A diastereoselective Mannich reaction of α-fluoroketones with ketimines: Construction of β-fluoroamine motifs with vicinal tetrasubstituted stereocenters

Article abstract of DOI:10.1016/j.tetlet.2018.04.051

A diastereoselective Mannich reaction has been developed for the synthesis of chiral β-fluoroamine motifs by the reaction of α-fluoroketones with ketimines, including isatin-derived ketimines and phenylglyoxylate-derived ketimines. This method provides a

Full text of DOI:10.1016/j.tetlet.2018.04.051

Accepted Manuscript
A diastereoselective Mannich reaction of α-fluoroketones with ketimines: con-
struction of β-fluoroamine motifs with vicinal tetrasubstituted stereocenters
Jian-bo Zhao, Xinfeng Ren, Bu-quan Zheng, Jian Ji, Zi-bin Qiu, Ya Li
PII:
S0040-4039(18)30524-0
https://doi.org/10.1016/j.tetlet.2018.04.051
TETL 49914
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 March 2018
18 April 2018
20 April 2018
Please cite this article as: Zhao, J-b., Ren, X., Zheng, B-q., Ji, J., Qiu, Z-b., Li, Y., A diastereoselective Mannich
reaction of α-fluoroketones with ketimines: construction of β-fluoroamine motifs with vicinal tetrasubstituted
stereocenters, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.051
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A diastereoselective Mannich reaction of α-
fluoroketones with ketimines: construction of
β-fluoroamine motifs with vicinal
tetrasubstituted stereocenters
Jian-bo Zhao, Xinfeng Ren,* Bu-quan Zheng, Jian Ji, Zi-bin Qiu, and Ya Li*

1
Tetrahedron Letters
A diastereoselective Mannich reaction of α-fluoroketones with ketimines:
construction of β-fluoroamine motifs with vicinal tetrasubstituted stereocenters
Jian-bo Zhao, Xinfeng Ren,* Bu-quan Zheng, Jian Ji, Zi-bin Qiu, Ya Li*
Department of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai, 201620, P. R. China.
Email: renxf@sues.edu.cn, ya.li@sues.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A diastereoselective Mannich reaction has been developed for the synthesis of chiral β-
fluoroamine motifs by the reaction of α-fluoroketones with ketimines, including isatin-derived
ketimines and phenylglyoxylate-derived ketimines. This method provides a concise route to a
variety of biologically important 3-aminooxindoles and α-amino acids featuring fluorine-
containing vicinal tetrasubstituted stereocenters.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Amines
Diastereoselective addition
Ketones
Ketimines
Introduction
We have been interested in the use of simple α-
fluorocarbonyl compounds to construct stereogenic
carbon−fluorine centers. Recently, we have shown that α-
Fluorine is extremely important in medicinal chemistry, as
the introduction of fluorine into bioactive molecules can often
lead to improved binding affinity, metabolic stability and
bioavailability. Nowadays, around 20% of pharmaceuticals on
the market contain at least one fluorine atom. In this context, the
β-fluoroamine unit is a privileged structural motif which has been
found in many bioactive molecules and drug candidates. A
fluorine substitution can reduce the basicity of nearby amines,
and thus can modulate the pharmacokinetic properties of the
molecule and its binding affinity. Therefore, efficient methods
8
fluoroketones are competent fluorocarbon nucleophiles and can
undergo highly diastereoselective Mannich reactions with
1
9,10
Ellman’s aldimines.
Herein, we disclose the Mannich reaction
between α-fluoroketones and isatin-derived ketimines to provide
access to β-fluoroamine motifs containing fully substituted
adjacent stereocenters (Scheme 1). This method was also
extended to ethyl benzoylformate-derived ketimines.
2
3
providing access to β-fluoroamine motifs are highly valuable.
