Alkylation of oxazolones and related heterocycles through an SN1 reaction

Article abstract of DOI:10.1002/ejoc.201100046

The alkylation of oxazolones through an S_N1 reaction by using stabilized carbocations is reported. The reaction (catalyzed by Bronsted acids, such as TFA or thioureas) affords the final compounds in excellent yields. Reaction with other heteroc

Full text of DOI:10.1002/ejoc.201100046

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100046
Alkylation of Oxazolones and Related Heterocycles through an S 1 Reaction
N
[a]
[b]
[b]
[a]
Andrea-Nekane R. Alba, Teresa Calbet, Mercé Font-Bardía, Albert Moyano, and
Ramon Rios*[
a,c]
Dedicated to the memory of Prof. Rafel Suau
Keywords: Alcohols / Lewis acids / Brønsted acids / Nucleophilic substitution / Green chemistry
The alkylation of oxazolones through an S
N
1 reaction by
the final compounds in excellent yields. Reaction with other
using stabilized carbocations is reported. The reaction (cata- heterocycles has also been studied, rendering pyrazolone or
lyzed by Brønsted acids, such as TFA or thioureas) affords
oxindole derivatives in good yields.
Introduction
oxyaminals has attracted much attention in organoca-
[
2]
talysis. Recently, Jørgensen’s research group and ours have
developed several methodologies for the synthesis of qua-
ternary amino acids. Concretely, Jørgensen and co-workers
have reported the use of 5-oxazolones (azlactones) in the
Oxazol-5-(4H)-ones are common starting materials, due
to their importance in the synthesis of chiral amino acids.
They have a dual behavior, presenting both nucleophilic
and electrophilic nature. As shown in Figure 1, there are
three different nucleophilic sites and one electrophilic site.
This makes the reactivity of oxazolones rich and interesting.
[
1]
[3]
asymmetric organocatalytic Michael addition to α,β-un-
[4]
[5]
saturated aldehydes, nitroalkenes, and unsaturated acyl
[6]
phosphonates, On the other hand, our research group has
developed the addition of oxazolones to maleimides, 1,1-
bisphenylsulfonyl)ethene, and 1,2-(bisphenylsulfonyl)eth-
ene. Terada and co-workers have described efficient access
to β-hydroxy-α-amino acid derivatives having a quaternary
stereocenter at the α-carbon atom by an aldol reaction be-
[7]
[
8]
(
[
9]
[
10]
tween oxazolones and aldehydes.
All these methodolo-
gies afforded the desired oxazolone precursors in excellent
yields and enantioselectivities.
However, one of the characteristics of those methodolo-
gies is the increase in molecular complexity, as several func-
tional groups are present in the final compound. An impor-
tant drawback of all these procedures remains in the diffi-
cult synthesis of very bulky disubstituted oxazolones due
the Michael nature of all these methodologies. Interestingly,
bulky quaternary α-amino acids (in the case of C-4 ad-
dition) included in the amino end of a peptide sequence can
Figure 1. Reactive sites of oxazolones.
The use of oxazolones as suitable nucleophile starting induce a determined structural conformation and increase
materials for the synthesis of quaternary amino acids or the enzymatic stability of the peptide.[11] With this infor-
mation in mind, and interested in the synthesis of bulkily
[
a] Department of Organic Chemistry, Universitat de Barcelona,
C/ Martí i Franqués 1-11, 08028 Barcelona, Spain
Fax: +34-93-3397878
substituted quaternary oxazolones, we turned our attention
to S 1 reactions that overcome the previously discussed
N
E-mail: rios.ramon@icrea.cat
limitations. Very recently, Cozzi and co-workers reported
[b] Departament de Cristalografia, Mineralogia i Dipòsits Min-
erals, Universitat de Barcelona,
Martí i Franqués s/n, 08028 Barcelona, Spain
[c] ICREA,
the use of highly stabilized carbocations in the α-alkylation
[
12]
of aldehydes catalyzed by secondary amines.
Based on
those previous reports, in conjunction with our experience
Passeig Lluis Companys 23, 08010 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100046.
