A new and efficient synthesis of substituted 2-hydroxymethyl-2-methyl-2H-chromenes

Article abstract of DOI:10.1055/s-2002-19763

A new and efficient three step procedure for the synthesis of functionalized 2H-chromenes 1 is described, starting from commercially available salicylaldehydes 2 and 2-methylpropenyl-magnesium chloride 3, which involves catalytic acid-mediated intramolecular cyclization of phenolic epoxide 5 as the key step.

Full text of DOI:10.1055/s-2002-19763

322
LETTER
A New and Efficient Synthesis of Substituted 2-Hydroxymethyl-2-methyl-2H-
chromenes
Synthesis
.
of Substitute
Y
d
2-Hydroxymethy
.
l-2-methyl-2
G
H
-chromene
s
oujon, F. Zammattio,* S. Pagnoncelli, Y. Boursereau, B. Kirschleger
Laboratoire de Synthèse Organique, CNRS UMR 6513, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, 44072 Nantes
cédex 03, France.
Fax +33(251)125402; E-mail: zammattio@chimie.univ-nantes.fr
Received 23 October 2001
OH
O
OH
OH
Abstract: A new and efficient three step procedure for the synthe-
sis of functionalized 2H-chromenes 1 is described, starting from
commercially available salicylaldehydes 2 and 2-methylpropenyl-
magnesium chloride 3, which involves catalytic acid-mediated in-
tramolecular cyclization of phenolic epoxide 5 as the key step.
R
O
R
R
OH
OH
dehydratation
O
6-exo
cyclization
1
5
Key words: 2H-chromenes, chromenemethanols, 2,2-disubstituted
2H-chromenes, 2-hydroxymethyl-2-methyl-2H-chromenes, 2H-1-
benzopyran
Scheme 2
Preparation of epoxide 5 is outlined in Scheme 3. The
Synthesis of Substituted 2-Hydroxymethyl-2-methyl-2H- treatment of salicylaldehydes 2 with an excess of 2-meth-
chromenes
ylpropenylmagnesium chloride 3 in THF afforded the cor-
responding homoallylic alcohols 4 in good to excellent
yields (Table 1). For the preparation of key epoxides 5,
homoallylic alcohols 4 were subjected to standard epoxi-
dation with m-CPBA in CH2Cl2. The reaction was carried
out at 0 °C for 4 hours. Purified by column chromatogra-
phy on silica, the corresponding epoxides 5a–d were ob-
tained in a 70–75% yield. It will be noteworthy that in the
case of compounds 4e,f, m-CPBA epoxidation leads to ep-
oxides 5e,f in only 20–30% yields. These low yields are
due to the instability of compounds 5e,f on silica. To im-
prove these yields, phenolic groups of compounds 2e,f
were protected by the TBS group,7 then allylmetallation
and epoxidation reactions were successful (Table 1, en-
tries 7 and 8). Subsequent O-silyldeprotection of 5g,h
with TBAF7 gave corresponding phenolic epoxides 5e,f in
quantitative yields. These epoxides were, then, immedi-
ately used in the next step without further purification.
2H-Chromenes are key heterocyclic units in many natural
and biologically polyoxygenated active compounds.1
Moreover, they are widely employed as useful intermedi-
ates in the synthesis of medicinal agents such as cordia-
chromene,2 potassium channel activating drugs3 and a
range of tannins.4 A common building block for the syn-
thesis of such structures is 2-hydroxymethyl-2-methyl-
chromene 1 (Scheme 1).
R
HO
OH
O
O
Cordiachromene
1
Scheme 1
Although several methods have been reported in
literature5 for the construction of such various 2,2-dialky-
lchromene skeletons, only few direct preparations of 2-
functionalized chromenes have been described.2,6 We
herein report a new and facile route to diverse 2-hy-
droxymethyl-2-methylchromenes 1, starting from com-
mercially available salicylaldehydes 2, which involves the
cyclization of 5, a nucleophilic epoxide opening reaction
as the key step. The synthetic strategy requires the prepa-
ration of epoxides 5, whose aryl ether-forming reaction
provides chromenemethanols 1 via a (6-exo) mode of cy-
clization, followed by an intramolecular dehydratation re-
action (Scheme 2).
