Novel defluorinative alkylation of trifluoroacetaldehyde N,O-acetal derivatives and its application to multi-component reaction

Article abstract of DOI:10.1039/b817599c

The reaction of trifluoroacetaldehyde N,O-acetal derivatives with 2 molar equivalents of alkyllithium reagents proceeded via β-elimination of fluoride followed by alkyl transfer from excess alkyllithium to the generated ketene N,O-acetal intermediate at t

Full text of DOI:10.1039/b817599c

View Article Online / Journal Homepage / Table of Contents for this issue
Chemical Communications
www.rsc.org/chemcomm
Number 9 | 7 March 2009 | Pages 977–1140
ISSN 1359-7345
FEATURE ARTICLES
COMMUNICATION
Eric Meggers
Hikaru Yanai and Takeo Taguchi
Novel defluorinative alkylation of
trifluoroacetaldehyde N,O-acetal
derivatives and its application to
multi-component reaction
Targeting proteins with metal complexes
Hiroshi Shinokubo and Atsuhiro Osuka
Marriage of porphyrin chemistry with
metal-catalysed reactions
1359-7345(2009)9;1-Y

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Novel defluorinative alkylation of trifluoroacetaldehyde N,O-acetal
derivatives and its application to multi-component reactionw
Hikaru Yanai and Takeo Taguchi*
Received (in Cambridge, UK) 7th October 2008, Accepted 18th November 2008
First published as an Advance Article on the web 1st December 2008
DOI: 10.1039/b817599c
The reaction of trifluoroacetaldehyde N,O-acetal derivatives
with 2 molar equivalents of alkyllithium reagents proceeded
via b-elimination of fluoride followed by alkyl transfer from
excess alkyllithium to the generated ketene N,O-acetal
intermediate at the b-carbon of fluorine groups.
designed the defluorinative alkylation of trifluoroacetaldehyde
N,O-acetals (eqn (1)), which are easily prepared from amino
alcohols and TFAE. That is, the treatment of these substrates
with more than 2 molar equivalents of strongly basic alkyl-
lithium reagents probably results in the elimination of fluoride
to give difluoroketene N,O-acetal intermediates A.17 If an
equilibrium between highly polarized ketene N,O-acetal form
A and zwitterionic ketene iminium form B exists, the following
alkylation by excess alkyllithium would be expected to proceed
at the b-carbon of fluorine groups. In contrast, it is known that
the similar defluorinative alkylation of trifluoroacetaldehyde
aminals selectively proceeds at the a-carbon of fluorine groups
(eqn (2)).18 In this paper, we disclose this unusual regioselec-
tivity in the defluorinative alkylation of trifluoroacetaldehyde
N,O-acetals. Furthermore, as a synthetic application of the
present defluorinative alkylation, novel multi-component
reaction of trifluoroacetaldehyde N,O-acetals, alkyllithiums
and carbonyl compounds was developed.
In the fields of medicinal and bioorganic chemistry, unique
properties of organofluorine compounds are well known.1
Especially, since difluoromethyl and difluoromethylene groups
perform as bioisosteric structures for hydroxymethylene
group2 or ethereal oxygen,3 these functionalities are widely
found in the structure of biologically active molecules. The
a,a-difluoroketone structure also performs as a transition state
mimic against several peptidases, such as HIV protease,4
elastase,5 renin,6 and human heart chymase.7
For these reasons, the development of effective synthetic
strategies for difluoromethylene compounds has been one of the
top concerns in organofluorine chemistry for a long time.8–10
Among a number of difluoromethylene syntheses, functionaliza-
tion of trifluoromethyl compounds through mono-defluorination
is highly useful, because a wide range of CF3-containing mole-
cules can be obtained from commercial source or by simple
preparation. For examples, Xu and co-workers reported that
the treatment of trifluoroacetyltriphenylsilane with alkyllithiums
results in the formation of 2,2-difluoroenol silyl ethers through
1,2-alkylation of silylketone moiety, the Brook rearrangement
of the resultant lithium alkoxide intermediates followed by
b-elimination of fluoride ion.11,12 Uneyama and co-workers also
reported the effective synthesis of 2,2-difluoroenol silyl ethers