[
13]
in organocatalysis
and the fascinating studies of Mayr
[
14]
about the stability of carbocations,
we envisioned easy
Eur. J. Org. Chem. 2011, 2053–2056
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2053

A.-N. R. Alba, T. Calbet, M. Font-Bardía, A. Moyano, R. Rios
SHORT COMMUNICATION
entry to bulky quaternary amino acids taking advantage of and a new functionality (a base) increased the rate of the
our previous experience in the use of oxazolones and re- reaction, it negatively affected the enantioselectivity
lated heterocycles.
(Table 1, Entries 5 and 7). Surprisingly, when a phosphoric
As is well known, benzylic, propargylic, and allylic acid derivative was used, no reaction was observed.
alcohols can form, in the presence of acids, carbocations
that are found on the electrophilicity scale of Mayr. Strong
Table 1. Screening of the reaction conditions.[a]
electron-donating substituents enhance the stability of the
carbocations. For this reason, we choose compound 5a
(with strong electron-donating groups: p-dimethylamino) to
study the reaction.
Results and Discussion
First of all, we were concerned about the nature of the
addition. When enals or vinyl sulfones are used as nucleo-
philes, the addition takes place at C-4. On the other hand,
acylphosphonates, nitrostyrenes, and maleimides make the
nature of the addition strongly dependent of the structures
of both the nucleophile and the electrophile. Because highly
reactive electrophiles – such as enals (in their iminium form)
or vinyl sulfones – react exclusively at C-4, we expected,
accordingly, similar behavior when stabilized carbocations
were used. As a study reaction, we chose the addition of
oxazolone 1a to alcohol 5a. This alcohol has been chosen
based on the previous work of Cozzi and the parameters of
Mayr.
Entry
Catalyst
T [°C]
Solvent
Conversion [%][b]
To our delight, when azlactone 1a was treated with
alcohol 5a the final product was obtained after 14 h under
TFA catalysis. The regiochemistry was determined by X-ray
diffraction of compound 6a. As expected, the regiochemis-
try of 6a corresponds to addition at C-4 (Figure 2). Next,
we tried different catalysts, including bases (Table 1, En-
try 2) and thioureas (Table 1, Entries 3–7). Remarkably,
1
2
3
TFA
TEA
7a
r.t.
r.t.
r.t.
r.t.
r.t.
4
Et
Et
Et
Et
2
2
2
2
O
O
O
O
100
0
100
100
100
0
[
c]
4
5
6
7
8
7b
7b
toluene
7b
Et O
2
7c
r.t.
r.t.
Et
Et
2
O
O
33
0
[
d]
8a
2
when base was used, no reaction was observed, probably [a] In a small vial, oxazolone 1a (0.225 mmol) and alcohol 5a
(
(
0.15 mmol) were stirred in the presence of the desired catalyst
because it is impossible to generate the carbocation. A dif-
ferent set of thioureas was used, revealing that the thiourea
moiety is able to promote carbocation formation. However,
20 mol-%, 0.03 mmol) at room temperature overnight. [b] Deter-
1
mined by H NMR spectroscopic analysis of the crude mixture.
[c] ee = 13% (determined by chiral HPLC analysis). [d] 50% con-
although the inclusion of a chiral moiety in the thiourea version was obtained at 60 °C in toluene.
Once suitable reaction conditions for the reaction had
been found (TFA as catalyst, Et O at room temperature),
2
we explored the scope of the reaction in terms of the oxaz-
olone substitution pattern. To our delight, final products
6a–f were obtained in good yields (Table 2, Entries 1–6),
and only when a very bulky oxazolone, such as 1g (with two
tert-butyl moieties), was used did the reaction not occur.