OH
OH
O
R
R
R
CHO
OH
i
ii
OH
OH
5
2
4
Scheme 3 Reagents and conditions i) CH2=C(CH3)CH2MgCl (3),
THF, –20°C. ii) m-CPBA, CH2Cl2, 0 °C.
In the last step (Scheme 4), the crucial cyclization of ep-
oxides 5a–e with AlCl3 (2 equiv) in THF at 0 °C did not
give the expected chromanemethanols 1a–e but instead
bicyclic compounds 7a–e. The naphthalene derivative 5f
leads, under these conditions, to the expected chromene
1f. Alternatively, by using catalytic amounts of camphor
sulfonic acid (20 mol%) in CH2Cl2 at room temperature,
epoxides 5a-e were also converted into 7a–e. Heating 7a–
e in benzene at reflux for 16 hours in the presence of 4
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0322,0324,ftx,en;G31201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of Substituted 2-Hydroxymethyl-2-methyl-2H-chromenes
323
Table 1 Allylation and Epoxidation Reactions
R
O
ii
i
En- Aldehyde
try
Alcohola
Epoxidea
O
7
OH
OH
R
O
R
1
OH
CHO
OH
O
iii
OH
O
OH
1
5
OH
OH
2a
4a (98)
5a (75)
Scheme 4 Reagents and conditions: Method A i) AlCl3, THF, 0 °C
or CSA (20 mol%), DCM, r.t. ii) p-TSA or CSA (4 mol%), benzene,
reflux. Method B iii) p-TSA or CSA (4 mol%), benzene, reflux.
2
3
4
5
6
HO
CHO
OH
OH
OH
OH
OH
O
HO
HO
2b
4b (98)
5b (70)
Table 2 Cyclization Reactions
OH
MeO
CHO
OH
OH
En- Epoxide
try
Bicyclic
Chromeneb
O
MeO
MeO
Compounda
OH
OH
2c
1
2
3
4
5
6
OH
O
O
4c (97)
5c (74)
OH
O
O
OH
Cl
CHO
OH
OH
OH
O
1a (85%)
Cl
Cl
7a (97%)
5a
OH
OH
OH
OH
OH
OH
OH
OH
O
HO
2d
HO
O
4d (98)
5d (70)
HO
OH
O
O
CHO
OH
O
1b (78%)
7b (88%)
5b
HO
HO
HO
2e
MeO
OH
O
MeO
O
4e (48)
5e (20)
MeO
OH
O
O
OH
OH
OH
1c (78%)
O
7c (89%)
CHO
OH
5c
OH
Cl
O
OH
OH
Cl
O
4f (75)
Cl
5f (30)
2f
OH
O
O
7
8
OH
OH
OH
OH
CHO
OH
1d (65%)
O
7d (82%)
5d
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
O
2g
O
4g (60)
5g (65)
OH
HO
O
HO
O
HO
1e (65%)
OH
OH
7e (74%)
O
5e
CHO
OTBS
OTBS
OTBS
OH
OH
O
-
2h
4h (80)
5h (55)
OH
a Isolated yield of pure products, all new compounds gave satisfactory
analytical data.
O
1f (80%)
5f
a Isolated yield of pure products, all new compounds gave satisfactory
analytical data.
b Yield obtained with Method B.
mol% of p-TSA afforded the expected chromenes 1a–e in
excellent yields (Table 2). On the other hand, treatment of
epoxides 5a–f in refluxing benzene with 4 mol% of CSA
for 2 hours gave directly chromenemethanols 1a–f in ex-
cellent yields (Table 2).
In summary, a simple and general three step procedure for
the preparation of 2-functionalized chromenes is now
available. This approach constitutes an attractive alterna-
tive strategy for the formation of variously substituted
chromene systems. Further synthetic application of this
methodology is currently in progress and will be reported
in due course.
These results can be explained through the formation of a
very stable benzylic carbocation. This carbocation can
lead, depending on the reaction conditions, to either com-
pounds 1 or 7. These results are consistent with those of
Yoshioka1a for analogues of 1 (Scheme 5).
