Synthesis of β-trifluoromethylated Δ1-pyrrolines

Article abstract of DOI:10.1002/adsc.201000487

Trifluoromethylated Δ¹-pyrrolines have been easily synthesized in a one-pot procedure from β-(trifluoromethyl)enones. These substrates are valuable building blocks for further syntheses. For example, trifluoromethylated prolines have been obtained.

Full text of DOI:10.1002/adsc.201000487

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DOI: 10.1002/adsc.201000487
Synthesis of b-Trifluoromethylated D1-Pyrrolines
Olivier Marrec,a Carole Christophe,a Thierry Billard,a,* Bernard Langlois,a
Jean-Pierre Vors,b and Sergii Pazenokc
a
Universitꢀ de Lyon, Universitꢀ Lyon 1, CNRS, ICBMS (UMR CNRS 5246), 43 Bd du 11 novembre 1918, Bat Raulin,
69622 Villeurbanne, France
Fax : (+33)-9-5948-3994; phone: (+33)-4-7244-8129; e-mail: billard@univ-lyon1.fr
Bayer CropScience AG, Centre R&D de La Dargoire, 14-20 rue Pierre Baizet, 69009 Lyon, France
Bayer CropScience AG, Product Technology, Process Research, Alfred-Nobel-Str. 50, 40789 Monheim am Rhein,
b
c
Germany
Received: June 23, 2010; Published online: September 23, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000487.
Abstract: Trifluoromethylated D1-pyrrolines have ample, trifluoromethylated prolines have been ob-
been easily synthesized in a one-pot procedure from tained.
b-(trifluoromethyl)enones. These substrates are val-
uable building blocks for further syntheses. For ex- Keywords: enones; fluorine; Michael addition; pyr-
rolines; Schiff bases
Introduction
Results and Discussion
Nitrogen heterocyclic moieties are structural elements We have previously described two efficient syntheses
of many alkaloidic natural products and drug candi- of b-trifluoromethylated enones.[7] Such compounds
dates.[1] On the other hand, the last years have shown could represent interesting starting materials to
a tremendous increase of new organofluorine com- obtain 5-membered nitrogen heterocycles. Conse-
pounds[2] due to the unique properties exhibited by quently, the following retrosynthesis of b-trifluorome-
such substrates.[3] Among them, trifluoromethyl-sub- thylated
D1-pyrrolines
has
been
elaborated
stituted molecules constitute a particular class be- (Scheme 1). Indeed, such fluorinated pyrrolines could
cause of the specific properties, such as the high lipo- constitute valuable building blocks for further synthe-
philicity brought by the CF3 moiety.
ses of molecules containing trifluoromethylated 5-
Recently, syntheses of a-trifluoromethylated piperi- membered nitrogen heterocycles.
dines[4,5] and lactams[4a,5] have been described starting
This strategy is based on a Michael addition be-
from a-trifluoromethylated homoallylamine. Such a tween b-trifluoromethylated enones and Schiff bases.
methodology has been also applied to the construc- Next, this Michael adduct could be deprotected and
tion of bicyclic nitrogen compounds bearing a CF3 then cyclized, as described in the literature.[8]
moiety in the a position.[6,4b]
With the objective to design potential new drugs
bearing a fluoroalkyl group, the synthesis of nitrogen
heterocycles bearing a trifluoromethyl group in anoth-
er position than the a-position has been considered.
Consequently, the development of a five-membered
cyclic nitrogen building block, trifluoromethylated in
the b-position, has been envisaged for the design of
various fluorinated compounds affording a 3-trifluoro-
methylpyrrolidine core.
Scheme 1. Retrosynthesis of b-trifluoromethylated D1-pyrro-
lines.
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Scheme 2. Michael addition and cyclization with 1a and 2a.
The Michael addition has been tested on 1a with (Figure 1). All the expected pyrrolines 4 were ob-
glycine Schiff base 2a in the presence of DBU as base tained in good yields. This strategy has been extended
(Scheme 2). This conjugate addition gave rise to a to other fluorinated enones which led to 4l–4q with
good yield and a good diastereomeric excess. It can similar results.
be noticed that only a catalytic amount of DBU was
The identification of the major diastereomers has
required to achieve the total conversion of 1a. Then, been realized by Overhauser enhancement experi-
the subsequent product 3a was treated under acidic ments (NOESY and HOESY H-F) on each isolated
conditions to generate the free amino group. During diastereomer (Figure 2).
