Novel approach for asymmetric synthesis of fluorinated β-amino sulfones and allylic amines

Article abstract of DOI:10.1021/ol034892u

(Matrix presented) Enantiomerically pure γ-fluoroalkyl β-amino sulfones are readily synthesized in three steps starting from fluorinated imidoyl chlorides and arylmethyl sulfones. A complementary two-step sequence starting from chiral fluorinated β-amino

Full text of DOI:10.1021/ol034892u

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2707-2710
Novel Approach for Asymmetric
Synthesis of Fluorinated â-Amino
Sulfones and Allylic Amines
Santos Fustero,* Juan Garc´ıa Soler, Ana Bartolome´, and Mar´ıa Sa´nchez Rosello´
Departamento de Qu´ımica Orga´nica, Facultad de Farmacia, UniVersidad de Valencia,
E-46100 Burjassot (Valencia), Spain
santos.fustero@uV.es
Received May 21, 2003
ABSTRACT
Enantiomerically pure γ-fluoroalkyl â-amino sulfones are readily synthesized in three steps starting from fluorinated imidoyl chlorides and
arylmethyl sulfones. A complementary two-step sequence starting from chiral fluorinated â-amino sulfoxides has also been developed. To
illustrate the application of this procedure, a new method for the synthesis of r-fluoroalkyl allylic amines in optically pure form involving a
Julia methylenation−desulfonylation reaction is presented.
Optically pure â-amino sulfones, readily available from
serine1a and other R-amino acid derivatives,1b have demon-
strated their utility in asymmetric synthesis. In particular,
they are useful in the preparation of cyclic and acyclic
nonproteinogenic R-amino acids,1 peptide isosteres,1b,2 natural
products such as alkaloids3 and carbohydrate derivatives,4
and other systems with diverse pharmacological properties.5
Other procedures involving these compounds, including
stereoselective additions of sulfonyl carbanions to chiral
N-sulfinyl imines6 and intramolecular7 and intermolecular8,9
aza-Michael additions to R,â-unsaturated sulfones, have also
appeared in the literature.
The introduction of fluorine in organic molecules has been
shown to cause changes in the reactivity and pharmacology
of the containing molecules, thus providing new insight into
these processes.10 It is worth noting that although the
synthesis of nonfluorinated â-amino sulfones is relatively
well-documented in the literature, very little has been
published about the corresponding fluorinated derivatives,
either in the racemic or in the chiral nonracemic versions.
In this Letter, we report on two simple and complementary
methods of synthesis of chiral nonracemic fluorinated
â-amino sulfones 5 using imidoyl halides 1 as fluorinated
building blocks.11 Application of this methodology to the
asymmetric synthesis of N-aryl allylic amines 7 is also
described.
(1) (a) Wang, Q.; Tran Huu Dau, M.-E.; Sasaki, N. A.; Potier, P.
Tetrahedron 2001, 57, 6455-6462 and references therein. (b) Lehman de
Gaeta, L. S. Czarniecki, M.; Spaltenstein, A. J. Org. Chem. 1989, 54, 4004-
4005.
(2) Paik, S.; White, E. H. Tetrahedron Lett. 1996, 37, 4663-4366.
(3) Knight, D. W.; Sibley, A. W. Tetrahedron Lett. 1993, 34, 6607-
6610.
(4) Ermolenko, L.; Sasaki, N. A.; Potier, P. J. Chem. Soc., Perkin Trans.
1 2000, 2465-2473.
(5) See for example: (a) Rao, A. V. R.; Gurjar, M. K.; Pal, S.; Pariza,
R. J.; Chorghade, M. S. Tetrahedron Lett. 1995, 36, 2505-2508. (b)
Nakamura, H.; Wu, H.; Kobayashi, J.; Kobayashi, M.; Ohizumi, Y.; Hirata.
Y. J. Org. Chem. 1985, 50, 2494-2497.
(8) See, for example: (a) Alonso, D. A.; Costa, A.; Manchen˜o, B.; Na´jera,
C. Tetrahedron 1997, 53, 4791-4814. (b) Wu, J.-C.; Pathak, T.; Tong,
W.; Vial, J-M.; Remaud, G.; Chattopadhyaya, J. Tetrahedron 1988, 44,
6705-6722.
