Direct N-H/α,α,β,β-C(sp3)-H functionalization of piperidine via an azomethine ylide route: synthesis of spirooxindoles bearing 3-substituted oxindoles

Article abstract of DOI:10.1039/c6cc08996h

A protocol for the direct functionalization of N-H/α,α,β,β-C(sp³)-H of piperidine without any metal or external oxidants is reported. This reaction is promoted by 4-(trifluoromethyl)benzoic acid via an azomethine ylide intermediate. This is a simple method for the synthesis of spirooxindoles bearing 3-substituted oxindole moieties.

Full text of DOI:10.1039/c6cc08996h

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Direct N-H/α, α, β, β-C(sp3)-H functionalization of piperidine via
an azomethine ylide route: synthesis of spirooxindoles bearing 3-
substituted oxindoles
Received 00th January 20xx,
Accepted 00th January 20xx
Yanlong Du, Aimin Yu, * Jiru Jia, Youquan Zhang and Xiangtai Meng *
DOI: 10.1039/x0xx00000x
www.rsc.org/
A protocol for the direct functionalization of N-H/α,α,β,β-C(sp3)-H
of piperidine without any metal or external oxidants is reported.
These reactions are promoted by 4-(trifluoromethyl)benzoic acid
via an azomethine ylide intermediate. This is a simple method for
the synthesis of spirooxindoles bearing 3-substituted oxindole
moieties.
OH
O
O
F
O
N
O
HO
HO
H
H
MeO
OH
O
Cl
N
H
CO2Me
O
N
H
N
H
Alvocidib
Paroxetine
Tabernoxidine
Fig. 1 Representative examples of pharmaceutical molecules containing a piperidine
core structure.
Substituted
piperidine
derivatives
are
ubiquitous
in
pharmaceutical compounds. For example, they are found in drugs
used to treat depression (paroxetine) and leukemia (alvocidib),
and also in natural products (tabernoxidine) (Fig. 1).1 Therefore,
there has been much work to analyze the potent biological
activities of substituted piperidines and to explore different routes
to synthesize them.2 Among the reported synthetic methods,
direct C-H functionalization of piperidine via a removable directing
group catalyzed by transition metal catalysts appears to be a
powerful strategy (Scheme 1a).3 Compared with the transition
metal catalyzed C-H bond activation of piperidine, the azomethine
ylide route is another powerful method for functionalization of the
C-H bond of piperidine without transition metal and external
oxidants.4 This method is attractive since the removal of metal
impurities to attain the pure pharmaceutical can be costly.
However, certain limitations remain unsolved in the azomethine
ylide route. For instance, most examples only give α-C(sp3)-H
bond functionalization.5 Reports on the direct functionalization of
more challenging β-C(sp3)-H bonds without transition metals and
sacrificial oxidants are limited. There is only one example for
piperidine which simultaneously gives α,β-difunctionalization via
transient enamines, reported by the Seidel group (Scheme 1b).4c
The direct functionalization of the β-C(sp3)-H bond in cyclic
amines would provide more convenient methods for the synthesis
of drug molecules and other high-value compounds.
considerable medicinal potential, combining both skeletons into
one molecule may produce a new type of medicinal compound. In
continuation of our research on the organo-catalyzed domino
reactions of oxindoles,8 here, we report an unexpected acid-
promoted N-H/α,α,β,β-C(sp3)-H functionalization of piperidine via
an azomethine ylide intermediate (Scheme 1c). To the best of our
knowledge, functionalization of the N-H and the α,α,β,β-C(sp3)-H
of piperidine in one step has never been reported.
The reaction between 5-methyl-N-methyl isatin (1a), piperidine
(2), and (E)-(prop-1-ene-1,3-diyldisulfonyl)dibenzene (3a) (1a:2:3a
o
= 1.2:1.2:1) in toluene at 110 C for 2 h yielded the new product
4a in 52% yield as a single diastereomer (Table 1, entry 1). After
purification by column chromatography, 4a was characterized by
Transition metal-catalyzed β-C-H bond functionalization of piperidine
Pd(OAc)2 (10 mol%)
O
O
N
N
2,6-dimethylbenzoicacid (0.25 eq.)
