Selective formal transesterification of fluorinated 2-(trimethylsilyl)ethyl α-imino esters mediated by TBAF

Article abstract of DOI:10.1021/jo800567a

(Chemical Equation Presented) The scope of the transesterification reaction between β-fluorinated α-imino esters and various electrophiles in the presence of TBAF as fluorine source is described. The reaction is highly selective for alkyl iodides, bromide

Full text of DOI:10.1021/jo800567a

SCHEME 1. Methods for Preparing Fluorinated r-Imino
Esters
Selective Formal Transesterification of
Fluorinated 2-(Trimethylsilyl)ethyl r-Imino
Esters Mediated by TBAF
Santos Fustero,*,†,‡ Mar´ıa Sa´nchez-Rosello´,†
Vanessa Rodrigo,‡ Amador Garc´ıa,‡ Silvia Catala´n,† and
Carlos del Pozo†
Departamento de Qu´ımica Orga´nica, UniVersidad de
Valencia, E-46100 Burjassot, Spain, and Laboratorio de
Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe
Felipe, E-46013 Valencia, Spain
santos.fustero@uV.es
and difluoroserine or difluorocysteine derivatives.6 Furthermore,
FRIE have also been used as substrates for the preparation of
other non-natural fluorinated nitrogen derivatives, such as cyclic
and acyclic fluorinated quaternary R-amino acids7 and difluo-
romethyl aziridines.8
ReceiVed March 12, 2008
Few different methodologies that gain access to fluorinated
R-imino esters have been described in the literature, namely
aza-Wittig reactions,7f,h condensation of carbamates9 or amines7b,10
with trifluoropyruvates, and palladium-catalyzed alkoxycarbo-
nylation of fluorinated imidoyl iodides11 (Scheme 1). The scope
of both, the aza-Wittig protocol and the reaction with amines
or carbamates, is limited since they involve the condensation
with a fluorinated R-keto ester (it is noteworthy that only ethyl
and methyl trifluoropyruvates are commercially available). In
addition, the condensation reaction is highly dependent on the
nature of the amine.12 On the other hand, the alkoxycarbony-
lation reaction offers more possibilities in the substitution pattern
of the final products, due to the easy preparation of the starting
imidoyl iodides. However, this reaction usually requires rela-
tively long reaction times and it is also sensitive to the steric
hindrance of the alcohol nucleophiles. Thus, in general, primary
alcohols react faster and give higher chemical yields than
secondary or tertiary ones.11
The scope of the transesterification reaction between ꢀ-flu-
orinated R-imino esters and various electrophiles in the
presence of TBAF as fluorine source is described. The
reaction is highly selective for alkyl iodides, bromides, and
mesylates, while alkyl chlorides react at a significantly slower
rate and tosylates do not react under the reaction conditions.
This methodology represents a simple and useful alternative
for the preparation of a wide variety of fluorinated R-imino
esters.
Fluorinated R-imino esters (FRIE) are important building
blocks in fluorine chemistry. They are synthetic intermediates
for the preparation of ꢀ-fluorinated R-amino acids,1 compounds
that are witnessing a growing interest in medicinal, agricultural,
and material sciences. Thus, starting from fluorinated R-imino
esters, the synthesis of several synthetic analogues of naturally
occurring amino acids has been devised, such as trifluoroalani-
nates,2 trifluoromethyl aspartic acids,3 difluoro and trifluoro-
methyl ornithine,4 difluoroglutamic acids and difluoroprolines,5
(6) Mae, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41, 7893–
7896.
(7) (a) Fustero, S.; Flores, S.; Cun˜at, A. C.; Jime´nez, D.; del Pozo, C.; Bueno,
J.; Sanz-Cervera, J. F. J. Fluorine Chem. 2007, 128, 1248–1254. (b) Chaume,
G.; Van Severen, M.-C.; Marinkovic, S.; Brigaud, T. Org. Lett. 2006, 8, 6123–
6126. (c) Fustero, S.; Sa´nchez-Rosello´, M.; Rodrigo, V.; del Pozo, C.; Sanz-
Cervera, J. F.; Simo´n, A.; Ram´ırez de Arellano, C. Org. Lett. 2006, 8, 4129–
4132. (d) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.; Bruneau, C.; Picquet,
M.; Dixneuf, P. H. Eur. J. Org. Chem. 2001, 3891–3897. (e) Se´rneril, D.; Le
Noˆtre, G.; Bruneau, C.; Dixneuf, P. H.; Kolomiets, A. F.; Osipov, S. N. New
J. Chem. 2001, 25, 16–18. (f) Asensio, A.; Bravo, P.; Crucianelli, M.; Farina,
A.; Fustero, S.; Garc´ıa-Soler, J.; Meille, S. V.; Panzeri, W.; Viani, F.; Volonterio,
A.; Zanda, M. Eur. J. Org. Chem. 2001, 1449–1458. (g) Osipov, S. N.; Bruneau,
C.; Picquet, M.; Kolomiets, A. F.; Dixneuf, P. H. Chem. Commun. 1998, 2053–
2054. (h) Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett.
