Microwave-assisted regioselective cycloaddition reactions between 9-substituted anthracenes and levoglucosenone

Article abstract of DOI:10.1021/ol062254g

The cycloaddition reactions of 9-substituted anthracenes and levoglucosenone were investigated under microwave irradiation and conventional heating conditions. Considering time, yields, and regioselectivity, microwave technology has proven to be an ideal

Full text of DOI:10.1021/ol062254g

ORGANIC
LETTERS
2
006
Vol. 8, No. 24
561-5564
Microwave-Assisted Regioselective
Cycloaddition Reactions between
5
9-Substituted Anthracenes and
Levoglucosenone
†
,‡
†
Ariel M. Sarotti, Madeleine M. Joulli e´ ,* Rolando A. Spanevello, and
Alejandra G. Su a´ rez*,
†
Instituto de Qu ´ı mica Org a´ nica de S ´ı ntesis, Facultad de Ciencias Bioqu ´ı micas y
Farmac e´ uticas, UniVersidad Nacional de Rosario - CONICET, Suipacha 531,
S2002LRK Rosario, Argentina, and Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104
asuarez@fbioyf.unr.edu.ar
Received September 11, 2006
ABSTRACT
The cycloaddition reactions of 9-substituted anthracenes and levoglucosenone were investigated under microwave irradiation and conventional
heating conditions. Considering time, yields, and regioselectivity, microwave technology has proven to be an ideal tool to achieve this chemical
transformation.
Levoglucosenone (1,6-anhydro-3,4-dideoxy-â-D-glycero-hex-
levoglucosenone as a chiral building block in the develop-
ment of new tools for asymmetric synthesis.
3
3-enopyranos-2-ulose or (1S,5R)-6,8-dioxabicyclo[3.2.1]oct-
2
-en-4-one) (1) is a versatile and readily available member
The Diels-Alder reaction has been among the most
popular and successful synthetic applications of carbohydrate
auxiliaries, especially when they are attached to the dieno-
phile. Recently, we have reported the design and synthesis
of alcohol 2 derived from levoglucosenone (Scheme 1) and
of the carbohydrate-derived chiral pool. The synthesis of 1
is most efficiently accomplished by the pyrolysis of cellulose
or cellulose-containing material such as waste paper. Levo-
glucosenone possesses several features that make it an
attractive chiral raw material for the synthesis of a wide
1
2
variety of compounds. As part of our program on the
pyrolytic conversion of biomass into useful chemicals, we
have been concerned with the synthetic application of
Scheme 1
†
Universidad Nacional de Rosario.
University of Pennsylvania.
‡
(1) (a) Witczak, Z. J., Ed. LeVoglucosenone and LeVoglucosans: Chem-
istry and Applications; ATL Press: Mount Prospect, 1994. (b) Witczak, Z.
J.; Tatsuta, K., Eds. Carbohydrate Synthons in Natural Products Chemistry.
Synthesis, Functionalization, and Applications. ACS Symposium Series 841;
American Chemical Society: Washington, DC, 2003.
(2) For examples, see: (a) Nishikawa, T.; Urabe, D.; Isobe, M. Angew.
Chem., Int. Ed. 2004, 43, 4782. (b) G o´ mez, M.; Quincoces, J.; Peseke, K.;
Michalik, M.; Reinke, H. J. Carbohydr. Chem. 1999, 18, 851. (c) Swenton,
J. S.; Freskos, J. N.; Dalidowicz, P.; Kerns, M. L. J. Org. Chem. 1996, 61,
its use as a chiral inductor in Diels-Alder reactions of the
corresponding acrylate with cyclopentadiene yielding the
4
4
59.
product with 98% diastereomeric excess.
1
0.1021/ol062254g CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/02/2006