The syntheses of β-fluoroamine motifs have been reported in
numerous publications, and can be divided into two main
approaches: fluorination, and use of fluorinated building
4,5
blocks. However, the asymmetric synthesis of β-fluoroamine
motifs, especially with fully substituted adjacent stereocenters,
6,7
remains a formidable challenge. There are only a few literature
reports that document the construction of chiral β-fluoroamine
7
motifs with tetrasubstituted stereocenters. Among them, the
asymmetric condensation of the trisubstituted fluoroenolate of α-
fluoroketones with ketimines represents a straightforward
approach to such structural motifs. For example, Wang and co-
workers described an elegant Mannich reaction of 2-fluoro-1,3-
diketone hydrates with isatin-derived ketimines catalyzed by a
Scheme 1. Construction of β-fluoroamine motifs containing vicinal
tetrasubstituted stereocenters
Results and discussion
7a
chiral copper-diamine complex, while Zhou et al developed an
We initially evaluated isatin-derived ketimine 1a as a model
substrate, as the resulting 3-aminooxindole motifs can be found
in a wide range of important pharmaceutical agents and bioactive
enantioselective addition of fluorinated silyl enol ether with
7b
cyclic N-sulfonyl ketimines. While efficient, the use of such
activated α-fluoroketone nucleophiles is not green from the
perspective of atom economy, and their preparation is difficult
compared with that of simple α-fluoroketones.
11,12
molecules.
When 1a was reacted with 1.2 equivalents of α-
fluoroketone 2a in the presence of NaHMDS, only a trace

2
Tetrahedron
amount of the desired Mannich product 3aa was observed
Table 1, entry 1). The use of KHMDS as base gave a good yield,
diastereoisomers. The influence of the N-substituent on the
outcome of reaction was also evaluated. N-Allyl, N-benzyl and
(
but with low diastereoselectivity (entry 2 and 3). When LiHMDS
was used, 3aa was obtained in 82% yield, with an improved
diastereoselectivity of 60:40:0:0 (entry 4). The reaction solvent
was then screened; DMF proved to be an unsuitable solvent (13%
yield, entry 5), while DCM and toluene gave comparable yields
and diastereoselectivities (entries 6 and 7). The inclusion of
additives was also evaluated. While HMPA inhibited the reaction
almost completely (entry 8), a beneficial effect was observed
when TMEDA was used (entries 9 and 10). Optimal reaction
conditions involving a combination of toluene and TMEDA gave
the product 3aa in 95% yield and synthetically useful
diastereoselectivity (d.r. = 72:28:0:0) (entry 10).
N-CPh
products 3ag–3ai in good yields. Importantly, compared with the
N-CH substrate 1a, the bulky N–CPh group proved to be
3
derivatives 1g–1i were all tolerated, giving the desired
3
3
beneficial to the stereoselectivity of the reaction, with 3ai being
formed with a 90:10:0:0 diastereoselectivity. The 5-fluoro-6,7-
dihydrobenzo[b]thiophen-4(5H)-one 2b and 3-fluorochroman-4-
one 2c were also successfully reacted to give 3bi (71%, d.r. =
71:29:0:0) and 3ca (65%. d.r. = 45:33:17:5). It is worth noting
that for each substrate, the major diastereomer could be easily
separated from the crude products through routine flash column
chromatography.
Table 2
Table 1
The diastereoselective addition of α-fluoroketones 2 to isatin-
derived ketimines 1
a,b
Optimization of the addition of α-fluoroketone 2a to isatin-
derived imine 1a
a
b
c
entry
base
Solvent/additive
THF
Yield (%)
d.r.
d
1
2
3
4
5
6
7
8
NaHMDS
KHMDS
KHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
<5
70
56
82
13
80
85
<5
N
THF
51:49:0:0
57:43:0:0
60:40:0:0
toluene
THF
d
DMF
N
DCM
57:43:0:0
60:40:0:0
toluene
toluene/HMPA
d
N
(
v/v=10/1)
THF/TMEDA
v/v=10/1)
toluene/TMEDA
v/v=10/1)
Reaction conditions: under a N atmosphere, the base (0.6 mL, 1.0 mol/L in
9
LiHMDS
LiHMDS
85
95
60:40:0:0
72:28:0:0
(
1
0
(
a
2
THF) was added slowly to a reaction mixture of 1a (0.5 mmol), and 2a (0.6
mmol) in the specified solvent/additive (3.0 mL) at −70 °C.
b
Yields refer to isolated yields of the stereoisomers.
c
19
1
d.r. Determined by F NMR or H NMR spectroscopy on the crude
products.
d
Not determined.
