Convenient one-pot synthesis of fluorinated DHPs derivatives and their further transformations

Article abstract of DOI:10.1016/j.tetlet.2010.05.110

One-pot four-component reactions of aromatic aldehyde, Meldrum's acid, ethyl-4,4,4-trifluoro-1,3-dioxobutanoate, and ammonium acetate afford ethyl 2-hydroxy-6-oxo-4-aryl-2-(trifluoromethyl)piperidine-3-carboxylate in good yields. The one-pot four-component process consists of an initial Michael addition, and a subsequent intramolecular cyclization. The effect of solvents on the reaction efficiency and yield is briefly investigated. The structure of product is further confirmed by XRD analysis. Meanwhile, the further transformation of hemi-aminal moiety to the corresponding dehydrated product is also achieved under the mild reaction conditions. The possible mechanism for the formation of product is presented.

Full text of DOI:10.1016/j.tetlet.2010.05.110

Tetrahedron Letters 51 (2010) 3975–3977
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient one-pot synthesis of fluorinated DHPs derivatives and their
further transformations
a
a
b,
c
c
Pengyuan Wang a, Liping Song a,b, , Hai Yi , Min Zhang , Shizheng Zhu , Hongmei Deng , Min Shao
*
*
a Department of Chemistry, School of Science, Shanghai University, No. 99, Shangda Road, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
c Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, China
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot four-component reactions of aromatic aldehyde, Meldrum’s acid, ethyl-4,4,4-trifluoro-1,3-
dioxobutanoate, and ammonium acetate afford ethyl 2-hydroxy-6-oxo-4-aryl-2-(trifluoromethyl)piperi-
dine-3-carboxylate in good yields. The one-pot four-component process consists of an initial Michael
addition, and a subsequent intramolecular cyclization. The effect of solvents on the reaction efficiency
and yield is briefly investigated. The structure of product is further confirmed by XRD analysis. Mean-
while, the further transformation of hemi-aminal moiety to the corresponding dehydrated product is also
achieved under the mild reaction conditions. The possible mechanism for the formation of product is
presented.
Received 23 March 2010
Revised 18 May 2010
Accepted 25 May 2010
Available online 27 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Fluorine-containing compounds have attracted much interest
since the introduction of fluorine atoms or fluoroalkyl moieties to
an organic compound can bring about remarkable changes in the
physical, chemical, and biological properties.1–3 For example, the
introduction of fluorine atoms or fluoroalkyl groups (particularly
the CF3 group) to molecules constitutes a classical and systematic
modification of biological properties used in medicinal chemistry
for the design of new drugs.4 Consequently, more and more fluor-
oalkylated molecules have recently been found to be applied in the
pharmaceutical fields.5
On the other hand, it is well known that the dihydropyridine
(DHP) heterocyclic ring is a part of the fundamental skeleton of
important classes of drugs.6,7 For example, 1,4-dihydropyridines
(1,4-DHPs) are the most important calcium channel modulators.8
In fact, it is well established that slight structural modification on
the DHP ring may bring about remarkable changes in pharmaco-
logical effect.9 Due to these observations, fluoroalkylated DHP ring
should be valuable building blocks to construct medicinally rele-
vant complex structures.
In our initial study, the one-pot four-component reaction was
conducted by stirring the mixture of equivmolecular of corre-
sponding aromatic aldehyde 1a, Meldrum’s acid 2, ethyl-4,4,4-tri-
fluoro-1,3-dioxobutanoate 3, and ammonium acetate 4 in ethanol
at room temperature for 2 h, however, no desired product 5a was
detected. Subsequently, the mixture was heated to reflux and stir-
red for 4 h, TLC showed that a new compound, which turned out to
be the desired product, was formed and general workup afforded
the product 5a in 21% yield.
To optimize this reaction conditions, the same reaction was car-
ried out in various solvents. The reaction results are summarized in
Table 1. It was found that the reactions gave the product 5a in rel-
atively low yields in the solvents of ethanol, methanol, acetone,
acetonitrile, and CH2Cl2 (Table 1, entries 1–5). Moreover, it was
observed that the solvent effect played an important role in the
transformation, and the reaction yield could be enhanced to 54%
when AcOH was employed as the solvent (Table 1, entry 6). Pro-
longed reaction time (6 h) slightly increased the yield up to 61%
(Table 1, entry 7).