through electrochemical or Mg(0)-mediated reductions of tri-
fluoromethylketones.13 However, the further functionalization
of 2,2-difluoroenol silyl ethers by the Mukaiyama aldol and
related reactions has a disadvantage from a viewpoint of the
atom economy. In addition, somewhat troublesome purification
or isolation procedure of fluorinated enol silyl ethers is often
required to use these as fluorine-containing building blocks.14,15
Recently, our research interest has been focused on the
synthetic utility of polyfluorinated aldehyde hemiacetals such
as trifluoroacetaldehyde ethyl hemiacetal (TFAE),16 which is a
commercially available material. As the second project, we
ð1Þ
ð2Þ
To confirm the regioselectivity of the defluorinative alkyl-
ation reaction, we examined the reaction of trifluoroacetalde-
hyde N,O-acetal 1 with 2.4 molar equivalents of various
alkyllithium reagents in Et2O. Selected results are summarized
in Table 1. The reaction of N-allyl substrate 1a and n-butyl-
lithium (n-BuLi) completed within 3 h at ꢀ78 1C to give
defluorinative alkylation product 2aa as a sole regioisomer
in 83% yield (entry 1). 2aa was slightly unstable on silica gel,
although rapid purification by the short silica gel pad resulted
in the reasonable isolated yield of 2aa. Since the reaction of 1a
and methyllithium under similar conditions resulted in the
poor conversion due to low solubility of methyllithium in
Et2O, synthetically useful yield of 2ab was realized by
the reaction at ꢀ24 1C in Et2O–THF (2 : 1) mixed solvent
(entry 2; 81% yield). Cyclopropyllithium is also used as good
School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
E-mail: taguchi@ps.toyaku.ac.jp; Fax: +81 42 676 3257;
Tel: +81 42 676 3257
w Electronic supplementary information (ESI) available: Details of
experiments, NMR data of all new compounds, and crystal structure
of 2ca (CCDC 702162) and anti-3h (CCDC 702163). For ESI
and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b817599c
ꢁc
This journal is The Royal Society of Chemistry 2009
1034 | Chem. Commun., 2009, 1034–1036

Table 1 Defluorinative alkylation of N,O-acetals 1
diastereoselectivity (entries 2,3). Heteroaromatic aldehydes and
cinnamaldehyde were also used as examples of electrophiles
to give the corresponding 1,2-adducts in excellent yield
(entries 4–6). Interestingly, in the reaction with 2-pyridine-
carbaldehyde, acceleration of the reaction rate and moderate
diastereoselectivity were observed. Thus, after the reaction for
only 15 min, pyridyl carbinol product 3e was obtained in 87%
yield as a mixture of diastereomers in a ratio of 3.4 : 1 (entry 5).
This finding possibly indicates that the coordination of basic
nitrogen of pyridine ring to the lithium center of the reactive
intermediate effected the increase in both reaction rate and
diastereoselectivity. In contrast to aromatic or a,b-unsaturated
aldehydes, aliphatic aldehydes such as 3-phenylpropionaldehde
and cyclohexanecarbaldehyde showed low reactivity, therefore,
higher reaction temperature and prolonged reaction time were
required to complete the reaction (entries 7, 8). For example,
the reaction with cyclohexanecarbaldehyde proceeded at 0 1C
for 8 h to give 3h in 81% yield with excellent anti selectivity
(anti/syn = 10.5 : 1). The stereochemistry of 3h was determined by
an X-ray crystallographic analysis of the major isomer (see ESIw).
Although it is known that 2,2-difluoroketene silyl acetals did
not smoothly react with ketones under several conditions, we
found that defluorinative butylation of 1a with n-BuLi followed
by the reaction with various ketones proceeded smoothly at
0 1C or at room temperature to give the difluoromethylated
tertiary alcohol products in excellent yield (Table 3). For
example, after the treatment of 1a with 2.5 molar equivalents
of n-BuLi at ꢀ78 1C for 4 h, the reaction with cyclohexanone
provided tertiary alcohol 4a in 84% yield (entry 1). Under the
similar conditions, the reaction with acetone gave an excellent
result (89% yield, entry 2). Furthermore, acetophenone was
found to be a nice electrophile and 4c was obtained in 79% yield
as a mixture of diastereomers in a ratio of 1.8 : 1 (entry 3).
