An improved approach to trifluoromethyl substituted Morita-Baylis-Hillman adduct: Fluorinated dehydro-β-amino acids

Article abstract of DOI:10.1016/S0022-1139(01)00434-1

The [α-(alkoxycarbonyl)vinyl]diisobutylaluminium reagents generated by hydroalumination from α,β-acetylenic esters and DIBAL-H were reacted with N-acylimines of hexafluoroacetone and methyl trifluoropyruvate to give trifluoromethyl substituted dehydro-β-a

Full text of DOI:10.1016/S0022-1139(01)00434-1

Journal of Fluorine Chemistry 111 52001) 41±44
An improved approach to tri¯uoromethyl substituted
Morita±Baylis±Hillman adduct: Fluorinated dehydro-b-amino acids
b
a
a
Natalia N. Sergeevaa,Alexander S. Golubev ,Lothar Hennig ,Matthias Findeisen ,
Eckhard Paetzoldc,GuÈnther Oehmec,Klaus Burger
Institut fur Organische Chemie, Universitat Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
bA.N. Nesmeyanov Institute of Organoelement Compounds )INEOS), Russian Academy of Sciences, Vavilov Str. 28,
GSP-1, V-334, Rus-117813 Moscow, Russia
a,*
a
È
È
c
È È
Institut fur Organische Katalyseforschung an der Universitat Rostock e.V., Buchbinderstraûe 5-6, D-18055 Rostock, Germany
Received 17 April 2001; accepted 29 May 2001
Abstract
The [a-5alkoxycarbonyl)vinyl]diisobutylaluminium reagents generated by hydroalumination from a, b-acetylenic esters and DIBAL-H
were reacted with N-acylimines of hexa¯uoroacetone and methyl tri¯uoropyruvate to give tri¯uoromethyl substituted dehydro-b-amino
acid derivatives. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: Hydroalumination; [a-5Alkoxycarbonyl)vinyl]diisobutylaluminium; N-acylimines; b-Tri¯uoromethyldehydro-b-amino acids; b, b-Bis5tri¯uoro-
methyl)-dehydro-b-amino acids
1. Introduction
overcomes some of the above disadvantages [12±16]. It
was shown that aldehydes and ketones on reaction with in
situ prepared [a-5alkoxycarbonyl)vinyl]-diisobutylalumi-
nium are transformed to give hydroxyalkyl ole®ns at
room temperature in good yields. Optimal results were
reported when a mixture prepared from ethyl propiolate
and diisobutylaluminum hydride 5DIBAL-H,molar ratio:
1:1.5) in tetrahydrofuran 5THF) in the presence of hex-
amethylphosphoric triamide 5HMPT,two equivalents) was
reacted with the carbonyl compound [14,15]. The vinyl
transfer process does not need activation by Lewis acids,
especially when activated carbonyl compounds are used
[15] 5Scheme 1).
When we applied the Ramachandran protocol [14,15] for
the reaction of N-acylimines of hexa¯uoroacetone 54),we
obtained rather poor yields of the expected adducts 6,since
the DIBAL-H present in excess caused substantial reduction
of the imines. Therefore,we modi®ed the procedure: ®rst we
prepared the aluminum reagent 53) by mixing stoichiometric
amounts of propiolate 51) and DIBAL-H 52) in THF in the
presence of HMPT 5two equivalents),which was then
reacted with the corresponding N-acylimine in a 1.3:1 molar
ratio. We found that N-acylimines 54) derived from hexa-
¯uoroacetone and methyl tri¯uoropyruvate 55) reacted
rapidly and cleanly with the vinyl transfer reagent 53) in
the presence of BF3ÁEt2O to give the Morita±Baylis±Hill-
man products 6 and 7,respectively 5Scheme 2).
The Morita±Baylis±Hillman reaction is an important
carbon±carbon bond formation process [1±3]. The reaction
of activated ole®ns with aldehydes or imines in the presence
of certain tert-amines or phosphines has attracted consider-
able interest among synthetic chemists. The preparatively
simple method provides ready access to hydroxyalkyl and
aminoalkyl ole®ns having a multifunctional array of groups
[4±6]. However,the Morita±Baylis±Hillman reaction has
some serious limitations,like slow reaction rates and incon-
sistent yields. Moreover,the procedure is not applicable to b-
branched ole®ns [1,7,8], and extreme reaction conditions are
required for ketones [3]. Nevertheless,activated ketones,like
highly ¯uorinated ketones [9] and a-ketoesters [10] as well as
some of their derivatives,like N-acylimines,react to give
valuable ¯uorinated multifunctional building blocks [11].
2. Results and discussion
Recently,an improved methodology for the synthesis
of Morita±Baylis±Hillman adducts was described,which
* Corresponding author. Tel.: ‡49-341-9736529;
fax: ‡49-341-9736599.
E-mail address: burger@organik.chemie.uni-leipzig.de 5K. Burger).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 5 0 1 ) 0 0 4 3 4 - 1

