Room temperature MgI2-catalyzed Friedel–Crafts reaction between electron-rich (het)arenes and ethyl glyoxylate

Article abstract of DOI:10.1016/j.mencom.2018.07.030

Magnesium iodide-catalyzed addition of electron-rich (het)arenes to ethyl glyoxylate proceeds at room temperature with high chemoselectivity to afford ethyl 2-(het)aryl- 2-hydroxyacetates in yields up to 95%.

Full text of DOI:10.1016/j.mencom.2018.07.030

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 429–430
Room temperature MgI2-catalyzed Friedel–Crafts reaction
between electron-rich (het)arenes and ethyl glyoxylate
Mikhail N. Feofanov,* Boris A. Lozhkin, Maksim V. Anokhin,
Alexey D. Averin and Irina P. Beletskaya
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow,
Russian Federation. E-mail: feofanovmn@gmail.com
DOI: 10.1016/j.mencom.2018.07.030
O
HO
Ar
Magnesium iodide-catalyzed addition of electron-rich
(het)arenes to ethyl glyoxylate proceeds at room tempera-
ture with high chemoselectivity to afford ethyl 2-(het)aryl-
2-hydroxyacetates in yields up to 95%.
MgI2
+
ArH
CO2Et
CH2Cl2, 20 °C
CO2Et
13 examples
up to 95% yield
The Friedel–Crafts reaction with carbonyl compounds (Friedel–
Crafts hydroxyalkylation) is one of the fundamental organic
reactions known since the end of the 19th century. For example,
bakelite synthesis by polycondensation of phenol with form-
aldehyde is the most valuable example of this reaction.1 Other
aromatic and carbonyl compounds can also enter into such a
hydroxyalkylation.2–17
The 3-substituted indole motif commonly occurs among
natural and biologically active compounds.18 The addition of
indole 1a to ethyl glyoxylate 2 is not studied sufficiently although
their adduct 3a should be a promising indole analogue of mandelic
acid ester (Scheme 1). The published data on such a transformation
are scarce.19–23
We used the previously optimized conditions (10 mol% MgI2 in
CH2Cl2)24 at room temperature for the addition of unsubstituted
indole 1a to ethyl glyoxylate 2. It is known that bis-adduct 4a
(see Scheme 1) can also be formed in this reaction under Lewis
acid catalysis (for the mechanism, see ref. 30 and Scheme S1,
Online Supplementary Materials). Surprisingly, under our con-
ditions no bis-adduct was formed, and hydroxy ester 3a was
obtained in 80% yield (see Scheme 1).
To evaluate the scope of the reaction, we studied the effect of
substituents in the indole ring on outcome of the process. The
introduction of fluorine or chlorine into 5-position of the indole
ring leads to increase in the yields of products 3b,c to 92 and 90%,
respectively (see Scheme 1), while in the case of 5-bromoindole
1d the yield of product 3d is the same as for 3a. To our surprise,
the introduction of electron-donating substituents into 5-position
raises the yields of products 3e,f to 87 and 89%, respectively.
The introduction of electron-withdrawing NO2 group (indole 1g)
led to a lower 70% yield of the adduct 3g. In case of 6-methoxy-
carbonylindole 3h, the yield of diester 3h was almost quantitative.
On moving to 1-methyl-1H-indole 1i, yield of mono-adduct 3i
dropped to 58% due to formation of bis-adduct 4i (see Scheme 1)
which was detected by 1H NMR but was not isolated.
In our previous study of the Friedel–Crafts reaction,24–29 we
found that addition of indole to activated olefins could be
catalyzed by magnesium iodide,24 a very effective Lewis acid.
We hypothesized that the unique properties of MgI2 could also
show up in the reaction between indole and ethyl glyoxylate.
Herein, we present the addition of indole and other electron-rich
(het)arenes to ethyl glyoxylate catalyzed by MgI2.
R1
O
i
As compared to other Lewis acids,19–22 magnesium iodide has
advantages in the addition of 1a to 2. In the cases of SmI2(THF)2,
Ti(OPri)4/S-BINOL, LiCl/(CF3)2CHOH (Table 1, entries 1–3) the
yields of product 3a are lower, while for systems Ti(OPri)4/S-BINOL
(entry 2) and Sc(OTf)3 with sophisticated N,N'-dioxide ligands
(entry 4) high yields were achieved only at lower temperatures.
Moreover, the advantage of our procedure is the possibility to
+
CO2Et
R2
N
R3
2
1a–i
HO
CO2Et
CO2Et
R1
R2
+
N
N
N
R3
Table 1 Influence of the catalyst nature on the yield of product 3a in the
addition of 1a to 2.
Me
Me
4
3a–i
Inert
Yield of
Entry Catalyst
T/°C
Reference
a R1 = R2 = R3 = H, 80%
f R1 = MeO, R2 = R3 = H, 89%
g R1 = NO2, R2 = R3 = H, 70%
h R1 = R3 = H, R2 = CO2Me, 95%
atmosphere 3a (%)
b R1 = F, R2 = R3 = H, 92%
c R1 = Cl, R2 = R3 = H, 90%
d R1 = Br, R2 = R3 = H, 80%
e R1 = Me, R2 = R3 = H, 87%
1
2
3
4
SmI2·(THF)2
20
0
–
+
+
+
38
72
74
90
19
20
21
22
Ti(OPri)4/S-BINOL
i
R1 = R2 = H, R3 = Me, 58%
LiCl/(CF3)2CHOH
20
0
Sc(OTf)3/
Scheme 1 Reagents and conditions: i, 1a–i (0.5 mmol), 2 (0.25 mmol),
MgI2 (0.025 mmol), CH2Cl2 (0.5 ml), 20°C, 24 h (for 1f, 18 h and for 1g,
30 h). Yields are preparative after column chromatography.
N,N'-dioxide ligand
5
MgI2
20
–
80
This work
© 2018 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 429 –

