Stereoselective Barbier-type allylation reaction of trifluoromethyl aldimines

Article abstract of DOI:10.1021/jo034205c

Trifluoromethyl aldimines could react, under Barbier conditions in the presence of activated zinc, in DMF at room temperature or in THF at reflux, with various allyl bromides to provide the corresponding homoallylamines. Secondary homoallyl trifluoromethy

Full text of DOI:10.1021/jo034205c

TABLE 1. Allyla tion Rea ction Cou p lin g of Allyl
Br om id es w ith Im in e 1 a n d Meta l
Ster eoselective Ba r bier -Typ e Allyla tion
Rea ction of Tr iflu or om eth yl Ald im in es
J ulien Legros, Franck Meyer, Matthieu Coliboeuf,
Benoˆıt Crousse,* Danie`le Bonnet-Delpon,* and
J ean-Pierre Be´gue´
BioCIS, Centre d’Etudes Pharmaceutiques, rue J .B.
Cle´ment, Chaˆtenay-Malabry 92296 Cedex, France
benoit.crousse@cep.u-psud.fr;
daniele.bonnet-delpon@cep.u-psud.fr
Received February 17, 2003
Abstr a ct: Trifluoromethyl aldimines could react, under
Barbier conditions in the presence of activated zinc, in DMF
at room temperature or in THF at reflux, with various allyl
bromides to provide the corresponding homoallylamines.
Secondary homoallyl trifluoromethylamines were stereose-
lectively obtained from the optically active aldimine 12 with
an excellent diastereoisomeric excess (98%).
a
b
In ether at rt. In DMF at rt.
8
CH2NR2 and on N-acyl-1-chloro-2,2,2-trifluoro ethy-
lamine,9 and more recently, the addition of allyllithium,
generated from tetraallyltin with phenyllithium, on
trifluoromethylated hydrazones.10 Nevertheless, it was
previously reported that the N-(R)-phenethyltrifluorom-
ethyl aldimine was unreactive toward the allyl bro-
moester in the Barbier-type conditions with zinc powder
in THF.11 These surprising results prompted us to explore
more deeply this organometallic approach for the prepa-
ration of trifluoromethyl homoallylamines. First, we
investigated the allylation reaction of the N-benzyltrif-
luoroacetaldimine 1 with the allyl bromides 2a ,b in the
presence of two different metals, magnesium in ether,
and indium in DMF12 in the Barbier conditions. Results
are summarized in Table 1.
With both magnesium and indium reagents generated
from the allyl bromide 2a , the homoallylamine 3a was
obtained in good yield. Under these conditions, the
reductive homocoupling of the imine was not detected by
1H NMR or 19F NMR. With organometallic reagents
generated from the allyl bromide 2b, reactions were not
efficient. None or very low conversion into the homoallylic
amine 3b was observed at room or at higher tempera-
tures (50-80 °C).
The allylation of imines, providing the corresponding
homoallylamines, is an important synthetic transforma-
tion.1 Important classes of compounds such as 1,3-amino
acids, 1,3-amino alcohols, and 1-amino-3,4-epoxides2 and
even pyrrolidines and piperidines3 are accessible by this
approach.
Despite the possible interest in fluorinated analogues
of these synthons,4 the preparation of homoallyl trifluo-
romethylamines has not been intensively studied so far.
One synthesis has been reported from the N-(p-toluene-
sulfonyl)trifluoromethyl aldimine by an ene reaction.5
More recently, a Lewis acid-mediated addition of an
allylsilane to aldimines or hemiaminals, derived from
fluoral, has been described in racemic6 and in chiral
versions.6,7 Concerning the organometallic approach, to
our knowledge few examples were reported: reactions
involve the addition of allylmagnesium on a trifluorom-
ethyl sulfenimine generated by electrooxidation of CF3-
(1) (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207-2293.
(b) Li, C.-J .; Chan, T.-H. Tetrahedron 1999, 55, 11149-11176. (c)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. Chem. Rev. 2002,
102, 2227-2302.
(2) Laschat, S.; Kunz, H. J . Org. Chem. 1991, 56, 5883.
(3) (a) Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R. J .; Villieras,
J .; Lebreton, J . J . Org. Chem. 2001, 66, 6305. (b) Wright, D. L.; Schulte,
J . P., II.; Page, M. A. Org. Lett. 2000, 2, 1847.
(4) (a) Filler, R.; Kobayashi, Y.; Yagulpolskii, Y. L. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications;
Elsevier: Amsterdam, 1993. (b) Banks, R. E.; Smart, B. E.; Tatlow, J .
C. Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (c) Hudlicky, M.; Pavlath, A. E.
Chemistry of Organic Fluorine Compounds II. A Critical Review; ACS
Monograph 187; American Chemical Society: Washington, DC, 1995.
(d) Welch, J . T., Ed. Selective Fluorination in Organic and Bioorganic
Chemistry; ACS Symposium Series 456; American Chemical Society:
Washington, DC, 1991.
(5) (a) Kumadaki, I.; J onoshita, S.; Harada, A.; Omote, M.; Ando,
A. J . Fluorine Chem. 1999, 97, 61. (b) J oshita, S.; Harada, A.; Omote,
M.; Ando, A.; Kumadaki, I. Chem. Pharm. Bull. 1999, 47, 656.
(6) (a) Billard, T.; Langlois, B. R. J . Org. Chem. 2002, 67, 997-1000.
(b) Langlois, B. R.; Billard, T. Synthesis 2003, 2, 185.
We then revisited the allylation reaction involving zinc
reagents with the following changes: turnings of zinc
were used and they were activated in situ by TMSCl,13
and the reaction was conducted in DMF which has been
proved to be an excellent solvent in allylation reactions.14
Zn-mediated allylation reaction was performed with the
imine 1 and a range of allyl bromides (1.3 equiv) in the
presence of 1.3 equiv of zinc. Results are reported in
Table 2.
(8) Fuchigami, T.; Ichikawa, S.; Konno, A. Chem. Lett. 1992, 2405.
(9) Weygand, F.; Steglich, W.; Pietta, P. Chem. Ber. 1967, 100, 3841.
(10) Funabiki, K.; Nagamori, M.; Matsui, M.; Enders, D. Synthesis
2002, 17, 2585.
(11) Murata, K.; Kanedo, S.; Kitazume, T. Bioorg. Med. Chem. Lett.
1993, 3, 2685.
(12) Li, C.-J .; Chan, T.-H. Tetrahedron 1999, 55, 11149.
(13) Zinc was activated in situ by TMSCl: Picotin, G.; Miginiac, P.
J . Org. Chem. 1987, 52, 4796.
(7) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetrahe-
dron Lett. 2002, 43, 2827.
(14) Shono, T.; Ishifune, M.; Kashimura, S. Chem. Lett. 1990, 449.
10.1021/jo034205c CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/10/2003
6444
J . Org. Chem. 2003, 68, 6444-6446