Next, we explored the scope of the electrophile. Oxaz-
olone 1a was treated with different electrophiles (based on
Mayr’s parameters). The term E of alcohol 5a was calcu-
lated to be –7.0. We then chose different alcohols with a
Mayr parameter between –7.0 and 0 (Scheme 1). Benzylic
carbocations are of moderate stability and high reactivity
(for this reason, we decided to include compound 5c, al-
though its E value does not belong to the initially proposed
range of E parameters), and ferrocenyl compounds are well
known for their capacity to stabilize a carbocation. Because
of the low ability of the alkynyl group to stabilize a positive
charge, reactions of propargyl cations are quite limited;
Figure 2. X-ray analysis of 6a.[15]
054
2
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2053–2056

Alkylation of Oxazolones and Related Heterocycles by an S
Table 2. Oxazolone scope.[a]
N
1 Reaction
[
a] In a small vial, oxazolone 1a–g (0.225 mmol) and alcohol 5a
(
(
0.15 mmol) were stirred in the presence of trifluoroacetic acid
20 mol-%, 0.03 mmol) at room temperature overnight. [b] Isolated
1
yield after column chromatography. [c] 1.4:1dr (determined by H
NMR spectroscopic analysis of the crude mixture). [d] Compound
6h is the double addition product.
N
Scheme 2. S 1 reactions performed with different heterocycles.
Next, we decided to use these substrates with different
carbocations. Unfortunately, we did not observe any reac-
tion with ferrocenyl or dibenzyl alcohols. To overcome this
limitation, we run the reaction in water this time (a strategy
that could not be employed with azlactones due to their
inherent instability in water). To our delight, the reaction
afforded, under these conditions, the corresponding alkyl-
ated compounds in good yields when pyrazolones were em-
ployed (Scheme 3).
however, the complexation of an alkyne with Co(CO) re-
duces the electrophilicity of the carbocation generated, sta-
bilizing it (Nicholas reaction).
8
Scheme 1. Different studied alcohols and the expected or calculated
E parameter of the corresponding carbocations.
Unfortunately, under our reaction conditions, none of
the selected substrates reacted with oxazolone 1a, probably
due to the difficult formation of the corresponding carbo-
cation under the optimized reaction conditions. One impor-
tant limitation of the use of oxazolones is the need to avoid
water as solvent, due to their inherent reactivity in water Scheme 3. Reactions between pyrazolones and ferrocenes in water.
(formation of the opened N-substituted amino acid).
Encouraged by the results obtained when testing oxazol-
ones in this reaction, we decided to expand this methodol-
Conclusions
[
16]
ogy by using different nucleophiles, such as oxindole,
[
17]
[18]
pyrazolones,
and benzofuranones
(Scheme 2), which
In conclusion, we have developed a new methodology for
could be interesting targets in medicinal chemistry. In all the alkylation of azlactones through the formation of stable
the examples, we obtained the desired final products in carbocations. This methodology allows the construction of
good yields, showing that this methodology can be useful bulky amino acid derivatives that cannot be built with other
for the synthesis of bulky quaternary centers.
methodologies. The reaction renders the final bulky disub-
Eur. J. Org. Chem. 2011, 2053–2056
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2055

A.-N. R. Alba, T. Calbet, M. Font-Bardía, A. Moyano, R. Rios
SHORT COMMUNICATION
[
[
10] M. Terada, H. Tanaka, K. Sorimachi, J. Am. Chem. Soc. 2009,
stituted oxazolones in good yields, albeit with low enantio-
selectivities when then Takemoto catalyst was employed
1
31, 3430–3431.
11] B. E. Haug, W. Stensen, T. Stiberg, J. S. Svendsen, J. Med.
Chem. 2004, 47, 4159–4162 and references cited therein.
(Table 1, footnote). We studied the scope of the reaction by
using different stabilized carbocations. However, the reac- [12] a) F. Benfatti, E. Benedetto, P. G. Cozzi, Chem. Asian J. 2010,
tion did not render the final products. We expanded the
reaction scope by employing other interesting scaffolds such
as pyrazolones or oxindoles, affording the final alkylated
products in excellent yields.[
5, 2047–2052; b) P. G. Cozzi, F. Benfatti, L. Zoli, Angew. Chem.
009, 121, 1339; Angew. Chem. Int. Ed. 2009, 48, 1313–1316;
for a highlight on organocatalytic aldehyde alkylations by an
1 reaction, see: c) A.-N. R. Alba, M. Viciano, R. Rios,
ChemCatChem 2009, 1, 437–439 and references cited there in;
for other examples in asymmetric organocatalytic S 1 alky-
2
S
N
19]
N
lations, see: d) L. Zhang, L. Cui, X. Li, J. Li, S. Luo, J.-P.
