Convenient procedure for the indium-mediated hydroxymethylation of active bromo compounds: Transformation of ketones into α-hydroxymethyl nitroalkanes

Article abstract of DOI:10.1055/s-0030-1258581

A very simple, safe and powerful method for the hydroxymethylation of 2-bromoesters and lactones under anhydrous conditions that avoids the use of gaseous formaldehyde is described. Moreover, under these conditions, bromonitroalkanes were converted into the corresponding α- monohydroxymethylated nitroalkanes, which are precursors of the corresponding α-amino acids. Considering the easy transformation of ketones into bromonitroalkanes, this represents a method for the formal synthesis of α-amino acids from ketones. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258581

LETTER
2625
Convenient Procedure for the Indium-Mediated Hydroxymethylation of
Active Bromo Compounds: Transformation of Ketones into a-Hydroxymethyl
Nitroalkanes
I
ndium-Mediate
d
a
H
ydroxym
q
ethylation o
u
Active
B
ro
e
o
Compou
l
nds G. Soengas,*a Amalia M. Estévezb
a
Departmento de Química Fundamental, Universidad de A Coruña, Campus de A Zapateira, s/n, 15071, A Coruña, Spain
b
Departmento de Química Orgánica, Universidad de Santiago de Compostela,
Avda. da Ciencias, s/n, 15782, Santiago de Compostela, Spain
Fax +34(981)167065; E-mail: rsoengas@udc.es
Received 6 July 2010
In memory of Professor Jose M. Concellón
The initial studies were performed with commercially
available ethyl bromoisobutyrate (1: Scheme 1).
Abstract: A very simple, safe and powerful method for the hy-
droxymethylation of 2-bromoesters and lactones under anhydrous
conditions that avoids the use of gaseous formaldehyde is de-
scribed. Moreover, under these conditions, bromonitroalkanes were
converted into the corresponding a-monohydroxymethylated ni-
troalkanes, which are precursors of the corresponding a-amino ac-
ids. Considering the easy transformation of ketones into
bromonitroalkanes, this represents a method for the formal synthe-
sis of a-amino acids from ketones.
The reaction was tested under different conditions in
terms of temperature, solvents and concentration and the
results are summarized in Table 1.
1. In
2. (HCHO)n
HO
Br
CO2Et
CO2Et
Key words: hydroxymethylation, indium, esters, nitroalkanes,
amino acids
1
2
Scheme 1 Indium-mediated reaction of ethyl bromoisobutyrate and
paraformaldehyde
Formaldehyde is one of the most important C1 electro-
philes in organic synthesis and is widely used in chemistry
despite its limited availability as a pure material. Formal-
Table 1 Hydroxymethylation of Ethyl Bromoisobutyrate
dehyde is available in aqueous solutions (‘formalin’), in Entry Conditions
which the aldehyde is predominantly in its hydrate struc-
Solvent
toluene
DMF
THF
In (equiv) 1 (equiv) Yield
1
2
r.t.
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.4
1.2
–
ture. Evidently, this solution cannot be used for substrates
and reactions that are moisture sensitive. In these cases
formaldehyde is usually generated from its polymeric pre-
cursors (i.e., trioxane or polyoxomethylene). Thermal
cracking, however, produces self-reactive and highly tox-
ic gaseous formaldehyde.1 Consequently, even though hy-
droxymethylation of enolates with formaldehyde provides
an efficient method to introduce a C1 functional group at
the a-position of carbonyl groups, the hydroxymethyla-
tion of enolates under Reformatsky conditions is not com-
mon in the literature.2 In general, polymeric precursors of
formaldehyde, such as paraformaldehyde, are poorly reac-
tive but there are a few examples in the literature in which
paraformaldehyde is reactive enough to be used directly in
the reaction,3 including a couple of metal-mediated proce-
dures.4
r.t.
–
3
r.t.
–
4
reflux
toluene
DMF
THF
42%
58%
55%
62%
75%
80%
78%
80%
5
80 °C
6
reflux
7
sonication
sonication
sonication
sonication
sonication
toluene
DMF
THF
8
9
10
11
THF
THF
We wish to report here an extremely simple, safe and ver-
satile method for the hydroxymethylation of enolates and
nitronates based on an indium-mediated reaction with sol-
id paraformaldehyde. This reaction proceeds under very
mild and nonbasic conditions.
The reaction failed to give the desired hydroxymethylated
esters at room temperature under any of the conditions
tested. On heating the reaction mixture, however, the hy-
droxymethylated esters were successfully obtained using
DMF, THF or toluene as solvents. Ultrasonic irradiation
has previously proven useful in indium-mediated proto-
cols.5 As a result, the reaction was also carried out with the
vessel immersed in an ultrasonic cleaning bath, a process
that gave the hydroxymethylated esters in better yields.
SYNLETT 2010, No. 17, pp 2625–2627
x
x
.x
x
.2
0
1
0
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258581; Art ID: D18110ST
© Georg Thieme Verlag Stuttgart · New York

