Asymmetric aza-Henry reaction of chiral fluoroalkyl α,β- unsaturated N-tert-butanesulfinyl ketoimines: An efficient approach to enantiopure fluoroalkylated α,β-diamines and α,β-diamino acids

Article abstract of DOI:10.1039/c1ob05132f

The aza-Henry reaction of chiral fluoroalkyl α,β-unsaturated N-tert-butanesulfinyl ketoimines and nitromethane was achieved in the presence of 0.2 equivalent of anhydrous potassium carbonate to give the corresponding adducts diastereoselectively in high yields. Transformations which highlighted the synthetic potential of these aza-Henry adducts were also performed.

Full text of DOI:10.1039/c1ob05132f

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Asymmetric aza-Henry reaction of chiral fluoroalkyl a,b-unsaturated
N-tert-butanesulfinyl ketoimines: an efficient approach to enantiopure
fluoroalkylated a,b-diamines and a,b-diamino acids†
Fan Zhang, Zhen-Jiang Liu and Jin-Tao Liu*
Received 25th January 2011, Accepted 23rd March 2011
DOI: 10.1039/c1ob05132f
The aza-Henry reaction of chiral fluoroalkyl a,b-unsaturated
N-tert-butanesulfinyl ketoimines and nitromethane was
achieved in the presence of 0.2 equivalent of anhydrous
potassium carbonate to give the corresponding adducts
diastereoselectively in high yields. Transformations which
highlighted the synthetic potential of these aza-Henry adducts
were also performed.
Owing to the unique properties of fluorine, the introduction of a
fluoroalkyl group into organic compounds could bring profound
changes to their physical, chemical and biological properties.8
Accordingly, the development of methods for the asymmetric
synthesis of chiral fluoroalkylated diamines is of great significance,
and the aza-Henry reaction of fluoroalkyated imines might be
a simple and convenient approach. However, this attempt met
with a big challenge because most fluoroalkylated imines are
unstable at room temperature or suffer from easily hydrolyzing
or decomposing during work-up. Recently, it was found in our
group that different from usual fluoroalkylated N-sulfinyl imines,
fluoroalkyl a,b-unsaturated N-tert-butanesulfinyl ketoimines, de-
rived from fluoroalkyl a,b-unsaturated ketones, were quite stable
at room temperature and could be converted to the corresponding
allylic amines diastereoselectively by asymmetric reduction with
DIBAL-H or L-Selectride.9 Further studies showed that the aza-
Henry reaction of these stable fluoroalkylated imines occurred
readily in the presence of catalytic amount of anhydrous potas-
sium carbonate under mild conditions, giving the corresponding
adducts diastereoselectively in good to excellent yields. This is the
first example of aza-Henry reaction of fluoroalkylated imines and
the first systematic investigation on aza-Henry reaction of N-tert-
butanesulfinyl ketoimine. The results are reported in this paper.
1. Introduction
Aza-Henry reaction (nitro-Mannich reaction), which involves the
nucleophilic addition of nitroalkanes to imines and related com-
pounds, is a powerful synthetic method that allows the creation
of a carbon-carbon bond with concomitant generation of two
vicinal stereogenetic centers bearing nitro and amino functional
groups.1 The resulting b-nitroamines are attractive targets in
asymmetric synthesis mainly due to their easy conversions to a-
amino acids or vicinal diamines via Nef-reaction2 or the reduction
of nitro group.3 Additionally, the two nitrogenated functions are
present in different oxidation states, thus giving access to further
transformations with complete chemoselectivity.1
Although catalytic asymmetric synthesis has undergone tremen-
dous growth in the last decade, chiral auxiliary-aided asymmetric
synthesis continues to attract considerable attention. Chiral N-
sulfinamides are undoubtedly of the most efficient auxiliaries
to date.4 In 2005, Garc´ıa Ruano et al. reported their research
on asymmetric aza-Henry reaction of N-p-tolylsulfinylimines, in
which excellent yield and selectivity were achieved.5 Two years
later, Terada reported organic base catalyzed aza-Henry reac-
tion of the very same imines, but poor diastereoselectivity was
obtained.6 However, to our best knowledge, there is no report
on the chiral N-tert-butanesulfinamide aided aza-Henry reaction
until now, despite tert-butanesulfinamide is another well developed
chiral auxiliary except for p-tolylsulfinylamide.7
2. Results and discussion
We embarked on our investigation by searching appropriate
catalyst for the reaction of chiral (R)-N-tert-butanesulfinyl tri-
fluoromethyl vinylketoimine (1a) with nitromethane. As shown in
Table 1, the catalyst had a crucial effect on both diastereoselectivity
and yield. Organic bases were not suitable for this reaction. When
strong guanidine base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) or 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), was used,
aza-Henry adduct 2a was obtained in moderate yield with low
diastereoselectivity (entries 1–2). In the presence of 0.2 equivalent
of 1,4-diazabicyclo[2.2.2]octane (DABCO), which is less basic
than DBU and TBD and was expected to decrease side reactions,
the reaction was sluggish and low conversion was observed with
low diastereoselectivity and yield (entry 3).