(9) (a) Enders, D.; Mu¨ller, S. F.; Raabe G. Angew. Chem., Int. Ed. 1999,
38, 195-197. (b) Enders, D.; Mu¨ller, S. F.; Raabe G.; Runsink, J. Eur. J.
Org. Chem. 2000, 879-892.
(10) For an overview, see: (a) Banks, R. E.; Tatlow, J. C.; Smart, B. E.;
Organofluorine Chemistry: Principles and Commercial Aplications; Ple-
num: New York, 1994. (b) Organofluorine Compounds; Houben Weyl
Methods of Organic Chemistry, ed. E10a-c; Georg Thieme Verlag: Stuttgart,
2000, Workbench. (c) Fluorine-Containing Amino Acids: Synthesis and
Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester,
1995. (d) Enantiocontrolled Synthesis of Fluoro-organic Compounds;
Soloshonok, V. A., Ed.; Wiley: Chichester, 1999.
(6) (a) Kumareswaran, R.; Balasubramanian, T.; Hassner, A. Tetrahedron
Lett. 2000, 41, 8157-8162. (b) Balasubramanian, T.; Hassner, A. Tetra-
hedron: Asymmetry 1998, 9, 2201-2205.
(7) (a) Carretero, J. C.; Go´mez Arraya´s, R. Synlett 1999, 49-52. (b)
Carretero, J. C.; Go´mez Arraya´s, R. J. Org. Chem. 1998, 63, 2993-3005.
10.1021/ol034892u CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/03/2003

Table 1. Synthesis of Fluorinated â-Imino Sulfones 3 and â-Amino Sulfones 4 and 5
entry
RF
Ar
R1
3 or 4 yield (%)a
reduction conditionsb
l-4:u-4c
5 (%)a
1d
2
3e
4f
5
6
7
8
9
10
11
12h
13
14
15
16
CF3
CF3
CF3
CF3
CF3
CF3
CClF2
CClF2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF2Ph
C6H5
C6H5
(S)-C6H5(Me)CH
(S)-C6H5(Me)CH
(S)-C6H5(Me)CH
(S)-C6H5(Me)CH
(S)-C6H5(Me)CH
(S)-C6H5(Me)CH
(S)-C6H5(Me)CH
(S)-C6H5(Me)CH
(()-R-C10H7(Me)CH
(()-R-C10H7(Me)CH
(()-R-C10H7(Me)CH
(()-R-C10H7(Me)CH
(()-R-C10H7(Me)CH
(()-R-C10H7(Me)CH
p-MeOC6H4
3a (84)
4a (>99)
4a (>99)
4b (>99)
4b (>99)
4c (>99)
4c (95)
4d (>99)
4e (>99)
4f (>99)
4g (>99)
4g (93)
4h (>99)
4h (94)
4h (>99)
4i (>99)
4j (>99)
EtOH, 40 h, 25°C
EtOH, 48 h, -20°C
70:30
73:27
76:24
77:23
77:23
79:21
79:21
81:19
83:17
82:18
85:15
89:11
93:7
(S)-5a (90)
p-MeC6H4
p-MeC6H4
â-C10H7
â-C10H7
â-C10H7
p-MeC6H4
C6H5
â-C10H7
â-C10H7
R-C10H7
R-C10H7
R-C10H7
C6H5
3b (82)
3c (90)
THF/MeOH, 72 h, 25°C
THF/MeOH, 96 h, -20°C
THF/MeOH, 72 h, 25°C
EtOH, 96 h, -20°C
THF/MeOH, 96 h, 25°C
THF/MeOH, 96 h, 25°C
THF/MeOH, 72 h, 25°C
THF/MeOH, 72 h, 25°C
EtOH, 96 h, -20°C
EtOH, 48 h, 25°C
EtOH, 72 h, -20°C
EtOH, 240 h, -40°C
THF/MeOH, 0.5 h, 0°C
THF/MeOH, 0.5 h, 0°C
3d (93)
3e (88)
3f (72)
3g (68)
(R)-5bg (92)
(()-5a (80)
3h (94)
(()-5c (97)i
96:4
3i (87)
3j (77)
C6H5
p-MeOC6H4
a Isolated overall yields. b NaBH4 (10 equiv) was used as reducing agent except for entries 15 and 16 [NaBH4 (3.0 equiv)]. c Determined upon examination
of 19F NMR data of the crude reaction mixture. d THF/MeOH as solvent, 72 h, 25 °C, l-4a:u-4a 70:30, >99%. e Similar results have been obtained starting
from (R)-3b [l-4b:u-4b 74:26, >99%]. f EtOH as solvent, 96 h, -20 °C, l-4b:u-4b 78:22, >99%. g (S)-5b was obtained from (2S,RS)-6b in two steps (overall
yield 45%) (see Scheme 2). h THF/MeOH as solvent, 72 h, 25 °C, l-4h:u-4h 90:10, >99%. i The pure enantiomer (S)-5c ([R] +11.5 (c 0.62, HCCl3)) was
also prepared from (2S,SS)-6a in two steps (overall yield 65%) (see Table 2 and Scheme 2).
