Indium-mediated regioselective mono-allylation of 1,5-dicarbonyl compounds and dehydrative cyclization to 2,3-dihydro-4H-pyran-4-ones and 3,4-dihydro-2H-[1,4]oxazines

Article abstract of DOI:10.1016/j.tetlet.2012.07.022

An indium-mediated Barbier type mono-allylation of 1,5-dicarbonyl compounds and a subsequent acid-catalyzed dehydrative cyclization afforded 2,3-dihydro-4H-pyran-4-ones and 3,4-dihydro-2H-[1,4]oxazines.

Full text of DOI:10.1016/j.tetlet.2012.07.022

Tetrahedron Letters 53 (2012) 4979–4983
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Tetrahedron Letters
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Indium-mediated regioselective mono-allylation of 1,5-dicarbonyl
compounds and dehydrative cyclization to 2,3-dihydro-4H-pyran-4-ones
and 3,4-dihydro-2H-[1,4]oxazines
Sung Hwan Kim a, Sangku Lee b, Se Hee Kim a, Jin Woo Lim a, Jae Nyoung Kim a,
⇑
a Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
b Immune Modulator Research Center, KRIBB, Daejeon 305-806, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An indium-mediated Barbier type mono-allylation of 1,5-dicarbonyl compounds and a subsequent acid-
catalyzed dehydrative cyclization afforded 2,3-dihydro-4H-pyran-4-ones and 3,4-dihydro-2H-
[1,4]oxazines.
Received 5 June 2012
Revised 30 June 2012
Accepted 6 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indium
2,3-Dihydro-4H-pyran-4-ones
3,4-Dihydro-2H-[1,4]oxazines
1,5-Dicarbonyl compounds
2,3-Dihydropyran-4-ones occur widely as key structural sub-
units in numerous natural products and have been used as useful
intermediates for the synthesis of various biologically important
compounds.1 The synthesis of 2,3-dihydropyran-4-ones has been
carried out in a variety of methods2–6 including a hetero-Diels–
Alder reaction.2 Gouverneur and co-workers reported a palla-
dium(II)-mediated oxidative cyclization of b-hydroxyenones3a
O
O
O
O
O
O
NaH/n-BuLi
(problematic)
+
R
R
Ph
Ph
R
OH O
In-mediated regioselective
mono-allylation (This work)
O
Ph
and
a
gold(I)-catalyzed cyclization of b-hydroxyynones.3b An
Scheme 1.
acid-catalyzed cyclization of 5-hydroxy-1,3-diketones has also
been used quite frequently.4,5 The synthesis of 5-hydroxy-1,3-dike-
tones could be carried out by the reaction between a dianion of
1,3-diketone and a carbonyl compound under strongly basic condi-
tions; however, the synthesis faced with a problem when the car-
bonyl compound has an acidic proton such as allyl phenyl ketone.
pyran-4-ones1–6 and 3,4-dihydro-2H-[1,4]oxazines,9 as shown in
Scheme 2.
At the outset of our experiment, an indium-mediated allylation
of 1,3,5-triketone 1a was examined. The reaction was not com-
pleted with an equivalent amount of allyl bromide in THF (reflux)
or DMF (rt to 40 °C). As shown in Scheme 3, the reaction provided a
monoallyl compound 2a in moderate yield (69%) in the presence of
excess amounts of allyl bromide (3.0 equiv) and indium (2.0 equiv)
in refluxing THF.7k A regioisomeric compound 2a0 and diallylated
compounds were not produced, although 1a has three carbonyl
groups. The selective mono-allylation at the C-1 position of 1a oc-
curred presumably due to the formation of an intermediate I,
which could be stabilized by a chelation of indium center with
the oxygen atom of the carbonyl at C-3 position and an additional
intramolecular hydrogen bonding. The yield of 2a was slightly
improved to 72% in DMF at 40 °C (20 h).10
4a–d
In this case, a regioselective mono-allylation of a 1,3,5-tricar-
bonyl compound could be a method of choice, as exemplified in
Scheme 1.
Indium-mediated allylations have received much attention,
because the reaction provided an allylated product in high yield
under mild conditions.7,8 As a continuous study in our recent in-
dium-mediated allylations,8 we presumed that an allylation of
1,5-dicarbonyl compounds could provide an efficient way to
six-membered heterocyclic compounds such as 2,3-dihydro-4H-
With this compound 2a, an acid-catalyzed dehydrative cycliza-
tion was examined in the presence of p-TsOH. Refluxing the
⇑
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.022

4980
S. H. Kim et al. / Tetrahedron Letters 53 (2012) 4979–4983
dehydrative
cyclization
X
X
X
allylindium
Ph
Ph
Ph
Ph
Ph
Ph
O
O HO
O
O
1
3
2
X = CO, N-Ts, CH2
Scheme 2.
Ph
Ph
O
H
H
O
1
O
O
O
3
H
O
O
O
O
via I
Conditions
O
O
OH
or
O
In
Ph
Ph
Ph
3
1
In
Ph
Ph
1
O
3
Ph
Ph
Ph
O
1a
2a
2a' (not formed)
I (C-1 attack)
(more favorable)
II (C-3 attack)
(less favorable)
Conditions
allyl bromide (3.0 equiv), In (2.0 equiv), THF, reflux, 8 h: 2a (69%)
allyl bromide (3.0 equiv), In (2.0 equiv), DMF, 40 oC, 20 h: 2a (72%)
Scheme 3.
impossible. The indium-mediated Barbier type reaction of 1a with
cinnamyl bromide failed presumably due to steric hindrance.