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai,
200032, China. E-mail: jtliu@sioc.ac.cn; Fax: +86-21-64166128; Tel: +86-
21-54925188
† Electronic supplementary information (ESI) available. CCDC reference
number 756867. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob05132f
Both as fluoride ionic compounds, tetra-n-butylammonium
fluoride (TBAF) and potassium fluoride (KF) gave contrasting
results. While 95% de value and 59% yield were obtained in the
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Table 1 The aza-Henry reaction of 1a under various catalysts
a
Entry
Catalyst (eq)
Time (h)
Conversion (%)a
Yield (%)b
2a:2a¢
1
2
3
4
5
6
7
8
9
DBU (0.4)
TBD (0.2)
3
3
12
48
12
6
3
3
48
100
100
47
45
69
34a
—
59
86
98
55
28
53 : 47
71 : 29
79 : 21
—
>95 : 5
95 : 5
>95 : 5
87 : 13
>95 : 5
DABCO (0.2)
Bu4NF (0.2)
KF (0.2)
KOH (0.2)
K2CO3 (0.2)
Cs2CO3 (0.2)
Na2CO3 (0.2)
0
100
100
100
100
35
a Determined by 19F NMR of the reaction mixture; b Isolated yield of 2a and 2a¢.
presence of KF (entry 5), no aza-Henry product was obtained
with TBAF (entry 4). Comparing these results, we speculated
that potassium ion might play an important role in the reaction.
Therefore several inorganic bases were tried next (entries 6–9). It
was found that potassium carbonate was the best catalyst for the
reaction among all bases tested (entry 7).
The absolute configuration of 2 was confirmed by X-ray crystallo-
graphic analysis of 2a.10 Ketoimines with aromatic substitutions at
the b-position were proved to be excellent substrates for this reac-
tion (entries 1–4). The reaction also tolerated alkyl substituent at
the b-position, giving excellent diastereoselectivity albeit moderate
yield (entry 5). The fluoroalkyl group in ketoimines had a profound
effect on the reaction. While chlorodifluoromethylated ketoimine
1f afforded the corresponding aza-Henry adduct in good yield with
excellent diastereoselectivity, hydrodifluoromethylated ketoimine
1g exhibited decreases both in yield and diastereoselectivity (en-
tries 6–7). Furthermore, it is noteworthy that perfluoropropylated
ketoimine 1h gave 1,4-adducts 2h-1 and 2h-2 in a ratio of about
40 : 60 (Scheme 1). Only one diastereoisomer was observed for
either 2h-1 or 2h-2. The reason is still unknown.
To further demonstrate the effect of the fluoroalkyl substituent
on the reaction, the aza-Henry reaction of non-fluoro ketoimine 1i
and 1j were also investigated under similar conditions (Scheme 2).
In the presence of 1.0 equivalent of potassium carbonate, no
reaction occurred after 3 days in both cases, indicating that
the presence of strong electron-withdrawing fluoroalkyl group is
crucial for the success of this reaction.