It should be mentioned that, although the diastereoselective
reduction of â-imino sulfones12 represents a simple and direct
way to synthesize â-amino sulfones, the correct utilization
of this strategy requires the presence of a stereocenter in the
imino nitrogen substituent. Our strategy, illustrated in Scheme
1, entails the initial preparation of chiral fluorinated â-imino
yields (68-94%, Table 1) and results in the isolation of
compounds 3 as a tautomeric imino/enamino mixture.14 In
the second step, compounds 3 are then stereoselectively
reduced to the corresponding â-amino sulfones 4. Use of
NaBH4 as reducing agent and ethanol or THF/methanol as
solvent seems to provide the best diastereocontrol (dr up to
92%, Table 1). Chromatographic separation of the predomi-
nant diastereoisomer (l-4 in Scheme 1) followed by hydro-
genolysis over palladium on carbon of the chiral amino
nitrogen substituent furnishes enantiomerically pure â-amino
sulfones 5 in high yields15 (Scheme 1).
Scheme 1a
Table 1 summarizes selected results obtained for the
synthesis of â-amino sulfones 4 and 5 under different
conditions. The observed selectivity was affected by the size
of the aromatic substituents, particularly those on the imino
nitrogen grouping. The larger R-naphthyl group in R1
provided a higher diastereocontrol than the smaller phenyl
group (entries 1-14, Table 1). Lowering the reaction
temperature improved the diastereoselectivity, albeit only
slightly. In the end, 4h was the compound for which the
optimal yield and diastereomeric ratio was obtained (entries
12-14, Table 1).
(11) (a) Fustero, S.; Pina, B.; Salavert, E..; Navarro, A.; Ram´ırez de
Arellano, C.; Simo´n, A. J. Org. Chem. 2002, 67, 4667-4679. (b) Fustero,
S.; Garc´ıa de la Torre, M.; Pina, B.; Simo´n, A. J. Org. Chem. 1999, 64,
5551-5556.
(12) Very little about the preparation of such compounds has appeared
in the literature. See, for example: (a) Field, L.; Lawson, J. E.; McFarland,
J. W. J. Am. Chem. Soc. 1956, 78, 4389-4394. (b) Muraoka, M.;
Yamamoto, T.; Ebisawa, T.; Kobayashi, W.; Takeshima, T. J. Chem. Soc.,
Perkin Trans. 1 1978, 1017-1022.
a (a) LDA (2.0 equiv), THF, -78 °C. (b) NaBH4 (10.0 equiv),
for solvent, temperature, and reaction time, see Table 1. (c) H2
(1 atm), Pd/C (10%), MeOH, 25 °C, 48 h for 5a,b and H2 (20 bar),
Pd/C (10%), HCl/MeOH, 25 °C, 20 days for 5c.
(13) Tamura, K.; Mizukami, H.; Maeda, K. Uneyama, K. J. Org. Chem.
1993, 58, 32-36.
(14) Fustero, S.; Navarro, A.; Pina, B.; Asensio, A.; Bravo, P.; Cru-
cianelli, M.; Volonterio, A.; Zanda, M. J. Org. Chem. 1998, 63, 6210-
6219.