1998, 39, 7771–7774. (i) Uneyama, K.; Yan, F.; Hirama, S.; Katagiri, T.
Tetrahedron Lett. 1996, 37, 2045–2048.
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) Enantiocontrolled Synthesis of Fluoro-Organic Compounds; Solos-
honok, V. A., Ed.; Wiley-VCH Ltd.: New York, 1999; pp 391-418. (b) Fluorine-
containing Amino Acids. Synthesis and Properties; Kukhar, V. P., Soloshonok,
V. A., Eds.; John Wiley & Sons Ltd.: New York, 1995; pp 188-207.
(2) (a) Crucianelli, M.; De Angelis, F.; Lazzaro, F.; Malpezzi, L.; Volonterio,
A.; Zanda, M. J. Fluorine Chem. 2004, 125, 573–577. (b) Abe, H.; Amii, H.;
Uneyama, K. Org. Lett. 2001, 3, 313–315. (c) Sakai, T.; Yan, F.; Kashino, S.;
Uneyama, K. Tetrahedron 1996, 52, 233–244. (d) Sakai, T.; Yan, F.; Uneyama,
K. Synlett 1995, 753–754.
(8) Mae, M.; Matsuura, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2002,
43, 2069–2072.
(9) (a) Burger, K.; Sewald, N. Synthesis 1990, 115–118. (b) Osipov, S. N.;
Goluveb, A. S.; Sewald, N.; Michel, T.; Kolomiets, A. F.; Fokin, A. V.; Burger,
K. J. Org. Chem. 1996, 61, 7521–7528.
(3) Lazzaro, F.; Crucianelli, M.; De Angelis, F.; Frigerio, M.; Malpezzi, L.;
Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 2004, 15, 889–893.
(4) Osipov, S. N.; Goluveb, A. S.; Sewald, N.; Burger, K. Tetrahedron Lett.
1998, 38, 5965–5966.
(10) Abid, M.; Teixera, L.; To¨ro¨k, B. Org. Lett. 2008, 10, 933–935.
(11) (a) Watanabe, H.; Hashizume, Y.; Uneyama, K. Tetrahedron Lett. 1992,
33, 4333–4336. (b) Amii, H.; Kishikawa, Y.; Kageyama, K.; Uneyama, K. J.
Org. Chem. 2000, 63, 3404–3408.
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(12) Soloshonok, V. A.; Kukhar, V. P. Tetrahedron 1997, 53, 8307–8314.
10.1021/jo800567a CCC: $40.75
Published on Web 06/21/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5617–5620 5617

TABLE 1. Preparation of Fluorinated TMSE-r-Imino Esters 2
SCHEME 2. Deprotection of TMSE-Esters
entry
1
Rf
PG
2
yield (%)a
1
2
3
4
5
6
7
1a CF3
1b CF3
1c CF2CH2CHdCH2
1d CF2CH2CHdCH2
1e CF2CF3
PMPb
(S)-PhCH(Me)
2a
2b
2c
88
66
52
51
78
40
54
Additionally, as an extension of the methods described, it is
possible to perform a magnesium metal promoted activation of
the C-F bonds followed by addition of electrophiles, which
allows further functionalizations in the trifluoromethyl-derived
imino esters13 (Scheme 1).
PMP
(S)-phegly-OMec 2d
PMPb
PMPb
2e
2f
1f CF2Cl
1g (E)-CF2CHdCHPh (R)-phegly-OMec 2g
a Isolated yields. b PMP ) p-MeOC6H4. c phegly-OMe ) PhCH-
(CH2OMe).
