioxines (prepared from 1-vinylnaphthalenes) to
1-(β-keto)-2-naphthols which reacted with methyl(triphenylphosphoranylidene)acetate to afford
2,2-disubstituted 1,2-dihydronaphtho[2,1-b]furans.16 PdCl2-catalyzed cleavage of the
cyclopropane ring in 1-(2-ethylcyclopropyl)naphthalen-2-ol resulted in formation of 2-ethyl-2-
methyl-1,2-dihydronaphtho[2,1-b]furan.17 Treatment of 2-naphthols with ethyl 2,3-
dibromopropanoate in the presence of potassium carbonate gave the ethyl 1,2-
dihydronaphtho[2,1-b]furan-2-carboxylates.18 Reaction of 2,2-dialkylacetaldehydes with 2-
naphthols in the presence of p-TSA under microwave irradiation conditions resulted in formation
of 2,2-dialkyl-1,2-dihydronaphtho[2,1-b]furans.11 Unsubstituted 1,2-dihydronaphtho[2,1-b]furan
was prepared by reaction of 2-naphthol Mannich bases or their quaternized derivatives with
dimethylsulphoxonium methylide or diazomethane.19,20 7-Bromo-1,2-dihydronaphtho[2,1-
b]furan was produced by o-allylation of 6-bromo-2-naphthol followed by ozonolysis, reduction
cleavage and finally ring closure under the action of acid.9 Besides, 1-methyl-1,2-
dihydronaphtho[2,1-b]furan was prepared from allyl 1-bromo-2-naphthyl ether by SRN1
photostimulated cyclization21 and 2-(1-hydroxy-1-methyl-ethyl)-1,2-dihydronaphtho[2,1-
b]furan-1-ol from corresponding β-hydroxy-α-tosyloxy ester.22 Regarding the synthesis 2-acyl-
1,2-dihydronaphtho[2,1-b]furans, to date only three reports can be found. Known approaches
involve the Friedel-Crafts alkylation/annulation cascade reaction between chalcone epoxides and
2-naphthols,23 the reaction of dimethylsulfonium ylides with quaternary salt on the base of 1-
dimethylaminomethyl-2-naphthol24 and the condensation of 2-naphthol with 3,4-dibromobutan-
2-one in the presence of potassium carbonate.18
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Cascade reactions have attracted considerable attention in organic synthesis as they can
produce target products from readily available starting materials in a single operation without
isolating the intermediates thus reducing reaction times, labor, cost.25 Compared to stepwise
reactions, cascade processes minimize waste since the amounts of solvents, reagents, adsorbents
and energy are decreased. As part of an overall synthetic program directed towards the
development of new cascade transformations utilising o-quinone methides (o-QMs)26 we have
focused attention on the synthesis of 1,2-dihydronaphtho[2,1-b]furans.
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Results and discussion
A retrosynthetic analysis of the 2-acyl-1,2-dihydronaphtho[2,1-b]furans shows that they
can be obtained starting from o-QMs and acyl carbenes as a result of the formal [4+1]-
cycloaddition (Scheme 3). As synthetic equivalents of acyl carbenes the pyridinium ylides 2 can
be used. Pyridinium ylides have a rich chemistry that can be used for rapid preparation of highly
functionalized compounds from relatively simple compounds.27
Scheme 3. Retrosynthetic approach to 1,2-dihydronaphtho[2,1-b]furans
The o-QM moiety is known to be a powerful synthon for preparation of various fused
pyran and furan derivatives.28 They are highly reactive, short-lived intermediates used in organic
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synthesis, acting as electrophilic enones towards nucleophiles. The high reactivities of o-QMs
are due mainly to the tendency of their quinoid system of bonds to convert to a more stable
aromatic system. There are many strategies, which have been established in order to generate o-
QMs in situ in the past years.29 In our work, o-QMs have been generated from different o-
hydroxybenzyl derivatives, basically, from 2-naphtholic Mannich bases 1 via base-induced
desamination. It is interesting to note that in solutions a number of Mannich bases of type 1
exhibited thermochromic properties due to their reversible dissociation into dimethylamine and
o-QMs. In organic solvents, solutions of 1, colorless at first, gradually became yellow as a result
of the establishment of an equilibrium. Heating of the solutions resulted in deepening of the
color due to shift of the equilibrium towards formation of o-QMs.
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Using 1-[(dimethylamino)methyl]-2-naphthol 1a and N-(4-bromophenacyl)pyridinium
bromide 2a (pKa 9.430) in equimolar amounts as a model system, a comprehensive review of
reaction conditions for the synthesis of 1,2-dihydronaphtho[2,1-b]furan 3a is presented in Table
1. The reaction was completed within 5 h in the absence of base at reflux temperature in
acetonitrile (entry 1). However, under the same reaction conditions, by employing 0.1 eq. of
DBU (pKa 12), the reaction afforded expected product in up to 82% yield within 3 h of reaction
time (entry 2). Increasing of the catalyst to 0.5 and 1 eq. results in slight decrease of the reaction
yields. When this reaction was repeated at room temperature, no desired product was formed.
We also used different bases for this reaction. Replacement of DBU with 1,1,3,3-
tetramethylguanidine (pKa 13.6) or triethylamine (pKa 10.75) also led to similar reaction yields
(entries 3,4) indicating a slight effect on the nature of the base on this process. Further, the effect
of different solvents, such as EtOH, 1,4-dioxane, dichloroethane, and DMF was also investigated
in the presence of 1 eq. of DBU. EtOH and DMF also gave good results (entries 5,6,8). 1,4-
Dioxane and dichloroethane gave less satisfactory results because of the poor solubility of the
pyridinium salt 2a (entries 7,9). In the case of EtOH and CH3CN the product 3a precipitated
from the reaction mixture and was isolated by filtration. Conventional chromatographic
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purification was not required. The reaction was repeated on several different scales (up to 20
mmol), all with comparable yields.
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Table 1. Optimization of reaction conditions for the synthesis of 3a
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entry solvent / t ºC
base / quantity (eq.) time (h) yielda (%)
1
2
CH3CN / 81 ºC
CH3CN / 81 ºC
–
5
82
82
80
79
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85
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75
83
73
DBU / 0.1 eq.
DBU / 0.5 eq.
DBU / 1 eq.
TMG / 1 eq.
TEA / 1 eq.
–
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CH3CN / 81 ºC
CH3CN / 81 ºC
EtOH / 78 ºC
EtOH / 78 ºC
3
3
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DBU / 1 eq.
3
dioxane / 101 ºC DBU / 1 eq.
10
3
DMF / 80 ºC
DBU / 1 eq.
DBU / 1 eq.
C2H4Cl2 / 84 ºC
10
a Isolated yield.
Under the optimized reaction conditions, the scope and generality of this new one-pot
process were then explored. As shown in Table 2, the cascade reaction proceed without any
problems for a wide range of substrates bearing electron-donating or electron-withdrawing
substituents on the aryl ring, providing 1,2-dihydronaphtho[2,1-b]furans in good yields and
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excellent diastereoselectivity. In particular, the sterically hindered adamantyl-substituted 1,2-
dihydronaphtho[2,1-b]furans were obtained in good yields, indicating that steric hindrance had
no obvious influence on the efficiency of our method. Formation of cis-isomers was not noticed
according to 1H NMR data. 1-Unsubstituted 1,2-dihydronaphtho[2,1-b]furans can be prepared in
good yields without any base (entries 1–6, Table 2). Moreover, in the case of 4-
nitrophenacylpyridinium bromide 2b the corresponding 1,2-dihydronaphtho[2,1-b]furan 3b can
not be isolated in the presence of 1 eq. of DBU or TMG. The deep colored unidentifiable
products were noticed. In the absence of any base, dimethylamine (pKa 10.7) released during the
thermal decomposition of Mannich base acts as a base deprotonating the pyridinium salt.