42
N.N. Sergeeva et al. / Journal of Fluorine Chemistry 111 )2001) 41±44
the b-methyl group at 2.02 ppm has been observed. On the
other hand,in the case of 9b no signi®cant NOE between the
methoxy group and the phenyl ring could be detected.
However,a strong cross-peak between the tri¯uoromethyl
groups and the ole®nic proton in the HOESY spectrum
unambiguously proves Z-con®guration at the C=C double
bond for both compounds 9a and 9b.
Scheme 1.
The ¯uoroalkyl-substituted dehydroamino acids 6, 7 and
9 represent a new type of monomers. Their incorporation
into strategical positions of peptides should generate pro-
teolytically stable domains,increase lipophilicity and sta-
bilize secondary structures. In summary,they should be a
versatile tool to improve the pharmacokinetic pro®le of
peptidomimetics. Furthermore,they are valuable precursors
for the synthesis of homochiral b-tri¯uoromethyl and b, b-
bis5tri¯uoromethyl) substituted b-amino acids 5for ¯uori-
nated b-amino acids see [19±22]) via enantioselective
hydrogenation.
Compared with the yields of compounds 6 obtained under
standard conditions from the Morita±Baylis±Hillman pro-
cedure [11],the yields were increased by 15±20%. In the
case of N-tert-butoxycarbonylimine derived from methyl
tri¯uoropyruvate 55),which is unreactive under Morita±
Baylis±Hillman conditions,yields of about 60% were
obtained when the new vinyl transfer reagent was applied
5Scheme 3).
Another drawback of the Morita±Baylis±Hillman reac-
tion,the unreactivity of b-branched ole®nes,can easily be
overcome by the new nucleophilic vinyl transfer process
[17,18]. The b-branched propiolates are transformed on
reaction with DIBAL-H 52) into the corresponding alumi-
nium reagents 58),which are suited for transfer of the vinyl
moiety 54a ‡ 8 ! 9). The stereochemistry of the C=C
double bond of compounds 9a and 9b was determined by
NOE difference and 1H, 19F HOESYexperiments. For 9a an
NOE effect between the methoxy group and the doublet of
3. Experimental
Melting points were determined on a Boetius heating
table. IR spectra were obtained with a FTIR spectrometer
5Genesis ATI Mattson/Unicam). 1H NMR spectra were
recorded with VARIAN Gemini 2000 spectrometers at
200 and 300 MHz. Chemical shifts are reported in part
Scheme 2.
Scheme 3.

