Efficient multicomponent reaction for the synthesis of piperidine derivatives: Yb(OTf)3/AgOTf cocatalyzed preparation of trimethyl 3,5,5-piperidonetricarboxylate

Article abstract of DOI:10.1080/00397910802323122

A novel and convenient one-pot synthesis of trimethyl 3,5,5- piperidonetricarboxylate was reported. Cocatalyzed by Yb(OTf)3 and AgOTf under mild conditions, a piperidone containing a β-amino acid template was synthesized from dimethyl malonate and formaldehyde O-benzyl oxime in high yield. It could be a useful building block for the synthesis of multisubstituted piperidine derivatives. Copyright Taylor & Francis Group, LLC.

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Efficient Multicomponent
Reaction for the Synthesis
of Piperidine Derivatives:
Yb(OTf)3/AgOTf Cocatalyzed
Preparation of Trimethyl 3,5,5-
Piperidonetricarboxylate
Gao-Yan Lian a , Feng Lin a , Jin-Di Yu a & Dan-Wei
Zhang a
a Department of Chemistry, Fudan University,
Shanghai, China
Version of record first published: 08 Nov 2008
To cite this article: Gao-Yan Lian, Feng Lin, Jin-Di Yu & Dan-Wei Zhang (2008):
Efficient Multicomponent Reaction for the Synthesis of Piperidine Derivatives:
Yb(OTf)3/AgOTf Cocatalyzed Preparation of Trimethyl 3,5,5-Piperidonetricarboxylate,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:24, 4321-4327
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Synthetic Communications1, 38: 4321–4327, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802323122
Efficient Multicomponent Reaction for the
Synthesis of Piperidine Derivatives:
Yb(OTf)3/AgOTf Cocatalyzed Preparation of
Trimethyl 3,5,5-Piperidonetricarboxylate
Gao-Yan Lian, Feng Lin, Jin-Di Yu, and Dan-Wei Zhang
Department of Chemistry, Fudan University, Shanghai, China
Abstract: A novel and convenient one-pot synthesis of trimethyl 3,5,5-piperidone-
tricarboxylate was reported. Cocatalyzed by Yb(OTf)3 and AgOTf under mild
conditions, a piperidone containing a b-amino acid template was synthesized from
dimethyl malonate and formaldehyde O-benzyl oxime in high yield. It could be a
useful building block for the synthesis of multisubstituted piperidine derivatives.
Keywords: Cocatalyst, multicomponent reaction, piperidine derivatives
Multisubstituted piperidines are key building blocks for the synthesis of
bioactive compounds or natural products (e.g., agonists of human
GABA-A receptors,[1] farnesyl-protein transferase inhibitors,[2] and opti-
cally active indole alkaloids[3]). Consequently, stereoselective construc-
tion of piperidine derivatives is of great interest.[4] Among these
compounds, as show in Scheme 1, 3,5-cis-piperidine-dicarboxylates (A)
are common intermediates for the preparation of biologically important
compounds, for example, conformational constrained cyclic b,c0-diamino
acid units (B), which serve as inducing factors of the peptidomimetic sec-
ondary structures[5], and N-(indol-3-ylglyoxylyl) 3,5-cis-piperidinedicar-
boxylate (C), which was reported to be a high-affinity agonist of
human GABA-A receptors.[1] Usually, structure-related compound A is
Received April 25, 2008.
Address correspondence to Dan-Wei Zhang, Department of Chemistry,
Fudan University, 220 Handon Road, Shanghai 200433, China. E-mail:
zhangdw@fudan.edu.cn
4321

4322
G.-Y. Lian et al.
Scheme 1. Examples of bioactive piperidine derivatives.
synthesized by hydrogenation of corresponding pyridine derivatives
under strict reaction conditions in medium yield.
In our continuous study of asymmetric synthesis of b-amino acids, an
efficient multicomponent synthesis of 3,5,5-piperidonetricarboxylate 3[6]
(which can be easily transferred to the key intermediate 3,5-piperidinedi-
carboxylate A, followed literature methods[7,8]), from dimethyl malonate
1 and formaldehyde O-benzyl oxime 2 was found accidentally. In the pre-
sent work, we describe our preliminary results on this Lewis acid and
metal triflate cocatalyzed, one-pot, multicomponent reaction.
Initially, we predicted a simple Mannich base product from the reac-
tion of dimethyl malonate 1 to oxime 2. To our surprise, a multisubsti-
tuted piperidone 3 was obtained in almost quantitative yield (Scheme 2).
The structure of piperidone 3 has been characterized by a detailed analysis
1
by NMR spectroscopy, including H NMR, 13C NMR, distortionless
enhancement by polarization transfer (DEPT 135), H-H correlation spec-
troscopy (COSY), and heteronuclear multiple-quantum coherence
(HMQC) spectra. Three singlet methoxy group signals (d 3.80, 3.76, and
3.75 ppm) and four carbonyl group signals (d 169.3, 168.5, 168.1, and
1
162.5 ppm) are indicated in H and 13C NMR spectra. DEPT 135 spec-
trum proves that the product possesses one quaternary carbon at d
Scheme 2. Synthesis of piperidone derivative 3.