2626
R. G. Soengas, A. M. Estévez
LETTER
Increases in the concentration of bromoester or indium did Taking into account these satisfactory results, we decided
not alter the yields.
to investigate the application of this procedure to the
hydroxymethylation of bromonitroalkanes. We recently
reported a novel indium-mediated reaction of bromoni-
troalkanes and aldehydes, a process that constitutes an in-
teresting alternative to the Henry reaction and allows the
corresponding 2-nitroalkanols to be obtained in high
yields and under mild conditions.8 In order to investigate
the indium-mediated hydroxymethylation of bromonitro
compounds, bromonitromethane (1.5 equiv) was reacted
with indium powder (1 equiv) and paraformaldehyde (1
equiv) in THF under sonication. This reaction gave 2-ni-
troethanol (17) in good yield after aqueous workup
(Scheme 4).
In summary, the best conditions to carry out the reaction
described here, both in terms of yield and simplicity of the
procedure, are given in entry 9 (Table 1). Once the reac-
tion conditions had been optimized, the method was ap-
plied to a series of commercial bromoesters. Thus, 1.5
equivalents of 3–6, one equivalent of indium powder and
one equivalent of solid paraformaldehyde were reacted in
THF under sonication (Scheme 2).6
1. In
2. (HCHO)n
HO
Br
NO2
NO2
Scheme 2 Indium-mediated reaction of bromoesters and paraform-
THF
aldehyde
17
Scheme 4 Indium-mediated reaction of bromonitromethane and
paraformaldehyde
Under these conditions the corresponding hydroxymethy-
lated esters 7–107 were obtained after aqueous workup in
excellent yields and without further purification
(Table 2).
This indium-mediated hydroxymethylation of bromoni-
troalkanes has many advantages in comparison to the hy-
droxymethylation of nitronates based on the Henry
reaction with formaldehyde, including the possibility of
avoiding basic conditions and the higher yields obtained.
However, the most important drawback of the classical
Henry reaction of nitronates and formaldehyde, which is
overcome in the new procedure reported here, is the lack
of regioselectivity. Thus, when primary nitronates are
treated with formaldehyde under classical Henry condi-
tions, the a,a-dihydroxymethylated derivative is always
the major product isolated from the reaction mixture.9
However, the indium-mediated reaction of bromonitroal-
kanes with a-hydrogens, in this case bromonitromethane
with paraformaldehyde, afforded the monohydroxymeth-
ylated derivative 17 as the only product.
Table 2 Hydroxymethylation of a-Bromoesters under the Opti-
mized Conditions
Ester
R1
R2
H
H
H
H
Product
Yield
69%
61%
75%
72%
3
4
5
6
Me
Et
7
8
n-Pr
Ph
9
10
The scope of this new methodology was further investi-
gated by using cyclic enolates as starting materials.
2-Bromolactones 11–13 were submitted to the same reac-
tion conditions as above (Scheme 3) and this gave the cor-
responding 2-hydroxymethyllactones 14–16 in good
yields (Table 3).
Considering the satisfactory results obtained in the indi-
um-mediated hydroxymethylation of bromonitromethane
using solid paraformaldehyde as a source of formalde-
hyde electrophile, as well as the previously described pro-
cedure to obtain bromonitroalkanes from ketones via the
corresponding oximes,10 we decided to investigate the
conversion of several ketones 18–22 into bromonitroal-
kanes 23–27 and the hydroxymethylation of the latter
compounds under the same conditions used for bromoni-
tromethane (Scheme 5).
1. In
2. (HCHO)n
O
O
R2
O
R2
O
R1
R1
THF
OH
Br
11–13
14–16
Scheme 3 Indium-mediated reaction of bromolactones and para-
formaldehyde
Under these conditions, a-hydroxymethyl nitro com-
pounds 28–3211 were obtained in good yields after aque-
Table 3 Hydroxymethylation of a-Bromolactones
1. In
2. (HCHO)n
Oxone
R1 R2
R1
Me
Me
H
R2
Me
H
Product
14
Yield
78%
69%
70%
R1 R2
Br NO2
23–27
R1 R2
Lactone
11
KBr
HO
THF
[ref. 10b]
NO2
O
18–22
28–32
12
15
Scheme 5 Conversion of ketones into a-hydroxymethyl nitroal-
13
Me
16
kanes
Synlett 2010, No. 17, 2625–2627 © Thieme Stuttgart · New York