Mendeleev Commun., 2018, 28, 429–430
3 P. Menegheli, M. C. Rezende and C. Zucco, Synth. Commun., 1987,
O
MgI2
+
ArH
17, 457.
CH2Cl2, 20 °C
CO2Et
2
4 A. W. Bridge, G. Fenton, F. Halley, M. B. Hursthouse, C. W. Lehmann
and D. J. Lythgoe, J. Chem. Soc., Perkin Trans. 1, 1993, 2761.
5 S. R. Adams, J. P. Y. Kao, G. Grynkiewicz, A. Minta and R. Y. Tsien,
J. Am. Chem. Soc., 1988, 110, 3212.
5a–d
CO2Et
HO
Ar
6 M. P. A. Lyle, N. D. Draper and P. D. Wilson, Org. Lett., 2005, 7, 901.
7 C. Li, F. Guo, K. Xu, S. Zhang, Y. Hu, Z. Zha and Z. Wang, Org. Lett.,
2014, 16, 3192.
8 Y. Yuan, X. Wang, X. Li and K. Ding, J. Org. Chem., 2004, 69, 146.
9 Z. Huang, J. Zhang,Y. Zhou and N.-X. Wang, Eur. J. Org. Chem., 2011,
843.
+
CO2Et
Et2N
NEt2
6a–d
7
a Ar = 2,4-(MeO)2C6H3, 32%
b Ar = 2,4,6-(MeO)3C6H2, 75%
c Ar = 5-methylfuran-2-yl, 70%
d Ar = 4-Et2NC6H4, 42%
(for 7, 21%)
10 G. Blay, I. Fernández, A. Monleón, J. R. Pedro and C. Vila, Org. Lett.,
2009, 11, 441.
Scheme 2
11 A. Ishii, V. A. Soloshonok and K. Mikami, J. Org. Chem., 2000, 65, 1597.
12 J. Majer, P. Kwiatkowski and J. Jurczak, Org. Lett., 2009, 11, 4636.
13 G. Blay, I. Fernández, M. C. Muñoz, J. R. Pedro, A. Recuenco and
C. Vila, J. Org. Chem., 2011, 76, 6286.
carry out the reaction under atmospheric air (entry 5). On scaling
the reaction up to 1 g of indole 1a, the yield of adduct 3a was
as good as 730 mg (79%).
14 W. Zhuang, N. Gathergood, R. G. Hazell and K. A. Jørgensen, J. Org.
Chem., 2001, 66, 1009.
Further on, we investigated addition of other (het)arenes
using our procedure. Polymethoxybenzenes 5a,b react with ethyl
glyoxylate 2 to form the corresponding alcohols 6a,b in 32 and
75% yields, respectively (Scheme 2). 2-Methylfuran 5c gives
the product 6c in 70% yield.
The similar reaction of N,N-diethylaniline 5d affords a 2:1
mixture of mono- and bis-adducts 6d and 7 (see Scheme 2) in
total 63% yield (calculated from 1H NMR). Pyrrole and N-methyl-
pyrrole form complex mixtures of products of mono- and poly-
alkylation. These mixtures cannot be separated by column
chromatography.
15 H. Ren, P. Wang, L. Wang and Y. Tang, Org. Lett., 2015, 17, 4886.
16 J.-L. Zhao, L. Liu, Y. Sui, Y.-L. Liu, D. Wang andY.-J. Chen, Org. Lett.,