The reaction of 2,4,6-heptatrione (1b) was performed similarly
as in Scheme 6, and the product 3d was obtained in 64% yield. Sim-
ilarly, the reactions with methallyl bromide and crotyl bromide
afforded 3e and 3f, respectively, in similar yields. Compound 3f
was isolated as a syn/anti mixture (major/minor, 2:1), as in the case
of 3c.
O
p-TsOH (20%)
benzene, reflux, 1h
72%
Ph
2a
1a
Ph
O
93%
3a
(i) allyl bromide (3.0 equiv), In (2.0 equiv), DMF, 40 oC, 20 h
(ii) aqueous extractive workup
As a next substrate we selected N-tosyl derivative 1c, as shown
in Scheme 7. However, diallyl compound 2g0 was obtained as a ma-
jor product (54%) along with a low yield (4%) of monoallyl com-
pound 2g under the influence of allyl bromide (3.0 equiv) and
indium (2.0 equiv) in DMF. When we reduced the amounts of allyl
bromide (1.1 equiv), a mixture of mono- and di-allyl derivatives
was formed again in a low combined yield (30–40%). Fortunately,
the reaction in THF afforded a monoallyl compound 2g as a major
product (68%) even in the presence of excess amounts of allyl bro-
mide (3.0 equiv) although the reason is not clear at this stage.
The monoallyl derivative 2g was converted into 3,4-dihydro-
2H-[1,4]oxazine 3g in good yield (91%) by a dehydrative cyclization
with p-TsOH in benzene (1 h), as shown in Scheme 8. When we
skipped the separation step of 2g, compound 3g was obtained in
63% directly from 1c. The yield of 63% is very close to that of the
two-step procedure (62%:68% for 2g and 91% for 3g).
(iii) p-TsOH (20%), benzene, reflux, 1 h
overall 56%
Scheme 4.
benzene solution of 2a in the presence of p-TsOH (20%) afforded
pyranone derivative 3a in good yield (93%) in a short time (1 h),
as shown in Scheme 4.10 Compound 3a could also be synthesized
in 56% by the dehydrative cyclization of crude 2a, which was ob-
tained by simple aqueous extractive workup of the allylation mix-
ture of 1a.
Encouraged by the successful results, we carried out the reac-
tions of 1a with methallyl bromide and crotyl bromide under the
same reaction conditions without the separation of the corre-
sponding homoallylic alcohol intermediates.11 As shown in
Scheme 5, the pyranones 3b and 3c were obtained in moderate
yields (54% and 52%, respectively).10 Compound 3c was formed
as a diastereomeric mixture (85:15), and the separation was
The reaction of 1c and methallyl bromide afforded monoallyl
derivative 2h in 63%. It is interesting to note that the reaction of
2h under the same reaction conditions (p-TsOH, benzene, reflux)
O
methallyl bromide (3.0 equiv)
p-TsOH (20%)
benzene, reflux, 1 h
O
O
HO Ph
In (2.0 equiv), DMF, 40 oC, 20 h
Ph
Ph
2b (used without separation)
Ph
O
3b (54%)
1a
O
O
O
crotyl bromide (3.0 equiv)
p-TsOH (20%)
benzene, reflux, 1 h
HO Ph
In (2.0 equiv), DMF, 40 oC, 20 h
Ph
Ph
Ph
O
2c (diastereomeric mixture)
(used without separation)
3c (52%)
85:15 mixture
Scheme 5.

S. H. Kim et al. / Tetrahedron Letters 53 (2012) 4979–4983
4981
O
O
(i) allyl bromide (3.0 equiv), In (2.0 equiv), THF, reflux, 5 h
(ii) aqueous extractive workup
O
O
O
(iii) p-TsOH (20%), benzene, reflux, 1 h
1b
3d (64%)
O
O
methallyl bromide
same conditions
crotyl bromide
same conditions
1b
1b
O
O
3e (60%)
3f (62%)
2:1 mixture
Scheme 6.
Ts
N
Ts
N
Ts
N
Conditions
+
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
OH
OH HO
1c
2g
2g'
(meso/dl = 2:1)
Condition A: Allyl bromide (3.0 equiv), In (2.0 equiv), DMF, rt, 5 h: 2g, 4%; 2g', 54%.
Condition B: Allyl bromide (3.0 equiv), In (2.0 equiv), THF, reflux, 2 h: 2g, 68%; 2g', 6%.
Scheme 7.
Ts
N
of 3g cannot.13 Compound 3h could be synthesized in good yield
(78%) from 2h by using a lesser amount of p-TsOH (10%) at room
temperature for 24 h. Compound 4 was also formed together, al-
beit in low yield (13%), even at this low temperature.
p-TsOH (20%), benzene, reflux, 1 h
2g
(68%)
Ph
Ph
O
3g (91%)
As a next substrate, 1,3-dibenzoylpropane (1d) was examined.