Stability, selectivity, and cost will usually dictate how an
imino ester is to be prepared. However, although a great number
of methodologies exist to accomplish this task,14 in particular
cases, a mild, generally applicable protocol is still missing. The
transesterification reaction is one of most useful synthetic
methods for the preparation of esters.15 Often, transesterifications
are more advantageous than the direct ester synthesis from
carboxylic acids (or their derivatives, such as alkanoyl halides
or carboxylic acid anhydrides) and alcohols. Thus, the ester-
to-ester transformation is particularly useful when the parent
carboxylic acids are labile and/or difficult to isolate. Fluorinated
R-imino esters are included in this category, and the corre-
sponding R-imino acids are not stable under the conditions
needed to release the acid functionality.
TABLE 2. Transesterification Reaction of Fluorinated
TMSE-Imino Esters 2
entry
2
R-X
Bn-Br
Bn-OH
Allyl-Br
homoallyl-Br
iPr-I
tBu-I
allyl-Br
Bn-Br
3
t (h)
yield (%)a
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2c
2c
2c
2c
2c
2c
2b
2d
2e
2f
3a
3a
3b
3c
3d
3e
3f
3g
3g
3g
3g
3h
3i
1
95
N.R.
75
1
3
4
24
1
1
95
95
40
85
94
20
77
Gerlach16 and Sieber17 independently developed 2-(trimeth-
ylsilyl)ethyl (TMSE) esters as a protecting group of the
carboxylic moiety, which can be selectively unmasked in the
presence of other esters under mild conditions. Since their
introduction, TMSE esters have been appreciated for the ease
and selectivity of their deprotection.18 Upon treatment with
TBAF, these esters undergo a fragmentation reaction to afford
ethylene, trimethylsilyl fluoride (TMSF), and the tetra-n-
butylammonium salt of the carboxylic acid, which can be
obtained in free form through acidification (Scheme 2).
We have found that fluorinated 2-(trimethylsilyl)ethyl imino
esters can undergo a mild transesterification process when the
deprotection of the TMSE ester moiety is carried out in the
presence of an appropriate electrophile, which in situ reacts with
the deprotected carboxylate under mild conditions to afford the
corresponding ester in moderate to excellent yields. Herein, we
report a new and selective transesterification protocol, which
constitutes an alternative method to the alkoxycarbonylation
process for the preparation of FRIE, dramatically reducing the
reaction times once the starting TMSE ester is prepared.
Following the methodology described by Uneyama and co-
workers,11 we obtained chiral and achiral TMSE-derived
fluorinated R-imino esters 2 in moderate to good isolated yields
(Table 1) from imidoyl chlorides 1,19 via their imidoyl iodides,
9
Bn-Cl
5
2
10
11
12
13
14
15
16
17
Bn-OMs
Bn-OTs
iPr-OMs
Bn-Br
Bn-Br
Bn-Br
N.R.
48
24
1
1
1
1
79
94
89
95
3j
3k
3l
Bn-Br
Bn-Br
2g
3m
1
80
a Isolated yields.
which in turn underwent an alkoxycarbonylation reaction with
trimethylsilyl ethanol in the presence of a palladium catalyst.
When we attempted the standard TMSE ester deprotection
with TBAF on compounds 2, we realized that the resulting
carboxylic acids were too sensitive to withstand the reaction
conditions. Thus, the corresponding carboxylic acids could not
be isolated, probably due to the presence of the labile imine
moiety. At that point, instead of trying to isolate the carboxylic
acid, we decided to attempt an in situ alkylation of the
carboxylate as a convenient means to avoid this problem. To
our delight, we found out that when imino ester 2a was treated
with TBAF, in the presence of benzyl bromide, a smooth
transesterification process took place to afford benzyl ester 3a
with excellent yield (Table 2, entry 1). In contrast, when benzyl
alcohol was used instead of benzyl bromide, in the presence of
a coupling reagent such as DIC, no benzyl ester was formed
(Table 2, entry 2). At this point, we tried to extend this simple
transesterification protocol to other electrophiles to prepare a
wide variety of fluorinated R-imino esters.
(13) (a) Kobayashi, T.; Nakagawa, T.; Amii, H.; Uneyama, K. Org. Lett.