Multicomponent Synthesis of Piperidine Derivatives
4323
1
Figure 1. Characterization of H NMR and 13C NMR signals of compound 3.
1
The chemical shifts of H NMR are in parenthesis.
53.1 ppm, one tertiary carbon at d 46.8 ppm (which is related to the dd sig-
nal of d 3.63 presented in 1H NMR spectrum), and other three secondary
carbons of d 76.1, 53.49, and 29.8 ppm (attributed by benzyloxy methylene
and two methylenes of the piperidine ring, respectively). The characteriza-
1
tion of the signals of H and 13C NMR spectra are indicated in Fig. 1.
Further studies revealed that both Yb(OTf)3 and AgOTf are essential
to this multicomponent reaction. The results are shown in Table 1. No
reaction happened without either of the catalysts (entries 2 and 3). When
Table 1. Reaction of dimethyl malonate 1 and oxime 2 cocatalyzed by silver tri-
flate and ytterbium triflate
Isolated yield (%)
Entry 1=2=Yb(OTf)3=
AgOTf
Conc. of
Substrate 2
Conditions
3
4
1
2
3
4
5
6
7
8
1.1=1=0.3=0.2
1.1=1=0.3=—
1.1=1=—=0.2
1.1=1=0.3=0.05
1.1=1=0.3=0.2
1.1=1=0.3=0.2
2.1=1=0.3=0.2
1=1.8=0.3=0.4
0.5 M
0.5 M
0.5 M
0.5 M
0.5 M
0.05 M
0.5 M
0.5 M
Reflux, 17 h
Reflux, 17 h
Reflux, 5.5 h NR
Quantitative
No reaction (NR)
Reflux, 17 h
rt 23 h
NR
NR
Reflux, 17 h
Reflux, 17 h
Reflux, 17 h
19
11
18
72
Quantitative

4324
G.-Y. Lian et al.
the loading amount of AgOTf was too low (0.05 equiv.), the reaction did
not happen (entry 4). The reaction temperature and concentration were
found among other prominent effects to the reaction. At room tempera-
ture, no reaction was detected (entry 5). When the concentration of the
reaction mixture was as low as 0.05 M, the yield of 3 dropped dramati-
cally to 19%. Simultaneously, 18% of tetramethyl propane-1,1,3,3-tetra-
carboxylate 4[9] was produced (entry 6). To make a conjecture about
the reaction mechanism, we examined the reactions carried out at differ-
ent ratios of malonate 1 to oxime 2. The results showed that the ratio of
the two reactants is very important to the population of the two products.
When the ratio of 1 to 2 was 2.1:1, the yield of 3 decreased to 11% while
the yield of 4 increased to 72% (entry 7). When the oxime 2 was more
then 1.8 equiv of that of malonate 1, compound 3 was quantitatively pro-
duced, just like the result of the reaction of equal equivalents of the two
reactants (cf. entry 8 and entry 1).
A possible mechanism of this reaction is presented in Scheme 3. The
formation of compounds 3 and 4 could constitute the process of the
following domino reactions. Dimethyl malonate 1, activated by Lewis
acid Yb(OTf)3, undergoes nucleophilic addition to oxime 2, which is
Scheme 3. Possible reaction mechanism.

