Enantioselective addition of anthrones to α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.04.037

The first examples of enantioselective addition of anthrones to α,β-unsaturated aldehydes are disclosed. The reaction was performed at -40 °C achieving high yields and enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2009.04.037

Tetrahedron Letters 50 (2009) 3067–3069
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective addition of anthrones to a,b-unsaturated aldehydes
*
*
Andrea-Nekane Alba, Natalia Bravo, Albert Moyano , Ramon Rios
Departament de Química Orgànica, Universitat de Barcelona, Facultat de Química, C. Martí i Franquès 1-11, 08028 Barcelona, Catalonia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The first examples of enantioselective addition of anthrones to a,b-unsaturated aldehydes are disclosed.
Received 17 March 2009
Revised 2 April 2009
Accepted 6 April 2009
Available online 14 April 2009
The reaction was performed at ꢀ40 °C achieving high yields and enantioselectivities.
Ó 2009 Elsevier Ltd. All rights reserved.
Since the rediscovery of proline as organocatalyst by List et al.,1
and the first example of imonium catalysis reported by MacMillan
soon after in the Diels–Alder reaction,2 the field of organocatalysis
O
R
N
O
O
HO
O
Guanidine catalyst
has grown exponentially.
a,b-Unsaturated aldehydes have been
+
N R
widely used as Michael acceptors in a huge variety of reactions cat-
alyzed by chiral secondary amines, achieving high levels of
enantioselectivity.3
O
up to 99% ee
up to 96% yield
In our research group, we focused on the development of new
asymmetric methodologies based on organocatalysis.4 Interested
by new methodologies that allow us to form C–C bonds in an enan-
tioselective fashion, we turned our attention to the addition of
Scheme 1. Anthrone addition to maleimides.
O
anthrones to a,b-unsaturated aldehydes.
O
Anthrones usually behave as reactive dienes toward a variety of
dienophiles, in the presence of base and in aprotic solvents, as first
demonstrated by Rickborn and co-workers.5 More recently, Tan
and co-workers reported the enantioselective Diels–Alder cycload-
dition of anthrones with maleimides catalyzed by chiral bicyclic
guanidines which takes place with excellent yields and enantiose-
lectivities (Scheme 1).6
On the other hand, anthracenolate ion generated from the
deprotonation of anthrone usually leads to consecutive double
Michael reactions (Scheme 2a).7
EtONa/EtOH
a
b
+
CO2Me
CO2Me
MeO2C
O
O
Cinchona alkaloid
NO2
+
R
NO2
R
In 2007, Shi et al. described a highly enantioselective addition of
anthrones to nitroalkenes catalyzed by Cinchona alkaloid deriva-
tives (Scheme 2b).8
Scheme 2. Michael addition of anthrones.
With this information in mind, and based on our previous expe-
rience in organocatalysis, we were interested to study the unprec-
OHC
HO
R
edented addition of anthrones to
a,b-aldehydes catalyzed by
secondary amines in order to determine the nature of the addition
(Scheme 3)
O
Diels-Alder
O
To our delight, when anthrone 1a was added to cinnamalde-
hyde in toluene using different chiral amines as catalysts, only
the Michael addition product was obtained (Table 1).
Next we decided to optimize the reaction conditions in order to
achieve high yields and enantioselectivities. In an initial solvent
CHO
R
CHO
Michael addition
R
* Corresponding authors. Tel.: +34 934021245; fax: +34 933397878 (R.R.).
E-mail addresses: amoyano@ub.edu (A. Moyano), rios.ramon@icrea.cat (R. Rios).
