The enantioselective addition of 1-fluoro-1-nitro(phenylsulfonyl)methane to isatin-derived ketimines

Article abstract of DOI:10.1039/c7ob02408h

An asymmetric organocatalytic addition of fluorinated phenylsulfonylnitromethane to isatin-derived ketimines was developed. The reaction was efficiently catalyzed by a chiral tertiary amine, cinchonine. This methodology provides a new type of optically active compound with two adjacent quaternary carbon stereocenters in good yield (up to 96%), with moderate diastereoselectivity (up to 5.7:1 dr) and excellent enantioselectivity (up to 98/96% ee).

Full text of DOI:10.1039/c7ob02408h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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The Enantioselective Addition of 1-Fluoro-1-
nitro(phenylsulfonyl)methane to Isatin-Derived Ketimines
M. Urban,a M. Franc,a Markéta Hofmanová,a I. Císařová,b and J. Veselý* a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An asymmetric organocatalytic addition of fluorinated into bioactive molecules is an area of high interest.7 However,
phenylsulfonylnitromethane to isatin-derived ketimines was the enantioselective addition reactions of fluor-containing
developed. The reaction was efficiently catalyzed by chiral tertiary nucleophiles to isatin-derived ketimines have been rarely
amine, cinchonine. This methodology provides a new type of describe.8
Beside
α-Fluoro-bis(phenylsulfonyl)methane
optically active compounds with two adjacent quaternary carbon (FBSM)9 also α-fluoro-nitro(phenylsulfonyl)methane (FNSM)
stereocenters in good yields (up to 96%), moderated has been recognized as versatile nucleophile in various
diastereoselectivity (up to 5.7:1 dr) and excellent organocatalytic reactions, as demonstrated by Prakash and
enantioselectivities (up to 98/96% ee).
Olah10 and others.11 In this context, we herein report the
highly
enantioselective
addition
to
of
α-
fluoronitro(phenylsulfonyl)-methane
isatin-derived
Introduction
ketimines under mild organocatalytic conditions affording the
fluoro-containing compounds bearing adjacent quaternary
stereogenic centers.
Preparation of enantiomerically pure organic compounds
bearing a quaternary stereogenic center is one of the most
challenging research areas in asymmetric catalysis.1 In
addition, quaternary 3-amino-2-oxindole moiety is an
ubiquitous motif in natural products and pharmaceutical
Results and Discussion
agent.2 Among the methods developed for the preparation of At the outset we decided to study nucleophilic addition of α-
such compounds, enantioselective addition of nucleophiles to fluoro-nitro(phenylsulfonyl)methane (FNSM, 2a) to tert-
isatin-derived ketimines is straightforward and probably the butyl(1-benzyl-2-oxoindolin-3-ylidene)carbamate (1a) in the
most efficient approach. Easy access to N-Boc isatin imines3 presence of cinchona alkaloids (Figure 1). Initially, the reaction
together with its modulate reactivity towards nucleophiles and was performed with 1a and 2a in 1:1.1 ratio at room
facile removal of Boc protection group from the adducts have temperature in toluene (Table 1, Entry 1). It provided the
made those imines as attractive substrates for a number of desired adduct 3a/3a’ within few hours in high yields (varying
catalytic addition reactions.4 Not only metal-based complexes from 93 to 98 %) and moderate diastereoselectivity (up to
(Pd, Rh, Ni,)5 but also small organic molecules (H-bonding 3.5:1). Unfortunately, the obtained enantiomeric purity of 3a
donors) can effectively catalyze those processes. To date a was unsatisfactory, further screening of the reaction
variety of organocatalytic addition reactions were developed, conditions was required. Initially, we tested the influence of
including Strecker reaction, Mannich reaction and its temperature on the course of the reaction (Table SI 1, ESI).
vinylogous variant, aza-Morita-Baylis-Hillman reaction, Cinchonine (CN, Figure 1) has shown the most promising
cycloadditions and others.6 With the impact in medicinal results in terms of effectivity and enantiocontrol on the model
research and chemical biology, development of efficient reaction performed at lowered temperature (-50 °C, Entry 5).
methods for selective introduction of fluoro-containing groups Full conversion of isatin-derived ketimine 1a was reached
within 18 hours and the adduct 3a was isolated in high yield
(85 %), with moderate diastereoselectivity (3.5:1) and
excellent enantioselectivity of both diastereoisomers (96/95 %
ee). Noteworthy, further decrease of the reaction temperature
led to significant drop of the yield of 3a (Table 1, Entry 6).
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Table 1. Optimization Studies in the Reaction of Ketimine 1a
and FNSM 2a
.
Figure 1. Bifunctional Organocatalysts Screened in the
Reaction of Ketimine 1a with FNSM 2a
.