(15) More drastic reaction conditions were necessary in the case of 5c
(see Scheme 1).
sulfones 3, which can be easily carried out via a reaction of
fluorinated chiral imidoyl chloride 113 with the appropriate
sulfonyl carbanion. The process produces generally high
2708
Org. Lett., Vol. 5, No. 15, 2003

To test the general applicability of this reaction, we
examined the reduction of N-aryl â-imino sulfones. The
reduction took place in minutes and quantitatively afforded
the corresponding racemic N-aryl â-amino sulfones 4i,j
(entries 15 and 16, Table 1).
These same compounds, however, can also be obtained
in enantiomerically pure form when chiral N-aryl â-amino
sulfoxides 6 are used as the starting material16 (see scheme
in Table 2). Thus, MCPBA-oxidation of N-PMP-protected
spectroscopic data, and unfortunately we were not able to
obtain adequate single crystals for X-ray crystallographic
analysis of N-alkyl â-amino sulfones 4 (Scheme 1). There-
fore, the configuration of the newly created stereocenter in
4 was determined by means of chemical correlation (Scheme
2). In this fashion, using the chemical methods described
above, compound (S)-3e was easily converted into (R)-5b
in high yield. In a separate process, enantiomerically pure
(S)-5b was prepared in two steps from chiral â-amino
sulfoxide (2S,RS)-6b via MCPBA-oxidation followed by
deprotection of the PMP group (vide supra and Scheme 2).
Comparison of the obtained [R]D values in the two pathways
(see Scheme 2) allowed us to assign as R (S when RF )
CF3, see Table 1 and Figure 1) the configuration of the newly
created center in 4e, that is, (2R,2′S)-4e.
Table 2. Fluorinated N-Aryl â-Amino Sulfones 4 Obtained by
Oxidation of â-Amino Sulfoxides 6
entry
6a
RF
Ar
product yield (%)b
1
2
3
(2S,Ss)-6a
(2S,Rs)-6b CClF2 p-MeC6H4
(2S,Ss)-6c C2F5 R-C10H7
CF3
R-C10H7
(S)-4k
(S)-4l
(S)-4m
83
75
45
a R1 ) p-MeOC6H4 (PMP) in all cases. b Isolated yield.
derivatives 6 cleanly afforded the corresponding N-aryl
â-amino sulfones 4k-m (Table 2), which were then con-
verted into enantiomerically pure â-amino sulfones 5 by
oxidative cleavage (CAN, 5 equiv) of the PMP group
(Scheme 2).
Figure 1.
Taking these results into consideration, we can explain
the formation of the major diastereoisomer l-4 [i.e., (2S,2′S)-
4a] by assuming that hydride attacks the imino carbon from
the opposite side (re face) of the R-methyl group (ul-1,3-
addition),17 as depicted in Figure 1.
Scheme 2. Determination of Absolute Configuration of 5
This methodology has remarkable potential for the prepa-
ration of fluorine-containing amino derivatives. With this in
mind, we applied the strategy described above to the
synthesis of enantiomerically pure R-fluoroalkyl allylic
amines (Table 3).
Allylic amines are recognized as versatile building blocks
for the preparation of a variety of synthetically and biologi-
cally important organic derivatives.18 However, although
much effort has been devoted to the study of nonfluorinated
allylic amines, very little is known about the synthesis and
reactivity of their fluorinated counterparts.19
Furthermore, descriptions of the preparation of these
derivatives in enantiomerically pure form are rare in the
(16) Compounds 6 were easily prepared, in two steps, from fluorinated
imidoyl chlorides and arylmethyl sulfoxides. See: Fustero, S.; Navarro,
A.; Pina, B.; Garc´ıa Soler, J.; Bartolome´, A.; Asensio, A.; Simo´n, A.; Bravo,
P.; Fronza, G.; Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621-2624.
(17) Ab initio molecular orbital (MO) calculations (HF/6-31G*) for (S)-
3a predict the (Z)-imino geometry as the most stable tautomer [Erel (kcal
mol-1): imino (Z)-(S)-3a 0.0; imino (E)-(S)-3a 10.7; enamino (Z)-(S)-3a
9.2].
(18) For reviews, see: (a) Johannsen, M.; Jørgensen, K. A. Chem. ReV.
1998, 98, 1689-1708. (b) Cheikh, R. B.; Chaabouni, R.; Laurent, A.; Mison,
P.; Nafti, A. Synthesis 1983, 685-700. (c) Stu¨tz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 320-328. For other recent examples, see: (d) Evans,
P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761-
6762. (e) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001,
123, 1004-1005. (f) Katritzky, A. R.; Cheng, D.; Li, J. J. Org. Chem. 1998,
63, 3438-3444.
