One-pot fluorination and Mannich reactions of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2015.02.117

Abstract One-pot fluorination of 1,3-dicarbonyl compounds with Selectfluor followed by the Mannich reaction with anilines and benzaldehydes is developed for the synthesis of α-fluoro and aminomethylated 1,3-dicarbonyl compounds.

Full text of DOI:10.1016/j.tetlet.2015.02.117

Accepted Manuscript
One-pot fluorination and Mannich reactions of 1,3-dicarbonyl compounds
Kenny Pham, Xin Huang, Wei Zhang
PII:
S0040-4039(15)00410-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.117
TETL 45987
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 January 2015
22 February 2015
24 February 2015
Please cite this article as: Pham, K., Huang, X., Zhang, W., One-pot fluorination and Mannich reactions of 1,3-
dicarbonyl compounds, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.117
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
One-pot fluorination and Mannich reactions of
1,3-dicarbonyl compounds
Leave this area blank for abstract info.
Kenny Pham, Xin Huang, and Wei Zhang

1
Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot fluorination and Mannich reactions of 1,3-dicarbonyl compounds
Kenny Pham, Xin Huang and Wei Zhang*
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
One-pot fluorination of 1,3-dicarbonyl compounds with SelectfluorTM followed by the Mannich
reaction with anilines and benzaldehydes is developed for the synthesis of α-fluoro and
aminomethylated 1,3-dicarbonyl compounds.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
One-pot synthesis
Mannich reaction
1,3-Dicarbonyl compounds
Fluorination
Step economy synthesis
Organofluorine molecules could have significantly different
physical, chemical, and biological properties from their non-
fluorinated parent compounds.1 The synthesis of fluorinated
small molecules has become increasingly important in medicinal
chemistry2 and agricultural chemistry.3 Shown in Figure 1 are
biologically interested α-fluorinated 1,3-dicarbonyl compounds,
including schizophrenia and anxiety agent I,4 human
Kv1.1/Kvβ1.3 potassium channel inhibitor II,5 antimalarial
candidate compound III,6 and antibacterial erythromycin
compound IV.7 Compounds 3 with a tertiary fluorinated carbon
at the 2-position of 1,3-dicarbonyl could be prepared by the
Michael or Mannich reactions of fluorinated substrates 2 (route
1),8,9 or by fluorination of the tertiary carbon of substrates 4
(route 2) (Scheme 1).10 However, to the best of our knowledge,
no one-pot fluorination and intermolecular Mannich reactions of
1,3-dicarbonyl compounds 1 to form both C-F and C-C bonds
have been reported.
Scheme 1. C-F & C-C bond formation for 1,3-dicarbonyl compounds 3
amount of waste solvent by eliminating the intermediate
purification step. As part of our continuous efforts in the
development of efficient and green synthetic methods,13,14 we
have recently reported a one-pot fluorination and Michael
addition for the synthesis of α-fluoro-β-ketoesters.8,15 Introduced
in this paper is the extension of the method for one-pot
fluorination and Mannich reaction of 1,3-dicarbonyl compounds
1 for the synthesis of α-fluoro and aminomethylated 1,3-
dicarbonyl compounds 3.
The Mannich reaction of an enolizable carbonyl compound, an
amine, and a nonenolizable aldehyde is a good method for the
synthesis of aminomethylated 1,3-dicarbonyl compounds. An α-
fluorinated and enolizable carbonyl compound has an acidic
proton, which is favorable for the Mannich reaction. We first
screened a range of salts as potential catalysts for the Mannich
reaction of α-fluorinated β-keto ester 2aa for the formation of
3ac. Under microwave heating at 120 oC for 30 min with 20
mol% of salt, only a trace or small amount of product was
detected from the reactions using AlCl3, CuCl2, TiCl2, Fe(NO3)3,
Mg(NO3)2, and Zn(OAc)2 (see Supporting Information). The
reaction with Zn(NO3)2 gave much high product yield. Further
exploring of reaction time (20-40 min), temperature (100-140
oC), and catalyst amount (0.1-0.4 equiv) confirmed that 20 mol%
of Zn(NO3)2 under microwave heating at 120 oC for 30 min was
the best condition which gave product in 89% yield (Table 1,
Figure 1. α-Fluorinated 1,3-dicarbonyl compounds.
One-pot synthesis is a green technique with a good step
economy.11,12 It saves reaction time and energy, and reduces the
_____________________________
* Corresponding author. Tel.: +1 617 287 6147; fax: +1 617 287 6030.
E-mail address: wei2.zhang@umb.edu.