(Het)ArI
(Het)Ar
NH
H
NH
(a)
Ag2CO3, neat
N
N
Boc
Boc
First example of α, β-C-H bond difunctionalizationof piperidine
H
H
Ph
H
(b)
N
OH
CHO
Toluene (0.25 M)
200 oC, 15 min
Ph
+
Spirooxindoles6 and 3-substituted oxindoles7 are ubiquitous
N
O
ꢀ
W
H
Ph
motifs in biologically-active compounds. Because of their
Our work: First example of N-H/ α, α, β, β-C(sp3)-H bond
functionalization of piperidine
a.Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion,
School of Chemistry & Chemical Engineering Tianjin University of Technology
Tianjin 300384 (P. R. China)
N
O
O
O
SO2Ph
PhO2S
PhO2S
H
H
H
H
N
4-TFBA (1.0 eq.)
Toluene, 110 oC
+
b.E-mail: aiminyu@tjut.edu.cn; mengxiangtai23@mail.nankai.edu.cn
Electronic Supplementary Information (ESI) available: Full experimental details,
characterization and NMR spectra of all new compounds. CCDC 1508878, 1508773
and 1509577. For ESI and crystallographic data in CIF or other electronic format.
See DOI: 10.1039/x0xx00000x
O
+
(c)
N
N
H
H
SO2Ph
N
1a
2
3a
4a
Scheme 1 Examples of functionalization of piperidine.
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1H NMR, 13C NMR, and HRMS. And conclusive evidence for the (4-TFBA)). Surprisingly, the addition of one equivalent of 4-
structure and stereochemistry was obtained by single crystal X- (trifluoromethyl)benzoic acid improved the reaction yield to 70%
ray diffraction of 4b (see the ESI).9 Surprisingly, the N-H/α,α,β,β- (Table 1, entries 12-20). A brief screening of the ratio of 1a to 2 to
C(sp3)-H functionalization of piperidine occurred without transition 3a revealed that a ratio of 1.2:1.2:1 gave the best yield of 4a (see
metal complexes or external oxidants via a domino process.
In view of the above interesting result, this domino reaction was
the ESI).
After the optimal reaction conditions were established, the
optimized to improve the chemical yield of 4a (Table 1). The effect substrate scopes with respect to substitutions on the isatin
of the solvent was first studied. However, all other solvents tested, derivatives 1 and 3 were explored. As shown in Table 2, diversely
including CH3CN, EtOH, DMF, dioxane, DCE, THF, and xylene substituted isatins bearing alkyl, alkoxy, halogen, and nitro groups
produced inferior results compared to toluene (Table 1, entries 2- were evaluated and various substituents at C5, C6, and C7 were
8). The addition of one equivalent of inorganic base (Na2CO3) or well tolerated. For example, non-substituted N-methyl isatin (1b)
organic base (DBU) into the reaction mixture in toluene led to no and isatins bearing alkyl (1a, 1d) or alkoxy (1c) at C5 position of
