Facile synthesis of 2,2-Dimethylchromans by Mo(CO)6 Catalyzed reaction of aryl prenyl ethers

Article abstract of DOI:10.1055/s-1998-2035

2,2-Dimethylchromans 3a-g are synthesized in good yields by a one-pot reaction of the aryl prenyl ethers 1a-g with a catalytic amount of Mo(CO)₆ in refluxing toluene.

Full text of DOI:10.1055/s-1998-2035

SHORT PAPERS
256
Facile Synthesis of 2,2-Dimethylchromans by Mo(CO)6 Catalyzed Reaction
of Aryl Prenyl Ethers
Angela M.Bernard,a Maria T.Cocco,b Valentina Onnis,b Pier P.Piras*a
a Dipartimento di Scienze Chimiche, Università di Cagliari, Via Ospedale 72, I-09124 Cagliari, Italy
b Dipartimento Farmaco Chimico Tecnologico, Università di Cagliari, Via Ospedale 72, I-09124 Cagliari, Italy
Fax +39(70)6758605; E mail: pppiras@vaxca1.unica.it
Received 30 July 1997
Abstract: 2,2-Dimethylchromans 3a–g are synthesized in good
yields by a one-pot reaction of the aryl prenyl ethers 1a–g with a
catalytic amount of Mo(CO)6 in refluxing toluene.
survival of the fragile cyclopropane ring of cyclopropyl-
idene aryloxy derivatives. We found that the reaction was
strongly affected by the presence of substituents on the ar-
omatic ring and by the substitution pattern of the allylic
moiety. As a matter of fact para electron-donating substit-
uents favoured the reaction, while para electron-with-
drawing substituents decreased the cyclization rate. On
the other hand, based on the substitution pattern of the al-
lylic moiety, it was found that, in the presence of the same
amount of catalyst, methallyl ethers gave higher yields of
the cyclized products as compared to the allyl ethers,
while the crotyl phenyl ether led to a complex reaction
mixture.
Key words: molybdenum hexacarbonyl, transition metal cataly-
sis, chromans, chromenes, prenyl ethers
2,2-Dimethylchromans are natural products1 which have
been shown to exhibit different bioactivities. They consti-
tute a useful starting material for the synthesis of 2,2-dim-
ethyl chromenes by dehydrogenation with 2,3-dichloro-
5,6-dicyanobenzoquinone (DDQ)2 or N-bromosuccinim-
ide (NBS),3 and for the synthesis of 2,2-dimethyl-4-chro-
manones, by oxidation with ceric ammonium nitrate
(CAN).4 2,2-Dimethylchromans are usually prepared by With the aim of studying the effect of substitution at the
multistep syntheses with not very satisfactory yields. The allylic moiety on the reactivity of allyl aryl ethers towards
direct synthesis based on the reaction of phenols with iso- Mo(CO)6, we decided to examine the methallyl deriva-
prene, under catalysis of acidic species, or with 1,1-dime- tives 1a–g. These were prepared, in almost quantitative
thylallene using platinum, rhodium or palladium as yields (91–98%) as previously reported for 1g,8 by react-
catalysts leads to low or moderate yields of 2,2-dimethyl- ing the appropriate phenols with 4-bromo-2-methylbut-2-
chromans.5 Better yields are obtained by reacting sodium ene in acetone in the presence of K2CO3 and KI.
or potassium phenoxide with isoprene in the presence of a
Much to our surprise we found that, under the usual con-
Lewis acid (AlCl3, FeCl3, SnCl4).6 Since the above men-
ditions with 40 mol % of catalyst in refluxing toluene for
tioned methods give only low or moderate yields of 2,2-
55 hours, the prenyl ethers 1a–g gave good yields of the
dimethylchromans, we sought for new synthetic methods
corresponding 2,2-dimethylchromans 3a–g accompanied,
to improve their yields.
sometimes, by small quantities (5–10%) of the corre-
Recently we reported7 that molybdenum hexacarbonyl sponding phenols 4a–g (Scheme, Table). Only in two cas-
can be used in the one-pot conversion of allyl aryl ethers es (1a, c) small amounts (5%) of side products were found
to dihydrobenzofurans under conditions that allow the in the reaction mixture. On the basis of the 1H NMR and
Scheme