this deprotection step, cyclization occurred simultane-
ously to give the expected cyclic imine 4a.[8] The opti- butyl ester 2b) were used, the expected pyrrolines
mal conditions showed that substoichiometric (4a–4i, 4l–4o) were obtained with a diastereoselectiv-
When glycine Schiff bases (ethyl ester 2a or tert-
a
amount of concentrated aqueous HCl is enough to cy- ity higher than 70%, the trans product being the
clize 3a into 4a. The tedious purification of 3a (crude major diastereomer. On the other hand, when a Schiff
yield: 80%; isolated yield: 50%) led us to consider a base bearing a CN group (2c) was used, poor diaste-
possible two-step/one-pot procedure. In this case, the reoselectivity (10–33%) was observed, the cis diaste-
amount of acid was doubled to neutralize also the reomer being preponderant.
DBU present in the reaction mixture (Scheme 3).
It can be reasonably supposed that this diastereose-
This procedure provided a better overall yield than lectivity comes from the Michael addition since, start-
the separate two-step procedure and avoided the tedi- ing from 1a, the same de is observed after conjugated
ous purification of 3a. The final de was the same in addition and after cyclization (Scheme 2). Then, the
both cases. The catalytic role of DBU and HCl in syn Michael adducts (3) provide the trans pyrrolines
these reactions could be explained by the following (4) and the anti-3 give the cis-4.
mechanism (Scheme 4).
A mechanistic proposal is detailed in Scheme 5.
In this proposal, it clearly appears that a catalytic The attack of the anions 2a–c onto enones is realized
amount of base is only needed since its conjugated following a Mukayama-like open transition state. Be-
acid (DBU-H+) acts as a reprotonating agent of the cause of electronic delocalization, these anions could
Michael adduct, thus regenerating the DBU. Concern- exist under different forms (A, B for 2a, b and A’, B’
ing the deprotection of the amino group, catalytic for 2c). Depending on the electron-withdrawing
amounts of acid and water are also sufficient since group onto the Schiff base, the anion of 2 can present
they are regenerated after cyclization and formation a more favorable structure than another. Indeed,
of imine.
Bordwell et al. have demonstrated that a CO2R
This efficient two-step/one-pot method was then moiety possesses a high ratio resonance/polar effect,
applied to others enones 1 and Schiff bases 2 in contrast with a CN group which has a lower similar
ratio.[9] Such properties entail a low resonance stabili-
zation of the carbanion by the cyano group, compared
with the ester group. Consequently, for the anion of
2a, b, the form A largely predominates whereas for
anion of 2c, form B’ is slightly the major form.
For the A form, only the A1 approach is possible
because of steric hindrance in A2. For the same rea-
sons, approach B2 is the most favorable on the B
form. Consequently, as A1 gives the 3-syn adduct, 4-
Scheme 3. One-pot synthesis of 4a.
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Synthesis of b-Trifluoromethylated D1-Pyrrolines
Scheme 4. Mechanism for the formation of 4a.
Figure 1. b-Fluoroalkylated D1-pyrrolines.
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The conditions described by Liu et al.[10] (DMF,
NaOH) for conjugated addition of nitromethane onto
enones gave only a complex mixture with b-fluoroal-
kylated enones 1. Other conditions, using nitrome-
thane as co-solvent,[11] allowed the obtention of 5 in
very good yields (Scheme 7).
Figure 2. Identification of diastereomers of 4.
Reduction of the nitro moiety has been attempted
by using the Zn/HCl system.[10,12] but a mixture of 3
trans pyrrolines are mostly formed with Schiff bases inseparable products was obtained. Surprisingly, when
2a, b. For Schiff base 2c, as B’ is only slightly predom- 5 were treated by TiCl3 in acidic media (Nef reaction
inant over A’, the de is low, with a small prevalence conditions), the pyrrolines 6 were obtained with satis-
for 4-cis, arising from 3-anti through B’2.
factory yields (Scheme 8) whereas McMurry reports
In the precedent strategy, the obtained pyrrolines the reduction to aldehydes, and not to CH2NH2,
bear an electron-withdrawing group (CO2R or CN) in under these conditions.[13]
the a-position. Another retrosynthesis, always starting
In order to demonstrate the synthetic potential of
from enones, has been elaborated to obtain b-fluo- such trifluoromethylated D1-pyrrolines, some prelimi-
roalkylated pyrrolines without any substituents in the nary reduction reactions have been studied
a-position (Scheme 6).[10]
(Scheme 9). Trifluoromethylated proline derivatives 7
The first step is a Michael addition of nitromethane have been obtained with satisfactory yields. A good
onto enones 1. The obtained adducts could be re- diastereoselectivity is observed with pyrrolines substi-
duced into amines and, then, cyclized to give 6.
tuted in the a-position (4a, b). The configuration of
Scheme 5. Mechanistic proposal for the observed diastereoselectivities.
