One-pot, three-component synthesis of 4-Aryl-5,6-dihydropyran via prins-friedel-crafts reaction

Article abstract of DOI:10.1055/s-0029-1219779

An efficient method for the synthesis of 4-aryldihydropyrans has been developed from the reaction of aldehydes or epoxides with homopropargylic alcohols in the presence of arenes promoted by boron trifluoride etherate. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219779

LETTER
1027
One-Pot, Three-Component Synthesis of 4-Aryl-5,6-dihydropyran via
Prins–Friedel–Crafts Reaction
S
ynthesis of 4-Ary
d
l-5,6-dihydro
a
pyran gandla C. Reddy, Anil K. Saikia*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
Fax +91(361)2690762; E-mail: asaikia@iitg.ernet.in
Received 20 January 2010
O
R
O
BF3⋅OEt2
arene
r.t. to 40 °C
OH
Abstract: An efficient method for the synthesis of 4-aryldihydro-
+
pyrans has been developed from the reaction of aldehydes or ep-
oxides with homopropargylic alcohols in the presence of arenes
promoted by boron trifluoride etherate
R
H
Ar
where R = Alk, Ar
Key words: Lewis acid, multicomponent, Prins cyclization,
Friedel–Crafts reaction, dihydropyran
Scheme 1 Synthesis of 4-aryl-dihydropyran
this reaction. The general conversion is shown in
Multicomponent reactions have attracted considerable at- Scheme 1.
tention in synthetic organic chemistry due to their ability
The scope of the reaction was examined by considering a
to form a series of bonds in a single step.1 In particular,
multicomponent reactions can provide functionalized het-
erocyclic compounds with high stereoselectivity.2 Among
heterocyclic compounds tetrahydropyrans are found in
many biologically active natural products and pharmaceu-
ticals.3 The synthesis of 5,6-dihydropyran is synthetically
attractive since the olefin function can be further function-
alized to obtain polysubstituted tetrahydropyrans.4 2-
Alkyl-4-aryldihydropyrans are used as flavoring and aro-
ma agents.5 There are several methods for the synthesis of
dihydropyrans in the literature.6 Among these the Prins
cyclization is the most convenient because it provides the
desired product in a single step. Usually a Lewis acid is
used for this reaction and, in most of the cases, the product
is a 4-halosubstituted dihydropyran, but synthetic access
to 4-aryldihydropyrans is limited.7 The existing methods
have limitations such as formation of side products, low
yield, and use of multistep processes. Recently, we have
reported the synthesis of 4-aryltetrahydropyrans by
Sakurai–Hosomi–Prins–Friedel–Crafts8a and Prins–
Friedel–Crafts reactions8b using a carbonyl compound, a
homoallylic alcohol, and an arene mediated by boron tri-
fluoride etherate. We now report herein an efficient meth-
od for the synthesis of 4-aryldihydropyran from carbonyl
compounds or epoxides, homopropargyl alcohols, and
arenes mediated by boron trifluoride etherate.
range of aldehydes as shown in Table 1. It was observed
that the reaction holds good for simple aromatic aldehydes
and aldehydes having electron-withdrawing groups on the
aromatic ring. Aromatic aldehydes having electron-donat-
ing groups such as anisaldehyde failed to give products.
This can be attributed to the stability of the benzylic car-
bocation due to the presence of methoxy group on the ar-
omatic ring, which leads to oxina-[3,3]-sigmatropic
rearrangement.6i On the other hand aliphatic aldehydes
were very good substrates and give good yields.