The reaction of 1d and allyl bromide both in THF or DMF produced
a diallylated compound as a major product. Thus, we used excess
amounts of 1,3-dibenzoylpropane (2.0 equiv) in order to prepare
the monoallyl derivative 2i as a major. Actually, 2i was obtained
in 82% when we adjusted the ratio of 1d/allyl bromide/In to 2.0/
1.0/0.7 (DMF, 40 °C, 5 h), as shown in Scheme 10. The acid-cata-
lyzed dehydrative cyclization of 2i at refluxing temperature pro-
duced a complex mixture, while 3,4-dihydro-2H-pyran 3i was
formed as a major product at room temperature in good yield
(80%). However, this compound 3i was somewhat unstable and re-
turned to the starting material 2i slowly.14 Similarly, the reaction
of 1d and methallyl bromide provided 2j (74%),14 and an acid treat-
ment of 2j produced a 9-oxa-bicyclo[3.3.1]non-2-ene derivative 5
in good yield (87%) even at room temperature. As in the case of
4, the corresponding 2-methallyl-3,4-dihydro-2H-pyran derivative
must be converted into 5 via the acid-catalyzed oxonium-ene
(i) Condition B in Scheme 7
(ii) extractive workup
1c
3g (63%)
(iii) p-TsOH (20 %), benzene, reflux, 1 h
Scheme 8.
afforded a bicyclic compound 4 in moderate yield (60%) instead of
3h. Compound 4 might be formed via the oxonium-ene reaction12
of 3h under the acidic conditions, as shown in Scheme 9. Such an
oxonium-ene reaction was not observed during the synthesis of al-
lyl derivative 3g. The reaction of 3g in the presence of an acid cat-
alyst (p-TsOH or InCl3) even after a long reaction time (20 h) did
not produce the corresponding bicyclic compound at all. The differ-
ence between 3g and 3h might be due to the electron density at the
double bond. Electron-rich methallyl moiety of 3h could provide
its
p
-electrons to the oxonium intermediate while the allyl group
Ts
N
- H2O
Ph
O
Ph
Ts
N
Ts
N
Br
3h (not formed)
p-TsOH (20%)
(3.0 equiv)
benzene
H+
Ph
Ph
OH
1c
Ph
Ph
reflux, 1 h
O
O
In (2.0 equiv)
THF, reflux, 2 h
OH
Ts
N
Ts
oxonium-ene
reaction
H+
N
O
2h (63%)
Ph
O
Ph
- H2O
p-TsOH (10%)
benzene, rt, 24 h
Ph
Ph
4 (60%)
3h (78%) + 4 (13%)
Scheme 9.

4982
S. H. Kim et al. / Tetrahedron Letters 53 (2012) 4979–4983
Br
p-TsOH (10%)
(1.0 equiv)
benzene
rt, 18 h
Ph
Ph
Ph
Ph
Ph
O
OH
Ph
Ph
O
In (0.7 equiv)
DMF, 40 oC, 5 h
O
O
3i (80%)
2i (82%)
Ph
Ph
Br
1d (2.0 equiv)
p-TsOH (10%)
benzene, MgSO4
(1.0 equiv)
O
O
Ph
OH
In (0.7 equiv)
rt, 6 h
DMF, 40 oC, 5 h
2j (74%)
5 (87%)
Scheme 10.
5. For the synthesis of natural products bearing a 2,3-dihydro-4H-pyran-4-one
moiety using an acid-catalyzed cyclization protocol of 5-hydroxy-1,3-
diketones, see: (a) Tsubone, K.; Hashizume, K.; Fuwa, H.; Sasaki, M.
Tetrahedron 2011, 67, 6600–6615; (b) Jung, M. E.; Chaumontet, M.; Salehi-
Rad, R. Org. Lett. 2010, 12, 2872–2875; (c) Nakazaki, A.; Kobayashi, S. Synlett
2009, 1605–1608; (d) Nakazaki, A.; Kobayashi, S. Chem. Lett. 2007, 36, 42–43;
(e) Lopez, R.; Poupon, J.-C.; Prunet, J.; Ferezou, J.-P.; Ricard, L. Synthesis 2005,
644–661; (f) Wender, P. A.; Koehler, M. F. T.; Sendzik, M. Org. Lett. 2003, 5,
4549–4552; (g) Walkup, R. D.; Boatman, P. D., Jr.; Kane, R. R.; Cunningham, R. T.
Tetrahedron Lett. 1991, 32, 3937–3940; (h) Hayakawa, I.; Takemura, T.;
Fukasawa, E.; Ebihara, Y.; Sato, N.; Nakamura, T.; Suenaga, K.; Kigoshi, H.
Angew. Chem., Int. Ed. 2010, 49, 2401–2405; (i) Perkins, M. V.; Jahangiri, S.;
Taylor, M. R. Tetrahedron Lett. 2006, 47, 2025–2028; (j) Perkins, M. V.; Sampson,
R. A.; Joannou, J.; Taylor, M. R. Tetrahedron Lett. 2006, 47, 3791–3795.
6. For the other synthetic approaches of 2,3-dihydro-4H-pyran-4-ones, see: (a)
Yang, F.; Ji, K.-G.; Zhao, S.-C.; Ali, S.; Ye, Y.-Y.; Liu, X.-Y.; Liang, Y.-M. Chem. Eur. J.
2012, 18, 6470–6474; (b) Lian, Z.; Zhao, Q.-Y.; Wei, Y.; Shi, M. Eur. J. Org. Chem.
2012, 3338–3341; (c) Lian, Z.; Shi, M. Eur. J. Org. Chem. 2012, 581–586; (d)
Matsuo, J.-i.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem. Soc. 2008, 130,
11600–11601; (e) Sibi, M. P.; Zimmerman, J. J. Am. Chem. Soc. 2006, 128, 13346–
13347.
reaction. In the reaction, removal of trace amounts of moisture
with MgSO4 was beneficial for the effective formation of 5.14 With-
out MgSO4, the reaction was sluggish and many compounds were
observed including 2j, 5, and the corresponding 3,4-dihydro-2H-
pyran derivative.