Concerning the present reaction, we propose the reaction
mechanism as shown in Scheme 1. First, the b-elimination of
N,O-acetal 1 by 1 molar equivalent of alkyllithium reagent gives
difluoroketene N,O-acetal intermediate C.20 Regioselective
alkylation of C by excess alkyllithium reagents is possibly
induced by the coordination of N,O-acetal oxygen to the lithium
center to give lithium phenoxide E via zwitterion D. Since it is
known that a-fluorinated methyllithium species without the
stabilization by electron withdrawing groups rapidly decompose
at low temperature through the a-elimination of LiF, lithium
phenoxide E should be a reactive species in the present
C–C bond formation.21 That is, in the presence of carbonyl
Entry
1
R1
R2Li
t/h
2
Yielda (%)
1
1a
1a
1a
1b
1c
Allyl
Allyl
Allyl
n-Pr
Bn
n-BuLi
MeLi
c-C3H5Li
n-BuLi
n-BuLi
3
4
4
4
5
2aa
2ab
2ac
2ba
2ca
83
81
74
58
73
2b
3
4c
5
a
b
Isolated yield. Reaction was carried out in Et2O-THF (2 : 1) at ꢀ24 1C.
c
29% of difluoromethyl ketone was formed (based on 19F NMR).
alkyl donor for this reaction to result in clean formation of
defluorinative cyclopropylation product 2ac (entry 3; 74%
yield). In contrast, the use of less basic organolithium reagents
such as phenyllithium and allyllithium resulted in no reaction
(not shown). These results suggest that the deprotonation at
CF3-substituted methine position is the initiation step for the
present reaction. Furthermore, we examined the effects of
N-substituent of substrate 1. Under similar conditions, the
reaction of N-propyl substrate 1b with 2 molar equivalents of
n-BuLi gave alkylated product 2ba in 58% with the formation
of the corresponding ketone in 29% yield. The reaction of
N-benzylated N,O-acetal 1c with n-BuLi also provided
alkylated product 2ca in 73% yield.
Since the hydrogen of difluoromethyl group in the defluori-
native alkylation product 2 was delivered by aqueous workup,19
we examined the treatment of the in situ generated reactive
intermediate with various aldehydes (Table 2). After the reaction
of 1a with 2.5 molar equivalents of n-BuLi for 4 h at ꢀ78 1C, the
reaction mixture was treated with 2.0 molar equivalents of
benzaldehyde to give difluoromethylenyl carbinol 3a in 85%
yield as a mixture of diastereomers in a ratio of 1 : 1.5 (entry 1).
In the reaction with 4-substituted benzaldehyde derivatives, little
or no substituent effects were observed giving rise to the
corresponding carbinol products in excellent yield with low
Table 2 Multi-component reaction of 1a, n-BuLi and aldehydes
Table 3 Multi-component reaction of 1a, n-BuLi and ketones
Entry
R
T/1C
t/h
3
Yielda (%)
Drb
1 : 1.5
1 : 1.5
1 : 1.7
1.2 : 1
3.4 : 1
1 : 1.2
11 : 1
11 : 1c
1
2
3
4
5
6
7
8
Ph
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ24
0
0.5
0.5
0.5
1
0.25
1
3a
3b
3c
3d
3e
3f
85
79
85
87
87
87
76
81
4-MeOC6H4
4-CF3C6H4
2-Furyl
2-Pyridyl
CHQCHPh
CH2CH2Ph
c-C6H11
Entry
R1
–CH2(CH2)3CH2–
R2
T/1C
t/h
4
Yielda (%)
1
2
3
0
rt
rt
6
9
9
4a
4b
4c
84
89
3
8
3g
3h
Me
Ph
Me
Me
79b
a
b
c
a
b
Isolated yield. Dr = 1.8 : 1
Isolated yield. Based on 19F NMR. anti/syn selectivity.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1034–1036 | 1035

Bioorg. Med. Chem. Lett., 1994, 4, 241; H. L. Sham, N. E. Wideburg,
S. G. Spanton, W. E. Kohlbrenner, D. A. Betebenner, D. J. Kempf,
D. W. Norbeck, J. J. Plattner and J. W. Erickson, J. Chem. Soc.,
Chem. Commun., 1991, 110; A. M. Silva, R. E. Cachau, H. L. Sham
and J. W. Erickson, J. Mol. Biol., 1996, 255, 321.
5 J. W. Skiles, C. Miao, R. Sorek, S. Jacober, P. W. Mui, G. Chow,
S. M. Weldon, G. Possanza, M. Skoog, J. Keirns, G. Letts and
A. S. Rosenthal, J. Med. Chem., 1992, 35, 4795.
6 A. M. Doherty, I. Sircar, B. E. Kornberg, J. Quin, R. T. Winters,
J. S. Kaltenbronn, M. D. Taylor, B. L. Batley, S. R. Rapundalo,
M. J. Ryan and C. A. Painchaud, J. Med. Chem., 1992, 35, 2;
D. Schirlin, C. Tarnus, S. Baltzer and J. M. Remy, Bioorg. Med.
Chem. Lett., 1992, 2, 651.