To further explore the potentials of such kind of strategy for
fluoroalkylated heterocyclic synthesis, we have recently started
systematic studies on the synthesis of fluorine-containing com-
pounds based on trifluoromethyl-1,3-dicarbonyl compound, a
versatile fluorine-containing building block.10 Herein, we wish to
report a one-pot, four-component reaction to synthesize the 1,4-
DHPs derivatives, together with their further dehydration reactions
to the corresponding dehydrated 1,4-DHPs derivatives.
The amount of ammonium acetate was the next considered fac-
tor. As shown in Table 1, the reactions gave the best yield when
1.2 equiv of NH4OAc was used (Table 1, entry 9). When the amount
of NH4OAc was further increased to 2.0 equiv, the yield did not im-
prove significantly (Table 1, entry 11). It should be noted that the
reaction exclusively gave the N-heterocyclic compound 5a, and
no corresponding O-heterocyclic compound was obtained even
though the reaction was carried out in the presence of 0.3 equiv
of NH4OAc (Table 1, entry 8).
With the optimal results in hand as shown in Table 1, entry 9,
we investigated the scope and limitation of this one-pot, four-com-
* Corresponding authors. Tel.: +86 21 66132190; fax: +86 21 66132797 (L.S.).
E-mail address: lpsong@shu.edu.cn (L. Song).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.110

3976
P. Wang et al. / Tetrahedron Letters 51 (2010) 3975–3977
Table 1
ther coupled with H3 with JH–H = 12.5 Hz. The coupling constant
further revealed that the trans configuration of the two vicinal
hydrogen atoms, H3 and H4, respectively. The chemical shift of
CF3 group in 19F NMR was a singlet peak nearly at d À84.4 ppm
(s, 3F), which indicated that the CF3 group was bonded to a quater-
nary carbon atom. Furthermore, the structure of product 5l was
confirmed by XRD analysis (Fig. 1).13
Reaction of ethyl-4,4,4-trifluoro-1,3-dioxobutanoate 3 with benzaldehydes 1, Mel-
drum’s 2, and NH4OAc 4 under various conditionsa
Ph
O
O
O
O
O
O
CO2Et
CF3
+
+
NH4OAc
+
PhCHO
F3C
OEt
O
N
H
OH
1a
2
3
4
5a
From the results described above, a possible mechanism for the
formation of compounds 5 was proposed in Scheme 1. It was con-
ceivable that the initial event was the formation of A from arylde-
hyde 1 and Meldrum’s acid 2 via Knoevenagel condensation, which
underwent Michael addition with ethyl-4,4,4-trifluoro-1,3-dioxo-
butanoate 3 to produce the intermediate B. Intermediate B reacted
with the ammonia, by losing one molecular acetone, to give ketene
C, and then underwent intramolecular cyclization and decarboxyl-
ation to produce 5. It was worth mentioning that the cyclic prod-
ucts must be formed by N-attack of intermediate C, other than
by O-attack to afford the corresponding O-heterocyclic compounds.
Finally, we studied dehydration of compounds 5. It should be
indicated that the hemi-aminal moiety in 5 is stable, which resists
dehydration under the present reaction conditions due to the
strong electron-withdrawing effect of trifluoromethyl group on
the six-membered ring.14 However, it was found that water was
smoothly eliminated from compounds 5 and the corresponding
dehydrated 1,4-DHP derivatives were obtained in good yields in
the presence of an excess of TsOH in refluxing CHCl3 (Table 3). It
was noted that when compared with the non-fluorinated sub-
strates, most b-ketoester compounds studied resulted in the for-
mation of the corresponding dehydrated products directly.15
In summary, we have shown that the one-pot four-component
reaction provides a simple and convenient approach to ethyl 2-hy-
droxy-6-oxo-4-aryl-2-(trifluoromethyl)piperidine-3-carboxylate
and ethyl 6-oxo-4-aryl-2-(trifluoromethyl)-1,4,5,6-tetrahydropyri-
dine-3-carboxylate from readily available starting materials by
dehydration of hemi-aminal moiety under mild conditions, which
may be considered as useful CF3-containing substrates for the syn-
thesis of a wide variety of heterocyclic compounds with potential
Entry
Solvent
NH4OAca (equiv)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
EtOH
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.3
1.2
1.5
2.0
4
4
4
4
4
4
6
6
6
6
6
21
20
24
19
17
54
61
26
67
65
67
MeOH
MeCN
CH3COCH3
CH2Cl2
AcOH
AcOH
AcOH
AcOH
AcOH
10
11
AcOH
a
All reactions were carried out at the reflux temperature with the NH4OAc.
