Stereoselective Mannich Reaction of N-(tert-Butylsulfinyl)imines with 3-Fluorooxindoles and Fluoroacetamides

Article abstract of DOI:10.1002/adsc.201700353

A diastereoselective Mannich reaction has been developed for the construction of stereogenic C?F units by the reaction of α-fluoro-substituted amides, including highly activated 3-fluoro-oxindoles, and simple linear fluoroacetamides with N-tert-butylsulfinylimines. This method provides a concise route to a variety of structurally diverse α-fluoro-β-amino amides containing stereogenic fluorinated carbon centers. This protocol has the benefit of using readily accessible starting materials and is operationally simple. The Mannich reactions of cyclic and linear α-fluoro-substituted amides resulted in different stereochemical outcomes, suggesting that these substrates reacted via closed and open transition states, respectively. (Figure presented.).

Full text of DOI:10.1002/adsc.201700353

Title: Stereoselective Mannich Reaction of N-(tert-Butylsulfinyl)imines
with 3-Fluorooxindoles and Fluoroacetamides
Authors: Xiangyu Chen, Ya Li, Jianbo Zhao, Buquan Zheng, Qi Lu, and
Xinfeng Ren
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700353
Link to VoR: http://dx.doi.org/10.1002/adsc.201700353

10.1002/adsc.201700353
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Stereoselective Mannich Reaction of N-(tert-
Butylsulfinyl)imines with 3-Fluorooxindoles and
Fluoroacetamides
Xiangyu Chen, Ya Li,* Jianbo Zhao, Buquan Zheng, Qi Lu, and Xinfeng Ren
a
Department of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road,
Shanghai 201620, People’s Republic of China
Fax: (+86)-21-67791214; E-mail: ya.li@sues.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
α-Fluorocarbonyl compounds are important
developed for the construction of stereogenic C–F units by fluorocarbon nucleophiles[3-7] that have been widely
Abstract. A diastereoselective Mannich reaction has been
the reaction of α-fluoro-substituted amides, including
highly activated 3-fluoro-oxindoles, and simple linear
fluoroacetamides with N-tert-butylsulfinylimines. This
method provides a concise route to a variety of structurally
diverse α-fluoro-β-amino amides containing stereogenic
fluorinated carbon centers. This protocol has the benefit of
using readily accessible starting materials and is
operationally simple. The Mannich reactions of cyclic and
linear α-fluoro-substituted amides resulted in different
stereochemical outcomes, suggesting that these substrates
reacted via closed and open transition states, respectively.
used in the synthesis of stereogenic C–F units. The
best results reported in this area to date have been
achieved using α-fluoro-β-ketoesters,[4] 2-fluoro-1,3-
diketo hydrates,[5] fluoromalonic acid halfthioesters,[6]
and relatively reactive cyclic α-fluoroketones.[7] α-
fluoro-substituted amides are also regarded as readily
accessible fluorocarbon nucleophiles. However, the
use of α-fluoro-substituted amides for the asymmetric
construction of C–F motifs has been limited by the
reluctance of these systems to enolize.[8-10] In this
respect, highly activated 3-fluorooxindoles have often
been used as surrogates for these systems and several
reports have recently been published in the literature
pertaining to the conjugate addition and asymmetric
allylic alkylation reactions of these systems.[8] The
use of simple α-fluoro-substituted amides in the
asymmetric synthesis of C–F units is even less
common. Very recently, Shibasaki, Kumagai and co-
workers reported the first enantioselective addition of
N-(fluoroacetyl)-7-azaindoline to N-Cbz-imines.[9]
The diastereoselective aldol reactions of chiral
fluoroacetyl-ephedrine-oxazolidinone with α-amino
aldehydes have also been documented.[10]
Keywords: fluorine; asymmetric synthesis; amides;
amines; chiral auxiliaries
Fluorine is highly regarded in medicinal chemistry,
where the replacement of a hydrogen atom or a
hydroxyl group with a fluorine atom can lead to
improved binding affinity, metabolic stability and
bioavailability.[1] It is therefore not surprising that
there has been
a
resurgence in synthetic
organofluorine chemistry during the past decade,
which has led to considerable progress in this area.[2]
In this context, research efforts towards the synthesis
of stereogenic C–F units has attracted considerable
attention because these units occur in many
pharmaceuticals
and
bioactive
molecules,[1c]
including sofosbuvir (Figure 1), which is used in
clinical practice to treat patients infected with the
hepatitis C virus.