Scheme 3. Expected products.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.037

3068
A.-N. Alba et al. / Tetrahedron Letters 50 (2009) 3067–3069
Table 1
Table 3
Catalyst screeninga
Aldehyde scopea
O
O
O
O
III (20%)
Catalyst (20%)
Toluene, -20 ºC
CHO
Ph
+
CHO
+
R
Toluene, -40 ºC
1a
3a
3a-g
CHO
CHO
2a
1a-g
2a
Ph
F3C
R
CF3
Entry
Product
R
Time
36 d
Yieldb (%)
88
eec (%)
Ph
CF3
COOH
Ph
N
H
II
N
H
I
OH
1
3a
80
N
H
III
OTMS
N
OTMS
IV
H
CF3
2d
3
3b
3c
5 d
85
75
99
78
Entry
Catalyst
Time (h)
Conversionb (%)
eec (%)
NC
1
2
3
4
I
II
III
IV
48
48
48
48
8
23
76
Traces
0
0
48
n.d.
36 d
O2N
4
5
6
7
3d
3e
3f
Me
Et
n-Pr
n-Bu
10 d
10 d
10 d
10 d
95
82
84
92
94
96
96
86
a
Experimental conditions: A mixture of 1a (0.25 mmol), catalyst (20%), and 2a
(0.30 mmol) in toluene (1 mL) was stirred at ꢀ20 °C for 48 h.
b
Conversion determined by NMR analysis of the crude reaction.
3g
c
ee determined by chiral HPLC analysis.
a
Experimental conditions: A mixture of 1a–g (0.25 mmol), catalyst III (20%), and
2a (0.30 mmol) in toluene (1 mL) was stirred at ꢀ40 °C for the time reported in the
table. After full conversion the crude product was purified by column
chromatography.
screening, we found that amine III efficiently catalyzes the reaction
at room temperature, although no significant enantioselective
induction was observed (Table 2, entry 1). For this reason, we per-
formed the reaction at lower temperature. We were pleased to find
that at ꢀ40 °C the enantiomeric excess of the product was
increased to 80% (Table 2, entry 5). Furthermore, the use of differ-
ent additives such as acids (entry 6) and hydrogen bond donors
(entry 7) did not bring about any positive effects in terms of yield
or selectivity.
Once we found suitable reaction conditions for the enantiose-
lective addition of anthrones to cinnamaldehyde, we studied the
scope of the reaction with different unsaturated aldehydes, as
shown in Table 3.
Gratifyingly, in all cases the anthrone addition took place with
good yields and enantioselectivities. For example, when para-nitro
cinnamaldehyde was used, the addition product was obtained in
75% yield and 78% ee (entry 3). Surprisingly, when 4-cyanocinnam-
aldehyde was used, the reaction proceeded extremely well, afford-
ing the final adduct 3b in 85% yield and 99% ee (entry 2). When
aliphatic unsaturated aldehydes were used, the reaction took place
with high yields and enantioselectivities (entries 4–7). Further
studies show that the final adducts racemize very fast, probably
due to a retro-Michael process, especially when aromatic alde-
b
Isolated yield.
ee determined by chiral HPLC analysis.
Reaction run at ꢀ30 °C.
c
d
hydes are used. This could be the reason why we obtained better
enantioselectivities with aliphatic aldehydes.
Spurred by these results, next we tried to expand this method-
ology to dithranols. It is well known that anthranols are more
nucleophilic than anthrones, so that normally only 1,4 addition is
observed. For example, Tan and coworkers reported that while
anthrones react with maleimides affording the expected Diels–Al-
der adducts, dithranol only gives the 1,4-Michael addition.6
As expected, when dithranol was used in our reaction with a,b-
unsaturated aldehydes, only Michael addition was observed. In
order to study the scope of the process, dithranol 2b was reacted
with different aliphatic aldehydes as shown in Table 4. In all the
examples, we obtained the final adducts in good yields and in very
high enantioselectivities. Unfortunately, when aromatic aldehydes
were used, only complex mixtures were obtained.