To extend the utility of this method, various arenes as nu-
cleophiles were investigated under these reaction condi-
tions. The results are summarized in Table 2. It was
observed that methyl-substituted arenes gave good yields
in comparison to benzene. Thus, the reaction with toluene
gave o-/p-15 as an inseparable mixture of regioisomers
with a ratio of 2:1 and 72% overall yield. Similarly, p-xy-
lene and mesitylene gave single isomers 16 and 17 in 78%
and 92% yields, respectively. On the other hand methoxy-
substituted benzenes such as anisole gave regioisomeric
triarylmethane adducts o-18 and p-18 with a ratio of 4:1
and 76% overall yield.10 Similarly, 1,3,5-trimethoxyben-
zene gave triarylmethane adduct 19 in 82% yield.10
The reaction with ketone was not satisfactory. Thus, the
reaction of acetone and cyclohexanone with homopropar-
gylic alcohol in benzene gave spirocyclic compounds 20
and 21 (Figure 1) in 13% and 28% yields, respectively.
This is due to the lower reactivity of the ketones than al-
dehydes.
To start with we reacted benzaldehyde with homopropar-
gylic alcohol in the presence of boron trifluoride etherate
in benzene at room temperature. The product, 2,4-diphe-
nyl-5,6-dihydropyran, was obtained in 45% yield.9 Other
nonhalogenated Lewis acids such as TMSOTf, Sc(OTf)3,
In(OTf)3, and Bi(OTf)3 were found to be inefficient for
Me
Me
O
O
SYNLETT 2010, No. 7, pp 1027–1032
Advanced online publication: 17.03.2010
x
x.
x
x.
2
0
1
0
21 28%
20 15%
DOI: 10.1055/s-0029-1219779; Art ID: D01910ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1

1028
U. C. Reddy, A. K. Saikia
LETTER
Table 1 Synthesis of 4-Aryldihydropyran
Entry
1
Aldehyde (a)
Time (h)
8
Temp (°C)
40
Product (b)
Yield (%)a
CHO
O
45
61
63
66
Ph
O
NO2
CHO
2
3
4
8
8
7
40
40
40
O2N
CHO
NO2
Ph
O
NO2
CF3
Ph
O
CHO
F3C
Ph
O
Cl
CHO
5
6
7
8
8
8
40
40
40
54
64
67
Cl
Ph
O
CHO
Br
Br
Ph
O
CO2Me
CHO
MeO2C
Ph
O
SO3Ph
CHO
8
9
40
72
PhO3S
Ph
O
9
5
5
r.t.
r.t.
95
95
CHO
CHO
Ph
O
10
Ph
Synlett 2010, No. 7, 1027–1032 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Aryl-5,6-dihydropyran
1029
Table 1 Synthesis of 4-Aryldihydropyran (continued)
Entry
Aldehyde (a)
Time (h)
Temp (°C)
r.t.
Product (b)
Yield (%)a
O
4
11
4
87
81
CHO
4
Ph
O
13
12
13
14
5
4
5
r.t.
r.t.
r.t.
CHO
13
Ph
O
CHO
92
75
Ph
O
CHO
Ph
a Yields refer to isolated yield. Compounds are characterized by IR, NMR, and MS.
Table 2 Reaction of 3-Butyn-1-ol with p-Nitrobenzaldehyde with other Nucleophiles (Arenes)
Entry
Arene
Time (h)a
Product
Yield (%)b
NO2
NO2
O
O
Me
1
5
72
78
94
Me
Me
o-15
p-15
NO2
O
Me
2
5
Me
Me
Me
16
NO2
O
Me
Me
3
5
Me
Me
Me
Me
17
Synlett 2010, No. 7, 1027–1032 © Thieme Stuttgart · New York

1030
U. C. Reddy, A. K. Saikia
LETTER
Table 2 Reaction of 3-Butyn-1-ol with p-Nitrobenzaldehyde with other Nucleophiles (Arenes) (continued)
Entry
Arene
Time (h)a
Product
Yield (%)b
O2N
OMe
O2N
OMe
OMe
4
6
76
OMe
OMe
o-18
p-18
MeO
OMe
O2N
MeO
OMe
OMe
OMe
5
4
82
MeO
OMe
OMe
19
a Reactions are performed at r.t.
b Compounds are characterized by IR, NMR, and MS.