Scheme 1. Mannich Reactions of α-Fluoro Amides
with Ellman’s Imines
We have an ongoing interest in the use of simple
α-carbonyl compounds to synthesize stereogenic C–F
centers.[11] Very recently, we showed that weakly
Figure 1. Sofosbuvir
1
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10.1002/adsc.201700353
Advanced Synthesis & Catalysis
acidic α-fluoro carboxylate esters are competent
fluorocarbon reagents that can be converted to α-
fluoro-β-amino acid derivatives through a highly
diastereoselective Mannich reaction.[11b,11c] Herein,
we disclose an efficient Mannich reaction between 3-
fluorooxindoles and Ellman’s imines[12] to provide
access to a wide variety of β-amino amides
containing α-fluorinated stereogenic carbon centers
(Scheme 1). This method was also extended to N-
(fluoroacetyl)-indoline.
We initially evaluated 3-fluorooxindole 1a as a
model substrate because this structural motif can be
found in a wide range of important pharmaceutical
agents.[13] This substrate was also selected as a model
system because it would react via a stereodefined
enolate intermediate. After a quick survey of the
reaction parameters, we identified an optimized
reaction system consisting of 1a (1.2 mmol), imine
2a (1.0 mmol) and LiHMDS (1.2 mmol) in THF at
−70 °C, which afforded 3aa in 92% yield with
excellent diastereoselectivity up to 99:1 (Table 1).
The current reaction can be scaled to 5 mmol (for 1a),
yielding compound 3aa in a slightly higher yield
(1.74 g, 93% yield, 99:1 dr).
yield and diastereoselectivity (3da, 92% yield, 99:1
dr). Last, the N-allyl and N-propargyl substituted
substrates 1e and 1f also reacted smoothly to afford
the corresponding products 3ea and 3fa in 77% and
82% yields with diastereoselectivities of 89:7:4 and
91:7:2, respectively. It is noteworthy that the double
and triple bonds in these products could be used as
handles for further functionalization.[14]
Table 1. The Mannich Reaction of 3-Fluoro-
oxindoles 1a with Ellman’s Imines[a,b]
We then checked the substrate scope of the
reaction with regard to the imines. As shown,
aromatic (3aa–3af), heteroaromatic (3ag and 3ah)
and aliphatic imines (3ai and 3aj) all reacted as
anticipated to afforded the desired products in
satisfactory yields with good to excellent
diastereoselectivities. The introduction of
a
substituent at the para-position of the aromatic rings
had a considerable impact on the yield of reaction.
For example, substrates bearing an electron-donating
group afforded the desired products in excellent
yields with excellent diastereoselectivities (3ab and
3ac), whereas those bearing an electron-withdrawing
group at the same position gave lower yields and
diastereoselectivities (3ad–3ae). Importantly, 4-
pyridinyl and 2-furanyl imines also reacted smoothly
under the standard reaction conditions to afford the
corresponding addition products 3ag and 3ah with
excellent diastereoselectivities. Aliphatic α,β-
unsaturated imine 2i also reacted as expected to
afford the desired product 3ai in 92% yield with 99:1
[a]
The yields refer to isolated yields of the major
stereoisomers. dr determined by 19F NMR spectroscopy
on the crude products.
