Reactivity of stable trifluoroacetaldehyde hemiaminals. 2. Generation and synthetic potentialities of fluorinated iminiums

Article abstract of DOI:10.1021/jo016265t

Under Lewis acid activation, hemiaminals of trifluoroacetaldehyde and related (fluoroalkyl)-aldehydes generate iminium species that can react with various nucleophiles to provide fluorinated amines.

Full text of DOI:10.1021/jo016265t

J . Org. Chem. 2002, 67, 997-1000
997
Rea ctivity of Sta ble Tr iflu or oa ceta ld eh yd e Hem ia m in a ls. 2.
Gen er a tion a n d Syn th etic P oten tia lities of F lu or in a ted Im in iu m s
Thierry Billard* and Bernard R. Langlois*
Laboratoire SERCOF (UMR CNRS 5622), Universite´ Claude Bernard - Lyon 1,
Baˆt. Chevreul, 43, Bd du 11 novembre 1918, 69622 Villeurbanne, France
billard@univ-lyon1.fr
Received November 5, 2001
Under Lewis acid activation, hemiaminals of trifluoroacetaldehyde and related (fluoroalkyl)-
aldehydes generate iminium species that can react with various nucleophiles to provide fluorinated
amines.
Ch a r t 1. Silyla ted Hem ia m in a l of F lu or a l
Interest in fluorine-containing compounds is continu-
ously growing1 since fluorinated organic products present
unique properties2 that are of great interest for a variety
of applications3-5 and, in particular, for the design of
bioactive compounds.3 Thus, because of this tremendous
interest, research for new methodologies to prepare
fluorinated compounds, by the shortest route, is still a
challenge.
Generally speaking, synthetic routes involving imini-
ums species are useful strategies for amino compound
functionalization.6 Following this concept, Fuchigami et
al.7-9 and Dolbier et al.10 have demonstrated the ef-
fectiveness of trapping in situ generated trifluoromethy-
lated iminiums by various nucleophiles. However, the
trifluoroacetaldehyde N,O-acetals7-9 or N,N-aminals10
they used suffer from a difficult access and a lack of
variety in amino moieties.
We have recently shown that the easy accessible (even
on a multigram scale11) silylated hemiaminal of trifluo-
roacetaldehyde 1a (Chart 1) is a very efficient precursor
of the corresponding iminium salt under Lewis acid
activation.12
Furthermore, a lot of bioactive substances bearing a
piperazino group13 are described in the literature, and
several of them led to commercial drugs.14 Thus, we
focused our interest on the use of our iminium strategy
for the synthesis of fluorinated compound bearing a
piperazino moiety and studied the reactivity of 1, under
Lewis acid activation, toward various nucleophiles. The
first ones we envisaged were heteronucleophiles as
alcohols and amines (Table 1).
This reaction generally provides satisfactory yields
which, however, are lower with secondary alcohols (Table
1, entry 3) because they are probably more sensitive to
Lewis acids and lead to side reactions. Such side re-
actions are especially important with sugar derivatives
(Table 1, entry 5) that are poly-oxygenated reagents.
Indeed, under usual conditions (see the Experimental
Section), no 2a e was obtained, but this target sub-
strate can be successfully synthesized when 1a is pre-
chelated with the Lewis acid before introduction of
the carbohydrate. Tertiary alcohols have not been
tested because of their high sensitivity toward Lewis
acids.
This strategy provides more elaborated N,O-acetals of
fluoral than previously described and constitutes the
unique possibility to reach such compounds since the
standard O-alkylation of fluoral hemiaminolate under
basic conditions failed in our hands.
As we previously described the preparation of other
fluorinated hemiaminals,12 they were reacted in the same
way to deliver the corresponding N,O-acetals (Table 1,
entries 6 and 7).
(1) Schofield, H. J . Fluorine Chem. 1999, 100, 7-11.
(2) Smart, B. E. J . Fluorine Chem. 2001, 109, 3-11.
(3) Filler, R.; Kobayashi, Y.; Yagulpolskii, Y. L. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications;
Elsevier: Amsterdam, 1993.
(4) Banks, R. E.; Smart, B. E.; Tatlow, J . C. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press:
New York, 1994.
(5) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine
Compounds II. A critical Review; ACS Monograph 187; American
Chemical Society: Washington, DC, 1995.
(6) Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000, 56, 3817-
3856.
(7) Fuchigami, T.; Ichikawa, S.; Konno, A.; Nonaka, T. Chem. Lett.
1989, 1987-1988.
(8) Fuchigami, T.; Ichikawa, S.; Kandeel, Z. E.; Konno, A.; Nonaka,
T. Heterocycles 1990, 31, 415-417.
(9) Fuchigami, T.; Ichikawa, S. J . Org. Chem. 1994, 59, 607-615.
(10) Xu, Y.; Dolbier, W. R., J r. J . Org. Chem. 2000, 65, 2134-2137.
(11) Billard, T.; Langlois, B. R.; Blond, G. Tetrahedron Lett. 2000,
41, 8777-8780.
(12) Blond, G.; Billard, T.; Langlois, B. R. J . Org. Chem. 2001, 66,
4826-4830.
The reaction with sulfur-centered nucleophiles is under
study in our laboratory and will be reported in due
course.
Then, to create C-C bonds, we turned our attention
to carbon nucleophiles. However, carbon-centered anions,
like Grignard’s reagents or organolithium derivatives,
failed to give the expected products, certainly because of
their high affinity toward Lewis acid. To circumvent this
disappointing result, neutral carbon nucleophiles were
engaged. In this respect, allylsilane was very efficient and
provided fluoroalkylated homoallylic amines at room
temperature (Table 2).
(13) The Merk Index, 12th ed.; Merck & Co., Inc.: Rahway, NJ , 1996.
(14) Index Nominum: International drug directory, 16th ed.; Swiss
Pharmaceutical Society, Ed.; MedPharm Scientific Publishers: Stut-
tgart, 1995.
10.1021/jo016265t CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/11/2002

