Novel intramolecular rearrangement of 3-bromo-3,3-difluoroalanine Schiff bases via radical ipso-substitution at the aromatic ring

Article abstract of DOI:10.1039/a803944e

3-Bromo-3,3-difluoroalanine Schiff bases are synthesized by bromodifluoromethylation of the corresponding glycine Schiff bases with CF₂Br₂; their intramolecular rearrangement involving radical ipso-substitution at the aromatic ring o

Full text of DOI:10.1039/a803944e

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Novel intramolecular rearrangement of 3-bromo-3,3-difluoroalanine Schiff
bases via radical ipso-substitution at the aromatic ring
Hideki Amii, Susumu Kondo and Kenji Uneyama*†
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushimanaka 3-1-1, Okayama 700-0082, Japan
3-Bromo-3,3-difluoroalanine Schiff bases are synthesized by
bromodifluoromethylation of the corresponding glycine
Schiff bases with CF2Br2; their intramolecular rearrange-
ment involving radical ipso-substitution at the aromatic ring
of the imine moiety provides 3,3-difluoro-3-arylpropanoates
in good yields.
cyclohexadienyl radical 6. Extrusion of aromatic nitrile 7 from
6 then occurs to furnish the carbon radical 8.11 Subsequent
hydrogen abstraction gives rise to b,b-difluorocarboxylic acid
ester 4 as the final product.
R
Organofluorine compounds are receiving increasing attention in
the medicinal, agricultural, and material sciences. In particular,
interest in fluorine-containing amino acids and their derivatives
has existed for many years, since they have potentially unique
biological activities and thus are a current synthetic target.1
Herein we report a new approach to the preparation of 3-bromo-
3,3-difluoroalanine Schiff bases 2 and their intramolecular
rearrangement via radical ipso-substitution at the aromatic ring,
which provides b,b-difluoroalkanoates.2,3
Ar
CF2Br
N CO2Et
Bu3SnH
AIBN
CF2
CO2Et
Ar
Ar
N
2
5
Ar = 4-RC6H4
R
F
F
3-Bromo-3,3-difluoroalanine Schiff bases 2 are synthesized
using commercially available CF2Br2, the simplest CF2 unit.4
Appropriate choice of reaction conditions was essential to avoid
the decomposition of the bromodifluoromethyl moiety of 2 due
to nucleophilic attack of the bases, such as NaH and even LDA.
When Schiff base 1 was treated with lithium 2,2,6,6-tetra-
methylpiperidide (LTMP) in THF at 278 °C followed by
CF2Br2, difluoromethylene compounds 2 were obtained in good
yields [eqn (1)].
F
–ArCN 7
SH
F
CO2Et
4
Ar
8
CO2Et
Ar
N
6
Scheme 1
Other examples of selective formation of 4 are given in Table
1. The Schiff bases 2 which possess either electron-donating or
-withdrawing substituents on the aryl ring of the imine moiety
provide 4 in high yields. It is noted that the reactions of 2c and
2d, which have electron-donating substituents, required more
forcing conditions (entries 2 and 3), whereas electron-with-
drawing substituents enhanced the reaction rates (entries 4 and
5).
Ph
Ph
CF2Br
N CO2R
(1) LTMP / THF
(1)
Ph
N
CO2R
Ph
(2) CF2Br2, -78 °C
1a R = Et
b R = Bn
2a R = Et 84%
b R = Bn 61%
Table 1 Radical rearrangement of Schiff base 2a
3-Bromo-3,3-difluoroalanine Schiff bases 2 are interesting
fluorinated synthetic building blocks, and their transformations
were examined next. Firstly, we explored Bu3SnH/AIBN
mediated radical cleavage of the carbon–bromine bond in 2.
Treatment of 2a with Bu3SnH/AIBN/benzene at 80 °C for 2.5 h
gave not only the reduction product 3a (10%), but also
unexpectedly gave ethyl 3,3-difluoro-3-phenylpropanoate5 4a
(60%) as the major product [eqn (2)]. Raising the reaction
F
F
Ar
CF2Br
Bu3SnH / AIBN
benzene
CO2Et
Ar
Ar
N CO2Et
2
4
Entry
Ar
T/°C
t/h
Product Yieldb (%)
1
2
3
4
5
Ph
110
130
2.5
7.0
7.0
1.5
2.0
4a
4c
4d
4e
4f
93
90
99
80 (99)c
90
4-MeC6H4
4-MeOC6H4 130
4-FC6H4 110
4-CF3C6H4 110
Bu3SnH
Ph
CF2Br
CO2Et
Ph
CF2H
N CO2Et Ph
F
F
AIBN
+
(2)
CO2Et
Ph
N
Ph
benzene
a All reactions were carried out in sealed glass tubes containing 2, Bu3SnH
(2 equiv.) and AIBN (0.1 equiv.). After the reactions were completed, an
equimolar amount of aromatic nitrile was generated (90–95% isolated yield
in each case). Reported yields are isolated yields unless specified. The
number in parentheses is the yield determined by 19F NMR analysis.
2a
3a
10%
< 5%
4a
80 °C, 2.5 h
110 °C, 2.5 h
60%
93%
b
c
temperature ( > 110 °C) favoured the rearrangement (2a?4a).
The formation of 4a can be explained by assuming the pathway
pictured in Scheme 1. Initially, Bu3SnH/AIBN mediated
homolytic fission of the C–Br bond in 2 generates a,a-
difluoroalkyl radical species 5. The resultant a-fluorinated
carbon radical 5 undergoes intramolecular ipso attack to the
aromatic group6–10 of the imine moiety of 5, forming the spiro
The Schiff bases 1 are easily synthesized in one pot from the
corresponding arylmagnesium bromides, aryl cyanides and
glycine ethyl ester hydrochloride [eqn (3)].12 In the net
transformation to 4, aryl cyanides were regenerated after
completion of the intramolecular radical rearrangement, as
shown in Scheme 1. Thus, the construction of 4 was formally
Chem. Commun., 1998
1845