TABLE 2. Allyla tion Rea ction w ith Zin c in DMF a n d
THF
TABLE 3. Zn -Med ia ted Ba r bier -Typ e Rea ction w ith
Allyl Br om id es 2 a n d Im in e 6
a
b
2 (1.5 equiv) + Zn activated by TMSCl (1.5 equiv). 20% of
de determined by 19F NMR of the crude product.
SCHEME 1
the corresponding homoallylic amines 3a ,b in good yields
(85%, 82% respectively), and similarly, imine 4 could
react with allyl bromide 2a to afford the homoallylamine
5a in 92% yield.
The allylation reaction was then investigated from
chiral trifluoromethyl aldimines. First, the reaction was
undertook with the (R)-N-phenethyl aldimine 6 and
conducted as precedently with the allyl bromide 2a ,
activated zinc in both THF and DMF solvents. The
homoallylic amine 7a was obtained in good yield, 78%
in THF and 87% in DMF, respectively. The reaction was
not diastereoselective (60/40). For comparison with the
previously reported unsuccessful experiment,11 the reac-
tion was also performed with the allyl bromide 2d in
THF, and the butyrolactam 8 was obtained in 60% yield
with a (60/40) ratio of diastereoisomers (Table 3).
It is worth noting that butyrolactams could also be
obtained from CF3-aldimines in DMF when reactions
were conducted at reflux (Scheme 1).
a
b
At room temperature. At reflux.
Under these new conditions, in all cases reactions were
fast and clean, and yields were good to excellent (75-
97%). Even hindered allyl bromides 2b-d were reactive;
the nonsymmetric allyl bromide 2b reacted at the γ
position (>98%). This result confirms the tendency of
prenyl bromide to add to carbonyl compounds and imines
at the most substituted allylic terminus15 despite the
steric hindrance of the CF3 group.16 The reaction was
then extended to the N-p-methoxyphenyl aldimine 417
with the same success. Homoallylic amines 5a -c were
isolated in good yields (79-83%). To define whether the
success of the reaction was due to the activated metal or
to the choice of solvent, reactions were also attempted
in THF with aldimines 1 and 4 (Table 2). Reflux was
required for the reaction to occur. Under these conditions,
imine 1 could react with allyl bromides 2a ,b to afford
We searched to induce a better diastereoselectivity
using other chiral N-substituents. Oxazolidines 10 (62/
38), which are prepared from fluoral and phenyl glyci-
nol,18 had been shown to provide a 70/30 mixture of
diastereoisomers of chiral homoallylamine in BF3‚Et2O-
promoted reaction with an allylsilane.7 When placed
under our Barbier conditions in THF at reflux and DMF
at room temperature, with 1.5 equiv of zinc, oxazolidines
10 provided amines in very poor yield. Three to four
equivalents of zinc were required to obtain the N-
phenylglycinol allylamines 11 in 65% and 45% yields,
respectively. Compared to reactions from 6, the diaste-
reoisomeric excess was improved in DMF (de ) 61%) but
1
very poor in THF (de ) 9%) (Scheme 2). Analysis of H
and 19F NMR data indicating that the minor isomer
obtained in our experiments is the major isomer obtained
from oxazolidine 10 under Lewis acid conditions, which
was assumed to be (R,R).7
(15) (a) Gosmini, C.; Rollin, Y.; Perichon, J .; Wakselman, Tordeux,
M.; Marival, L. Tetrahedron 1997, 53, 6027. (b) Fiumana, A.; Lom-
bardo, M.; Trombini, C. J . Org. Chem. 1997, 62, 5623. (c) Martelli, G.;
Morri, S.; Savoia, D. Synlett 2002, 158.
(16) Kumadaki, I. Reviews on Heteroatom Chemistry; Oae, S., Ed.;
Tokyo, 1993; Vol. 9, p 181.
The change in ratio of diastereoisomers in starting
material and products suggests the intermediate forma-
(17) Guanti, G.; Banfi, E.; Narisano, C.; Scolastico, E. Synthesis
1985, 609.
(18) Ishii, A.; Higashiyama, K.; Mikami, K. Synlett 1997, 1381.
J . Org. Chem, Vol. 68, No. 16, 2003 6445