Synlett 2002, No. 2, 322–324 ISSN 0936-5214 © Thieme Stuttgart · New York

324
J. Y. Goujon et al.
LETTER
H, J = 9.8 Hz, CHO), 4.15 (d, 1 H, J = 9.8 Hz, CHO), 4.91 (d, 1 H,
J = 4.6 Hz, CHO), 6.72–7.19 (m, 4 H, Har). 13C NMR (50.3 MHz,
DMSO), 20.8, 38.2, 76.1, 79.0, 83.4, 115.7, 119.9, 125.6, 127.7,
130.7, 153.9. m/z (EI): 176 (77), 159 (24), 147 (62) 131 (100), 91
(27). IR (liquid film): 2975, 2941, 2876, 1482 cm–1. Anal. Calcd for
C11H12O2: C, 74.98; H, 6.86; O, 18.16. Found: C, 74.75; H, 6.89; mp
= 28 °C.
R
O
H
a
b
O
7
R
+
a
b
H
OH
R
O
OH
Typical Data for New compounds 1
O
1a: 1H NMR (200 MHz, CDCl3), 1.36 (s, 3 H, CH3), 2.03 (br s, 1
H, OH), 3.59 (d, 1 H, J = 11.6 Hz, CH-O), 3.68 (d, 1 H, J = 11.6 Hz,
CH-O), 5.56 (d, 1 H, J = 9.9 Hz, CH=), 6.45 (d, 1 H, J = 9.9Hz,
CH=), 6.76-7.15 (m, 4 H, Har). 13C NMR (50.3 MHz, CDCl3),
22.6, 68.7, 79.2, 116.1, 120.8, 121.1, 124.7, 126.6, 126.7, 129.3,
153.9. m/z (EI): 176 (3), 145 (100), 115 (13), 91 (5). IR (liquid
film): 3396, 2972, 2927, 1486, 1240, 1053, 773 cm–1. Anal. Calcd
for C11H12O2: C, 74.98; H, 6.86; O, 18.16. Found : C, 74.82; H, 6.91.
1
Scheme 5
Allylmetallation of Aldehydes
To a solution of metallylmagnesium chloride 3 (0.6 M, 6.3 mmol)
in THF was added dropwise aldehyde 2 (2.1 mmol) in THF (10 mL)
at –20 °C. At the end of the addition, the mixture was stirred for 1 h
at r.t. and quenched with an aq soln of NH4Cl. The aq layer was ex-
tracted with EtOAc (2 20 mL). The combined organic layers were
washed with H2O and brine, dried (MgSO4), and concentrated. The
crude product was purified by column chromatography on silica gel
(hexane–EtOAc mixtures).
References
(1) (a) Aizawa, Y.; Kanaï, T.; Fujita, T.; Yoshioka, H.;
Yoshioka, T. Heterocycles 1991, 32, 285. (b) Holley, J. H.;
Hadley, K. W.; Turner, C. E. J. Pharm. Sci. 1975, 892.
(c) Mc Hale, D.; Green, J. J. Chem. & Ind. 1962, 1867.
(d) Benslimane, A. F.; Pouchus, Y. F.; Verbist, J. F.; Petit, J.
Y.; Brion, J. D.; Welin, L. J. Clin. Pharmacol. 1995, 35,
298. (e) Schweizer, E. E.; Meeder-Nyez, D. Chromenes,
Chromanones and Chromones, 2H and 4H-1-Benzopyrans;
Ellis, G. P., Ed.; John Wiley and sons: New York, 1977,
Chap. II, 81; and references cited therein. (f) Dave, E.;
Kusuni, T.; Ishitsuka, M.; Iwaschita, T.; Kakisawa, H.
Heterocycles 1984, 22, 2301. (g) Nomura, T.; Fukai, T.;
Hano, Y.; Tsukamoto, K. Heterocycles 1983, 20, 661.
(h) Ellis, G. P. In The Chemistry of Heterocyclic
Compounds, Chromenes, Chromanes, and Chromones;
Weissberger, A.; Taylor, E. C., Eds.; John Wiley: New York,
1977, Chap. II, 13.