[b]
Table 2. The Mannich Reaction of 3-Fluoro-
oxindoles 1b–1f with Ellman’s Imine 2a[a,b]
diastereoselectivity.
Even
the
aliphatic
isovaleraldehyde sulfinyl imine 2j, which has a
tendency to undergo enolization under strongly basic
conditions, was well tolerated, affording the
corresponding products 3aj in very good yield (86%).
We subsequently proceeded to investigate the
generality of this reaction using a variety of different
3-fluorooxindole derivatives. As shown (Table 2), the
introduction of an electron-donating methoxy (3ba vs
3aa) or electron-withdrawing chloro (3ca vs 3aa)
substituent led to decreases in the diastereoselectivity,
indicating that steric interactions between the
reactants may play an important role in determining
the stereochemical outcome of the reaction. The
influence of the N-substituent on the outcome of
reaction was also evaluated. The N-benzyl substituted
substrate 1d gave the expected product in excellent
[a]
The yields refer to the isolated yields of the major
stereoisomers. [b] dr determined by 19F NMR spectroscopy
on the crude products.
2
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10.1002/adsc.201700353
Advanced Synthesis & Catalysis
Linear α-fluoro-substituted amides, especially
Using KHMDS as the base (Table 3, entry 5), we
evaluated the substrate scope of the imine moiety. As
shown in Table 4, aromatic (5aa–5aj),
heteroaromatic (5ak and 5al) and α,β-unsaturated
aliphatic imines (5am) were all found to be suitable
substrates for this reaction, generally affording the
corresponding products with diastereoselectivities
(around 90:10) in moderate to good yields. The
results revealed that the position of the substituent on
the aromatic ring had very little impact on the
outcome of the reaction, as exemplified by the ortho-,
meta- and para-methyl substituted substrates 5ab,
5ad and 5af, which gave comparable yields and
diastereoselectivities. However, the electronic
properties of the substituent had a noticeable effect
on the reaction. For example, substrates bearing an
electron-donating substituent (5ac, 5ad, 5af and 5ag)
gave higher yields than those bearing an electron-
withdrawing substrate (5ae, 5ah and 5ai). 2-Furanyl
imines were also found to be good substrates,
although the inclusion of a methyl group at the 2-
position led to a slight decrease in the yield and
diastereoselectivity (5ak vs 5al). The α,β-unsaturated
aliphatic imine substrate 2m also reacted smoothly
under the standard conditions to afford the desired
product 5am with a diastereoselectivity of 92:5:3.
However, aliphatic imines bearing an α-hydrogen
such as the butylaldehyde imine 2n failed to react as
expected because of their tendency to enolize under
the strongly basic reaction conditions, with
compound 4a being recovered almost quantitatively.
We also evaluated the performance of several
other fluoromethyl amides in the Mannich reaction,
including amides derived from the reaction of methyl
fluoroacetate with various amines, including N,N-
diethyl amine (4b), N,N-dibutyl amine (4c),
morphine (4d) and piperidine (4e). The results
revealed that these reaction generally proceeded well,
albeit with low diastereoselectivities (see the
Supporting Information), which indicated that the
structure of the amide had a considerable impact on
fluoroacetamides, are challenging substrates for the
asymmetric synthesis of stereogenic C–F units,
because they do not tend to form stereodefined
enolate intermediates. To determine whether this new
Mannich process was amenable to the reaction of
linear α-fluoro-substituted amides with N-sulfinyl
imines, we investigated the reaction of the readily
accessible substrate 4a with N-sulfinylimine 2a under
the reaction conditions used in Table 2.
Disappointingly, however, this reaction resulted in a
low diastereoselectivity (dr = 55:24:17:4) (Table 3,
entry 1). Furthermore, changing the solvent to toluene
or the base to NaHMDS had no discernible impact on
the outcome of the reaction (Table 3, entries 2 and 3).
Further optimization revealed that the use of KHMDS
as a base afforded the desired product 5aa with a
diastereoselectivity of 93:7 (Table 3, entry 5).