Isolated yields.
b
ponent reaction with a variety of aromatic aldehydes, and the cor-
responding products 5 were generally obtained in moderate to
good yields and the reaction results are summarized in Table 2.
On one hand, the aryldehydes bearing either electron-donating
or electron-withdrawing group have slightly influenced the effi-
ciency of the reaction. The substrates with electron-donating
groups resulted in lower yield (Table 2, entries 12 and 13), while
the substrates with electron-withdrawing groups (Table 2, entries
1–10) afforded the corresponding products in higher yield. On the
other hand, the substituents located at para, ortho, or meta posi-
tions of aryldehydes have not shown much effect on the formation
of products (Table 2, entries 7–9).
The structures of products 5 were fully confirmed by 1H NMR,
19F NMR, IR spectroscopy, mass spectrometry, and elemental anal-
ysis. For instance, the 1H NMR spectrum of 5 exhibited a character-
istic ABX system corresponding to the three protons of the
heterocyclic ring, H4, H5a, and H5b. Usually H4 exhibited a dd peak
in ABX system. However, in our cases, the H4 appeared as a ddd
peak nearly at d 3.6 ppm due to this characteristic dd peak was fur-
Table 2
Synthesis of 511,12 under the optimal conditiona
Ar
O
O
O
O
O
CO2Et
CF3
+
+
NH4OAc
+
ArCHO
F3C
OEt
O
N
H
OH
O
1
2
3
4
5
Entry
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
67
73
71
63
69
74
70
67
65
68
64
63
61
4-O2NC6H4
2-O2NC6H4
2,4-(NO2)2C6H3
4-ClC6H4
2-ClC6H4
4-BrC6H4
2-BrC6H4
3-BrC6H4
4-CNC6H4
2-CNC6H4
4-MeC6H4
4-MeOC6H4
5j
5k
5l
5m
a
All reactions were carried out at the reflux temperature with the 1.2 equiv of
NH4OAc in the solvent of AcOH.
b
Isolated yields.
Figure 1. Crystal structure of compound 5l.

P. Wang et al. / Tetrahedron Letters 51 (2010) 3975–3977
3977
4. Burger’s Medicinal Chemistry and Drug Discovery; Abraham, D. J., Ed.; John Wiley
and Sons: New York, 2003; Vol. 1,.
5. (a) Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27–33; (b) Welch, J. T.;
Ewarakrishnan, S. E. Fluorine in Bioorganic Chemistry; John Wiley: New York,
1991; (c) Becker, A. Inventory of Industrial Fluoro-Biochemicals; Eyrolles: Paris,
1996.
O
O
O
O
+
ArCHO
1
2
6. (a) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141–1156; (b) Sausins, A.;
Duburs, G. Heterocycles 1988, 27, 269–289.
O
O
Ar
O
O
7. (a) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamatsu, Y.; Nagaoka, A. Chem. Pharm.
Bull. 1985, 33, 3787–3797; (b) Triggle, D. J. Cell. Mol. Neurobiol. 2003, 23, 293–
303; (c) De Simone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D.
A. Comb. Chem. 2004, 7, 473–493; (d) Loev, B.; Ehrreich, S. J.; Tedeschi, R. E. J.
Pharm. Pharmacol. 1972, 24, 917–918; (e) Harrold, M. In Foye’s Principles of
Medicinal Chemistry; Williams, D. A., Lemke, T. L., Eds., 5th ed.; Lippin-cott
Williams and Wilkins: Baltimore, 2002; pp 533–561; (f) Mojarrad, J. S.; Vo, D.;
Velázquez, C.; Knaus, E. E. Bioorg. Med. Chem. 2005, 13, 4085–4091.
8. (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed. 1981, 20, 762–769;
(b) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223–243; (c) Janis, R. A.;
Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309–591; (d) Bossert, F.; Vater,
W. Med. Res. Rev. 1989, 9, 291–324; (e) Marchalin, S.; Chudik, M.; Mastihuba,
V.; Decroix, B. Heterocycles 1998, 48, 1943–1958; (f) Achiwa, K.; Kato, T. Curr.