LETTER
Indium-Mediated Hydroxymethylation of Active Bromo Compounds
2627
ous workup (Table 4). This procedure constitutes an
interesting new route for the transformation of ketones
into a-hydroxymethyl nitro compounds, which in turn are
precursors of the corresponding a-amino acids.
Acknowledgment
This work was supported by the Spanish Ministry of Science and In-
novation (CTQ2008-06493). R.G.S. thanks the Xunta de Galicia for
financial support (Isidro Parga Pondal program) and A.M.E. thank
the Spanish Ministry of Science and Innovation for a FPU grant.
We would like to thank Professors Ramón J. Estévez and Juan C.
Estévez for helpful discussions.
Table 4 Hydroxymethylation of Bromonitroalkanes Derived form
Ketones
Bromonitroalkane
Product
Yield
71%
References and Notes
HO
(1) Numerous examples account for the use of gaseous
formaldehyde. For a device for continuous production by
trioxane cracking, see:Kachi, H.; He, F.; Sakamoto, K.
Chem. Express 1990, 5, 701.
Br
NO2
NO2
28
23
(2) (a) Coe, P. L.; Löhr, M.; Rochin, C. J. Chem. Soc., Perkin
Trans. 1 1998, 2803. (b) Weyerstahl, P.; Kressin, H.;
Nerdel, F. Liebigs Ann. Chem. 1969, 725, 106. (c) Pernot,
R. Bull. Soc. Chim. Fr. 1950, 17, 682.
(3) Otero, J. M.; Soengas, R. G.; Estévez, J. C.; Estévez, R. J.;
Watkin, D. J.; Evinson, E. L.; Nash, R. J.; Fleet, G. W. J.
Org. Lett. 2007, 9, 623.
75%
75%
HO
Br
NO2
NO2
24
29
HO
Br
NO2
NO2
(4) (a) Park, J.; Pedersen, S. F. Tetrahedron 1992, 48, 2069.
(b) Morimoto, T.; Yamasaki, K.; Hirano, A.; Tsutsumi, K.;
Kagawa, N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.;
Chatani, N.; Nishioka, T. Org. Lett. 2009, 11, 1777.
(5) Soengas, R. G. Tetrahedron Lett. 2010, 51, 105.
(6) General Procedure: To a suspension of indium powder (0.5
mmol) in THF (1 mL), the 2-bromocompound (0.75 equiv)
was added and the mixture was sonicated for 20 min.
Paraformaldehyde (0.5 mmol) was then added and
sonication was continued for a further 4 h. The reaction
mixture was quenched with sat. aq NaHCO3 (10 mL) and
extracted with Et2O (3 × 25 mL). The combined organic
layers were dried over MgSO4, filtered and the solvent was
evaporated in vacuo to obtain pure hydroxymethylated
compounds.
(7) (a) Birkhofer, L.; Ritter, A.; Wieden, H. Chem. Ber. 1962,
95, 971. (b) Vieregge, H.; Arens, J. F. Recl. Trav. Chim.
Pays-Bas 1959, 78, 921. (c) Kawai, Y.; Kondo, S.;
Tsujimoto, M.; Nakamura, K.; Ohno, A. Bull. Chem. Soc.
Jpn. 1994, 67, 2244. (d) Atuu, M. R.; Mahmood, S. J.; Laib,
F.; Hossain, M. M. Tetrahedron: Asymmetry 2004, 15, 3091.
(8) Soengas, R. G.; Estévez, A. M. Eur. J. Org. Chem. 2010,
5109.
(9) (a) Knochel, P.; Seebach, D. Tetrahedron Lett. 1982, 23,
3897. (b) Otero, J. M.; Estévez, A. M.; Soengas, R. G.;
Estévez, J. C.; Nash, R. J.; Fleet, G. W. J.; Estévez, R. J.
Tetrahedron: Asymmetry 2008, 19, 2443.
(10) (a) Marchand, A. P.; Arney, B. E.; Dave, P. R. J. Org. Chem.
1988, 53, 443. (b) Curini, M.; Epifano, F.; Marcotullio,
M. C.; Rosati, O.; Rossi, M. Tetrahedron 1999, 55, 6211.
(11) (a) Dornow, A.; Muller, A. Chem. Ber. 1960, 93, 41.
(b) Taub, B.; Hino, J. B. US Patent, US 319485, 1985.
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25
30
73%
76%
NO2
NO2
Br
HO
26
31
NO2
Br
NO2
OH
27
32
In summary, a simple, safe and efficient procedure for the
hydroxymethylation of 2-bromoesters and lactones has
been developed. The process occurs under anhydrous con-
ditions and is based on an indium-mediated Reformatsky
reaction with solid paraformaldehyde. The application of
the procedure to bromonitroalkanes was also successful,
and this constitutes a new access to a-hydroxymethyl ni-
tro compounds, which are precursors of the corresponding
a-amino acids. Together with the previously reported pro-
cedure for the transformation of ketones into bromoni-
troalkanes, we now have a method for the formal
synthesis of a-amino acids from ketones.
Work is currently under way in our laboratory aimed at
developing an enantiospecific version of this reaction.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 17, 2625–2627 © Thieme Stuttgart · New York

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