formation of 4a (Table 1, entries 9-10). However, the addition of the phenyl ring, reacted smoothly under the optimized conditions,
one equivalent of benzoic acid into the reaction mixture increased furnishing the corresponding products 4a-4d in 70-85% yields
the yield of 4a to 54% (Table 1, entry 11). Therefore, the influence (Table 2, entries 1-4). For the C7 substituted substrate, a similar
of several other acids was investigated (i.e. 4-fluorobenzoic acid, product yield was obtained from the reaction of 1l with piperidine
4-nitrobenzoic
acid,
4-chlorobenzoic
acid,
3,5- and 3a (Table 2, entry 12). N-methyl isatin 1h bearing 5-OCF3
bis(trifluoromethyl)benzoic acid (3,5-BTFBA), 3,5-dinitrobenzoic group also reacted well (Table 1, entry 8). However, for substrate
acid, 2-methylbenzoic acid, 3-methoxybenzoic acid, 2,4- 1i bearing a strong electron withdrawing group (5-NO2), no
dichlorobenzoic acid, and 4-(trifluoromethyl)benzoic acid
Table 2 Scope of the domino reaction for various 1a
Table 1 Optimization of the domino reactionsa
N
O
SO2Ph
O
PhO2S
PhO2S
H
Additive
+
+
O
N
H
Solvent, T
N
SO2Ph
N
O
N
1a
2
3a
4a
Entry
R1
R2
Time (h)
4
Yield (%)b
Entry
Additive
Solvent
T
Time
(h)
Yield
(%)b
(oC)
1
5-CH3 (1a)
H (1b)
CH3
1
4a
4b
4c
4d
4e
4f
70
73
79
85
53
76
65
53
0
1
-
Toluene
CH3CN
EtOH
110
80
2
2
1
1
1
1
1
2
2
2
1
1
1
1
1
1
1
1
1
1
52
0
2
CH3
1
2
-
3
5-CH3O (1c)
5-tBu (1d)
5-F (1e)
CH3
1
3
-
78
0
4
CH3
1
4
-
DMF
110
101
85
18
21
0
5
CH3
1
5
-
Dioxane
DCE
6
5-Cl (1f)
CH3
1
6
-
7
5-Br (1g)
5-OCF3 (1h)
5-NO2 (1i)
5,6-F2 (1j)
6-Br (1k)
7-CH3 (1l)
7-Cl (1m)
7-Br (1n)
4-Br (1o)
H (1p)
CH3
1
4g
4h
4i
7
-
THF
65
0
8
CH3
1.5
1
8
-
Xylene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
135
110
110
110
110
110
110
110
110
110
110
110
110
0
9
CH3
9
Na2CO3
DBU
0
10
11
12
13
14
15
16
17
18
19
20
21
22
CH3
1
4j
41
51
75
61
58
0
10
11
12
13
14
15c
16
17
18
19
0
CH3
1.5
1
4k
4l
PhCOOH
54
51
64
58
56
50
56
51
60
70
CH3
4-fluorobenzoic acid
4-nitrobenzoic acid
4-chlorobenzoic acid
3,5-BTFBA
CH3
1
4m
4n
4o
4p
4q
4r
CH3
1
CH3
6
CH2OEt
CH2OEt
CH2OEt
CH2Ph
CH2Ph
CH2Ph
CH2Ph
1
90
66
61
78
70
79
68
3,5-dinitrobenzoic acid
2-methylbenzoic acid
3-methoxybenzoic acid
2,4-dichlorobenzoic acid
4-TFBA
5-CH3 (1q)
5-Br (1r)
H (1s)
1
1
1
4s
4t
5-CH3 (1t)
5-Cl (1u)
5-Br (1v)
1
20d
1
4u
4v
a
Unless otherwise indicated, the reaction was performed at the 0.5 mmol scale
1
in a solvent (3 mL) with additives (1 equiv.), and the molar ratio of 1a : 2 : 3a was
b
c
d
a Reaction conditions: 1 (1.2 eq.), 2 (1.2 eq.), 3 (1.0 eq.) in toluene under 110 oC.
b Isolated yields.
1.2 : 1.2 : 1. Isolated yield. 3,5-BTFBA = 3,5-bis(trifluoromethyl)benzoic acid.
4-TFBA = 4-(trifluoromethyl)benzoic acid.