The stereochemical outcome of the CdN bond reduction
could not be determined upon simple examination of the
Org. Lett., Vol. 5, No. 15, 2003
2709

of γ-fluoroalkyl allylic amines by means of enantiospecific
Pd-catalyzed allylic substitution of nonracemic mesylates.20b
Table 3. Fluorinated Allylic Amines 7 Obtained from Amino
Sulfones 4
Our approach consists of a Julia-type methylenation-
desulfonylation reaction21 of â-amino sulfones 4 (R1 ) PMP).
Treatment of compounds 4 with 2 equiv of n-butyllithium
at -78 °C followed by consecutive addition of ClCH2I (1.0
equiv) and methyllithium (1.0 equiv) thus furnished the
organolithium intermediate 8, which underwent spontaneous
â-elimination to afford the corresponding fluorinated allylic
amines 7. The process, which appears in general to be
independent of the RF substituent, works well and generally
takes place with good yields (45-73%). Table 3 summarizes
the obtained results.
In conclusion, we have developed a new and very simple
enantioselective approach to fluorinated â-amino sulfones 5
based on the unprecedented diastereoselective reduction of
chiral â-imino sulfones. An alternative and complementary
two-step strategy to 5 has been accomplished from chiral
â-amino sulfoxides. In addition, the synthetic utility of
â-amino sulfones has been demonstrated in the synthesis of
enantiomerically pure R-fluoroalkyl allylic amines.
entry
compound
RF
CF3
CF3
CClF2
C2F5
Ar
C6H5
R-C10H7
p-MeC6H4
R-C10H7
C6H5
product
yieldb
1
2
3
4
5
(()-4i
(S)-4k
(R)-4l
(S)-4m
(()-4j
(()-7a
(R)-7a
(S)-7b
(R)-7c
(()-7d
73
70
70
45
47c
CF2Ph
a R1 ) p-MeOC6H4 (PMP) in all cases. b Isolated yield (%). c Not
optimized. Starting material (35%) was recovered.
Acknowledgment. The authors thank the Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica (PPQ 2000-
0824) for financial support. J.G.S., A.B., and M.S.R. express
their thanks for predoctoral fellowships.
literature. In fact, to the best of our knowledge only two
examples have been reported: one in 2001, when Prakash,
Olah, et al. reported the first asymmetric synthesis of
R-trifluoromethylated allylic amines via nucleophilic trif-
luoromethylation of chiral R,â-unsaturated sulfinimines,20a
and more recently, when Konno developed a new synthesis
Supporting Information Available: Experimental pro-
cedures and analytical and spectroscopic data for compounds
3-7. This material is available free of charge via the Internet
at http://pubs.acs.org.
(19) For racemic synthesis, see: (a) Weygand, F.; Steglich, W.; Oettmeir,
W.; Maierhofer, A.; Loy, R. S. Angew. Chem. 1966, 78, 640-640; Angew.
Chem., Int. Ed. Engl. 1966, 5, 600-600. (b) Be´gue´, J.-P.; Bonnet-Delpon,
D.; Rock, M. H. Synlett 1995, 659-660. (c) Xu, Y.; Dolbier, W. R. J.
Org. Chem. 2000, 65, 2134-2137. (d) Prakash, G. K. S.; Mandal, M.; Olah,
G. A. Synlett 2001, 77-78. (e) Sergeeva, N. N.; Golubev, A. S.; Hennig,
L.; Findeisen, M.; Paetzold, E.; Oehme, G.; Burger, K. J. Fluorine Chem.
2001, 111, 41-44. (f) Palacios, F.; Pascual, S.; Oyarzabal, J.; Ochoa de
Retana, A. M. Org. Lett. 2002, 4, 769-772.
OL034892U
(20) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3,
2847-2850. (b) Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org.
Chem. 2002, 67, 1768-1775.
(21) (a) De Lima, C.; Julia, M.; Verpeaux, J.-N. Synlett 1992, 133-
134. (b) Review: Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547-10658.
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Org. Lett., Vol. 5, No. 15, 2003