To further improve the reaction, solvents with different polarity
were further screened. It was found that the polarity of solvent
held a significant impact on the reaction. As shown in Table 2, no
conversion of 1a was observed after stirring in non-polar solvent
toluene for 3 days (entry 1). Good yield and diastereoselectivity
were obtained in both dichloromethane and nitromethane, but
the reaction in nitromethane proceeded much faster than in
dichloromethane (entries 2–3). Using acetonitrile as solvent led
to full conversion and excellent diastereoseletivity but moderate
yield (entry 4). In high polar dimethylsulfoxide (DMSO), more by-
products were formed and 2a was obtained in low yield (entry 5).
Under the optimized conditions (0.2 equiv. anhydrous potas-
sium carbonate in nitromethane at room temperature), the
reaction of various fluoroalkyl a,b-unsaturated (R)-N-tert-
butanesulfinyl ketoimines was investigated to probe the generality
of this reaction.10 The results are summarized in Table 3. In most
cases, the (RS,S)-diastereoisomer of the corresponding aza-Henry
adduct was obtained in high yields with high diastereoselectivities.
Fluoroalkylated b-nitroamines 2 obtained in the above re-
action are versatile multifunctional fluorine-containing building
blocks. To demonstrate their synthetic potentials, 2a was further
Table 2 The aza-Henry reaction of 1a catalyzed by potassium carbonate in various solvents
b
Entry
Solvent
Dielectric constanta
Time (h)
Conversion (%)b
Yield (%)c
2a:2a¢
1
2
3
4
5
Toluene
CH2Cl2
CH3NO2
CH3CN
DMSO
2.4
9.1
39.4
37.5
55.0
72
12
3
3
3
0
—
—
100
100
100
100
>95
>95
59
>95 : 5
>95 : 5
>95 : 5
n.d.d
47
a Dielectric constants under 20 ◦C; b Determined by 19F NMR of the reaction mixture; c Isolated yield of 2a and 2a¢; d Not determined.
3626 | Org. Biomol. Chem., 2011, 9, 3625–3628
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Table 3 The aza-Henry reaction of 1 catalyzed by potassium carbonate in nitromethane
Entry
1
R1
R2
2
Dra
Yield (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
CF3
CF3
CF3
CF3
CF3
CF2Cl
CF2H
C6H5
2a
2b
2c
2d
2e
2f
> 95 : 5
> 95 : 5
95 : 5
> 95 : 5
> 95 : 5
> 95 : 5
72 : 28
85
95
91
91
68
80
54
4-CH3OC6H4
4-ClC6H4
1-Naphthyl
n-C8H17
C6H5
1g
C6H5
2g
a Determined by 19F NMR; b Isolated yield of 2.
Scheme 1
access to a-fluoroalkyl amino acids have been developed, there are
few reports on the asymmetric synthesis of a-trifluoromethylated
diamino acid derivatives.11 To our best knowledge, the only report
about the synthesis of chiral fluoroalkylated a,b-diamino acid was
contributed by Uneyama in 2003 in which aziridinyl anion was
utilized as a precursor.12
With optically pure 4a in hand, we next performed the synthesis
of 8a (Scheme 4). Through a four-step procedure involving the pro-
tection of amino groups, the oxidation of double bond with ozone,
the oxidation of aldehyde with sodium chlorite, and the removal
of protecting group, 8a was obtained in high overall yield. This
provided an efficient and practical access to either enantiomer of
a-fluoroalkyl-a,b-diamino acids since the other enantiomer could
potentially be obtained by utilizing (SS)-tert-butanesulfinamide as
auxiliary rather than (RS)-tert-butanesulfinamide.
Scheme 2
transformed to its corresponding trifluoromethyl diamine 4a
(Scheme 3). Treatment of 2a with ethereal solution of hydrogen
chloride, followed by reduction with zinc powder, gave enantiopure
diamine 4a in 69% overall yield with 99.3% ee (determined by
HPLC).