We then investigated the substrate scope of the reaction with
regard to isatin-derived ketimines, and the results are
summarized in Table 2. As shown, steric interactions between the
reactants played an important role in dictating the efficiency of
the reaction, as exemplified by the 1-, 4- , 5-, and 6-substituted
ketimines 1b–1i, which gave a lower yield due to the incomplete
conversation of the ketimines. The electronic nature of the
substituents also has impact on the outcome of the reaction. For
example, 4-methyl ketimine 1b seems to work well under the
a
The yields refer to isolated yields of the two or three stereoisomers.
d. r. determined by F NMR or H NMR spectroscopy.
b
19
1
reaction conditions, giving 3ab in
diastereoselectivity (d.r. = 94:6:0:0), whereas a decreased
diastereoselectivity (3ac, d.r. = 81:19:0:0) was obtained when the
a
very good
Phenylglyoxylate-derived ketimines are important building
blocks and have been frequently used in the synthesis of chiral α-
13
4
-bromo substrate 1c was used. The 5-substituted substrates 1d–
amino acids bearing a tetrasubstituted carbon. Thus, we wished
to develop a method to synthesize α-amino acids with fluorine-
containing vicinal tetrasubstituted stereocenters. However, when
4a was reacted with 2a under the reaction conditions used in
Table 2, the Mannich product 5aa was not observed (Table 3,
entry 1). Switching the base to NaHMDS only gave a trace
amount of 5aa (entry 3). The reaction proved to work well when
1e also worked with similar efficiency to successfully give
products 3ad–3ae in good yields; the electron-donating 5-methyl
substituent 3ad gave a higher diastereoselectivity (d.r. =
8
=
3
8:6:6:0), compared with that of the 5-chloro substituent 3ae (d.r.
70:30:0:0). The 6-chloro ketimine 1f also afforded the product
af in a very good yield as a 67:26:7:0 mixture of

3
KHMDS was used (entries 4 and 5). Optimal reaction conditions
involving KHMDS as base in toluene gave 5aa in 85% yield with
The absolute configurations of 3ag and 5aa were determined
14
97:3:0:0 diastereoselectivity (entry 4). The current reaction can
by single-crystal X-ray analysis, and compounds 3 and 5 were
thus assigned by analogy. Notably, the absolute configuration of
the β-fluoroamine motifs in compound (RC-F, RC-N)-3 is the
opposite compared with that in the Mannich product (SC-F, SC-N)-
5. These results showed that different transition states were
involved in the reactions of isatin-derived ketimines 1 and
phenylglyoxylate-derived ketimines 4 with α-fluoroketones 2.
The stereoselectivity observed for compound 3 was tentatively
explained based on an open transition state (Fig. 1a). The sulfinyl
unit and the C=N bond is proposed to adopt an s-cis arrangement,
and the Z-enolate of fluoroketone would attack the sterically less
hindered Si face of isatin-derived ketimines 1 in an antiperiplanar
fashion to give the observed stereoselectivity. For the
stereochemical outcome of compound 5, a chair-like transition
state is proposed where the potassium is coordinated to the
nitrogen atom and the C=O oxygen atom of phenylglyoxylate-
derived ketimine 4 (Fig. 1b).
be carried out on a gram scale (3 mmol), yielding 5aa in a
comparable yield (1.12 g, 84% yield, 96:4:0:0 dr).
We then investigated other α-fluorinated ketones in this
reaction. As shown in Table 4, the α-fluoroketones 2b–2d were
competent nucleophiles and gave the Mannich products 5ab–5ad
in moderate to good yields, with moderate diastereoselectivities.
Of note, the 5-fluoro-6,7-dihydrobenzo[b]thiophen-4(5H)-one 2b
worked well under the reaction conditions, giving 5ab in a good
yield (82%). The 3-fluorochroman-4-one 2c and 2d also reacted
smoothly to give the corresponding products 5ac and 5ad, albeit
in
a lower diastereoselectivity (75:25:0:0 and 75:17:8:0
respectively).
Table 3
Optimization of the addition of α-fluoroketone 2a to
a
phenylglyoxylate-derived imine 4a
b
c
entry
1
base
Solvent
Yield (%)
0
d.r.
d
LiHMDS
toluene/TMEDA
N
(
v/v=10:1)
d
2
3
4
5
LiMDS
toluene
toluene
toluene
THF
trace
trace
85
N
d
NaHMDS
KHMDS
KHMDS
N
97:3:0:0
d
55
N
a
2
Reaction conditions: under a N atmosphere, the base (0.6 mL, 1.0 mol/L in
THF) was added slowly to a reaction mixture of 2a (0.5 mmol), and 4a (0.6
mmol) in the specified solvent/additive (3.0 mL) at −70 °C.
b
Yields refer to isolated yields of the major stereoisomers.