However, in the case of the pyridinium salts with poor solubility the addition of a base not only
decreases the reaction time but also increases the product yields.
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Table 2. Synthesis of 1,2-dihydronaphtho[2,1-b]furans
entry R1
(Mannich base)
R2
product solvent
base
time yielda
(pyridinium salt)
(h)
(%)
1
H (1a)
4-Br-C6H4 (2a)
3a
CH3CN
–
3
3
3
3
8
3
82
74b
34
79
81
72
CH3CN DBU
2
3
4
5
H (1a)
H (1a)
H (1a)
H (1a)
4-NO2-C6H4 (2b) 3b
4-F-C6H4 (2c) 3c
4-CH3-C6H4 (2d) 3d
1-naphthyl (2e) 3e
CH3CN
CH3CN
CH3CN
CH3CN
–
–
–
–
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H (1b)
1-Ad (2f)
Ph (2g)
3f
EtOH
CH3CN TMG
EtOH TMG
CH3CN DBU
CH3CN
CH3CN DBU
CH3CN
TMG
5
5
5
3
10
4
4
4
5
4
4
4
4
3
3
4
8
5
5
5
12
5
8
77
71
54
89
67
62
90
80
75
84
72
63
88
72
78
84
71
84
80
61
64
81
69c
Ph (1b)
3g
8
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Ph (1b)
Ph (1b)
4-Br-C6H4 (2a)
1-naphthyl (2e)
3h
3i
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–
–
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Ph (1b)
(CH3)3C (2h)
cyclopropyl (2i)
1-Ad (2f)
3j
CH3CN TMG
CH3CN TMG
Ph (1b)
3k
3l
Ph (1b)
EtOH
CH3CN DBU
EtOH TMG
TMG
4-CH3O-C6H4 (1c)
4-Cl-C6H4 (2j)
3m
3n
3o
3p
3q
3r
4-CH3O-C6H4 (1c) 1-Ad (2f)
4-Cl-C6H4 (2j)
4-Cl-C6H4 (1d)
4-Cl-C6H4 (1d)
4-Cl-C6H4 (1d)
4-Cl-C6H4 (1d)
4-Cl-C6H4 (1d)
2-thienyl (1e)
2-thienyl (1e)
3-NO2-C6H4 (1f)
2-F-C6H4 (1g)
4-pyridyl (1h)
H (1a)
CH3CN DBU
CH3CN DBU
(CH3)3C (2h)
1-Ad (2f)
EtOH
DBU
4-F-C6H4 (2c)
CH3CN
CH3CN
–
–
4-CH3-C6H4 (2d) 3s
(CH3)3C (2h)
1-Ad (2f)
1-Ad (2f)
1-Ad (2f)
1-Ad (2f)
NH2 (2k)
3t
CH3CN TMG
3u
3v
3w
3x
3y
EtOH
EtOH
EtOH
EtOH
TMG
TMG
TMG
TMG
CH3CN TMG
a Isolated yield.
b Methiodide of 1a is used instead of Mannich base 1a
c 1-(2-Amino-2-oxoethyl)pyridinium chloride 2k was used
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It is known that in the N-phenacylpyridinium salts the reactivity of N-methylene group is
comparable with that of the methylene group of β-keto esters.31 In particular, the action of base
rapidly generates ylides and further action results in cleavage to an acid and an alkylpyridinium
salt (acid splitting) by a mechanism similar to that involved in the fission of β-dicarbonyl
compounds. Protic solvents promote acid splitting of reactive ylides (Scheme 4).32 For this
reason in the case of reactivity ylides acetonitrile should be used as a solvent instead of ethanol.
Scheme 4. Base-catalysed decomposition of N-phenacylpyridinium salts
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Many carbonyl-stabilised pyridinium ylides are stable under normal conditions and thus
can be both used in the individual state and generated from the appropriate pyridinium salts
under the action of bases. When the pyridinium ylides 4a and 4b, instead of pyridinium salts 2a
and 2f, were directly used without base, products 3h and 3l were also obtained in 77 and 79%
yields, respectively (Scheme 5).
Scheme 5. Synthesis of 3h and 3l from pyridinium acylmethylides
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Pyridinium salts bearing other functional groups (CO2Et, CN, CONH2 instead of RCO)
were also investigated under the reaction conditions. However, the reaction was very sluggish
and a complicated mixture of products, including the expected dihydronaphthofuran, was
obtained which was difficult to separate. Nevertheless, we have succeeded in preparing the
amide 3y (entry 25, Table 2) in 69% yield. The highly stabilised ylide 4c, phosphonic 5 and
ammonium 6 salts in the presence of DBU also failed to effect addition even after 12 h at reflux
temperature (Scheme 6).
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Scheme 6. Studying the possibility of interaction of Mannich base 1b with other ylides
It is interesting to note that 2-bromopyridinium salt 7 in the presence of TEA or DBU did
not react with 1,2-naphthoquinone-1-methide generated from Mannich base 1b but underwent
cyclization in oxazolo[3,2-a]pyridinium salt 8 (Scheme 7).
Scheme 7. Synthesis of oxazolo[3,2-a]pyridinium salt 8
Instead of carbonyl-stabilised pyridinium ylides arylmethylides can also be used in this
cascade reaction (Scheme 8). The pyridinium salts 9a,b gave lower yields than 1 in the few
examples investigated, but this result may well be due to failure to find the best experimental and
isolation procedures. In this way 2-aryl-1,2-dihydronaphtho[2,1-b]furans 10a-c were synthesized
from Mannich bases 1a,b. This reaction was then extended to heterocyclic precursors of o-QMs.
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From Mannich bases 1i,j heterocyclic systems 7,8-dihydrofurano[3,2-e][1]benzofuran 10d and
1,6-dihydro-2H-furo[3,2-e]indole 10e were prepared in moderate yields.
Scheme 8.
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The 1,2-dihydronaphtho[2,1-b]furans can be easily aromatized to the corresponding
naphtho[2,1-b]furans by oxidation with DDQ in refluxing toluene. For example, the heating of
1,2-dihydronaphtho[2,1-b]furans 3i,r,s,v with 1.1 eq. of DDQ gives naphtho[2,1-b]furans 11a-d
in 65–81% yields (Scheme 9). In some cases, the reaction of 2-naphthol Mannich bases with N-
phenacylpyridinium bromides gave the aromatization products as an impurity with the 1,2-
dihydronaphtho[2,1-b]furans. The high tendency towards oxidation is related to the extension of
the conjugation involving the benzene ring.
Scheme 9. Aromatization of 1,2-dihydronaphtho[2,1-b]furans
Structural assignment was based on elemental analyses and absence of an OH-band in the
1
IR- and of the phenolic proton signal in the H NMR spectra of the dihydroarenofuran
derivatives. The IR spectra of compounds 3a-x show the presence of a carbonyl group (υmax
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1670–1717 cm-1). The structure of 1,2-disubstituted dihydronaphtho[2,1-b]furans are clearly
assigned as trans by the analysis of the vicinal coupling constant of the two methine protons.
These protons at 1- and 2-positions of dihydronaphtho[2,1-b]furan ring display two doublets at
5.13–6.02 ppm with the vicinal coupling constant J=4.9–5.6 Hz. It has been established that in
cis-1,2-dihydronaphtho[2,1-b]furans the vicinal coupling constant of the two methine protons is
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9.5–10.0 Hz, while in trans-isomers vicinal coupling constant is 5.3–5.7 Hz.23 In the H NMR
spectra of 1-unsubstituted 1,2-dihydronaphtho[2,1-b]furans the H-2 proton signal of the
dihydrofuran ring is seen in the 5.41–6.53 ppm region as a doublet of doublets due to a vicinal
splitting by the methylene group protons. The latter also appear as doublets of doublets at 3.13–
3.90 ppm. In the 13C NMR spectra of the 1,2-disubstituted dihydronaphtho[2,1-b]furans the
carbonyl carbon signals are found in the region of 193.6–211.4 ppm, and the signals of carbon
atoms in the 1- and 2-positions of the dihydrofuran fragment appear at 42.9–51.3 and 88.6–94.4
ppm, respectively.