However, the conversion ratio of 4a was low, with
35% of the material being recovered unchanged. We
also investigated the effect of adding an additive to
the reaction (Table 3, entry 6–8) or a large amount of
base (Table 3, entry 9), but all of these changes failed
to produce an increase in the yield. With the optimum
conditions (Table 3, entry 5), the current reaction can
be performed on a 5 mmol scale, furnishing the
product 5aa in a comparable yield (1.32 g, 68% yield,
94:6 dr).
Table 3. Survey of Reaction Conditions for the
Addition of Fluoromethyl Amide 4a to Imine 2a[a]
Entry
base
Solvent
/additive
Yield
(%)
dr[g]
1[b]
2[b]
3[b]
4[b]
5[c]
6[c]
7[c]
8[c]
9[d]
LHMDS
LHMDS
THF
92[e]
85[e]
90[e]
58[f]
70[f]
67[f]
57[f]
60[f]
66[f]
55:24:17:4
82:18
82:16:2
94:6
PhMe
the
diastereoselectivity
of
the
reaction.
NaHMDS THF
Fluoroacetamide 4f derived from indole was not a
competent substrate; complex reaction mixtures were
afforded.
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
THF
THF
93:7
The absolute configurations of 3ag and 5ah were
determined by single-crystal X-ray analysis.[15]
Notably, the fluoro and amino substituents in
compound 3ag adopted a anti configuration, whereas
the same substituents adopted a syn configuration in
compound 5ah. This result indicated that different
transition states were involved in the reactions of the
3-fluoro-oxindoles 1 and fluoromethyl amides 4 with
Ellman’s imines. A chair-like transition state was
proposed to explain the stereochemical outcome of
compound 3, where the Z-fluoroenolate of the α-
fluoro-substituted amide would approach the less
hindered Si face of the (R)-sulfinylimine substrate
(Figure 2a). Similar transition states have been
suggested by Davis, Ellman and several other
researchers to rationalize the condensation reactions
of metal enolates with sulfinylimines.[12] It is
THF/HMPA
THF/LiBr
THF/ MgBr2
THF
89:6:5
92:8
90:10
90:10
[a] A combination of 1.5 mL of THF and/or 0.15 mL of
HMPA (or 0.1 mmol metal additive) was used on a 0.5
[b]
mmol scale (for 2a).
The ratio of 2a/4a/base is
1.0/1.2/1.2. [c] The ratio of 2a/4a/base is 1.0/1.2/1.4. [d] The
[e]
ratio of 2a/4a/base is 1.0/1.5/1.7. The yields refer to the
combined yields of the stereoisomers. [f] The yields refer to
[g]
the isolated yields of the major stereoisomers.
dr
determined by 19F NMR spectroscopy on the crude
products.
3
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10.1002/adsc.201700353
Advanced Synthesis & Catalysis
Table 4. The Mannich Reaction of Fluoromethyl Amide 4a with Ellman’s Imine 2[a,b,c]
[a] The yields refer to isolated yields of the major stereoisomers. [b] dr determined by 19F NMR spectroscopy on the crude
product. [c] For 5ae, 5ah and 5ai, a combination of KHMDS (1.0 equiv) and NaHMDS (0.4 equiv) was used (to increase
the yield).