In summary, various 2,3-dihydro-4H-pyran-4-ones, 3,4-dihy-
dro-2H-[1,4]oxazines, and 3,4-dihydro-2H-pyrans have been
synthesized via a sequential In-mediated Barbier type allylation
of suitable 1,5-dicarbonyl compounds and the following acid-cata-
lyzed dehydrative cyclization. Some bicyclic compounds, 9-oxa-
3-azabicyclo[3.3.1]non-6-ene and 9-oxabicyclo[3.3.1]non-2-ene,
were prepared in some cases where the monocyclic compounds
have a methallyl moiety.
Acknowledgments
7. For the leading references on indium-mediated reactions, see: (a) Kim, S. H.;
Lee, H. S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron 2010, 66, 7065–7076; (b)
Auge, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739–1764; (c) Kargbo, R.
B.; Cook, G. R. Curr. Org. Chem. 2007, 11, 1287–1309; (d) Lee, P. H. Bull. Korean
Chem. Soc. 2007, 28, 17–28; (e) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55,
11149–11176; (f) Pae, A. N.; Cho, Y. S. Curr. Org. Chem. 2002, 6, 715–737; (g) Li,
C.-J.; Chan, T.-H. Tetrahedron Lett. 1991, 32, 7017–7020; (h) Nair, V.; Ros, S.;
Jayan, C. N.; Pillai, B. S. Tetrahedron 2004, 60, 1959–1982; (i) Podlech, J.; Maier,
T. C. Synthesis 2003, 633–655; (j) Bowyer, W. J.; Singaram, B.; Sessler, A. M.
Tetrahedron 2011, 67, 7449–7460; An example of a selective allylation was
reported by Baba and co-workers, see: (k) Babu, S. A.; Yasuda, M.; Shibata, I.;
Baba, A. Synlett 2004, 1223–1226; For the isolation and crystallographic
characterization of allylindium species, see: (l) Yasuda, M.; Haga, M.; Baba, A.
Eur. J. Org. Chem. 2009, 5513–5517; (m) Yasuda, M.; Haga, M.; Nagaoka, Y.;
Baba, A. Eur. J. Org. Chem. 2010, 5359–5363.
8. For our recent contributions on indium-mediated Barbier-type allylations, see:
(a) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 1696–
1698; (b) Kim, S. H.; Kim, S. H.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2009, 50,
5744–5747; (c) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett.
2009, 50, 6476–6479; (d) Kim, S. H.; Kim, S. H.; Kim, K. H.; Kim, J. N. Tetrahedron
Lett. 2010, 51, 860–862; (e) Kim, S. H.; Kim, S. H.; Kim, T. H.; Kim, J. N.
Tetrahedron Lett. 2010, 51, 2774–2777; (f) Kim, Y. M.; Lee, S.; Kim, S. H.; Kim, K.
H.; Kim, J. N. Tetrahedron Lett. 2010, 51, 5922–5926; (g) Lim, J. W.; Kim, K. H.;
Park, B. R.; Kim, J. N. Tetrahedron Lett. 2011, 52, 6545–6549; (h) Park, B. R.; Kim,
K. H.; Lim, J. W.; Kim, J. N. Tetrahedron Lett. 2012, 53, 36–40; (i) Kim, Y. M.; Lee,
S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2011, 52, 3240–3242; (j) Park, B. R.;
Kim, S. H.; Kim, Y. M.; Kim, J. N. Tetrahedron Lett. 2011, 52, 1700–1704; (k) Park,
B. R.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2010, 51, 6568–6571; (l) Kim, S. H.;
Lee, S.; Kim, Y. M.; Kim, J. N. Bull. Korean Chem. Soc. 2010, 31, 3822–3825; (m)
Kim, S. H.; Kim, Y. M.; Park, B. R.; Kim, J. N. Bull. Korean Chem. Soc. 2010, 31,
3031–3034; (n) Kim, S. H.; Kim, Y. M.; Kim, J. N. Bull. Korean Chem. Soc. 2010, 31,
2351–2356.
This study was financially supported by Chonnam National Uni-
versity, 2011. Spectroscopic data were obtained from the Korea Ba-
sic Science Institute, Gwangju branch.
References and notes
1. For the synthesis of 2,3-dihydro-4H-pyran-4-ones and their synthetic
applications of natural products, see: (a) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793–3798; (b) Williams, D. R.;
Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843–1850; (c) Cox, J. M.;
Rainier, J. D. Org. Lett. 2001, 3, 2919–2922; (d) Rainier, J. D.; Allwein, S. P.; Cox, J.
M. Org. Lett. 2000, 2, 231–234; (e) Danishefsky, S. J.; Selnick, H. G.; Zelle, R. E.;
DeNinno, M. P. J. Am. Chem. Soc. 1988, 110, 4368–4378.
2. For the synthesis of 2,3-dihydro-4H-pyran-4-ones by a hetero-Diels–Alder
reaction, see: (a) Jorgensen, K. A. Eur. J. Org. Chem. 2004, 2093–2102; (b)
Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558–3588; (c) Winkler, J. D.;
Oh, K. Org. Lett. 2005, 7, 2421–2423; (d) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc.
2002, 124, 9662–9663; (e) Evans, P. A.; Nelson, J. D. J. Org. Chem. 1996, 61,
7600–7602; (f) Barluenga, J.; Aznar, F.; Fernandez, M. Tetrahedron Lett. 1995, 36,
6551–6554.