A mechanistic rationale portraying the probable sequence of events is given in Scheme 10.
The first step is the formation of the two reaction intermediates. o-QM A is formed by the
thermal decomposition of the Mannich base and deprotonation of the pyridinium salt gives ylide
B. The second step is a Michael-type addition of a pyridinium ylide to the electron-deficient o-
QM to afford the zwitterion intermediate C which might react further according to three different
paths to give three different products. In the first path, the three-membered ring C-cyclization
could give the cyclopropane derivative,27b which is not observed here. The 1,3-dipolar character
of the ylides, normally observed with a wide variety of electron-poor olefins,33 is in this case not
expressed (path 2). Probably, cyclopropanation and 1,3-dipolar cycloaddition are highly
disfavoured energetically due to the necessity for loss of aromaticity. In the third path, phenolate
form C undergoes a five-membered ring O-cyclization to produce the final product 1,2-
dihydronaphtho[2,1-b]furan (5-exo-tet ring closure). The driving force of the reaction is the
resulting rearomatization of the naphthalene fragment.
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Scheme 10. Proposed mechanism for the formation of 1,2-dihydronaphtho[2,1-
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The last step is a typical intramolecular SN2 substitution reaction. The stereochemistry of
the SN2 reaction requires phenolate attack from the back side of the electrophilic carbon atom
bearing the leaving pyridyl group, which subsequently assumes two steric larger 2-acyl and 1-
aryl groups in an opposite position for the sake of stereohindrance in the transition state. As
shown in Newman projections C1 and C2, intermediate C1 is the favored one, followed by SN
substitution to give the thermodynamically more stable 1,2-disubstituted dihydronaphtho[2,1-
b]furan with trans-configuration (Scheme 11).
Scheme 11. Newman projections of intermediate C
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Thus, the combination of ylides and electron-deficient o-QMs with the Michael-initiated
ring closure strategy is very useful methodology for preparing highly substituted
dihydronaphthofurans. As Mannich bases 1 can easily be synthesized by the Mannich reaction
from naphthols and pyridinium salts 2 are readily accessible from pyridines and α-bromoketones,
the reaction described herein represents a convenient synthesis of dihydronaphthofurans.
Having successfully applied the ‘Mannich route’ to the synthesis based on the
naphthoquinone methides, it was of interest to see if we might be successful in applying the
synthesis to benzoquinone methides. Attempts to extend this reaction to the Mannich bases of
phenols, however, gave less satisfactory results to furnish the expected products. The reason may
be due to the relatively greater thermal stability of these phenolic Mannich bases compared to
that of the 2-naphthol series and consequent difficulty in generating the o-QMs under the
conditions mentioned in this paper.
Mannich base 12 did not react with N-(1-adamantylcarbonyl)methylpyridinium bromide 2f
in ethanol under reflux. At a higher temperature (boiling in DMF), however, 2,3-
dihydrobenzofuran 13a was obtained in 58% yield (Scheme 12).
Scheme 12.
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In the reaction of pyridinium salt 2f with 2,4-dihydroxy-3-morpholin-4-yl-
methylacetophenone 14 only 2,3-dihydrobenzo[b]furan 13b was isolated (Scheme 13). The
structure of the product was determined on the basis of a sharp, low field chemical shift (12.70
ppm) of the unreacted phenolic proton due to intramolecular hydrogen bond. Thus, only one o-
QM D is generated from Mannich base 14.
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Scheme 13. Regioselective synthesis of 2,3-dihydrobenzo[b]furan 13b
Attempts to extend this reaction to the 2-dimethylaminomethyl-4-nitrophenol, however,
failed may be due to the relatively greater thermal stability of this phenolic Mannich base.
Nevertheless, in the reaction with ammoniophenolate 1534 which is more reactivity precursor of
o-QM 2,3-dihydrobenzofurans 13c and 13d were prepared in 46% and 52% yields, respectively
(Scheme 14).
Scheme 14.
We have also studied reaction of quaternary ammonium salt 16a with pyridinium salt 2f in
the presence of DBU. Two products were isolated. One of these appears to be a 2,3-
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dihydrobenzofuran, assigned the structure 13e. The other product appears to be a pyridinium salt,
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assigned the structure 17a (Scheme 15). The NMR H spectrum of 17a shows two two-proton
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triplets at 3.05 and 4.82 ppm (J=6.5 Hz), assigned to methylene protons and one two-proton
doublet (J=6.0 Hz) at low field (δ=8.81 ppm) corresponding to the α hydrogen atoms of the
pyridine ring which can be explained by a positive charge on an adjacent nitrogen atom. The salt
17a was not converted to dihydrobenzofuran 13e during chromatography on silica gel, a possible
acidic catalyst. The possible formation of dihydrobenzofuran 13e from the thermal
rearrangement of pyridinium salt 17a was also investigated by refluxing the pure salt 17a in
CH3CN in the presence of DBU. No dihydrobenzofuran 13e was observed. It is likely that the
salt 17a is formed as a result of migration of an acyl group to the phenolic hydroxy group in the
intermediate E. From the reaction of the quaternary ammonium salt 16a with
phenacylpyridinium bromides 2a and 2d pyridinium salts 17b and 17c were isolated as major
products.
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Scheme 15.
In the case of other quaternary ammonium salts 16b-g in the reaction with pyridinium
acylmethylides only 2,3-dihydrobenzofurans 13f-k were isolated with moderate to good yields
(Scheme 16, Table 3).
Scheme 16.
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Table 3. Synthesis of 2,3-dihydrobenzofurans 13f-k
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entry R1
R2
R3
R4
product yielda (%)
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CHO
H
OCH3 4-BrC6H4
4-BrC6H4
OCH3 4-BrC6H4
13f
13g
13h
13i
13j
13k
71
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81
NO2
H
H
CO2CH3
H
H
CO2CH3
H
H
H
H
CH3
CH3
1-Ad
CH3CO
CH3
CH3
a Isolated yield.
Thus, in the reaction with pyridinium salts the better results obtained with the Mannich
bases in the 2-naphthol series probably reflect the ease of formation of a o-QM adjacent to an
aromatic ring as compared with the benzene series in which formation of the o-QM implies the
disappearance of the only aromatic ring.
Instead of Mannich bases other o-QM precursors can be used in this reaction including
salicylic alcohols and 2-acetoxybenzyl acetates. 1-Adamantyl-2,3-dihydrobenzofuran-2-
ylmethanone 13l was prepared from salicylic alcohol 18 and pyridinium salt 2f in 37% yield.
The reaction was performed in refluxing DMF, at sufficiently high temperature to ensure the
thermal decomposition of the o-QM precursor. When 2-acetoxybenzyl acetate 19a and
pyridinium salt 2f were heated in ethanolic solution in the presence of DBU, the 2,3-
dihydrobenzofuran 13l was obtained in 23% yield only. Besides, undesired 2-
(ethoxymethyl)phenol 20 and ethyl adamantane-1-carboxylate 21 were identified in reaction
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mixture. The first product is formed by 1,4-addition of ethanol to o-QM, the second as a result of
acid splitting of pyridinium ylide. When acetonitrile was used in this reaction, the desired
product 13l was isolated in 73% yield. The diacetates 19b,c also react with pyridinium salt 2f
under these conditions to afford the corresponding 2,3-dihydrobenzofurans 13m and 13n in 73
and 82% yields, respectively (Scheme 17).