Next, we focused on the role of the catalyst on enantiomeric
addition of 2a to isatin-derived ketimine 1a with respect to
efficiency and stereoselectivity (Table 2). Beside Cinchona
alkaloids, screened initially, chiral thioureas such as
Takemoto’s bifunctional catalyst
Sharpless bases and squaramides
A
and Soós’s catalysts
D, E were examined in
B, C
Next, we assessed the influence of the solvent in the reaction
of 1a and 2a (Table SI 1, ESI). As shown in Table 1, apart from
toluene, the addition reaction performed well in several
nonpolar chlorinated and etheric solvents, but with lower
diastereo- and enantioselectivity and also yield (Table 2,
Entries 1-6). On the other hand no reaction was observed in
polar protic and aprotic solvents, such as methanol and DMSO.
reaction between 1a and 2b (Figure 1). Surprisingly, none of
the above mentioned organocatalysts catalysed the model
reaction as effectively as cinchonine (Table 3, Entry 1-6, more
details in SI). We also screened the dependence of reaction
efficiency and selectivity on loading of catalysts. Interestingly,
no significant change in selectivity and yield was observed
when 5 mol% of the catalyst was used. On the other hand
Screening of the solvents and temperature is summarized in lowered catalyst loading dramatically influenced reaction time
(Table 3, Entry 9) Reduced yield was observed, when 2.5 mol%
of the catalyst was used, nevertheless, the selectivity of the
reaction retained (Table 3, Entry 10).
ESI (Tables SI 1) in details.
Table 2. Solvent Optimization Studies in the Reaction of
Ketimine 1a with FNSM 2a
.
Once we uncovered optimized reaction conditions for the
enantioselective nucleophilic addition of FNSM to isatin-
derived ketimine 1a, we proceeded with the scope of the
process (Scheme 1). First we studied the reactivity of FNSM
towards ketimines 1a-1h having different protecting groups on
nitrogen of 3-amino-2-oxindole moiety. The desired products
3a/3a´-3g/3g´ were prepared in good yields with high to
excellent enantioselectivity (93-99 % ee for major and 93-95 %
ee for minor diastereoisomer). Moderate degree of
diastereoselectivity (3:1 to 5:1) was obtained in reaction of 2a
with most ketimines 1a-1h. The highest diastereocontrol was
observed in reaction with Boc protected ketamine 1d (dr 5:1).
On the other hand, the reaction between 2a and ketimine 1h
with tosyl protecting group proceeded with low diastereo- (dr
1:1.9) and enantioselectivity (70/75% ee); the corresponding
adduct 3h was isolated in low yield (31 %) as a mixture of
diastereoisomers.
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yield (94 %) with low diastereoselectivity (dr 2.3:1) and
unsatisfactory enantioselectivity (3/32 ee). Both
Table 3. Catalyst Optimization Studies in the Reaction of
%
Ketimine 1a and FNSM 2a
.
subsequential turn of temperature down to -50 °C and also the
change of the solvent from toluene to DCM did not lead
to improved selectivity of the reaction (dr 2.9:1, 30/59 % ee,
Scheme 1).
Scheme 1. Substrate scope of ketimines 1a-p and fluorinated
sulfones 2a-3 in organocatalytic alkylation reaction.
Entry
Time [h] Yield [%]a d.r.b
e.e. [%]c
Catalyst
1
2
Takemoto's
A
18
18
96
96
96
90
89
76
80
85
68
-
3.3:1
3.7:1
5.9:1
4:1
-27/-25
64/56
70/62
35/28
18/47
-75/-16
96/95
96/96
96/95
-
Soós's with QN
Soós's with CD
(DHQ)2AQN
Rawal's with QN
Rawal's with CN
CN (10 mol%)
CN (5 mol%)
CN (2.5 mol%)
-
B
D
20
3
4
24
E
24
4.3:1
4.5:1
3.5:1
3.7:1
3.6:1
-
5
F
168
24
6
7
8
36
9
48
10
168
a Isolated yield after column chromatography. b Determined by 19F NMR
of reaction mixture. c Determined by HPLC analysis of the purified
product for two diastereoisomers.
Subsequently, we focused on ketimine derivatives with
different substitution on the aromatic ring (1i-1o). Substitution
at 5-position on aromatic ring of ketimines led to formation of
corresponding products 3i-3l in high yield (81-95 %) and
excellent enantiomeric excess for both enantiomers (major
diastereoisomer 96-98 % ee, minor diastereoisomer 94-96 %
ee). On the other hand, diastereoselectivity reached moderate
values (dr 3.7:1-5.7:1). Significant change in reactivity was
observed, when ketimine 1o substituted at 4-position with
bromine was used. The formation of the corresponding adduct
3o was not observed even after prolonged reaction time (96
hrs). This can be probably caused due to the higher steric
hindrance of imine group with bulky bromine substituent at 4-
position, because all other adducts 3l, 3m and 3n having
bromine atom at positions 5-,6- and 7 were obtained in high
yields with good levels of enantioselectivity. Replacement of
Boc group for Cbz group on nitrogen of imine moiety led to
considerable drop of enantioselectivity (75/64
% ee).
Corresponding product 3p was obtained in 88 % yield and with
good diastereoselectivity (dr 5.1:1).