2
Tetrahedron
entry 5). Regular heating at 120 oC only gave 60% product even
after 18 h (entry 9).
such as NO2 or CF3 gave good to excellent product yields
because of increased electrophilicity of imines are more
favorable for the reaction with the enoles, whereas anilines
without an electron-withdrawing group gave trace or no products
(3ad, 3bc and 3bd) due to low electrophilicity of the imines. The
Mannich products 3a or 3b have two stereogenic centers. The
ratio of two diastereomers determined by 1H MNR is in the range
of 1:1 to 4:1.
Table 1. Optimization of the reaction conditionsa
The one-pot reactions of 1,3-diketone 1c were also carried out
using a 1:1:1 ratio of diketone, aniline, and benzaldehydes under
similar conditions developed for the reactions of β-ketoesters 1a
and 1b. It was found that the R2 group of anilines has a
significant impact on the yields, whereas the R3 of benzaldehydes
only have a minimal impact (Table 3). 1,3-Diketones 1c seems
to have a similar reactivity as β-ketoesters 1a and 1b. Again the
reactions of anilines without an electron-withdrawing group gave
no product (3ci and 3cj).
Entry
Zn(NO3)2
(equiv)
0.2
Temp
(oC)
Time
(min)
30
Yieldb
(%)
1
2
3
4
5
6
7
8
9
µw, 120
85
0.2
0.2
0.2
0.2
0.2
0.1
0.4
0.2
µw, 120
µw, 120
µw, 100
µw, 120
µw, 140
µw, 120
µw, 120
heating,120
20
40
30
30
30
30
30
18 h
62%
85%
73%
89%
89%
62%
87%
60%
Table 3. One-pot reactions of 1,3-diketone 1ca
a
Reactions were carried out using 0.2 mmol each of benzaldehydes and
aniline, and 20 mol% of Zn(NO3)2.
b LC-MS yield.
With an optimized condition for the Mannich reaction in
hands, we then explored the one-pot fluorination and Mannich
reactions (Table 2). The fluorination of 1a was conducted
following the reported procedure of heating a β-ketoester with
one equiv. of SelectfluorTM under microwave heating at 90 oC for
30 h.15 After completion of the fluorination, one equiv. each of
aniline and benzaldehyde, and 0.2 equiv. of Zn(NO3)2 was added
to the reaction mixture for the Mannich reaction. The reaction
o
mixture was then heated under microwave at 120 C for 30 min
to afford α-fluoro and aminomethylated β-ketoesters 3.16 It was
found that products with Ph as R1 (3aa-3ad) have slightly better
yields than that with Me as R1 (3ba-3bd) except for 3ae and 3be
which have strong electron-withdrawing CF3 groups on aniline
(Table 2). Anilines bearing an electron-withdrawing R2 group
a
Reactions were carried out using 0.5 mmol each of 1,3-ditekone and
SelectfluorTM, followed by addition of 0.5 mmol each of benzaldehyde and
aniline, and 20 mol% of Zn(NO3)2
Table 2. One-pot reactions of β-ketoesters 1a and 1ba
b
Isolated yield, diastereomeric ratio in parenthesis was determined by 1H
NMR.
Heteroaromatic amines and aldehydes were also employed for
the one-pot reactions (Table 4). 2-Aminopyridine with an
electron-withdrawing Cl gave 3af in a better yield than that of 2-
aminopyridine and 2-aminopyridine with a Me group to form 3ag
and 3ah. 2-Aminopyrimidine and its MeO analog gave products
3ck and 3cl in 45% and 50% yield, respectively.
Pyridinecarboxaldehydes were also employed for the one-pot
reactions. 3-Pyridinecarboxaldehyde gave products 3cm and 3cn
in good yields, but no products 3co-3cq were observed from the
reaction of 4-pyridinecarboxaldehyde under the same reaction
condition.
In summary, a one-pot and two-step reaction process involving
electrophilic fluorination of an enolizable 1,3-dicarbonyl
compound followed by the Mannich reaction with aromatic
amine and nonenolizable aromatic aldehyde has been developed.
This simple and efficient method has been demonstrated in the
synthesis of a series of α-fluoro and aminomethylated 1,3-
dicarbonyl compounds. The extension of this method for
asymmetric one-pot fluorination and Mannich reactions is
currently under investigation and will be reported in due course.
a
Reactions were carried out using 0.5 mmol each of β-ketoester and
SelectfluorTM, followed by addition of 0.5 mmol each of benzaldehydes and
aniline, and 20 mol% of Zn(NO3)2.
b
Isolated yield, diastereomeric ratio in parenthesis was determined by 1H
NMR.