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Scheme 17. Synthesis of 2,3-dihydrobenzofurans 13l-n from salicylic alcohol and 2-
acethoxybenzyl acetates
The proposed mechanism for the generation of o-QMs from 2-acethoxybenzyl acetates in
the presence of DBU is shown in Scheme 18.
Scheme 18. Proposed mechanism for the generation of o-QMs from 2-acetoxybenzyl
acetates
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We have also applied our method to the synthesis of methyl (±)-7-methoxyanodendroate
which was first isolated in 2008 from Zanthoxylum wutaiense.35 This compound was shown to
possess antitubercular activity against Mycobacterium tuberculosis H37Rv with a minimum
inhibitory concentration of 35 µg/mL. The first synthesis of methyl (+)-7-methoxyanodendroate
was achieved in 2011 utilising a Claisen rearrangement, a Grubbs cross-methathesis, and a Shi
epoxidation–cyclisation sequence.36 We have prepared dihydrobenzofuran 13p in two steps from
quaternary ammonium salt 16d and pyridinium salt 2l with an overall yield 54% (Scheme 19).
Scheme 19. Synthesis of methyl (±)-7-methoxyanodendroate
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CONCLUSION
A new method for the synthesis of 1,2-dihydronaphtho[2,1-b]furans from Mannich bases
and pyridinium salts has been developed. The reaction proceeds via Michael-type addition
between o-QMs and pyridinium ylides formed in situ followed by intramolecular nucleophilic
substitution. This protocol can provide a novel and efficient methodology for the preparation of
1
2-acyl-1,2-dihydronaphtho[2,1-b]furans in a diastereoselective fashion. H NMR spectroscopy
indicates that the products are formed exclusively as the trans isomers. The reaction is applicable
to a range of Mannich bases and pyridinium salts with a variety of versatile functional groups.
Some of the prepared products may be useful intermediates for the obtaining of highly
functionalised 1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans. The advantages of
this approach include the use of readily available starting materials, simple experimental steps
and product isolation, and chromatographic purification is not usually required.
EXPERIMENTAL SECTION
General information
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FTIR-spectra were taken in KBr pellets. 1H, 13C, and DEPT NMR spectra were recorded using a
400 MHz NMR spectrometer in CD3CN, CDCl3 or DMSO-d6 solutions with TMS as internal
standard. Chemical shifts and coupling constants were recorded in units of ppm and Hz,
respectively. The melting points were uncorrected. Elemental analysis was carried out on an
automatic CHNS-analyzer. Mass spectra were recorded with 70 eV electron ionization energy.
Thin-layer chromatography was carried out on aluminium-backed silica gel plates with
visualisation of components by UV light (254 nm) or exposure to I2. Known Mannich bases and
their quaternary ammonium salts were prepared according to the literature procedures.20,37–39
Pyridinium 4-bromobenzoylmethylide 4a was obtained by deprotonation of N-(4-
bromophenacyl)pyridinium bromide 2a under the action of potassium carbonate.40 Phosphonic 5
and ammonium 6 salts were prepared from 1-(1-adamantyl)-2-bromoethanone and
triphenylphosphine or DABCO in acetonitrile.41
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N-(1-Adamantylcarbonyl)methylpyridinium bromide (2f). Pyridine (10 mL, 0.124 mol)
was added to 1-(1-adamantyl)-2-bromoethanone (25 g, 0.097 mol) in diethyl ether (150 mL).
After stirring overnight at room temperature, a precipitate which formed was filtered off and
recrystallized from acetonitrile. Yield 24.5 g (75%). Colorless crystals; mp 226–227 ºC
(decomp.); IR νmax (KBr): 3500–3300 (H2O), 3028 (CH Ar), 2909, 2851 (CH Ad), 1713 (C=O),
1636, 1489, 1366, 1335, 1312, 1196, 1165, 1011, 745, 687 cm-1; 1H NMR (400 MHz, DMSO-d6)
δ: 1.65–1.73 (m, 6H), 1.88–1.91 (m, 6H), 2.02 (br s, 3H), 6.03 (s, 2H), 8.19 (dd, 2H, J=7.8, 6.6
13
Hz), 8.67 (tt, 1H, J=8.0, 1.4 Hz), 8.87 (d, 2H, J=5.5 Hz) ppm; C NMR (100 MHz, DMSO-d6)
δ: 27.7 (3CH), 36.4 (3CH2), 37.6 (3CH2), 45.6 (C), 65.5 (CH2), 128.3 (2CH), 146.6 (2CH), 146.7
(CH), 206.5 (C) ppm. Anal. Calcd (%) for C17H22BrNO·0.35H2O: C, 59.60; H, 6.68; N, 4.09.
Found (%): C, 59.42; H, 6.66; N, 4.11.
Pyridinium (1-adamantylcarbonyl)methylide (4b). DBU (4.5 mL, 0.03 mol) was added
with stirring at room temperature to a solution of pyridinium salt 2f (10 g, 0.03 mol) in water
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(100 mL). The mixture was strirred for 5 min, and then extracted with dichloromethane. The
extract was dried (Na2SO4) and evaporated as rapidly as possible under reduced pressure at room
temperature. The residue was dissolved in CH2Cl2 and precipitated by hexane. N-Pyridinium
ylide began to darken after a few hours therefore was stored in refrigerator. Yield 6.91 g (91%).
Bright yellow powder; mp 155–157 ºC (decomp.); IR νmax (KBr): 3063 (CH Ar), 2905, 2849
(CH Ad), 1551, 1524, 1485, 1466, 1423, 1342, 1288, 1177, 1150, 1007, 976, 914, 864, 760, 671
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cm-1; H NMR (400 MHz, CDCl3) δ: 1.68 (br s, 6H), 1.84 (br s, 6H), 1.98 (br s, 3H, CH Ad),
6.01 (br s, 1H), 7.23–7.26 (m, 3H), 9.42 (d, J=6.0 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ:
28.8 (3CH), 37.2 (3CH2), 40.2 (3CH2), 42.1 (C), 96.6 (CH), 125.8 (2CH), 128.5 (CH), 132.5
(2CH), 184.7 (C) ppm. Anal. Calcd (%) for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C (%),
80.12; H, 8.26; N, 5.50.
[2-Hydroxy-3-methoxy-5-(methoxycarbonyl)benzyl]trimethylammonium iodide (16d).
Dimethylamine (3 mL of 33% aqueous solution, 0.02 mol) and formaldehyde (1.5 mL of 37%
aqueous solution, 0.02 mol) were added to a solution of methyl 4-hydroxy-3-methoxybenzoate
(3.28 g, 0.018 mol) in methanol (20 mL). The reaction mixture was stirred at room temperature
for 20 h. The solvent was evaporated in vacuo, the residue was dissolved in acetonitrile (50 mL)
and treated with CH3I (5 mL). The resulting solution was stirred at room temperature for 12 h,
the solvent was evaporated in vacuo, the residue was recrystallized from acetonitrile. Yield 5.07
g (74%). Colorless solid; mp >210 ºC (decomp.); IR νmax (KBr): 3275, 3001, 2940, 1705 (C=O),
1605, 1462, 1427, 1385, 1312, 1234, 1180, 1111, 1088, 953, 883, 760 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ: 3.03 (9H, s), 3.79 (3H, s), 3.87 (3H, s), 4.52 (2H, s), 7.52 (1H, d, J=1.8 Hz), 7.68
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(1H, d, J=1.8 Hz), 10.52 (1H, br s) ppm; C NMR (100 MHz, DMSO-d6) δ: 52.6 (CH3), 52.7
(3CH3), 56.7 (CH3), 63.1 (CH2), 113.9 (CH), 115.6 (C), 120.8 (C), 128.6 (CH), 148.3 (C), 152.1
(C), 166.2 (C) ppm. Anal. Calcd (%) for C13H20INO4: C, 40.96; H, 5.29; N, 3.67. Found: C (%),
41.03; H, 5.31; N, 3.63.
