Titanocene(III)-Catalyzed Three-Component Reaction of Secondary Amides, Aldehydes, and Electrophilic Alkenes

Article abstract of DOI:10.1002/anie.201506907

An umpolung Mannich-type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one-pot formation of C-N and C-C bonds by a titanocene-catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N-substituted γ-amido-acid derivatives and γ-amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α-amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.

Full text of DOI:10.1002/anie.201506907

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506907
German Edition: DOI: 10.1002/ange.201506907
Multicomponent Reactions
Titanocene(III)-Catalyzed Three-Component Reaction of Secondary
Amides, Aldehydes, and Electrophilic Alkenes
Xiao Zheng,* Jiang He, Heng-Hui Li, Ao Wang, Xi-Jie Dai, Ai-E Wang, and Pei-Qiang Huang
Abstract: An umpolung Mannich-type reaction of secondary
amides, aliphatic aldehydes, and electrophilic alkenes has been
À
disclosed. This reaction features the one-pot formation of C N
À
and C C bonds by a titanocene-catalyzed radical coupling of
the condensation products, from secondary amides and
aldehydes, with electrophilic alkenes. N-substituted g-amido-
acid derivatives and g-amido ketones can be efficiently
prepared by the current method. Extension to the reaction
between ketoamides and electrophilic alkenes allows rapid
assembly of piperidine skeletons with a-amino quaternary
carbon centers. Its synthetic utility has been demonstrated by
a facile construction of the tricyclic core of marine alkaloids
such as cylindricine C and polycitorol A.
T
he three-component reaction[1] of an amine, an aldehyde,
and a ketone, known as the Mannich reaction,[2] is the most
widely utilized chemical transformation for the tandem
À
À
construction of C N and C C bonds. In recent years, similar
three-component reactions using amides, instead of amines, as
a component have been reported, and can be viewed as an
amide-based Mannich-type reaction.[3] In the Mannich-type
reactions, the addition of C-nucleophiles to N-acyliminium
ions are generally involved. The resulting a-amidoalkylation
products[4] are versatile synthetic intermediates for the syn-
thesis of various nitrogen-containing natural products and
bioactive compounds.[5]
Scheme 1. Umpolung of Mannich-type reaction of secondary amides,
aldehydes, and electrophilic alkenes. Cp=cyclopentadienyl, EWG=
electron-withdrawing group, TMS=trimethylsilyl.
component reaction of secondary amides, aldehydes, and
electrophilic alkenes, which involves the addition of B to
electrophilic alkenes, was thus envisaged as an umpolung of
À
À
Our group has long been interested in the development of
C C bond-formation methodologies based on the radical
the Mannich-type reaction to construct C N and C C bonds
in one pot (Scheme 1). To the best of our knowledge, such
a three-component reaction has never been reported. Herein,
we report the results of our investigations on this reaction.
The extension of the methodology to the reaction of
ketoamides with electrophilic alkenes to build piperidine
skeletons with a-amino quaternary carbon centers, and its
application in the synthesis of the tricyclic core of marine
alkaloids are also included.
À
cross-coupling of a-acylaminoalkyl radicals,[6] which are
generated by single-electron transfer (SET) reduction from
N-acyliminium ions.[7] We recently reported a titanocene-
catalyzed[8] radical umpolung cross-coupling reaction[9] of
hemiaminals with electrophilic alkenes to give a-amidoalky-
lated derivatives.[10] In this reaction, chloroamide A was
proposed to act as the precursor of a-acylaminoalkyl radical
B. Since A could also be formed by the reaction of amides
with aldehydes in the presence of TMSCl,[11] the three-
The three-component reaction of the carbamate 1,
paraformaldehyde, and ethyl acrylate was chosen as the
model study (Table 1). After extensive trials (see Table S1 in
the Supporting Information), optimized reaction conditions
were established: condensation of an amide (1.0 mmol) with
(CH2O)n (1.6 mmol) in anhydrous CH2Cl2 (4.0 mL) in the
presence of TMSCl (3.0 mmol) under an argon atmosphere at
room temperature for 2 hours. Then coupling of the resulting
mixture with electrophilic alkenes (2.0 mmol) in a green
suspension of Sm (3.0 mmol),[12] [Cp2TiCl] (0.1 mmol), and
Et3N·HCl (3.0 mmol)[13] in THF (4.0 mL), for additional
6 hours. Under the optimized reaction conditions, the desired
cross-coupling product 2a was obtained in 73% yield, along
with the byproduct 3 in 13% yield. Other acrylates could also
undergo this one-pot reaction with 1 and paraformaldehyde
[*] Dr. X. Zheng, J. He, H.-H. Li, A. Wang, X.-J. Dai, Dr. A.-E Wang,
Prof. P.-Q. Huang
Department of Chemistry and The Key Laboratory for Chemical
Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University
Xiamen, Fujian 361005 (P.R. China)
E-mail: zxiao@xmu.edu.cn
Dr. X. Zheng
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506907.