Tentatively, we assign the absolute configuration of adducts 3
by assuming that the mechanism and transition states are similar
to those described for other organocatalytic Michael additions
catalyzed by diphenylprolinol derivatives reported in the litera-
Table 2
Conditions screeninga
O
O
Table 4
Dithranol reactionsa
III
(20%)
CHO
Ph
+
OH
O
OH
OH
O
OH
1a
Solvent, T
3a
III (20%)
CHO
2a
CHO
Ph
+
R
Toluene, -40 ºC
3h-k
b
Entry
Solvent
T
Time (h)
Conversion (%)
eec (%)
CHO
1d-g
2b
R
1
2
3
4
Toluene
Toluene
CH2Cl2
Toluene
Toluene
Toluene
Toluene
rt
3
100
76
43
48
23
33
23
4
eec (%)
ꢀ20 °C
ꢀ30 °C
ꢀ30 °C
ꢀ40 °C
ꢀ40 °C
ꢀ40 °C
48
24
72
240
48
48
48
14
63
80
54
60
b
Entry
Product
R
Time
Yield (%)
1
2
3
4
3h
3i
3j
Me
Et
n-Pr
10 d
10 d
10 d
10 d
88
95
93
92
97
99
99
99
5
6d
7e
3k
n-Bu
a
a
Experimental conditions: A mixture of 1d–g (0.375 mmol), catalyst III (20%),
and 2b (0.25 mmol) in toluene (1 mL) was stirred at ꢀ40 °C for the time reported in
the table. After full conversion the crude product was purified by column
chromatography.
Experimental conditions: A mixture of 1a (0.25 mmol), catalyst (20%), and 2a
(0.30 mmol) in solvent (1 mL) was stirred at temperature reported in the table.
b
Conversion determined by NMR analysis of the crude reaction.
ee determined by chiral HPLC analysis.
0.2 mmol of benzoic acid added.
0.2 mmol of Schreiner’s thiourea added.
c
b
d
Isolated yield.
ee determined by chiral HPLC analysis.
c
e

A.-N. Alba et al. / Tetrahedron Letters 50 (2009) 3067–3069
OH
3069
References and notes
1. List, B.; Lerner, R. A.; Barbas, C., III J. Am. Chem. Soc 2000, 122, 2395–2396.
2. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243–4244.
3. For recent reviews of asymmetric organocatalytic 1,4-conjugated additions,
see: (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716; (b) Vicario, J. L.;
Badía, D.; Carrillo, L. Synthesis 2007, 2065–2092; (c) Erkkilä, A.; Majander, I.;
Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470.
Ph
Ph
OTMS
OH-
R
N+
O
2a
4
1
H2O
R
4. (a) Valero, G.; Balaguer, A.-N.; Moyano, A.; Rios, R. Tetrahedron Lett. 2008, 49,
6559–6562; (b) Balaguer, A.-N.; Companyó, X.; Calvet, T.; Font-Bardía, M.;
Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 199–203; (c) Valero, G.; Schimer, J.;
Cisarova, I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 1943–
1946.
Ph
Ph
OTMS
Ph
Ph
N
5. (a) Koerner, M.; Rickborn, B. J. Org. Chem. 1991, 56, 1373–1381; (b) Koerner, M.;
Rickborn, B. J. Org. Chem. 1990, 55, 2662–2672; (c) Koerner, M.; Rickborn, B. J.
Org. Chem. 1991, 54, 6–9.
N
H
OTMS
III
R
6. Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.; Xu, J.; Tan, C.-H. J. Am. Chem.
Soc. 2006, 128, 13692–13693.
7. Baik, W.; Yoon, C. H.; Koo, S.; Kin, H.; Kim, J.; Kim, J.; Hong, S. Bull. Korean Chem.
Soc. 2004, 25, 491–500.
O
O
8. Shi, M.; Lei, Z.-Y.; Zhao, M.-X.; Shi, J.-W. Tetrahedron Lett. 2007, 48, 5743–5746.
9. (a) Ibrahem, I.; Córdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952–1956; (b)
Vesely, J.; Rios, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Córdova, A. Chem Eur. J.
2008, 14, 2693–2698; (c) Zhao, G.-L.; Córdova, A. Tetrahedron Lett. 2006, 47,
7417–7421; (d) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2004, 43, 1272–1277; (e) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J.