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General Experimental Procedure for the Synthesis of 1,2-Dihydronaphtho[2,1-
b]furans
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A mixture of 2-naphthol Mannich base (3 mmol), pyridinium salt (3 mmol), base (3 mmol,
TMG or DBU, if required) in CH3CN or EtOH (20 mL) under an Ar atmosphere was heated at
reflux temperature for 3–12 h. After the indicated time period (see Table 2), the solvent was
removed by evaporation under reduced pressure. The crude product was purified by
recrystallization. The reaction conditions and yields of 3a-y were summarized in Table 2.
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Characterization Data of 1,2-Dihydronaphtho[2,1-b]furans
(4-Bromophenyl)(1,2-dihydronaphtho[2,1-b]furan-2-yl)methanone (3a): yield 82%;
0.87 g; colorless crystals; mp 173–175 ºC (from CH3CN); IR νmax (KBr): 3059 (CH Ar), 2970,
2940, 1686 (C=O), 1628, 1582, 1516, 1447, 1396, 1366, 1312, 1219, 1161, 1069, 1049, 988,
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964, 895, 845, 802, 748 cm-1; H NMR (400 MHz, CDCl3) δ: 3.79 (dd, 1H, J=15.6, 11.0 Hz),
3.89 (dd, 1H, J=15.6, 7.3 Hz), 6.03 (dd, 1H, J=11.0, 7.3 Hz), 7.16 (d, 1H, J=8.7 Hz), 3.33 (td,
1H, J=8.2, 1.4 Hz), 7.48 (td, 1H, J=8.2, 0.9 Hz), 7.59 (d, 1H, J=8.2 Hz), 7.66 (d, 2H, J=8.7 Hz),
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7.71 (d, 1H, J=8.7 Hz), 7.81 (d, 1H, J=8.2 Hz), 7.95 (d, 2H, J=8.7 Hz) ppm; C NMR (100
MHz, CDCl3) δ: 31.4 (CH2), 83.6 (CH), 112.1 (CH), 117.1 (C), 122.8 (CH), 123.5 (CH), 127.1
(CH), 128.9 (CH), 129.1 (C), 129.6 (CH), 129.7 (C), 130.6 (C), 130.8 (2CH), 132.2 (2CH),
133.4 (C), 156.5 (C), 194.8 (C) ppm. MS (EI) m/z (%) 353 (M+, 5), 335 (6), 197 (8), 183
(BrC6H4CO, 22), 169 (62), 168 (43), 155 (BrC6H4, 24), 141 (100), 139 (63), 115 (58). Anal.
Calcd (%) for C19H13BrO2: C, 64.61; H, 3.71. Found (%): C, 64.75; H, 3.68.
1,2-Dihydronaphtho[2,1-b]furan-2-yl(4-nitrophenyl)methanone (3b): yield 34%; 0.27
g; yellow crystals; mp 194–196 ºC (decomp., from EtOH/DMF); IR νmax (KBr): 3051 (CH Ar),
2932, 1697 (C=O), 1628, 1601, 1520 (NO2), 1466, 1350 (NO2), 1323, 1265, 1246, 1219, 1161,
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968, 903, 856, 810, 772, 714 cm-1; 1H NMR (400 MHz, DMSO-d6) δ: 3.67 (dd, 1H, J=15.9, 6.5
Hz), 3.88 (dd, 1H, J=15.9, 11.1 Hz), 6.53 (dd, 1H, J=11.1, 6.5 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.31
and 7.46 (t, 2H, J=7.4 Hz), 7.63 (d, 1H, J=8.2 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.85 (d, 1H, J=8.2
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Hz), 8.28 (d, 2H, J=8.7 Hz), 8.38 (d, 2H, J=8.7 Hz) ppm; C NMR (100 MHz, DMSO-d6) δ:
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31.3 (CH2), 83.4 (CH), 112.3 (CH), 117.7 (C), 123.4 (CH), 123.8 (CH), 124.5 (2CH), 127.5
(CH), 129.1 (CH), 129.6 (C), 129.8 (CH), 130.6 (C), 130.9 (2CH), 139.5 (C), 150.8 (C), 156.7
(C), 195.2 (C) ppm. Anal. Calcd (%) for C19H13NO4: C, 71.47; H, 4.10; N, 4.39. Found (%): C,
71.58; H, 4.13; N, 4.37.
1,2-Dihydronaphtho[2,1-b]furan-2-yl(4-fluorophenyl)methanone (3c): yield 79%; 0.69
g; colorless crystals; mp 161–162 ºC (from CH3CN); IR νmax (KBr): 3074 (CH Ar), 2913, 1694
(C=O), 1597, 1504, 1466, 1412, 1366, 1227, 1157, 1053, 991, 964, 914, 849, 806, 764, 741 cm-1;
1H NMR (400 MHz, CDCl3) δ: 3.79 (dd, 1H, J=15.6, 10.8 Hz), 3.90 (dd, 1H, J=15.6, 7.4 Hz),
6.04 (dd, 1H, J=10.8, 7.4 Hz), 7.16–7.22 (m, 3H), 7.34 (ddd, 1H, J=8.0, 6.9, 1.2 Hz), 7.48 (ddd,
1H, J=8.2, 6.9, 1.2 Hz), 7.60 (d, 1H, J=8.2 Hz), 7.71 (d, 1H, J=9.0 Hz), 7.81 (d, 1H, J=8.2 Hz),
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8.10–8.15 (m, 2H) ppm; C NMR (100 MHz, CDCl3) δ: 31.5 (CH2), 83.6 (CH), 112.1 (CH),
116.1 (d, 2CH, JCF=21.9 Hz), 117.2 (C), 122.8 (CH), 123.5 (CH), 127.0 (CH), 128.8 (CH), 129.6
(CH), 129.7 (C), 130.6 (C), 131.0 (d, C, JCF=2.9 Hz), 132.1 (d, 2CH, JCF=9.5 Hz), 156.5 (C),
166.2 (d, C, JCF=255.5 Hz), 194.1 (C) ppm. Anal. Calcd (%) for C19H13FO2: C, 78.07; H, 4.48.
Found (%): C, 77.89; H, 4.51.
1,2-Dihydronaphtho[2,1-b]furan-2-yl(4-methylphenyl)methanone (3d): yield 81%;
0.70 g; colorless crystals; mp 143–144 ºC (from EtOH); IR νmax (KBr): 3028, 2922, 1699 (C=O),
1628, 1603, 1574, 1520, 1464, 1445, 1408, 1371, 1260, 1244, 1231, 1209, 1180, 1152, 1053,
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995, 970, 908, 827, 818, 760, 729 cm-1; H NMR (400 MHz, CDCl3) δ: 2.44 (s, 3H), 3.79 (dd,
1H, J=15.6, 10.3 Hz), 3.84 (dd, 1H, J=15.6, 8.0 Hz), 6.10 (dd, 1H, J=10.3, 8.0 Hz), 7.20 (d, 1H,
J=8.7 Hz), 7.31–7.35 (m, 3H), 7.47 (td, 1H, J=7.0, 1.2 Hz), 7.58 (d, 1H, J=8.0 Hz), 7.71 (d, 1H,
J=8.7 Hz), 7.81 (d, 1H, J=8.2 Hz), 7.98 (d, 2H, J=8.2 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ:
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21.9 (CH3), 32.0 (CH2), 83.5 (CH), 112.2 (CH), 117.2 (C), 122.8 (CH), 123.3 (CH), 127.0 (CH),
128.8 (CH), 129.4 (2CH), 129.5 (CH), 129.6 (2CH, C), 130.7 (C), 132.0 (C), 144.8 (C), 156.8
(C), 195.1 (C) ppm. Anal. Calcd (%) for C20H16O2: C, 83.31; H, 5.59. Found (%): C, 83.42; H,
5.54.