3. For the synthesis of 2,3-dihydro-4H-pyran-4-ones via
a cyclization of b-
hydroxyenones, b-hydroxyynones, and related compounds see: (a) Reiter, M.;
Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91–94; (b) Schuler, M.; Silva, F.;
Bobbio, C.; Tessier, A.; Gouverneur, V. Angew. Chem., Int. Ed. 2008, 47, 7927–
7930; (c) Silva, F.; Reiter, M.; Mills-Webb, R.; Sawicki, M.; Klar, D.; Bensel, N.;
Wagner, A.; Gouverneur, V. J. Org. Chem. 2006, 71, 8390–8394; (d) Shu, X.-Z.;
Liu, X.-Y.; Ji, K.-G.; Xiao, H.-Q.; Liang, Y.-M. Chem. Eur. J. 2008, 14, 5282–5289;
(e) Dreeben, S.; Schabbert, S.; Schaumann, E. Eur. J. Org. Chem. 2001, 245–251;
(f) Egi, M.; Azechi, K.; Saneto, M.; Shimizu, K.; Akai, S. J. Org. Chem. 2010, 75,
2123–2126.
4. For the synthesis of 2,3-dihydro-4H-pyran-4-ones via an acid-catalyzed
cyclization of 5-hydroxy-1,3-diketones and related compounds see: (a)
Ahmad, R.; Khera, R. A.; Villinger, A.; Langer, P. Tetrahedron Lett. 2009, 50,
3020–3022; (b) Khera, R. A.; Hussain, M.; Ahmad, R.; Saeed, A.; Villinger, A.;
Fischer, C.; Langer, P. J. Fluorine Chem. 2010, 131, 892–897; (c) Khera, R. A.;
Ahmad, R.; Ullah, I.; Abid, O.-U.-R.; Fatunsin, O.; Sher, M.; Villinger, A.; Langer,
P. Helv. Chim. Acta 2010, 93, 1705–1715; (d) Wang, H.; Shuhler, B. J.; Xian, M. J.
Org. Chem. 2007, 72, 4280–4283; (e) Andrews, P. C.; Gee, W. J.; Junk, P. C.;
Krautscheid, H. Org. Biomol. Chem. 2010, 8, 698–705; (f) Light, R. J.; Hauser, C. R.
J. Org. Chem. 1961, 26, 1716–1724; (g) MacDonald, F. K.; Burnell, D. J. J. Org.
Chem. 2009, 74, 6973–6979; (h) Denmark, S. E.; Heemstra, J. R., Jr. J. Org. Chem.
2007, 72, 5668–5688; (i) Gao, B.; Yu, Z.; Fu, Z.; Feng, X. Tetrahedron Lett. 2006,
47, 1537–1539; (j) Greg Zipp, G.; Hilfiker, M. A.; Nelson, S. G. Org. Lett. 2002, 4,
1823–1826.
9. For the synthesis and applications of 3,4-dihydro-2H-[1,4]oxazine derivatives,
see: (a) Brice, H.; Gill, D. M.; Goldie, L.; Keegan, P. S.; Kerr, W. J.; Svensson, P. H.
Chem. Commun. 2012, 48, 4836–4838; (b) Tovar, A.; Pena, U.; Hernandez, G.;
Portillo, R.; Gutierrez, R. Synthesis 2007, 22–24; (c) Laroche, C.; Kerwin, S. M. J.
Org. Chem. 2009, 74, 9229–9232; (d) Rekka, E. A.; Kourounakis, P. N. Curr. Med.
Chem. 2010, 17, 3422–3430.
10. Typical procedure for the synthesis of 2a and 3a: A stirred solution of 1,5-
diphenylpentane-1,3,5-trione (1a, 133 mg, 0.5 mmol), allyl bromide (182 mg,
1.5 mmol), and indium (115 mg, 1.0 mmol) in DMF (1.5 mL) was heated to
40 °C for 20 h. After aqueous extractive workup and column chromatographic
purification process (hexanes/EtOAc, 10:1) compound 2a was isolated as
colorless oil, 111 mg (72%).
A stirred solution of compound 2a (62 mg,
0.2 mmol) and p-TsOH (8 mg, 20 mol%) in benzene (0.5 mL) was heated to
reflux for 1 h. After aqueous extractive workup and column chromatographic

S. H. Kim et al. / Tetrahedron Letters 53 (2012) 4979–4983
4983
purification process (hexanes/EtOAc, 6:1) compound 3a was isolated as a pale
yellow solid, 54 mg (93%). Other compounds were synthesized similarly, and
the selected spectroscopic data of 2a, 3a–f, 2g, 2g0, 3g–i, 4, and 5 are as follows.
Compound 2a: 72%; colorless oil; IR (film) 3487, 1605, 1574, 1564, 1545, 1493,
7.22–7.36 (m, 6H), 7.43–7.46 (m, 4H), 7.53 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 21.42, 43.89, 62.43, 76.97, 119.69, 125.63, 127.10, 127.56, 128.33,
129.74, 133.23, 135.57, 143.64, 143.76; ESIMS m/z 514 (M++Na). Minor isomer
18%; colorless oil; IR (film) 3489, 3368, 1599, 1493, 1445, 1337, 1161 cmꢀ1 1H
;
1460, 1296 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 2.56 (dd, J = 14.1 and 7.8 Hz,
NMR (CDCl3, 300 MHz) d 2.36 (dd, J = 14.1 and 8.4 Hz, 2H), 2.42 (s, 3H), 2.64
(dd, J = 14.1 and 6.0 Hz, 2H), 3.42 (d, J = 15.3 Hz, 2H), 3.51 (d, J = 15.3 Hz, 2H),
4.10 (br s, 2H), 4.83 (dt, J = 17.1 and 0.9 Hz, 2H), 4.97 (dd, J = 10.2 and 2.1 Hz,
2H), 5.34–5.48 (m, 2H), 7.23–7.38 (m, 8H), 7.42–7.46 (m, 4H), 7.68 (dt, J = 8.4
and 1.8 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.50, 45.11, 60.27, 76.48, 119.56,
125.96, 127.04, 127.79, 128.23, 129.71, 132.89, 135.14, 143.83, 143.94; ESIMS
m/z 514 (M++Na). Further assignment of meso/dl was not performed.