Cheng, Chem. Eur. J. 2010, 16, 2045–2049; e) B. Han, Y.-C.
Xiao, Y. Yao, Y.-C. Chen, Angew. Chem. Int. Ed. 2010, 49,
Experimental Section
10189–10191; f) A. R. Brown, W.-H. Kuo, E. N. Jacobsen, J.
General Procedure: Bis[4-(dimethylamino)phenyl]methanol (41 mg,
Am. Chem. Soc. 2010, 132, 9286–9288.
0
1
.15 mmol, 1 equiv.), the desired oxazol-5(4H)-one (0.225 mmol,
.5 equiv.), and trifluoroacetic acid (3 mg, 0.03 mmol, 0.2 equiv.)
[
13] a) G. Valero, A.-N. Balaguer, A. Moyano, R. Rios, Tetrahedron
Lett. 2008, 49, 6559–6562; b) G. Valero, J. Schimer, I. Cisarova,
J. Vesely, A. Moyano, R. Rios, Tetrahedron Lett. 2009, 50,
were added to a vial containing diethyl ether (2 mL). The reaction
mixture was stirred at room temperature overnight. The crude reac-
tion mixture was directly subjected to flash chromatography [silica
gel/triethylamine 10:1 (v/v) as stationary phase and hexane/ethyl
acetate of increasing polarity as mobile phase].
1943–1946; c) X. Companyó, G. Valero, L. Crovetto, A. Moy-
ano, R. Rios, Chem. Eur. J. 2009, 15, 6564–6568; d) X. Com-
panyó, M. Hejnová, M. Kamlar, J. Vesely, A. Moyano, R. Rios,
Tetrahedron Lett. 2009, 50, 5021–5024; e) X. Companyó, A.-
N. Balaguer, F. Cárdenas, A. Moyano, R. Rios, Eur. J. Org.
Chem. 2009, 3075–3080; f) A.-N. Alba, X. Companyó, A. Moy-
ano, R. Rios, Chem. Eur. J. 2009, 15, 7035–7038; g) A.-N. Alba,
X. Companyó, A. Moyano, R. Rios, Chem. Eur. J. 2009, 15,
Supporting Information (see footnote on the first page of this arti-
cle): Experimental data for all compounds and crystallographic
data.
1
1095–11099.
14] a) H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36,
6–77; b) B. Kempf, N. Hampel, A. R. Ofial, H. Mayr, Chem.
Eur. J. 2003, 9, 2209–2218.
[
Acknowledgments
6
We thank the Spanish Ministry of Science and Innovation
[15] The structure is disordered: A C atom of the two methyl groups
occupies two alternative positions with occupancy factors of
(MICINN) for financial support (Project AYA2009-13920-C02-02).
0
.5/0.5. Tests with several solvents were made at different tem-
A.-N.R.A. is also grateful to MICINN, for her predoctoral fellow-
ship.
peratures, but it was not possible to obtain single crystals of
suitable quality. CCDC-802149 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[
1] For an authoritative review on stereoselective syntheses of qua-
ternary-substituted α-amino acids using oxazolones, see: a)
R. A. Mosey, J. S. Fisk, J. J. Tepe, Tetrahedron: Asymmetry
[16] For some examples or oxindoles as nucleophiles in organocata-
lytic reactions, see: a) N. Bravo, I. Mon, X. Companyó, A.-N.
Alba, A. Moyano, R. Rios, Tetrahedron Lett. 2009, 50, 6624–
6626; see also: b) P. Galzerano, G. Bencivenni, F. Pesciaioli, A.
Mazzanti, B. Giannichi, L. Sambri, G. Bartoli, P. Melchiorre,
Chem. Eur. J. 2009, 15, 7846–7849; c) S. Ogawa, N. Shibata, J.
Inagaki, S. Nakamura, T. Toru, M. Shiro, Angew. Chem. 2007,
119, 8820; Angew. Chem. Int. Ed. 2007, 46, 8666–8669; d) T.
Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura,
T. Toru, M. Shiro, Angew. Chem. 2008, 120, 4225; Angew.
Chem. Int. Ed. 2008, 47, 4157–4161; e) T. Ishimaru, N. Shibata,
J. Nagai, S. Nakamura, T. Toru, S. Kanesmasa, J. Am. Chem.
Soc. 2006, 128, 16488–16489; f) X. Companyó, A. Zea, A.-
N. R. Alba, A. Mazzanti, A. Moyano, R. Rios, Chem. Com-
mun. 2010, 46, 6953–6955.
[17] For some examples of pyrazolones as nucleophiles in organoca-
talytic reactions, see: a) W.-B. Chen, Z.-J. Wu, Q.-L. Pei, L.-F.
Cun, X.-M. Zhang, W.-C. Yuan, Org. Lett. 2010, 12, 3132–
3135; b) A.-N. R. Alba, A. Zea, T. Calbet, M. Font-Bardia, A.
Moyano, R. Rios, Eur. J. Org. Chem. 2011, 1318–1325.
[18] For a recent example of benzofuranones as nucleophiles in or-
ganocatalytic reactions: C. Cassini, X. Tian, E. C. Escudero-
Adan, P. Melchiorre, Chem. Commun. 2011,47, 233–235.
2
008, 19, 2755–2762; for excellent reviews of azlactones, see: b)
J. S. Fisk, R. A. Mosey, J. J. Tepe, Chem. Soc. Rev. 2007, 36,
1432–1440; c) N. M. Hewlett, C. D. Hupp, J. J. Tepe, Synthesis
2009, 2825–2839.
[
2] For a review of organocatalytic reactions with oxazolones, see:
A.-N. R. Alba, R. Rios Chem. Asian J. 2011, 4, 720–735.
3] For authoritative reviews on the topic of asymmetric organoca-
talytic Michael additions, see: a) A. Erkkilä, I. Majander, P. M.
Pihko, Chem. Rev. 2007, 107, 5416–5470; b) D. Almasi, D. A.
Alonso, C. Nájera, Tetrahedron: Asymmetry 2007, 18, 299–365;
c) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701–1716; d) P. I.
Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248; Angew.
Chem. Int. Ed. 2004, 43, 5138–5175; e) J. Christoffers, A. Baro,
Angew. Chem. 2003, 115, 1726; Angew. Chem. Int. Ed. 2003,
[
42, 1688–1690; f) A.-N. Alba, X. Companyó, M. Viciano, R.
Rios, Curr. Org. Chem. 2009, 13, 1432–1474.
[
[
[
[
[
[
4] S. Cabrera, E. Reyes, J. Alemán, A. Milelli, S. Kobbelgaard,
K. A. Jorgensen, J. Am. Chem. Soc. 2008, 130, 12031–12037.
5] J. Alemán, A. Milelli, S. Cabrera, E. Reyes, K. A. Jørgensen,
Chem. Eur. J. 2008, 14, 10958–10966.
6] H. Jiang, M. W. Paixao, D. Monge, K. A. Jørgensen, J. Am.
Chem. Soc. 2010, 132, 2775–2783.
7] A.-N. R. Alba, G. Valero, T. Calbet, M. Font-Bardía, A. Moy- [19] A few days before the submission of this manuscript an excep-
ano, R. Rios, Chem. Eur. J. 2010, 16, 9884–9889.
8] A.-N. R. Alba, X. Companyo, G. Valero, A. Moyano, R. Rios,
Chem. Eur. J. 2010, 16, 5354–5361.
9] N. Bravo, A.-N. R. Alba, G. Valero, X. Companyo, A. Moy-
ano, R. Rios, New J. Chem. 2010, 34, 1816–1820.
tional review about this topic was published: E. Emer, R. Sinisi,
M. G. Capdevila, D. Petruzziello, F. De Vicentiis, P. G. Cozzi,
Eur. J. Org. Chem. 2011, 647–666
Received: January 12, 2011
Published Online: February 23, 2011
2056
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2053–2056