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1,2-Dihydronaphtho[2,1-b]furan-2-yl(1-naphthyl)methanone (3e): yield 72%; 0.70 g;
Colorless crystals; mp 120–122 ºC (from DMF/MeOH); IR νmax (KBr): 3048 (CH Ar), 2920,
1682 (C=O), 1628, 1570, 1508, 1462, 1439, 1362, 1261, 1234, 1177, 1161, 1096, 964, 899, 818,
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775, 756 cm-1; H NMR (400 MHz, CDCl3) δ: 3.78 (dd, 1H, J=15.6, 10.3 Hz), 3.84 (dd, 1H,
J=15.6, 7.8 Hz), 6.20 (dd, 1H, J=10.3, 7.8 Hz), 7.18 (d, 1H, J=8.7 Hz), 7.33 (t, 1H, J=7.3 Hz),
7.46 (t, 1H, J=7.8 Hz), 7.52–7.59 (m, 4H), 7.71 (d, 1H, J=8.7 Hz), 7.82 (d, 1H, J=8.2 Hz), 7.89
(d, 1H, J=8.7 Hz), 8.00 (d, 1H, J=7.1 Hz), 8.05 (d, 1H, J=8.0 Hz), 8.57 (d, 1H, J=7.8 Hz) ppm;
13C NMR (100 MHz, CDCl3) δ: 32.2 (CH2), 84.6 (CH), 112.2 (CH), 117.0 (C), 122.8 (CH),
123.4 (CH), 124.4 (CH), 125.7 (CH), 126.8 (CH), 127.0 (CH), 128.4 (CH), 128.7 (2CH), 128.9
(CH), 129.6 (CH), 129.7 (C), 130.6 (C), 131.0 (C), 132.9 (C), 133.5 (CH), 134.1 (C), 156.9 (C),
199.7 (C) ppm. Anal. Calcd (%) for C23H16O2: C, 85.16; H, 4.97. Found (%): C, 85.26; H, 4.95.
1-Adamantyl-1,2-dihydronaphtho[2,1-b]furan-2-ylmethanone (3f): yield 77%; 0.77 g;
Colorless crystals; mp 116–117 ºC (from EtOH); IR νmax (KBr): 2901, 2847 (CH Ad), 1701
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(C=O), 1628, 1582, 1520, 1443, 1381, 1312, 1242, 1049, 976, 810, 752 cm-1; H NMR (400
MHz, CDCl3) δ: 1.74–1.82 (m, 6H), 1.93–2.03 (m, 6H), 2.10 (br s, 3H), 3.52 (dd, 1H, J=15.3,
8.0 Hz), 3.63 (dd, 1H, J=15.3, 10.5 Hz), 5.65 (dd, 1H, J=10.5, 8.0 Hz), 7.17 (d, 1H, J=8.7 Hz),
7.32 (dd, 1H, J=8.2, 7.0 Hz), 7.47 (dd, 1H, J=8.2, 7.0 Hz), 7.55 (d, 1H, J=8.2 Hz), 7.69 (d, 1H,
J=8.7 Hz), 7.80 (d, 1H, J=8.2 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ: 27.9 (3CH), 32.4 (CH2),
36.6 (3CH2), 38.0 (3CH2), 46.0 (C), 81.8 (CH), 112.0 (CH), 117.0 (C), 122.7 (CH), 123.2 (CH),
126.9 (CH), 128.8 (CH), 129.5 (CH), 129.6 (C), 130.6 (CH), 156.9 (C), 210.7 (C) ppm. MS (EI)
m/z (%): 332 (M+, 8), 197 (M+ – Ad, 92), 196 (M+ – Ad – H, 65), 169 (M+ – AdCO, 35), 168
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(M+ – AdCO – H, 56), 141 (51), 135 (Ad+, 100). Anal. Calcd (%) for C23H24O2: C, 83.10; H,
7.28. Found (%): C, 83.22; H, 7.31.
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trans-Phenyl-1-phenyl-1,2-dihydronaphtho[2,1-b]furan-2-ylmethanone (3g): yield
71%; 0.75 g; colorless crystals; mp 137–138 ºC (from EtOH); IR νmax (KBr): 3059, 3028, 2920,
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1690 (C=O), 1632, 1597, 1578, 1520, 1462, 1447, 1377, 1234, 984, 810, 744, 702 cm-1; H
NMR (400 MHz, CDCl3) δ: 5.32 and 5.95 (d, 2H, J=5.1 Hz), 7.23–7.33 (m, 9H), 7.49 (dd, 2H,
J=7.8, 7.3 Hz), 7.63 (t, 1H, J=7.3 Hz), 7.80 (d, 2H, J=8.7 Hz), 7.99 (d, 2H, J=8.3 Hz) ppm; 13C
NMR (100 MHz, CDCl3) δ: 50.8 (CH), 91.7 (CH), 112.2 (CH), 120.0 (C), 122.9 (CH), 123.3
(CH), 127.0 (CH), 127.6 (CH), 128.1 (2CH), 128.9 (2CH), 128.9 (CH), 129.2 (2CH), 129.5
(2CH), 130.2 (C), 130.4 (C), 130.6 (CH), 134.0 (CH), 134.4 (C), 142.4 (C), 157.3 (C), 194.7 (C)
ppm. MS (EI) m/z (%): 350 (M+, 30), 333 (M+ – OH, 10), 273 (M+ – Ph, 4), 245 (M+ – PhCO,
49), 217 (32), 215 (36), 202 (C16H10, 33), 168 (M+ – Ph – PhCO, 7), 139 (11), 105 (PhCO, 100),
77 (Ph, 39). Anal. Calcd (%) for C25H18O2: C, 85.69; H, 5.18. Found (%): C, 85.78; H, 5.15.
trans-4-Bromophenyl-1-phenyl-1,2-dihydronaphtho[2,1-b]furan-2-ylmethanone (3h):
yield 89%; 1.15 g; colorless crystals; mp 184–186 ºC (from EtOH); IR νmax (KBr): 3059, 2905,
1697 (C=O), 1628, 1582, 1516, 1458, 1396, 1231, 1177, 1065, 984, 841, 814, 752, 702 cm-1; 1H
NMR (400 MHz, CDCl3) δ: 5.35 and 5.87 (d, 2H, J=5.5 Hz, H-1,2), 7.25–7.36 (m, 9H), 7.63 (d,
2H, J=8.7 Hz), 7.80 (d, 2H, J=8.7 Hz), 7.86 (d, 2H, J=8.3 Hz) ppm; 13C NMR (100 MHz,
CDCl3) δ: 50.6 (CH), 91.7 (CH), 112.2 (CH), 119.9 (C), 123.0 (CH), 123.5 (CH), 127.1 (CH),
127.7 (CH), 128.1 (2CH), 128.9 (CH), 129.3 (2CH), 130.2 (C), 130.4 (C), 130.7 (CH), 131.0
(2CH), 132.2 (2CH), 133.2 (C), 142.3 (C), 157.0 (C), 194.0 (C) ppm. MS (EI) m/z (%): 428 (M+,
6), 273 (M+ – C6H4Br, 5), 245 (M+ – C7H4BrO, 100), 226 (13), 215 (82), 202 (C16H10, 75), 183
(C7H4BrO, 54), 168 (25), 155 (C6H4Br, 28), 139 (35). Anal. Calcd (%) for C25H17BrO2: C, 69.94;
H, 3.99. Found (%): C, 70.09; H, 4.02.