Scheme 3
a-Fluoroalkyl a,b-diamino acids are extremely interesting
anologues of natural a-amino acids owing to the unique properties
of fluoroalkyl group, such as high electronegativity, electron
density, steric hindranceand hydrophobic character.8 However, the
relatively difficult availability of most a-fluoroalkyl amino acids
in enantiopure form, whose asymmetric synthesis often requires
complex experimental protocols and hard to handle starting
materials, obstructs a systematic investigation on the biomedicinal
and structural features of a-fluoroalkyl amino acids and their
peptidic derivatives. Although a number of procedures which give
Scheme 4
3. Conclusion
In summary, the aza-Henry reaction of chiral fluoroalkylated
a,b-unsaturated N-tert-butanesulfinyl ketoimines was achieved
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for the first time under mild conditions, providing a highly
efficient method for the asymmetric synthesis of fluoroalkylated b-
nitroamines with high diastereoselectivities. Further conversions
of these fluoroalkylated b-nitroamines to both fluoroalkylated
diamines and fluoroalkylated diamino acids were also illustrated.
Given the abundance of biologically active compounds, valuable
building blocks, chiral auxiliaries and metal ligands that contain
the fluoroalkylated diamine moiety, this method should find wide
application in the asymmetric synthesis of a range of substituted
derivatives.
6 N. K. Pahadi, H. Ube and M. Terada, Tetrahedron Lett., 2007, 48,
8700.
7 There is only one report involving the aza-Henry reaction ofN-tert-
butanesulfinyl aldimine: J. Weng, Y.-B. Li, R.-B. Wang, F.-Q. Li, C.
Liu, A. S. C. Chan and G. Lu, J. Org. Chem., 2010, 75, 3125.
8 (a) B. E. Smart, J. Fluorine Chem., 2001, 109, 3; (b) Biomedical Frontiers
of Fluorine Chemistry (ed., I. Ojima, J. R. McCarthy and J. T. Welch),
ACS, Washington, 1996; (c) P. N. Edwards, in Organofluorine Chem-
istry: Principles and Commercial Applications (ed., R. E. Banks and
J. C. Tatlow), Plenum Press, New York, 1994; (d) Organofluorine
Compounds in Medicinal Chemistry and Biochemical Applications (ed.,
R. Filler, Y. Kobayashi and L. Agupolskii, Elsevier, Amsterdam, 1993.
9 Z.-J. Liu and J.-T. Liu, Chem. Commun., 2008, 5233.
10 Typical procedure for the synthesis of 2a: Potassium carbonate
anhydrous (2.8 mg, 0.02 mmol) was added to a solution of 1a
(30.0 mg, 0.1 mmol) in nitromethane (0.5 mL) at room tem-
Acknowledgements
perature. The reaction mixture was stirred for
3 h. After re-
We thank the National Natural Science Foundation of China for
financial support (No. 20872166).
moval of the volatile solvent under vacuum, 2a was obtained
via silica gel chromatography (Petroleum Ether/EtOAc = 5/1) in
85% yield (31.0 mg). (E)-2-methyl-N-(1,1,1-trifluoro-2-(nitromethyl)-4-
phenylbut-3-en-2-yl)propane-2-sulfinamide (2a) Colorless crystal, yield
85%; mp: 72–74 ◦C; IR (film): n 3306, 3285, 2962, 1560, 1471, 1368,
1397, 1185, 1124, 1081, 1054 cm-11H NMR (300 MHz, CDCl3): d 7.48–
7.36 (m, 5 H), 6.91 (d, J = 16.2 Hz, 1 H), 6.30 (d, J = 16.2 Hz, 1 H), 5.45
(s, 1H), 5.08–4.99 (m, 2 H), 1.32 (s, 9 H); 19F NMR (282 MHz, CDCl3):
d -76.4 (s, 3 F); MS (ESI, m/z,%): 365 [M+1]+; Anal. Calcd. For
C15H19F3N2O3S: C, 49.44; H, 5.26; N, 7.69. Found: C, 49.24; H, 5.37; N,
7.56. The chiral HPLC analytical data: chiralpak IC column, detected
at 214 nm, eluent: n-hexane/iso-propanol = 60/40, 0.7 mL min-1,
retention times: tr (minor) = 5.85 min, tr (major) = 6.19 min; ee% =
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3628 | Org. Biomol. Chem., 2011, 9, 3625–3628
This journal is
The Royal Society of Chemistry 2011
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