2 | J. Name., 2012, 00, 1-3
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desired product was obtained (Table 2, entry 9). In addition, for N- (Scheme 3). The structure of 7 was confirmed by X-ray diffraction
methyl substituted isatins, halo-substituted derivatives 1e-1g, 1j, (see the ESI).9 Moreover, under the optimized conditions,
1k and 1m-1n were also tolerated in the current domino reactions compound 7 could transformed into 6 in 20% yield.
to afford the corresponding products in moderate to good yields
R3
R4
O
O
O
(Table 2, entries 5-7, 10-11,13-14). It should be noted that the
desired product with bromo substituent (R1) on the phenyl ring
was particularly useful, which provides an opportunity for further
functionalization. Unfortunately, 4-Br substituted substrate did not
give the desired product under the optimized conditions. This is
likely due to the steric hindrance (Table 2, entry 15). Furthermore,
isatin derivative 1 with other N-protected groups, such as CH2OEt-
protected 1p-1r and Bn-protected 1s-1v that also contain
electron-neutral (1p, 1s), electron-donating (1q, 1t) and halogen
groups (1r, 1u, 1v) on the phenyl ring performed well and
furnished the corresponding products 4p-4v in good to high yields
(Table 2, entries 16-22).
H
4-TFBA (1.0 eq.)
Toluene,110 oC
R3
+
R4
+
N
N
H
O
2
3
5
R3 = PhSO2, R4 = PhSO2CH2
5a
( , 1.5 h, 58%)
R3 = p-ClPhSO2, R4 = p-ClPhSO2CH2 (5b, 1.5 h, 78%)
R3 = Ts, R4 = TsCH2 (5c, 2 h, 74%)
1w = acenaphthylene-1,2-dione
R3 = PhSO2, R4 = PhSO2CH2
(
5d
, 1.5 h, 73%)
R3 = p-ClPhSO2, R4 = p-ClPhSO2CH2 (5e, 1.5 h, 71%)
1x = aceanthrylene-1,2-dione
R3 = Ts, R4 = TsCH2
, 2 h, 84%)
5f
(
Scheme 2 Scope of other 1,2-diones in this domino reaction.
The scope of this domino reaction with regard to 3 was also
explored. The results are shown in Table 3. Chloro-substituted 3b,
Methyl-substituted 3c and (vinylsulfonyl)benzene 3d were also
compatible in this domino reaction, regardless of the electron-
neutral, electron-donating and halogen substituted isatin
derivatives 1, to afford the desired products 4w-4ac in moderate
to good yields (Table 3, entries 1-7). Moreover, we also examined
the effect of sulfonyl group. Methyl (E)-4-(phenylsulfonyl)but-2-
enoate (3e) was used in this domino reaction, however, no
desired product was obtained (Table 3, entry 8). This result
indicates that the sulfonyl group is crucial for this reaction.
Scheme 3 Scope of 2-(vinylsulfonyl)pyridine in this domino reaction.
All test reactions were performed at a small scale but scale-up
was easily accomplished. For example, to demonstrate the
potential utility of this methodology, the desired product 4b was
obtained in 68% yield when the reaction was scaled up to 1.2 g
(1b) under the optimized reaction conditions.
Table 3 Scope of the domino reaction for various 3a
The detailed mechanism of these domino reactions has not
been clarified. According to our experimental results and some
O
N
N
OCOR
O
- RCOOH
RCOOH
O
+
O
N
N
N
H
N
1a
B
2
A
En
try
R1
R3
R4
4
Yield
(%)b
ROCO
N
N
1
2
3
4
H (1b)
p-ClPhSO2 (3b)
p-ClPhSO2 (3b)
p-ClPhSO2 (3b)
Ts (3c)
p-ClPhSO2CH2
p-ClPhSO2CH2
p-ClPhSO2CH2
TsCH2
4w
4x
4y
4z
77
78
61
51
1a
aldol reaction
RCOOH
- RCOOH
O
O
5-CH3 (1a)
5-Br (1g)
5-CH3 (1a)
N
N
C
D
N
O
N
O
N
O
OH
N
O
N
5
6
7
8
5-Br (1g)
H (1b)
Ts (3c)
TsCH2
H
4aa
4ab
4ac
4ad
48
62
59
0
RCOOH
RCOO
-H2
O
PhSO2 (3d)
PhSO2 (3d)
CO2Me (3e)
N
5-CH3 (1a)
H (1b)
H
O
O
O
N
N
N
TsCH2
F
E
G
a Reaction conditions: 1 (1.2 eq.), 2 (1.2 eq.), 3 (1.0 eq.) in toluene under 110 C,
o
N
1h. b Isolated yields.