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Communications
Table 1: The scope of electrophilic alkenes of the umpolung of the
Table 2: The scope of secondary amides of the umpolung of the
Mannich-type reaction.[a]
Mannich-type reaction.[a]
R=Et, 2a (73%) and
3 (13%)
R=tBu, 2b (70%) and
3 (5%)
2c (58%) and
3 (11%)
2d (43%) and
3 (12%)
2i (71%)
10b (64%)
12 (70%)
11 (70%)
13 (47%)
10a (70%)
2e (53%) and
3 (13%)
2 f (54%)
E/Z (59:41)[b]
and 3 (9%)
2g (78%) and
3 (10%)
14 (50%)
15a (81%)
15b (78%)
[a] Under standard reaction conditions as detailed in Table 1. Yield of the
product isolated after chromatographic separation is given within
parentheses. Ts =4-toluenesulfonyl.
2h (55%) and
3 (10%)
2i (71%) and
3 (13%)
2j (64%) and
3 (10%)
[a] Standard reaction conditions: 1.0 mmol of amide 1, 1.6 mmol of
(CH2O)n, 3.0 mmol of TMSCl, 4.0 mL of anhydrous CH2Cl2, 2.0 mmol of
electrophilic alkenes, 3.0 mmol of Sm, 0.1 mmol of [Cp2TiCl2] and
3.0 mmol of Et3N·HCl, 4.0 mL of THF. Yields of products isolated after
chromatographic separation are given within parentheses. [b] Deter-
mined upon isolation of the products. Cbz=benzyloxycarbonyl,
THF=tetrahydrofuran.
obtained, along with a lot of recovered amide substrates,
when aldehydes other than paraformaldehyde were used. To
our delight, when BF3·Et2O was added (see Scheme S1), the
condensation of amides (1 and 9) with aldehydes [propanal or
2-(benzyloxy)acetaldehyde] at À408C for 2 hours, followed
by the coupling with electrophilic alkenes in the presence of
Et3N·HCl/TMSCl led to the desired coupling products in 67%
to 94% yields (Table 3). Higher yields were obtained with 2-
(benzyloxy)acetaldehyde (17 and 19) than with propanal (16
and 18), thus suggesting a strong influence of the electro-
philicity of aldehydes. Notably, low diastereoselectivities (18
and 19) were obtained even though the optically pure amide 9
was used. Aromatic aldehydes and ketones, however, could
not produce the desired products.
This three-component reaction was expanded further to
ketoamides (Table 4). By using the same reaction conditions
as in Table 3, the ketoamides 20–23 (for preparation, see the
Supporting Information) were treated with BF3·Et2O and the
resulting mixture was then subjected to titanocene-catalyzed
coupling with the electrophilic alkenes in the presence of
TMSCl and Et3N·HCl. To our delight, the N-Boc piperidines
24 and 25, having a-amino quaternary carbon center, were
obtained in excellent yields (92–96%). Apart from N-Boc
carbamates, N-benzyl amides were also applicable, thus
providing the piperidin-2-ones 26 and 27 in moderate to
good yields.
to give the corresponding coupling products 2b–d in moder-
ate to good yields. Ethyl buta-2,3-dienoate and methyl
propiolate were also applicable to produce the cross-coupling
products in moderate yields (2e and 2 f). In addition, both the
endo- and exo-cyclic a,b-unsaturated lactones could also
participate in this one-pot reaction in good to moderate yields
(2g and 2h). Besides a,b-unsaturated esters, a,b-unsaturated
nitriles and ketones, were all well tolerated under the
standard reaction conditions (2i and 2j).
We next investigated a wide array of secondary amides
(Table 2). Various R substituents on the nitrogen atoms of the
carbamates seemed to have little influence on the reaction
outcome. The coupling of Cbz-protected carbamates (1, 4 and
5) with paraformaldehyde and acrylonitrile gave the desired
products in comparable yields (2i, 10b, and 11). The acyl
protecting groups, in contrast, strongly affected the reactions.
Moderate to good yields (2i, 10–12) were obtained with N-
Cbz carbamates (1, 4, and 5) and the Eoc-protected carba-
mate 6, while low yields (13 and 14) were observed with the
N-Boc carbamate 7 and N-Ts amide 8. The low yields in the
latter cases might be caused by the decreased nucleophilicity
of 7 and 8, as a lot of the starting amides were recovered. In
addition, when the chiral oxazolidone 9 was used as the
secondary amides, the desired a-amidoalkylated products
were obtained in satisfactory yields (15a and 15b).
To demonstrate the synthetic utility of our methodology,
a concise synthesis of the tricyclic lactam 34 was carried out
(Scheme 2). The lactam 34 is the core skeleton of cylindrici-
ne C (28)[14] and polycitorol A (29),[15] two tricyclic marine
alkaloids with a perhydropyrrolo[1,2-j]quinoline ring system.