The mechanism of the reaction can be explained as fol- reactivity of epoxides varies from 2,2-disubstituted to
lows (Scheme 2). Lewis acid activates the aldehyde for monosubstituted epoxides. In the case of monosubstituted
nucleophilic attack by the homopropargyl alcohol to give epoxides only a trace amount of dihydropyran was detect-
acetal 22. The intermediate 22 after Prins cyclization ed. On the other hand styrene oxide gave better yields than
forms carbocation 23, which undergoes Friedel–Crafts re- the aliphatic epoxides.11
action to give dihydropyran 24.
The mechanism of the reaction with epoxide can be ex-
The same dihydropyran can also be prepared using ep- plained by considering the already reported fact that ep-
oxides as aldehyde equivalents, as shown in Table 3. The oxides after opening with Lewis acid rearrange to
aldehydes (Scheme 3).12
LA
+
In conclusion, we have developed an efficient methodol-
O
OLA
ogy for the synthesis of 4-aryldihydropyrans using Prins
cyclization reaction.7 Although this method gives good to
moderate yields; it is free from 4-halosubstituted side
products. Furthermore, this method can be extended to ep-
oxides where aldehydes are not easily accessible. The
scope and synthetic applications of this novel reaction are
under investigation in our laboratory.
R
H
Prins
cyclization
O
R
R
O
R
O
+
23
HO
22
Friedel–Crafts
reaction
Ar
O
R
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
24
Scheme 2 Mechanism of the reaction
LA
H
O
+
O
O
LA
LA
LA
R
R
+
R
H
30
31
29
OH
Ar
+
Prins
cyclization
ArH
OLA
R
Friedel–Crafts
reaction
O
O
O
O
+
R
34
32
R
R
33
Scheme 3 Mechanism of the Prins cyclization reaction with epoxide
Synlett 2010, No. 7, 1027–1032 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Aryl-5,6-dihydropyran
1031
References and Notes
Table 3 Reaction of 3-Butyn-1-ol with Epoxides
R2
(1) (a) Tieze, L. F. Chem. Rev. 1996, 96, 115. (b) Yus, D. J.;
Ramon, M. Angew. Chem. Int. Ed. 2005, 44, 1602.
R2
O
O
BF3⋅OEt2
OH
R1
+
(c) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (d) Multicomponent Reaction; Zhu, J.; Bienaymé, H.,
Eds.; Wiley-VCH: Weinheim, 2005.
R1
arene
r.t. to 40 °C
Ar
(2) (a) Strubing, D.; Neumann, H.; Hubner, S.; Klaus, S.; Beller,
M. Tetrahedron 2005, 61, 11345. (b) Nair, V.; Sreekumar,
V.; Bindu, S.; Suresh, E. Org. Lett. 2005, 7, 2297.
Entry Epoxide
Time Product
(h)
Yield
(%)a
(3) (a) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045.
(b) Class, Y. J.; DeShong, P. Chem. Rev. 1995, 95, 1843.
(c) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc.
2001, 123, 8420. (d) Wang, Y.; Janjic, J.; Kozmin, S. A.
J. Am. Chem. Soc. 2002, 124, 13670. (e) Aubele, D. L.;
Wan, S.; Floreancig, P. E. Angew. Chem. Int. Ed. 2005, 44,
3485. (f) Bahnck, K. B.; Rychnovsky, S. D. Chem. Commun.
2006, 2388. (g) Tian, X. T.; Jaber, J. J.; Rychnovsky, S. D.
J. Org. Chem. 2006, 7, 3176.
O
1
6
Trace
O
9b
(4) (a) Yet, L. Chem. Rev. 2000, 100, 2963. (b) Boivin, T. L. B.
Tetrahedron 1987, 43, 3309. (c) Coppi, L.; Ricci, A.;
Taddei, M. J. Org. Chem. 1988, 53, 911. (d) Li, C.-J.;
Zhang, W.-C. Tetrahedron 2000, 56, 2403. (e) Schmidt, B.;
Westhus, M. Tetrahedron 2000, 56, 2421.