998 J . Org. Chem., Vol. 67, No. 3, 2002
Ta ble 1. Rea ction of F lu or oa lk yla ted Im in iu m s w ith Alcoh ols a n d Am in es
Billard and Langlois
a
Isolated yield.
Sch em e 1. On e-P ot Syn th esis of
r-Tr iflu or om eth ylh om oa llylic Am in e
This reaction delivered good yields and was applied,
as above, to hemiaminals of different fluoroaldehydes (RF
) CF3, ClCF2, C2F5). As such, hemiaminals also can be
produced from various amines; this strategy was ex-
tended to the preparation of different homoallylic amines.
In particular, the derivative of benzophenone imine 5
(Table 2, entry 5) is very interesting because 7 can be
deprotected to provide primary R-trifluoromethyl ho-
moallylic amines. It is noteworthy that allylation and
deprotection can be carried out in the same pot (Scheme
1).
Such an allylation reaction can also be carried out with
allyl-n-tributyltin instead of allyltrimethylsilane (Scheme
2), but the presence of tin makes purification more tricky.
In contrast, vinylsilanes failed to deliver R-fluoroalky-
lated allylamines, but under the conditions used for allyl-
silane, potassium styryltrifluoroborates did (Scheme 3).
Concerning the mechanism of this reaction, two hy-
potheses can be formulated. First, boron trifluoride
activates the hemiaminal to form an iminium species that
then reacts with styryltrifluoroborate to deliver the