Attempts to improve the π-facial diastereoselectivity in
this cycloaddition reaction led us to envisage new chiral
auxiliaries derived from levoglucosenone. Different substit-
uents at the benzylic position would introduce a new element
of steric control, therefore imposing greater restrictions to
the transition state.
The key step to obtain the chiral auxiliaries was a Diels-
Alder reaction between levoglucosenone and the aromatic
dienes. Our approach for the design of new molecular
scaffolds relied on the use of suitable 9-substituted anthracene
derivatives 3 (easily prepared from commercially available
general, the products were obtained in good to excellent
yields with high ortho selectivity. It was already observed
5
that the ortho product is generally preferred in cycloaddition
reactions in which 9-substituted anthracenes are used as
6
,7
dienes.
Regardless of the good yields and selectivities observed
in these cycloadditions, all the reactions needed long reaction
times (between 6 and 12 days) to obtain good conversion of
the starting material. For this reason, the use of a microwave-
assisted cycloaddition procedure was considered to improve
the outcome of these reactions. This approach would save
energy by shortening the reaction time and also by making
the overall process more efficient and sustainable. Diels-
Alder cycloadditions were the first reaction types to be
examined in conjunction with microwave irradiation, and
these conditions reduced significantly the reaction times
9-anthracenemethanol or anthracen-9-ylmethanol) as the
source of molecular diversity to tune the efficiency of the
asymmetric inductor.
Cycloaddition reactions of 1 with 3a-e would be expected
to yield up to four isomeric products because the aromatic
substrate can add from the bottom or the top face of the
dienophile. However, after column chromatography to
remove the excess of the diene, only one or two regioisomers
were isolated depending on the diene employed (Scheme 2).
8
compared to conventional heating methods.
To make a systematic study of the different variables
involved in these microwave-irradiated cycloaddition reac-
tions, we decided to study the reaction of 3a with levoglu-
cosenone. This substrate was selected among the others
because it was shown to give both good yields and regiose-
lectivity under thermal conditions. The assays were per-
formed at 150 W in different solvents because solvents are
Scheme 2
9
a crucial factor in the outcome of the reaction. The solvents
were chosen to compare a selection that included high and
low microwave energy absorbers. A key feature of these
microwave-assisted reactions was the reagent concentration.
The reaction only proceeded with a dienophile concentration
of 1.5 M that involved solutions 8 times more concentrated
than the ones used under conventional heating. Table 2 shows
The stereochemical assignments of the new compounds
1
were based on H NMR spin decoupling and NOE data. All
Table 2. Cycloaddition Reactions of 1 (1.5 M) with 3a at 150
W for 10 min
the reactions afforded the adducts derived from the diene
approach opposite to the 1,6-anhydro bridge of 1. Adducts
temp
(°C)
yield
(%)a
4a-e and 5a-e were identified as the ortho and meta
entry
solvent
ortho/meta
regioisomers, respectively.
The failure of the cycloaddition reactions performed with
Lewis acid catalysis (such as FeCl
1
2
3
4
5
6
7
8
xylene
DMF
CyHex
THF
MTBE
MeCN
EtOH
H2O
170
170
54
43
41
47
50
22
20
29
60:40
32:68
82:18
83:17
52:48
84:16
86:14
86:14
b
3 3 3 4
, ScTf , AlCl , LiClO ,
155
165
140
146
140
130
and BF ‚OEt ) prompted us to carry out the Diels-Alder
3
2
reaction under thermal conditions (Table 1).
Table 1. Cycloaddition Reaction of 1 with 3 in Refluxing
Toluene
a
Yield corresponds to isolated products. b Performed under controlled
temperature at 170 °C.
diene
3: R
time
(days)
yield
(%)a
entry
ortho/meta
1
2
3
4
5
a: Me
b: TBDMS
c: Ph
d: Ac
e: H
7
10
7
6
12
100
92
75
82
47
88:12
85:15
100:0
100:0
100:0
the cycloaddition reactions of 1 with 3a performed in a
pressurized environment.
The experimental data shown in Table 2 demonstrate that
the best results, considering yield and ortho/meta selectivity,
were obtained when employing cyclohexane or THF. With
a
Yield corresponds to isolated products.
(
3) (a) Sarotti, A. M.; Spanevello, R. A.; Su a´ rez, A. G. Tetrahedron Lett.
004, 45, 8203. (b) Sarotti, A. M.; Spanevello, R. A.; Su a´ rez, A. G.
Tetrahedron Lett. 2005, 46, 6987.
4) Sarotti, A. M.; Spanevello, R. A.; Su a´ rez, A. G. Org. Lett. 2006, 8,
1487.
2
As shown in Table 1, the yield and selectivity of the
cycloaddition reaction varied with the reagent employed. In
(
5562
Org. Lett., Vol. 8, No. 24, 2006