O
2
3
4
5
45
O
(5) Vinals, J. F.; Kiwala, J.; Hruza, D. E.; Hall, J. B.; Vock,
M. H. A. US 4070491, 1978.
(6) (a) Markó, I. E.; Bayston, D. J. Tetrahedron 1994, 50, 7141.
(b) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425.
(c) Miranda, P. O.; Carballo, R. M.; Martín, V. S.; Padrón, J.
I. Org. Lett. 2009, 11, 357. (d) Lian, Y.; Hinkle, R. J. J. Org.
Chem. 2006, 71, 7071. (e) Dobbs, A. P.; Martinović, S.
Tetrahedron Lett. 2002, 43, 7055. (f) Viswanathan, G. S.;
Yang, J.; Li, C.-J. Org. Lett. 1999, 1, 993. (g) Miranda, P.
O.; Díaz, D. D.; Padrón, J. I.; Bermejo, J.; Martín, V. S. Org.
Lett. 2003, 5, 1979. (h) Miranda, P. O.; Ramírez, M. A.;
Martín, V. S.; Padrón, J. I. Org. Lett. 2006, 8, 1633. (i) Liu,
F.; Loh, T.-P. Org. Lett. 2007, 9, 2063. (j) Dobbs, A. P.;
Parker, R. J.; Skidmore, J. Tetrahedron Lett. 2008, 49, 827.
(k) Hu, X.-H.; Liu, F.; Loh, T.-P. Org. Lett. 2009, 11, 1741.
(7) (a) Yadav, V. K.; Kumar, N. V. J. Am. Chem. Soc. 2004, 126,
8652. (b) Romanov, N. A.; Kantor, E. A.; Brudnik, I. M.;
Musavirov, R. S.; Kiladze, T. K.; Rakhmankulov, D. L. Zh.
Prikl. Khim. 1982, 55, 2778. (c) Romanov, N. A.;Kantor, E.
A.; Karakhanov, R. A.; Rakhmankulov, D. L. Zh. Org.
Khim. 1982, 18, 403. (d) Romanov, N. A.; Kantor, E. A.;
Musavirov, R. S.; Karakhanov, R. A.; Rakhmankulov, D. L.
Zh. Prikl. Khim. 1982, 55, 157. (e) Balaban, T.-S.; Balaban,
A. T. Tetrahedron Lett. 1987, 28, 1341.
25
O
O
5
60
26
O
OBn
5
45b
OBn
O
27
O
O
5
5
75b
(8) (a) Reddy, U. C.; Bondalapati, S.; Saikia, A. K. Eur. J. Org.
Chem. 2009, 1625. (b) Reddy, U. C.; Bondalapati, S.;
Saikia, A. K. J. Org. Chem. 2009, 74, 2605.
(9) Synthesis of 2,4-Diphenyl-5,6-dihydro-2H-pyran (1b)
To a mixture of benzaldehyde (0.10 mL, 1.0 mmol) and
homopropagyl alcohol (140 mg, 2.0 mmol) in dry benzene
(2.0 mL) was added freshly distilled BF3·OEt2 (0.15 mL, 1.2
mmol) under nitrogen atmosphere. The reaction mixture was
stirred at 40 °C for 8 h. The progress of the reaction was
monitored by TLC with EtOAc and hexane as eluents. After
completion of the reaction, the reaction mixture was treated
with aq NaHCO3, the mixture was extracted with Et2O, and
the combined organic extracts washed with brine and water.