Epoxidation of Homoallylic Alcohols
To a solution of homoallylic alcohol 4 (2.4 mmol) in CH2Cl2 (15
mL) was added at 0 °C a solution of m-CPBA (1.2 g, 4.8 mmol) in
CH2Cl2 (20 mL) and the mixture was stirred at this temperature for
4 h. After filtration, the solution was concentrated and then the
crude product was diluted with EtOAc (30 mL) and washed with aq
NaHCO3 (20 %, 3 20 mL) and brine, dried (MgSO4), and concen-
trated. The residue was purified by column chromatography on sil-
ica gel (hexane–EtOAc mixtures).
Cyclisation of Epoxides
Method A: A solution of epoxide 5 (2.57mmol) in THF (5 mL) at 0
°C was treated with AlCl3 (5.15 mmol). After 1 h, an aq soln of
NH4Cl (10 mL) was added, the aq layer was extracted with EtOAc
(2 20 mL) and the combined organic layers were washed with
brine, dried (MgSO4), and concentrated. The residue was purified
by column chromatography on silica gel (hexane–EtOAc mixtures)
to give the bicyclic compound 7.
(2) Bouzbouz, S.; Goujon, J. Y.; Deplanne, J.; Kirschleger, B.
Eur. J. Org. Chem. 2000, 3223.
(3) Bell, D.; Davies, M. R.; Green, G. R.; Mann, I. S. Synthesis
1995, 707.
(4) (a) Rochfort, S. J.; Metzger, R.; Hobbs, L.; Capon, R. J. Aust.
J. Chem. 1996, 49, 1217. (b) Van Rensburg, H.; Van
Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D.
Tetrahedron Lett. 1997, 38, 3089. (c) Covington, A. D.
Chem. Soc. Rev. 1997, 111.
(5) (a) Sukbok, C.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864.
(b) Chauder, B. A.; Kalinin, A. V.; Snieckus, V. Synthesis
2001, 140. (c) Larock, R. C.; Wei, L.; Hightowei, T. R.
Synlett 1998, 522. (d) Solladié, G.; Boeffel, D.; Maignan, J.
Tetrahedron 1996, 52, 2065. (e) Chauder, B. A.; Lopes, C.
C.; Lopes, R. S. C.; Da Silva, A. J. M.; Snieckus, V.
Synthesis 1998, 279. (f) Cruz-Almanza, R.;Perez-Florès, F.;
Lemini, C. Heterocycles 1994, 37, 759. (g) Garcias, X.;
Ballester, P.; Saà, J. M. Tetrahedron Lett. 1991, 32, 7739.
(6) David, M.; Boustie, J.; Peilloux, A.; Poupon, E.; Amoros,
M.; Sauleau, A. Pharmaceutical Sciences 1997, 3, 305.
(7) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag:
New York NY, 1994.
A solution of 7 (2 mmol) in benzene (20 mL) with TsOH H2O (75
mg, 0.4mmol) was refluxed for 16 h. After cooling, the solution was
washed with aq NaHCO3, brine, dried (MgSO4), and concentrated.
The crude product was purified by column chromatography on sili-
ca gel (hexane–EtOAc mixtures) to give chromenemethanol 1.
Method B: A solution of epoxide 5 (2.57 mmol) and CSA (23.9 mg,
4 mol%) in benzene (10 mL) was refluxed for 2 h. After cooling, the
solution was washed with aqueous NaHCO3, brine, dried (MgSO4),
and concentrated. The crude product was purified by column chro-
matography on silica gel (hexane–EtOAc mixtures) to give chrome-
nemethanol 1.
Typical Data for New Compounds 7
7a: 1H NMR (200 MHz, DMSO), 1.54 (s, 3 H, CH3), 2.06 (d, 1 H,
J = 12 Hz, CH), 2.16 (dd, 1 H, J = 4.6Hz, J = 12Hz, CH), 3.74 (d, 1
Synlett 2002, No. 2, 322–324 ISSN 0936-5214 © Thieme Stuttgart · New York