2006, 8, 6127.
17 K. Aikawa, Y. Asai, Y. Hioki and K. Mikami, Tetrahedron: Asymmetry,
2014, 25, 1104.
18 A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010,
110, 4489.
19 M. Soueidan, J. Collin and R. Gil, Tetrahedron Lett., 2006, 47, 5467.
20 H.-M. Dong, H.-H. Lu, L.-Q. Lu, C.-B. Chen and W.-J. Xiao, Adv.
Synth. Catal., 2007, 349, 1597.
21 M. Willot, J. C. Chen and J. Zhu, Synlett, 2009, 577.
22 Y. Hui, Q. Zhang, J. Jiang, L. Lin, X. Liu and X. Feng, J. Org. Chem.,
2009, 74, 6878.
In conclusion, we have developed an efficient convenient
procedure for the preparation of indole analogues of mandelic
acid esters. The reaction is promoted by magnesium iodide
serving as the Lewis acid and proceeds at room temperature. The
method can be extended to some other electron-rich (het)arenes to
obtain new promising compounds for biomedical applications.31
23 W. Zhuang and K. A. Jørgensen, Chem. Commun., 2002, 1336.
24 M. V. Anokhin, M. N. Feofanov, A. D. Averin and I. P. Beletskaya,
Synthesis, 2017, 49, 5045.
25 V. G. Desyatkin and I. P. Beletskaya, Synthesis, 2017, 49, 4327.
26 E. A. Tarasenko and I. P. Beletskaya, Synthesis, 2017, 49, 1689.
27 V. G. Desyatkin, M. V. Anokhin, V. O. Rodionov and I. P. Beletskaya,
Russ. J. Org. Chem., 2016, 52, 1717 (Zh. Org. Khim., 2016, 52, 1727).
28 I. P. Beletskaya and A. D. Averin, Curr. Organocatal., 2016, 3, 60.
29 M. V. Anokhin, M. N. Feofanov, A. D. Averin and I. P. Beletskaya,
ChemistrySelect, 2018, 3, 1388.
This work was supported by the Russian Science Foundation
(grant no. 14-23-00186P).
30 J. A. Joule, K. Mills and G. F. Smith, Heterocyclic Chemistry, 3rd
edn.,
Chapman & Hall, London, 1995.
31 B. A. Lozhkin, A. V. Shlyakhtin, V. V. Bagrov, P. V. Ivchenko and
Online Supplementary Materials
Supplementary data associated with this article (procedures
and characteristics of products) can be found in the online version
at doi: 10.1016/j.mencom.2018.07.030.
I. E. Nifant’ev, Mendeleev Commun., 2018, 28, 61.
References
1 L. H. Baekeland, Patent US 942699, 1909.
2 R. C. Fuson, H. H. Weinstock, Jr. and G. E. Ullyot, J. Am. Chem. Soc.,
1935, 57, 1803.
Received: 17th January 2018; Com. 18/5454
– 430 –