TABLE 4. Allyla tion Rea ction w ith th e Ald im in e 12
SCHEME 2
tion of an iminium ion, as already postulated in reactions
using Lewis acids.6,7 This is probably due to the excess
of zinc used in these reactions, and the requirement
indicates that oxazolidines are less reactive than aldi-
mines toward allyl zinc reagents. This problem does not
occur in nonfluorinated series since aldimines prepared
from aldehydes and phenyl glycinol are not prone to
cyclize. In this case, the organometallic agent reacts
directly with the imines, and homoallylic amines are
obtained with good stereoselectivities.19 To prevent the
formation of oxazolidines, we chose the methyl ether of
the (R)-phenylglycinol20 as chiral N-substituent.21 The
allylation reaction of the CF3-aldimine 12 was performed
in THF and DMF with allyl bromides 2a ,b,d (Table 4).
In all cases, the reactivity of 12 was excellent, and only
1.3 equiv of allyl bromide and zinc were required for a
complete conversion. Yields of 13a , 13b, and 13d were
good to high, and diastereoselectivities were excellent in
THF (>96%) and good in DMF (84%) for 13a , excellent
in THF (98%) for 13b, and good in DMF (85%) for 13d .
Compared to the phenylethyl substituent, the presence
of heteroatom on the N-substituent likely allows a good
chelation with the metal and, hence, increases the
diastereoselection. Unfortunately, great differences be-
tween NMR data of 13a , 13b, 13d , and that of 11 did
not allow a comparison of their configuration.
a
Determined by 19F NMR of the crude product.
with TMSCl. When the reaction was performed with
optically active aldimines, the diastereoselectivity was
dependent on the chiral N-substituent and on the solvent
of reaction. Conditions were found to prepare chiral
trifluoromethyl homoallylamines in good yields and in
high purity (up to 98%).
Ack n ow led gm en t. We thank DSM Co. for the gift
(R)-phenylglycine, Rhodia Co. for financial support, and
Serge Ratton and J ean-Marc Paris (Rhodia) for fruitful
discussions. Miche`le Oure´vitch is gratefully acknowl-
edged for the fine structure determination by NMR
experiments.
In conclusion, we have described a highly efficient and
gentle method for the preparation of a new series of
trifluoromethyl homoallylamines. Under Barbier-type
conditions, aldimines derived from fluoral could react
with allyl bromides, providing zinc was activated in situ
(19) Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8,
1895 and references therein.
(20) Preparation of the methyl ether of the (R)-phenylglycinol:
Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P.
Tetrahedron 2000, 56, 3951.
(21) Yanada, R.; Negoro, N.; Okaniwa, M.; Ibuka, T. Tetrahedron
1999, 55, 13947.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion data for compounds 3a -d , 5a -c, 7a , 8, 9, 11, 12, 13a ,b,d ,
and some experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O034205C
6446 J . Org. Chem., Vol. 68, No. 16, 2003