2003, 5, 4297–4300. (b) Uneyama, K.; Amii, H. J. Fluorine Chem. 2002, 114,
127–131. (c) Uneyama, K.; Kato, T. Tetrahedron Lett. 1998, 39, 587–590.
19.(14) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10–
(15) Otera, J. Chem. ReV. 1993, 93, 1449–1470.
(16) Gerlach, H. HelV. Chim. Acta 1977, 60, 3039–3044.
(17) Sieber, P. H. HelV. Chim. Acta 1977, 60, 2711–2716.
(18) (a) Kocienski, P. Protecting Groups, 3rd ed.; Georg Thieme Verlag:
Stuttgart, Germany, 2005; pp 433-436. (b) Greene, T. W.; Wuts, P. G. M.
Protecting Groups in Synthesis, 3rd ed.; Wiley-Interscience, John Wiley and
Sons, Inc.: New York, 1999; p 401.
We were able to determine that our method was also effective
for the preparation of allylic, homoallylic, secondary, and even
tertiary esters 3 from TMSE esters 2 (Table 2, entries 3-7).
(19) (a) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe,
H. J. Org. Chem. 1993, 58, 32–35. (b) Uneyama, K. J. Fluorine Chem. 1999,
97, 11–25.
5618 J. Org. Chem. Vol. 73, No. 14, 2008

TABLE 3. Further Transesterification Reactions of TMSE-Esters 2b
a Isolated yields. b Imino ester 2a did not react with CF3(CF2)7(CH2)2I in the presence of TBAF, probably due to a competitive ꢀ-elimination reaction.
With regard to the electrophile leaving group (X), we found
that bromides and iodides (Table 2, entries 3-8 and 13-17),
as well as primary mesylates20 (Table 2, entry 10), worked
adequately in this reaction. On the other hand, chlorides (Table
2, entry 9) and secondary mesylates (Table 2, entry 12) reacted
slower, while tosylates (Table 2, entry 11) completely failed to
react under the same reaction conditions.21
From these results it became apparent that our transesterifi-
cation protocol was selective for alkyl iodides, bromides, and
primary mesylates. Therefore, we decided to study the scope
and utility of this new synthetic methodology by employing
differently functionalized electrophiles (Table 3).
for the preparation of novel compound libraries in the drug
discovery process.23 One of the key steps in solid-phase as well
as fluorous-phase synthesis is the development of new proce-
dures to anchor substrates to either the resin or the perfluoroalkyl
chain. We thought that our transesterification protocol might
be a useful method for the linking of TMSE imino esters 2 to
a modified Wang resin bearing bromobenzylic groups (Table
3, entries 1 and 2). In a similar way, when imino esters 2a and
2c were treated with TBAF in the presence of a perfluoroalky-
lated iodo compound, the attachment of the fluorous tag occurred
after 2 h of reaction time in excellent yields (Table 3, entries 4
and 5).24
In an ongoing project in our laboratory directed toward the
asymmetric synthesis of fluorinated cyclic quaternary R-amino
acids,7c we are attempting to prepare these kinds of compounds
on solid- and fluorous-phase techniques,22 due to their usefulness
After having shown that tosylates are unreactive as alkylating
agents and alkyl chlorides are significatively less reactive than
bromides and iodides, we subjected imino esters 2 to our
standard transesterification conditions in the presence of dielec-
J. Org. Chem. Vol. 73, No. 14, 2008 5619

trophiles, such as 1-bromo-4-chlorobutane and 1-bromo-3-
chloropropane. We found that these reactions were completely
regio- and/or chemoselective, affording the corresponding
chloroesters 3s,t in excellent yields (Table 3, entries 7 and 8).
In the same fashion, when the reaction was performed with
1-iodo-3-tosylpropane, the alkylation took place exclusively at
the iodide terminus to afford 3u, together with the allylic ester
3f derived from tosyl ꢀ-elimination (Table 3, entry 9).
Finally, the reaction with ethyl bromoacetate gave the
corresponding functionalized imino ester 3r in excellent yield
(Table 3, entry 6).
In conclusion, we have shown that fluorinated R-imino esters
derived from 2-(trimethylsilyl)ethanol undergo a selective
transesterification process with alkyl halides and mesylates in
the presence of TBAF. This simple methodology allows for the
preparation of a wide variety of fluorinated R-imino esters and
it is also compatible with solid-phase and fluorous syntheses.
