Stereoselective nucleophilic monofluoromethylation of N-(tert- butanesulfinyl)imines with fluoromethyl phenyl sulfone

Article abstract of DOI:10.1021/ol060322t

Highly stereoselective nucleophilic monofluoromethylation of (R)-(tert-butanesulfinyl)imines with fluoromethyl phenyl sulfone was achieved to afford α-monofluoromethylamines with a nonchelation-controlled stereoselectivity mode. By using the same chemistr

Full text of DOI:10.1021/ol060322t

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1693-1696
Stereoselective Nucleophilic
Monofluoromethylation of
N-(tert-Butanesulfinyl)imines with
Fluoromethyl Phenyl Sulfone
Ya Li, Chuanfa Ni, Jun Liu, Laijun Zhang, Ji Zheng, Lingui Zhu, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
jinbohu@mail.sioc.ac.cn
Received February 7, 2006
ABSTRACT
Highly stereoselective nucleophilic monofluoromethylation of (R)-(tert-butanesulfinyl)imines with fluoromethyl phenyl sulfone was achieved to
afford -monofluoromethylamines with a nonchelation-controlled stereoselectivity mode. By using the same chemistry, (R)-(tert-butanesulfinyl)-
imines bearing a terminal tosylate (OTs) group can be converted to
r
r-monofluoromethylated cyclic secondary amines with high stereoselectivity.
Fluorine is truly “a small atom with a big ego”, and in many
cases the replacement of a hydrogen atom with fluorine in a
drug molecule can cause 10-fold enhancement of its biologi-
cal potency and bioavailability.1 Today, selective incorpora-
tion of fluorine atom(s) into organic molecules to modulate
their biological properties has become a routine and powerful
strategy in drug design. Since Kollonitsch’s first report of
R-monofluoromethylamines as selective inhibitors of bio-
synthesis of aminergic neurotransmitters,2 R-monofluoro-
methylamines have been extensively used as important
building blocks in the design of many anticholinergic,
antiemetic, and antispastic drugs and enzyme inhibitors,
given the fact that the fluorine atom lowers the basicity of
the amine functionality, decreases acute toxicity, and in-
creases the metabolic stability of a target drug.1-5 However,
there are very few synthetic methods available to effectively
synthesize R-monofluoromethylamines,6 mostly based on the
fluorination reactions with toxic reagents such as SF4,7 HF,8
and FCH2CN.9 Other preparative methods of R-monofluo-
romethylamines with fluoromethyl ketones10 and cyclic
sulfamidates11 suffer from multistep transformations and
unavailability of the precursors.
(3) Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Slavica, M.; Criscione,
K. R.; Borchardt, R. T.; Wang, W. J. Med. Chem. 1999, 42, 3588-3601.
(4) Silverman, R. B.; Nanavati, S. M. J. Med. Chem. 1990, 33, 931-
936.
(5) Bey, P.; Gerhart, F.; Dorsselaer, V. V.; Danzin, C. J. Med. Chem.
1983, 26, 1551-1556.
(6) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishman,
S., Eds.; Wiley: New York, 1991.
(1) (a) McCarthy, J. R. Fluorine in Drug Design: A Tutorial ReView;
17th Winter Fluorine Conference, St. Pete Beach, FL, 2005. (b) McCarthy,
J. R. Utility of Fluorine in Biologically ActiVe Molecules; 219th National
Meeting of the American Chemical Society, San Francisco, CA, 2000;
Division of Fluorine Chemistry Turtorial.
(2) Kollonitsch, J.; Perkins, L. M.; Patchett, A. A.; Doldouras, G. A.;
Marburg, S.; Duggan, D. E.; Maycock, A. L.; Aster, S. D. Nature 1978,
274, 906-908.
(7) Kollonitsch, J.; Marburg, S.; Perkins, L. M. J. Org. Chem. 1975, 40,
3808-3809.
10.1021/ol060322t CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/16/2006