The organic layer was dried (Na2SO4) and evaporated to
leave the crude product, which was purified by short column
chromatography over silica gel to give 2,4-diphenyl-5,6-
dihydro-2H-pyran 1b (106 mg, 45% yield) as a liquid. 1H
NMR (400 MHz, CDCl3): d = 2.45–2.52 (m, 1 H), 2.70–2.80
(m, 1 H), 3.92 (ddd, J = 11.6, 8.8, 4.0 Hz, 1 H), 4.18 (ddd,
J = 11.6, 5.2, 3.6 Hz, 1 H), 5.30 (d, J = 2.4 Hz, 1 H), 6.22 (d,
28
a Yields refer to isolated yield. Compounds are characterized by IR,
NMR, and MS.
b Mixture of two inseparable isomers with a ratio of 2:3 (27) and 1:1
(28).
Acknowledgment
A.K.S. is grateful to the Department of Science and Technology
(DST), New Delhi, for financial support (Grant No. SR/S1/OC-33/
2007) and C.M.R. is grateful to the Council of Scientific & Industri-
al Research (CSIR) for a fellowship.
Synlett 2010, No. 7, 1027–1032 © Thieme Stuttgart · New York

1032
U. C. Reddy, A. K. Saikia
LETTER
J = 1.2 Hz, 1 H), 7.23–7.45 (m, 10 H). 13C NMR (100 MHz,
CDCl3): d = 27.3, 63.6, 72.4, 124.3, 124.4, 125.1, 127.9,
128.6 (2 C), 129.6, 133.4, 135.5, 136.9, 139.9, 148.5. IR:
3029, 2923, 2854, 1600, 1493, 1453, 1273, 1119, 1075,
1029, 886, 749, 698 cm–1. HRMS (APCI): m/z calcd for
C17H16O [M + H]+: 237.1279; found: 237.1258.
6-Isopropyl-4-phenyl-5,6-dihydro-2H-pyran (22)
To a mixture of 1,2-epoxy-2-methylpropane (0.09 mL, 1.0
mmol) and homopropagyl alcohol (140 mg, 2.0 mmol) in dry
benzene (3.0 mL) was added freshly distilled BF3·OEt2 (0.15
mL, 1.2 mmol) under nitrogen atmosphere. The reaction
mixture was stirred at r.t. for 5 h. The progress of the reaction
was monitored by TLC with EtOAc and hexane as eluents.
After completion of reaction, the reaction mixture was
treated with aq NaHCO3, and the product was extracted with
Et2O, and then the combined organic extracts washed with
brine and H2O. The organic layer was dried (Na2SO4) and
evaporated to leave the crude product, which was purified by
short column chromatography over silica gel to give 6-
isopropyl-4-phenyl-5,6-dihydro-2H-pyran 25 (90 mg, 45%
yield) as a liquid. 1H NMR (400 MHz, CDCl3): d = 0.99 (t,
J = 6.8 Hz, 6 H), 1.82–1.93 (m, 1 H), 2.27–2.40 (m, 1 H),
2.60–2.71 (m, 1 H), 3.73 (dt, J = 10.4, 3.2 Hz, 1 H), 4.00–
4.06 (m, 1 H), 4.16 (ddd, J = 10.8, 5.6, 1.6 Hz, 1 H), 6.10 (m,
1 H), 7.24–7.28 (m, 1 H), 7.30–7.36 (m, 2 H), 7.38–7.42 (m,
2 H). 13C NMR (100 MHz, CDCl3): d = 18.1, 18.6, 27.7,
33.3, 64.2, 79.4, 125.0 (2C), 127.5, 127.7, 135.6, 140.8. IR:
2960, 2853, 1645, 1494, 1363, 1115, 1089, 880, 751, 699
cm–1. HRMS (APCI): m/z calcd for C14H18O [M + H]+:
203.1436; found: 203.1431.
(10) Podder, S.; Choudhury, J.; Roy, U. K.; Roy, S. J. Org. Chem.
2007, 72, 3100.
(11) The product 26 was sensitive to silica gel. While purifying
the compound by column chromatography, it was
decomposed. Therefore, the silica gel of the column
chromatography was impregnated with 3% Et3N in hexane
during the purification
(12) (a) Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212.
(b) Li, J.; Li, C.-J. Tetrahedron Lett. 2001, 42, 793.
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