3
Table 4. One-pot reactions with heteroaromatic amines and aldehydesa
3352–3365; (c) Wender, P.; Verma, V. A.; Paxton, T. J.; Pillow, T. H.
Acc. Chem. Res. 2008, 41, 40–49.
12. Review on one-pot synthesis: Vaxelaire, C.; Winter, P.; Christmann, M.
Angew. Chem. Int. Ed. 2011, 50, 3605–3607.
13. Zhang, W. Green Chem. 2009, 11, 911–920.
14. Other examples of one-pot synthesis from our lab: (a) Lu, Q.; Song, G.;
Jasinski, J. P.; Keeley, A. C.; Zhang, W. Green Chem. 2012, 14, 3010–
3012. (b) Zhang, W.; Lu, Y.; Geib, S. J. Org. Lett. 2005, 7, 2269–2272.
(c) Kadam, A.; Bellinger, S.; Zhang, W. Green Process. Synth. 2013, 2,
491–497.
15. Yi, W.-B.; Huang, X.; Cai, C.; Zhang, W. Green Chem. 2012, 14, 3185–
3189.
16. General procedure for the one-pot synthesis: 1,3-dicarbonyl compound 1
(0.5 mmol) and SelectfluorTM (from Sigma, 0.5 mmol) in 1.0 mL of
CH3CN was heated under Biotage Initiator microwave reactor at 90°C for
30 min. Then a benzaldehyde (0.5 mmol), an aniline (0.5 mmol) and
Zn(NO3)2 (20 mol%) were carefully added to the fluorinated reaction
mixture at room temp. The mixture was then heated under microwave at
120 °C for another 30 min. After an aqueous work up, the crude product
was purified by flash column chromatography on silica gel to give
fluorinated Mannich product 3.
a
Reactions were carried out using 0.5 mmol each of 1,3-dicarbonyl
compounds and SelectfluorTM, followed by addition of 0.5 mmol each of
benzaldehydes and aniline, and 20 mol% of Zn(NO3)2.
b
Isolated yield, diastereomeric ratio in parenthesis was determined by 1H
NMR.
Acknowledgments
We thank the UMass Boston Healey Grant for their support of
this work.
Supplementary data
Supplementary data associated with this article can be found in
the online version at
References and notes
1. Banks, R. E.; Smart, B. E.; Tatlow J. C. Organofluorine Chemistry:
Principles and Commercial Applications, Springer: New York, 1994.
2. Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I. Ed.;
Wiley-Blackwell, Chichester, 2009.
3. Jeschke, P. ChemBioChem. 2004, 5, 570–589.
4. Austin, J. F.; Kim; S.-G. Sinz, C. J.; Xiao, W.J.; Macmillan, D. W. C.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482-5487.
5. Sarantakis, D.; Bicksler, J. J.; Wu, J. C. US 20060014826, 2006.
6. Abad, A.; Agullo, C.; Cunat, A. C.; Gonzalez-Coloma, A.; Pardo, D.
Eur. J. Org. Chem. 2010, 2182–2198.
7. Phan, L. T.; Clark, R. F.; Rupp, M.; Or, Y. S.; Chu, D. T. W.; Ma, Z.
Org. Lett. 2000, 2, 2951–2954.
8. Examples of asymmetric Michael additions of α-fluorinated 1,3-
dicarbonyl compounds: (a) Huang, X.; Yi, W.-B.; Ahad, D.; Zhang, W.
Tetrahedron Lett. 2013, 54, 6064–6066; (b)Yi, W.-B.; Zhang, Z.; Huang,
X.; Tanner, A.; Cai, C.; Zhang, W. RSC Advances 2013, 3, 18267–18270,
and the references cited therein; (c) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.;
Lee, R.; Yang, Y.; Huang, K.-W.; Wong, M. W.; Tan, C.-H. Angew.
Chem. Int. Ed. 2009, 48, 3627–3631; (d) Li, F.; Nie, J.; Wu, J.-W.;
Zheng, Y.; Ma, J.-A. J. Org. Chem. 2012, 77, 2398−2406.
9. Examples of asymmetric Mannich reactions of α-fluorinated 1,3-
dicarbonyl compounds: (a) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.
W.; Lu, Y. Angew. Chem. Int. Ed. 2009, 48, 7604–7607; (b) Pan, Y.;
Zhao, Y.; Ma, T. Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem. Eur. J.
2010, 16, 779–782; (c) Lee, J. H.; Kim, D. Y. Synthesis 2010, 1860-1864;
(d) Kang, Y. K.; Yoon, S. J.; Kim, D. Y. Bull. Korean Chem. Soc. 2011,
32, 1195–1200; (e) Yoon, S. J.; Kang, Y. K.; Kim, D. Y. Synlett 2011,
420–424; (f) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2011, 52, 2356–
2358;
10. Yi, W.-B.; Huang, X.; Zhang, Z.; Zhu, D.-Z.; Cai, C.; Zhang, W.
Beilstein J. Org. Chem. 2012, 8, 1233–1240, and the references cited
therein.
11. Reviews on atom- and step-economy synthesis: (a) Trost, B. M. Acc.
Chem. Res. 2002, 35, 695–705; (b) Sheldon, R. Chem. Commun. 2008,