Table 1. Survey of Reaction Conditions
molar ratio
(1:2:3)
facial selectivitya
((4a + 4a′):4a′′)
isomer ratioa
(4a:4a′)
unreacted
2 (equiv)a
yield (%)b
(4a + 4a′)
entry
base 3
1c
n-BuLi
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.0:1.05
99:1
99:1
99:1
99:1
99:1
1:1.6
1:1.9
1:2.2
1:1.3
1:2.0
0.14
0.14
0.19
0.19
trace
95
98
99
99
99
2c
LHMDS
LHMDS
LHMDS
LHMDS
3c,d
4e
5e
a Facial selectivity, isomer ratio, and unreacted 2 were determined by 19F NMR spectroscopy of the crude products. Compounds 4a (-179 ppm) and 4a′
(-188 ppm) were also identified by 19F NMR. b Isolated yield of 4a and 4a′. c Method A: The mixture of base and 2 was stirred at -78 °C for 3 min, then
1a was added. d The reaction temperature was -90 °C. e Method B: The base was added dropwise into the mixture of 1a, 2, and THF at -78 °C.
Nucleophilic fluoroalkylation is a straightforward way to
introduce fluoroalkyl groups into the target molecules, and
with this strategy both nucleophilic trifluoromethylation and
difluoromethylation have been tamed.12 To the best of our
knowledge, however, owing to the lack of efficient nucleo-
philic monofluoromethylating agents, nucleophilic mono-
fluoromethylation (nucleophilic incorporation of a CH2F
group into electrophiles) has never been reported. As part
of our continuing effort in selective fluoroalkylation chem-
istry,13 we wish to disclose the unprecedented stereoselective
synthesis of R-monofluoromethylamines by nucleophilic
monofluoromethylation of Ellman’s N-(tert-butanesulfinyl)-
imines14 using fluoromethyl phenyl sulfone (PhSO2CH2F)15
as the monofluoromethylating agent.
reaction with fluoromethyl phenyl sulfone 2. The reaction
conditions were carefully tuned as shown in Table 1. In all
cases, the facial selectivities [(4a + 4a′):4a′′], i.e., the
diastereoselectivity during the nucleophilic addition of in situ
generated (phenylsulfonyl)fluoromethyl anion into imine
functionality of 1a, were excellent (99:1). The absolute
configuration of sulfinamide 4a was confirmed by single-
crystal X-ray analysis (see Figure 1), which indicates that
In the first set of experiments, we chose (R)-(tert-butane-
sulfinyl)benzaldimine 1a as a model compound to study the
(8) Alvernhe, G.; Lacombe, S.; Laurent, A. J. Fluorine Chem. 1980, 16,
526-527.
(9) Bey, P.; Gerhart, F.; Jung, M. J. Org. Chem. 1986, 51, 2835-2838.
(10) (a) Kanai, M.; Ueda, K.; Yasumoto, M.; Kuriyama, Y.; Inomiya,
K.; Ootsuka, T.; Katsuhara, Y.; Higashiyama, K.; Ishii, A. J. Fluorine Chem.
2005, 126, 377-383. (b) Bravo, P.; Cavicchio, G.; Crucianelli, M.; Poggiali,
A.; Zanda, M. Tetrahedron: Asymmetry 1997, 8, 2811-2815.
(11) (a) Ok, D.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T. Tetrahedron
Lett. 1999, 40, 3831-3834. (b) Posakony, J. J.; Tewson, T. J. Synthesis
2002, 766-770.
(12) Prakash, G. K. S.; Hu, J. New Nucleophilic Fluoroalkylation
Chemistry. In Fluorine-Containing Synthons; Soloshonok, V. A., Ed.;
American Chemical Society: Washington, DC, 2005, and references therein.
(13) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882-5886.
(14) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995 and references therein.
(15) Fluoromethyl phenyl sulfone is commercially available, and it can
also be readily prepared with known methods. It has been used to prepare
fluoroolefins. However, its application as a CH2F- equivalent has never
been reported. See: (a) Matthews, D. P.; Persichetti, R. A.; McCarthy, J.
R. Org. Prep. Proced. Int. 1994, 26, 605-608. (b) Inbasekaran, M.; Peet,
N.; McCarthy, J. R. J. Chem. Soc., Chem. Commun. 1985, 678-679.
Figure 1. ORTEP drawing for sulfinamide 4a.
the stereochemistry of nucleophilic addition was nonchelation
controlled.13,14 Interestingly, we found that there were some
moderate stereoselectivities (4a:4a′) 1:1.3-2.2) during the
formation of another neighboring stereogenic center (the
fluorine-bearing carbon). The chemical yields of all experi-
1694
Org. Lett., Vol. 8, No. 8, 2006