(Figure 2b). As shown, the Z-enolate of fluoromethyl
amide 4 would adopt an antiperiplanar orientation
and attack the sterically less hindered Si face of (R)-
sulfinylimine
to
afford
the
observed
stereoselectivity.[16] We previously reported
a
comparable transition state to explain the
stereochemical outcome of the reaction of methyl
fluoroacetate with N-sulfinyl imines. [11b]
To demonstrate the utility of our method for
preparing useful organofluorine compounds, we
selected compound 5 as a representative substrate for
further elaborations. As shown in Scheme 2a,
compound 5ac was initially treated with HCl/MeOH
to remove its tBuS(O) group. The resulting
ammonium salt was then treated with Boc2O to give
the N-Boc product 6 as a single diastereomer in 93%
yield (Scheme 2a). This highlights the robust nature
of this newly formed fluorinated α-carbon center to
mildly acidic or basic conditions. Moreover, the
amide moiety in compound 5aa can be reduced
efficiently with borane-SMe2 complex giving the 3-
indolinyl intermediate which, without purification,
further underwent the removal of the tBuS(O) group
with HCl/MeOH to afford the free amine 7 in 91%
yield over the two steps (Scheme 2b).
Figure 2. (a) Closed transition-state mode proposed for the
addition of 3-fluoro-oxindole 1 to Ellman’s imine. (b)
Open transition-state mode proposed for the addition of
fluoromethyl amide 4a to Ellman’s imine.
noteworthy that the addition of the fluoroenolate of 3-
fluoro-oxindole (derived from the β-keto-amide
hydrate via an in situ detrifluoroacetylation) to N-
sulfinyl imine afforded the syn-configured product,
with the Z-fluoroenolate attacking the Si face of the
(S)-sulfinylimine substrate. [5d]
The synthetic utility of our protocol was further
demonstrated by the synthesis of compound 8
containing the 3-aminomethyl-oxindole scaffold. The
tBuS(O) group was readily cleaved with HCl/MeOH
affording the corresponding intermediate which,
The diastereoselectivity observed for compound 5
was explained based on an open transition state
4
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10.1002/adsc.201700353
Advanced Synthesis & Catalysis
without purification, was subjected to copper-
flash column chromatography on silica gel, gave the
corresponding product 3.
[17]
catalyzed couping with PhB(OH)2
to give
compound 8, and its 3-ethyl analogue 9 has been
reported to be bioactive against human breast cancer
MCF-7 cells (Scheme 3).[18]
Acknowledgements
Support of our work by Natural Science Foundation of Shanghai
(16ZR1413800), and Shanghai University of Engineering Science
(2012td09, 2017RC062015 and nhrc-2015-09) is gratefully
acknowledged.
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In summary, we have developed
diastereoselective Mannich reaction of α-fluoro-
substituted amides. 3-Fluoro-oxindoles and
a
highly
fluoromethyl amides behaved as competent substrates
for this reaction, affording the corresponding α-
fluoro-β-amino amides in a concise and efficient
manner. The differences observed in the
stereoselectivities of these two different types of
substrate were attributed to them progressing via
closed and open transition states. This new process
represents a robust approach for the syntheses of
diverse α-fluoro-β-amino carbonyl compounds
bearing a stereogenic C–F unit.
Experimental Section
Typical Procedure for the Diastereoselective Addition
of N-Methyl 3-Fluoro-oxindoles (1a) to N-tert-
Butylsulfinyl Imine (2).
Under a N2 atmosphere, LHMDS (1.2 equiv, 0.6 mL, 1.0
mol/L in THF) was added slowly to a mixture of 1a (0.6
mmol, 1.2 equiv), imine 2 (0.5 mmol, 1.0 equiv), and THF
(1.5 mL) at −70 °C. Reaction mixtures were stirred at this
temperature for 30 min. Then, 1 N TFA/THF (2 mL) was
added, and the quenched reaction mixture was extracted
three times with ethyl acetate (20 mL × 3). The combined
organic layers were dried over anhydrous MgSO4.
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10.1002/adsc.201700353
Advanced Synthesis & Catalysis
COMMUNICATION
Stereoselective Mannich Reaction of N-(tert-
Butylsulfinyl)imines with 3-Fluorooxindoles and
Fluoroacetamides
Adv. Synth. Catal. Year, Volume, Page – Page
Xiangyu Chen, Ya Li,* Jianbo Zhao, Buquan
Zheng, Qi Lu, and Xinfeng Ren
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