N.N. Sergeeva et al. / Journal of Fluorine Chemistry 111 )2001) 41±44
43
per million relative to tetramethylsilane 5TMS) in CDCl3; J
132.1,152.9,165.1,166.0.
d 5.60 5s). IR 5®lm): n 1738 5CO),1489 5C=CH) cm
19F NMR 5282 MHz,CDCl ):
3
À1
values are given in Hertz 5Hz). 13C NMR spectroscopy was
performed at 50 and 75 MHz. 19F NMR spectra were
recorded at 188 MHz with tri¯uoroacetic acid 5TFA) as
an external standard. NOE spectra were recorded with a
BRUKER DRX-600 at 600 MHz 51H) and 565 MHz 519F).
For ¯ash chromatography,silica gel 532±63 mm) was used
with the solvent systems given in the text. Organic solvents
were dried and distilled prior to use. Imines 4a, 4b and 5
were synthesised according to Steglich et al. [23] and Burger
et al. [24],respectively.
.
‡
HRMS: Anal. Calcd. for C13H18F3NO6 5M ‡ Na )
364.09839. Found 364.09776.
3.5. Methyl 3-)N-benzoyl)amino-4,4,4-trifluoro-3-
trifluoromethyl-2-ethylidenebutanoate )9a):
Yield 32%,5236 mg); white crystals,mp 64 8C. 1H NMR
5300 MHz,CDCl 3): d 2.02 53H,d, J ˆ 7:0 Hz),3.73 53H,s),
6.55 51H,s),6.63 51H,q, J ˆ 7:0 Hz),7.47±7.57 53H,m),
7.74±7.78 52H,m). 13C NMR 550 MHz,CDCl ): d 16.2,
3
2
1
3.1. General procedure
52.2,67.1 5q, JC;F ˆ 29 Hz),122.7 5q, JC;F ˆ 288 Hz),
123.5,129.0,132.6,133.5,140.5,165.2,166.5.
19F NMR
To a stirred solution of HMPT 5932 mg,5.2 mmol) in
anhydrous THF 550 ml) was added at 08C,2.6 ml of 1 M
DIBAL-H 52.6 mmol) in hexane. After 0.5 h methyl pro-
piolate 51) 5219 mg,2.6 mmol) was added to this mixture at
08C. The mixture was stirred until the colour changed to
yellow 5ca. 1 h). Then BF3ÁEt2O 5301 mg,2.1 mmol) and the
¯uorinated imine 54, 5) 52 mmol),dissolved in 2 ml of dry
THF,were added to the mixture at À788C. The reaction
mixture was allowed to warm up to RTand stirred overnight,
quenched with 25 ml of saturated NH4Cl at 08C,and
extracted with CH2Cl2 53 Â 15 ml). The organic layer was
dried with MgSO4. The solvents were removed in vacuo and
the residue was puri®ed by column chromatography 5eluent:
hexanes/ethyl acetate,4:1) to give the corresponding pro-
ducts 56a, 6b and 7).
5282 MHz,CDCl 3): d 7.21 5s). IR 5KBr): n 1732 5CO),1676
5CO),1544 5C=CH) cm À1. Anal. Calcd. for C15H13F6NO3:
C,48.79; H,3.55; N,3.79. Found: C,48.7; H,3.36; N,
3.66%.
3.6. Methyl 3-)N-benzoyl)amino-4,4,4-trifluoro-3-
trifluoromethyl-2-benzylidenebutanoate )9b):
Yield 58%,5500 mg); white crystals mp 107 8C. 1H NMR
5300 MHz,CDCl ): d 3.55 53H,s),6.63 51H,s),7.26±7.39
3
56H,m),7.47±7.50 52H,m),7.55±7.60 51H,m),7.80±7.83
52H,m). 13C NMR 550 MHz,CDCl 3): d 52.5,67.8 5q,
2JC;F ˆ 29 Hz),122.7 5q, 1JC;F ˆ 291 Hz),122.9,127.4,
128.3,128.5,129.1,129.4,132.7,133.5,134.7,140.7,
166.2,166.3. 19F NMR 5282 MHz,CDCl ): d 8.97 5s). IR
3
The procedure is similar to the preparation and reaction of
8,with the exception that the mixture was additionally
stirred at RT 52 h for R ˆ Me and 3 h for R ˆ Ph) before
the ¯uorinated imines were added. The products 59a and 9b)
were puri®ed by column chromatography 5eluent: hexanes/
ethyl acetate,4:1).
5KBr): n 1730 5CO),1670 5CO),1535 5C=CH) cm À1. Anal.
Calcd. for C20H15F6NO3: C,55.69; H,3.51; N,3.25. Found:
C,55.5; H,3.5; N,3.06%.
Acknowledgements
The authors are grateful for ®nancial support from Volks-
wagen Stiftung,the Fonds der Chemischen Industrie,and
Aventis AG.
3.2. Methyl 3-)N-benzoyl)amino-4,4,4-trifluoro-3-
trifluoromethyl-2-methylenebutanoate )6a):
Yield 74%,5526 mg); spectroscopic and physical data of
6a agree with literature values [11].
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