Fig. 1. (a) Open transition-state mode proposed for the diastereoselective
addition of α-fluoroketones 2 to isatin-derived ketimines 1; (b) Closed
transition-state mode proposed for the diastereoselective addition of α-
fluoroketones 2 to phenylglyoxylate-derived ketimines 4.
c
19
d.r. Determined by F NMR spectroscopy on the crude products.
d
Not determined.
Table 4
To demonstrate the utility of the method, some elaboration of
the obtained products 3 was performed. As shown in Scheme 2,
compound 3ae was subjected to the NaBH C=O reduction to
4
The diastereoselective addition of α-fluoroketones
phenylglyoxylate-derived ketimines 4
2 to
a,b
give compound 6 in 61% yield and with 3:1 diastereoselectivity.
The configuration of compound 6 was confirmed by single-
14
crystal X-ray analysis. Treatment of compound 6 with
HCl/MeOH afforded the corresponding compound 7 as a single
diastereomer in 80% yield.
a
The yields refer to isolated yields of the two or three stereoisomers.
d. r. Determined by F NMR spectroscopy.
b
19
Scheme 2. Elaboration of compound 3ae

4
Tetrahedron
Conclusions
(b) Verniest G, Surmont R, Van Hende E, Deweweire A, Deroose F,
Thuring JW, De Kimpe N. J Org Chem. 2008; 73: 5458;
c) Ruano JLG, Parra A, Alonso I, Fustero S, del Pozo C, Arroyo Y,
Sanz-Tejedor A. Chem Eur J. 2011; 17: 6142;
In summary, we have developed a diastereoselective Mannich
(
reaction of α-fluoroketones and ketimines. Isatin-derived
ketimines and phenylglyoxylate-derived ketimines are competent
substrates for this reaction, affording 3-aminooxindoles and α-
amino acids bearing fluorine-containing vicinal tetrasubstituted
stereocenters. This new process represents a viable approach for
the syntheses of diverse fluorinated compounds bearing a fully
substituted fluorinated carbon center.
(
(
d) Vara BA, Johnston JN. J Am Chem Soc. 2016; 138: 13794;
e) Brewitz L, Arteaga FA, Yin L, Alagiri K, Kumagai N, Shibasaki
M. J Am Chem Soc. 2015; 137: 15929;
6
For selected examples, see: (a) Zhao Y, Pan Y, Liu H, Yang Y, Jiang
Z, Tan C-H. Chem Eur J. 2011; 17: 3571;
(
b) Vaithiyanathan V, Kim MJ, Liu Y, Yan H, Song CE. Chem Eur J.
017; 23: 1268;
c) Trost BM, Saget T, Lerchen A, Hung C-I. Angew Chem Int Ed.
2
Acknowledgements
(
Support of our work by the National Natural Science
Foundation of China (21102089), the Natural Science Foundation
of Shanghai (16ZR1413800), and Shanghai University of
Engineering Science (2012td09, nhrc-2015-09) is gratefully
acknowledged.
2016; 55: 781;
(d) Xie C, Sha W, Zhu Y, Han J, Soloshonok VA, Pan Y. RSC Adv.
2017; 7: 5679;
(e) Saidalimu I, Fang X, He XP, Liang J, Yang X, Wu FH. Angew
Chem Int Ed. 2013; 52: 5566;
(
f) Xie C, Wu L, Han J, Soloshonok VA, Pan Y. Angew Chem Int Ed.
015; 54: 6019;
References
2
(
(
g) Appayee C, Brenner-Moyer SE. Org Lett. 2010; 12: 3356;
1
(a) ꢀꢁguꢁ JP, Bonnet-Delpon D. Bioorganic and Medicinal
Chemistry of Fluorine. Hoboken, NJ: Wiley-Interscience; 2008;
h) Shunatona HP, Fruh N, Wang Y-M, Rauniyar V, Toste FD.