N
O
O
PhO2
S
S
H
N
PhO2
3a
[3+2]
annulation
RCOO
It was surprising that acenaphthylene-1,2-dione (1w) and
aceanthrylene-1,2-dione (1x) exhibited good performance and
gave the corresponding products in 58-84% yields (Scheme 2).
The structure of product 5f was unambiguously assigned by X-ray
diffraction (see the ESI).9 However, 1H-indene-1,2,3-trione,
phenanthrene-9,10-dione and 9H-fluoren-9-one were unreactive
under the optimized conditions.
N
O
O
N
N
H
J
O
N
N
proton
transfer
N
O
RCOOH = 4-TFBA
PhO2S
4a
SO2Ph
I
Furthermore, we also examined 2-(vinylsulfonyl)pyridine (3f) in
this domino reaction. Surprisingly, only 24% desired product 6
was obtained and accompanied with new product 7 in 48% yield
Scheme 4 Proposed mechanism for the domino reaction.
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related literature,10 a possible mechanism is proposed in Scheme
4. The isatin derivative 1a reacts with piperidine to give
intermediater A, which is converted to the azomethine ylide B.
A. A. Kulago and B. U. W. Maest, ACS Catal., 2016, 6,
4486−4490.
4
(a) M. T. Richers, M. Breugst, A. Y. Platonova, A. Ullrich, A.
Dieckmann, K. N. Houk and D. Seidel, J. Am. Chem. Soc. 2014,
136, 6123-6135; (b) C. Zhang, D. Das and D. Seidel, Chem.
Sci., 2011, 2, 233-236; (c) W. Chen, Y. Kang, R. G. Wilde and
D. Seidel, Angew. Chem. Int. Ed., 2014, 53, 5179-5182; (d) A.
Dieckmann, M. T. Richers, A. Y. Platonova, C. Zhang, D. Seidel
and K. N. Houk, J. Org. Chem., 2013, 78, 4132-4144; (e) C. L.
Jarvis, M. T. Richers, M. Breugst, K. N. Houk and D. Seidel,
Org. Lett. 2014, 16, 3556-3559.
(a) S. Haddad, S. Boudriga, F. Porzio, A. Soldera, M. Askri, M.
Knorr, Y. Rousselin, M. M. Kubicki, C. Golz, and C.
Strohmann, J. Org. Chem., 2015, 80, 9064-9075; (b) I.
Coldham and R. Hufton, Chem. Rev., 2005, 105, 2765-2810;
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2947; (d) H. Ardill, X. L. R. Fontaine, R. Grigg, D. Henderson, J.
Montgomery, V. Sridharan and S. Surendrakumar,
Tetrahedron, 1990, 46, 6449-6466; (e) R. Jazzar, J. Hitce, A.
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The intermediate
B
subsequently transforms to enamine
intermediate D from C. Both steps can be catalyzed by 4-TFAB.10b
Enamine D undergoes an aldol-type reaction with 1a to give
intermediate E, and then E was acidized to form intermediate F.
Dehydration of F gives iminium ion G, which will then form
azomethine ylide H. The subsequent high diastereoselectivity
[3+2] annulation reaction of H with 3a would produce the
cycloaddition product J probably via transition state I. Finally,
intermediate J isomerizes to form product 4a.
5
In conclusion, we have developed an acid-promoted N-
H/α,α,β,β-C(sp3)-H functionalization reaction of piperidine in one
step. This transformation produced spirooxindoles bearing 3-
substituted oxindoles. Future work involves the in-depth
mechanistic study of this domino reaction as well as investigating
the applications of this reaction in the synthesis of drug molecules.
This work was supported financially by the National Natural
Science Foundation of China (Grant No. 21403154), the
Natural Science Foundation of Tianjin (Grant No.
13JCYBJC38700),
the
Tianjin
Municipal
Education
Commission (Grant No. 20120502). X. M. is grateful for the
support from the 131 talents program of Tianjin.
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