March 1998
SYNTHESIS
257
the mass spectra of the crude reaction mixture, the side normal or an abnormal Claisen rearrangement at 180–
200°C.13
products could be assigned as the 2,3,3-trimethyl-2,3-di-
hydrobenzofurans or the 2,2,3-trimethyl-2,3-dihydroben-
As far as we know, this represents also the first example
zofurans, expected from a normal or an abnormal Claisen
of the use of Mo(CO)6 in the synthesis of 2,2-dimethyl-
rearrangement–cyclization reaction, respectively.
chromans through what appears to be a Claisen rearrange-
A 75:25 mixture of the two possible regioisomers, 7- ment–cyclization reaction. Only one previous example of
methoxy-2,2-dimethyl- and 5-methoxy-2,2-dimethyl-
chroman, was obtained with derivative 1d carrying a m-
methoxy substituent, showing that the reaction is moder-
ately regioselective in this case. This ratio was worked out
by comparison of the integral of a clear separated triplet at
d = 7.02, in the 1H NMR spectrum, attributable only to the
5-methoxy-2,2-dimethylchroman and the complete inte-
gral of the aromatic region. This data was further con-
firmed by comparison of the integral of the two separate
methoxy signals and by GC of the reaction mixture. The
the use of Mo(CO)6 in the synthesis of chromans via a
Friedel–Crafts reaction has been reported.14
Reagent-grade commercially available reagents and solvents were
used. Toluene was freshly distilled from sodium. Mo(CO)6 was used
as received from Aldrich Chemistry. Column chromatography was
performed with Fluka silica gel (70–230 mesh). Derivatives 1a–b,15
1
1c–d,16 1g,8 3a, c, d,17 3b,6 3g12 have been previously reported. H
NMR and 13C NMR spectra were recorded on a Varian Unity 300
spectrometer in CDCl3 using TMS as internal standard. Mass spectra
were obtained by EI (70 eV) using a mass spectrometer HP 5989A
mixture of the two isomers,9 treated with two equivalents equipped with a GC HP 5890. Elemental analyses, carried out on a
Carlo Erba model 1106 Element analyzer, gave satisfactory results:
of DDQ in refluxing benzene for 100 hours, gave good
C, H + 0.3 %.
yields (90% evaluated by GC) of a mixture of 7-methoxy-
and 5-methoxy-2,2-dimethylchromene,10 easily identified
Aryl Preuyl Ethers 1a–g; General Procedure:
1
by their H NMR and mass spectra. The two chromenes
A mixture of the appropriate phenol (0.1 mol), 4-bromo-2-methylbut-
2-ene (0.1 mol), K2CO3 (12.8 g, 0.1 mol) and KI (1 g), in acetone
(60 mL) was refluxed for 15 h. The mixture was poured into H2O (50
mL) and extracted with CH2Cl2 (2 ´ 50 mL). The organic layer was
washed with 10% NaOH solution (2 ´ 50 mL), H2O and brine. After
drying (Na2SO4) and filtration the solution was concentrated to afford
the corresponding aryl prenyl ether which was purified by vacuum
distillation; yield: 91–98 %.
are reported to be separable10 by preparative GC, and the
ready synthesis of the mixture enriched (70:30) in 7-meth-
oxy-2,2,-dimethyl-3-chromene (precocene I) represents
an important result. Precocene I is a natural product isolat-
ed by Bowers11 from the Ageratum Houstonianum that
shows growth regulatory effect on a range of insects,
causing the necrosis of their corpora allata.
1-Bromo-4-[(3-methylbut-2-enyloxy)]benzene (1e): Yield 91%;