polar solvents (entries 6-8), the selectivities obtained were
good but the yields were very low. On the other hand,
solvents such as xylene (entry 1) or MTBE (entry 5) gave
the best yields but very low ortho/meta ratio. These results
led us to make a more detailed experimental study using
THF and cyclohexane. We analyzed the effects of varying
diene equivalents, microwave power, and reaction time on
the outcome of the Diels-Alder reaction. Table 3 shows the
The ortho isomer undergoes a retro Diels-Alder reaction
leading to the formation of the thermodynamically more
stable meta isomer. This experimental evidence explains the
results shown in Table 3: longer reaction times produce
better yields but reduce the ortho selectivity.
We also demonstrated experimentally that the retro Diels-
Alder reaction did not take place under conventional thermal
conditions. The reaction of 1 with 3a or 3b was carried out
in refluxing toluene, and the reaction mixture was controlled
1
by H NMR every 48 h. The results obtained showed that
the yield increased with time and the regioselectivity
remained constant. Moreover, ortho adducts 4a or 4b were
refluxed under toluene during 192 h and the starting materials
were recovered quantitatively.
Table 3. Cycloaddition Reaction of 1 with 3a-e at 150 W
diene
3: R (equiv)
time
solvent (min)
yield
(%)a
entry
ortho/meta
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
a: Me (2)
a: Me (2)
a: Me (2)
a: Me (2)
a: Me (3)
b: TBDMS (2) CyHex
b: TBDMS (2) CyHex
b: TBDMS (2) THF
b: TBDMS (2) THF
b: TBDMS (2) THF
b: TBDMS (2) THF
c: Ph (2)
c: Ph (2)
d: Ac (2)
d: Ac (3)
e: H (2)
a: H (3)
CyHex
CyHex
THF
THF
THF
10
20
10
30
10
10
20
10
20
50
10
10
10
20
10
20
10
41
67
47
54
62
40
57
47
58
57
57
82:18
71:29
83:17
27:73
73:27
80:20
78:22
77:23
69:31
24:76
90:10
-
Hitherto, microwave conditions produced an important
acceleration of the reaction rate that could be rationalized
in terms of thermal effects and increased concentration of
the reagents. Under these conditions, it is also possible to
observe the reversibility of the cycloaddition process to form
the thermodynamically more stable meta adduct.10
To optimize yields and selectivities in this cycloaddition
process, we investigated the effect of applying lower
microwave irradiation power. The quantity of the applied
energy should be high enough to obtain good conversion in
a reasonable period of time but, on the other hand, low
enough to avoid or at least minimize the retro Diels-Alder
path. Table 4 describes the results of the cycloaddition
1
1
1
1
1
1
1
1
b
CyHex
THF
CyHex
THF
CyHex
THF
-
-
b
-
38
34
31
53
41:59
41:59
33:77
92:8
a
Yield corresponds to isolated products. b Compound 3c decomposes
Table 4. Cycloaddition Reaction of 1 with 3a-e in THF
at 150 W.
diene
3: R (2 equiv)
power
(W)
time
(min)
yield
(%)a
entry
ortho/meta
results of the microwave-assisted cycloaddition reaction of
1
2
3
4
5
6
7
8
9
a: Me
a: Me
a: Me
a: Me
a: Me
a: Me
b: TBDMS
b: TBDMS
b: TBDMS
b: TBDMS
b: TBDMS
b: TBDMS
c: Ph
c: Ph
c: Ph
c: Ph
d: Ac
d: Ac
d: Ac
d: Ac
d: Ac
e: H
e: H
e: H
e: H
100
100
100
50
50
50
100
100
100
50
50
50
30
60
90
180
240
300
30
44
58
75
70
80
82
45
69
75
65
75
79
-b
60
65
67
31
52
60
57
67
43
56
70
65
71
85:15
81:19
76:24
85:15
79:21
74:26
92:8
76:24
43:57
86:14
85:15
75:25
-
100:0
100:0
100:0
49:51
38:62
35:65
88:12
75:25
68:32
68:32
67:33
85:15
85:15
1
with 3a-e under different experimental conditions and a
registered reaction temperature between 155 and 165 °C. The
analysis of these results demonstrates that an increment in
the equivalent of diene produces better yields. When the
reaction time is increased, the selectivity toward the ortho
regioisomer decreases. In some cases, the selectivity reverts
giving the meta adduct as the major product. This effect can
be attributed to the retro Diels-Alder reaction of the initially
formed ortho isomer, which is the thermodynamically less
stable adduct.
60
90
10
180
240
300
30
180
240
300
30
60
90
180
240
30
11
12
13
14
100
50
50
To test the possibility of a retro Diels-Alder mechanism,
we subjected a THF solution of pure 4a to microwave
irradiation at 150 W for 20 min. The reaction produced a
mixture of meta isomer 5a, levoglucosenone (1), and
15
16
17
18
19
20
21
22
23
24
25
26
50
100
100
100
50
9-(methoxymethyl)anthracene (3a) (Scheme 3).
50
100
100
100
50
Scheme 3
60
90
180
240
e: H
50
a
Yield corresponds to isolated products. b Compound 3c decomposes
at 100 W.
Org. Lett., Vol. 8, No. 24, 2006
5563