Angew Chem Int Ed. 2013; 52: 7724;
i) Cresswell AJ, Davies SG, Lee JA, Roberts PM, Russell AJ,
Thomson JE, Tyte MJ. Org Lett. 2010; 12: 2936.
(
(
b) Müller K, Faeh C, Diederich F. Science. 2007; 317:1881;
(
c) Gouverneur V, Müller K. Fluorine in Pharmaceutical and
Medicinal Chemistry: From Biophysical Aspects to Clinical
(
(
j) Fadeyi OO, Lindley CW. Org Lett. 2009; 11: 943;
Applications. London: Imperial College Press; 2012;
k) Xie C, Dai Y, Mei H, Han J, Soloshonok VA, Pan Y. Chem
(
d) Purser S, Moore PR, Swallow S, Gouverneur V. Chem Soc Rev.
008; 37: 320.
Commun. 2015; 51: 9149.
2
7
For the synthesis of β-fluoroamine motifs with vicinal tetrasubstituted
stereocenters, see: (a) Liu X, Zhang J, Zhao L, Ma S, Yang D, Yan W,
Wang R. J Org Chem. 2015; 80: 12651;
2
(a) Murray TK, Whalley K, Robinson CS, Ward MA, Hicks E, Gates
M, Ogden AM. J Pharmacol Exp Ther. 2003; 306: 752;
(
b) Van Niel MB, Beer MS, Broughton HB, Cheng SKF, Goodacre
(
(
b) Yu J-S, Zhou J. Org Chem Frontiers. 2016; 3: 298;
SC, Heald A, Locker KL, MacLeod AM, Morrison D, Moyes CR,
O'Connor D, Pike A, Rowley M, Russel MGN, Sohal B, Stanton JA,
Thomas S, Verrier H, Watt AP, Castro JL. J Med Chem. 1999; 42:
c) Bao X, Wang B, Cui L, Zhu G, He Y, Qu J, Song Y. Org Lett.
2
015; 17: 5168;
(
d) Chauhan P, Mahajan S, Kaya U, Peuronen A, Rissanen K, Enders
2
087;
D. J Org Chem. 2017; 82: 7050.
(
c) Ullrich T, Sasmal S, Boorgu V, Pasagadi S, Cheera S,
8
(a) Shang H, Li Y, Li X, Ren X. J Org Chem. 2015; 80: 8739;
Rajagopalan S, Bhumireddy A, Shashikumar D, Chelur S, Belliappa
C, Pandit C, Krishnamurthy N, Mukherjee S, Ramanathan A,
Ghadiyaram C, Ramachandra M, Santos PG, Lagu B, Bock MG,
Perrone MH, Weiler S, Keller H. J Med Chem. 2014; 57: 7396;
(
(
b) Li X, Li Y, Shang H. Org Biomol Chem. 2016; 14: 6457;
c) Chen H, Li Y, Zhao J, Zheng B, Lu Q, Ren X. Adv Synth Catal.
2
017; 359: 3057;
d) Li Y, Li X, Shang H, Chen H, Ren X. J Org Chem. 2016; 81:
858.
(
(
d) Withers S, Watts AG, Kim J-H, Wennekes T. U.S. Patent
815941, 2011.
9
8
9
1
For reviews of N-sulfinyl imines in synthesis, see: (a) Robak MT,
3
4
For a review, see: Bohm H-J, Banner D, Bendels S, Kansy M, Kuhn
B, Muller K, Obst-sander U, Stahl M. ChemBioChem. 2004; 5: 637.
For the use of fluorination, see selected examples: (a) Liu L, Gerstner
NC, Oxtoby LJ, Guzei IA, Schomaker JM. Org Lett. 2017; 19: 3239;
Herbage MA, Ellman JA. Chem Rev. 2010; 110: 3600;
(
(
b) Davis FA. J Org Chem. 2006; 71: 8993;
c) Morton D, Stockman RA. Tetrahedron. 2006; 62: 8869.
0
1
For the use of N-sulfinyl imines in the synthesis of chiral amines in
(
(
(
b) Chen H, Kaga A, Chiba S. Org Biomol Chem. 2016; 14: 5481;
c) Wu T, Yin G, Liu G. J Am Chem Soc. 2009; 131: 16354;
d) Lu D-F, Zhu C-L, Sears JD, Xu H. J Am Chem Soc. 2016; 138:
our group, see; (a) Li Y, Li D, Zheng T, Li H, Ren X. Chem Eur J.