Multicomponent Synthesis of Piperidine Derivatives
4325
combined with AgOTf through the Mannich reaction. Then, followed by
the Hoffmann elimination, the Michael acceptor 5 is obtained. Another
molecular of activated dimethyl malonate plays the role of the Michael
donor; a 1,4-addition reaction with this Michael acceptor 5 produces
the product 4. The compound 4 can react with another equivalent of
oxime 2 to construct the Mannich base with a quaternary carbon center.
Following intramolecular aminolysis, this crowd builds six-membered
ring piperidone derivative 3. If not enough oxime 2 exists, the reaction
would be favored to stop at compound 4 (Table 1, entry 7).
In conclusion, we developed a novel Yb(OTf)3 and AgOTf cocata-
lyzed multicomponent reaction for synthesis of trimethyl 3,5,5-piperido-
netricarboxylate. A domino-sequence mechanism was put forward to
explain this one-pot synthesis.
EXPERIMENTAL
All the starting materials are commercial available. Formaldehyde
O-benzyl oxime 2 was prepared according to the reported process.[10]
CH2Cl2 was used directly without pretreatment. Flash-column chromato-
graphy was performed on Qing Dao Hai Yang silica gel 60 (230–400 mesh
ASTM) using ethyl acetate=n-hexane as eluting solvents. NMR spectra
were recorded on a Jeol ECA-400 or Bruker DMX-400. Mass spectra were
recorded with a Finnigan MAT 95 mass spectrometer for both low-
resolution and high-resolution mass spectra (LRMS and HRMS).
Typical Procedure for Yb(OTf)3 and AgOTf Cocatalyzed Reaction
Between Dimethyl Malonate (1) and Formaldehyde O-Benzyl Oxime (2)
Formaldehyde O-benzyl oxime 2 (68 mg, 0.5 mmol) and dimethyl malo-
nate 1 (60 mL, 0.55 mmol) was dissolved in CH2Cl2 (1 mL); AgOTf
(26 mg, 0.1 mmol) and Yb(OTf)3 (91 mg, 0.15 mmol) were added subse-
quently. The reaction was warmed up to reflux. After 17 h, the reaction
was quenched by water (1 mL). The mixture was extracted by CH2Cl2
(2 mL ꢀ 2). The aqueous layer was combined and dried with anhydrous
Na2SO4. After concentration, the residue was purified by flash-column
chromatography to get 3 (105 mg, quantitative).
Trimethyl 1-(Benzyloxy)-piperidone-3,5,5-tricarboxylate (3)
Yellow oil; EtOAc–n-hexane¼1:2, Rf¼0.54; 1H NMR (400 HMz, CDCl3)
d 7.44–7.26 (m, 5H, Ph), 4.96 (AB, JAB¼10.2 Hz, 2H, OCH2), 4.10 (dd,

4326
G.-Y. Lian et al.
J¼11.7, 2.0 Hz, 1H, e-bond NCH2), 3.86 (d, J¼12.2 Hz, 1H, a-bond
NCH2), 3.80 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
3.63 (dd, J¼12.0, 6.4 Hz, 1H, CH), 2.69 (ddd, J¼13.7, 6.4, 2.0 Hz, 1H,
e-bond CH2), 2.48 (dd, J¼13.7, 11.2 Hz, 1H, a-bond CH2); 13C NMR
(100 HMz, CDCl3) d 169.3 (C¼O), 168.5 (C¼O), 168.1 (C¼O), 162.5
(C¼O), 134.8 (C), 129.6 (CH), 128.8 (CH), 128.5 (CH), 76.1 (OCH2),
53.6 (OCH3), 53.51 (OCH3), 53.49 (NCH2), 53.1 (C), 52.8 (OCH3),
46.8 (CH), 29.8 (CH2); LRMS (EI) m=z 214 (Mþ þ 1–CO2Me–OBn,
100); HRMS (EI) for C18H21NO8 (Mþ): calcd. 379.1267, found 379.1286.
Tetramethyl Propane-1,1,3,3-tetracarboxylate (4)[9]
Colorless oil; EtOAc–n-hexane¼1:2, Rf¼0.37; 1H NMR (400 HMz,
CDCl3) d 3.75 (s, 12H, 4OCH3), 3.52 (t, J¼7.5 Hz, 2H, 2CH), 2.50 (t,
J¼7.5 Hz, 2H, CH2); 13C NMR (100 HMz, CDCl3) d 168.9 (C¼O),
52.7 (OCH3), 49.0 (CH), 27.4 (CH2). Its data were identical to those
reported in the literature.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of
China (Project No. 20229201), Science and Technology Commission of
Shanghai Municipality (STCSM), Fudan University. D.-W. Z. thanks
the Century Star Award from Fudan University. We thank Prof. Dan
Yang for kindly suggestions and discussion.
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