Org. Chem. 1999, 3, 77–106.
O
NH4OAc
HOAc
O
O
O
OEt
CF3
+
O
O
F3C
OEt
Ar
O
NH3
O
3
B
A
acetone
Ar
Ar
O
CO2Et
OH
HOOC
-CO2
OEt
OH
C
O
9. (a) Schramm, M.; Thomas, G.; Towan, I. L.; Franckowiak, G. Nature 1983, 303,
535–537; (b) Brown, A. M.; Kunz¢, D. L.; Yatani, A. Nature 1984, 311, 570–572;
(c) Chorvat, R. J.; Rorig, K. J. J. Org. Chem. 1988, 53, 5779–5781; (d) Kappe, C. O.
Tetrahedron 1993, 49, 6937–6963; (e) Kappe, C. O.; Fabian, W. M. F. Tetrahedron
1997, 53, 2803–2816.
O
N
H
CF3
H2N CF3
C
5
Scheme 1. A possible mechanism for formation of 5.
10. (a) Song, L. P.; Li, X. F.; Xing, C. H.; Li, D. M.; Zhu, S. Z.; Deng, H. M.; Shao, M.
Synlett 2010, 5, 830–834; (b) Dai, B. F.; Song, L. P.; Wang, P. Y.; Yi, H.; Jin, G. F.;
Zhu, S. Z.; Shao, M. Synlett 2009, 11, 1842–1846; (c) Song, S. D.; Song, L. P.; Dai,
B. F.; Yi, H.; Jin, G. F.; Zhu, S. Z.; Shao, M. Tetrahedron 2008, 64, 5728–5735; (d)
Li, D. M.; Song, L. P.; Li, X. F.; Xing, C. H.; Peng, W. M.; Zhu, S. Z. Eur. J. Org. Chem.
2007, 3520–3525; (e) Li, D. M.; Song, L. P.; Song, S. D.; Zhu, S. Z. J. Fluorine Chem.
2007, 128, 952–957; (f) Li, X. F.; Song, L. P.; Xing, C. H.; Zhao, J. W.; Zhu, S. Z.
Tetrahedron 2006, 62, 2255–2263.
Table 3
Dehydration reaction of 5 to compound 616,17
O
O
NH
OH
NH
11. Typical experimental procedure for synthesis of 5a: A mixture of ethyl-4,4,4-
trifluoro-1,3-dioxobutanoate 3 (1.0 mmol, 184.0 mg), corresponding aromatic
aldehyde 1a (1.0 mmol, 106.0 mg), Meldrum’s acid 2 (1.0 mmol, 144.0 mg),
and ammonium acetate 4 (1.2 mmol, 94.0 mg) in acetic acid (8.0 mL) was
heated at 118 °C for 6 h. After the evaporation of AcOH under reduced pressure,
saturated aqueous NaHCO3 solution and EtOAc were added. The two layers
were separated and the aqueous layer was further extracted with EtOAc. The
combined organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure to give a residue, which was purified by column
chromatography on silica gel using petroleum ether/ethyl acetate, 10:1(v/v) as
eluent to give the pure product 5a 221.0 mg, 67% yield.
CF3
CO2Et
CF3
CO2Et
R
R
5
6
Entry
R
Product
Time (h)
Yieldb (%)
1
2
3
H
4-O2N
2-Cl
6a
6b
6c
5
3
3
81
89
85
aReaction conditions: 5 (0.5 mmol), p-TsOH (1.5 mmol, 3 equiv), solvent: CHCl3
12. Spectroscopic data for products 5: Compound 5a: White solid; mp: 169–170 °C;
(8 ml), refluxing.
IR (KBr)
m
max: 3448, 3212, 3110, 2983, 1734, 1691, 1496, 1377, 1201, 1028, 769,
;
b
Isolated yields.
703 cmÀ1
1H NMR (500 MHz, CDCl3): d = 0.77 (t, J = 7.0 Hz, 3H), 2.71 (dd,
J1 = 18.0 Hz, J2 = 12.5 Hz, 1H), 2.82 (dd, J1 = 18.0 Hz, J2 = 5.0 Hz, 1H), 3.18 (d,
J = 12.5 Hz, 1H), 3.62 (ddd, J1 = J2 = 12.5 Hz, J3 = 5.0 Hz, 1H), 3.81 (q, J = 7.0 Hz,
2H), 6.08 (s, 1H), 6.39 (s, 1H), 7.22–7.24 (m, 2H), 7.29–7.37 (m, 3H). 19F NMR
(470 MHz, CDCl3): d = À84.38 (s, 3F, CF3); MS (ESI) m/z: 332 [M+H]+; Anal.