The treatment of the commercially available 2-oxo-1-cyclo-
hexanepropionitrile (30) with lithium aluminum hydride
(LAH) in refluxing THF, followed by an acidic aqueous
(HCl, 3m) work-up, afforded the corresponding aminoalcohol
The scope with respect to the aldehydes was subsequently
explored. Unfortunately, under the standard reaction con-
ditions, only a small amount of the desired products were
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Table 3: The scope of aldehydes of the umpolung of the Mannich-type
reaction.[a]
EWG=CO2tBu, 16a (72%)
and 1 (9%)
EWG=CO2tBu, 17a (81%)
EWG=CN, 17b (85%)
EWG=CN, 16b (67%)
and 1 (9%)
EWG=CO2Et, 18a
(87%; 52:48[b])
EWG=CN, 19a (94%; 60:40[b])
EWG=COEt, 19b
EWG=CN, 18b (79%; 58:42[b])
(84%; 55:45[b])
Scheme 2. Concise construction of the tricyclic core of marine alka-
loids.
[a] Reaction conditions: an amide (1.0 mmol) with an aldehyde
(1.6 mmol) in anhydrous CH2Cl2 (4.0 mL) in the presence of BF3·Et2O
(1.0 mmol) at À408C for 2 h. The resulting mixture with electrophilic
alkenes (2.0 mmol) was added to a green suspension of Sm (3.0 mmol),
[Cp2TiCl2] (0.1 mmol), Et3N·HCl (3.0 mmol), and TMSCl (3.0 mmol) in
THF (4.0 mL) at RT for an additional 6 h. Yields of products isolated after
chromatographic separation are given within parentheses. [b] The d.r.
values were determined by integration of the peaks in the 1H NMR
spectrum (see the Supporting Information).
azadecalin) 33 in 80% yield with 6:1 diastereoselectivity.
Notably, a large-scale synthesis of 33 (1.73 g, 4.81 mmol) can
be performed efficiently without a decrease in either the yield
or diastereoselectivity. Removal of the Cbz protecting group
of 33 in the presence of 20% Pd(OH)2/C under an atmos-
phere of H2 afforded the cis-tricyclic lactam 34 in 84% yield,
1
along with the uncyclized trans-amine in 16% yield. The H
Table 4: The construction of a-amino quaternary carbon centers from
and 13C NMR spectra of 34 were consistent with literature
data,[16b,c] and thus confirmed the cis-1-azadecalin configura-
tion of 34. The core skeleton of tricyclic the marine alkaloids
28 and 29 was thus synthesized in only five steps with an
overall yield of 39%.
ketoamides with electrophilic alkenes.[a]
In conclusion, a three-component reaction of secondary
amides, aliphatic aldehydes, and electrophilic alkenes has
been developed. The reaction can be regarded as the
umpolung of the amide-based Mannich-type reaction, which
features a titanocene-catalyzed radical coupling of electro-
philic alkenes with the condensation products from secondary
À
À
amides and aldehydes to construct C N and C C bonds in
one pot. Extension of the method to ketoamides to furnish
piperidine skeletons with a-amino quaternary carbon centers
has been achieved in satisfactory yields. The synthetic value of
this methodology has been demonstrated by a concise con-
struction of the tricyclic lactam 34, the core of cylindricine C
(28) and polycitorol A (29). Notably, these reactions can
produce cyclic tertiary amides which recently have been used
[a] A ketoamide (1.0 mmol) under the reaction conditions as detailed in
Table 3. Yield is that of the product isolated after chromatographic
separation. Boc=tert-butoxycarbonyl.
À
in C C bond formation to give a-alkylated amines directly,
hydrochloride salt. After careful neutralization, by solid
NaOH, to pH 7–8, solid NaHCO3 and a solution of CbzCl
in THF were added successively to furnish the N-Cbz
aminoalcohol 31 in 79% yield in one pot. Oxidation of 31
by Dess–Martin periodinane (DMP) gave the ketoamide 32 in
86% yield. By using a modified sequence, 32 was treated by
BF3·Et2O in CH2Cl2 at À408C, and then coupled with methyl
acrylate under the titanocene-cataylzed conditions at 58C for
8 hours to afford the substituted octahydroquinoline (1-
and been applied for the synthesis of alkaloids.[17] Further
studies on the mechanism and the application of this method
to synthesize those marine alkaloids are in progress.
Acknowledgements
The authors are grateful to the NSF of China (21172183,
21472157), the Fundamental Research Funds for the Central
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Universities (No. 2013121016), the SRF for ROCS, SEM, the
NFFTBS (No. J1310024), and the Program for Changjiang
Scholars and Innovative Research Team in University
(PCSIRT) for financial support.
Keywords: amides · multicomponent reactions · radicals ·
titanium · umpolung
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13739–13742
Angew. Chem. 2015, 127, 13943–13946
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Received: July 25, 2015
Published online: September 25, 2015
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