1H), 2.67 (dd, J = 14.1 and 6.6 Hz, 1H), 2.97 (d, J = 15.3 Hz, 1H), 3.08 (d,
J = 15.3 Hz, 1H), 4.29 (br s, 1H), 5.06–5.11 (m, 2H), 5.63–5.77 (m, 1H), 6.05 (s,
1H), 7.19–7.24 (m, 1H), 7.30–7.35 (m, 2H), 7.38–7.53 (m, 5H), 7.75–7.78 (m,
2H), 15.76 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 47.87, 49.86, 75.74, 98.20,
118.77, 125.15, 126.86, 126.98, 128.19, 128.64, 132.48, 133.41, 133.98, 145.58,
180.90, 197.85; ESIMS m/z 331 (M++Na). Anal. Calcd for C20H20O3: C, 77.90; H,
6.54. Found: C, 77.68; H, 6.71.
Compound 3g: 91%; colorless oil; IR (film) 1653, 1597, 1495, 1449, 1356, 1333,
Compound 3a: 93%; pale yellow solid, mp 72–73 °C; IR (KBr) 1663, 1601, 1572,
1167 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 2.39 (s, 3H), 2.57 (ddt, J = 14.7, 7.2, and
;
1449, 1366 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 2.86 (dt, J = 6.9 and 0.9 Hz, 2H),
1.2 Hz, 1H), 2.69 (dd, J = 14.7 and 7.2 Hz, 1H), 3.52 (d, J = 11.7 Hz, 1H), 3.68 (d,
J = 11.7 Hz, 1H), 4.93–5.02 (m, 2H), 5.50–5.64 (m, 1H), 6.73 (s, 1H), 7.23–7.38
(m, 10H), 7.57 (dt, J = 6.9 and 1.5 Hz, 2H), 7.63 (dt, J = 8.4 and 1.8 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 21.51, 42.56, 49.94, 78.75, 101.90, 119.12, 123.47,
125.20, 127.00, 127.58, 127.72, 128.39 (2C), 129.83, 131.58, 133.87, 134.51,
136.90, 140.15, 143.89; ESIMS m/z 432 (M++H). Anal. Calcd for C26H25NO3S: C,
72.36; H, 5.84; N, 3.25. Found: C, 72.29; H, 5.99; N, 3.12.
3.02 (d, J = 16.8 Hz, 1H), 3.09 (d, J = 16.8 Hz, 1H), 5.05–5.14 (m, 2H), 5.61–5.75
(m, 1H), 5.96 (s, 1H), 7.28–7.51 (m, 8H), 7.81–7.85 (m, 2H); 13C NMR (CDCl3,
75 MHz) d 44.39, 46.16, 85.62, 102.41, 119.76, 125.11, 126.46, 127.98, 128.52,
128.71, 131.58, 131.66, 132.87, 140.83, 167.56, 192.31; ESIMS m/z 313
(M++Na). Anal. Calcd for C20H18O2: C, 82.73; H, 6.25. Found: C, 82.69; H, 6.43.
Compound 3b: 54%; pale yellow solid, mp 87–88 °C; IR (KBr) 1665, 1601, 1572,
1449, 1364 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 1.61 (s, 3H), 2.76 (dd, J = 14.1
Compound 3h: 78%; colorless oil; IR (film) 1651, 1597, 1495, 1447, 1358, 1333,
and 0.6 Hz, 1H), 2.84 (d, J = 14.1 Hz, 1H), 3.07 (d, J = 16.8 Hz, 1H), 3.13 (d,
J = 16.8 Hz, 1H), 4.72 (s, 1H), 4.94 (s, 1H), 5.96 (s, 1H), 7.25–7.51 (m, 8H), 7.82–
7.85 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 24.19, 44.20, 50.12, 86.12, 102.46,
116.99, 125.17, 126.44, 127.98, 128.49, 128.75, 131.55, 132.88, 140.12, 141.15,
167.46, 192.62; ESIMS m/z 327 (M++Na). Anal. Calcd for C21H20O2: C, 82.86; H,
6.62. Found: C, 82.98; H, 6.72.
1167 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 1.39 (s, 3H), 2.31 (s, 3H), 2.48 (d,
;
J = 14.1 Hz, 1H), 2.60 (d, J = 14.1 Hz, 1H), 3.42 (d, J = 11.7 Hz, 1H), 3.68 (d,
J = 11.7 Hz, 1H), 4.51 (s, 1H), 4.68 (s, 1H), 6.65 (s, 1H), 7.14–7.30 (m, 10H), 7.51
(d, J = 7.2 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.49,
24.07, 46.47, 50.25, 79.27, 101.89, 116.09, 123.37, 125.24, 126.98, 127.46,
127.64, 128.27, 128.40, 129.80, 133.85, 134.55, 136.93, 139.99, 140.36, 143.83;
ESIMS m/z 468 (M++Na). Anal. Calcd for C27H27NO3S: C, 72.78; H, 6.11; N, 3.14.
Found: C, 72.94; H, 6.43; N, 3.10.