Next, we turned our attention to other types of fluorinated
sulfones 2b-e. Nitro group was replaced by various functional
groups such as nitrile, ester, acetyl, phenylcarbonyl group, etc.
In all cases significantly lowered reactivity towards 1a under
optimized reaction conditions (QN, toluene, -50 °C) was
observed. From that reason we approached to set up the
reactions with appropriate sulfones 2b-e at 25 °C. It showed up
that apart from model reaction between 1a and 2a, reactions
proceeded
smoothly
only
with
2-fluoro-2-
(phenylsulfonyl)acetonitrile (2b), affording product 3q in high
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Next, the potential versatility of phenylsulfanyl group as line indicates the intramolecular hydrogen bond N2-H2…O7,
traceless activating group was verified. Standard procedure for N2…O7 2.894(2) Å; angle on H2 138.7°.15
removal of using either Mg failed12 Nevertheless,
On the basis of crystallographic analysis of 3a an envisaged
desulfonation of enantioenriched adducts 3a was
transition-state structure was proposed. As shown in Figure 3,
accomplished using AIBN as a radical agent in the presence of
cinchonine can act as a dual catalyst and activate both reaction
BNAH as hydrogen transfer (Scheme 4).13 α-Fluoronitro alkane
substrates via hydrogen-bonding. Tertiary amine of
4
was isolated in 96% yield as a mixture of diastereoisomers
(dr = 1:1) with retained enantioselectivity (95/96 % ee).
Further, Boc deprotection of 4a 4b was successfully
chinuclidine moiety deprotonates FNSM forming the
corresponding anionic nucleophile, that preferentially
approaches the ketimine from Re-face due to H-bonding of
ketimine and hydroxyl group of cinchonine.
Ph
,
performed using TFA (Scheme 2).14 The corresponding amines
5a and 5b were obtained in good yields 48 % and 47 %,
respectively, with excellent enantiomeric excess (97/96%).
Ph
H
O2S
N
O
O
O
O
S
F
NO2
S
F
NO2
R3N
Scheme 2. Further transformation of alkylation product 3a
.
O
O
F
NO2
HO
R3NH+
N
F
F
F
Boc
Boc
H+N
Q
NO2
H
NO2
H
NO2
NH
NH
Unfavored
Boc
NH
AIBN (0.2 eq.)
BNAH (3.0 eq.)
O
SO2Ph
O
O
+
O
N
N
Toluene,
Temperature
Ph
N
Ph
Ph
Ph
4a
4b
N
F
3a
1:1 dr
R3N
O
Yield [%]b
e.e. [%]c
PhO2S
O
NO2
HO
Entry
Temp. [°C]
Time [h]
N
R3NH+
F
H+N
Q
F
NO2
S
NO2
S
O
O
Favored
O
1a
2
O
O
60
reflux
40
1
1
3
84
62
96
95/94
95/96
95/96
H
Figure 3. Proposed transition state.
3
Conclusion
a
Reaction under microwave radiation. b Isolated yield after column
chromatography. c Determined by HPLC analysis of the purified product for
In summary, we have explored the stereoselective
fluoroalkylation of isatin-derived ketimines with
two diastereoisomers.
F
F
F
α-fluoronitro(phenylsulfonyl) methane. The reaction was
effectively catalyzed with cinchonine furnishing the
corresponding adducts in good yields, good diastereo- (dr up
to 6:1) and high enantioselectivity (up to 98 % ee). The
reactivity of isatin-derived ketimines toward other fluorinated
compounds was also studied. Outcome of the reported
procedure was demonstrated by the preparation of rarely
available β-fluoro-β-nitro amines using desulfonylation/Boc-
removal reaction sequence. Further studies and synthetic
applications based on the reported methodology are currently
ongoing in our group.
NO2
H
NO2
H
NO2
H
Boc
NH
H2N
H2N
TFA
O
O
O
+
N
N
N
DCM,
0 °C to 25 °C
Ph
Ph
Ph
4a + 4b
5a,
5b,
47 %, 96 ee
48 %, 97 ee
1:1 dr
To determine absolute configuration of alkylated products 3a
,
we performed single-crystal X-ray diffraction analysis of 3a
,
obtained from the reaction of ketimine 1a with fluoro-
nitro(phenylsulpfonyl)methane 2a. As shown in Figure 3, the
C3 and C1’ stereogenic centres have (S) and (R) absolute
configuration, respectively.
Acknowledgments
Jan Veselý gratefully acknowledges the Czech Science
Foundation (No 16-23597S) for financial support. Michal Urban
thanks the Charles University Grant Agency (grant number
392315) for financial support. We also thank Dr.
Hybelbauerová for NMR service and Dr. Štícha for MS analysis.
Conflicts of interest
There are no conflicts to declare”.
Notes and references
‡Experimental procedure and spectral data for all prepared
1
compounds with copies of the H NMR, 13C NMR and 19F NMR
Figure 2. View on the molecular structure of 3a, the
displacement ellipsoids at 30% probability level. The dashed
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DOI: 10.1039/C7OB02408H
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15 X-ray crystallographic data have been deposited with the
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