Am. Chem. Soc. 2005, 127, 15710–15711; (f) Yamamoto, Y.; Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962–5963; (g) Marigo, M.; Franzén,
J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964–
6965; (h) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441,
861; (i) Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2006, 47, 99–103;
(j) Rios, R.; Sundén, H.; Ibrahem, I.; Zhao, G.-L.; Córdova, A. Tetrahedron Lett.
2006, 47, 8679–8682; (k) Rios, R.; Sundén, H.; Ibrahem, I.; Córdova, A.
Tetrahedron Lett. 2007, 48, 2181–2184; (l) Rios, R.; Ibrahem, I.; Vesely, J.;
Zhao, G.-L.; Córdova, A. Tetrahedron Lett. 2007, 48, 5701–5705; (m) Rios, R.;
Vesely, J.; Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2007, 48, 5835–
5839.
H2O
3
CHO
R
Scheme 4. Proposed mechanism and stereochemical outcome.
ture.4c,9 Thus, efficient shielding of the Si-face of the chiral iminium
intermediate 4 by the bulky aryl groups of chiral pyrrolidine III,
leads to stereoselective Re-facial nucleophilic conjugate addition
by anthrone in enol form, as shown in Scheme 4.
In summary, we have reported a highly chemo- and enantiose-
lective anthrone addition to a,b-unsaturated aldehydes. The reac-
tion is efficiently catalyzed by commercially available chiral
pyrrolidine derivatives and gives the corresponding adducts in
high yields and in moderate to excellent enantioselectivities.10
Mechanistic studies, synthetic applications of this new methodol-
ogy, and the discovery of new reactions based on this concept
are ongoing in our laboratory.
10. Typical experimental procedure for the synthesis of compound 3j: To a stirred
solution of catalyst III (16 mg, 0.05 mmol, 20 mol %) in toluene (1.0 mL), were
added E-2-hexenal 1f (37 mg, 0.375 mmol, 1.0 equiv), and dithranol 2b (57 mg,
0.25 mmol, 1.0 equiv). The reaction mixture was vigorously stirred at ꢀ40 °C
for 10 days. Next, the crude product was purified by silica gel chromatography
(hexane/EtOAc mixtures) to give the corresponding dithranol derivative 3j.
Compound 3j: Colorless oil. 1H NMR (400 MHz. CDCl3, TMSint): d (ppm) = 12.12
(d, J = 2.6 Hz, 2H), 9.56 (t, J = 1.6 Hz, 1H), 7.52–7.46 (m, 2H), 6.95–6.90 (m, 3H),
6.85–6.82 (m, 1H), 4.33 (d, J = 3.1 Hz, 1H), 2.50–2.41 (m, 1H), 2.29 (ddd,
Acknowledgments
J
J
1 = 1.6 Hz,
J J J J
2 = 6.6 Hz, 3 = 17.4 Hz, 1H), 2.03 (ddd, 1 = 1.8 Hz, 2 = 6.9 Hz,
3 = 17.4 Hz, 1H), 1.38–1.20 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz. CDCl3): d (ppm) = 201.3, 193.8, 162.6, 144.9, 144.2, 136.2, 136.1,
We thank the Spanish Ministry of Science and Education for
financial support (Project AYA2006-15648-C02-01), and A.-N.A.
thanks UB for a predoctoral fellowship. R.R. thanks ICREA for finan-
cial support.
119.6, 119.5, 116.5, 116.4, 116.3, 45.1, 44.6, 44.1, 32.5, 20.5, 13.9. ½a 2
ꢁD5 ꢀ5.7 (c
1.0, CHCl3, 99% ee). HRMS(ESI): calcd for [C20H20NaO4]+: 347.1254; found:
347.1255. HPLC (ChiralpakÒ IC,
1 , hexanes:IPA 90:10, 254 nm):
mL minꢀ1
tR = 17 min (major), 27 min (minor).