Calcd for C15H16F3NO4: C, 54.38; H, 4.87; N, 4.23. Found: C, 54.13; H, 4.87; N,
4.13.
biological activity. Further studies on the synthetic application of
this method are now in progress.
Acknowledgments
13. CCDC-765386 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
14. Zhu, S. Z.; Song, L. P.; Jin, G. F.; Dai, B. F.; Hao, J. Curr. Org. Chem. 2009, 13, 1015–
1027.
The authors thank the National Natural Science Foundation of
China (NNSFC) (Nos. 20672072, 20772080), Leading Academic Dis-
cipline Project of Shanghai Municipal Education Commission (No.
J50102), the Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, and the Innovation Fund of Shang-
hai University for financial support.
ˇ
ˇ
15. (a) Svetlik, J.; Goljer, I.; Turecek, F. J. Chem. Soc., Perkin. I 1990, 1315–1318; (b)
Ochoa, E.; Suárez, M.; Verdecia, Y.; Pita, B.; Martin, N.; Quinteiro, M.; Seoane,
C.; Soto, J. L.; Duque, J.; Pomés, R. Tetrahedron 1998, 54, 12409–12420; (c)
Rodriguez, H.; Suarez, Z.; Pérez, R.; Petit, A.; Loupy, A. Tetrahedron Lett. 2003,
44, 3709–3712.
16. Typical experimental procedure for preparation of 6a: A solution of compounds 5
(0.5 mmol, 165.5 mg) and p-TsOH (1.5 mmol, 3.0 equiv, 285.0 mg) in CHCl3
(8.0 mL) was refluxed (62 °C) for indicated hours until completion of the
reaction (monitored by TLC). The solvent was removed by rotavapor and the
residue was purified by column chromatography on silica gel using petroleum
ether/ethyl acetate 8:1 (v/v) as eluent to afford the pure product 6a 253.0 mg,
81% yield.
References and notes
1. (a) Hiyama, T. Organofluorine Compounds; Springer: Berlin, 2000; (b) Hudlicky,
M. Chemistry of Organic Fluorine Compounds, 2nd ed.; Ellis Harwood: Chichester,
1976.
2. (a)Fluorine in Bioorganic chemistry; Welch, J. T., Eswarakrishnan, S., Eds.; Wiley:
New York, 1991; (b) Prabhakaran, J.; Underwood, M. D.; Parsey, R. V.; Arango,
V.; Majo, V. J.; Simpson, N. R.; Heertum, R. V.; Mann, J. J.; Kumar, J. S. D. Bioorg.
Med. Chem. 2007, 15, 1802–1807.
3. (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine Chemistry; Kodansha
& Elsevier Biomedical: Tokyo, 1982; (b) Filler, R.; Kobayashi, Y.; Yagupolskii, L.
M. Organofluorine Compounds in Medical Chemistry and Boimedical Application;
Elsevier: Amsterdam, 1993.
17. Spectroscopic data for products 6: Compound 6a: White solid; mp: 145–146 °C;
IR (KBr)
m
max: 3224, 3135, 2993, 1720, 1689, 1598, 1484, 1368, 1217, 1013,
786, 772, 748 cmÀ1
;
1H NMR (500 MHz, CDCl3): d = 1.16 (t, J = 7.0 Hz, 3H), 2.80
(dd, J1 = 17.0 Hz, J2 = 4.5 Hz, 1H), 2.96 (dd, J1 = 17.0 Hz, J2 = 7.5 Hz, 1H), 4.12 (q,
J = 7.0 Hz, 2H), 4.22–4.26 (m, 1H), 7.19–7.21 (m, 2H), 7.26–7.29 (m, 1H), 7.31–
7.34 (m, 2H), 7.74 (s, 1H). 19F NMR (470 MHz, CDCl3): d = À64.27 (s, 3F, CF3);
MS (ESI) m/z: 336 [M+Na]+; Anal. Calcd for C15H14F3NO3: C, 57.51; H, 4.50; N,
4.47. Found: C, 57.72; H, 4.49; N, 4.36.