Reactivity of Stable Trifluoroacetaldehyde Hemiaminals
J . Org. Chem., Vol. 67, No. 3, 2002 999
Ta ble 2. Rea ction of F lu or in a ted Im in iu m s w ith
Allylsila n e
Sch em e 2. Allyla tion of Tr iflu or om eth yla ted
Im in iu m s w ith Allyltr ibu tyltin
Sch em e 3. Vin yla tion of F lu or in a ted Im in iu m s
Sch em e 4. F ir st Mech a n ism of Vin yla tion
expected product and regenerate boron trifluoride; in this
case, the Lewis acid could be used in a catalytic amount
(Scheme 4). Second, BF3‚Et2O reacts first with styryltri-
fluoroborate to provide, as described by Kaufmann et
al.,15 styrylboron difluoride, which is also a Lewis acid16
able to activate the hemiaminal and generate iminium
and nucleophilic species (Scheme 5). In this second case,
BF3 could not be used in a catalytic amount.
a
After heating at 50 °C for 12 h.
All these reactions provide a very easy access to various
R-functionalized fluoroalkylated amines. Nevertheless, no
stereoselectivity was observed since reagents 1a -c, 4,
and 5 were racemic in nature.
Indeed, when the reaction was carried out with a
catalytic amount of BF3‚Et2O (10% mol), around 10% of
the expected product was obtained. Furthermore, when
the reaction was monitored by 11B NMR, styrylboron
difluoride (δ ) 23 ppm)17 was detected. These experi-
mental observations led us to postulate that the second
mechanism is the most probable.
Continuing our search for C-C bond formation, we
then examined the electrophilic substitution of electron-
rich aromatic compounds with 1a -c (Scheme 6).
Finally, this iminium strategy was applied to other
miscellaneous silicon-containing nucleophiles in order to
extend its scope (Table 3).
To circumvent that, we tried to induce diastereoselec-
tivity by using an optically pure hemiaminal. Such a
compound has been prepared starting from ephedrine,
following the strategy of Mikami et al.18 (Scheme 7).
The resulting trifluoromethylated oxazolidine 13 re-
acted under usual conditions with allylsilane to give 14
with a high diastereoselective excess but in a moderate
yield.
It can be noticed that, during the progress of this
study, Brigaud et al. presented a similar work using
various amino alcohols for the oxazolidine synthesis
and different silylated nucleophiles for the second
step.19
Sch em e 5. Secon d Mech a n ism of Vin yla tion

1000 J . Org. Chem., Vol. 67, No. 3, 2002
Billard and Langlois
Sch em e 7. Ster eoselective Access to
Sch em e 6. F r ied el-Cr a fts Rea ction w ith
F lu or in a ted Im in iu m s
r-Tr iflu or om eth yl Hom oa llylic Am in es
Ta ble 3. Rea ction of F lu or in a ted Im in iu m s w ith
Miscella n eou s Nu cleop h iles
fluoroalkylated iminium species that can be trapped by
various nucleophiles to provide R-substituted R-(fluoro-
alkyl)amines. Their use for targeted synthetic applica-
tions is under study in our laboratory.
Exp er im en ta l Section
Gen er a l Rem a r k s. Solvents were distilled prior to use.
Other reagents were used as received. Flash chromatography
was performed on silica gel 60 M (0.04-0.063 mm). Reagents
1a -c and 4 were prepared according to our previous work.11,12
Hemiaminal 5 were prepared with the same procedures.
Typ ica l P r oced u r e. BF3‚Et2O (1 mmol) was added, at
room temperature, to a solution of 1a -c, 4, or 5 (1 mmol) and
the nucleophile (1 mmol) in CH2Cl2 (1 mL). Then, the mixture
was stirred at the temperature and for the time indicated in
the text. At the end of the reaction, N-methylethanolamine
was added to complex boron byproducts, and the crude mixture
was stirred for 1 h.Then, it was deposited at the top of a silica
gel column and eluted.
Ack n ow led gm en t. The CNRS is thanked for finan-
cial support.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O016265T
(16) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J . Org. Chem. 1995, 60, 3020-3027.
(17) This 11B NMR shift was close to the one described in ref 15.
When the reaction is monitored by 1B NMR, a new peak appears at
14.3 ppm, which could be attributed to Me3SiOBF2. However, attempts
to isolate this compound failed.
(18) Ishii, A.; Higashiyama, K.; Mikami, K. Synlett 1997, 1381-
1382.
a
After heating at 50 °C for 24 h.
In conclusion, we have shown that hemiaminals of
fluoroalkylaldehydes are very efficient precursors of
(19) Brigaud, T.; Lebouvier, N. Abstracts of Papers, 13th European
Symposium on Fluorine Chemistry, 15-20 J uly 2001, Bordeaux,
France; Abstract 2-P29.
(15) Bir, G.; Schacht, W.; Kaufmann, D. J . Organomet. Chem. 1988,
340, 267-271.