reactions under 100 or 50 W of irradiation power. Under
these experimental conditions, the registered reaction tem-
perature was 125 and 95 °C, respectively.
4), we found that microwave-assisted reactions occurred at
50 times higher reaction rates but also proceeded with 8 times
more concentrated solutions. In general, the products are
obtained in similar selectivities and only slightly lower yields,
compared to the thermal conditions.
In conclusion, we developed a microwave-assisted pro-
cedure to prepare adducts derived from levoglucosenone and
9-substituted anthracenes in good yields and selectivities. The
methodology allows us to control the regioselectivity by
modifying the experimental conditions. We believe that
microwave techniques are a suitable approach to obtain chiral
auxiliaries from biomass under mild and efficient conditions.
The experimental results show that in general the yields
and selectivity were improved under low-power microwave
irradiation. The best results for all dienes studied were
obtained in 240 min at 50 W. It is important to mention that
even under low irradiation conditions the selectivity for
dienes 3a and 3b decreased with time. This observation may
be explained if we consider that the retro Diels-Alder
process is not completely inhibited under the conditions
employed. Noticeably, the ortho/meta ratio for dienes 3d and
3
e did not change with time, indicating that under these
Acknowledgment. This research was supported by
Agencia Nacional de Promoci o´ n Cient ´ı fica y Tecnol o´ gica,
Argentina, the International Foundation for Science, Sweden,
and the Organization for the Prohibition of Chemical
Weapons, The Netherlands. A.M.S. thanks CONICET and
Fundaci o´ n Josefina Prats for the award of a fellowship.
Thanks are also due to Wyeth Research and NSF for an
internship.
experimental conditions the retro Diels-Alder reaction was
not observed. Comparing the results obtained under con-
ventional heating (Table 1) and microwave conditions (Table
(5) The ortho adduct 4e is obtained as a mixture of the free carbonyl
compound and the corresponding intramolecular hemiketal derivative. As
both products are in equilibrium, it was not possible to separate the mixture.
The structure elucidation was achieved by acetylation of the mixture and
subsequent separation of each component (see Supporting Information).
(6) (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
John Wiley & Sons: New York, 1990; Chapter 6. (b) Atherton, J. C. C.;
Jones, S. Tetrahedron 2003, 59, 9039.
Supporting Information Available: Experimental pro-
cedures for the synthesis of all compounds, characterization
(7) (a) The preference for meta regioselectivity in Diels-Alder reactions
1
13
of 9-substituted anthracenes and 2-acetamidoacrylate under forcing con-
ventional heating or microwave irradiation conditions was reported
recently. However, this regioselectivity was achieved at the expense of
the overall yield of the reaction. (b) Yang, B. V.; Doweyco, L. D.
Tetrahedron Lett. 2005, 46, 2857.
data, and copies of H and C NMR spectra of new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
6
b
(8) (a) Hayes, B. L. MicrowaVe Synthesis. Chemistry at the Speed of
OL062254G
Light; CEM Publishing: Matthews, NC, 2002; Chapter 4. (b) Mart ´ı nez
Palau, R. Qu ´ı mica en Microondas; CEM Publishing: Matthews, NC, 2006;
Chapter 3. (c) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (d)
Lidstrom, P.; Tierney, J. P.; Wathey, B.; Westman, J. Tetrahedron, 2001,
(9) Solvent-free microwave-assisted cycloaddition did not give the desired
results. The reactions performed at 300 W produced a very low yield of
product due to decomposition of the reagent.
(10) The cycloaddition reaction of 1 and 3a in THF at 200 W during 10
min affords the meta adduct as the unique product.
5
7, 9225. (e) de la Hoz, A.; D ´ı az-Ortis, A.; Moreno, A.; Langa, F. Eur. J.
Org. Chem. 2000, 3659.
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Org. Lett., Vol. 8, No. 24, 2006