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Synthesis of b-Trifluoromethylated D1-Pyrrolines
Scheme 6. Retrosynthesis of 6.
Scheme 9. Reduction of trifluoromethylated D1-pyrrolines
with NaBH3CN.
Two complementary factors can explain the diaste-
reoselectivity observed with 7a, b. The approach of
the hydride from the face occupied by CF3 is disfa-
vored because of steric and electronic repulsions,
whereas the approach from the other face can be fa-
vored by a chelation between NaBH3CN and the
ester group (Figure 4).
This “assistance” of the ester group is confirmed by
the lower de observed with 7c where only the steric
and electronic repulsions of the CF3 group can act.
Surprisingly, the reduction of 4a with NaBH4 led to
the corresponding dehydroprolinol derivative 8a, by
selectively reducing the ester group (Scheme 10).
This result can be rationalized by considering that
the imine is hindered and conjugated with the aro-
matic ring; consequently, it is poorly reactive and re-
quires acidic activation to be reduced. Concerning the
unusual reduction of the ester function by NaBH4 we
can suppose that the electrophilicity of the ester
Scheme 7. Conjugated addition of nitromethane onto 1.
Figure 3. Configuration of diastereomer 7a.
Scheme 8. Cyclization of 5 to give 6.
the major diastereomer has been determined by nu-
clear Overhauser effect correlations (NOESY and
HOESY H-F). Indeed, the hOe (H-F) showed a cor-
relation between CF3 and H1 and one of the H3 pro-
tons (H3B). The nOE experiment indicated a correla-
tion between H4 and the other H3 proton (H3A); H2
also correlates with H3A (Figure 3).
Figure 4. Approach of the hydride towards iminium of 4a.
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stirred at room temperature for 36 h, then a saturated aque-
ous solution of NH4OAc was added until pH 6. After filtra-
tion over celite, the mixture was extracted with EtOAc. The
organic layers were combined, washed with a saturated
aqueous solution of NaHCO3, brine, dried over MgSO4, fil-
tered and concentrated under vacuum. Pure compounds 6
were isolated after purification by flash chromatography
over silica gel.
Scheme 10. Reduction of 4a with NaBH4.
group is enhanced by the presence of the strong elec-
tron-withdrawing CF3 moiety at the vicinal position.
Acknowledgements
One of the authors (O.M.) gratefully acknowledges the Bayer
CropScience Co. for a grant for his PhD work.
Conclusions
We have elaborated an efficient way to quickly syn-
thesize 3-trifluoromethylated cyclic imines that consti-
tute valuable building blocks for the further synthesis
of fluorinated compounds. A short preliminary study
of the reactivity has shown that these compounds can
be reduced to give proline derivatives or prolinol de-
rivatives.
A more accurate reactivity study is under investiga-
tion in our laboratory. Some synthetic applications of
these new fluorinated building blocks will be pub-
lished in due course.
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Experimental Section
General Procedure for the Preparation of
b-Perfluoroalkylated D1-Pyrrolines
To a solution of b-perfluoroalkylated enone (4, 1 equiv.) and
Schiff base (1 equiv.) in CH2Cl2 (1 mL per mmol) cooled to
58C was added DBU (0.1 equiv.). After stirring at room
temperature for the appropriate time (monitored by fluorine
NMR), 12N HCl (0.3 equiv.) was added and the reaction
mixture was stirred at room tempertaure overnight. Then,
water was added and the mixture was extracted with
CH2Cl2. The organic layers were combined, dried over
MgSO4, filtered and concentrated under vacuum. The crude
residue was then purified by flash chromatography over
silica gel.
General Procedure for the Addition of Nitromethane
onto Enones
To a solution of enone 4 (1 equiv.) in nitromethane (5 mL
per mmol) was added water (0.3 mL per mmol) followed by
solid Na2CO3 (0.15 equiv.). The biphasic mixture was then
refluxed for 1 h, cooled to room temperature and water was
added. After extraction with CH2Cl2, the organic layers
were combined, washed with brine, dried over MgSO4 and
filtered and concentrated under vacuum.
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General Procedure for the Nef Reaction
To a solution of nitroalkane 5 (1 equiv.) in THF (5 mL per
mmol) was slowly added a solution of TiCl3 (20% w/w in
HCl 2N) (10 equiv.). The dark/purple reaction mixture was
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