bp 98 °C/0.2 Torr.
Table. Mo(CO)6 catalyzed synthesis of 2,2-dimethylchromans 3
1H NMR (CDCl3): d = 1.70 (s, 3 H), 1.77 (s, 3 H), 4.41 (d, 2 H, J =
6.8 Hz), 5.44 (m, 1 H), 6.70–7.35 (m, 4 H).
Entry
Product
R
Yielda
(%)
13C NMR (CDCl3): d = 18.03, 25.64, 64.78, 112.50, 116.28, 119.24,
132.00, 138.14, 157.77.
1
2
3
4
3a
3b
3c
3d
H
6-Me
6-MeO
7-MeO or
5-MeO
6-Br
65
70
80
75b
1-Ethyl- 4-[(3-methylbut-2-enyloxy)]benzene (1f): Yield 99%;
bp 81 °C/0.05 Torr.
1H NMR (CDCl3): d = 1.18 (t, 3 H, J = 7.5 Hz), 1.70 (s, 3 H), 1.75 (s,
3 H), 2.55 (q, 2 H, J = 7.5 Hz), 4.44 (d, 2 H, J = 6.6 Hz), 5.47 (m, 1
H), 6.82–7.10 (m, 4 H).
5
6
7
3e
3f
3g
60
70
60
13C NMR (CDCl3): d = 15.75, 17.94, 25.62, 27.85, 64.53, 114.32,
119.92, 128.48, 136.05, 137.48, 156.78.
6-Et
6-CHO
a Isolated yield after column chromatography.
2,2-Dimethylchromans 3a–g; General Procedure:
b The product is a 75:25 mixture of 7-methoxy- and 5-methoxy-2,2-
dimethylchroman.
A solution of the aryl prenyl ethers 1a–g (3–5 mmol) in toluene (6–
10 mL) containing Mo(CO)6 (40 mol %), was stirred under argon in
a stoppered Schlenk flask at 115 °C (external oil bath) for 55 h. This
solution, after cooling and dilution with Et2O (10ml), was treated with
10% NaOH and brine, filtered through Al2O3 and concentrated in
vacuo. The residue was chromatographed on a silica gel column using
light petroleum (bp 40–70 °C)/Et2O (10:1) as eluent, to give the pure
product.
The fragile aldehyde function survives our reaction condi-
tions allowing easy access to 6-formyl-2,2-dimethylchro-
man (3g). This chroman, prepared otherwise, using a
multistep protocol is a useful intermediate12 in the synthe-
sis of some components of the family of the acid pigments
6-Bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (3e):
Pulvinones, recently isolated from the common larch 1H NMR (CDCl3): d = 1.31 (s, 6 H), 1.77 (t, 2 H, J = 6.9 Hz), 2.73 (t,
22 H, J = 6.9 Hz), 6.63–7.33 (m, 3 H).
mushroom Suillus grevillei and from cultures of Aspergil-
lus terreus.
13C NMR (CDCl3): d = 22.32, 26.74, 32.41, 74.48, 111.53, 119.05,
123.09, 130.09, 131.86, 153.16.
MS (EI): m/z = 242 (M+ + 2, 98), 240 (M+, 100), 227 (29), 225 (30),
The results we have obtained are quite impressive in view
of the fact that our catalyst allows an easy synthesis of oth-
213 (13), 211 (13), 85 (96), 83 (97), 161 (M+ – Br, 47).
erwise unaccessible products by the uncatalyzed thermal
6-Ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (3f):
1H NMR (CDCl3): d = 1.20 (t, 3 H, J = 7.5 Hz), 1.31 (s, 6 H), 1.76 (t,
2 H, J = 6.7 Hz), 2.55 (q, 2 H, J = 7.5 Hz), 2.73 (t, 2 H, J = 6.7 Hz),
6.70–6.89 (m, 3 H).
reaction of aryl prenyl ethers. As a matter of fact, these
ethers are reported to give the corresponding 2,3,3-trime-
thyl- or 2,2,3- trimethyl-2,3-dihydrobenzofurans via a

258
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SYNTHESIS
13C NMR (CDCl3): d = 15.84, 22.45, 26.79, 27.93, 32.84, 73.74,
116.98, 120.35, 126.62, 128.47, 135.11, 151.82.
MS (EI): m/z = 190 (M+, 47), 175 (M+ – Me, 30), 161 (M+ – Et, 13),
135 (100).
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This work was supported by the Consiglio Nazionale delle Ricerche
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