Compound 3c: (syn/anti = 15:85): 52%; pale yellow oil; IR (film) 1663, 1603,
1572, 1449, 1364 cmꢀ1 1H NMR (CDCl3, 300 MHz, anti-form)
; d 1.10 (d,
J = 6.9 Hz, 3H), 2.77–2.86 (m, 1H), 3.01 (dd, J = 16.5 and 1.2 Hz, 1H), 3.17 (d,
J = 16.5 Hz, 1H), 5.06–5.15 (m, 2H), 5.69–5.81 (m, 1H), 5.92 (s, 1H), 7.24–7.32
(m, 5H), 7.44–7.52 (m, 3H), 7.83–7.87 (m, 2H); 13C NMR (CDCl3, 75 MHz, anti-
form) d 14.72, 42.81, 48.71, 87.93, 102.58, 117.25, 125.88, 126.33, 127.85,
128.23, 128.77, 131.55, 132.87, 138.22, 139.20, 167.33, 192.49; ESIMS m/z 327
(M++Na). Anal. Calcd for C21H20O2: C, 82.86; H, 6.62. Found: C, 82.92; H, 6.39.
Compound 3i: 80%; colorless oil; IR (film) 1682, 1651, 1599, 1493, 1447 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 1.73–1.84 (m, 1H), 1.89–2.09 (m, 2H), 2.14–2.21
(m, 1H), 2.59 (dd, J = 7.5 and 0.9 Hz, 2H), 4.90–4.96 (m, 2H), 5.24–5.26 (m, 1H),
5.63–5.76 (m, 1H), 7.13–7.31 (m, 8H), 7.63 (d, J = 7.2 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 18.81, 30.52, 47.09, 80.06, 97.05, 117.91, 124.24, 125.21, 126.72,
127.72, 128.14, 128.17, 133.35, 136.05, 143.79, 149.41; ESIMS m/z 299
(M++Na). Anal. Calcd for C20H20O: C, 86.92; H, 7.29. Found: C, 86.77; H, 7.56.
Compound 3d: 64%; colorless oil; IR (film) 2978, 1668, 1614, 1393, 1360 cmꢀ1
;
1H NMR (CDCl3, 500 MHz) d 1.31 (s, 3H), 1.90 (s, 3H), 2.26 (d, J = 16.5 Hz, 1H),
2.36 (dd, J = 14.0 and 7.0 Hz, 1H), 2.43 (dd, J = 14.0 and 7.0 Hz, 1H), 2.46 (d,
J = 16.5 Hz, 1H), 5.03–5.11 (m, 2H), 5.24 (s, 1H), 5.68–5.77 (m, 1H); 13C NMR
(CDCl3, 125 MHz) d 21.42, 23.58, 43.32, 44.87, 82.36, 103.39, 119.51, 131.98,
172.10, 192.49; ESIMS m/z 167 (M++H). Anal. Calcd for C10H14O2: C, 72.26; H,
8.49. Found: C, 72.55; H, 8.32.
Compound 4: 60%; colorless oil; IR (film) 1599, 1495, 1449, 1350, 1339 cmꢀ1
;
1H NMR (CDCl3, 500 MHz) d 1.74 (s, 3H), 2.27 (s, 3H), 2.30 (d, J = 11.5 Hz, 1H),
2.36 (d, J = 11.0 Hz, 1H), 2.43 (d, J = 18.0 Hz, 1H), 2.60 (d, J = 18.0 Hz, 1H), 3.76
(dd, J = 11.5 and 1.5 Hz, 1H), 3.82 (dd, J = 11.0 and 1.5 Hz, 1H), 5.71 (s, 1H), 7.14
(d, J = 8.5 Hz, 2H), 7.21-7.26 (m, 2H), 7.30–7.36 (m, 4H), 7.45–7.48 (m, 4H), 7.55
(d, J = 7.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) d 21.42, 22.65, 40.25, 53.62,
56.51, 73.48, 74.42, 123.02, 123.74, 124.51, 127.33, 127.42, 127.55, 128.44,
128.50, 129.68, 133.37, 135.34, 142.48, 143.54, 145.42; ESIMS m/z 468
(M++Na). Anal. Calcd for C27H27NO3S: C, 72.78; H, 6.11; N, 3.14. Found: C,
72.86; H, 6.37; N, 3.02.
Compound 3e: 60%; colorless oil; IR (film) 2976, 1668, 1614, 1393, 1360 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 1.32 (s, 3H), 1.74 (s, 3H), 1.90 (s, 3H), 2.24 (d,
J = 16.5 Hz, 1H), 2.28 (d, J = 13.5 Hz, 1H), 2.42 (d, J 8 13.5 Hz, 1H), 2.52 (d,
J = 16.5 Hz, 1H), 4.68 (s, 1H), 4.89 (s, 1H), 5.24 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 21.44, 23.77, 24.22, 45.34, 46.75, 82.85, 103.30, 116.35, 140.64, 171.79,
192.66; ESIMS m/z 203 (M++Na). Anal. Calcd for C11H16O2: C, 73.30; H, 8.95.
Found: C, 73.61; H, 9.03.
Compound 5: 87%; colorless oil; IR (film) 1601, 1493, 1447, 1366, 1227 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 1.55–1.73 (m, 3H), 1.68 (s, 3H), 1.78–1.86 (m, 1H),
1.90–2.05 (m, 2H), 2.26 (d, J = 17.7 Hz, 1H), 2.37 (d, J = 17.7 Hz, 1H), 5.55 (s,
1H), 7.12–7.21 (m, 2H), 7.25–7.34 (m, 4H), 7.47–7.50 (m, 2H), 7.55–7.59 (m,
2H); 13C NMR (CDCl3, 75 MHz) d 18.65, 22.66, 35.27, 39.52, 41.33, 73.95, 75.16,
123.45, 124.63, 125.66, 126.26, 126.59, 128.11, 128.17, 133.58, 147.00, 150.58;
ESIMS m/z 313 (M++Na). Anal. Calcd for C21H22O: C, 86.85; H, 7.64. Found: C,
86.58; H, 7.79.