2
014; 20: 14986;
(
b) Li Y, Zheng T, Wang W, Xu W, Ma Y, Zhang S, Wang H, Sun Z.
1
1360;
e) Qiu S, Xu T, Zhou J, Guo Y, Liu G. J Am Chem Soc. 2010; 132:
856;
f) Lu D-F, Zhu C-L, Sears J-D, Xu H. J Am Chem Soc. 2016; 138:
1360;
g) Moens M, D’hooghe M, De Kimpe N. Tetrahedron Lett. 2013; 54:
110;
Adv Synth Catal. 2012; 354: 308.
(
1
For the use of isatin-derived ketimine in the synthesis of amines, see
selected examples: (a) Yan W, Wang D, Feng J, Li P, Zhao D, Wang
R. Org Lett. 2012; 14: 2512;
2
(
1
(
(
b) Jung HH, Buesking AW, Ellman JA. Org Lett. 2011; 13: 3912;
c) Guo Q-X, Liu Y-W, Li X-C, Zhong L-Z, Peng Y-G. J Org Chem.
(
6
2
012; 77: 3589;
(
(
h) Katcher MH, Doyle AG. J Am Chem Soc. 2010; 132: 17402;
i) Verniest G, Van Hende E, Surmont R, De Kimpe N. Org Lett.
(
(
d) Chen D, Xu M-H. Chem Commun. 2013; 49: 1327;
e) Rao VUB, Jadhav AP, Garad D, Singh RP. Org Lett. 2014; 16:
2
006; 8: 4767.
j) Zhang Q, Zheng G, Zhang Q, Li Y, Zhang Q. J Org Chem. 2017;
2: 8258;
6
48;
(
(
f) Lesma G, Landoni N, Pilati T, Sacchetti A, Silvani A. J Org
8
Chem. 2009; 74: 4537.
(
(
k) Schulte ML, Lindsley CW. Org Lett. 2011; 13: 5684;
1
2
(a) Girgis AS. Eur J Med Chem. 2009; 44: 91;
l) Phipps RJ, Hiramatsu K, Toste FD. J Am Chem Soc. 2012; 134:
(
b) Ali MA, Ismail R, Choon TS, Yoon YK, Wei AC, Pandian S,
Kumar RS, Osman H, Manogaran E. Bioorg Med Chem Lett. 2010;
0: 7064;
c) Zhou F, Liu Y-L, Zhou J. Adv Synth Catal. 2010; 352: 1381.
8
376.
5
For the use of fluorinated building blocks, see selected examples: (a)
2
Moskowitz M, Balaraman K, Wolf C. J Org Chem. 2018; 83: 1661;
(

5
1
3
(a) Marsini MA, Reeves JT, Desrosiers JN, Herbage MA, Savoie J, Li
Z, Fandrick KR, Sader CA, McKibben B, Gao DA, Cui J, Gonnella
NC, Lee H, Wei X, Roschangar F, Lu BZ, Senanayake CH. Org Lett.
(d) Wieland LC, Vieira EM, Snapper ML, Hoveyda AH. J Am
Chem Soc. 2009; 131: 570;
(e) Sun L-H, Liang Z-Q, Jia W-Q, Ye S. Angew Chem Int Ed. 2013;
52: 5803;
2
015; 17: 5614;
(
(
b) Maciá E, Foubelo F, Yus M. Tetrahedron. 2016; 72: 6001;
(f) Huang G, Yin Z, Zhang X. Chem Eur J. 2013; 19: 11992.
14 CCDC 1812528 (3ag), 1812299 (5aa) and 1818742 (6) contain the
supplementary crystallographic data for this paper.
c) Curto JM, Dickstein JS, Berritt S, Kozlowski MC. Org. Lett. 2014;
1
6: 1948;

6
Tetrahedron
Highlights
·
·
·
·
The Mannich reaction of simple α-
fluoroketones with ketimines was described.
Isatin-derived ketimines and phenylglyoxylate-
derived ketimines were used.
β-Fluoroamine
motifs
with
vicinal
tetrasubstituted stereocenters were obtained.
Open- and closed transition-state modes were
proposed.