ments were high within 15 min (entries 1-5), and finally
we decided to choose the reaction condition of entry 5 as
the standard condition (1.05 equiv of lithium hexamethyl-
disilazide (LHMDS) was added dropwise into the mixture
of 1.0 equiv of 1 and 2 in THF at - 78 °C) to study the
reactions of 2 with other (R)-(tert-butanesulfinyl)imines 1.
The results were summarized in Table 2. A variety of
nucleophilic addition step was performed under the strong
basic condition in the presence of LHMDS, but was still
amenable to sulfinylimines bearing R hydrogen atoms (see
entries 8-10). To ensure that there was no racemization
during the deprotection process, we converted amine salts
5a and 5g into the corresponding benzamide derivatives 6a
and 6g (see Scheme 1). The high optical purity of 6a (98.4%
Scheme 1. Preparation of Benzamide Derivatives 6a and 6g
Table 2. Facile Synthesis of R-Monofluoromethyl Amines
ee) and 6g (98.2% ee) was determined by chiral HPLC,
indicating that the current synthetic method promises to be
a general and convenient approach for the preparation of
enantiomerically pure R-monofluoromethylamines.
Taking into consideration that the (phenylsulfonyl)fluoro-
methylated sulfinamide anion species (the nitrogen-anion
species of 4) generated from the first nucleophilic addition
step (before protonation) could further attack other electro-
philic sites, we synthesized the tosylate (OTs)-bearing (R)-
(tert-butanesulfinyl)imines 1k and 1l and applied them in a
nucleophilic addition-substitution tandem reaction (see
Scheme 2).16 To our satisfaction, R-(phenylsulfonyl)fluoro-
Scheme 2. Synthesis of R-Monofluoromethylated Cyclic
Amines
a The synthesis of 5 from 1 was carried out in three continuous steps
without purification of the intermediate products such as (phenylsul-
fonyl)fluoromethylated sulfinamides 4. b Both the facial selectivity data and
the yield (for the first step) of 4 were determined by 19F NMR spectroscopy.
c Isolated overall yield of 5 from 1. The configurations of 5 were assigned
from the X-ray structure of 4a and the transition state models.
methylated cyclic amines formed smoothly with excellent
stereoselectivity (in both cases, facial selectivity ) 99:1),
which were further converted into corresponding homochiral
R-monofluoromethylated pyrrolidine 5k and piperidine 5l in
52% and 71% overall yield, respectively.
structurally diverse (R)-(tert-butanesulfinyl)imines 1 reacted
with (phenylsulfonyl)fluoromethyl anion (generated in situ
from 2 and LHMDS) to give the corresponding (phenylsul-
fonyl)fluoromethylated homochiral sulfinamides 4 in excel-
lent chemical yields (for the first step) with high stereose-
lectivity (facial selectivity ) 99:1 or 98:2). Without
purification, compounds 4 were readily converted into
R-monofluoromethylamine salts 5 in good overall yields via
reductive desulfonylation (with Na-Hg in methanol) and
removal of the tert-butanesulfinyl group (with HCl in
dioxane).13 It is still noteworthy to mention that the first
In conclusion, the unprecedented nucleophilic monofluoro-
methylation of N-(tert-butanesulfinyl)imines with fluoro-
methyl phenyl sulfone has been shown to be a highly
stereoselective and convenient method for the synthesis of
enantiomerically pure R-monofluoromethylamines. The same
methodology can also be used to synthesize homochiral
R-monofluoromethylated cyclic secondary amines by using
tosylate (OTs)-bearing (R)-(tert-butanesulfinyl)imine precur-
(16) The same experimental procedures were applied as those for Table
2, except that 1.2 equiv (instead of 1.0 equiv) of 1k and 1l were used.
Org. Lett., Vol. 8, No. 8, 2006
1695

sors. The application of the present synthetic methodology
in the synthesis of biologically interesting molecules is
currently under investigation in our laboratory.
(Hundreds-Talent Program) and the National Science Foun-
dation of China (20502029) for funding.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This paper is dedicated to Professor
G. K. Surya Prakash on the occasion of his receipt of the
2006 George A. Olah Award in Hydrocarbon or Petroleum
Chemistry. We thank the Chinese Academy of Sciences
OL060322T
1696
Org. Lett., Vol. 8, No. 8, 2006