Compound 3f: (syn/anti = 1:2): 62%; colorless oil; IR (film) 2978, 1668, 1614,
1393, 1360 cmꢀ1 1H NMR (CDCl3, 300 MHz, anti-form) d 1.01 (d, J = 6.9 Hz,
;
3H), 1.24 (s, 3H), 1.89 (s, 3H), 2.15 (dd, J = 16.5 and 0.6 Hz, 1H), 2.48–2.59 (m,
1H), 2.59 (dd, J = 16.5 and 0.6 Hz, 1H), 4.98–5.07 (m, 2H), 5.23 (s, 1H), 5.68–
5.80 (m, 1H); 13C NMR (CDCl3, 75 MHz, anti-form) d 14.24, 20.35, 21.33, 42.88,
45.55, 84.52, 103.26, 116.57, 138.32, 172.00, 192.58; 1H NMR (CDCl3, 300 MHz,
syn-form) d 1.01 (d, J 8 6.9 Hz, 3H), 1.23 (s, 3H), 1.90 (s, 3H), 2.20 (d, J = 16.8 Hz,
1H), 2.46–2.59 (m, 1H), 2.53 (d, J = 16.8 Hz, 1H), 4.98–5.07 (m, 2H), 5.23 (s, 1H),
5.60–5.72 (m, 1H); 13C NMR (CDCl3, 75 MHz, syn-form) d 13.97, 19.69, 21.33,
43.72, 44.97, 84.37, 103.41, 117.16, 138.06, 171.81, 192.55; ESIMS m/z 203
(M++Na). Anal. Calcd for C11H16O2: C, 73.30; H, 8.95. Found: C, 73.54; H, 8.79.
Compound 2g: 68%; pale yellow oil; IR (film) 3470, 1697, 1597, 1447, 1337,
11. The reaction in refluxing THF gave somewhat complex mixtures in the
allylation step. Thus we used DMF as a solvent.
12. For the selected examples on the oxonium-ene reaction, see: (a) Saha, P.;
Saikia, A. K. Tetrahedron 2012, 68, 2261–2266; (b) Saha, P.; Bhunia, A.; Saikia, A.
K. Org. Biomol. Chem. 2012, 10, 2470–2481; (c) Saha, P.; Reddy, U. C.;
Bondalapati, R. S.; Saikia, A. K. Org. Lett. 2010, 12, 1824–1826; (d) Ohmura,
H.; Smyth, G. D.; Mikami, K. J. Org. Chem. 1999, 64, 6056–6059; (e) Chen, S.-L.;
Hu, Q.-Y.; Loh, T.-P. Org. Lett. 2004, 6, 3365–3367; (f) Loh, T.-P.; Hu, Q.-Y.; Tan,
K.-T.; Cheng, H.-S. Org. Lett. 2001, 3, 2669–2672; (g) Nakamura, M.; Niiyama,
K.; Yamakawa, T. Tetrahedron Lett. 2009, 50, 6462–6465; (h) Cho, Y. S.; Kim, H.
Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.; Chang, M. H. Org. Lett. 2002, 4,
2025–2028.
1157 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 2.34 (s, 3H), 2.62 (d, J = 7.5 Hz, 2H),
;
3.34 (d, J = 15.0 Hz, 1H), 3.47 (s, 1H), 3.84 (d, J = 15.0 Hz, 1H), 4.38 (d,
J = 18.5 Hz, 1H), 4.49 (d, J = 18.5 Hz, 1H), 4.98–5.05 (m, 2H), 5.48–5.56 (m, 1H),
7.06 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.28–7.33
(m, 4H), 7.47 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H) ;
13C NMR (CDCl3, 125 MHz) d 21.56, 44.59, 54.47, 57.90, 75.38, 119.47, 125.47,
126.94, 127.61, 127.65, 128.29, 128.56, 129.51, 132.76, 133.62, 134.69, 136.18,
143.61, 143.98, 194.37; ESIMS m/z 472 (M++Na). Anal. Calcd for C26H27NO4S: C,
69.46; H, 6.05; N, 3.12. Found: C, 69.72; H, 6.13; N, 3.04.
13. In addition, the oxonium-ene reaction of methallyl derivative 3b (Scheme 5)
was not observed even after
a long reaction time (20 h) under acidic
conditions. The carbon–carbon double bond of 3b is conjugated with C@O,
thus an oxonium ion intermediate cannot be formed efficiently.
14. Compound 2i was also unstable and converted slowly into 3i even without an
acid catalyst. The results stated that 2i and 3i could be converted into each
other in the solution state depending on the amount of moisture. Similarly,
compound 2j was unstable and the corresponding 3,4-dihydro-2H-pyrane
derivative was contaminated.
Compound 2g0: Major isomer 36%; colorless oil; IR (film) 3466, 3389, 1599,
1493, 1447, 1341, 1161 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 2.37 (s, 3H), 2.95
;
(dd, J = 14.4 and 8.7 Hz, 2H), 3.04 (dd, J = 14.4 and 5.7 Hz, 2H), 3.14 (d,
J = 15.3 Hz, 2H), 3.87 (d, J = 15.3 Hz, 2H), 4.37 (br s, 2H), 5.09 (dd, J = 9.9 and
1.8 Hz, 2H), 5.16 (d, J = 17.1 Hz, 2H), 5.44–5.58 (m, 2H), 7.19 (d, J = 8.1 Hz, 2H),