trans-1-Naphthyl(1-phenyl-1,2-dihydronaphtho[2,1-b]furan-2-yl)methanone (3i): yield
90%; 1.08 g; colorless crystals; mp 161–163 ºC (from EtOH); IR νmax (KBr): 3055, 3024 (CH
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Ar), 1670 (C=O), 1628, 1597, 1574, 1508, 1458, 1231, 976, 806, 779, 755, 706 cm-1; H NMR
(400 MHz, CDCl3) δ: 5.27 and 6.02 (d, 2H, J=5.3 Hz), 7.08–7.11 (m, 2H), 7.22–7.27 (m, 6H),
7.30 (d, 1H, J=8.2 Hz), 7.48 (dd, 1H, J=8.2, 7.3 Hz), 7.54–7.60 (m, 2H), 7.78–7.85 (m, 3H),
7.90–7.92 (m, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.58–8.61 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ: 51.2 (CH), 92.9 (CH), 112.3 (CH), 119.6 (C), 122.9 (CH), 123.3 (CH), 124.3 (CH),
125.7 (CH), 126.9 (СН), 127.0 (СН), 127.5 (CH), 127.9 (2CH), 128.5 (CH), 128.7 (СН), 128.9
(СН), 129.1 (2CH), 129.2 (CH), 130.2 (C), 130.4 (C), 130.7 (CH), 131.1 (C), 132.5 (C), 133.7
(CH), 134.1 (C), 142.5 (С), 157.5 (C), 198.7 (C) ppm. Anal. Calcd (%) for C29H20O2: C, 86.98;
H, 5.03. Found (%): C, 87.12; H, 4.99.
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trans-2,2-Dimethyl-1-(1-phenyl)-1,2-dihydronaphtho[2,1-b]furan-2-yl)-1-propanone
(3j): yield 80%; 0.79 g; colorless crystals; mp 92–93 ºC (from EtOH); IR νmax (KBr): 3059 (CH
Ar), 2974, 1717 (C=O), 1632, 1601, 1578, 1520, 1466, 1369, 1250, 1227, 1076, 964, 818, 748,
733, 698 cm-1; H NMR (400 MHz, CDCl3) δ: 1.27 (s, 9H), 5.25 and 5.42 (d, 2H, J=5.5 Hz),
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7.25–7.29 (m, 9H), 7.78–7.81 (m, 2H) ppm; C NMR (100 MHz, CDCl3) δ: 26.3 (3CH3), 44.1
(C), 51.3 (CH), 91.4 (CH), 112.0 (CH), 120.2 (C), 123.0 (CH), 123.3 (CH), 127.0 (CH), 127.4
(CH), 128.1 (2CH), 128.9 (CH), 129.1 (2CH), 130.2 (C), 130.5 (CH, C), 142.7 (C), 157.1 (C),
211.4 (C). Anal. Calcd (%) for C23H22O2: C, 83.61; H, 6.71. Found (%): C, 83.54; H, 6.74.
trans-Cyclopropyl-1-phenyl-1,2-dihydronaphtho[2,1-b]furan-2-ylmethanone
(3k):
yield 75%; 0.71 g; colorless crystals; mp 129–130 ºC (from EtOH); IR νmax (KBr): 3051, 3024,
3005, 2947, 2897, 1713 (C=O), 1628, 1597, 1578, 1516, 1462, 1377, 1254, 1219, 1192, 1153,
984, 818, 729, 698 cm-1; 1H NMR (400 MHz, CD3CN) δ: 0.87-0.94 (m, 1H), 0.95-1.07 (m, 3H),
2.26–2.32 (m, 1H,), 5.16 and 5.21 (d, 2H, J=5.0 Hz), 7.21–7.34 (m, 9H), 7.82–7.86 (m, 2H)
ppm; 13C NMR (100 MHz, CD3CN) δ: 11.1 (CH2), 11.4 (CH2), 16.5 (CH), 51.2 (CH), 94.4 (CH),
112.0 (CH), 120.3 (C), 122.7 (CH), 123.4 (CH), 127.0 (CH), 127.4 (CH), 127.7 (2CH), 128.9
(CH), 129.1 (2CH), 130.1 (C), 130.3 (C), 130.7 (CH), 143.1 (C), 157.3 (C), 207.9 (C) ppm.
Anal. Calcd (%) for C22H18O2: C, 84.05; H, 5.77. Found (%): C, 83.89; H, 5.80.
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yield 84%; 1.03 g; colorless crystals; mp 185–186 ºC (from EtOH); IR νmax (KBr): 3059 (CH
Ar), 2912, 2851 (CH Ad), 1705 (C=O), 1632, 1577, 1520, 1450, 1373, 1261, 1227, 1120, 1157,
999, 976, 922, 814 cm-1; 1H NMR (400 MHz, CDCl3) δ: 1.71–1.80 (m, 6H), 1.91–2.01 (m, 6H),
2.08 (br s, 3H), 5.22 and 5.46 (d, 2H, J=5.5 Hz), 7.23–7.37 (m, 9H), 7.78–7.82 (m, 2H) ppm; 13C
NMR (100 MHz, CDCl3) δ: 27.9 (3CH), 36.6 (3CH2), 37.8 (3CH2), 46.4 (C), 50.8 (CH), 90.3
(CH), 112.0 (CH), 120.3 (C), 123.0 (CH), 123.2 (CH), 126.9 (CH), 127.4 (CH), 128.1 (2CH),
128.9 (CH), 129.1 (2CH), 130.1 (C), 130.5 (CH, C), 142.7 (C), 157.2 (C), 210.0 (C) ppm. MS
(EI) m/z (%): 408 (M+, 1), 273 (M+ – Ad, 100), 245 (11), 217 (16), 202 (C16H10, 14), 168 (12),
135 (Ad+, 100). Anal. Calcd (%) for C29H28O2: C, 85.26; H, 6.91. Found (%): C, 85.40; H, 6.88.
trans-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1,2-dihydronaphtho[2,1-b]furan-2-
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ylmethanone (3m): yield 72%; 0.90 g; colorless crystals; mp 165–166 ºC (from EtOH); IR νmax
(KBr): 3047 (CH Ar), 2959, 2928, 2905, 2835, 1690 (C=O), 1632, 1612, 1585, 1512, 1462,
1377, 1231, 1177, 1088, 1034, 980, 810, 748 cm-1; 1H NMR (400 MHz, CDCl3) δ: 3.78 (s, 3H),
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MHz, CDCl3) δ: 50.1 (CH), 55.4 (CH3), 91.9 (CH), 112.1 (CH), 114.6 (2CH), 120.0 (C), 122.9
(CH), 123.4 (CH), 127.0 (CH), 128.9 (CH), 129.1 (2CH), 129.2 (2CH), 130.2 (C), 130.4 (C),
130.6 (CH), 130.9 (2CH), 132.8 (C), 134.4 (C), 140.4 (C), 156.9 (C), 159.0 (C), 193.9 (C) ppm.