7 M. Eda, A. Ashimori, F. Akahoshi, T. Yoshimura, Y. Inoue,
C. Fukaya, M. Nakajima, H. Fukuyama, T. Imada and
N. Nakamura, Bioorg. Med. Chem. Lett., 1998, 8, 913; M. Eda,
A. Ashimori, F. Akahoshi, T. Yoshimura, Y. Inoue, C. Fukaya,
M. Nakajima, H. Fukuyama, T. Imada and M. Nakamura, Bioorg.
Med. Chem. Lett., 1998, 8, 919; F. Akahoshi, A. Ashimori,
H. Sakashita, T. Yoshimura, M. Eda, T. Imada, M. Nakajima,
N. Mitsutomi, S. Kuwahara, T. Ohtsuka, C. Fukaya, M. Miyazaki
and N. Nakamura, J. Med. Chem., 2001, 44, 1297.
Scheme 1 Proposed reaction mechanism.
compounds, the intramolecular nucleophilic attack by the
phenoxide moiety of E to the polarized difluoroenamine moiety
and the simultaneous C–C bond formation with carbonyl
compounds smoothly provide the corresponding carbinol pro-
ducts. In the reaction of difluoroketene aminal, which has a
symmetric structure, and n-BuLi reported by Dolbier and co-
workers (eqn (2)),18 similar equilibria between the ketene aminal
form and zwitterionic form should not exist due to insufficient
ability of dimethylamino group as a leaving group. For this
reason, the reaction of difluoroketene aminal and n-BuLi
proceeded an via addition–elimination mechanism.
8 For a review, see: M. J. Tozer and T. F. Herpin, Tetrahedron, 1996,
52, 8619.
9 Selected examples on nuclephilic difluoromethylation reactions, see:
O. Kitagawa, T. Taguchi and Y. Kobayashi, Tetrahedron Lett.,
1988, 29, 1803; O. Kitagawa, A. Hashimoto, Y. Kobayashi and
T. Taguchi, Chem. Lett., 1990, 1307; K. Iseki, Y. Kuroki, D. Asada,
M. Takahashi, S. Kishimoto and Y. Kobayashi, Tetrahedron, 1997,
53, 10271; A. K. Yudin, G. K. S. Prakash, D. Deffieux, M. Bradley,
R. Bau and G. A. Olah, J. Am. Chem. Soc., 1997, 119, 1572; G. K.
S. Prakash, J. Hu, T. Mathew and G. A. Olah, Angew. Chem., Int.
Ed., 2003, 42, 5216; G. K. S. Prakash, J. Hu, Y. Wang and
G. A. Olah, Org. Lett., 2004, 6, 4315.
10 Electrophilic difluorination and difluoromethylation reactions, see:
T. Nakano, M. Makino, Y. Morizawa and Y. Matsumura, Angew.
Chem., Int. Ed. Engl., 1996, 35, 1019; G. K. S. Prakash, C. Weber,
S. Chacko and G. A. Olah, Org. Lett., 2007, 9, 1863; W. Zhanga,
J. Zhua and J. Hu, Tetrahedron Lett., 2008, 49, 5006.
11 F. Jin, Y. Xu and W. Huang, J. Chem. Soc., Chem. Commun.,
1993, 814; F. Jin, Y. Xu and W. Huang, J. Chem. Soc., Perkin
Trans. 1, 1993, 795.
12 T. Brigaud, P. Doussot and C. Portella, J. Chem. Soc., Chem.
Commun., 1994, 2117; O. Lefebvre, T. Brigaud and C. Portella,
J. Org. Chem., 2001, 66, 1941.
13 K. Uneyama, K. Maeda, T. Kato and T. Katagiri, Tetrahedron
Lett., 1998, 39, 3741; H. Amii, T. Kobayashi, Y. Hatamoto and
K. Uneyama, Chem. Commun., 1999, 1323.
14 K. Iseki, Y. Kuroki, D. Asada and Y. Kobayashi, Tetrahedron
Lett., 1997, 38, 1447.