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was stirred at 278 °C for a further 5 h. The reaction mixture was quenched
with aq. NH4Cl, and the organic layer was washed with brine and dried over
Na2SO4. Purification of the products by recrystalization from hexane gave
colorless plates. (ii) A solution of 2a (19.9 mg, 0.05 mmol), Bu3SnH (34.9
mg, 0.12 mmol) and AIBN (1.0 mg, 6.0 mmol) in benzene (2 ml) was heated
at 110 °C in a sealed glass tube for 2.5 h. The reaction mixture was cooled,
reduced in volume, and purified by chromatography on silica gel (hexane–
EtOAc) to afford 4a (10.0 mg, 93%) as a colorless oil.
Ar
+
+
HCl•H2NCH2CO2R
ArMgBr
ArCN
Ar
N
CO2R
1
CF2Br2
(3)
F
F
1 V. P. Kukhar’ and V. A. Soloshonok, Fluorine-containing Amino Acids,
Wiley, Chichester, UK, 1995.
H2N
CO2Et
CO2Et
ArMgBr
Ar
2 A [3,3]-sigmatropic rearrangement route to b,b-difluoro-carbonyl
compounds has been reported: see S. T. Patel, J. M. Percy and R. D.
Wilkes, Tetrahedron, 1995, 51, 11 327.
3 T. Takagi, N. Okikawa, S. Johnoshita, M. Koyama, A. Ando and I.
Kumadaki, Synlett, 1996, 82.
4 Reaction of an alanine Schiff base with CF2Br2 in the presense of LDA
has been reported: see P. Bay and J. P. Vevert, Tetrahedron Lett., 1978,
14, 1215.
5 Compound 4a was identified by comparison with an authentic sample
synthesized by difluorination of ethyl benzoylacetate using DAST, see
S. C. Sondej and J. A. Katzenellenbogen, J. Org. Chem., 1986, 51,
3508.
6 L. Benati, P. Spagnolo, A. Tundo and G. Zanardi, J. Chem. Soc., Chem.
Commun., 1979, 141.
7 J. Grimshaw, R. Hamilton and J. Trocha-Grimshaw, J. Chem. Soc.,
Perkin Trans. 1, 1982, 229.
8 J. Aubé, X. Peng, Y. Wang and F. Takusagawa, J. Am. Chem. Soc.,
1992, 114, 5466.
9 E. Lee, H. S. Whang and C. K. Chung, Tetrahedron Lett., 1995, 36,
913.
10 M. L. E. N. da Mata, W. B. Motherwell and F. Ujjainwalla, Tetrahedron
Lett., 1997, 38, 137 and 141.
achieved by the coupling of three components, i.e. ArMgBr,
CF2Br2 and glycine derivatives.
In conclusion, the synthesis and a novel reaction of 3-bromo-
3,3-difluoroalanine Schiff bases were developed, which provide
a new route to difluoromethylene compounds via intra-
molecular rearrangement involving radical ipso-substitution at
the aromatic ring.
We thank to the SC NMR laboratory of Okayama University
for 19F NMR analyses and the Ministry of Education, Science,
Sports and Culture of Japan for financial support (Grant-in-Aid
for scientific research, No. 09305058).
Notes and References
† E-mail: uneyamak@cc.okayama-u.ac.jp
‡ Representive experimental procedures. (i) To a solution of 2,2,6,6-tetra-
methylpiperidine (106 mg, 0.75 mmol) in freshly distilled THF (1 ml)
11 An equimolar amount of aromatic nitrile was isolated and identified by
GC, NMR and IR analysis and comparison with authentic material.
12 M. J. O’Donnell and R. L. Polt, J. Org. Chem., 1982, 47, 2663.
cooled down to 0 °C under argon atmosphere, 1.53
M BuLi in hexane (0.50
ml, 0.75 mmol) was added dropwisely and then stirred for an additional 30
min. The LTMP solution was cooled to 278 °C, and the solution of glycine
Schiff base (0.5 mmol) in THF (1 ml) was added dropwisely to the LTMP
solution. After 1 h, CF2Br2 (525 mg, 2.5 mmol) was added, and the mixture
Received in Cambridge, UK, 27th May 1998; 8/03944E
1846
Chem. Commun., 1998