Other applications of this methodology are currently underway.
Experimental Section
General Procedure for the TBAF-Mediated Transesterifica-
tion Reaction. To a stirred solution of silylated R-imino ester 2
(1.0 equiv) in THF (0.1M) were added TBAF (1 M in THF, 1.5
equiv) and the corresponding electrophile R-X (2.0 equiv). The
reaction mixture was stirred at room temperature until TLC
indicated the total disappearance of the starting material. The
solvents were then removed under reduced pressure and the residue
was purified by means of flash chromatography.
Synthesis of 3r. Following the general procedure described
1
above, 3r was obtained as a yellow oil in 95% yield from 2c. H
NMR (300 MHz, CDCl3) δ 1.26 (t, J ) 7.2 Hz, 3H), 3.09 (dt, J1
) 7.1, J2 ) 16.7 Hz, 2H), 3.81 (s, 3H), 4.21 (q, J ) 7.2, 2H), 4.64
(s, 2H), 5.27-5.35 (m, 2H), 5.82-5.96 (m, 1H), 6.87 (d, J ) 9.0
Hz, 2H), 7.03 (d, J ) 8.9 Hz, 2H); 13C NMR (75.5 MHz, CDCl3)
2
(20) For a similar transesterification process with a mesylate in an intramo-
lecular macrolactonization reaction, see: Vedejs, E. J.; Larsen, S. D. J. Am. Chem.
Soc. 1984, 106, 3030–3032.
δ 14.0, 39.5 (t, JCF ) 24.4 Hz), 55.4, 61.5, 61.7, 114.3, 118.5
1
3
(t, JCF)245.5 Hz), 121.3, 122.1, 127.9 (t, JCF ) 4.9 Hz), 139.8,
152.9 (t, JCF ) 33.6 Hz), 158.9, 161.5, 166.3; 19F NMR (282.4
2
(21) (a) Other fluoride sources were also tested in the reaction of 2a with
benzyl bromide: CsF did not work, while TBAT and TASF afforded the expected
product 3a although in lower yields (67% and 72%, respectively) and longer
reaction times (6 h) than TBAF (Table 2, entry 1). (b) An analogue example of
this protocol with n-BuBr promoted by NaH was previously reported: Serrano-Wu,
M. H.; Regueiro-Ren, A.; Carroll, T. M.; Balasubramanian, B. N.; St. Laurent,
D. R. Tetrahedron Lett. 2001, 42, 8593–8595. In our case, the reaction with
NaH turned out to be a complex mixture in which only 8% of the desired product
could be detected after 6 h by GC-MS.
MHz, CDCl3) δ -99.97 (t, JFH ) 16.4 Hz, 2F). HRMS calcd for
C17H19F2NO5 (M+) 355.1231, found 355.1221.
Acknowledgment. We thank the Ministerio de Educacio´n y
Ciencia (CTQ2007-61462) of Spain for their financial support.
V.R., A.G., and S.C. express their thanks for predoctoral
fellowships, M.S.-R. for a postdoctoral contract, and C.P. for a
Ramo´n y Cajal contract.
(22) (a) Studer, A.; Hadida, S.; Ferrito, S. Y.; Kim, P. Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823–826. (b) Curran, D. P. Angew. Chem.,
Int. Ed. 1998, 37, 1174–1196. (c) Curran, D. P. Med. Res. ReV. 1999, 19, 432–
438.
Supporting Information Available: Experimental proce-
dures and characterization data for compounds 1g, 2a,b, 2e-g,
3b,c, 3f, and 3h-u and copies of NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) For recent revisions see: (a) Chauhan, P. M. S.; Srivastava, S. K. Comb.
Chem. High Throughput Screening 2001, 4, 35–51. (b) Andres, C. J.; Denhart,
D. J.; Deshpande, M. S.; Gillman, K. V. Comb. Chem. High Throughput
Screening 1999, 2, 191–210. (c) Franze´n, R. G. J. Comb. Chem. 2000, 2, 195–
214.
(24) The alkoxycarbonylation reaction of the corresponding imidoyl iodide
in the presence of 3-(perfluorooctyl)propanol also gave the desired R-imino ester
3q but it took place slowly (5 days) and in low yield (<30%).
JO800567A
5620 J. Org. Chem. Vol. 73, No. 14, 2008