Anal. Calcd (%) for C26H19ClO3: C, 75.27; H, 4.62. Found (%): C, 75.34; H, 4.58.
trans-1-Adamantyl-1-(4-methoxyphenyl)-1,2-dihydronaphtho[2,1-b]furan-2-
ylmethanone (3n): yield 63%; 0.83 g; Colorless crystals; mp 179–180 ºC (from EtOH); IR νmax
(KBr): 3063 (CH Ar), 2908, 2847 (CH Ad), 1709 (C=O), 1628, 1612, 1512, 1462, 1246, 1223,
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1177, 1034, 1007, 984, 968, 841, 814, 752 cm-1; H NMR (400 MHz, CDCl3) δ: 1.70–1.78 (m,
6H), 1.89–1.99 (m, 6H), 2.06 (br s, 3H), 3.77 (s, 3H), 5.13 and 5.41 (d, 2H, J=5.5 Hz), 6.84 (d,
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(100 MHz, CDCl3) δ: 27.9 (3CH), 36.6 (3CH2), 37.8 (3CH2), 46.3 (C), 50.2 (CH), 55.3 (CH3),
90.3 (CH), 112.0 (CH), 114.4 (2CH), 120.4 (C), 123.0 (CH), 123.2 (CH), 126.8 (CH), 128.9
(CH), 129.1 (2CH), 130.1 (C), 130.4 (CH), 130.5 (C), 134.7 (C), 157.1 (C), 158.8 (C), 210.1 (C)
ppm. MS (EI) m/z (%): 438 (M+, 2), 303 (M+ – Ad, 100), 275 (M+ – AdCO, 7), 247 (14), 215
(12), 207 (7), 168 (M+ – AdCO – C6H4OCH3, 8), 135 (Ad+, 33). Anal. Calcd (%) for C30H30O3:
C, 82.16; H, 6.89. Found (%): C, 82.30; H, 6.86.
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trans-(4-Chlorophenyl)-1-(4-chlorophenyl)-1,2-dihydronaphtho[2,1-b]furan-2-
ylmethanone (3o): yield 88%; 1.11 g; colorless crystals; mp 123–125 ºC (from EtOH); IR νmax
(KBr): 3067 (CH Ar), 2963, 2820, 2778, 1690 (C=O), 1620, 1597, 1582, 1520, 1489, 1466,
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1408, 1373, 1265, 1234, 1092, 1007, 949, 814, 745 cm-1; H NMR (400 MHz, CDCl3) δ: 5.38
and 5.78 (d, 2H, J=5.5 Hz), 7.20 (d, 2H, J=8.5 Hz), 7.23–7.32 (6H, m), 7.47 (d, 2H, J=8.7 Hz),
7.77–7.81 (m, 2H), 7.95 (d, 2H, J=8.5 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ: 49.7 (CH), 91.6
(CH), 112.1 (CH), 119.4 (C), 122.8 (CH), 123.6 (CH), 127.2 (CH), 129.0 (CH), 129.2 (2CH),
129.4 (2CH), 129.5 (2CH), 130.2 (C), 130.3 (C), 130.9 (2CH), 130.9 (CH), 132.8 (C), 133.5 (C),
140.6 (C), 140.8 (C), 157.0 (C), 193.6 (C) ppm. Anal. Calcd (%) for C25H16Cl2O2: C, 71.61; H,
3.85. Found (%): C, 71.75; H, 3.90.
trans-(2,2-Dimethyl-1-[1-(4-chlorophenyl)-1,2-dihydronaphtho[2,1-b]furan-2-yl]-1-
propanone (3p): yield 72%; 0.79 g; colorless crystals; mp 108–110 ºC (from EtOH); IR νmax
(KBr): 3059 (CH Ar), 2982, 2940, 2901, 2874, 1713 (C=O), 1632, 1578, 1516, 1485, 1466,
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1369, 1246, 1215, 1246, 1215, 1088, 991, 972, 934, 829, 802, 741 cm-1; H NMR (400 MHz,
CDCl3) δ: 1.26 (s, 9H), 5.24 and 5.31 (d, 2H, J=5.5 Hz), 7.18–7.30 (m, 8H), 7.78–7.82 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ: 26.3 (3CH3), 44.1 (C), 50.5 (CH), 91.4 (CH), 111.9 (CH),
119.6 (C), 122.9 (CH), 123.4 (CH), 127.1 (CH), 129.0 (CH), 129.3 (2CH), 129.4 (2CH), 130.2
(C), 130.3 (C), 130.8 (CH), 133.2 (C), 141.2 (C), 157.0 (C), 211.3 (C) ppm. Anal. Calcd (%) for
C23H21ClO2: C, 75.71; H, 5.80. Found (%): C, 75.81; H, 5.77.
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The Journal of Organic Chemistry
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trans-1-Adamantyl-1-(4-chlorophenyl)-1,2-dihydronaphtho[2,1-b]furan-2-
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ylmethanone (3q): yield 78%; 1.04 g; colorless crystals; mp 166–167 ºC (from EtOH); IR νmax
(KBr): 3063 (CH Ar), 2926, 2903, 2849 (CH Ad), 1707 (C=O), 1632, 1578, 1489, 1464, 1450,
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1375, 1252, 1223, 1092, 984, 961, 922, 833, 806, 754 cm-1; H NMR (400 MHz, CDCl3) δ:
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1.71–1.78 (m, 6H), 1.89–1.98 (m, 6H), 2.06 (br s, 3H), 5.19 and 5.34 (d, 2H, J=5.5 Hz), 7.17–
7.27 (m, 8H), 7.77–7.80 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ: 27.9 (3CH), 36.6 (3CH2),
37.8 (3CH2), 46.4 (C), 50.1 (CH), 90.3 (CH), 112.0 (CH), 119.7 (C), 122.8 (CH), 123.3 (CH),
127.0 (CH), 129.0 (CH), 129.3 (2CH), 129.4 (2CH), 130.2 (C), 130.3 (C), 130.7 (CH), 133.1
(C), 141.1 (C), 157.1 (C), 209.8 (C) ppm. MS (EI) m/z (%): 442 (M+, 4), 307(M+ – Ad, 67), 306
(M+ – Ad – H, 84), 216 (64), 215 (100), 168 (46), 135 (Ad+, 76), 93 (40), 79 (27). Anal. Calcd
(%) for C29H27ClO2: C, 78.63; H, 6.14. Found (%): C, 78.78; H, 6.16.
trans-[1-(4-Chlorophenyl)-1,2-dihydronaphtho[2,1-b]furan-2-yl](4-
fluorophenyl)methanone (3r): yield 84%; 1.01 g; colorless crystals; mp 173–174 ºC (from
EtOH); IR νmax (KBr): 3067, 2926, 1690 (C=O), 1632, 1595, 1578, 1506, 1491, 1464, 1412,
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1379, 1234, 1159, 1090, 1015, 984, 849, 812, 785, 752 cm-1; H NMR (400 MHz, CDCl3) δ:
5.40 and 5.79 (d, 2H, J=5.5 Hz), 7.14–7.22 (m, 4H), 7.25–7.31 (m, 6H), 7.78–7.82 (m, 2H), 8.06
(dd, 2H, J=9.2, 5.5 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ: 49.7 (CH), 91.6 (CH), 112.1 (CH),
116.1 (d, 2CН, JCF=21.9 Hz), 119.4 (C), 122.8 (CH), 123.6 (CH), 127.2 (CH), 129.0 (CH), 129.4
(2CH), 129.5 (2CH), 130.3 (2C), 130.8 (C), 130.9 (CH), 132.3 (d, 2СН, JCF=9.5 Hz), 133.4 (C),
140.9 (C), 157.0 (C), 166.3 (d, C, JCF=255.5 Hz), 193.1 (C) ppm. Anal. Calcd (%) for
C25H16ClFO2: C, 74.54; H, 4.00. Found (%): C, 74.62; H, 3.99.
trans-[1-(4-Chlorophenyl)-1,2-dihydronaphtho[2,1-b]furan-2-yl](4-
methylphenyl)methanone (3s): yield 71%; 0.85 g; colorless crystals; mp 177–178 ºC (from
EtOH/DMF); IR νmax (KBr): 3065 (CH Ar), 2920, 1686 (C=O), 1632, 1607, 1578, 1520, 1489,
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1464, 1410, 1379, 1234, 1207, 1186, 1088, 1015, 984, 835, 812, 777, 748 cm-1; H NMR (400
MHz, CDCl3) δ: 2.45 (s, 3H), 5.33 and 5.86 (d, 2H, J=5.5 Hz), 7.20–7.31 (m, 10H), 7.78–7.82
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