In summary, we found that the treatment of trifluoroacetalde-
hyde N,O-acetal derivatives with 2 molar equivalents of alkyl-
lithium provides difluoromethyl ketone N,O-acetal products in
excellent yield with complete regioselectivity. The observed re-
gioselectivity is opposite to that in the similar reaction of aminal
derivatives. This result suggests the unique properties and the
synthetic utilities of asymmetric N,O-acetal derivatives. As a
further extension of this regioselective defluorinative alkylation,
novel multi-component reaction of trifluoromethylated N,O-
acetals, alkyllithiums and carbonyl compounds was also deve-
loped. This multi-component reaction provides an effective and
convergent construction method for b-hydroxy-a,a-difluoro-
ketone derivatives. Further study on the synthetic utility and
the mechanistic insight is under progress in our laboratory.
The authors gratefully acknowledge Mr. Hideyuki
Mimura and Dr. Kosuke Kawada (TOSOH F-TECH Inc.)
for supplying TFAE.
15 Y. Guo, K. Fujiwara, H. Amii and K. Uneyama, J. Org. Chem., 2007,
72, 8523; H. Amii and K. Uneyama, ACS Symp. Ser., 2005, 911, 455.
16 H. Yanai, H. Mimura, K. Kawada and T. Taguchi, Tetrahedron,
2006, 63, 2153.
17 For instance, defluorination reaction of trifluoroethyl ethers or
trifluoroacetaldehyde O,O-acetals by alkyllithium reagents is well
known: J. M. Percy, Tetrahedron Lett., 1990, 31, 3931; S. T. Patel,
J. M. Percy and R. D. Wilkes, Tetrahedron, 1995, 51, 9201;
J. A. Howarth, W. M. Owton, J. M. Percy and M. H. Rock,
Tetrahedron, 1995, 51, 10289; Y. He, C. P. Junk, J. J. Cawley and
D. M. Lemal, J. Am. Chem. Soc., 2003, 125, 5590; P. J. Kocienski
and T. N. Snaddon, Org. Synth., 2008, 85, 45.
18 Y. Xu, W. R. Dolbier, Jr. and X. X. Rong, J. Org. Chem., 1997, 62,
1576.
19 By D2O quench of the reaction mixture of 1a and n-BuLi,
deuterium introduction at difluoromethinic position of 2aa was
observed.
Notes and references
1 Bioorganic and Medicinal Chemistry of Fluorine, ed. J.-P. Begue
´ ´
and D. Bonnet-Delpon, Wiley, New York, 2008; Organofluorine
Chemistry, ed. K. Uneyama, Blackwell Publishing Ltd., Oxford,
UK, 2005; Fluorine in Bioorganic Chemistry, eds. J. T. Welch and
S. Eswarakrishnan, Wiley, New York, 1991; Biomedicinal Aspects
of Fluorine Chemistry, eds. R. Filler and Y. Kobayashi, Elsevier,
Amsterdam, 1982.
2 L. W. Hertel, G. B. Boder, J. S. Kroin, S. M. Rinzel, G. A. Poore,
G. C. Todd and G. B. Grindey, Cancer Res., 1990, 50, 4417;
M. A. Szarek, X. Wu and W. A. Szarek, Carbohydr. Res., 1997,
299, 165; R.-W. Wang, X.-L. Qiu, M. Bols, F. Ortega-Caballero
and F.-L. Qing, J. Med. Chem., 2006, 49, 2989.
20 Reaction of 1a with an equimolar amount of n-BuLi gave 2aa in
38% yield with the recovery of 1a in 41%.
3 S. Halazy, A. Ehrhard and C. Danzin, J. Am. Chem. Soc., 1991,
113, 315.
21 We examined the thermal stability of intermediate E by stepwise
reaction of 1a, n-BuLi and benzaldehyde. After simple evaporation at
room temperature of the reaction mixture of 1a and n-BuLi, treat-
ment of the resultant residue with benzaldehyde in Et2O gave 3a
without significant decrease in the product yield. This finding strongly
indicates that intermediate E is stable at least at room temperature.
4 D. Schirlin, S. Baltzer, V. van Dorsselaer, F. Weber, C. Weill,
J. M. Altenburger, B. Neises, G. Flynn, J. M. Remy and
C. Tarnus, Bioorg. Med. Chem. Lett., 1993, 3, 253; D. Schirlin,
V. van Dorsselaer, C. Tarnus, D. L. Taylor, A. S. Tyms, S. Baltzer,
F. Weber, J. M. Remy, T. Brennan, R. Farr and D. Janowick,
ꢁc
This journal is The Royal Society of Chemistry 2009
1036 | Chem. Commun., 2009, 1034–1036